Atlas of Genetic Diagnosis and Counseling, 2nd Edition

Atlas of Genetic Diagnosis and Counseling

Harold Chen

Atlas of Genetic Diagnosis and Counseling Second Edition

With 2427 Figures and 1 Table

Harold Chen Perinatal and Clinical Genetics Department of Pediatrics LSU Health Sciences Center 1501 Kings Highway Shreveport, LA 71130 USA

ISBN 978-1-4614-1036-2 e-ISBN 978-1-4614-1037-9 Print and electronic bundle under ISBN 978-1-4614-1038-6 DOI 10.1007/978-1-4614-1037-9 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011942140 The first edition was published by # Humana Press Inc. 2006 Second Edition: # Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Cover illustration: Courtesy of Harold Chen Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

I would like to dedicate this Atlas to Children’s Hospital, Louisiana State University Health Sciences Center in Shreveport, Louisiana.

Preface to the Second Edition

It has been 5 years since the publication of the first edition of this atlas in 2006. Since then, significant progress has been made in the field of genetic diagnosis and counseling. The first edition of the atlas covered 203 chapters which were revised with current literature and addition of many illustrations, mostly in color. Fifty two new chapters have been added to this edition. Selected references have also been added to the text for the sources of the information. As with the previous edition, a detailed outline of each disorder is provided, describing the genetics, basic defects, clinical features, diagnostic investigations, and genetic counseling, including recurrence risk, prenatal diagnosis, and management. Relevant references are added in the second edition. The cases are supplemented by case history and diagnostic confirmations by imaging, cytogenetic, biochemical, and/or molecular studies. I am grateful to the following individuals for their contribution and support of this edition: Dr. Susonne Ursin, my genetic colleague and Chief of Perinatal Genetics, for case studies (Joubert syndrome, Mowatt-Wilson syndrome, otopalatodigital syndrome, rigid spine syndrome, Saethre-Chotzen syndrome, Silver-Russell syndrome); Dr. RMS Riel-Romero for megalencephalic leukoencephalopathy with subcortical cysts; Dr. Amal Anga for Duncan syndrome; Drs. Richard McCall, Phillip Gates, and Anne Hollister, Shreveport Shriners Hospital for Children; Dr. Ghali Ghali, Chairman of Oral and Maxillofacial Surgery; and Dr. Renata Pilatova, Pinecrest Development Center, for providing patients for studies and inclusion into this edition; Dr. Leonard Prouty, Ms. Rhonda Lee Young, and Mr. Jozo Ivancic, LSU Cytogenetics Laboratory for part of the karyotypes used in this edition; Mrs. Lynn Martin, Beverely Gildon, and Diane Dunki-Jacobs-Nolten for nursing care; and Ms. Ashli Daigle and Mrs. Barbara McHenry for their excellent clerical and secretarial help. My apologies in the event that I failed to mention others who have contributed to this edition. Without the patience and encouragement of my dear wife, Cheryl, this edition of the atlas would not have been possible. I would like to express my sincere appreciation to Dr. Joseph Bocchini, Chairman of the Department of Pediatrics, for his encouragement and support. I would like to dedicate this edition of the atlas to the Children’s Hospital, Louisiana State University Health Sciences Center in Shreveport, for its excellence in pediatric care and education. As previously, I would welcome comments, corrections, and criticism from readers. Harold Chen, Shreveport, LA, USA October 2011

vii

Preface to the First Edition

This book, Atlas of Genetic Diagnosis and Counseling, reflects my experience in 38 years of clinical genetics practice. During this time, I have cared for many patients and their families and taught innumerable medical students, residents, and practicing physicians. As an academic physician, I have found that a picture is truly “worth a thousand words,” especially in the field of dysmorphology. Over the years, I have compiled photographs of my patients, which are incorporated into this book to illustrate selected genetic disorders, malformations, and malformation syndromes. A detailed outline of each disorder is provided, describing the genetics, basic defects, clinical features, diagnostic investigations, and genetic counseling, including recurrence risk, prenatal diagnosis, and management. Color photographs are used to illustrate the clinical features of patients of different ages and ethnicities. Photographs of prenatal ultrasounds, imaging, cytogenetics, and postmortem findings are included to help illustrate diagnostic strategies. The cases are supplemented by case history and diagnostic confirmation by cytogenetic, biochemical, and molecular studies, if available. An extensive literature review was done to ensure up-to-date information and to provide a relevant bibliography for each disorder. This book was written in the hope that it will help physicians improve their recognition and understanding of these conditions and their care of affected individuals and their families. It is also my intention to bring the basic science and clinical medicine together for the readers. Atlas of Genetic Diagnosis and Counseling is designed for physicians involved in the evaluation and counseling of patients with genetic diseases, malformations, and malformation syndromes, including medical geneticists, genetic counselors, pediatricians, neonatologists, developmental pediatricians, perinatologists, obstetricians, neurologists, pathologists, and any physicians and health care professionals caring for handicapped children such as craniofacial surgeons, plastic surgeons, otolaryngologists, and orthopedics. I am grateful to many individuals for their invaluable help in reading and providing cases for illustration. The acknowledgments are provided on a separate page. Without the patience and encouragement of my dear wife, Cheryl, this atlas would not have been possible. I would like to dedicate this book to the Children’s Hospital, Louisiana State University Health Sciences Center in Shreveport, for its continued excellence in pediatric care and education. I would welcome comments, corrections, and criticism from readers. Harold Chen, M.D., FAAP, FACMG

ix

Biography

Harold Chen, M.D., M.S., FAAP, FACMG Dr. Chen was born in I-Lan, Taiwan, and was a graduate from the National Taiwan University School of Medicine (M.D. degree) in Taipei, Taiwan. He received M.S. degree in Human Genetics from the University of Michigan Graduate School in Ann Arbor, Michigan. He finished pediatric residency and fellowship training from Wayne State University School of Medicine in Detroit, Michigan. He had been faculty at Wayne State University (Detroit), Wright State University (Dayton, Ohio), and University of South Alabama (Mobile, Alabama). Currently, he is professor of Pediatrics, Obstetrics and Gynecology, and Pathology at the Louisiana State University Health Sciences Center and Chief of Genetic Laboratory Services in Shreveport, Louisiana. Dr. Chen is board-certified in American Board of Pediatrics and American Board of Medical Genetics in Clinical Genetics and Clinical Cytogenetics.

xi

Table of Contents

Acardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Achondrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

Adams–Oliver Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

Agnathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

Aicardi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

Alagille Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55

Albinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

Alpha-Thalassemia X-linked Mental Retardation Syndrome . . . . . . . . . .

71

Ambiguous Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77

Amniotic Deformity, Adhesions, Mutilations (ADAM) Complex . . . . . . .

87

Androgen Insensitivity Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

99

Angelman Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

107

Apert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119

Aplasia Cutis Congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

135

Arthrogryposis Multiplex Congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

141

Asphyxiating Thoracic Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

157

Ataxia-Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

167

Atelosteogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175

Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

183

Bannayan–Riley–Ruvalcaba Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . .

197

Beckwith–Wiedemann Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

203

Behcet Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

213

Biotinidase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

221

Bladder Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

227

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome . . . . . . . .

233 xiii

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Table of Contents

Body Stalk Anomaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

239

Brachydactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

245

Branchial Cleft Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

255

Calcinosis Cutis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

261

Campomelic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

267

Carpenter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

275

Cat Eye Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

279

Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

285

Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

291

Cerebro-Costo-Mandibular Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .

305

Charcot–Marie–Tooth Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

311

CHARGE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

323

Cherubism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

331

Chiari Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337

Chondrodysplasia Punctata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

345

Chromosome Abnormalities in Pediatric Solid Tumors . . . . . . . . . . . . . .

357

Cleft Lip and/or Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

377

Cleidocranial Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

385

Cloacal Exstrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

395

Clubfoot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

401

Collodion Baby . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

409

Congenital Adrenal Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

415

Congenital Cutis Laxa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

429

Congenital Cytomegalovirus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . .

437

Congenital Generalized Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . .

447

Congenital Hemihyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

455

Congenital Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

463

Congenital Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

471

Congenital Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

479

Congenital Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

487

Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

495

Corpus Callosum Agenesis/Dysgenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . .

507

Craniometaphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

515

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xv

Cri-Du-Chat Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

521

Crouzon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

529

Cutis Marmorata Telangiectatica Congenita . . . . . . . . . . . . . . . . . . . . . . .

537

Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

545

Dandy–Walker Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

559

De Lange Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

563

Del(18p) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

577

Del(22q11.2) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

583

Del(Yq) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

593

Diabetic Embryopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

605

Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

613

Duncan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

631

Dyschondrosteosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

639

Dysmelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

651

Dysplasia Epiphysealis Hemimelica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

669

Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

677

Dystrophinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

687

Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) Syndrome . . . . . . . .

699

Ehlers-Danlos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

705

Ellis-van Creveld Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

719

Enchondromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

725

Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

737

Epidermolytic Palmoplantar Keratoderma . . . . . . . . . . . . . . . . . . . . . . . .

749

Faciogenital (Faciodigitogenital) Dysplasia . . . . . . . . . . . . . . . . . . . . . . . .

757

Facioscapulohumeral Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . .

765

Familial Adenomatous Polyposis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

775

Familial Hyperlysinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

785

Familial Mediterranean Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

789

Fanconi Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

795

Femoral Hypoplasia – Unusual Facies Syndrome . . . . . . . . . . . . . . . . . . .

805

Fetal Akinesia Deformation Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . .

809

Fetal Alcohol Spectrum Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

823

Fetal Hydantoin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

831

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Fibrodysplasia Ossificans Progressiva . . . . . . . . . . . . . . . . . . . . . . . . . . . .

835

Finlay–Marks Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

843

Floppy Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

847

Fragile X Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

863

Fraser Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

875

Freeman–Sheldon Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

883

Friedreich Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

891

Frontonasal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

897

Galactosemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

905

Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

913

Gaucher Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

919

Generalized Arterial Calcification of Infancy . . . . . . . . . . . . . . . . . . . . . .

929

Genitopatellar Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

937

Giant Congenital Melanocytic Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

945

Glucose-6-Phosphate Dehydrogenase Deficiency . . . . . . . . . . . . . . . . . . . .

953

Glycogen Storage Disease, Type II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

961

Goldenhar Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

971

Gorlin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

979

Greig Cephalopolysyndactyly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . .

987

Hallermann-Streiff Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

993

Harlequin Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

999

Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005 Hereditary Hearing Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013 Hereditary Hemochromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025 Hereditary Multiple Exostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033 Herlyn-Werner-Wunderlich Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041 Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045 Holt-Oram Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065 Huntington Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Hydrolethalus Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081 Hydrops Fetalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085 Hyper-IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097 Hypochondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105

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Hypoglossia-Hypodactylia Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113 Hypohidrotic Ectodermal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125 Hypomelanosis of Ito . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131 Hypophosphatasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137 Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147 I(1p), I(1q) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159 Idic(Yq) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165 Incontinentia Pigmenti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175 Infantile Myofibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183 Ivemark Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189 Jarcho–Levin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195 Joubert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203 Kabuki Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211 Kasabach–Merritt Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219 KID Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 Klinefelter Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231 Klippel–Feil Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241 Klippel–Trenaunay Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251 Kniest Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259 Larsen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1265 LEOPARD Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275 Lesch–Nyhan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1281 Lethal Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1287 Loeys–Dietz Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1295 Lowe Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1301 Marfan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1309 McCune-Albright Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327 Meckel–Gruber Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335 Megalencephalic Leukoencephalopathy with Subcortical Cysts . . . . . . . . 1341 Menkes Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1347 Metachromatic Leukodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357 Miller–Dieker Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1365 Mitochondrial Leber Hereditary Optic Neuropathy . . . . . . . . . . . . . . . . . 1373

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Mo¨bius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1383 Mowat–Wilson Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1391 Mucopolysaccharidosis I (MPS I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 Mucopolysaccharidosis II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1409 Mucopolysaccharidosis III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417 Mucopolysaccharidosis IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 Mucopolysaccharidosis VI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433 Mucolipidosis II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1441 Mucolipidosis III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449 Multiple Endocrine Neoplasia Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 1457 Multiple Epiphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 Multiple Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1479 Myotonic Dystrophy Type I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1487 Nail-Patella Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499 Neonatal Herpes Simplex Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505 Nephrogenic Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511 Netherton Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515 Neu–Laxova Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1521 Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1527 Neurofibromatosis I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1545 Neurofibromatosis 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1571 Noonan Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577 Oblique Facial Cleft Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1587 Oligohydramnios Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1595 Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1601 Oral–Facial–Digital Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607 Osteogenesis Imperfecta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1619 Osteopetrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 Osteopoikilosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655 Otopalatodigital Spectrum Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661 Pachyonychia Congenita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1671 Pallister–Killian Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1677 Phenylketonuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1683

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Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1693 Polycystic Kidney Disease, Autosomal Dominant Type . . . . . . . . . . . . . . . 1699 Polycystic Kidney Disease: Autosomal Recessive Type . . . . . . . . . . . . . . . 1709 Popliteal Pterygium Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1717 Prader–Willi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1723 Progeria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1735 Prune Belly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1743 Pseudoachondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1751 R(18) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759 Retinoid Embryopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1767 Rett Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773 Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1783 Rigid Spine Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1797 Roberts Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805 Robinow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811 Rubinstein-Taybi Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1817 Saethre-Chotzen Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825 Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis . . . . . . . . . . . . . . 1833 Schizencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1845 Schmid Metaphyseal Chondrodysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853 Seckel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1857 Severe Combined Immune Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1863 Short Rib–Polydactyly Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1873 Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1887 Silver–Russell Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1899 Sirenomelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1907 Smith-Lemli-Opitz Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1913 Smith-Magenis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923 Sotos Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929 Spinal Muscular Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1937 Spondyloepiphyseal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1947 Stickler Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1959

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Sturge-Webber Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1967 Tay-Sachs Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1973 Tetrasomy 9p Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1981 Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1987 Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1997 Thrombocytopenia-Absent Radius Syndrome . . . . . . . . . . . . . . . . . . . . . . 2007 Treacher-Collins Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2017 Trimethylaminuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2025 Triploidy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2031 Trismus-Pseudocamptodactyly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 2043 Trisomy 8 Mosaicism Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2051 Trisomy 13 Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2057 Trisomy 18 Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2069 Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2081 Turner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2097 Twin–Twin Transfusion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115 Ulnar-Mammary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2123 Urofacial Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2127 VATER (VACTERL) Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2131 Von Hippel–Lindau Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2137 Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2145 Weill–Marchesani Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2151 Williams Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2155 Wolf-Hirschhorn Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2165 X-Linked Agammaglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2179 X-Linked Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2185 XX Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2191 XXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2197 XXXXX Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203 XXXXY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2209 XY Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2213 XYY Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221

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Acardia

Acardia is a bizarre fetal malformation occurring only in twins or triplets. It is also called acardius acephalus, acardiac twinning, or twin reversed arterial perfusion (TRAP) syndrome or sequence. This condition is very rare and occurs in 1 in 34,600 births or 1 in 100 monozygotic twins (Gillim and Hendricks 1953) and 1 in 30 monozygotic triplets (Van Allen et al. 1983; Napolitani and Schreiber 1960; Moore et al. 1990; Sanjaghsaz et al. 1998; Blenc et al. 1999), and even in quintuplets. Almost all cases reported are monozygotic twins. However, there are reports of dichorionic monozygotic twin gestations with TRAP sequence (French et al. 1998; Gewolb et al. 1983). Arcadia requires the presence of arterial–arterial anastomosis in the placenta, with retrograde perfusion of poorly oxygenated blood from the normal twin (also called donor or pump twin) to the acardiac twin, venous–venous anastomosis carrying blood back from the acardiac to the donor twin, and circulatory failure of the acardiac twin (Steffensen et al. 2008).

Synonyms and Related Disorders Acardius acephalus; Acardiac twinning; reversed arterial perfusion sequence

Twin

Genetics/Basic Defects 1. Etiology a. Rare complication of monochorionic twinning, presumably resulting from the fused placentation of monochorionic twins.

b. Represents manifestation of abnormal embryonic and fetal blood flow rather than a primary defect of cardiac formation. c. Heterogeneous chromosomal abnormalities are present in nearly 50% of the cases, although chromosome errors are not underlying pathogenesis of the acardiac anomaly. Rather, the placental vascular anastomoses are the principal pathogenetic event (Benirschke and des Roches Harper 1977). i. 45,XX,t(4;21)del(4p) ii. 46,X,i(Xp) iii. 47,XX,+2 (Blaicher et al. 2000) iv. 47,XX,+11 v. 47,XY,+G vi. 47,XXY vii. 69,XXX viii. 70,XXX,+15 ix. 94,XXXXYY 2. Pathogenesis: reversal of fetal arterial perfusion a. First hypothesis i. A primary defect in the development of the heart ii. Survival of the acardiac twin as a result of the compensatory anastomoses that develop b. Second hypothesis i. The acardiac twin begins life as a normal fetus ii. The reversal of the arterial blood flow results in atrophy of the heart and the tributary organs 3. Classification of TRAP sequence (syndrome) a. Classification according to the status of the heart of the acardiac twin i. Hemiacardius (with incompletely formed heart) ii. Holoacardius (with completely absent heart)

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_1, # Springer Science+Business Media, LLC 2012

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b. Morphologic classification of the acardiac twin (Gillim and Hendricks 1953; Napolitani and Schreiber 1960; Nicolaidis et al. 1990; Alderman 1973; Thelmo et al. 2007; Obladen 2010) i. Acardius amorphous a) The least differentiated form b) Little more than a lump of connective tissue, covered by edematous skin c) No resemblance to classical human form d) Anatomical features: presence of only bones, cartilage, muscles, fat, blood vessels, and stroma ii. Acardius myelacephalus a) Resembles the amorphous type except presence of rudimentary limb formation b) Presence of rudimentary nerve tissue in addition to anatomical features in acardius amorphous iii. Acardius acephalus a) The most common type b) Missing head, part of the thorax, and upper extremities c) May have additional malformations in the remaining organs iv. Acardius anceps a) The least atrophied form b) Presence of a partially developed fetal head, a thorax, abdominal organs, and extremities c) Lacks even a rudimentary heart v. Acardius acormus a) The rarest type b) Presence of a rudimentary head only c) Lacks thorax d) The umbilical cord inserts in the head and connects directly to the placenta 4. The acardia a. Characterized by absence of a normally functioning heart b. Acardia as a recipient of twin transfusion sequence i. Reversal of blood flow in all various types of acardia, hence the term “twin reversed arterial perfusion (TRAP) sequence” has been proposed. ii. Receiving the deoxygenated blood from an umbilical artery of its co-twin through the single umbilical artery of the acardiac twin

Acardia

and returns to its umbilical vein. Therefore, the circulation is entirely opposite to the normal direction. c. Usually the severe reduction anomalies occur in the upper part of the body d. May develop various structural malformations i. Growth retardation ii. Anencephaly iii. Holoprosencephaly iv. Facial defects v. Absent or malformed limbs vi. Gastrointestinal atresias vii. Other abnormalities of abdominal organs 5. The co-twin a. Also known as the “pump twin or donor twin.” b. The donor “pump” twin perfuses itself and its recipient acardiac twin through abnormal arterial anastomosis in the fused placenta. c. Increased cardiac workload often leading to cardiac failure and causing further poor perfusion and oxygenation of the acardiac co-twin. d. May develop various malformations (about 10%).

Clinical Features 1. Perinatal problems associated with acardiac twinning a. Pump-twin congestive heart failure b. In utero fetal death of the pump fetus c. Maternal polyhydramnios d. Premature rupture of membrane e. Preterm delivery f. Spontaneous abortions g. Soft tissue dystocia h. Uterine rupture i. Postpartum hemorrhage j. Increased rate of cesarean section, up to 50% 2. Majority of acardiac twins and their normal twin counterparts are females 3. Nonviable 4. Gross features a. Severe reduction anomalies, particularly of the upper body b. Characteristic subcutaneous edema c. Internal organs: invariably missing

Acardia

5. 6.

7.

8.

9.

10.

11.

12.

13.

14.

d. Absent or rudimentary cardiac development: the key diagnostic feature i. Pseudoacardia (rudimentary heart tissue) ii. Holoacardia (completely lacking a heart) Growth abnormality Cranial vault a. Absent b. Partial c. Intact Brain a. Absent b. Necrotic c. Open cranial vault d. Holoprosencephaly Facial features a. Absent facial features b. Rudimentary facial features c. Present with defects d. Anophthalmia/microphthalmia e. Cleft lip/palate Upper limbs a. Absent b. Rudimentary c. Radial aplasia d. Syndactyly/oligodactyly Lower limbs a. Absent b. Rudimentary/reduced c. Syndactyly/oligodactyly d. Talipes equinovarus Thorax a. Absent b. Reduced c. Diaphragmatic defect Lungs a. Absent b. Necrotic or rudimentary c. Single midline lobe Cardiac a. Absent heart tissue b. Unfolded heart tube c. Folded heart with common chamber Gastrointestinal a. Esophageal atresia b. Short intestine c. Interrupted intestine d. Omphalocele e. Incomplete rotation of the gut

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20.

21.

f. Imperforated anus g. Ascites Liver a. Absent b. Reduced Kidney a. Absent (bilateral) b. Hypoplastic and/or lobulated Other viscera a. Absent gallbladder b. Absent spleen c. Absent to reduced pancreas d. Absent adrenal e. Absent to hypoplastic gonads f. Exstrophy of the cloaca g. Skin with myxedematous thickening Umbilical cord vessels a. Two vessels b. Three vessels Severe obstetrical complications a. Maternal polyhydramnios b. Preterm labor c. Cord accidents d. Dystocia e. Uterine rupture Severe neonatal complications a. Hydrops b. Intrauterine demise c. Prematurity d. Heart failure e. Anemia f. Twin-to-twin transfusion syndrome Outcome for the normal sib in an acardiac twin pregnancy (Healey 1994). a. Unsatisfactory i. Adapting to the increasing circulatory load, resulting in the following situations: a) Intrauterine growth retardation b) Hydrops c) Ascites d) Pleural effusion e) Hypertrophy of the right ventricle f) Hepatosplenomegaly g) Severe heart failure resulting in pericardial effusion and/or tricuspid insufficiency ii. Stillbirth

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iii. Prematurity iv. Neonatal death b. Mortality for the normal twin reported as high as 50% without intervention (Aggarwal et al. 2002)

Diagnostic Investigations 1. Radiography a. Absent or rudimentary skull b. Absent or rudimentary thorax c. Absent or rudimentary heart d. Vertebral anomalies e. Rib anomalies f. Limb defects, especially upper limbs 2. Pathology a. Microcephaly b. Severely rudimentary brain c. Developmental arrest of brain at the prosencephalic stage (holoprosencephaly) d. Hypoxic damage to the holospheric brain mantle with cystic change (hydranencephaly)

Genetic Counseling 1. Recurrence risk a. Patient’s sib: overall recurrence risk of about 1 in 10,000 (The recurrence risk is for monoamniotic twinning (1% for couples who have had one set of monozygotic twins) times the frequency of the occurrence of TRAP sequence with near-term survival (about 1% of monozygotic twin sets)) b. Patient’s offspring: not applicable (a lethal condition) 2. Prenatal ultrasonography (Sherer et al. 1989; Stiller et al. 1989; Langlotz et al. 1991; Donnenfeld et al. 1991; Shalev et al. 1992; Zucchini et al. 1993; Coulam 1996; Schwarzler et al. 1999; BonillaMusoles et al. 2001) a. Monochorionic placenta with a single umbilical artery in two-thirds of cases b. Acardiac fetus i. Unrecognizable head or upper trunk. ii. Without a recognizable heart or a partially formed heart. iii. A variety of other malformations.

iv. Reversal of blood flow in the umbilical artery with flow going from the placenta toward the acardiac fetus (reversed arterial perfusion). Such a reversal of the blood flow in the recipient twin can be demonstrated in utero by transvaginal Doppler ultrasound as early as 12 weeks of gestation. v. Early diagnosis by transvaginal sonography on the following signs: a) Monozygotic twin gestation (absence of the lambda sign) b) Biometric discordance between the twins c) Diffuse subcutaneous edema or morphologic anomalies of one of the twins or both d) Detection of reversed umbilical cord flow; cardiac activity likely to disappear as the pregnancy progresses e) Absence of cardiac activity, although hemicardia or pseudocardia may be present c. The donor fetus i. Hydrops ii. Cardiac failure (cardiomegaly, pericardial effusion, tricuspid regurgitation) 3. Amniocentesis to diagnose associated chromosome abnormalities (about 10% of pump twins) 4. Management of pregnancies complicated by an acardiac fetus (Donnenfeld et al. 1991; Hanafy and Peterson 1997; Søggard et al. 1999) a. Conservative treatment i. Monitor pregnancy by serial ultrasonography ii. Conservative approach as long as there is no evidence of cardiac circulatory decompensation in the donor twin b. Termination of pregnancies c. Treatment and prevention of preterm labor by tocolytics i. Magnesium sulfate ii. Beta sympathomimetics iii. Indomethacin d. Treatment of pump fetus heart failure involving maternal digitalization e. Treatment of polyhydramnios by therapeutic repeated amniocentesis f. Selective termination of the acardiac twin i. To occlude the umbilical artery of the acardiac twin in order to stop umbilical flow through the anastomosis

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a) Intrafunicular injection and mechanical occlusion of the umbilical artery b) Embolization by steel or platinum coil, alcohol-soaked suture material, or ethanol c) Hysterotomy and delivery of acardiac twin d) Ligation of the umbilical cord e) Hysterotomy and umbilical cord ligation ii. Fetal surgery: best available treatment for acardiac twinning (Arias et al. 1998) a) Endoscopic laser coagulation of the umbilical vessels at or before 24 weeks of gestation b) Endoscopic- or sonographic-guided umbilical cord ligation at 24 weeks of gestation iii. Summary of acardiac twins treated with invasive procedures reported in the literature a) Mortality of the pump twin (13.6%) b) Preterm delivery (50.3%) c) Delivery before 30 weeks gestation (27.2%) d) Perinatal mortality if untreated is at least 50%

References Aggarwal, N., Suri, V., Saxena, S. V., et al. (2002). Acardiac acephalus twins: A case report and review of literature. Acta Obstetricia et Gynecologica Scandinavica, 81, 983–984. Alderman, B. (1973). Foetus acardius amorphous. Postgraduate Medical Journal, 49, 102–105. Arias, F., Sunderji, S., Gimpelson, R., et al. (1998). Treatment of acardiac twinning. Obstetrics and Gynecology, 91, 818–821. Benirschke, K., & des Roches Harper, V. (1977). The acardiac anomaly. Teratology, 15, 311–316. Blaicher, W., Repa, C., & Schaller, A. (2000). Acardiac twin pregnancy: Associated with trisomy 2. Human Reproduction, 15, 474–475. Blenc, A. M., Go¨mez, J. A., Collins, D., et al. (1999). Pathologic quiz case. Pathologic diagnosis: Acardiac fetus, acardius acephalus type. Archives of Pathology & Laboratory Medicine, 123, 974–976. Bonilla-Musoles, F., Machado, L. E., Raga, F., et al. (2001). Fetus acardius. Two- and three-dimensional ultrasonographic diagnoses. Journal of Ultrasound in Medicine, 20, 1117–1127. Chen, H., Gonzalez, E., Hand, A. M., & Cuestas, R. (1983). The acardius acephalus and monozygotic twinning. Schumpert Medical Quarterly, 1, 195–199. Coulam, C. B. (1996). First trimester diagnosis of acardiac twins. Journal of Obstetrics and Gynaecology, 88, 729.

5 Donnenfeld, A. E., Van de Woestijne, J., Craparo, F., et al. (1991). The normal fetus of an acardiac twin pregnancy: Perinatal management based on echocardiographic and sonographic evaluation. Prenatal Diagnosis, 11, 235–244. French, C. A., Bieber, F. R., Bing, D. H., et al. (1998). Twins, placentas, and genetics: Acardiac twinning in a dichorionic, diamniotic, monozygotic twin gestation. Human Pathology, 29, 1028–1031. Gewolb, I. H., Freeman, R. M., Kleinman, C. S., et al. (1983). Prenatal diagnosis of a human pseudoacardiac anomaly. Obstetrics and Gynecology, 61, 657–662. Gillim, D. L., & Hendricks, C. H. (1953). Holoacardius: Review of the literature and case report. The Obstetrician and Gynaecologist, 2, 647–652. Hanafy, A., & Peterson, C. M. (1997). Twin-reversed arterial perfusion (TRAP) sequence: Case reports and review of literature. The Australian and New Zealand Journal of Obstetrics and Gynaecology, 37, 187–191. Healey, M. G. (1994). Acardia: Predictive risk factors for the cotwin’s survival. Teratology, 50, 205–213. Langlotz, H., Sauerbrei, E., & Murray, S. (1991). Transvaginal Doppler sonographic diagnosis of an acardiac twin at 12 weeks gestation. Journal of Ultrasound in Medicine, 10, 175–179. Moore, T., Gale, S., & Benirschke, K. (1990). Perinatal outcome of forty-nine pregnancies complicated by acardiac twining. American Journal of Obstetrics and Gynecology, 163, 907–912. Napolitani, F. H., & Schreiber, I. (1960). The acardiac monster: A review of the world literature and presentation of two cases. American Journal of Obstetrics and Gynecology, 80, 582–589. Nicolaidis, P., Nasrat, H., & Tannirandorn, Y. (1990). Review: Fetal acardia: Etiology, pathology and management. Journal of Obstetrics and Gynecology, 10, 518–525. Obladen, M. (2010). From monster to twin reversed arterial perfusion: A history of acardiac twins. Journal of Perinatal Medicine, 38, 247–253. Sanjaghsaz, H., Bayram, M. O., & Qureshi, F. (1998). Twin reversed arterial perfusion sequence in conjoined, acardiac, acephalic twins associated with a normal triplet. A case report. The Journal of Reproductive Medicine, 43, 1046–1050. Schwarzler, P., Ville, Y., Moscosco, G., et al. (1999). Diagnosis of twin reversed arterial perfusion sequence in the first trimester by transvaginal color Doppler ultrasound. Ultrasound in Obstetrics & Gynecology, 13, 143–146. Shalev, E., Zalel, Y., Ben-Ami, M., et al. (1992). First-trimester ultrasonic diagnosis of twin reversed arterial perfusion sequence. Prenatal Diagnosis, 12, 219–222. Sherer, D. M., Armstrong, B., Shah, Y. G., et al. (1989). Prenatal sonographic diagnosis. Doppler velocimetric umbilical cord studies and subsequent management of an acardiac twin pregnancy. The Obstetrician and Gynaecologist, 74, 472–475. Søgaard, K., Skibsted, L., & Brocks, V. (1999). Acardiac twins: Pathophysiology, diagnosis, outcome and treatment. Six cases and review of the literature. Fetal Diagnosis and Therapy, 14, 53–59.

6 Steffensen, T. S., Gilbert-Barnes, E., Spellacy, W., et al. (2008). Placental pathology in TRAP sequence: Clinical and pathogenetic implications. Fetal and Pediatric Pathology, 27, 13–29. Stiller, R. J., Romero, R., Pace, S., et al. (1989). Prenatal identification of twin reversed arterial perfusion syndrome in the first trimester. American Journal of Obstetrics and Gynecology, 160, 1194–1196. Thelmo, M. L. C., Fok, R. Y., & Schertukde, S. P. (2007). Acardiac twin fetus with severe hydrops fetalis and bilateral

Acardia talipes varus deformity. Fetal and Pediatric Pathology, 26, 235–242. Van Allen, M. I., Smith, D. W., & Shepard, T. H. (1983). Twin reversed arterial perfusion (TRAP) sequence: A study of 14 twin pregnancies with acardius. Seminars in Perinatology, 7, 285–293. Zucchini, S., Borghesani, F., Soffriti, G., et al. (1993). Transvaginal ultrasound diagnosis of twin reversed arterial perfusion syndrome at 9 weeks of gestation. Ultrasound in Obstetrics & Gynecology, 3, 209–211.

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7

a

b

Fig. 1 (a, b) Ventral view of an acardiac acephalus fetus (upper photo) shows a large abdominal defect, gastroschisis (arrow), through which small rudiments of gastrointestinal tract are seen. Dorsal view (lower photo) shows a very underdeveloped cephalic

end and relatively well-developed lower limbs. The co-twin had major malformations consisting of a large omphalocele, ectopia cordis, and absent pericardium, incompatible with life (Chen et al. 1983)

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a

b

Fig. 2 (a, b) Radiographs of the above acardiac fetus showing a missing head, cervical vertebrae and part of upper thoracic vertebrae, rudimental lower ribs, malformed lower thoracic and lumbar vertebrae, and relatively well-formed lower limbs

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Fig. 3 The head and part of the thorax of this acardiac fetus are completely missing with relatively well-formed lower limbs

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a

b

Fig. 4 (a, b) Another acardiac fetus with a missing head and part of the upper thorax. Radiograph shows missing head, cervical and part of thoracic vertebrae, and ribs. Pelvis and lower limbs are well formed

a

b

Fig. 5 (a, b) Acardius (second twin, 36 weeks gestation) showing spherical body with a small amorphous mass of leptomeningeal and glial tissue at the cephalic end. There were one deformed lower extremity and a small arm appendage. Small intestinal loops, nodules of adrenal glands, and testicles

were present in the body. There was no heart or lungs. The placenta was nonoamniotic monochorionic with velamentous insertion of the umbilical cord. The other identical twin was free of birth defects. Radiograph of acardius twin shows a short segment of the spine, a femur, a tibia, and a fibula

Achondrogenesis

Marco Fraccaro first described achondrogenesis in 1952 (Fraccaro 1952). He used the term to describe a stillborn female with severe micromelia and marked histological cartilage changes. The term was later used to characterize the most severe forms of chondrodysplasia in humans, which were invariably lethal before or shortly after birth. By the 1970s, researchers concluded that achondrogenesis was a heterogeneous group of chondrodysplasias lethal to neonates; achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria. Achondrogenesis type I was further subdivided, on the basis of convincing histological criteria, into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed recently by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene, making it allelic with diastrophic dysplasia.

Synonyms and Related Disorders Achondrogenesis type IA (Houston-Harris type); Achondrogenesis type IB (Fraccaro type); Achondrogenesis type II (Langer-Saldino type)

2. Type IB a. An autosomal recessive disorder b. Resulting from mutations of the DTDST gene, which encodes the SLC26A2 sulfate transporter, is located at 5q32–q33 (Superti-Furga et al. 1996) 3. Type II a. Autosomal dominant type II collagenopathy b. Resulting from mutations in the COL2A1 gene, which is located at 12q13.1–q13.3 c. Report of a familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and “patchy” expression in the mosaic father (Forzano et al. 2007) suggests that somatic mosaicism can lead to a milder but generalized clinical phenotype. 4. Mutations within the COL2A1 gene also cause the following skeletal dysplasias (Forzano et al. 2007): a. Hypochondrogenesis b. Spondyloepiphyseal dysplasia (SED) congenita c. SED Namaqualand type d. Mild SED with precocious osteoarthritis e. Spondyloepimetaphyseal dysplasia, Strudwick type f. Kniest dysplasia g. Multiple epiphyseal dysplasia with myopia and conductive deafness h. Spondyloperipheral dysplasia i. Stickler dysplasia type I

Genetics/Basic Defects Clinical Features 1. Type IA: an autosomal recessive disorder: caused by mutation in the thyroid hormone recepter interacter 11 (TRIP 11) gene which is mapped on 14q32.12) (Smits et al. 2010)

1. Prenatal/perinatal history a. Polyhydramnios b. Hydrops

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_2, # Springer Science+Business Media, LLC 2012

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c. Breech presentation d. Perinatal death 2. Achondrogenesis type I a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 1,200 g b. Craniofacial features i. Disproportionately large head ii. Soft skull iii. Sloping forehead iv. Convex facial plane v. Flat nasal bridge, occasionally associated with a deep horizontal groove vi. Small nose, often with anteverted nostrils vii. Long philtrum viii. Retrognathia ix. Increased distance between lower lip and lower edge of chin x. Double chin appearance c. Extremely short neck d. Thorax i. Short and barrel-shaped thorax ii. Lung hypoplasia e. Heart i. Patent ductus arteriosus ii. Atrial septal defect iii. Ventricular septal defect f. Protuberant abdomen g. Limbs i. Extremely short (micromelia), shorter than type II ii. Flipper-like appendages 3. Achondrogenesis type II (Langer-Saldino type) a. Growth i. Lethal neonatal dwarfism ii. Mean birth weight of 2,100 g b. Craniofacial features i. Disproportionately large head ii. Large and prominent forehead iii. Midfacial hypoplasia a) Flat facial plane b) Flat nasal bridge c) Small nose with severely anteverted nostrils iv. Normal philtrum v. Micrognathia vi. Cleft palate

Achondrogenesis

c. Extremely short neck d. Thorax i. Short and flared thorax ii. Bell-shaped cage iii. Lung hypoplasia e. Protuberant abdomen f. Extremely short limbs (micromelia)

Diagnostic Investigations 1. Radiological features a. Variable features b. No single obligatory feature c. Distinction between type IA and type IB on radiographs not always possible d. Degree of ossification: age dependent, and caution is needed when comparing radiographs at different gestational ages e. Achondrogenesis type I i. Skull: Varying degree of deficient cranial ossification consisting of small islands of bone in membranous calvaria ii. Thorax and ribs a) Short and barrel-shaped thorax b) Thin ribs with marked expansion at costochondral junction, frequently with multiple fractures iii. Spine and pelvis a) Poorly ossified spine, ischium, and pubis b) Poorly ossified iliac bones with short medial margins iv. Limbs and tubular bones a) Extreme micromelia, with limbs much shorter than in type II b) Prominent spike-like metaphyseal spurs c) Femur and tibia frequently presenting as short bone segments v. Subtype IA (Houston-Harris type) a) Poorly ossified skull b) Thin ribs with multiple fractures c) Unossified vertebral pedicles d) Arched ilium e) Hypoplastic but ossified ischium f) Wedged femur with metaphyseal spikes g) Short tibia and fibula with metaphyseal flare

Achondrogenesis

vi. Subtype IB (Fraccaro type) a) Adequately ossified skull b) Absence of rib fractures c) Total lack of ossification or only rudimentary calcification of the center of the vertebral bodies d) Ossified vertebral pedicles e) Iliac bones with ossification only in their upper part, giving a crescent-shaped, “paraglider-like” appearance on X-ray f) Unossified ischium g) Shortened tubular bones without recognized axis h) Metaphyseal spurring giving the appearance of a “thorn apple” or “acanthocyte” (a descriptive term in hematology) i) Trapezoid femur j) Stellate tibia k) Unossified fibula l) Poorly ossified phalanges f. Achondrogenesis type II i. Skull a) Normal cranial ossification b) Relatively large calvaria ii. Thorax and ribs a) Short and flared thorax b) Bell-shaped cage c) Shorter ribs without fractures iii. Spine and pelvis: relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins iv. Limbs and tubular bones a) Short, broad bones, usually with some diaphyseal constriction and flared, cupped metaphyseal ends b) Metaphyseal spurs, usually smaller than type I 2. Histologic features a. Achondrogenesis type IA i. Normal cartilage matrix ii. Absent collagen rings around the chondrocytes iii. Vacuolated chondrocytes iv. Presence of intrachondrocytic inclusion bodies (periodic acid-Schiff [PAS] stain positive, diastase resistant) v. Extraskeletal cartilage involvement

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vi. Enlarged lacunas vii. Woven bone b. Achondrogenesis type IB i. Abnormal cartilage matrix: presence of “demasked” coarsened collagen fibers, particularly dense around the chondrocytes, forming collagen rings ii. Abnormal staining properties of cartilage a) Reduced staining with cationic dyes, such as toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteoglycans b) This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern. c. Achondrogenesis type II i. Cartilage a) Slightly larger than normal b) Grossly distorted (lobulated and mushroomed) ii. Markedly deficient cartilaginous matrix iii. Severe disturbance in endochondral ossification iv. Hypercellular and hypervascular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm (vacuoles) (“Swiss cheese-like”) v. Overgrowth of membranous bones resulting in cupping of the epiphyseal cartilages vi. Decreased amount and altered structure of proteoglycans vii. Relatively lower content of chondroitin 4-sulfate viii. Lower molecular weight and decreased total chondroitin sulfation ix. Absence of type II collagen x. Increased amounts of type I and type III collagen 3. Biochemical testing a. Lack of sulfate incorporation: cumbersome and not used for diagnostic purposes b. Sulfate incorporation assay in cultured skin fibroblasts or chondrocytes: recommended in

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the rare instances in which the diagnosis of achondrogenesis type IB is strongly suspected but molecular genetic testing fails to detect SLC26A2 (DTDST) mutations 4. Molecular genetic studies a. Mutation analysis of the DTDST gene, reported in: i. Achondrogenesis type IB (the most severe form) ii. Atelosteogenesis type II (an intermediate form) iii. Diastophic dysplasia (the mildest form) iv. Recessive multiple epiphyseal dysplasia b. Achondrogenesis type IB i. Mutation analysis: testing of the following four most common SLC26A2 (DTDST) gene mutations (mutation detection rate about 60%) a) R279W b) IVS1 + 2 > C (“Finnish” mutation) c) delV340 d) R178X ii. Sequence analysis of the SLC26A2 (DTDST) coding region (mutation detection rate over 90%) a) Private mutations b) Common mutations c. Achondrogenesis type II: mutation analysis of the COL2A1 gene

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Achondrogenesis type IA and type IB (autosomal recessive disorders) a) Recurrence risk: 25% b) Unaffected sibs of a proband: two third chance of being heterozygotes ii. Achondrogenesis type II a) Usually caused by a new dominant mutation, in which case recurrence risk is not significantly increased b) Asymptomatic carrier parent (germline mutation for a dominant mutation) may be present in the families of affected

Achondrogenesis

patients, in which case recurrence risk can be up to 50%. b. Patient’s offspring: lethal entities not surviving to reproduction 2. Prenatal diagnosis a. Ultrasonography i. Polyhydramnios ii. Fetal hydrops iii. Disproportionally big head iv. Nuchal edema v. Cystic hygroma vi. A narrow thorax vii. Short limbs viii. Poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length) ix. Suspect achondrogenesis type I a) An extremely echo-poor appearance of the skeleton b) A poorly mineralized skull c) Short limbs d) Rib fractures b. Molecular genetic studies i. Prenatal diagnosis of achondrogenesis type IB and type II by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester ii. Achondrogenesis type IB a) Characterize both alleles of DTDST beforehand b) Identify the source parent of each allele c) Theoretically, analysis of sulfate incorporation in chorionic villi might be used for prenatal diagnosis, but experience is lacking. iii. Achondrogenesis type II a) The affected fetus usually with a new dominant mutation of the COL2A1 gene b) Possible presence of asymptomatic carriers in families of an affected patient c) Prenatal diagnosis possible if the mutation has been characterized in the affected family 3. Management a. Supportive care b. No treatment available for the underlying lethal disorder

Achondrogenesis

References Balakumar, K. (1990). Antenatal diagnosis of Parenti-Fraccaro type achondrogenesis. Indian Pediatrics, 27, 496–499. Benacerraf, B., Osathanondh, R., & Bieber, F. R. (1984). Achondrogenesis type I: Ultrasound diagnosis in utero. Journal of Clinical Ultrasound, 12, 357–359. Bonafe´, L., Crettol, L. M., Ballhausen, D., et al. (2009). Achondrogenesis type 1B. GeneReviews, Updated September 22, 2009. Available at: http://www.genetests.org. Borochowitz, Z., Lachman, R., Adomian, G. E., et al. (1988a). Achondrogenesis type I: Delineation of further heterogeneity and identification of two distinct subgroups. The Journal of Pediatrics, 112, 23–31. Borochowitz, Z., Lachman, R., Adomian, G. E., et al. (1988b). Achondrogenesis type I: Delineation of further heterogeneity and identification of two distinct subgroups. The Journal of Pediatrics, 112, 23–31. Borochowitz, Z., Ornoy, A., Lachman, R., et al. (1986). Achondrogenesis II-hypochondrogenesis: Variability versus heterogeneity. American Journal of Medical Genetics, 24, 273–288. Chen, H. (2009). Achondrogenesis. eMedicine from WebMD. Updated April 23, 2009. Available at: http://emedicine. medscape.com/article/941176-overview. Chen, H. (2009). Skeletal dysplasia. eMedicine from WebMD. Updated September 14, 2009. Available at: http://emedicine. medscape.com/article/943343-overview. Chen, H., Liu, C. T., & Yang, S. S. (1981). Achondrogenesis: A review with special consideration of achondrogenesis type II (Langer-Saldino). American Journal of Medical Genetics, 10, 379–394. Faivre, L., Le Merrer, M., Douvier, S., et al. (2004). Recurrence of achondrogenesis type II within the same family: Evidence for germline mosaicism. American Journal of Medical Genetics Part A Early View, 126, 308–312. Forzano, F., Lituania, M., Viassolo, V., et al. (2007). A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and “patchy” expression in the mosaic father. American Journal of Medical Genetics. Part A, 143A, 2815–2820. Fraccardo, M. (1952). Contributo allo studio delle malattie del mesenchima osteopoietico: l Achondrogenesi. Folia Hered Path, 1, 190–208. Godfrey, M., & Hollister, D. W. (1988). Type II achondrogenesis-hypochondrogenesis: Identification of abnormal type II collagen. American Journal of Human Genetics, 43, 904–913. Horton, W. A., Machado, M. A., Chou, J. W., et al. (1987). Achondrogenesis type II, abnormalities of extracellular matrix. Pediatric Research, 22, 324–329. Ko¨rkko¨, J., Cohn, D. H., Ala-Kokko, L., et al. (2000). Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. American Journal of Medical Genetics, 92, 95–100. Langer, L. O., Jr., Spranger, J. W., Greinacher, I., et al. (1969). Thanatophoric dwarfism. A condition confused with

15 achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology, 92, 285–294. Passim. Meizner, I., & Barnhard, Y. (1995). Achondrogenesis type I diagnosed by transvaginal ultrasonography at 13 weeks’ gestation. American Journal of Obstetrics and Gynecology, 173, 1620–1622. Molz, G., & Spycher, M. A. (1980). Achondrogenesis type I: Light and electron-microscopic studies. European Journal of Pediatrics, 134, 69–74. Mortier, G. R., Wilkin, D. J., Wilcox, W. R., et al. (1995). A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691– > Arg) in the type II collagen trimer. Human Molecular Genetics, 4, 285–288. Ornoy, A., Sekeles, E., Smith, P., et al. (1976). Achondrogenesis type I in three sibling fetuses. Scanning and transmission electron microscopic studies. American Journal of Pathology, 82, 71–84. Smith, W. L., Breitweiser, T. D., & Dinno, N. (1981). In utero diagnosis of achondrogenesis, type I. Clinical Genetics, 19, 51–54. Smits, P., Bolton, A. D., Funaari, V., et al. (2010). Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. New England Journal of Medicine, 362, 206–216. Soothill, P. W., Vuthiwong, C., & Rees, H. (1993). Achondrogenesis type 2 diagnosed by transvaginal ultrasound at 12 weeks’ gestation. Prenatal Diagnosis, 13, 523–528. Spranger, J. (1992). International classification of osteochondrodysplasias. European Journal of Pediatrics, 151, 407–415. Spranger, J., Winterpacht, A., & Zabel, B. (1994). The type II collagenopathies: A spectrum of chondrodysplasias. European Journal of Pediatrics, 153, 56–65. Superti-Furga, A. (1996). Achondrogenesis type 1B. Journal of Medical Genetics, 33, 957–961. Superti-Furga, A., H€astbacka, J., Wilcox, W. R., et al. (1996). Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nature Genetics, 12, 100–102. Superti-Furga, A., Rossi, A., Steinmann, B., et al. (1996). A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/ phenotype correlations. American Journal of Medical Genetics, 63, 144–147. Taner, M. Z., Kurdoglu, M., Taskiran, C., et al. (2008). Prenatal diagnosis of achondrogenesis type I: A case report. Cases Journal, 1, 406–410. Tongsong, T., Srisomboon, J., & Sudasna, J. (1995). Prenatal diagnosis of Langer-Saldino achondrogenesis. Journal of Clinical Ultrasound, 23, 56–58. Van der Harten, H. J., Brons, J. T., Dijkstra, P. F., et al. (1988a). Achondrogenesis-hypochondrogenesis: The spectrum of chondrogenesis imperfecta. A radiological, ultrasonographic, and histopathologic study of 23 cases. Pediatric Pathology, 8, 571–597. Van der Harten, H. J., Brons, J. T., Dijkstra, P. F., et al. (1988b). Achondrogenesis-hypochondrogenesis: The spectrum of chondrogenesis imperfecta. A radiological,

16 ultrasonographic, and histopathologic study of 23 cases. Pediatric Pathology, 8, 571–597. Yang, S. S., & Bernstein, J. (1975). Letter: Proposed readjustment of eponyms for achondrogenesis. The Journal of Pediatrics, 87, 333–334. Yang, S. S., & Bernstein, J. (1977). Achondrogenesis type I. Archives of Disease in Childhood, 52, 253–254. Yang, S. S., Brough, A. J., Garewal, G. S., et al. (1974). Two types of heritable lethal achondrogenesis. The Journal of Pediatrics, 85, 796–801.

Achondrogenesis Yang, S. S., & Gilbert-Barnes, E. (1997). Skeletal system. In E. Gilbert-Barness (Ed.), Potter’s pathology of the fetus and infant (pp. 1423–1478). St Louis: Mosby. Yang, S. S., Heidelberger, K. P., & Bernstein, J. (1976). Intracytoplasmic inclusion bodies in the chondrocytes of type I lethal achondrogenesis. Human Pathology, 7, 667–673. Yang, S.-S., Heidelberger, K. P., Brough, A. J., et al. (1976). Lethal short-limbed chondrodysplasia in early infancy. Perspectives in Pediatric Pathology, 3, 1–40.

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c

e

f

Fig. 1 (a–f) A neonate with achondrogenesis type I showing large head, short trunk, and extreme micromelia. Radiograph shows unossified calvarium, vertebral bodies, and some pelvic bones. The remaining bones are extremely small. There are multiple rib fractures. The sagittal section of the femora and the humeri are similar. An extremely small ossified shaft is capped by

a relatively large epiphyseal cartilage at both ends. Photomicrographs of resting cartilage with high magnification show many chondrocytes that contain large cytoplasmic inclusions which are within clear vacuoles (Diastase PAS stain). Electron micrograph shows inclusion as a globular mass of electron dense material. It is within a distended cistern of rough endoplasmic reticulum

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Achondrogenesis

a

b

d

Fig. 2 (a–e) Achondrogenesis type II. As in type I, this neonate shows large head, short trunk, and micromelia (Potter’s pathology of Fetus and Infant, by Gilbert-Barness). Sagittal section of the femur shows much better ossification of the shaft than type I. The cartilage lacks glistering appearance

c

e

due to cartilage matrix deficiency. Photomicrograph of the entire cartilage shows severe deficiency of cartilage matrix. The cartilage canals are large, fibrotic, and stellate in shape. Physeal growth zone is severely retarded

Achondrogenesis Fig. 3 (a–d) Two infants with achondrogenesis type II showing milder spectrum of manifestations, bordering the type II and spondyloepiphyseal congenita

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a

c

b

d

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Achondrogenesis

b

a

d

c

e

g

Fig. 4 (a–h) A newborn girl with achondrogenesis type II showing large head, midfacial hypoplasia, short neck, small chest, and short limbs. The radiographs shows generalized shortening of the long bones of the upper and lower extremities with marked cupping (metaphyseal spurs) at the metaphyseal ends of the bones. This is most evident at the distal ends of the tibia, fibular, radius and ulna, and distal ends of the digits. Radiographs also

f

h

shows short ribs without fractures and hemivertebrae involving thoracic vertebrae as well as the sacrum. Conformation sensitive gel electrophoresis analysis indicated a sequence variation in the fragment containing exon 19 and the flanking sequences of the COL2A1 gene (Gly244Asp). Similar mutations in this area have been seen in patients diagnosed with hypochondroplasia and achondrogenesis type II

Achondroplasia

Achondroplasia is the most common form of shortlimbed dwarfism. Gene frequency is estimated to be 1/16,000 and 1/35,000. There are about 5,000 achondroplasts in the U.S.A. and 65,000 on Earth. The incidence for achondroplasia is between 0.5 and 1.5 in 10,000 births. The mutation rate is high and is estimated to be between 1.72 and 5.57
105 per gamete per generation. Most infants with achondroplasia are born unexpectedly to parents of average stature.

Genetics/Basic Defects 1. Inheritance a. Autosomal dominant disorder with complete penetrance b. Sporadic in about 80% of the cases, the result of a de novo mutation c. Presence of paternal age effect (advanced paternal age in sporadic cases) d. Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents) 2. Caused by mutations in the gene of the fibroblast growth factor receptor 3 (FGFR3) on chromosome 4p16.3 a. About 98% of achondroplasia with G-to-A transition and about 1% G-to-C transversion at nucleotide 1138. Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 (G380A) of the mature protein in the transmembrane domain of FGFR3. b. A rare mutation causing substitution of a nearby glycine 375 with a cysteine (G375C)

c. Another rare mutation causing substitution of glycine346 with glutamic acid (G346E) d. The specific mechanisms by which FGFR3 mutations disrupt skeletal development in achondroplasia remain elusive 3. Different mutations in FGFR3 can cause the following spectrum of disorders (Lemyre et al. 1999; Superti-Furga and Unger 2007) a. Hypochondroplasia b. Severe achondroplasia with developmental delay and acanthosis nigricans c. Thanatophoric dysplasia 4. FGFR3 mutations affect the cartilaginous growth plate in the growing skeleton, therefore disturbing cartilage function during linear bone growth (Richette et al. 2008) 5. Basic defect: zone of chondroblast proliferation in the physeal growth plates a. Abnormally retarded endochondral ossification with resultant shortening of tubular bones and flat vertebral bodies, while membranous ossification (skull, facial bones) is not affected b. Physeal growth zones show normal columnization, hypertrophy, degeneration, calcification, and ossification. However, the growth is quantitatively reduced significantly. c. Achondroplasia as the result of a quantitative loss of endochondral ossification rather than the formation of abnormal tissue d. Normal diameter of the bones secondary to normal subperiosteal membranous ossification of tubular bones; the results being production of short, thick tubular bones, leading to short stature with disproportionately shortened limbs

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_3, # Springer Science+Business Media, LLC 2012

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Clinical Features 1. Major clinical symptoms a. Delayed motor milestones during infancy and early childhood b. Sleep disturbances secondary to both neurological and respiratory complications c. Breathing disorders i. A high prevalence (75%) of breathing disorders during sleep ii. Obstructive apnea caused by upper airway obstruction iii. The majority of respiratory complaints due to restrictive lung disease secondary to diminished chest size or upper airway obstruction and rarely due to spinal cord compression d. Symptomatic spinal stenosis in more than 50% of patients as a consequence of a congenitally small spinal canal i. Back pain ii. Lower extremity sensory changes iii. Incontinence iv. Paraplegia v. Onset of symptoms: usually after 20 s or 30 s e. Neurologic symptoms classified based on neurologic severity and presentation of spinal stenosis (Lutter and Langer 1977) i. Type I (back pain with sensory and motor change of an insidious nature) ii. Type II (intermittent claudication limiting ambulation) iii. Type III (nerve root compression) iv. Type IV (acute onset paraplegia) f. Symptoms secondary to foramen magnum stenosis i. Respiratory difficulty ii. Feeding problems iii. Cyanosis, quadriparesis iv. Poor head control g. Symptoms secondary to cervicomedullary compression i. Pain ii. Ataxia iii. Incontinence iv. Apnea v. Progressive quadriparesis vi. Respiratory arrest

Achondroplasia

2. Major clinical signs a. Disproportionate short stature (dwarfism) b. Hypotonia during infancy and early childhood c. Relative stenosis of the foramen magnum in all patients, documented by CT d. Foramen magnum stenosis considered as the cause of increased incidence of: i. Hypotonia ii. Sleep apnea iii. Sudden infant death syndrome e. Symptomatic hydrocephalus in infancy and early childhood rarely due to narrowing of the foramen magnum f. Characteristic craniofacial appearance i. Disproportionately large head ii. Frontal bossing iii. Depressed nasal bridge iv. Midfacial hypoplasia v. Narrow nasal passages vi. Prognathism vii. Dental malocclusion g. A normal trunk length h. A thoracolumbar kyphosis or gibbus usually present at birth or early infancy i. Exaggerated lumbar lordosis when the child begins to ambulate j. Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults k. Generalized joint hypermobility, especially the knees l. Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments) m. Limited elbow and hip extension n. Trident hands (inability to approximate the third and fourth fingers in extension produces a “trident” configuration of the hand) o. Short fingers (brachydactyly) p. Bowing of the legs (genu varum) due to lax knee ligaments q. Excess skin folds about thighs 3. Complications/risks a. Recurrent otitis media during infancy and childhood i. Conductive hearing loss ii. Delayed language development b. Thoraco-lumbar gibbus c. Osteoarthropathy of the knee joints

Achondroplasia

d. Neurological complications i. Small foramen magnum ii. Cervicomedullary junction compression causing sudden unexpected death in infants with achondroplasia iii. Apnea iv. Communicating hydrocephalus v. Spinal stenosis vi. Paraparesis vii. Quadriparesis viii. Infantile hypotonia e. Obesity i. Aggravating the morbidity associated with lumbar stenosis ii. Contributing to the nonspecific joint problems and to the possible early cardiovascular mortality in this condition f. Obstetric complications i. Large head of the affected infant ii. An increased risk of intracranial bleeding during delivery iii. Marked obstetrical difficulties secondary to very narrow pelvis of achondroplastic women 4. Prognosis a. Normal intelligence and healthy, independent, and productive lives in vast majority of patients. Rarely, intelligence may be affected because of hydrocephalus or other CNS complications. b. Mean adult height i. Approximately 131 cm  5.6 for males ii. Approximately 124 cm  5.9 for females c. Psychosocial problems related to body image because of severe disproportionate short stature d. Life span for heterozygous achondroplasia i. Usually normal unless there are serious complications ii. Mean life expectancy approximately 10 years less than the general population e. Homozygous achondroplasia i. A lethal condition with severe respiratory distress caused by rib-cage deformity and upper cervical cord damage caused by small foramen magnum. The patients die soon after birth. ii. Radiographic changes much more severe than the heterozygous achondroplasia

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f. Normal fertility in achondroplasia i. Pregnancy at high risk for achondroplastic women ii. Respiratory compromise common during the third trimester iii. Advise baseline pulmonary function studies before pregnancy to aid in evaluation and management iv. A small pelvic outlet usually requiring Cesarean section under general anesthesia since the spinal or epidural approach is contraindicated because of spinal stenosis g. Anticipatory guidance: Patients and their families can benefit greatly from anticipatory guidance published by American Academy of Pediatrics Committee on Genetics (1995) and Clinical Report (2005). h. Adaptations of patients to the environment to foster independence i. Lowering faucets and light switches ii. Using a step stool to keep feet from dangling when sitting iii. An extended wand for toileting iv. Adaptations of toys for short limbs i. Support groups: Many families find it beneficial to interact with other families and children with achondroplasia through local and national support groups.

Diagnostic Investigations 1. Diagnosis of achondroplasia made by clinical findings, radiographic features, and/or FGFR3 mutation analysis 2. Radiologic Features a. Skull i. Relatively large calvarium ii. Prominent forehead iii. Depressed nasal bridge iv. Small skull base v. Small foramen magnum vi. Dental malocclusion b. Spine i. Caudal narrowing of interpedicular distances in the lower lumbar spine ii. Short vertebral pedicles iii. Wide disc spaces

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iv. Dorsal scalloping of the vertebral bodies in the newborn v. Concave posterior aspect of the vertebral bodies in childhood and adulthood vi. Different degree of anterior wedging of the vertebral bodies causing gibbus c. Pelvis i. Lack of iliac flaring ii. Narrow sacroiliac notch iii. Horizontal acetabular portions of the iliac bones d. Limbs i. Rhizomelic micromelia ii. Square or oval radiolucent areas in the proximal humerus and femur during infancy iii. Tubular bones with widened diaphyses and flared metaphyses during childhood and adulthood iv. Markedly shortened humeri v. Short femoral neck vi. Disproportionately long fibulae in relation to tibiae 3. Craniocervical MRI a. Narrowing of the foramen magnum b. Effacement of the subarachnoid spaces at the cervicomedullary junction c. Abnormal intrinsic cord signal intensity d. Mild to moderate ventriculomegaly 4. Histology a. Normal histologic appearance of epiphyseal and growth plate cartilages b. Shorter than normal growth plate: The shortening is greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect. 5. Mutation analysis a. G1138A substitution in FGFR3 (about 98% of cases) b. G1138C substitution in FGFR3 (about 1% of cases)

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Recurrence risk after the conception of an affected child has always been considered

Achondroplasia

very low and less than 30 cases of recurrences among sibs have been reported so far (Natacci et al. 2008). It was possible to demonstrate somatic and germinal mosaicism in the mother (Henderson et al. 2000) and germinal mosaicism in the father (Natacci et al. 2008). ii. Recurrence risk of achondroplasia in the sibs of achondroplastic children with unaffected parents: presumably higher than twice the mutation rate because of gonadal mosaicism. Currently, the risk is estimated as 1 in 443 (0.2%). iii. Fifty percent affected if one of the parents is affected iv. Twenty-five percent affected with homozygous achondroplasia (resulting in a much more severe phenotype that is usually lethal early in infancy) and 50% affected with heterozygous achondroplasia if both parents are affected with achondroplasia b. Patient’s offspring i. Fifty percent affected (with heterozygous achondroplasia) if the spouse is normal ii. Twenty-five percent affected with homozygous achondroplasia and 50% affected with heterozygous achondroplasia if the spouse is also affected with achondroplasia. There is still a 25% chance that the offspring will be normal. 2. Prenatal diagnosis a. Prenatal ultrasonography i. Suspect achondroplasia on routine ultrasound findings of a fall-off in limb growth (95th percentile) and low nasal bridge (Cordone et al. 1993; Mesoraca et al. 1996), usually during the third trimester of pregnancy, in case of parents with normal heights. About one third of cases are suspected this way. However, one must be cautious because disproportionately short limbs are observed in a variety of conditions. ii. Inability to make specific diagnosis of achondroplasia with certainty by ultrasonography unless by radiography late in gestation or after birth iii. Request of prenatal ultrasonography by an affected parent, having 50% risk of having

Achondroplasia

a similarly affected child, to optimize obstetric management iv. Follow pregnancy by a femoral growth curve in the second trimester by serial ultrasound scans to enable prenatal distinction between homozygous, heterozygous, and unaffected fetuses, in case of both affected parents b. Prenatal radiography i. Shortened long bones with wide metaphyses ii. Slim and radiolucent area in the proximal femur iii. Horizontal acetabular roof iv. The above features not always detected c. 3-Dimensional computed tomography scan (3D CT scan) may be used after 30 weeks of gestation (Krakow et al. 2003; Ruano et al. 2004). i. Slightly flat vertebral bodies with medial spurs ii. Pointed femora with proximal extremity iii. Round and square ilia with an oval radiolucent area in the proximal femur d. On computed tomography and postnatal X-ray, proximal femoral metaphysis appeared rounded, with poor, uneven ossification. Connection to diaphysis was abnormal, with relative overgrowth of the periosteum, creating a new diagnostic sign, called the “collar hoop” sign (Boulet et al. 2009). e. Prenatal molecular testing i. Molecular technology applied to prenatal diagnosis of a fetus suspected of or at risk for having achondroplasia ii. Simple methodology requiring only one PCR and one restriction digest to detect a very limited number of mutations causing achondroplasia iii. Preimplantation genetic diagnosis a) Available at present (Moutou et al. 2003) b) The initial practice raising questions on the feasibility of such a test, specially with affected female patients 3. Management a. Adaptive environmental modifications i. Appropriately placed stools ii. Seating modification iii. Other adaptive devices b. Obesity control c. Obstructive apnea i. Adenoidectomy and tonsillectomy

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d.

e.

f.

g. h. i.

j.

k.

ii. Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) for clinically significant persistent obstruction iii. Extremely rare for requiring temporary tracheostomy Experimental growth hormone therapy (Horton et al. 1992; Shohat et al. 1996; Seino et al. 2000) i. Resulting in transient increases in growth velocity ii. Long term result not conclusive Hydrocephalus i. Observation for benign ventriculomegaly ii. May need surgical intervention for clinically significant hydrocephalus Kyphosis i. Adequate support for sitting in early infancy ii. Bracing using a thoracolumbosacral orthosis for severe kyphosis in young children iii. Surgical intervention for medically unresponsive cases Surgical decompression for unequivocal evidence for cervical cord compression Decompression laminectomy for severe and progressive lumbosacral spinal stenosis Limb lengthening through osteotomy and stretching of the long bones (Aldegheri et al. 1988; Lavini et al. 1990; Ganel et al. 1979; Ganel and Horoszowski 1996) i. Controversial ii. Difficult to achieve the benefits of surgery a) Need strong commitment on the part of the patients and their families for the time in the hospital and the number of operations b) A high risk of infection c) Occurrence of possible severe permanent sequelae (damage to joint and soft tissue) d) May result in poorer quality of life Potential anesthetic risks related to: i. Obstructive apnea ii. Cervical compression Risks associated with pregnancy in women with achondroplasia: relatively infrequent i. Worsening neurologic symptoms related to increasing hyperlordosis and maternal respiratory failure ii. Anticipate a scheduled cesarean delivery due to cephalopelvic disproportion iii. Preeclampsia iv. Polyhydramnios

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References Aldegheri, R., Trivella, G., Renzi-Brivio, L., et al. (1988). Lengthening of the lower limbs in achondroplastic patients. A comparative study of four techniques. The Journal of Bone and Joint Surgery, 70B, 69–73. Allanson, J. E., & Hall, J. G. (1986). Obstetrics and gynecologic problems in women with chondrodystrophies. Obstetrics and Gynecology, 67, 74–78. American Academy of Pediatrics Committee on Genetics. (1995). Health supervision for children with achondroplasia. Pediatrics, 95, 443–451. American Academy of Pediatrics: Clinical Report. (2005). Health supervision for children with achondroplasia. Pediatrics, 116, 771–783. Baujat, G., Legeai-Mallet, L., Finidori, G., et al. (2008). Achondroplasia. Best Practice & Research. Clinical Rheumatology, 22, 3–18. Bellus, G. A., Hefferon, T. W., Ortiz de Luna, R. I., et al. (1995). Achondroplasia is defined by recurrent G380R mutations of FGFR3. American Journal of Human Genetics, 56, 368–373. Boulet, S., Althuser, M., Nugues, F., et al. (2009). Prenatal diagnosis of achondroplasia: New specific signs. Prenatal Diagnosis, 29, 697–702. Carter, E. M., Davis, J. G., & Raggio, C. L. (2007). Advances in understanding etiology of achondroplasia and review of management. Current Opinion in Pediatrics, 19, 32–37. Chen, H., Mu, X., Sonoda, T., et al. (2000). FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q) Down syndrome: Phenotype-genotype correlation. Southern Medical Journal, 93, 622–624. Cordone, M., Lituania, M., Bocchino, G., et al. (1993). Ultrasonographic features in a case of heterozygous achondroplasia at 25 weeks’ gestation. Prenatal Diagnosis, 13, 395–401. Francomano, C. A. (2006). Achondroplasia. GeneReviews. Retrieved January 9, 2006. Available at: http://www.ncbi. nlm.nih.gov/books/NBK1152/ Fryns, J. P., Kleczkowska, A., Verresen, H., et al. (1983). Germinal mosaicism in achondroplasia: A family with 3 affected siblings of normal parents. Clinical Genetics, 24, 156–158. Ganel, A., & Horoszowski, H. (1996). Limb lengthening in children with achondroplasia. Differences based on gender. Clinical Orthopaedics and Related Research, 332, 179–183. Ganel, A., Horoszowski, H., Kamhin, M., et al. (1979). Leg lengthening in achondroplastic children. Clinical Orthopaedics, 144, 194–197. Hall, J. G., Dorst, J., Taybi, H., et al. (1969). Two probable cases of homozygosity for the achondroplasia gene. Birth Defects Original Article Series, V(4), 24–34. Hall, J. G., et al. (1988). The natural history of achondroplasia. In B. Nicoletti, S. E. Kopits, & E. Ascani (Eds.), Human achondroplasia: A multidisciplinary approach (pp. 3–10). New York: Plenum Press. Hecht, J. T., & Butler, I. J. (1990). Neurologic morbidity associated with achondroplasia. Journal of Child Neurology, 5, 84–97.

Achondroplasia Hecht, J. T., Francomano, C. A., Horton, W. A., et al. (1987). Mortality in achondroplasia. American Journal of Human Genetics, 41, 454–464. Henderson, S., Sillence, D., Loughlin, J., et al. (2000). Germline and somatic mosaicism in achondroplasia. Journal of Medical Genetics, 37, 956–958. Hoover-Fong, J. E., McGready, J., Schulze, K. J., et al. (2007). Weight for age charts for children with achondroplasia. American Journal of Medical Genetics. Part A, 143A, 2227–2235. Horton, W. A. (1996). Molecular genetic basis of the human chondrodysplasias. Endocrinology and Metabolism Clinics of North America, 25, 683–697. Horton, W. A. (1997). Fibroblast growth factor receptor 3 and the human chondrodysplasias. Current Opinion in Pediatrics, 9, 437–442. Horton, W. A., Hall, J. G., & Hecht, J. T. (2007). Achondroplasia. Lancet, 370, 162–172. Horton, W. A., Hecht, J. T., Hood, O. J., et al. (1992). Growth hormone therapy in achondroplasia. American Journal of Medical Genetics, 42, 667–670. Horton, W. A., Hood, O. J., Machado, M. A., et al. (1988). Growth plate cartilage studies in achondroplasia. In B. Nicoletti, S. E. Kopits, E. Ascani, et al. (Eds.), Human achondroplasia: A multidisciplinary approach (pp. 81–89). New York: Plenum Press. Horton, W. A., Rotter, J. I., Rimoin, D. L., et al. (1978). Standard growth curves for achondroplasia. Journal of Pediatrics, 93, 435–438. Hunter, A. G. W., Bankier, A., Rogers, J. G., et al. (1998). Medical complications of achondroplasia: A multicenter patient review. Journal of Medical Genetics, 35, 705–712. Hunter, A. G. W., Hecht, J. T., & Scott, C. I. (1996). Standard weight for height curves in achondroplasia. American Journal of Medical Genetics, 62, 255–261. King, J. A. J., Vachhrajani, S., Drake, J. M., et al. (2009). Neurosurgical implications of achondroplasia. A review. Journal of Neurosurgery. Pediatrics, 4, 297–306. Kornblum, M., & Stanitski, D. F. (1999). Spinal manifestations of skeletal dysplasias. Orthopedic Clinics of North America, 30, 501–520. Krakow, D., Williams, J., 3rd, Poehl, M., et al. (2003). Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound in Obstetrics & Gynecology, 21, 467–472. Langer, L. O., Jr., Baumann, P. A., & Gorlin, R. J. (1967). Achondroplasia. American Journal of Roentgenology, 100, 12–26. Lattanzi, D. R., & Harger, J. H. (1982). Achondroplasia and pregnancy. The Journal of Reproductive Medicine, 27, 363–366. Lavini, F., Renzi-Brivio, L., & de Bastiani, G. (1990). Psychologic, vascular, and physiologic aspects of lower limb lengthening in achondroplastics. Clinical Orthopaedics and Related Research, 250, 138–142. Lemyre, E., Azouz, E. M., Teebi, A. S., et al. (1999). Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: Review and update. Canadian Association of Radiologists Journal, 50, 185–197. Lutter, L. D., & Langer, L. O. (1977). Neurologic symptoms in achondroplastic dwarfs-surgical treatment. The Journal of Bone and Joint Surgery, 59(1), 87–92.

Achondroplasia Mesoraca, A., Pilu, G., Perolo, A., et al. (1996). Ultrasound and molecular mid-trimester prenatal diagnosis of de novo achondroplasia. Prenatal Diagnosis, 16, 764–768. Mettler, G., & Fraser, F. C. (2000). Recurrence risk for sibs of children with “sporadic” achondroplasia. American Journal of Medical Genetics, 90, 250–251. Mogayzel, P. J., Jr., Carroll, J. L., Loughlin, G. M., et al. (1998). Sleep-disordered breathing in children with achondroplasia. Journal of Pediatrics, 132, 667–671. Moutou, C., Rongieres, C., Bettahar-Lebugle, K., et al. (2003). Preimplantation genetic diagnosis for achondroplasia: Genetics and gynaecological limits and difficulties. Human Reproduction, 18, 509–514. Natacci, F., Baffico, M., Cavallari, U., et al. (2008). Germline mosaicism in achondroplasia detected in sperm DNA of the father of three affected sibs. American Journal of Medical Genetics. Part A, 146A, 784–786. Overlaid, F., Danks, D. M., Jensen, F., et al. (1979). Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. Journal of Medical Genetics, 16, 140–146. Patel, M. D., & Filly, R. A. (1995). Homozygous achondroplasia: US distinction between homozygous, heterozygous, and unaffected fetuses in the second trimester. Radiology, 196, 541–545. Pauli, R. M. (2001). Achondroplasia. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. New York: Wiley-Liss. Philip, N., Auger, M., Mattei, J. F., et al. (1988). Achondroplasia in sibs of normal parents. Journal of Medical Genetics, 25, 857–859. Pierre-Kahn, A., Hirsch, J. F., Renier, D., et al. (1980). Hydrocephalus and achondroplasia. A study of 25 observations. Child’s Brain, 7, 205–219. Prinos, P., Kilpatrick, M. W., Tsipouras, P., et al. (1994). A novel G346E mutation in achondroplasia. Pediatric Research, 37, 151. Richette, P., Bardin, T., & Stheneur, C. (2008). Achondroplasia: From genotype to phenotype. Joint, Bone, Spine, 75, 125–130. Rimoin, D. L. (1991). Limb lengthening: Past, present, and future. Growth Genetics and Hormones, 7, 4–6. Rousseau, F., Bonaventure, J., Legeal-Mallet, L., et al. (1994). Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature, 371, 252–254. Ruano, R., Molho, M., Roume, J., et al. (2004). Prenatal diagnosis of fetal skeletal dysplasias by combining two dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography. Ultrasound in Obstetrics & Gynecology, 24, 134–140.

27 Seino, Y., Yamanaka, Y., Shinohanora, M., et al. (2000). Growth hormone therapy in achondroplasia. Hormone Research, 533, 53–56. Shiang, R., Thompson, L. M., Zhu, Y.-Z., et al. (1994). Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell, 78, 335–342. Shirley, E. D., & Ain, M. C. (2009). Achondroplasia: Manifestations and treatment. Journal of the American Academy of Orthopaedic Surgeons, 17, 231–241. Shohat, M., Tick, D., Barakat, S., et al. (1996). Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia. The Journal of Clinical Endocrinology and Metabolism, 81, 4033–4037. Spranger, J. W., Langer, L. O., Jr., & Wiedemann, H. R. (1974). Bone dysplasias. An atlas of constitutional disorders of skeletal development. Philadelphia: WB Saunders. Stratbucker, W. B., & Serwint, J. R. (2009). In brief: Achondroplasia. Pediatrics in Review, 30, 114–115. Superti-Furga, A., & Unger, S. (2007). Nosology and classification of genetic skeletal disorders: 2006 revision. American Journal of Medical Genetics. Part A, 143A, 1–18. Todorov, A. B., Scott, C. I., Warren, A. E., et al. (1981). Developmental screening tests in achondroplastic children. American Journal of Medical Genetics, 9, 19–23. Vajo, Z., Francomano, C. A., & Wilkin, D. J. (2000). The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocrine Reviews, 21, 23–39. Velinov, M., Slaugenhaupt, S. A., Stoilov, I., et al. (1994). The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genetics, 6, 318–321. Wynn, J., King, T. M., Gambello, M. J., et al. (2007). Mortality in achondroplasia study: A 42-year follow-up. American Journal of Medical Genetics. Part A, 143A, 2502–2511. Yang, S. S., Corbett, D. P., Brough, A. J., et al. (1977). Upper cervical myelopathy in achondroplasia. American Journal of Clinical Pathology, 68, 68–72. Yang, S. S., & Gilbert-Barnes, E. (1997). Skeletal system. In E. Gilbert-Barness (Ed.), Potter’s pathology of the fetus and infant (pp. 1423–1478). St Louis: Mosby. Yasui, N., Kawahata, H., Kojimoto, H., et al. (1997). Lengthening of the lower limbs in patients with achondroplasia and hypochondroplasia. Clinical Orthopaedics, 344, 298–306. Zucconi, M., Weber, G., Castronova, V., et al. (1996). Sleep and upper airway obstruction in children with achondroplasia. Journal of Pediatrics, 129, 743–749.

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Achondroplasia

a

b

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Fig. 1 (a–d) A newborn with achondroplasia showing large head, depressed nasal bridge, short neck, normal length of the trunk, narrow chest, rhizomelic micromelia, and trident hands. The radiographs showed narrow chest, characteristic pelvis, micromelia, and oval radiolucent proximal portion of the femurs. Molecular analysis showed 1138 G ! C transversion mutation which has been observed in approximately 1.9% of achondroplasia chromosomes

Fig. 2 A 4-month-old boy with achondroplasia showing typical craniofacial features and rhizomelic shortening of limbs (confirmed by radiograms). Molecular study revealed 1138 G-to-A transition mutation which has been observed in approximately 98% of achondroplasia chromosomes

Achondroplasia

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a c

b

Fig. 3 (a–c) Another achondroplastic neonate with typical clinical features and radiographic findings. Note the abnormal vertebral column with wide intervertebral spaces and abnormal vertebral bodies

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a

Achondroplasia

b

Fig. 4 (a, b) A boy (7 month and 2 year 7-month old) with achondroplasia showing a large head, small chest, normal size of the trunk, rhizomelic micromelia, and exaggerated lumbar lordosis

Achondroplasia Fig. 5 (a–c) Two older children with achondroplasia showing rhizomelic micromelia, typical craniofacial features, exaggerated lumbar lordosis, and trident hands

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c

d G/A G G

Fig. 6 (a–f) A boy with achondroplasia and i(21q) Down syndrome presented with diagnostic dilemma. Besides craniofacial features typical for Down syndrome, the skeletal findings of achondroplasia dominate the clinical picture. The diagnosis of Down syndrome was based on the clinical features and the

cytogenetic finding of i(21q) trisomy 21. The diagnosis of achondroplasia was based on the presence of clinical and radiographic findings, and confirmed by the presence of a common FGFR3 gene mutation (Gly380Arg) detected by restriction enzyme analysis and sequencing of the PCR products

Achondroplasia

33

Fig. 7 Schematic of the FGFR3 gene and DNA sequence of normal allele and mutant FGFR3 achondroplasia allele (Modified from Shiang et al. 1994)

Fig. 8 Nucleotide change in the 1138 C allele creates a Msp1 site and nucleotide change in the 1138A allele creates a Sfc1. The base in the coding sequence that differs in the three alleles is boxed (Modified from Shiang et al. 1994)

34

a

Achondroplasia

b

c

Fig. 9 (a–c) Homozygous achondroplasia. Both parents are achondroplastic. The large head, narrow chest and severe rhizomelic shortening of the limbs are similar to those of thanatophoric dysplasia. Radiograph shows severe platyspondyly, small ilia and short limb bones. Photomicrograph of the physeal growth zone shows severe retardation and disorganization, similar to that of thanatophoric dysplasia

Adams–Oliver Syndrome

In 1945, Adams and Oliver described congenital transverse limb defects associated with aplasia cutis congenita in a three-generation kindred with typical autosomal dominant inheritance and intrafamilial variable expressivity.

Synonyms and Related Disorders Aplasia cutis congenita with terminal transverse limb defects

Genetics/Basic Defects 1. Genetic heterogeneity a. Autosomal dominant in most cases i. The family described by Adams and Oliver, and revisited by Whitley and Gorlin in 1991, illustrates vertical transmission, with multiple affected members spanning four generations and includes male-to-male transmission, consistent with autosomal dominant inheritance ii. Reports from over 20 further kindreds provide support for the role of a heterozygous autosomal gene mutation (Snape et al. 2009). b. Autosomal recessive in some cases i. The combination of aplasia cutis congenita and terminal transverse limb defects within sibships provides evidence for an autosomal recessive mode of inheritance ii. Further supported by the occurrence of affected siblings within inbred families 2. Pathogenesis a. Trauma b. Uterine compression

c. Amniotic band sequelae d. Vascular disruption sequence i. Concomitant occurrence of Poland sequence ii. Both Poland sequence and Adams–Oliver syndrome: secondary to vascular disruption due to thrombosis of subclavian and vertebral arteries e. Massive thrombus from the placenta occluding the brachial artery f. Abnormalities in small vessel structures manifesting during embryogenesis g. A developmental disorder of morphogenesis 3. Molecular basis of the syndrome remains unknown, although the common occurrence of cardiac and vascular anomalies suggests a primary defect of vasculogenesis (Snape et al. 2009).

Clinical Features 1. Marked intrafamilial and interfamilial variability 2. Terminal transverse limb defects a. Most common manifestation (84%) b. Usually asymmetrical c. Tendency toward bilateral lower limb rather than upper limb involvement d. Mild spectrum of defects i. Nail hypoplasia ii. Cutaneous syndactyly iii. Bony syndactyly iv. Ectrodactyly v. Brachydactyly e. Severe spectrum of transverse defects i. Absence of the hand

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ii. Absence of the foot iii. Absence of the limb 3. Aplasia cutis congenita a. Second most common defect (almost 75%) b. Associated with skull defect (64%): the most common site is the vertex, often with scalp defect extending to periosteum, skull, and dura i. Small lesion: 0.5 cm in diameter ii. Intermediate lesion: 8–10 cm involving the vertex iii. Severe lesion: involve most of the scalp with acrania c. Skull defect without scalp defect, often mistaken for an enlarged fontanelle d. May involve other areas of the body e. Severe end of the spectrum of scalp defects i. Encephalocele ii. Acrania f. Most severe manifestations can be associated with a mortality rate of 20–55% (Bjpai and Pal 2003) i. Associated with dilated and tortuous scalp veins with significant morbidity ii. Associated with hemorrhage or infection 4. Congenital cardiovascular malformations (13.4–20%) a. Mechanisms proposed to explain the pathogenesis of congenital cardiovascular malformations i. Alteration of mesenchymal cell migration resulting in conotruncal malformations, e.g., tetralogy of Fallot, double outlet right ventricle, and truncus arteriosus ii. Alteration of fetal cardiac hemodynamics resulting in different malformations such as coarctation of the aorta, aortic stenosis, perimembranous VSD, and hypoplastic left heart iii. Persistence of normal fetal vascular channels resulting in postnatal vascular abnormalities b. Diverse vascular and valvular abnormalities i. Bicuspid aortic valve ii. Pulmonary atresia iii. Parachute mitral valve iv. Pulmonary hypertension 5. Other associated anomalies a. Cutis marmorata telangiectasia congenita (12%) b. Dilated and tortuous scalp veins (11%) c. Poland anomaly d. Encephalocele e. Facial features

Adams–Oliver Syndrome

i. Hemihypoplasia ii. Hypertelorism iii. Epicanthal folds iv. Microphthalmia v. Esotropia vi. High arch palate vii. Cleft palate f. Cryptorchidism g. Lymphatic abnormalities i. Lymphedema of the leg ii. Chylothorax iii. Dilated pulmonary lymphatics iv. Intestinal lymphangiectasia v. Marmorata telangiectasia congenita (a cutaneous vascular abnormality) h. CNS abnormalities: unusual manifestation i. Mental retardation ii. Learning disability iii. Epilepsy i. Short stature j. Renal malformations k. Spina bifida occulta l. Accessory nipples 6. Major and minor features of Adams–Oliver syndrome (Snape et al. 2009): The presence of two major features is considered sufficient for a diagnosis. The combination of one major and one minor feature should place Adams–Oliver syndrome high in the differential diagnosis of such individuals. a. Major features i. Terminal transverse limb defects ii. Aplasia cutis congenita iii. Family history of Adams–Oliver syndrome b. Minor features i. Cutis marmorata telangiectasia congenita ii. Congenital cardiac defect iii. Vascular anomaly 7. Differential diagnosis (Snape et al. 2009) a. Amniotic band sequence b. Moebius and Poland syndromes (McGuirk et al. 2001) c. Teratogenic agents such as phenytoin, misoprostol, and ergotamine i. Asymmetric bilateral transverse terminal limb defects ii. Tend to affect the upper limb more severely than the lower limb (Spranger et al. 1980; Holmes 2002)

Adams–Oliver Syndrome

37

d. Limb anomalies i. Caused by thalidomide: tends to be symmetrical and longitudinal (Smithells and Newman 1992) ii. Caused by chorionic villus sampling during pregnancy (Holmes 2002) e. Isolated aplasia cutis congenita: substantial heterogeneity based on association with known abnormalities or exposure to teratogens such as methimazole (Frieden 1986) f. Cutis marmorata telangiectasia congenita i. Common in kindreds with Adams–Oliver syndrome ii. Can be seen in combination with both terminal transverse limb defects (Maniscalco et al. 2005) and aplasia cutis congenita (Verdyck et al. 2003) iii. Can be an isolated finding in otherwise unaffected family members (Scribanu and Temtamy 1975; Toriello et al. 1988) iv. Can be associated with skin atrophy and ulcerations, capillary malformations, capillary and cavernous vascular malformations, under- or overgrowth of the affected extremity, macrocephaly and glaucoma, and in association with vascular syndromes including Sturge–Weber and Klippel–Trenaunay (Amitai et al. 2000)

Diagnostic Investigations 1. Radiography a. Transverse limb defects b. Ectrodactyly c. Brachydactyly d. Syndactyly e. Nail hypoplasia f. Skull defect 2. CT scan or MRI of the brain a. Polymicrogyria b. Ventriculomegaly c. Irregular cortical thickening d. Cerebral cortex dysplasia e. Microcephaly f. Arhinencephaly g. Periventricular and parenchymal deposits

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant: not increased unless a parent is affected in which case the risk is 50% ii. Autosomal recessive: 25% b. Patient’s offspring i. Autosomal dominant: 50% ii. Autosomal recessive: not increased unless the spouse carries the gene or is affected 2. Prenatal diagnosis by ultrasonography a. Transverse limb defects b. Concomitant skull defect 3. Management a. Treat minor scalp lesions with daily cleansing of the involved areas with applications of antibiotic ointment b. Surgically close larger lesions and exposed dura with minor or major skin grafting procedure (split thickness or full thickness) c. Prevent sepsis and/or meningitis from an open scalp lesion which is highly vascular and rarely involves the sagittal sinus predisposing to episodes of spontaneous hemorrhage d. Urgent surgical intervention may be required with operative measures that include primary closure, skin grafting, local scalp flaps with or without tissue expansion, and cranial vault reconstruction using split rib grafts and free latissimus dorsi muscle flap (Bajpai and Pal 2003) e. Orthopedic care for various degree of limb defects

References

calcium

Adams, F. H., & Oliver, C. P. (1945). Hereditary deformities in man due to arrested development. Journal of Heredity, 36, 3–7. Amitai, D. B., Fichman, S., Merlob, P., et al. (2000). Cutis marmorata telangiectatica congenita: Clinical findings in 85 patients. Pediatric Dermatology, 17, 100–104. Anandan, V., Parveen, B., Prabhavathy, D., et al. (2008). Adams Oliver syndrome-a variant. International Journal of Dermatology, 47, 1260–1262. Arand, A. G., et al. (1991). Congenital scalp defects: AdamsOliver syndrome. A case report and review of the literature. Pediatric Neurosurgery, 17, 203–207.

38 Bajpai, M., & Pal, K. (2003). Aplasia cutis cerebri with partial acrania—Total reconstruction in a severe case and review of the literature. Journal of Pediatric Surgery, 38, e4. Bamforth, J. S., Kaurah, P., Byrne, J., et al. (1994). Adams Oliver syndrome: A family with extreme variability in clinical expression. American Journal of Medical Genetics, 49, 393–396. Baskar, S., Kulkarni, M. L., Kulkarni, A. M., et al. (2009). Adams-Oliver syndrome: Additions to the clinical features and possible role of BMP pathway. American Journal of Medical Genetics. Part A, 149A, 1678–1684. Becker, R., Kunze, J., Horn, D., et al. (2002). Autosomal recessive type of Adams-Oliver syndrome: Prenatal diagnosis. Ultrasound in Obstetrics & Gynecology, 20, 506–510. Benafede, R. P., & Beighton, P. (1979). Autosomal dominant inheritance of scalp defects with ectrodactyly. American Journal of Medical Genetics, 3, 35–41. Bonafede, R. P., & Beighton, P. (1979). Autosomal dominant inheritance of scalp defects with ectrodactyly. American Journal of Medical Genetics, 3, 35–41. Bork, K., & Pfeifle, J. (1992). Multifocal aplasia cutis congenita, distal limb hemimelia, and cutis marmorata telangiectatica in a patient with Adams-Oliver syndrome. British Journal of Dermatology, 127, 160–163. Burton, B. K., Hauser, H., & Nadler, H. L. (1976). Congenital scalp defects with distal limb anomalies: Report of a family. Journal of Medical Genetics, 13, 466–468. Frieden, I. (1986). Aplasia cutis congenita: A clinical review and proposal for classification. Journal of the American Academy of Dermatology, 14, 646–660. Fryns, J. P. (1987). Congenital scalp defects with distal limb reduction anomalies. Journal of Medical Genetics, 24, 493–496. Fryns, J. P., Leigius, E., Demaere, P., et al. (1996). Congenital scalp defects, distal limb reduction anomalies, right spastic hemiplegia and hypoplasia of the left arterial cerebri media. Clinical Genetics, 50, 505–509. Holmes, L. B. (2002). Teratogen-induced limb defects. American Journal of Medical Genetics, 112, 297–303. Hoyme, H. E., Der Kaloustian, V. M., Entin, M., et al. (1992). Possible common pathogenetic mechanisms for Poland sequence and Adams-Oliver syndrome: An additional clinical observation. American Journal of Medical Genetics, 42, 398–399. Klinger, G., & Merlob, P. (1998). Adams-Oliver syndrome: Autosomal recessive inheritance and new phenotypicanthropometric findings. American Journal of Medical Genetics, 79, 197–199. Koiffmann, C. P., Wajntal, A., Huyke, B. J., et al. (1988). Congenital scalp skull defects with distal limb anomalies (Adams-Oliver syndrome– McKusick 10030): Further suggestion of autosomal recessive inheritance. American Journal of Medical Genetics, 29, 263–268. K€uster, W., Lenz, W., Kaariainen, H., et al. (1988). Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): Report of ten cases and review of the literature. American Journal of Medical Genetics, 31, 99–115. Lin, A. E., Wesgate, M. N., van der Velde, M. E., et al. (1998). Adams-Oliver syndrome associated with cardiovascular malformation. Clinical Dysmorphology, 7, 235–241.

Adams–Oliver Syndrome Maniscalco, M., Zedda, A., Faraone, S., et al. (2005). Association of Adams-Oliver syndrome with pulmonary arteriovenous malformation in the same family: A further support to the vascular hypothesis. American Journal of Medical Genetics. Part A, 136A, 269–274. McGuirk, C. K., Westgate, M. N., & Holmes, L. B. (2001). Limb deficiencies in newborn infants. Pediatrics, 108, E64. Mempel, M., Abeck, D., Lange, I., et al. (1999). The wide spectrum of clinical expression in Adams-Oliver syndrome: A report of two cases. British Journal of Dermatology, 140, 1157–1160. Pauli, R. M., et al. (1985). Familial recurrence of terminal transverse defects of the arm. Clinical Genetics, 27, 555–563. Pereira-da-Silva, L., Leal, F., Cassiano Santos, G., et al. (2000). Clinical evidence of vascular abnormalities at birth in Adams-Oliver syndrome: Report of two further cases. American Journal of Medical Genetics, 94, 75–76. Pousti, T. J., & Bartlett, R. A. (1997). Adams-Oliver syndrome: Genetics and associated anomalies of cutis aplasia. Plastic and Reconstructive Surgery, 100, 1491–1496. Scribanu, N., & Temtamy, S. A. (1975). The syndrome of aplasia cutis congenita with terminal, transverse defects of limbs. Journal of Pediatrics, 87, 79–82. Shapiro, S. D., & Escobedo, M. K. (1985). Terminal transverse defects with aplasia cutis congenita (Adams-Oliver syndrome). Birth Defects Original Article Series, 21(2), 135–142. Smithells, R. W., & Newman, C. G. (1992). Recognition of thalidomide defects. Journal of Medical Genetics, 29, 716–723. Snape, K. M. G., Ruddy, D., Zenker, M., et al. (2009). The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects. American Journal of Medical Genetics. Part A, 149A, 1860–1881. Spranger, J. W., Schinzel, A., Myers, T., et al. (1980). Cerebroarthrodigital syndrome: A newly recognized formal genesis syndrome in three patients with apparent arthromyodysplasia and sacral agenesis, brain malformation and digital hypoplasia. American Journal of Medical Genetics, 5, 13–24. Stevenson, R. E., & Deloache, W. R. (1988). Aplasia cutis congenita of the scalp. Proceedings of the Greenwood Genetic Center, 7, 14–18. Sybert, V. P. (1989). Congenital scalp defects with distal limb anomalies (Adams-Oliver Syndrome– McKusick 10030): Further suggestion of autosomal recessive inheritance. American Journal of Medical Genetics, 32, 266–267. Tekin, M., Bodurtha, J., C¸iftc¸i, E., et al. (1999). Further family with possible autosomal recessive inheritance of AdamsOliver syndrome. American Journal of Medical Genetics, 86, 90–91. Temtamy, S. A., Aglan, M. S., Ashour, A. M., et al. (2007). Adams-Oliver syndrome: Further evidence of an autosomal recessive variant. Clinical Dysmorphology, 16, 141–149. Toriello, H. V., Graff, R. G., Florentine, M. F., et al. (1988). Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome? American Journal of Medical Genetics, 29, 269–276. Verdyck, P., Blaumeiser, B., Holder-Espinasse, M., et al. (2006). Adams-Oliver syndrome: Clinical description of a four

Adams–Oliver Syndrome generation family and exclusion of five candidate genes. Clinical Genetics, 69, 86–92. Verdyck, P., Holder-Espinasse, M., Hul, W. V., et al. (2003). Clinical and molecular analysis of nine families with Adams-Oliver syndrome. European Journal of Human Genetics, 11, 457–463.

39 Whitley, C. B., & Gorlin, R. J. (1991). Adams-Oliver syndrome revisited. American Journal of Medical Genetics, 40, 319–326. Zapata, H. H., Sletten, L. J., & Pierpont, M. E. M. (1995). Congenital cardiac malformations in Adams-Oliver syndrome. Clinical Genetics, 47, 80–84.

40 Fig. 1 A 9-month-old boy with Adams–Oliver syndrome showing alopecia, absent eyebrows and eyelashes, scalp defect, tortuous scalp veins, and limb defects (brachydactyly, syndactyly, broad great toes, and nail hypoplasia). Radiography showed absent middle and distal phalanges of second to fifth toes and absent distal phalanges of the great toes

Adams–Oliver Syndrome

Agnathia

Agnathia is an extremely rare lethal neurocristopathy. The disorder has also been termed agnathiaholoprosencephaly spectrum, agnathia-otocephaly complex, agnathia-astomia-synotia, or cyclopiaotocephaly association. The incidence is estimated to be 1 in 70,000 infants (Schiffer et al. 2002). The spectrum of agnathia ranges from isolated agnathia, or virtual absence of the mandible, to otocephaly, which refers to a broader malformation of mandibular hypoplasia or agnathia, downward displacement of the ears and/or synotia (approximation of the ears in the midline), with or without aglossia (no tongue), and microstomia (small mouth) (Petrikovsky 1999). Agnathia-otocephaly is a lethal malformation complex characterized by absence of the mandible, microstomia, aglossia, and positioning of the ears toward the midline (Pauli et al. 1981; Bixler et al. 1985). Although ear positioning is variable and the use of the term “otocephaly” does not seem always justified, otocephaly is commonly used to assemble all ear abnormalities with displacement toward the midline (Schiffer et al. 2002). Agnathia-otocephaly can occur alone or in combination with a variety of associated malformations, holoprosencephaly being the most commonly reported association.

Synonyms and Related Disorders Agnathia-holoprosencephaly otocephaly complex

spectrum;

Agnathia-

Genetics/Basic Defects 1. Sporadic occurrence in majority of cases 2. Rare autosomal recessive inheritance: two siblings with isolated dysgnathia complex who survived infancy (Baker et al. 2004) 3. Possible autosomal dominant inheritance a. Supported by an observation of dysgnathia in mother and daughter (Erlich et al. 2000) b. Possibility of a defect in the OTX2 gene as the basis of the disorder (Matsuo et al. 1995) 4. Teratogenic factors have been described in humans a. Salicylate (Benawra et al. 1980) b. Amidopyrine (Mollica et al. 1979) c. Theophylline (Ibba et al. 2000) 5. A prechordal mesoderm inductive defect affecting neural crest cells a. A developmental field defect b. Different etiologic agents (etiological heterogeneity) acting on the same developmental field producing a highly similar complex of malformations 6. Possible existence of a mild form of agnathia without brain malformation (holoprosencephaly) a. Situs inversus-congenital hypoglossia b. Severe micrognathia, aglossia, and choanal atresia 7. A well-recognized malformation complex in the mouse (Juriloff et al. 1985), guinea pig (Wright 1934), rabbit, sheep, and pig

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Clinical Features 1. Polyhydramnios due to persistence of oropharyngeal membrane or blind-ending mouth 2. Agnathia (absence of the mandible) 3. Microstomia or astomia (absence of the mouth) 4. Aglossia (absence of the tongue) 5. Blind mouth 6. Ear anomalies a. Otocephaly (variable ear positions) b. Synotia (external ears approaching one another in the midline) c. Dysplastic inner ear d. Atretic ear canal 7. Down-slanting palpebral fissures 8. Variable degree of holoprosencephaly: nearly 100 patients reported as having holoprosencephaly and features consistent with the spectrum of agnathia (Kauvar et al. 2010). a. Cyclopia b. Synophthalmia c. Arrhinencephaly 9. Other brain malformations a. Cerebellar hypoplasia b. Septum pellucidum cavum c. Absence of cranial nerves (I–IV) d. Absence of the corpus callosum e. Meningocele 10. Intrauterine growth retardation 11. Cleft lip/palate 12. Occular malformations a. Microphthalmos/anophthalmia b. Proptosis (protruding eyes) c. Absence of the eyelids d. Epibulbar dermoid e. Aphakia f. Retinal dysplasia g. Microcornea h. Anterior segment dysgenesis i. Uveal colobomas 13. Nasal anomalies a. Absence of the nasal cavity b. Cleft nose c. Blind nasal pharynx 14. Various visceral malformations a. Choanal atresia b. Tracheoesophageal fistula c. Absence of the thyroid gland

Agnathia

d. Absence of the submandibular and parotid salivary glands e. Abnormal glottis and epiglottis f. Thyroglossal duct cyst g. Carotid artery anomalies h. Situs inversus i. Cardiac anomalies j. Unlobulated lungs k. Renogenital anomalies i. Unilateral renal agenesis ii. Renal Ectopia iii. Cystic kidneys iv. Horseshoe kidneys v. Solitary kidney vi. Mullerian duct agenesis vii. Cryptorchidism 15. Skeletal anomalies a. Vertebral anomalies b. Rib anomalies c. Tetramelia 16. Anatomical variations a. Ears i. Absence of the tragus ii. Synotia b. Mandible i. Rudimentary ii. Absent iii. Two small separate masses c. Mouth: microstomia with vertical orientation d. Buccopharyngeal membrane: absent to present e. Tongue i. Small to absent body ii. Present in (hypo)pharynx f. Absent submandibular glands g. Other skull bones: approximated maxillae, palatine, zygomatic, and temporal

Diagnostic Investigations 1. Radiography a. Reduced maxilla b. Absence of the zygomatic process c. Absence of the hyoid bone d. Vertebral anomalies e. Absence of the ribs f. Sprengel deformity 2. Cranial ultrasonography to define holoprosencephaly

Agnathia

3. Postnatal reconstructed CT for detailed 3-D structure of the cranium in agnathia-otocephaly 4. Chromosome analysis a. Normal in majority of cases b. Unbalanced der(18),t(6;18)(pter ! p24.1; p11.21 ! qter) in two female sibs with agnathia-holoprosencephaly 5. Autopsy to define postmortem findings

Genetic Counseling 1. Recurrence risks a. Risk to patient’s sib: not increased unless in a rare autosomal recessive inheritance b. Risk to patient’s offspring i. Not applicable to lethal cases since the patients do not survive to reproductive age ii. Autosomal dominant (some case may survive to reproductive age): 50% 2. Prenatal diagnosis by 3-D ultrasonography (Ducarme et al. 2007; Tantbirojn et al. 2008). 3-D imaging by helical computed tomography (CT), and/or MRI imaging (Chen et al. 2003, 2007) a. Polyhydramnios: secondary to an atretic, constricted, or obstructed oropharynx that prevents the fetus from swallowing amniotic fluid efficiently or at all b. Intrauterine growth retardation c. Mandibular absence (agnathia) or major hypoplasia d. Holoprosencephaly e. Cyclopia, marked hypotelorism or frontal proboscis 3. Management a. Although a lethal entity, several survivals beyond infancy have been reported (Brecht and Johnson 1985; Kamiji et al. 1991; Walker et al. 1995; Shermak and Dufresne 1996; Baker et al. 2004). Our third case with agnathia is still surviving with normal neurological development at 20 years of age. b. All survivors required tracheotomy immediately soon after delivery since no laryngeal opening is most likely present for endotracheal tube insertion c. EXIT (ex utero intrapartum treatment) procedure, a technique for safely managing airway obstruction at birth, in which placental support is maintained until the airway can be evaluated and secured (Umekawa et al. 2007)

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References Baker, P. A., Aftimos, S., & Anderson, B. J. (2004). Airway management during an EXIT procedure for a fetus with dysgnathia complex. Pediatric Anesthesia, 14, 781–786. Benawra, R., Mangurten, H. H., & Duffell, D. R. (1980). Cyclopia and other anomalies following maternal ingestion of salicylates. Journal of Pediatrics, 96, 1069–1071. Bixler, D., Ward, R., & Gale, D. D. (1985). Agnathiaholoprosencephaly: A developmental field complex involving face and brain. Report of 3 cases. Journal of Craniofacial Genetics and Developmental Biology, 1(Suppl), 241–249. Blaas, H. G., Eriksson, A. G., Salvesen, K. A., et al. (2002). Brains and faces in holoprosencephaly: Pre- and postnatal description of 30 cases. Ultrasound in Obstetrics & Gynecology, 19, 24–38. Brecht, K., & Johnson, C. M., III. (1985). Complete mandibular agenesis. Report of a case. Archives of Otolaryngology, 111, 132–134. Carles, D., Serville, F., Mainguene, M., et al. (1987). Cyclopiaotocephaly association: A new case of the most severe variant of Agnathia-holoprosencephaly complex. Journal of Craniofacial Genetics and Developmental Biology, 7, 107–113. Chen, C. P., Chang, T. Y., Huang, J. K., et al. (2007). Early second-trimester diagnosis of fetal otocephaly. Ultrasound in Obstetrics & Gynecology, 29, 470–478. Chen, C. P., Wang, K. G., Huang, J. K., et al. (2003). Prenatal diagnosis of otocephaly with microphthalmia/anophthalmia using ultrasound and magnetic resonance imaging. Ultrasound in Obstetrics & Gynecology, 22, 214–217. Cohen, M. M. (1989). Perspectives on holoprosencephaly: Par III. Spectra, distinctions, continuities and discontinuities. American Journal of Medical Genetics, 34, 271–288. Ducarme, G., Largilliere, C., Amarenco, B., et al. (2007). Threedimensional ultrasound in prenatal diagnosis of isolated otocephaly. Prenatal Diagnosis, 27, 481–483. Ebina, Y., Yamada, H., Kato, E. H., et al. (2001). Prenatal diagnosis of agnathia-holoprosencephaly: Three-dimensional imaging by helical computed tomography. Prenatal Diagnosis, 21, 68–71. Erlich, M. S., Cunningham, M. L., & Hudgins, L. (2000). Transmission of the dysgnathia complex from mother to daughter. American Journal of Medical Genetics, 95, 269–274. Faye-Petersen, O., David, E., Rangwala, N., et al. (2006). Otocephaly: Report of five new cases and a literature review. Fetal and Pediatric Pathology, 25, 277–296. Henekam, R. C. (1990). Agnathia-holoprosencephaly: A midline malformation association. American Journal of Medical Genetics, 36, 525. Hersh, J. H., McChane, R. H., Rosenberg, E. M., et al. (1989). Otocephaly-midline malformation association. American Journal of Medical Genetics, 34, 246–249. Hinojosa, R., Green, J. D., Brecht, K., et al. (1996). Otocephalus: Histopathology and three-dimensional reconstruction. Otolaryngology Head Neck Surgery, 114, 44–53. Ibba, R. M., Zoppi, M. A., Floris, M., et al. (2000). Otocephaly: Prenatal diagnosis of a new case and etiopathogenetic considerations. American Journal of Medical Genetics, 90, 427–429.

44 Johnson, W. W., & Cook, J. B. (1961). Agnathia associated with pharyngeal isthmus atresia and hydramnios. Archives of Pediatrics, 78, 211–217. Juriloff, D. M., Sulik, K. K., Roderick, T. H., et al. (1985). Genetic and developmental studies of a new mouse mutation that produces otocephaly. Journal of Craniofacial Genetics and Developmental Biology, 5, 121–145. Kamiji, T., Takagi, T., Akizuki, T., et al. (1991). A long surviving case of holoprosencephaly agnathia series. British Journal of Plastic Surgery, 44, 386–389. Kauvar, E. F., Solomon, B. D., Curry, C. J. R., et al. (2010). Holoprosencephaly and agnathia spectrum: Presentation of two new patients and review of the literature. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 154C, 158–169. Krassikoff, N., & Sekhon, G. S. (1989). Familial agnathiaholoprosencephaly caused by an inherited unbalanced translocation and not autosomal recessive inheritance. American Journal of Medical Genetics, 34, 255–257. Lawrence, D., & Bersu, E. T. (1985). An anatomical study of human otocephaly. Teratology, 30, 155–165. Leech, R. W., Bowlby, L. S., Brumback, R. A., et al. (1988). Agnathia, holoprosencephaly, and situs inversus: Report of a case. American Journal of Medical Genetics, 29, 483–490. Matsuo, I., Kuratani, S., Kimura, C., et al. (1995). Mouse Otx2 functions in the formation and patterning of rostral head. Genes and Development, 9, 2646–2658. Meinecke, P., Padberg, B., & Laas, R. (1990). Agnathia, holoprosencephaly, and situs inversus: A third report. American Journal of Medical Genetics, 37, 286–287. Mollica, F., Pavone, L., Nuciforo, G., et al. (1979). A case of cyclopia. Role of environmental factors. Clinical Genetics, 16, 69–71. ¨ zden, S., Fic¸iciog˘lu, C., Kara, M., et al. (2000). AgnathiaO holoprosencephaly-situs inversus. American Journal of Medical Genetics, 91, 235–236. Pauli, R. M., Graham, J. M., Jr., & Barr, M., Jr. (1981). Agnathia, situs inversus, and associated malformations. Teratology, 23, 85–93.

Agnathia Pauli, R. M., Pettersen, J. C., Arya, S., et al. (1983). Familial agnathia-holoprosencephaly. American Journal of Medical Genetics, 14, 677–698. Petrikovsky, B. M. (1999). Fetal disorders. Diagnosis and management (p. 43). New York: Wiley-Liss. Rolland, M., Sarramon, M. F., & Bloom, M. C. (1991). Astomiaagnathia-holoprosencephaly association. Prenatal diagnosis of a new case. Prenatal Diagnosis, 11, 199–203. Santana, S. M., et al. (1987). Agnathia and associated malformations. Dysmorphic Clinical Genetics, 1, 58–63. Schiffer, C., Tariverdian, G., Schiesser, M., et al. (2002). Agnathia-otocephaly complex: Report of three cases with involvement of two different Carnegie stages. American Journal of Medical Genetics, 112, 203–208. Scholl, H. W., Jr. (1977). In utero diagnosis of agnathia, microstomia, and synotia. Obstetrics and Gynecology, 49(1 Suppl), 81–83. Shermak, M. A., & Dufresne, C. R. (1996). Nonlethal case of otocephaly and its implications for treatment. The Journal of Craniofacial Surgery, 7, 372–375. Suda, Y., Nakabayashi, J., Matsuo, I., & Aizawa, S. (1999). Functional equivalency between Otx2 and Otx1 in development of the rostral head. Development, 126, 743–757. Tantbirojn, P., Taweevisit, M., Sritippayawan, S., et al. (2008). Prenatal three-dimensional ultrasonography of agnathiaotocephaly. Journal of Obstetrics and Gynaecology Research, 34, 663–665. Umekawa, T., Sugiyama, T., Yokochi, A., et al. (2007). A case of agnathia-otocephaly complex assessed prenatally for ex utero intrapartum treatment (EXIT) by three-dimensional ultrasonography. Prenatal Diagnosis, 27, 679–681. Walker, P. J., Edwards, M. J., Petroff, V., et al. (1995). Agnathia (severe micrognathia), aglossia and choanal atresia in an infant. Journal of Paediatrics and Child Health, 31, 358–361. Wright, S. (1934). On the genetics of subnormal development of the head (otocephaly) in the guinea pig. Genetics, 19, 471–504.

Agnathia Fig. 1 (a, b) A neonate (28 week gestation) with agnathia-holoprosencephaly complex showing a large defect involving entire midface area with almost total absence of jaw, absence of eyes and nose, and severe microtia. Absence of olfactory bulbs and grooves (arrhinencephaly) were demonstrated by necropsy. Additional anomalies included 13 pairs of ribs, atresia of left ureter with resultant hydronephrosis, and left renal cortical cysts. Maternal hydramnios was present

a

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a

b

b

Fig. 2 (a–c) The female infant was born via elective caesarian section with Apgar scores of 1, 1, 1 at 1, 5 and 10 min respectively. After a failed attempt at nasotracheal intubation, an emergent tracheostomy was performed. However, the infant expired shortly after placement. Postmortem examination of

c

the baby revealed congenital absence of the mandible (agnathia), microstomia with a slit-like oral opening, posterior choanal atresia, proptosis, and external ears placed ventrally with posterior rotation approaching each other in the midline. Amniocentesis revealed normal chromosomes

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Agnathia

Fig. 3 Prenatal ultrasound showed absence of fetal jaw (arrow) (E fetal eye, B fetal brain)

Fig. 4 (a–c) Maternal abdominal T2 MRI showed agnathia (blue arrow) and the lower end of the large horizontal ear meeting at the jaw area (white arrow)

a

b

c

Agnathia

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a

b

Fig. 5 (a, b) Postmortem CT scan demonstrated mandibular agnathia with synotia (posterior rotation with ventromedial displacement of the external ear structures approaching fusion near

a

b

the midline), hypoplasia of the superior maxillary bone and persistece of the inner ears in their initial fetal position

c

Fig. 6 (a–c) A 20-year-old female with agnathia with tracheotomy. She has severe microretrognathia due to absence of mandible, cleft palate, Arnold-Chiari malformation, severe bilateral hearing loss, Klippel-Feil syndrome, and scoliosis

a

Fig. 7 (a, b) Radiographs of orofacial structures showed absence of mandible

b

Aicardi Syndrome

In 1965, Aicardi et al. reported a new syndrome consisting of spasms in flexion, callosal agenesis, and ocular abnormalities. Actual frequency of the condition is not known, but about 1–4% of cases of infantile spasms from tertiary referral centers may be due to Aicardi syndrome.

Synonyms and Related Disorders Agenesis of corpus callosum with chrioretinal abnormality

Genetics/Basic Defects 1. Inheritance (Aicardi 2005) a. An X-linked dominant, lethal in males (Aicardi 1999) b. Almost exclusively affects females with two X chromosomes (heterozygous for a particular mutant X-chromosome gene to manifest) c. Exceptions i. Boys with XXY chromosome constitution (Hopkins et al. 1979; Aicardi 2005; Chen et al. 2009) allowing heterozygous expression of the gene as in the female ii. Two phenotypic boys with 46,XY males (Curatolo et al. 1980; Aggarwal et al. 2000): Aicardi has disputed the observations that are too atypical for classification as Aicardi syndrome due to the presence of lissencephaly or chorioretinal lesions not reminiscent of lacunae (Aicardi 1980).

iii. 5-year-old male was reported to have clinical triad of Aicardi syndrome (Chappelow et al. 2008): Routine cytogenetic analysis showed 46, XY. A chromosome microarray analysis failed to detect any known microdeletion or microduplication. The possibility of low mosaic for 47,XXY Klinefelter cannot be ruled out. d. Not known to be a familial condition, except an isolated familial instance involving two sisters (Molina et al. 1989) e. The mutation i. Seems to arise de novo, accounting for the almost complete absence of familial cases ii. Could occur as a postzygotic event in early embryonic development as suggested by the observation of a monozygotic twin in a pair in which only one twin had Aicardi syndrome, the other being unaffected (Costa et al. 1997) 2. A gene responsible for Aicardi syndrome has not been identified 3. Gene map postulated on chromosome Xp22.3 from an observation in an affected girl with t(X;3)(p22;q12)

Clinical Features 1. Classic triad a. Pathognomonic chorioretinal lacunae i. Multiple, rounded, unpigmented, and yellowwhite lesions ii. Occasionally unilateral iii. May be absent in rare cases b. Infantile spasms: the most characteristic type of seizure

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2.

3.

4. 5.

6. 7.

8.

Aicardi Syndrome

i. Frequently asymmetric or even unilateral (Bour et al. 1986) ii. Often preceded or precipitated by a focal clonic or tonic seizure limited to the side in which the spasms predominate c. Agenesis of the corpus callosum Other CNS abnormalities a. Ependymal cysts b. Choroid plexus papillomas c. Cortical migration abnormalities d. Optic disc coloboma e. Hydrocephaly f. Porencephaly g. Cerebellar agenesis h. Heterotopias Variable neurologic abnormalities a. Hemiparesis or hemiplegia i. The most frequent abnormality ii. Often on the side where the spasms predominate b. Quadriplegia c. Hypotonia d. Hypertonia e. Development of microcephaly, though head circumference is normal at birth Microphthalmia Extra-CNS tumors a. Soft palatal benign teratoma b. Hepatoblastoma c. Parapharyngeal embryonal cell carcinoma d. Limb angiosarcoma e. Scalp lipoma f. Multiple gastrointestinal polyps Scoliosis or costovertebral anomalies Severe cognitive and physical handicaps a. Global developmental delay b. Moderate to severe mental retardation in most patients c. Unable to ambulate in most children d. Limited visual ability New diagnostic criteria (Aicardi 1999, 2005) a. Classic triad i. Infantile spasms ii. Chorioretinal lacunae iii. Agenesis/dysgenesis of the corpus callosum b. New major features (present in most patients studied by MRI)

i. Cortical malformations, mostly microgyria (probably constant but may not be possible to evidence) ii. Periventricular and subcortical heterotopia iii. Cysts around the third ventricle and/or choroid plexuses iv. Papillomas of choroid plexuses v. Optic disc/nerve coloboma c. Supporting features (present in some cases) i. Vertebral and costal abnormalities ii. Microphthalmia and/or other eye abnormalities iii. “Split-brain” EEG (associated suppressionburst tracing) iv. Gross hemispheric asymmetry 9. Estimated survival rate a. 76% at 6 years of age b. 40% at 15 years of age

Diagnostic Investigations 1. Ophthalmological examination a. Choroid retinal lacunae b. Optic disc coloboma 2. Electroencephalograms a. “Split-brain” EEG b. Asymmetry or asynchrony c. Quasiperiodicity d. Hypsarrhythmia 3. CT or MRI of the brain a. Agenesis or partial agenesis of the corpus callosum b. Choroid plexus papillomas c. Cerebellar dysgenesis d. Cortical heterotopias e. Porencephaly f. Agenesis or hypoplasias of the cerebellar vermis 4. Radiography for skeletal malformations 5. Chromosome analysis in case of Klinefelter syndrome 6. Not caused by copy number variants detectable with currently used high-resolution array platform (Wang et al. 2009) 7. Histopathology a. Multiple brain malformations i. Complete or partial agenesis of the corpus callosum ii. Cortical heterotopias

Aicardi Syndrome

iii. Gyral malformation iv. Intraventricular cysts v. Microscopic evaluation of the parenchyma a) Disordered cellular organization b) Disruption of the normal layered appearance of the cortex b. Chorioretinal lacunae i. Well-circumscribed, punched-out lesions in the retinal pigment epithelium and choroid ii. Severely disrupted retinal architecture a) All layers are thinned. b) Decreased choroidal vessel number and caliber are decreased c) Presence of pigmentary ectopia and pigmentary epithelial hyperplasia

Genetic Counseling 1. Recurrence risk a. Patient’s sibs: recurrence not likely (exception with one report of two affected sibs, likely due to gonadal mosaicism in one of the parent). b. Patient’s offspring: 50% of offspring of affected females are expected to carry the abnormal X chromosome but affected individuals are not expected to survive to reproduce. 2. Prenatal diagnosis: not available currently. The prenatal ultrasonographic findings include: a. Arachnoid cysts b. Agenesis of the corpus callosum (development of the corpus callosum may not be complete until 22 weeks of gestation) c. Ventriculomegaly 3. Management a. Anticonvulsants for control of seizures b. Specific therapy for infantile spasm i. Adrenocorticotropic hormone (ACTH): effective for some patients ii. Vigabatrin, a more recently introduced therapy for infantile spasm a) An enzyme that breaks down GABA, the major inhibitory neurotransmitter in the brain b) Effective for infantile spasm without the serious life-threatening adverse effects of ACTH

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c) Possible ophthalmologic sequelae of constriction of the visual fields d) Not currently approved for use in the USA c. A multidisciplinary team approach to developmental handicaps d. Orthopedic surveillance and treatment of scoliosis e. Vigorous treatment of any infection as pulmonary problems are the commonest cause of death

References Aggarwal, K. C., Aggarwal, A., Prasad, M. S., et al. (2000). Aicardi’s syndrome in a male child: An unusual presentation. Indian Pediatrics, 37, 542–545. Aicardi, J. (1980). Aicardi syndrome in a male infant. The Journal of Pediatrics, 97, 1040–1042. Aicardi, J. (1999). Aicardi syndrome: Old and new findings. International Pediatrics, 14, 5–8. Aicardi, J. (2005). Aicardi syndrome [Review article]. Brain and Development, 27, 164–171. Aicardi, J., Lefe`bvre, J., & Lerique-Koechlin, A. (1965). A new syndrome: Spasms in flexion, callosal agenesis, ocular abnormalities. Electroencephalography and Clinical Neurophysiology, 19, 609–610. Bertoni, J. M., von Loh, S., & Allen, R. J. (1979). The Aicardi syndrome: Report of 4 cases and review of the literature. Annals of Neurology, 5, 475–482. Bour, F., Chiron, C., Dulac, O., et al. (1986). Caracte`res e´lectrocliniques des crises dans le syndrome d’Aicardi. Revue d’E´lectroence´phalographie et de Neurophysiologie Clinique, 16, 341–353. Bromley, B., Krishnamoorthy, K. S., & Benacerraf, B. R. (2000). Aicardi syndrome: Prenatal sonographic findings. A report of two cases. Prenatal Diagnosis, 20, 344–346. Chappelow, A. V., Reid, J., Parikh, S., et al. (2008). Aicardi syndrome in a genotypic male. Ophthalmic Genetics, 29, 181–183. Chen, T.-H., Chao, M.-C., Lin, L.-C., et al. (2009). Aicardi syndrome in a 47, XXY male neonate with lissencephaly and holoprosencephaly. Journal of the Neurological Sciences, 278, 138–140. Costa, T., Greer, W., Rysiecki, M., et al. (1997). Monozygotic twins discordant for Aicardi syndrome. Journal of Medical Genetics, 34, 688–691. Curatolo, P., Libutti, G., & Dallapiccola, B. (1980). Aicardi syndrome in a male infant. The Journal of Pediatrics, 96, 286–287. Davis, R. G. & DiFazio, M. P. (2010). Aicardi syndrome. eMedicine from WebMD. Updated 5 Jan 2010. Available at http://emedicine.medscape.com/article/941426-overview De Jong, J. G. Y., Delleman, J. W., Houben, M., et al. (1976). Agenesis of the corpus callosum, infantile spasms, ocular

52 anomalies (Aicardi’s syndrome). Clinical and pathological findings. Neurology, 26, 1152–1158. Dennis, J., & Bower, B. D. (1972). The Aicardi syndrome. Developmental Medicine and Child Neurology, 14, 382–390. Donnenfeld, A. E., Packer, R. J., Zackai, E. H., et al. (1989). Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. American Journal of Medical Genetics, 32, 461–467. Donnenfield, A. E., Graham, J. M., Packer, R. J., et al. (1990). Microphthalmia and chorioretinal lesions in a girl with Adv Neurol Xp22-pter deletion and partial 3p trisomy: Clinical observation relevant to Aicardi syndrome gene location. American Journal of Medical Genetics, 37, 182–186. Font, R. L., Marines, H. M., Cartwright, J., et al. (1991). Aicardi syndrome. A clinicopathological case report including electron microscopic observations. Ophthalmology, 98, 1727–1731. Glasmacher, M. A., Sutton, V. R., Hopkins, B., et al. (2007). Phenotype and management of Aicardi syndrome: New findings from a survey of 69 children. Journal of Child Neurology, 22, 176–184. Gorrono-Echebarria, M. B. (1993). Genetics of Aicardi syndrome. Survey of Ophthalmology, 38, 321. Hoag, H. M., Taylor, S. A. M., Duncan, A. M. V., et al. (1997). Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome. Human Genetics, 100, 459–464. Hopkins, I. J., Humphrey, J., Keith, C. G., et al. (1979). The Aicardi syndrome in a 47, XXY male. Australian Pediatric Journal, 15, 278–280. Hopkins, B., Sutton, V. R., Lewis, R. A., et al. (2008). Neuroimaging aspects of Aicardi syndrome. American Journal of Medical Genetics Part A, 146A, 2871–2878. McMahon, R. G., Bell, R. A., Moore, G. R. W., et al. (1984). Aicardi syndrome. A clinicopathologic study. Archives of Ophthalmology, 102, 250–253.

Aicardi Syndrome Menezes, A. V., Enzenauer, R. W., & Buncic, J. R. (1994). Aicardi syndrome: The elusive mild case. British Journal of Ophthalmology, 78, 494–496. Menezes, A. V., McGregor, D. L., & Buncic, J. R. (1994). Aicardi syndrome: Natural history and possible predictors of severity. Pediatric Neurology, 11, 313–318. Molina, J. A., Mateos, F., Merino, M., et al. (1989). Aicardi syndrome in two sisters. The Journal of Pediatrics, 115, 282–283. Neidich, J. A., Nussbaum, R. L., Packer, R. J., et al. (1990). Heterogeneity of clinical severity and molecular lesions in Aicardi syndrome. The Journal of Pediatrics, 116, 911–917. Ohtsuka, Y., Oka, E., & Terasaki, T. (1993). Aicardi syndrome: A longitudinal clinical and electroencephalographic study. Epilepsia, 34, 627–634. Robinow, M., Johnson, G. J., & Minella, P. A. (1984). Aicardi syndrome: Papilloma of the choroid plexus, cleft lip and cleft of the posterior palate. The Journal of Pediatrics, 104, 404–405. Ropers, H. H., Zuffardi, O., Blanchi, E., et al. (1982). Agenesis of corpus callosum, ocular, and skeletal anomalies (X-linked dominant Aicardi’s syndrome) in a girl with balanced X/3 translocation. Human Genetics, 61, 364–368. Rosser, T. (2003). Aicardi syndrome. Archives of Neurology, 60, 1471–1473. Rosser, T. L., Acosta, M. T., & Packer, R. J. (2002). Aicardi syndrome: Spectrum of disease and long-term prognosis in 77 females. Pediatric Neurology, 27, 343–346. Tachibana, H., Matsui, A., Takeshita, K., et al. (1982). Aicardi syndrome with multiple papilloma of the choroids plexus. Archives of Neurology, 39, 194. Trifiletti, R. R., Incorpora, G., Polizzi, A., et al. (1995). Aicardi syndrome with multiple tumors: A case report with literature review. Brain and Development, 17, 283–285. Wang, X., Sutton, V. R., Eble, T. N., et al. (2009). A genomewide screen for copy number alterations in Aicardi syndrome. American Journal of Medical Genetics Part A, 149A, 2113–2121.

Aicardi Syndrome Fig. 1 (a, b) A 8 month old girl with Aicardi syndrome characterized by infantile spasms, chrioretinopathy, brain malformation, and costovertebral anomalies

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b

Alagille Syndrome

In 1969, Alagille et al. described a syndrome characterized by chronic cholestasis resulting from paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterfly-like vertebral arch defect, posterior embryotoxon, and peculiar facies. The syndrome is also known as arteriohepatic dysplasia. Alagille syndrome occurs in approximately 1 in 60,000 live births based on the presence of neonatal cholestasis (Danks et al. 1977). This may be an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease (Kamath and Poccoli 2003).

Synonyms and Related Disorders Arteriohepatic dysplasia; JAG1-related Alagille syndrome; NOTCH2-related Alagille syndrome

Genetics/Basic Defects 1. Inheritance: a. Sporadic in 45–50% of cases b. Autosomal dominant i. Reduced penetrance ii. Variable expressivity c. Alagille syndrome gene mapped to 20p12 (Li et al. 1996) 2. Molecular defect a. Caused by mutations or deletions of Jagged-1 gene (JAG1), encoding a ligand for the

NOTCH transmembrane receptor, implicated in cell differentiation (Li et al. 1997) b. More than 120 described intragenic mutations of the JAG1 gene c. No clear genotype–phenotype correlation in Alagille syndrome d. NOTCH2 mutations were identified in 2/11 individuals with classic Alagelle syndrome who do not have an identifiable JAG1 mutation (McDaniel et al. 2006)

Clinical Features 1. High variability of phenotypic findings 2. Major features a. Neonatal chronic cholestasis i. Episodes of jaundice separated by periods of remission ii. Pruritus iii. Hepatomegaly iv. Splenomegaly: may be associated with portal hypertension v. Xanthoma: progressive and observed in: a) Extensor surface of the fingers b) Palmar creases c) Nape of the neck d) Anal folds e) Popliteal fossa f) Inguinal areas b. Facial features i. Broad prominent forehead ii. Deep-set, widely spaced eyes iii. Long, straight nose iv. Underdeveloped mandible

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c. Complex congenital cardiovascular anomalies i. Pulmonary artery stenosis (67%) ii. Ventricular septal defects iii. Patent ductus arteriosus iv. Pulmonary valve atresia v. Tetralogy of Fallot (7–16%) vi. Tricuspid regurgitation vii. Right ventricular hypertrophy d. Vertebral arch anomalies (butterfly-like vertebrae) e. Posterior embryotoxon (prominent Schwalbe’s ring) 3. Less frequently associated features a. Growth retardation b. Neurologic complications from vitamin E deficiency c. Mental retardation (2–30%) d. Systemic vascular malformations i. Coarctation of the aorta ii. Middle aortic syndrome iii. Arterial hypoplasia (hepatic, renal, carotid, celiac) iv. Artery stenosis (renal, subclavian) v. Moyamoya disease vi. Carotid artery aneurysm vii. Intracranial hemorrhage viii. Hypoplastic portal vein branch e. Renal abnormalities i. Interstitial nephritis ii. Glomerular intramembranous and mesangial lipidosis iii. Tubular dysfunction iv. Renal hypoplasia v. Renal agenesis vi. Horseshoe kidney vii. Cystic disease f. Small bowel atresia or stenosis g. Pancreas i. Diabetes ii. Exocrine pancreatic insufficiency h. Lung: tracheal and bronchial stenosis i. Larynx: high-pitched voice j. Eye abnormalities i. Posterior embryotoxon ii. Optic disc drusen iii. Angulated retinal vessels iv. Pigmentary retinopathy v. Iris strands vi. Cataract vii. Myopia

Alagille Syndrome

viii. Strabismus ix. Glaucoma x. Fundus hypopigmentation k. Skeletal abnormalities i. Lack of normal progression of interpedicular distance in the lumbar spine ii. Spina bifida iii. Shortening of distal phalanges and metacarpal bones iv. Clinodactyly l. Hepatocellular carcinoma: a rare complication of Alagille syndrome (Bhadri et al. 2005) 4. Prognosis a. Characterized by recurrent episodes of cholestasis b. Often associated with common respiratory tract infections, especially during the first year of life c. Good long survival but mortality rate may be up to 25%

Diagnostic Investigations 1. Biochemical studies (Alagille et al. 1987) a. Hypercholesterolemia: Cholesterol levels ranging from 220–1,600 mg% in all children with xanthomas (Garcia et al. 2005) b. Hyperphospholipidemia c. Hypertriglyceridemia d. Prominent increase in the pre-b-lipoprotein and apolipoprotein B levels e. Very high total bile acids, gammaglutamyl transferase, and alkaline phosphatase blood levels 2. Ophthalmologic assessment for posterior embryotoxon and other ocular anomalies 3. Abdominal ultrasonography a. Evaluation of the hepatobiliary tree and hepatic parenchyma b. Evaluation of renal anomalies 4. Radiography for vertebral anomalies 5. Other imagings a. Dimethyl iminodiacetic acid scanning b. Magnetic resonance cholangiopancreatography c. Endoscopic retrograde cholangiopancreatography d. Intraoperative cholangiography 6. Echocardiography for cardiovascular malformations 7. Histology (liver biopsy) a. Paucity of interlobular bile ducts b. Cholestasis in hepatocytes and canaliculi

Alagille Syndrome

8. Molecular genetic analysis a. Sequence analysis of the JAG1 gene detects mutations in approximately 70% of individuals who meet clinical diagnostic criteria. b. FISH detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 5–7% of cases. c. Mutations in NOTCH2 gene have been observed in fewer than 1% of individuals with Alagille syndrome (McDaniell et al. 2006)

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. A low but slightly increased risk due to parental germline mosaicism in clinically normal appearing parents ii. A 50% risk if a parent is affected b. Patient’s offspring: a 50% risk of having an offspring with Alagille syndrome 2. Prenatal diagnosis a. Prenatal ultrasonography i. Severe pulmonary artery stenosis ii. Progressive severe intrauterine growth retardation b. Prenatal molecular diagnosis on fetal DNA obtained from amniocentesis or CVS is available if a disease-causing mutation (demonstrated by molecular genetic testing) or a deletion (detected by FISH) is identified in an affected family member c. Preimplantation genetic diagnosis (Renbaum et al. 2007) i. A polar body (PB)-based multiplex fluorescent PCR reaction for a female affected with Alagille syndrome ii. The protocol included analysis of the Jagged 1 (JAG1) familial mutation and five closely linked highly polymorphic markers (D20S162, D20S901, D20S894, and D20S186) iii. A reliable diagnosis was possible in all developing embryos 3. Management a. Medical care (Alagille et al. 1987) i. Low-fat diets with medium-chain triglyceride supplementation

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ii. Hypercaloric diets to severely malnourished patients iii. Vitamin supplements iv. Pruritus a) Antihistamine agents b) Cholestyramine or rifampin in management of bile acid-induced pruritus b. Surgical care for patients with refractory disease i. Biliary diversion ii. Eventual orthotopic liver transplantation (Englert et al. 2006; Arnon et al. 2010) a) Indications: Progressive hepatic dysfunction, severe portal hypertension, failure to thrive, intractable pruritus, and osteodystrophy b) Associated with good long-term graft survival, although it is lower than that in biliary atresia c) Death from graft failure, neurological, and cardiac complications was significantly higher than in patients with biliary atresia d) The higher rate of mortality and graft failure may be related to the multisystem involvement of Alagille syndrome iii. Cardiac surgery for complex congenital heart defects

References Alagille, D. (1996). Alagille syndrome today. Clinical and Investigative Medicine, 19, 325–330. Alagille, D., Estrada, A., Hadchouel, M., et al. (1987). Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases. The Journal of Pediatrics, 110, 195–200. Albayram, F., Stone, K., Nagey, D., et al. (2002). Alagille syndrome: Prenatal diagnosis and pregnancy outcome. Fetal Diagnosis and Therapy, 17, 182–184. Anad, F., Burn, J., Matthews, D., et al. (1990). Alagille syndrome and deletion of 20p. Journal of Medical Genetics, 27, 729–737. Arnon, R., Annunziato, R., Miloh, T., et al. (2010). Orthotopic liver transplantation for children with Alagille syndrome. Pediatric Transplantation, 14, 622–628. Berrocal, T., Gamo, E., Navalon, J., et al. (1997). Syndrome of Alagille: Radiological and sonographic findings. A review of 37 cases. European Radiology, 7, 115–118. Bhadri, V. A., Stormon, M. O., Srbuckle, S., et al. (2005). Hepatocellular carcinoma in children with Alagille syndrome. Journal of Pediatric Gastoenterology and Nutrition, 41, 676–678.

58 Brodsky, M. C., & Cunniff, C. (1993). Ocular anomalies in the Alagille syndrome (arteriohepatic dysplasia). Ophthalmology, 100, 1767–1774. Cardona, J., Houssin, D., Gauthier, F., et al. (1995). Liver transplantation in children with Alagille syndrome–a study of twelve cases. Transplantation, 60, 339–342. Colliton, R. P., Bason, L., Lu, F. M., et al. (2001). Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Human Mutation, 17, 151–152. Connor, S. E., Hewes, D., Ball, C., et al. (2002). Alagille syndrome associated with angiographic moyamoya. Child’s Nervous System, 18, 186–190. Crosnier, C., Attie-Bitach, T., Encha-Razavi, F., et al. (2000). JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology, 32, 574–581. Crosnier, C., Driancourt, C., Raynaud, N., et al. (1999). Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology, 116, 1141–1148. Crosnier, C., Driancourt, C., Raynaud, N., et al. (2001). Fifteen novel mutations in the JAGGED1 gene of patients with Alagille syndrome. Human Mutation, 17, 72–73. Crosnier, C., Lykavieris, P., Meunier-Rotival, M., et al. (2000). Alagille syndrome. The widening spectrum of arteriohepatic dysplasia. Clinics in Liver Disease, 4, 765–778. Danks, D. M., Campbell, P. E., Jack, I., et al. (1977). Studies of the aetiology of neonatal hepatitis and biliary atresia. Archives of Disease in Childhood, 52, 360–367. Deleuze, F., & Hadchouel, M. (1996). Submicroscopic deletions are rare in Alagille syndrome. American Journal of Human Genetics, 59, 477–478. Desmaze, C., Deleuze, J. F., Dutrillaux, A. M., et al. (1992). Screening of microdeletions of chromosome 20 in patients with Alagille syndrome. Journal of Medical Genetics, 29, 233–235. Emerick, K. M., Rand, E. B., Goldmuntz, E., et al. (1999). Features of Alagille syndrome in 92 patients: Frequency and relation to prognosis. Hepatology, 29, 822–829. Englert, C., Grabhorn, E., Burdelski, M., et al. (2006). Liver transplantation in children with Alagille syndrome: Indications and outcome. Pediatric Transplantation, 10, 154–158. Garcia, M. A., Ramonet, M., Ciocca, M., et al. (2005). Alagille syndrome: Cutaneous manifestations in 38 children. Pediatric Dermatology, 22, 11–14. Giannakudis, J., Ropke, A., Kujat, A., et al. (2001). Parental mosaicism of JAG1 mutations in families with Alagille syndrome. European Journal of Human Genetics, 9, 209–216. Hingorani, M., Nischal, K. K., Davies, A., et al. (1999). Ocular abnormalities in Alagille syndrome. Ophthalmology, 106, 330–337. Jones, E. A., Clement-Jones, M., & Wilson, D. I. (2000). JAGGED1 expression in human embryos: Correlation with the Alagille syndrome phenotype. Journal of Medical Genetics, 37, 663–668. Kamath, B. M., Bason, L., Piccoli, D. A., et al. (2003). Consequences of JAG1 mutations. Journal of Medical Genetics, 40, 891–895. Kamath, B. M., Loomes, K. M., Oakey, R. J., et al. (2002). Facial features in Alagille syndrome: Specific or cholestasis facies? American Journal of Medical Genetics, 112, 163–170.

Alagille Syndrome Kamath, B. M., & Poccoli, D. A. (2003). Heritable disorders of the bile ducts. Gastroenterology Clinics of North America, 32, 857–875. Kasahara, M., Kiuchi, T., Inomata, Y., et al. (2003). Livingrelated liver transplantation for Alagille syndrome. Transplantation, 75, 2147–2150. Kim, B. J., & Fulton, A. B. (2007). The genetics and ocular findings of Alagille syndrome. Seminars in Ophthalmology, 22, 205–210. Krantz, I. D., Colliton, R. P., Genin, A., et al. (1998). Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. American Journal of Human Genetics, 62, 1361–1369. Krantz, I. D., Piccoli, D. A., & Spinner, N. B. (1997). Alagille syndrome. Journal of Medical Genetics, 34, 152–157. Krantz, I. D., Piccoli, D. A., & Spinner, N. B. (1999). Clinical and molecular genetics of Alagille syndrome. Current Opinion in Pediatrics, 11, 558–564. Krantz, I. D., Rand, E. B., Genin, A., et al. (1997). Deletions of 20p12 in Alagille syndrome: Frequency and molecular characterization. American Journal of Medical Genetics, 70, 80–86. Laufer-Cahana, A., Krantz, I. D., Bason, L. D., et al. (2002). Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion. American Journal of Medical Genetics, 112, 190–193. Li, L., Krantz, I. D., Deng, Y., et al. (1997). Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genetics, 16, 243–251. Li, P. H., Shu, S. G., Yang, C. H., et al. (1996). Alagille syndrome with interstitial 20p deletion derived from maternal ins(7;20). American Journal of Medical Genetics, 63, 537–541. McDaniell, R., Worthen, D. M., Sanchez-Lara, P. A., et al. (2006). NOTCH2 mutation cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. American Journal of Human Genetics, 79, 169–173. Piccoli, D. A., & Spinner, N. B. (2001). Alagille syndrome and the Jagged1 gene. Seminars in Liver Disease, 21, 525–534. Raas-Rothschild, A., Shteyer, E., Lerer, I., et al. (2002). Jagged1 gene mutation for abdominal coarctation of the aorta in Alagille syndrome. American Journal of Medical Genetics, 112, 75–78. Renbaum, P., Brooks, B., Kaplan, Y., et al. (2007). Advantages of multiple markers and polar body analysis in preimplantation genetic diagnosis for Alagille disease. Prenatal Diagnosis, 27, 317–321. Ropke, A., Kujat, A., Graber, M., et al. (2003). Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Human Mutation, 21, 100. Scheimann, A. (2010). Alagille syndrome. eMedicine from WebMD. Updated March 22, 2010. Available at: http:// emedicine.medscape.com/article/926678-overview Shulman, S. A., Hyams, J. S., Gunta, R., et al. (1984). Arteriohepatic dysplasia (Alagille syndrome): Extreme variability among affected family members. American Journal of Medical Genetics, 19, 325–332. Spinner, N. B. (1999). Alagille syndrome and the notch signaling pathway: New insights into human development. Gastroenterology, 116, 1257–1260.

Alagille Syndrome Spinner, N. B., Colliton, R. P., Crosnier, C., et al. (2001). Jagged1 mutations in Alagille syndrome. Human Mutation, 17, 18–33. Spinner, N. B., Hutchinson, A. L., & Krantz, I. D. (2010). Allagile syndrome. GeneReviews. Updated July 20, 2010. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1273/. Spinner, N. B., Rand, E. B., Fortina, P., et al. (1994). Cytologically balanced t(2;20) in a two-generation

59 family with Alagille syndrome: Cytogenetic and molecular studies. American Journal of Human Genetics, 55, 238–243. Witt, H., Neumann, L. M., Grollmuss, O., et al. (2004). Prenatal diagnosis of Alagille syndrome. Journal of Pediatric Gastroenterology and Nutrition, 38, 105–106.

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Fig. 1 An infant with Alagille syndrome showing neonatal jaundice, broad forehead, and underdeveloped mandible. This infant had peripheral pulmonary artery stenosis and paucity of interlobular bile ducts

Alagille Syndrome

Fig. 2 A 2-month-old boy with Alagille syndrome showing neonatal jaundice (conjugated hyperbilirubinemia). Liver biopsy showed paucity of the bile ducts. He was put on Mephyton 2.5 mg qd

Albinism

Albinism, derived from the Latin albus, is a group of inherited disorders in which melanin biosynthesis is reduced or absent. It involves the skin, hair, and eyes (oculocutaneous albinism) or may be limited primarily to the eyes (ocular albinism). Current classification of albinism is determined by the affected gene, making the previously used terms “partial or complete” and “tyrosinase-positive or tyrosinase-negative” obsolete (King et al. 2007; Summers et al. 1996). The prevalence of all forms of albinism varies considerably worldwide, estimated at approximately 1/17,000 and about 1 in 70 people carry a gene for oculocutaneous albinism (OCA) (Grønskov et al. 2007).

Synonyms and Related Disorders Chediak–Higashi syndrome; Griscelli syndrome; Hermansky–Pudlak syndrome; Oculocutaneous albinism (OCA) type 1 (tyrosinase-negative OCA, tyrosinase-related OCA); OCA type 2 (tyrosinase-positive OCA); OCA type 3 (Brown albinism); OCA, X-linked

Genetics/Basic Defects 1. Classification of albinism (genetic heterogeneity) a. OCA: a common phenotype for a group of recessive genetic disorders of melanin synthesis. Mutations in at least 12 genes are responsible for this phenotype. Mutations in OCA-related

genes result in reduction of melanin synthesis by the melanocytes: i. Common types of OCA with cutaneous and ocular hypopigmentation without significant involvement of other tissue a) Oculocutaneous albinism 1 (OCA1): subdivided into OCA1A, OCA1B, OCA1ts b) Oculocutaneous albinism 2 (OCA2) c) Oculocutaneous albinism 3 (OCA3) ii. Less common types of OCA with more complex manifestations a) Hermansky–Pudlak syndrome b) Chediak–Higashi syndrome b. Ocular albinism: i. Ocular albinism 1 (OA1): X-linked recessive ii. Autosomal recessive ocular albinism (AROA) 2. Molecular defects causing four known types of OCA (Grønskov et al. 2007) a. OCA1 (tyrosinase-related albinism) i. Inherited in an autosomal recessive manner ii. Caused by mutations of tyrosinase gene (TYR) located at 11q14.3. iii. Several different types of mutations to the tyrosinase gene (missense, nonsense, and frameshift) are responsible for producing OCA1A and OCA1B. iv. OCA1A (“tyrosinase negative” albinism with inactive enzyme) produced by null mutations of the Tyr gene: a) 0% tyrosinase enzyme activity b) Over 100 mutations spanning all parts of the gene reported

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_8, # Springer Science+Business Media, LLC 2012

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c) Compound heterozygotes with different maternal and paternal alleles in majority of patients v. OCA1B (tyrosinase-related albinism with partially active enzyme) produced by leaky mutations of the Tyr gene: a) “Yellow” form of albinism with 5–10% activity of tyrosinase b) A base substitution within the gene may result in reduced rather than completely abolished enzyme activity vi. OCA1ts (tyrosinase-related albinism with thermolabile enzyme): a) A temperature-sensitive tyrosinase is only partly functional. b) The first reported cases had a missense substitution within the tyrosinase gene. b. OCA2 (“tyrosinase-positive” albinism): brown OCA in Africans i. OCA2 gene: the pink-eye dilution gene ( p) located at 15q11.2-q12 ii. Caused by mutations of the P gene on the chromosome 15, homologous to the mouse pinked-eye dilution, or p gene iii. Inherited in an autosomal recessive manner iv. The mutated region is also deleted in Prader–Willi syndrome (PWS) and Angelman syndrome (AS), accounting for close linkage of OCA2 to PWS and AS c. OCA3 (Brown albinism) i. OCA3 gene: tyrosinase-related protein-1 gene (TRP1) located at 9p23 ii. The gene homologous to the mouse “brown” gene iii. Mutation of the gene possibly synergistic with a polymorphism or partially active mutation in OCA1 or OCA2 iv. 1 in 8,500 in Africans v. Rare in white Europeans and Asians d. OCA4 i. Resulting from mutation in the SLC45A2 gene, formerly called membrane-associated transporter protein gene (MATP), located at 5p13.3 ii. 1 in 85,000 in Japanese iii. Rare in white Europeans 3. Molecular defects causing other types of albinism a. XLOA (X-linked ocular albinism, OA1) i. GPR143, located at Xp22.3-22.2, is the only gene known to be associated with XLOA

Albinism

ii. Intragenic deletions, frameshift mutations, and point mutations identified iii. Affects males because of X-linked recessive inheritance iv. 85–90% of obligate carriers show pigmentary mosaicism in the fundi, representing the lionization effect (X-inactivation), although there are no functional sequelae b. OAR (autosomal recessive ocular albinism) i. Gene mapping: 6q13-q15 ii. May not be a clinical entity iii. Tyrosinase in some cases iv. P protein in some cases c. Hermansky–Pudlak syndrome (HPS): a bleeding disorder due to absence of dense bodies in platelets i. Hermansky–Pudlak syndrome 1 is caused by mutations of the HPS1 gene which is localized to 10q23. ii. HPS2 gene was localized to 5q13. Hermansky–Pudlak syndrome 2 is caused by mutation of the APB1 gene, which is localized to 5q13, resulting in a defect in adapter complex 3 AP-3, b3A subunit. d. Chediak–Higashi syndrome i. Immunodeficiency associated with neurologic problems ii. Defect in CHS1 gene (lysosomal trafficking regular gene) located at 1q42-44 e. Griscelli syndrome: resulting from mutations in the RAB27A gene located or MYO5A gene, both located at 15q21 4. Pathophysiology a. Melanin in the skin i. Melanin, a photoprotective pigment in the skin, absorbs UV light from the sun, thus preventing skin damage. ii. Normal skin tans upon sun exposure due to increased melanin pigment in the skin. iii. Patient with albinism develop sunburn because of the lack of melanin. b. Consequence of the absence of melanin during the development of the eye i. Hypoplasia of fovea ii. Alteration of neural connections between the retina and the brain c. Melanin pathway i. Consisting of a series of reactions that converts tyrosine into two types of melanin,

Albinism

black-brown eumelanin and red-blond pheomelanin ii. Tyrosinase: a major enzyme in a series of conversions to melanin from tyrosine and it is also responsible for converting tyrosine to DOPA and then to dopaquinone, which subsequently converts to either eumelanin or pheomelanin iii. Two other enzymes involved in the formation of eumelanin: tyrosinase-related protein 1 (TRP1, DHICA oxidase) and tyrosinase-related protein 2 (TRP2, dopachrome tautomerase). Mutation of the TRP1 results in OCA3; mutation of the TRP2 does not cause albinism. iv. P protein, a melanosomal membrane protein, believed to be involved in the transport of tyrosine prior to melanin synthesis. Mutation of this P gene causes OCA2. 5. Pathogenesis of the ocular features a. Development of the optic system highly dependent on the presence of melanin b. Ocular features appear if melanin is reduced or absent c. Mechanisms i. Misrouting of the retinogeniculate projections resulting in abnormal decussation of optic nerve fibers ii. Sensation of photophobia and decreased visual acuity caused by light scattering within the eye iii. Light-induced retinal damage postulated as a contributing mechanism to decreased visual acuity iv. Foveal hypoplasia: the most significant factor causing decreased visual acuity

Clinical Features 1. General clinical features of albinism a. Skin, hair, and eye discoloration caused by abnormalities of melanin metabolism (might not be obvious in ocular albinism) b. Reduced visual acuity due to foveal hypoplasia (common to all types of albinism, even though a rudimentary annular reflex has been described in a few patients with better visual acuity) (Summers 2009)

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c. Translucent iris due to reduction in iris pigment d. Visible choroid vessels due to reduction in retinal pigment e. Photophobia due to iris pigmentary abnormalities f. Anomalous visual pathway projections due to misrouting of the optic nerves at the chiasm g. Nystagmus (Summers 2009) i. Due to abnormal decussation of optic nerve fibers ii. Typically pendular in nature iii. More noticeable with fatigue and illness iv. Amplitude of nystagmus diminishes as child matures h. Alternating strabismus i. Hyperopia, myopia, and astigmatism 2. Oculocutaneous albinism 1 (OCA1) a. Incidence: approximately 1 in 40,000 individuals b. Oculocutaneous albinism 1A (OCA1A) i. Classic “tyrosinase-negative” OCA: complete lack of melanin production throughout life ii. Most severe form of OCA iii. White hair and white skin that does not tan iv. Blue and translucent irides that do not darken with age v. Foveal hypoplasia vi. No tanning potential vii. At risk for sun burning and skin cancer viii. Diminished visual acuity as low as 20/400 ix. Photophobia and nystagmus worst in this subtype c. Oculocutaneous albinism 1B (OCA1B) i. Yellow mutant type OCA, referred to as Amish albinism, or xanthous albinism ii. Variable pigmentation ranging from very little cutaneous pigmentation to nearly normal skin pigmentation iii. Increased skin, hair, and eye pigment with age and tan with sun exposure iv. Yellow hair pigment develops in the first few years of life and continuously accumulates pigment, principally yellow-red pheomelanin, in the hair, eyes, and skin in the later life v. Decreased visual acuity improving with age d. Temperature-sensitive albinism (OCA1ts) i. A subtype of OCA1B ii. Mutation of the tyrosinase gene that produces a temperature-sensitive tyrosinase enzyme

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iii. The heat-sensitive tyrosinase enzyme activity is approximately 25% of the normal tyrosinase activity at 37 C. The activity improves at lower temperatures. iv. Dark hair pigment in the arms and legs (cooler areas of the body) while axillary and scalp hair remains white v. Pigment is absent in the fetus because of high fetal temperature. 3. Oculocutaneous albinism 2 (OCA2) a. “Tyrosinase-positive” OCA b. Incidence: approximately 1 in 15,000 individuals c. Most prevalent type of albinism in all races and especially frequent among African-American population (1 in 10,000) d. Phenotypic variability i. Ranging from absence of pigmentation to almost normal pigmentation ii. Absence of black pigment (eumelanin) in the skin, hair, or eyes at birth iii. Gradual development of pigmentation with age iv. Increased pigmentation resulting in improved vision 4. Oculocutaneous albinism 3 (OCA3) a. Previously known as red/rufous OCA b. Incidence of the disease unknown c. Phenotype in African patients i. Light brown skin and hair ii. Blue-brown irides iii. Ocular features not fully consistent with diagnosis of OCA (no iris translucency, nystagmus, strabismus, or foveal hypoplasia) d. Phenotype in Caucasians and Asians: not known 5. Oculocutaneous albinism 4 (OCA4) a. Cannot be distinguished from OCA2 on clinical findings b. Hypopigmentation of the skin and hair c. Characteristic ocular changes found in all other types of albinism i. Nystagmus ii. Reduced iris pigment with iris translucency iii. Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination iv. Foveal hypoplasia associated with reduction in visual acuity

Albinism

v. Misrouting of the optic nerves at the chiasm associated with alternating strabismus vi. Reduced stereoscopic vision vii. An altered visual-evoked potential (VEP) 6. Ocular albinism 1 (OA1) (Lewis 2011) a. X-linked recessive OA (XLOA) b. Incidence of the disease approximately 1 in 50,000 individuals c. Extreme variability in clinical expression d. Involving eyes only i. Decreased visual acuity ii. Refractive errors: typical findings a) Hypermetropia b) Astigmatism iii. Hypopigmentation of the fundus and the iris iv. Absent foveal reflex (foveal hypoplasia) v. Congenital nystagmus vi. Photophobia vii. Strabismus viii. Iris translucency ix. Posterior embryotoxon x. Loss of stereoscopic vision due to misrouting of the optic tracts e. Normal skin f. Male manifesting complete phenotype g. Carrier females i. Normal vision ii. Hypopigmented streaks (characteristic patchy hypopigmentation as a result of mosaic inactivation of the affected X chromosomes) in the periphery iii. Marked iris translucency h. Severity depending on ethnic background: less severe in races exhibiting very dark constitutive skin pigmentation than those more lightly pigmented 7. Autosomal recessive ocular albinism (OAR) a. Children with ocular features of albinism and normal cutaneous pigmentation born to normally pigmented parents b. Classified as autosomal recessive because both males and females are affected c. Not considered a clinical entity 8. Hermansky–Pudlak syndrome a. A group of related disorders i. Common oculocutaneous albinism

Albinism

ii. A platelet storage disorder iii. Ceroid-lipofuscin lysosomal storage disease b. An autosomal recessive disorder with very variable expression c. Incidence of the disease: rare, except in Puerto Rico where its frequency is 1 in 1,800 individuals (Witkop et al. 1990) d. Bleeding diathesis resulting from a platelet storage pool deficiency e. Patients exhibit severe immunologic deficiency with neutropenia and lack of killer cells (DePinho and Kaplan 1985) f. Ceroid storage disease i. Accumulation of a Ceroid-lipofuscin material in various organ systems ii. Interstitial pulmonary fibrosis iii. Granulomatous colitis and gingivitis iv. Kidney failure v. Cardiomyopathy 9. Chediak–Higashi syndrome (Russell-Eggitt 2001) a. An autosomal recessive disorder with variable expression b. Consisting of a very rare group of conditions c. Severe immune disorder i. Abnormal intracellular granules in most cells, especially white cells ii. Susceptible to bacterial infections iii. Defective neutrophils function iv. Episodes of macrophage activation known as accelerated phases: a) Fever b) Anemia c) Neutropenia d) Occasionally thrombocytopenia e) Hepatosplenomegaly f) Lymphadenopathy g) Jaundice d. Hypopigmentation of skin, hair, irides, and ocular fundi e. Bleeding diathesis i. Easy bruising ii. Mucosal bleeding iii. Epistaxis iv. Petechiae f. Eye symptoms i. Photophobia ii. Nystagmus

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iii. Reduced stereoacuity iv. Strabismus g. Often succumb during childhood to severe viral and bacterial infections, bleeding or development of the accelerated phase h. May develop a peripheral and cranial neuropathy in survivors i. Autonomic dysfunction ii. Weakness and sensory deficits iii. Loss of deep tendon reflexes iv. Clumsiness with a wide-based gait v. Seizures vi. Abnormal EEG vii. Abnormal EMG with decreased motor nerve conduction velocities 10. Griscelli syndrome (Mancini et al. 1998) a. A rare disorder b. Immune impairment c. Neurological deficit d. Hypopigmentation of skin and hair e. Presence of large clumps of pigment in hair shafts 11. Waardenburg syndrome: a syndrome of sensory deafness and partial albinism, referred to as the albinism-deafness syndrome (Waardenburg 1951)

Diagnostic Investigations 1. Ophthalmologic examination for detection of reduced retinal pigment with visualization of the choroidal blood vessels (OCA1) and foveal hypoplasia 2. Visual acuity reduction 3. Hair bulb incubation assay for tyrosinase activity a. OCA1A: no tyrosinase activity b. OCA1B: greatly reduced activity of tyrosinase but still present 4. Visual-evoked potential (VEP): an accurate diagnostic test for albinism by demonstrating an asymmetry of VEP between the two eyes secondary to misrouting of optic pathways 5. Electron microscopy of skin and hair bulb: not routinely performed but probably the best diagnostic method for albinism.

Albinism

c. Chediak–Higashi syndrome i. Treat infections ii. Bone marrow transplantation: improves immunological status but no effect on ocular and cutaneous albinism

References Abadi, R., & Pascal, E. (1989). The recognition and management of albinism. Ophthalmic & Physiological Optics, 9, 3–15. Bashour, M., Hasanee, K., & Ahmed, I. I. K. (2010). Albinism. EMedicine/WebMD. Updated February 11, 2010. Available at: http://emedicine.medscape.com/article/1200472-overview Biswas, S., & Lloyd, I. C. (1999). Oculocutaneous albinism. Archives of Disease in Childhood, 80, 565–569. Boissy, R. E., & Nordlund, J. J. (2009). Dermatologic Manifestations of Albinism. Updated October 30, 2009. Available at http://emedicine.medscape.com/article/1068184-overview Carden, S. M., Boissy, R. E., Schoettker, P. J., et al. (1998). Albinism: Modern molecular diagnosis. The British Journal of Ophthalmology, 82, 189–195. Creel, D. J., Summers, C. G., & King, R. A. (1990). Visual anomalies associated with albinism. Ophthalmic Paediatrics and Genetics, 11, 193–200. DePinho, R. A., & Kaplan, K. L. (1985). The Hermansky-Pudlak syndrome. Report of three cases and review of pathophysiology and management considerations. Medicine (Baltimore), 64, 192–202. Grønskov, K., Ek, J., & Brondum-Nielsen, K. (2007). Oculocutaneous albinism. Orphan Journal of Rare Disease, 2, 43–50. Hsieh, Y. Y., Wu, J. Y., Chang, C. C., et al. (2001). Prenatal diagnosis of oculocutaneous albinism two mutations located at the same allele. Prenatal Diagnosis, 21, 200–201. King, R. A. (2004). Oculocutaneous albinism type 1. Gene Reviews. Updated October 1, 2004. Available at: http:// www.ncbi.nlm.nih.gov/books/NBK1166/ King, R. A., Hearing, V. J., Creed, D. J., et al. (2001). Albinism. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic & molecular bases of inherited disease (8th ed., pp. 5587–5627). New York: McGraw-Hill. Chapter 220. King, R. A., & Oetting, W. S. (2007). Oculocutaneous albinism type 2. Gene Reviews. Updated June 20, 2007. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1232/ King, R. A., Oetting, W. S., Summers, C. G., et al. (2007). Abnormalities of pigmentation. In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Emery and Rimoin’s principles and practice of medical genetics (5th ed., pp. 3380–3427). Philadelphia, PA: Churchill Livingstone Elsevier. King, R. A., Pietsch, J., Fryer, J. P., et al. (2003). Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): Definition of the phenotype. Human Genetics, 113, 502–513. King, R. A., & Summers, C. G. (1988). Albinism. Dermatologic Clinics, 6, 217–228. Lang, G. E., Rott, H. D., & Pfeiffer, R. A. (1990). X-linked ocular albinism. Characteristic pattern of affection in female carriers. Ophthalmic Paediatrics and Genetics, 11, 265–271.

67 Lewis, R. A. (2011). Ocular albinism, X-linked. Gene Reviews. Updated April 5, 2011. Available at: http://www.ncbi.nlm. nih.gov/books/NBK1343/ Mancini, A. J., Chan, L. S., & Paller, A. S. (1998). Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature. Journal of the American Academy of Dermatology, 38, 295–300. Nagle, D. L., Karim, M. A., Woolf, E. A., et al. (1996). Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nature Genetics, 14, 307–311. Oetting, W. S. (1999). Albinism. Current Opinion in Pediatrics, 11, 565–571. Oetting, W. S. (2002). New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene. Human Mutation, 19, 85–92. Oetting, W. S., Brilliant, M. H., & King, R. A. (1996). The clinical spectrum of albinism in humans. Molecular Medicine Today, 2, 330–335. Oetting, W. S., Fryer, J. P., Shriram, S., et al. (2003). Oculocutaneous albinism type 1: The last 100 years. Pigment Cell Research, 16, 307–311. Oetting, W. S., Gardner, J. M., Fryer, J. P., et al. (1998). Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Human Mutation, 12, 434. Oetting, W. S., & King, R. A. (1999). Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism. Human Mutation, 13, 99–115. Okulicz, J. F., Shah, R. S., Schwartz, R. A., et al. (2003). Oculocutaneous albinism. Journal of the European Academy of Dermatology and Venereology, 17, 251–256. Peracha, M. O., Cosgrove, F. M., & Garcia-Valenzuela, E. (2008). Ocular manifestations of albinism. EMedicine/ WebMD. Updated October 13, 2008. Available at: http:// emedicine.medscape.com/article/1216066-overview Rosenberg, T., & Schwartz, M. (1998). X-linked ocular albinism: Prevalence and mutations–a national study. European Journal of Human Genetics, 6, 570–577. Russell-Eggitt, I. (2001). Albinism. Ophthalmology Clinics of North America, 14, 533–546. Sarangarajan, R., & Boissy, R. E. (2001). Tyrp1 and oculocutaneous albinism type 3. Pigment Cell Research, 14, 437–444. Shen, B., Samaraweera, P., Rosenberg, B., et al. (2001). Ocular albinism type 1: More than meets the eye. Pigment Cell Research, 14, 243–248. Spritz, R. A. (1993). Molecular genetics of oculocutaneous albinism. Seminars in Dermatology, 12, 167–172. Summers, C. G. (2009). Albinism: classification, clinical characteristics, and recent findings. Optometry and Vision Science, 86, 659–662. Summers, C. G., Oetting, W. S., & King, R. A. (1996). Diagnosis of oculocutaneous albinism with molecular analysis. American Journal of Ophthalmology, 121, 724–726. Waardenburg, P. J. (1951). A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. American Journal of Human Genetics, 3, 195–253. Witkop, C. J., Nunez, B. M., Rao, G. H., et al. (1990). Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Boletı´n de la Asociacio´n Me´dica de Puerto Rico, 82, 333–339.

68 Fig. 1 (a–e) Oculocutaneous albinism in different age groups including one set of identical twins

Albinism

a

c

e

b

d

Albinism

Fig. 2 A 7-month-old infant boy with light skin color, silverish white scalp hair, eyebrows, and eyelashes, and absence of nystagmus or strabismus. The infant possesses one detectable mutation in the OCA2 gene encoding the P protein, namely, V433I: c.1327G > A. This mutation has been reported in the literature and is a known cause of OCA2. The second variation, IVS1244C > T was noted. A homozygous sequence change (IVS717insA) was observed in the OCA3 gene. The intronic sequence changes in the OCA2 and OCA3 genes have not been reported in the literature and therefore clinical significance is unknown. No mutations were observed in the OCA1 gene, the OCA4 gene, or the OA1 gene

69

Alpha-Thalassemia X-linked Mental Retardation Syndrome

Alpha-thalassemia X-linked mental retardation (ATRX) syndrome, one form of X-linked mental retardation, is characterized by severe mental retardation, typical dysmorphic facies, genital abnormalities, and an unusually mild form of hemoglobin H disease (Gibbons et al. 1995a).

Synonyms and Related Disorders ATRX syndrome; X-linked hypotonic face syndrome

mental

v. XLMR with epilepsy vi. Nonsyndromic XLMR b. ATRX mutations are identified in the following two syndromes but not in the original reported families and therefore the relationship between ATRX syndrome and these two syndromes is unclear. i. Juberg–Marsidi syndrome ii. Smith–Fineman–Myers syndrome

retardation-

Genetics/Basic Defects 1. An X-linked recessive disorder 2. The gene involved in the disease, ATRX, is mapped to Xq13.3 3. The function of the ATRX protein: unknown but may play a role in gene expression based on the fact that alpha globin expression is perturbed in the patients 4. Genetically related (allelic) disorders a. Several X-linked mental retardation (XLMR) syndromes: These disorders should be considered to be in the phenotypic spectrum of ATRX syndromes and there are no compelling reasons to maintain the syndromic names. i. Carpenter–Waziri syndrome ii. Holmes–Gang syndrome iii. Chudley–Lowry syndrome iv. XLMR with spastic paraplegia

Clinical Features 1. Central nervous system features a. Global developmental delay i. Limited expressive language ii. Delayed walking until late childhood or unable to ambulate b. Generalized hypotonia, a hallmark of the condition, in early childhood, contributing to facial manifestations, drooling, and developmental retardation c. Seizures (1/3 of cases) 2. Characteristic craniofacial features a. Microcephaly b. Upsweep of the frontal hair c. Telecanthus or ocular hypertelorism d. Small triangular nose with retracted columella e. Tented upper lip f. Prominent or everted lower lip g. Open mouth h. Other features i. Irregular anatomy of the pinnae ii. Wide spacing of the teeth

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3.

4.

5.

6.

Alpha-Thalassemia X-linked Mental Retardation Syndrome

iii. Tongue protrusion iv. Coarse facial appearance particularly after the first few years of life Abnormal external genitalia: broad spectrum of possible genital anomalies but the type of genital anomaly appears to be consistent within a family a. Often minor anomalies i. First-degree hypospadias ii. Undescended testes iii. Underdevelopment of the scrotum b. More severe defects i. Second- and third-degree hypospadias ii. Micropenis iii. Ambiguous genitalia c. Occasional gonadal dysgenesis resulting in inadequate testosterone production and ambiguous genitalia or normally appearing female external genitalia Skeletal anomalies a. Short stature b. Digital anomalies i. Brachydactyly ii. Clinodactyly iii. Tapered digits c. Joint contractures d. Spine anomalies i. Pectus carinatum ii. Kyphosis iii. Scoliosis iv. Dimples over the lower spine e. Foot anomalies i. Varus and valgus foot deformation ii. Pes planus Gastrointestinal features a. Gastroesophageal reflux (2/3 of cases): may cause aspiration with a fatal complication in some b. Chronic constipation (1/3 of cases) c. Report of pseudo-obstruction (gastric pseudovolvulus) resulting from abnormal suspension of the stomach and constipation from colon hypoganglionosis Major malformations: uncommon a. Ocular coloboma b. Cleft palate c. Cardiac defects d. Inguinal hernia e. Heterotaxy f. Asplenia

Diagnostic Investigations 1. Diagnosis is suspected on the basis of characteristic craniofacial, genital, skeletal, other somatic features, and hematological findings and should be confirmed by molecular genetic testing 2. Hematologic studies: demonstration of evidence of alpha-thalassemia a. Hb H inclusions (b-globin tetramers) ranging from 0.01% to 30% in erythrocytes demonstrated in most individuals with ATRX mutations b. Hemoglobin electrophoresis: demonstration of Hb H (not highly sensitive) c. Red blood cell indices: microcytic hypochromic anemia in some affected individuals 3. Molecular genetic testing a. Sequence analysis and mutation scanning of select exons b. Sequence analysis and mutation scanning of all exons and splice junctions c. Deletion/duplication analysis d. X-chromosome inactivation studies: The finding of nonrandom X-chromosome inactivation is not unique to ATRX syndrome and is therefore not diagnostic 4. Carrier testing in at-risk females possible when the disease-causing mutation in the family is known

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Carrier mother a) A 50% chance of transmitting the ATRX mutation b) Offspring with a 46,XY karyotype who inherit the ATRX mutation will be affected c) Offspring with a 46,XX karyotype who inherit the mutation are unaffected female carriers ii. Sibs of proband with de novo gene mutation: at increased risk of inheriting the diseasecausing mutation because of possible germline mosaicism in the mother b. Patient’s offspring: Affected individual do not reproduce

Alpha-Thalassemia X-linked Mental Retardation Syndrome

2. Prenatal diagnosis and preimplantation genetic diagnosis: possible for pregnancies at increased risk for ATRX syndrome when the disease-causing mutation in the family is known 3. Management a. Multidisciplinary interventions i. Infant stimulation ii. Early intervention iii. Special education b. Management of feeding and gastrointestinal problems i. Gavage feeding for difficulty in sucking ii. Fundoplication and feeding gastrostomy may be required for gastroesophageal reflux iii. Surgical correction of pseudovolvulus iv. Prevention of constipation v. Consider biopsy to rule out Hirschsprung’s disease and colonic hypoganglionosis vi. Control of severe drooling a) Anticholinergics b) Botulinum toxin type A injection of the salivary glands c) Surgical redirecting of the submandibular ducts c. Seizure control d. Genitourinary problems i. Orchidopexy for cryptorchidism ii. Treat recurrent urinary tract infections e. Orthopedic management for musculoskeletal anomalies f. Hearing loss management g. Alpha-thalassemia i. No treatment required for the mild anemia ii. Iron not required unless iron stores are shown to be low

References Abidi, F., Schwartz, C. E., Carpenter, N. J., et al. (1999). Carpenter-Waziri syndrome results from a mutation in XNP (letter). American Journal of Medical Genetics, 85, 249–251. Bachoo, S., & Gibbons, R. J. (1999). Germline and gonosomal mosaicism in the ATR-X syndrome. European Journal of Human Genetics, 7, 933–936. Carpenter, N. J., Qu, Y., Curtis, M., et al. (1999). X-linked mental retardation syndrome with characteristic “coarse” facial appearance, brachydactyly, and short stature maps to

73 proximal Xq. American Journal of Medical Genetics, 85, 230–235. Donnai, D., Clayton-Smith, J., Gibbons, R. J., et al. (1991). The non-deletion alpha thalassaemia/mental retardation syndrome: Further support for X linkage. Journal of Medical Genetics, 28, 742–745. Fichera, M., Silengo, M., Spalletta, A., et al. (2001). Prenatal diagnosis of ATR-X syndrome in a fetus with a new G > T splicing mutation in the XNP/ATR-S gene. Prenatal Diagnosis, 21, 747–751. Gibbons, R. (2006). Alpha thalassaemia-mental retardation, X linked. Orpanet Journal of Rare Diseases, 1, 15. Review. Gibbons, R. J., Brueton, L., Buckle, V. J., et al. (1995a). Clinical and hematologic aspects of the X-linked alpha-thalassemia/ mental retardation syndrome (ATR-X). American Journal of Medical Genetics, 55, 288–299. Gibbons, R. J., & Higgs, D. R. (2000). Molecular-clinical spectrum of the ATRX syndrome. American Journal of Medical Genetics, 97, 204–212. Gibbons, R. J., Picketts, D. J., Villard, L., et al. (1995b). Mutations in a putative global transcriptional regulator cause Xlinked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell, 80, 837–845. Guerrini, R., Shanahan, J. L., Carrozzo, R., et al. (2000). A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy. Annals of Neurology, 47, 117–121. Holmes, L. B., & Gang, D. L. (1984). Brief clinical report: An X-linked mental retardation syndrome with craniofacial abnormalities, microcephaly and club foot. American Journal of Medical Genetics, 17, 375–382. Jezela-Stanek, A., Fisher, C., Szarras-Czapnik, M., et al. (2009). X-linked a thalassaemia/mental retardation syndrome: A case with gonadal dysgenesis, caused by a novel mutation in ATRX gene. Clinical Dysmorphology, 18, 168–171. Kurosawa, K., Akatsuka, A., Ochiai, Y., et al. (1996). Self induced vomiting in X-linked alpha-thalassemia/mental retardation syndrome. American Journal of Medical Genetics, 63, 505–506. Lossi, A. M., Millan, J. M., Villard, L., et al. (1999). Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: Demonstration that the mutation is involved in the inactivation bias. American Journal of Human Genetics, 65, 558–562. Martussiello, G., Lombardi, L., Savasta, S., et al. (2006). Gastrointestinal phenotype of ATR-X syndrome. American Journal of Medical Genetics. Part A, 140A, 1172–1176. Plenge, R. M., Stevenson, R. A., Lubs, H. A., Schwartz, C. E., & Willard, H. F. (2002). Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders. American Journal of Human Genetics, 71, 168–173. Saugier-Veber, P., Munnich, A., Lyonnet, S., et al. (1995). Lumping Juberg-Marsidi syndrome and X-linked alphathalassemia/mental retardation syndrome? American Journal of Medical Genetics, 55, 300–301. Stevenson, R. E. (2010). Alpha-thalassemia X-linked intellectual disability syndrome. Gene reviews. Updated June 3, 2010. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1449/ Stevenson, R. E., Abidi, F., Schwartz, C. E., et al. (2000). Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. American Journal of Medical Genetics, 94, 383–385.

74 Villard, L., Fontes, M., Ades, L. C., & Gecz, J. (2000). Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. American Journal of Medical Genetics, 91, 83–85. Villard, L., Gecz, J., Mattei, J. F., et al. (1996). XNP mutation in a large family with Juberg-Marsidi syndrome. Nature Genetics, 12, 359–360. Wada, T., Kubota, T., Fukushima, Y., et al. (2000). Molecular genetic study of Japanese patients with X-Linked

Alpha-Thalassemia X-linked Mental Retardation Syndrome a-thalassemia/mental retardation syndrome (ATR-X). American Journal of Medical Genetics, 94, 242–248. Wada, T., Sugie, H., Fukushima, Y., et al. (2005). Non-skewed X-inactivation may cause mental retardation in a female carrier of X linked alpha-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X. American Journal of Medical Genetics. Part A, 138, 18–20.

Alpha-Thalassemia X-linked Mental Retardation Syndrome

a

75

b

Fig. 1 (a, b) A 7-year-old boy with global developmental delay and the characteristic facial appearance of ATRX syndrome: upswept frontal hair line, ocular hypertelorism, epicanthal folds, a small triangular upturned nose, open mouth, tented upper lip, prominent everted lower lip, and hypotonic appearing face. He has mild microcytic, hypochromic anemia (mean cell volume

Fig. 2 A maternal uncle was similarly affected with recurrent pneumonias, anemia, and mental retardation

74.8 FL (76–90), MCH 23.6 pg (27–31), MCHC 31.5 g/dl (32–36)). Sequence analysis showed a C > T change at nucleotide 736 in the XNP gene (c.736C > T). This change results in the substitution of a cysteine for an arginine at amino acid 246 (R246C). This change is consistent with the diagnosis of ATRX syndrome. His mother has the same XNP gene mutation

Ambiguous Genitalia

Most cases of ambiguous genitalia are discovered at birth, occurring approximately once in every 1,000 live births. Genital ambiguity usually is due to virilization of genetic females or undervirilization of genetic males who have normal gonads. Less common are disorders of sexual differentiation that involve gonadal dysgenesis (Chi et al. 2008). In females, congenital adrenal hyperplasia (CAH), specifically 21-hydroxylase deficiency, is the most common condition leading to inappropriate virilization. In males, defects in testosterone production, metabolism, or peripheral action can lead to ambiguous genitalia. Later presentations of ambiguous genitalia often include previously unrecognized genital ambiguity, inguinal hernia in a girl (e.g., complete androgen insensitivity), delayed or incomplete puberty, primary amenorrhea or virilization in a girl, breast development in a boy, and gross or cyclic hematuria in a boy (unrecognized virilized 46,XX with CAH) (Lee et al. 2006).

Synonyms and Related Disorders Genetic disorders of sexual differentiation (gonadal dysgenesis, true hermaphroditism, sex reversal); Undervirilization of male infant; Virilization of female infant

Genetics/Basic Defects 1. Normal development of the human reproductive system (Chi et al. 2008) a. Sexual differentiation of the fetus begins at 6–7 weeks of gestation

b. During embryogenesis, the fetus contains both female (m€ullerian) and male (wolffian) genital ducts i. M€ullerian ducts: develop into fallopian tubes, uterus, and the upper one third of the vagina ii. Wolffian ducts: develop into the vas deferens, epididymis, and seminal vesicles c. “Default” pathway of the bipotential gonad and internal structures: female d. Presence of the sex-determining region Y gene (SRY) in males: activates a cascade of events that culminates in differentiation of the gonad as a testis which produces the following two key hormones i. Testosterone a) Function: stimulates wolffian duct differentiation b) Production: initially driven by placental human chorionic gonadotrophin (hCG) which subsequently replaced by fetal pituitary gonadotrophins after the first trimester, both acting through the luteinizing hormone (LH) receptor c) Local conversion of testosterone to dihydrotestosterone (DHT) by the enzyme 5-a reductase leads to fusion of the labioscrotal folds and formation of the scrotum and penis, both critical events occurring in the first trimester ii. M€ullerian inhibiting substance (MIS) or antim€ullerian hormone (AMH): stimulates m€ullerian duct regression e. Absence of testosterone and MIS in females leads to: i. Involution of the wolffian ducts.

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ii. Differentiation of the m€ ullerian ducts into female internal genitalia iii. Needs both X chromosomes to develop normally differentiated and functional ovaries; females with X chromosome deletion (Turner syndrome) have abnormal gonadal differentiation and oocytes loss, leading to streak gonads. 2. Broad categories of ambiguous genitalia a. XX baby with virilization i. In the virilized XX baby, the gonads are ovaries and the internal genitalia are female. ii. The external genitalia are masculinized by circulating androgens to a variable degree, ranging from subtle clitoromegaly to complete labial fusion with urethral tubularization to the tip of the enlarged phallus. iii. If exposure occurred late, clitoromegaly without labial fusion is seen. The gonads are not palpable. iv. The commonest cause of virilization in the XX “female” is congenital adrenal hyperplasia. This autosomal recessive condition results from an enzymatic defect in adrenal steroidogenesis, leading to accumulation of steroids proximal to the block, which are converted to androgens. The commonest of these is 21-hydroxylase deficiency, followed by 11b-hydroxylase and 3b-hydroxysteroid dehydrogenase deficiency. The serum and urinary steroid profile will help to confirm the diagnosis. Other possible causes include exposure to exogenous androgens, such as from maternal androgens or progestin ingestion, or rarely, maternal androgen-producing tumors. v. The majority of true hermaphrodites also have a 46 XX chromosomal makeup, but these form a distinct group. b. The XY baby with undervirilization i. The undervirilized XY baby presents with a small phallus with severe chordee, posterior hypospadias, poorly formed, bifid scrotum with or without testicular maldescent. Inadequate testosterone production, either as a result of testicular dysgenesis or autosomal recessive enzymatic defects, is rare. ii. The commonest cause is a group of disorders known as androgen insensitivity syndrome

Ambiguous Genitalia

(AIS), previously also known as testicular feminization syndrome. This is an X-linked disorder resulting from peripheral resistance to androgen action, either from mutations in the androgen receptor gene, or elsewhere in the molecular pathway. iii. Whether AIS may, in fact, be due to a defect in the conversion of dihydrotestosterone to 5-a-androstanediol remains to be seen. iv. 5-a-reductase deficiency, an autosomal recessive defect resulting in deficient dihydrotestosterone necessary in the virilization of the external genitalia in early embryogenesis, is another cause of undervirilization. c. True hermaphroditism i. In the true hermaphrodite, both testicular and ovarian tissues coexist. ii. The gonads are usually ovary-testis, or ovary-ovotestis. iii. The genotype is usually 46 XX, although 46 XY or mosaicism can occur. iv. Asymmetry of the gonads, internal and external genitalia is a feature in true hermaphroditism. The right side is more commonly the “masculine” side while the left side is often more “feminine.” d. Mixed gonadal dysgenesis i. In mixed gonadal dysgenesis, there is a testis on one side (more commonly the right side) and a streak gonad on the other. ii. The testis may be dysgenetic or initially normal, and the streak gonad histologically is composed of whorls of ovarian stroma without oocytes. iii. The karyotype is most commonly 45,X/46,XY, but other mosaic patterns have been described. iv. As with true hermaphrodites, asymmetry is a feature in mixed gonadal dysgenesis. 3. XX true hermaphroditism a. Mechanisms i. Hidden mosaicism with a Y-bearing cell line ii. Translocation of Y-material including SRY from paternal Y-to-X chromosome iii. An autosomal or X-linked mutation that permits testis differentiation in the absence of SRY b. An unusual cause of ambiguous genitalia i. Both ovarian and testicular tissue present either in the same or in a contralateral gonad ii. Predominantly 46,XX karyotype

Ambiguous Genitalia

c. Several familial forms reported although the great majority of cases are sporadic i. Occurring with a higher frequency in South African blacks suggesting a genetic origin ii. Several families in which 46,XX males coexist with 46,XX true hermaphrodites strongly suggest that both disorders are alternative manifestations of the same genetic defect d. SRY-negative true hermaphroditism could be the result of genetic defects at an unknown X-linked or autosomal sex-determining locus e. Mutations in SRY originated ovotestes development described in 46,XY patients f. Absence of SRY in gonadal tissue reported in cases of 46,XX true hermaphroditism g. Possible underestimate of gonadal hidden mosaicism for SRY in XX true hermaphrodites suggesting that true hermaphroditism is a genetically heterogeneous condition 4. Causes of ambiguous genitalia (Chi et al. 2008) a. Virilization of female infant i. Excessive androgen production: congenital adrenal hyperplasia a) 21-a hydroxylase deficiency b) 11-b hydroxylase deficiency c) 3-b hydroxysteroid dehydrogenase deficiency ii. Defects in androgen metabolism: placental aromatase deficiency iii. Maternal hyperandrogenism a) Maternal androgen production (luteoma of pregnancy, adrenal tumor, untreated CAH) b) Progestational agents b. Undervirilization of male infant i. Defects in testosterone production a) Leydig cell hypoplasia/agenesis b) Defects in testicular and adrenal steroidogenesis (steroid acute regulatory (StAR) protein deficiency, 3-b hydroxysteroid dehydrogenase deficiency, 17-a hydroxylase/17,20 lyase deficiency, 17-a hydroxysteroid dehydrogenase (ketosteroid reductase) deficiency ii. Defects in testosterone metabolism: 5-a reductase deficiency iii. Defects in testosterone action: androgen insensitivity syndrome iv. Exogenous estrogen/progestin exposure

79

c. Genetic disorders of sexual differentiation i. Gonadal dysgenesis a) 45,X (streak ovaries) b) 46,XX gonadal dysgenesis c) 46,XY complete and partial gonadal dysgenesis d) 45,X/46,XY mixed gonadal dysgenesis e) 47,XXY (seminiferous tubular dysgenesis) ii. True hermaphroditism iii. Sex reversal a) XX males (SRY) b) XY female (SRY) c) Smith–Lemli–Opitz Syndrome (SLOS) d) DAX1 mutations e) WT1 mutations

Clinical Features 1. Physical features suggestive of ambiguous genitalia (Lee et al. 2006) a. Overt genital ambiguity (e.g., cloacal exstrophy) b. Apparent female genitalia with enlarged clitoris and posterior labial fusion (e.g., CAH) c. Apparent male genitalia with undescended testes, hypospadias, or micropenis 2. Rules of thumb and clinical significance of internal genitalia (the gonads and the genital ducts) (Low et al. 2003) a. Testes descend, ovaries do not: Presence of a palpable gonad implies the presence of testicular tissue on the same side, which implies the presence of the SRY gene somewhere in the genome b. Testicular descent is directly linked to m€ullerian duct regression: i. Presence of two palpable gonads means there is no uterus. ii. With asymmetrical gonadal descent, similar ductal asymmetry internally can be predicted. iii. On the side of the descended gonad, there will be wolffian duct derivatives but no m€ullerian structures. Correspondingly, the contralateral hemi-uterus is likely to be present. iv. When there are no palpable gonads, the gonadal and ductal status is unknown. c. Presence of a uterus (digitally palpated or ultrasonically detected) means no m€ullerian

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inhibiting substance/anti-m€ ullerian hormone (MIS/AMH) action during the “sensitive” period in early gestation. This implies either no testes, dysgenetic nonfunctional testes, or defects in production or action of MIS/AMH as occurs in the rare syndrome of persistent m€ ullerian duct syndrome (PMDS). d. Testosterone, as well as MIS/AMH, functions as a locally acting exocrine hormone in the development of the internal genital ducts i. Gonadal asymmetry as occurs in true hermaphrodites and mixed gonadal dysgenesis results in corresponding duct asymmetry. ii. Circulating androgens in over-androgenized XX babies are insufficient to allow development of male internal genitalia. 3. Rules of thumb and clinical significance of external genitalia (Low et al. 2003) a. External virilization, of any degree, is due to the effect of androgens i. “Clitoromegaly” in an otherwise phenotypic female is always abnormal, indicating abnormal exposure to androgens ii. The genotype may be “XX” with virilization or “XY” with undervirilization b. The degree of external virilization proportionally predicts the degree of lower vaginal development i. A baby who is incompletely virilized externally, an incomplete vaginal remnant, is likely to be retained ii. In a 46 XX “female” baby, the greater the external virilization, the smaller the vaginal remnant and the higher its opening into the posterior urethra c. With the exception of the phallus, circulating androgens masculinize the external genitalia only during a critical period (8th–12th weeks) i. Scrotal fusion indicates the presence of early circulating androgens while an unfused scrotum means deficient early androgen effect ii. An enlarged phallus without urethral/scrotal fusion means there has been a delayed androgen effect (beyond 12 weeks) iii. Enlargement of the phallus to normal penile size means continued presence of an androgen effect throughout later gestation (12 weeks to term)

Ambiguous Genitalia

4. True hermaphroditism: contains both ovarian and testicular gonadal tissue separately or, more commonly, together as ovotestis a. During intrauterine life: presence of ovarian and testicular tissue with variability in hormonal production results in abnormal differentiation of internal and external genitalia b. At birth i. Variable degrees of genital ambiguity present in nearly all patients ii. Presence of labioscrotal folds, normally developed labia majora in most affected individuals iii. A hemiscrotum or even a normal scrotum in a minority of cases iv. A phallus of variable length with chordee and urethra generally opens as a urogenital sinus in majority of cases while less severe hypospadias in some cases v. Ovaries generally locate in ovarian position while testes locate in the scrotum generally, inguinal canal, or even intra-abdominally vi. Location of ovotestis depends on the amount of testicular or ovarian tissue present vii. Development of internal genitalia: variable depending on the neighboring gonad a) Presence of m€ullerian derivatives: an ovary is present and ovotestes in most cases b) Wolffian structures: observed in association with testes viii. A unicornate uterus is usually found c. At puberty i. Relative production rate of sex hormones vary depending on the composition of the gonads ii. Secondary sex characteristics depend on the type of predominant steroid hormone production iii. Breast development frequent after puberty iv. Menstruation occurring in approximately 50% of patients v. Ovulation common vi. Pregnancy reported in a few cases d. Pregnancy in true hermaphrodites (Schultz et al. 2009): i. Complications with preterm labor, neonatal death, or the delivery process itself

Ambiguous Genitalia

ii. Sex of the fetus likely male iii. Recommendation to remove the remaining gonad(s) due to an increased risk of germ cell malignancies after thorough discussion of the risks, benefits, alternatives, and implications of future sterility and hormone deprivation 5. Recently proposed revised nomenclature (Lee et al. 2006) a. Disorders of sex development (DSD) replacing “intersex” b. 46,XY DSD replacing “male pseudohermaphrodite, undervirilization of an XY male, and undermasculization of an XY male” c. 46,XX DSD replacing “female pseudohermaphrodite, overvirilization of an XX female, and masculinization of an XX female” d. Ovotesticular DSD replacing “true hermaphrodite” e. 46,XX testicular DSD replacing “XX male or XX sex reversal” f. 46,XY complete gonadal dysgenesis replacing “XY sex reversal”

Diagnostic Investigations 1. Approach to the baby with ambiguous genitalia (Low et al. 2003) a. History: i. Careful history taking: indispensable to an accurate diagnosis a) Maternal steroid ingestion b) Antenatal diagnosis of an androgenproducing tumor c) A positive family history of a known intersex disorder will give important clues to the underlying disorder d) Majority of cases, however, will not yield a positive history b. Steps in the evaluation of a baby with ambiguous genitalia i. Document the degree of external virilization: The greater the degree of virilization, the greater the amount of early androgen exposure (between 8 and 12 weeks) and the greater the extent of vaginal regression. ii. Examine the urogenital sinus carefully by pulling it open. If skin tags with a slight

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bluish hue are seen, then the hymen and therefore the vagina is confirmed present. iii. Determine the presence and location of gonads a) Palpable gonads predict the presence of SRY, testicular development, and m€ullerian regression on the ipsilateral side b) The degree of testicular descent correlates with the degree of androgen exposure in the second half of pregnancy iv. Three possible clinical scenarios a) Both gonads palpable and symmetrical: Palpable gonads are almost always testes and the implication, in general, is that the baby is an inadequately virilized male and m€ullerian duct structures are absent. The differential diagnoses include inadequate testosterone production, receptor deficiency, 5-a-reductase deficiency, minor testicular dysplasia (an exception is the occurrence of bilateral symmetrical ovotestes in a true hermaphrodite). b) Gonadal asymmetry with only one gonad palpable: This implies that at least one testis is present. The other may be an ovary, an ovotestis or a streak gonad. c) When gonadal asymmetry is encountered, always consider true hermaphroditism or mixed gonadal dysgenesis. v. Impalpable gonads a) Gonadal and duct status: unknown. b) Additional clues may be obtained by careful examination to determine if the external inguinal rings are open, which are felt as inverted V-shaped defects superior and medial to the pubic tubercle. Open external rings indicate a high likelihood of an undescended canalicular testis, while a closed external ring is consistent with the presence of ovaries or extremely dysplastic testes with minimal testosterone production. Per rectal examination is also useful in this circumstance. A gentle examination with the little finger will easily palpate the cervix and confirm the presence of the uterus. c) Look for other clues in the general physical examination, such as facial

82

2.

3. 4.

5.

6.

7.

8. 9. 10. 11.

Ambiguous Genitalia

dysmorphism or developmental abnormalities that may be part of a sex chromosome abnormality. Hyperpigmentation may occur in congenital adrenal hyperplasia. Pelvic ultrasonography: used to detect the presence of a uterus, as well as the presence and position of intra-abdominal gonads. However, visualization may be difficult in the small neonate. Urogenital sinugram: to confirm the presence of and delineate the anatomy of the lower vagina. MRI (Choi et al. 1998) a. Female pseudohermaphroditism: shows normal internal female genitalia with masculinized external genitalia b. Male pseudohermaphroditism: shows normal or mildly defective testes with incompletely masculinized external genitalia c. Gonadal dysgenesis: shows combinations of normal, dysgenetic, and streak gonads; no gonads are evident in gonadal agenesis d. True hermaphroditism: shows both testicular and ovarian tissue Hormonal investigations a. Serum analysis of 17-hydroxyprogesterone. b. Serum profile of adrenal steroids, gonadal androgens, and its precursors. c. Human chorionic gonadotrophin stimulation tests may be needed to confirm the normal rise of gonadal hormones with stimulation, while testosterone/dihydrotestosterone ratios reflect 5-a-reductase activity. Chromosomal analysis: to identify the genotype of the affected baby, either as XX, XY, or a mosaic pattern FISH analysis with SRY probes to identify the presence of Y sequences on the X chromosome in cases of 46,XX hermaphroditism and ambiguous genitalia Biopsy of the genital skin for androgen receptor assay Panendoscopy and/or laparoscopy to delineate the internal genitalia Gonadal biopsies on occasion Diagnostic evaluation and potential diagnoses based upon symmetry of genitalia (Mieszczak et al. 2009) a. Symmetrical external genitalia i. Palpable gonad: gene testing of SF1

ii. Nonpalpable gonad: ultrasound a) Uterus (lack of MIH): hormonal assessment (17a-hydroxyprogesterone, androstenedione, testosterone, plasma renin activity) for congenital adrenal hyperplasia and in utero androgen exposure b) No uterus (presence of MIH): hormonal assessment (MIH, LH, testosterone, FSH (follicle-stimulating hormone), inhibin B, androstenedione) for Leydig cell hypoplasia, 3b-HSD, 17b-HSD (hydroxysteroid dehydrogenase), androgen insensitivity, 5 a-reductase deficiency, and testicular regression b. Asymmetric external genitalia (virilization of labia different on each side): assessment includes: i. Fluorescence in situ hybridization for SRY (sex-determining region Y) ii. Hormonal assessment a) MIH b) LH c) Testosterone d) FSH iii. Inhibin B: androstenedione iv. Gene testing a) SOX9 (17q24) – male gonadal dysgenesis, campomelic dysplasia, or XY sex reversal b) WT1(11p13) – XX male (SRY+), Frasier syndrome, or Denys–Drash syndrome with Wilms’s tumor c) DAX1 (Xp21.3) – mixed gonadal dysgenesis, XY female (SRY-), or congenital adrenal hypoplasia d) WNT4 – XO/XY e) DHH – ovotesticular DSD f) ATRX – a-thalassemia X-linked mental retardation syndrome g) SLOS – Smith–Lemli–Opitz syndrome v. Imaging: ultrasound

Genetic Counseling 1. Recurrence risk: Recurrence risk depends on the inheritance pattern of the disorder (e.g., autosomal recessive disorders – congenital adrenal

Ambiguous Genitalia

hyperplasia, testosterone biosynthetic defects, Leydig cell hypoplasia; autosomal dominant disorders – campomelic dysplasia, Denys–Drash syndrome, Frasier syndrome; X-linked recessive disorders – androgen insensitivity syndrome, male pseudohermaphroditism due to testicular 17,20desmolase deficiency) a. Patient’s sib i. Autosomal recessive: 25% ii. Autosomal dominant: not increased unless a parent is affected or having gonadal mosaicism iii. X-linked recessive: 50% of male sibs affected if the mother is a carrier b. Patient’s offspring i. Autosomal recessive: not increased unless the spouse is also a carrier ii. Autosomal dominant: 50% iii. X-linked recessive: All daughters of affected males will be carriers. All sons of an affected male will be normal 2. Prenatal diagnosis a. Prenatal ultrasonography: Pitfalls in sonographic fetal sex determination (Odeh et al. 2009) include: i. Fetuses with malformations of the external genitalia represent a diagnostic challenge ii. Clues to the presence of congenital malformations of the external genitalia include: a) Nonvisualization of the fetal bladder (Wilcox and Chitty 2001) b) Diagnosis of female genitalia at early gestation based on caudal orientation of the genital tubercle, followed at a later time by observation of male genitalia (Borneshtien et al. 1995) c) Marked phallic size discrepancy for gestational age; curvature of the phallus; scrotal-phallus malpositions d) Nondescended testis in the third trimester e) Absence of phallic, labial, or scrotal structures (Mandell et al. 1995) f) Abnormalities of the genitalia should also be suspected whenever a mismatch is found between the sonographic fetal sex and the karyotypic fetal sex (Stephens 1984; Cheikhelard et al. 2000) b. Prenatal diagnosis is possible for pregnancies at increased risk for various genetic syndromes

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when the disease-causing mutation in the family is known 3. Management a. Ambiguous genitalia: likely the most devastating condition to face any parent of a newborn. b. Dealing with emotional, psychosocial, cultural, diagnostic, and treatment issues. c. Factors to consider when discussing sex assignment with families (Lee et al. 2006): i. Diagnosis ii. Genital appearance iii. Potential for fertility iv. Surgical options v. Long-term hormone replacement therapy vi. Family views vii. Cultural practices d. Challenge facing clinicians : come to an accurate and expeditious diagnosis, and then to a rational sex assignment: i. The condition is rare ii. Clinical diagnosis frequently difficult iii. Understanding of normal sexual differentiation is crucial to understanding these disorders e. Hormone replacement therapy is often required to induce and sustain puberty, optimize bone mineral accrual and psychosexual development in individuals with ambiguous genitalia (Warne et al. 2005; Nabhan and Lee 2007): i. Intramuscular injections of either testosterone cypionate or ethanate are used for pubertal induction for hypogonadal boys. Other testosterone preparations such as gels and patches are available, but there is limited experience of their use for the induction of puberty (Rogol 2005). ii. Estrogen replacement orally or injection to induce secondary sexual characteristic development and menses for girls with hypogonadism. A progestin is usually added after breakthrough bleeding or after 1–2 years of continuous estrogen. In women without a uterus, there is no evidence that the addition of cyclic progesterone is beneficial. f. Surgical care: i. Feminizing genitoplasty, including vaginoplasty and clitoroplasty, in a virilized female ii. Surgical reconstruction in undervirilized males who typically have hypospadias: gender

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Ambiguous Genitalia

reassignment may be considered in patients with male pseudohermaphrodism and genital inadequacy iii. Testes in individuals with 46,XY gonadal dysgenesis or fragments of Y-chromosome material raised female should be removed to prevent testicular malignancy

References Aleck, K. A., Argueso, L., Stone, J., et al. (1999). True hermaphroditism with partial duplication of chromosome 22 and without SRY. American Journal of Medical Genetics, 85, 2. Anhalt, H., Neely, E. K., & Hintz, R. L. (1996). Ambiguous genitalia (Review). Pediatrics in Review, 17, 213–220. Berkovitz, G. D., Fechner, P. Y., Marcantonio, S. M., et al. (1992). The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46, XX true hermaphroditism. Human Genetics, 88, 411. Borneshtien, M., Riechler, A., & Zimmer, E. Z. (1995). Prenatal sonographic signs of possible fetal genital anomalies. Prenatal Diagnosis, 15, 215–219. Byne, W. (2006). Developmental endocrine influences on gender identity: implications for management of disorders of sex development. The Mount Sinai Journal of Medicine, 73, 950–959. Cheikhelard, A., Luton, D., Philippe-Chomette, P., et al. (2000). How accurate is the prenatal diagnosis of abnormal genitalia? Journal of Urology, 164, 984–987. Chen, H. (1986). Genetic Disorders. In P. L. Liu (Ed.), Blue book of diagnostic tests (pp. 421–462). Philadelphia, PA: W. B Saunders. Chi, C., Lee, H. C., & Neely, E. K. (2008). Ambiguous genitalia in the newborn (Review). NeoReviews, 9, e78–e84. Choi, H. K., Cho, K.-S., Lee, H. W., et al. (1998). MR imaging of intersexuality. Radiographics, 18, 83–96. Damiani, D., Fellous, M., McElreavey, K., et al. (1997). True hermaphroditism: Clinical aspects and molecular studies in 16 cases. European Journal of Endocrinology, 136, 201. Drobac, S., Rubin, K., & Rogol, A. D. (2006). A workshop on pubertal hormone replacement options in the United States. Journal of Pediatric Endocrinology & Metabolism, 19, 55–64. Friedland, G. W. (1990). Congenital anomalies of the urinary tract. In H. M. Pollack (Ed.), Clinical urography (pp. 776–787). Philadelphia, PA: W. B. Saunders. Gonzalez, R., & Piaggio, L. A. (2006). Ambiguous genitalia. Current Opinion in Urology, 16, 273–276. Hadjiathanasiou, C. G., Brauner, R., Lortat-Jacob, S., et al. (1994). True hermaphroditism: Genetic variants and clinical management. Journal of Pediatrics, 125, 738. Hughes, I. A. (2008). Disorders of sex development: A new definition and classification. Best Practice and Research Clinical Endocrinology and Metabolism, 22, 119–134. Hughes, I. A., Houk, C., Ahmed, S. F., et al. (2006). Consensus statement on management of intersex disorders. Archives of Disease in Childhood, 91, 554–563.

Krob, G., Braun, A., & Kuhnle, U. (1994). True hermaphroditism: Geographical distribution, clinical findings, chromosomes and gonadal histology. European Journal of Pediatrics, 153, 2. Lee, P. A., Houk, C. P., Ahmed, S. F., et al., in collaboration with the participants in the International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology (2006). Consensus statement on management of intersex disorders (Review). Pediatrics, 118, 814–815. Low, Y., Hutson, J. M., & Murdoch Childrens Research Institute Sex Study Group. (2003). Rules for clinical diagnosis in babies with ambiguous genitalia. Journal of Paediatrics and Child Health, 39, 406–413. MacLaughlin, D. T., & Donahoe, P. K. (2004). Sex determination and differentiation (Review). The New England Journal of Medicine, 350, 367–378. MacLellan, D. L., & Diamond, D. A. (2006). Recent advances in external genitalia. Pediatric Clinics of North America, 53, 449–464. Mandell, J., Bromley, B., Peters, C. A., et al. (1995). Prenatal sonographic detection of genital malformations. Journal of Urology, 153, 1994–1996. Mendonca, B. B., Domenice, S., Arnhold, I. J., et al. (2009). 46, XY Disorders of sex development (DSD). Clinical Endocrinology, 70, 173–187. Mieszczak, J., Houk, C. P., & Lee, P. A. (2009). Assignment of the sex of rearing in the neonate with a disorder of sex development (Review). Current Opinion in Pediatrics, 21, 541–547. Nabhan, Z. M., & Lee, P. A. (2007). Disorders of sex development. Current Opinion on Obstetrics and Gynecology, 19, 440–445. Nicholl, R. M., Grimsley, L., Butler, L., et al. (1994). Trisomy 22 and intersex. Archives of Disease in Childhood, 71, F57–F58. Odeh, M., Grinin, V., Kais, M., et al. (2009). Sonographic fetal sex determination (Review). Obstetrical and Gynecological Survey, 64, 50–57. Rogol, A. D. (2005). New facets of androgen replacement therapy during childhood and adolescence. Expert Opinion on Pharmacotherapy, 6, 1319–1336. Schultz, B. A. H., Roberts, S., Rodgers, A., et al. (2009). Pregnancy in true hermaphrodites and all male offspring to date. Obstetrics and Gynecology, 113, 534–536. Stephens, J. D. (1984). Prenatal diagnosis of testicular feminization. Lancet, 310, 1038. Thyen, U., Lanz, K., Holterhus, P. M., et al. (2006). Epidemiology and initial management of ambiguous genitalia at birth in Germany. Hormone Research, 66, 195–203. Warne, G. L., Grover, S., & Zajac, J. D. (2005). Hormonal therapies for individuals with intersex conditions: Protocol for use. Treatments in Endocrinology, 4, 19–29. Wilcox, D. T., & Chitty, L. S. (2001). Non visualization of the fetal bladder: Aetiology and management. Prenatal Diagnosis, 21, 977–983. William son, H. O., Phansey, S. A., & Mathur, R. S. (1981). True hermaphroditism with term vaginal delivery and a review. American Journal of Obstetrics and Gynecology, 141, 262. Wunsch, L. (2007). Imaging and examination strategies of normal male and female sex development and anatomy. Best Practice and Research Clinical Endocrinology and Metabolism, 21, 367–379.

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Fig. 3 Penoscrotal hypospadias with a chordee in a male infant Fig. 1 Vaginal labia agglutination (adhesion) in a female infant

Fig. 2 Vaginal atresia in a female newborn

Fig. 4 Cloacal exstrophy with ambiguous genitalia in an infant

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Ambiguous Genitalia

Fig. 5 Ambiguous genitalia with clitoromegaly in a female infant

Fig. 7 Penoscrotal hypospadias in Smith–Lemli–Opitz syndrome

Fig. 6 Ambiguous genitalia in a female infant with congenital adrenal hyperplasia

Fig. 8 A 17-year-old male was followed for 46,XX true hermaphroditism. He was born with low shaft hypospadias and left inguinal hernia. He underwent left groin exploration and left inguinal hernia repair. At operation, the patient was noted to have an odd testicle which looked like a typical ovotestis. Two biopsied specimen were obtained: one revealed immature ovary containing numerous follicles and other a fragment of immature testicle containing seminiferous tubules. He was followed at age of 11. He had Tanner III gynecomastia, Tanner III-IV pubic hair, and Prader 5–8 cc volume testes that were somewhat irregular in size and firm. The LH and FSH were 3.2 and 21 m/ml (both were normal pubertal levels), respectively. A beta HCG was 30% e) Associated features: aniridia, genitourinary abnormalities f ) Mental retardation g) Associated aniridia: caused by deletion of the PAX6 gene in the 11p13 region in close proximity to WT1 gene ii. Denys–Drash syndrome a) Chromosomal loss: 11p13 b) Tumor suppressor gene: WT1 c) Mechanism of gene inactivation: mutation (DNA binding domain) d) Wilms’ tumor incidence: >90% e) Associated features: pseudohermaphroditism, mesangial sclerosis, renal failure iii. Beckwith–Wiedemann syndrome a) Chromosomal loss: 11p15 b) Tumor suppressor gene: (WT2/BWS) c) Mechanism of gene inactivation: unknown d) Wilms’ tumor incidence: 5% e) Associated features: organomegaly, hemihypertrophy, umbilical hernia,

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neonatal hypoglycemia, other tumors such as hepatoblastoma iv. Perlman syndrome a) Renal dysplasia b) Multiple congenital anomalies c) Gigantism d) Wilms’ tumor v. X-linked Simpson–Golabi–Behmel syndrome a) Overgrowth disorder b) Caused by mutations in the GPC3 gene located on Xq26 c) Overlapping physical features with Beckwith–Wiedemann syndrome d) Wilms’ tumor and other embryonal tumors 8. Primary tumors of the central nervous system (Martens 1994) a. Primitive neuroectodermal tumors (PNETs) i. Homozygous inactivation of the TP53 gene, a tumor-suppressor gene located in 17p, secondary to i(17p): implicated in the development of several tumor types ii. Molecular analyses indicating the existence of a second tumor-suppressor gene, distinct from and distal to the TP53 locus, that might be pathogenetically involved in a subset of primitive neuroectodermal tumors b. Gliomas i. A tumor suppressor gene in 22q implicated as an essential event in the genesis of a number of neurogenic neoplasms ii. A candidate for such a role is NF2, thought to be mutated in neurofibromatosis type 2, a dominantly inherited disorder predisposing for gliomas, neurinomas, and meningiomas

Clinical Features 1. Only retinoblastoma, neuroblastoma, and Wilms’ tumor will be discussed here. 2. Retinoblastoma (Martens 1994) a. The most common malignant ocular tumor in childhood and affects approximately 1 in 18,000 children under 5 years of age in the USA (Devesa 1975) b. A rare malignant tumor arising from cells of the embryonal neural retina

Chromosome Abnormalities in Pediatric Solid Tumors

c. Develops only in infants and young children d. Unifocal retinoblastoma: presence of a single retinoblastoma e. Multifocal retinoblastoma: presence of more than one tumor i. Unilateral: occurrence of multiple RB tumors in one eye ii. Bilateral: occurrence of RB tumors in both eyes iii. “Trilateral”retinoblastoma: occurrence of bilateral retinoblastoma plus a pinealoma f. Presenting signs i. White papillary reflex (leukocoria): the most common presenting sign ii. Strabismus: the second most common presenting sign iii. Less common signs a) Poor vision b) Orbital swelling c) Unilateral mydriasis d) Heterochromia iridis e) Glaucoma f ) Orbital cellulitis g) Uveitis h) Hyphema or vitreous hemorrhage i) Nystagmus g. Retinoma-associated eye lesions ranging from retinal scars to calcified phthisical eyes resulting from spontaneous regression of retinoblastoma (include benign retinal tumors called retinocytoma or retinoma) h. Patients with germline RB1 mutations: at an increased risk of developing tumors outside the eye i. Pinealomas ii. Osteosarcomas iii. Soft tissue sarcomas iv. Melanomas 3. Neuroblastoma (Davidoff and Hill 2001; Lee et al. 2003) a. The most frequently occurring solid tumor in children b. Responsible for 8–10% of all cancers in children and approximately 15% of all pediatric cancer deaths c. 40% of cases diagnosed in children under 1 year of age who have a very good prognosis d. 60% in older children and young adult who have a poor prognosis despite advanced medical and surgical management

Chromosome Abnormalities in Pediatric Solid Tumors

e. Amplification of MYCN gene found in neuroblastomas: i. A powerful prognostic indicator ii. Associated with: a) Advanced stages of disease b) Rapid tumor progression c) Poor outcome f. Clinical presentation i. Variable presentation a) Localized disease (one third to one fourth of cases) b) Metastatic disease (two third to three fourth of cases) c) Asymptomatic in small number of patients ii. Retroperitoneal and abdominal tumors (62–65%) a) A palpable mass b) Abdominal pain (34%) c) Weight loss (21%) d) Anorexia e) Vomiting f) Symptoms related to mass effect iii. Thoracic tumors (14%) a) Dysphagia b) Cough c) Respiratory distress iv. Pelvis (5%) and paraspinal tumors that compress the spinal cord a) Urinary dysfunction b) Constipation c) Fetal incontinence d) Lower extremity weakness v. Neck tumors a) Horner syndrome: present in patients with lesions in the cervical or upper thoracic sympathetic ganglia (1.7%) b) Airway distress vi. Liver metastasis a) Hepatomegaly b) Jaundice c) Abnormal liver function tests d) Abdominal pain vii. Bone metastases and bone marrow involvement a) Bone pain b) Palpable bony nodules c) Anemia d) Purpura

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viii. Fever (28%) ix. Lymph node metastases: palpable lymphadenopathy x. Retrobulbar and orbital metastases: periorbital ecchymoses xi. Severe diarrhea refractory to standard treatment due to production of vasoactive intestinal peptide by tumor cells (4%) xii. Acute cerebellar encephalopathy (2%) a) Cerebellar ataxia b) ”Dancing eyes and dancing feet syndrome” (involuntary eye fluttering and muscle jerking) c) Myoclonic jerks xiii. Symptoms related to high catecholamine levels (0.2%) a) Hypertension b) Palpitations c) Flushing d) Sweating e) Malaise f) Headache 4. Wilms’ tumor (Martens 1994) a. The most common kidney cancer in childhood b. Represents about 6% of all childhood cancers in the USA c. Clinical presentation i. Presence of an asymptomatic abdominal mass: the most common presentation a) Usually affects one kidney with multiple tumor foci in 8% of cases b) Bilateral in 6% of cases ii. Hypertension, gross hematuria, and fever observed in 5–30% of patients iii. Hypotension, anemia, and fever in a small number of patients who have hemorrhaged into their tumor iv. Rare respiratory symptoms related to the presence of lung metastases in patients with advanced-stage disease d. Association with congenital malformations i. Found in 60% of the bilateral cases and 4% of the unilateral cases ii. WAGR iii. Denys–Drash syndrome iv. Beckwith–Wiedemann syndrome v. Perlman syndrome vi. Beckwith–Wiedemann syndrome

362

Chromosome Abnormalities in Pediatric Solid Tumors

vii. X-linked Simpson–Golabi–Behmel syndrome e. Likelihood of developing Wilms’ tumor in aniridia patients i. Aniridia patients without other anomalies: 1–2% ii. Aniridia patients with WAGR syndrome: 25–40%

Diagnostic Investigations 1. Cytogenetic and molecular genetic techniques used in analyzing tumor materials from patients (Cooley et al. 2009) a. Conventional and molecular cytogenetic techniques most commonly used (Varella-Garcia 2003) i. Metaphase cytogenetics or karyotyping (G-, Q-, and R-bandings): a) Protein digestion and/or special dye generating banding pattern specific for each chromosome b) Identification of numerical and structural chromosomal anomalies ii. Fluorescence in situ hybridization (FISH) a) A small, labeled DNA fragment used as a probe to search for homologous target sequences in chromosome or chromatin DNA b) Identification of the presence, number of copies per cell, and localization of probe DNA c) Applicable to interphase cells iii. Comparative genomic hybridization (CGH) a) Comparative hybridization of differentially labeled total genomic tumor DNA and normal reference DNA to normal human metaphases used as templates b) Detection of variant DNA copy numbers at the chromosome level c) Applicable to fresh or preserved specimens iv. Multicolor karyotyping (M-FISH, SKY) a) Hybridization with 24 differentially labeled, chromosome-specific probes allowing the painting of every human chromosome in a distinct color

b) Detection of rearrangements involving one or more chromosomes within individual metaphase spreads c) Accurate origin identification of all segments in complex rearrangements d) Clarification of marker chromosomes b. Other techniques i. Flow cytometry ii. Reverse transcriptase-polymerase chain reaction (RT-PCR) iii. Quantitative PCR iv. Southern blot analysis of gene rearrangements v. Loss of heterozygosity analysis (LOH) vi. Restriction landmark genome scanning vii. Representational difference analysis viii. cDNA gene expression microarrays ix. Proteomic methods a) Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) b) Surface enhanced laser desorption ionization-time of flight (SELDI-TOF) 2. Cytogenetic studies in retinoblastoma a. Cytogenetically visible changes of 13q14: infrequent in retinoblastoma b. Deletions or unbalanced translocations leading to loss of 13q14 band (10%) c. Monosomy 13 (10%) d. i(6p), mostly detected as a supernumerary isochromosome (one third of cases) e. Gain of 1q material (one third of cases) f. Cytogenetic aberrations in retinoblastoma i. Secondary to RB1 mutations ii. More related to tumor progression than to tumor establishment 3. Other studies for retinoblastoma a. Indirect ophthalmoscopy to examine the fundus of the eye to detect retinomas, preferably by a retinal specialist b. Imaging studies (CT, MRI, ultrasonography) to support the diagnosis and stage the tumor c. Histopathological examination to confirm the diagnosis d. Direct DNA testing of the RB1 gene in WBC DNA i. Identify a germline mutation in about 80% of individuals with a hereditary predisposition to retinoblastoma

Chromosome Abnormalities in Pediatric Solid Tumors

ii. Probability of detection of the RB1 gene mutation in an index case dependent on the following: a) Whether the tumor is unifocal or multifocal b) Whether the family history is positive or negative c) The sensitivity of the testing methodology 4. Cytogenetic studies in neuroblastoma (Davidoff and Hill 2001; Lee et al. 2003) a. Identification of multiple cytogenetic abnormalities in neuroblastoma i. Allelic losses on chromosomes 1p (particularly 1p36), 11q, 14q, 7q, 2q, 3p, and 19q ii. Allelic gains on chromosomes 17q, 18q, 1q, 7q, and 5q b. Hyodiploid, triploid, or “near triploid”, or “neartetraploid” in modal chromosome number i. Majority (55%) with triploid or “near-triploid” (a chromosome number between 58 and 80) ii. Remainder with “near-diploid” (35–57 chromosomes) or “near-tetraploid” (81–103 chromosomes) c. Frequent partial 1p monosomy (70–80% of cases) with most commonly deleted region being between 1p32 and 1p36 d. Gain on the long arm of chromosome 17 (17q) i. Probably the most common genetic abnormality in neuroblastomas ii. Occurring in approximately 75% of primary tumors iii. Most often resulting from an unbalanced translocation of this region to other chromosomal sites, most frequently 1p or 11q iv. A powerful independent finding of adverse outcome e. Deletions of the long arms of chromosomes 11 (11q) and 14 (14q) i. Appears to be common in neuroblastomas ii. Both inversely related to MYCN amplification f. Frequent presence of extrachromosomal double minute chromatin bodies (DMs) or homogeneously staining regions (HSRs)

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i. Cytogenetic evidence of gene amplification ii. Amplified region derived from the distal short arm of chromosome 2 (2p24) that contains the MYCN proto-oncogene 5. Other studies for neuroblastoma a. Imaging studies i. Chest radiography ii. Ultrasound iii. CT iv. MRI v. Radionucleotide bone scan b. Blood tests i. Elevated urinary and serum catecholamine metabolites a) Homovanillic acid (HVA) b) Vanillylmandelic acid (VMA) ii. Abnormal liver function tests c. Molecular genetic testing (Castel et al. 2007) i. Array CGH analysis: a pangenomic technique allowing insights into gains and losses with high resolution ii. Multiplex ligation-dependent probe amplification (MILPA) 6. Cytogenetic studies in Wilms’ tumor a. A near-diploid chromosome count b. Triploid-tetraploid karyotypes in a few cases with tendency to have an anaplastic morphology c. Numerical aberrations i. Mainly involving gains of chromosomes a) Trisomy 12: particularly frequent b) Followed by trisomies 8, 6, 7, 13, 20, and 17 d. Structural rearrangements i. Involve all chromosomes except the Y chromosome ii. Recombinations of 11p (>20%) a) Vast majority of the breakpoints assigned to 11p13 and 11p15, indicating these loci are important in sporadic Wilms’ tumor b) Loss of heterozygosity studies indicating that alleles from 11p13 and 11p15 are often lost in Wilms’ tumor iii. Loss of the long arm of chromosome 16 occurring in about 20% of Wilms’ tumors: associated with poor prognosis independent of stage or tumor histology

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7. Other studies in Wilms’ tumor a. Renal ultrasound to monitor Wilms’ tumor b. Abdominal CT scanning to determine the tumor’s origin, lymph node involvement, bilateral kidney involvement, and invasion into major vessels (e.g., inferior vena cava or liver metastases) c. Chest radiography to detect lung metastases d. Histopathological examination to confirm the diagnosis e. Further studies of certain patients with either Wilms’ tumor or associated anomalies (Coppes and Egeler 1999) i. Hemihypertrophy/Beckwith–Wiedemann syndrome: uniparental disomy studies to evaluate constitutional or somatic alterations of 11p15 ii. WAGR syndrome: molecular evaluation of the 11p13 region if chromosomal studies do not reveal a deletion a) Fluorescence in situ hybridization (FISH) b) Pulsed-field electrophoresis iii. Denys–Drash syndrome: molecular evaluation of WT1 to determine whether the patient indeed carries a constitutional mutation. If the mutation is present, family members need to be screened. iv. Aniridia a) Cytogenetic analysis and molecular evaluation of the WAGR region by FISH or pulsed field to rule out contiguous deletion of Pax6 and WT1 b) No further screening for Wilms’ tumor if Pax6 mutation is identified in isolated cases of aniridia 8. Cytogenetic studies of primary tumors of the central nervous system (Martens 1994) a. Primitive neuroectodermal tumors i. Near-diploid in most tumors ii. I(17q): the most consistent rearrangement b. Gliomas i. Mostly astrocytomas and ependymomas ii. No specific structural rearrangement found iii. Loss of 1p and gain of 1q found in a subset of tumors iv. Loss of chromosome 22 common in childhood gliomas

Chromosome Abnormalities in Pediatric Solid Tumors

v. Loss of material from chromosome 22, either numeric or structural aberrations, found recurrently in rhabdoid tumors, meningiomas, and neurinomas 9. Cytogenetic studies in hepatoblastoma (Mertens et al. 1994) a. Trisomy 2 or duplications of part of 2q: detected in half of the cases b. Trisomy 20 c. Duplication of 8q through either i(8q) formation or trisomy 8 10. Cytogenetic studies in sarcomas a. Ewing sarcoma/primitive neuroectodermal tumor (Davidoff and Hill 2001) i. Reciprocal translocation t(11;22)(q24;q12) a) Characteristic primary rearrangement b) Found in nearly 90% of the tumors c) Causing a fusion of the transcription factor gene FLI1 on chromosome 11 with EWS on chromosome 22 (FLI1EWS, a fusion transcript). Only the chimeric gene expresses on the derivative chromosome 22 which contains a sequence encoding a DNA-binding domain from FLI1 ii. t(21;22)(q22;q12), ERG-EWS iii. t(7;22)(p22;q12), ETV1-EWS iv. t(17;22)(q12;q12), E1AF-EWS v. t(2;22)(q33;q12), FEV-EWS b. Additional chromosome changes i. Trisomy 8 ii. Der(16)t(1;16)(a10-q21;q10-13), leading to gain of 1q and loss of 16q c. Congenital or infantile fibrosarcoma (Mertens et al.1994) i. t(12;15)(p13;q25), ETV6-NTRK3 ii. Hyperdiploid with few or no structural rearrangements iii. Nonrandom numerical changes a) Trisomies 11 and 20, the most frequent changes, followed by: b) Trisomies 17 and 8 d. Osteosarcoma (Mertens et al. 1994) i. Highly complex karyotypes in the majority of cases ii. Chromosome number in the triploidtetraploid range iii. Most common numeric aberrations involving
3,
10,
13, and
15

Chromosome Abnormalities in Pediatric Solid Tumors

iv. Structural rearrangements involving chromosome arms 1p, 1q, 3p, 3q, 7q, 11p, 17p, and 22q v. Presence of many undefined chromosome markers e. Rhabdomyosarcoma (Mertens et al. 1994) i. The most common soft tissue sarcoma in childhood ii. Alveolar subtype a) Most contain 1 or 2 recurring translocations, namely, t(2;13)(q35-37; q14) or the rare t(1;13)(p36;q14), shown to juxtapose the PAX3 gene on chromosome 2 with the FKHR gene on chromosome 13, leading to the formation of a hybrid transcription factor (PAX3-FKHR) b) Found in about 70% of the alveolar tumors c) Only occasionally described in other subtypes iii. Embryonal subtype: numerical changes with +2, +8, +11, and +20, found in 35–50% of cases 11. Other common, recurrent translocation in solid and soft tissue tumors of childhood (Davidoff and Hill 2001) a. Alveolar soft part sarcoma: t(X;17)(p11;q25), ASPL-TFE3 b. Inflammatory myofibroblastic tumor: 2p23 translocations, ALK-TPM3 c. Desmoplastic small round cell tumor i. t(11;22)(p13;q12), WT1-EWS ii. t(11;22)(q24;q12), FLI1-EWS, ERG-EWS d. Synovial sarcoma i. t(X;18)(p11.23;q11.2), SSX1-SSXT ii. t(X;18)(p11.21;q11), SSX2-SSXT e. Malignant melanoma of soft part (clear cell sarcoma): t(12;22)(q13;q12), ATF1-EWS f. Myxoid liposarcoma i. t(12;16)(q13;p11), CHOP-TLS(FUS) ii. t(12;22)(q13;q12), CHOP-EWS g. Extraskeletal myxoid chondrosarcoma: t(9;22) (q22;q12), CSMF-EWS h. Dermatofibrosarcoma protuberans and giant cell fibroblastoma: t(17;22)(q22;q13), COLIAIPDGFB i. Lipomas: t(var;12)(var;q13-15), var, HMGI-C (Cooper 1996)

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j. Leiomyomas: t(12;14)(q13;15), HMGI-C, (Cooper 1996) 12. Other primary chromosome changes in solid tumors (Sandberg 1988) a. Benign tumors i. Meningioma and acoustic neuroma a)
22 b) 22q
ii. Mixed tumors of salivary glands a) t(3;8)(p21;q12) b) t(9;12)(p13-22;q13-15) iii. Colonic adenomas a) 12q
and/or +7 b) 12q
and/or +8 iv. Cortical adenoma of the kidney a) +7 b) +17 c)
Y b. Adenocarcinomas i. Bladder a) i(5p) b) +7 c)
9/9q
d) 11p
ii. Prostate: del(10)(q24) iii. Lungs (small cell carcinoma): del(3) (p14p23) iv. Colon a) 12q
b) +7 c) +8 d) +12 e) 17(q11) f) 17p– v. Kidney: del(3)(p11p21) vi. Uterus: 1q
vii. Ovary a) 6q
b) t(6;14)(q21;q24) viii. Endometrium a) Trisomy 1q b) +10 c. Embryonal and other tumors i. Testicular (germ cell tumors): i(12p) ii. Malignant melanoma a) Del(6)(q11q27) b) i(6p) c) Del(1)(p11p22) d) t(1;19)(q12;q13)

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iii. Mesothelioma: del(3)(p13p23) iv. Glioma:
22 13. Potential prognostic markers of neoplastic disease (Barcus et al. 2000) a. Breast cancer: allelic loss at 1p22-p31 (lymph node metastasis and tumor size >2 cm) b. Bladder cancer i. LOH RB (high grade/muscle invasion) ii. Genomic alterations (2q
, 5p+, 5q
, 6q
, 8p
, 10q
, 18q
, 20q+) (higher grade) c. Cervical carcinoma: LOH on chromosome (advanced stage) d. Colorectal cancer i. LOH at 18q21 or p53 expression (recurrence/poor survival) ii. MSI (microsatellite instability)and K-ras mutations in normal appearing colonic mucosa (predictive of colorectal cancer) iii. P16-hypermethylation (shorter survival in Stage T3N0M0 tumors) e. Gastric cancer i. LOH p53 (invasive disease) ii. LOH of 7q (D7S95) (poor prognosis (in Stage III/IV)) f. Glioma: chromosome 22q loss (astrocytomas progression) g. Head and neck squamous cell carcinoma i. LOH of 14q (poor outcome) ii. LOH on 2q (poor prognosis) iii. LOH on 17p (chemoresistance) h. Melanoma: LOH in plasma (advanced stage/ tumor progression) i. Neuroblastoma i. N-myc amplification (poor prognosis) ii. TrkA expression (good prognosis) iii. High telomerase expression (aggressive behavior) j. Neuroblastomas, 4s-: N-myc amplification, 1p deletion, 17q gains, elevated telomerase activity (poor prognosis) k. Non-small cell lung cancer i. Allelic imbalances on 9p (poor prognosis) ii. LOH 11p (poor prognosis) l. Primitive neuroectodermal tumor i. LOH of 17p (metastatic disease) ii. C-myc amplification (poor prognosis) m. Prostate cancer: LOH on 13q (advanced stage) n. Retinoblastoma: LOH at RB1 locus (tumoral differentiation, absence of choroidal invasion)

Chromosome Abnormalities in Pediatric Solid Tumors

14. Chromosome abnormalities observed in some solid tumors (Cooley et al. 2009) a. Genitourinary i. Renal a) Clear cell round cell carcinoma (RCC):
3 or del(3p), del(3p) with gain 5q, del(3p) with loss 5q,
14/del (14q) b) Papillary RCC: +7, +17,
Y, 9p
c) t(Xp11.2) RCC: (X;17)(p11.2;q25), t (X;17) (p11.2;q23), t(X;1)(p11.2;p34) d) t(6;11) RCC: t(6;11)(p21;q12) e) Chromophobe RCC: loss 1, 2, 6, 10, 13, 17, 21 f) Oncocytoma: 1p
, t(11q13) g) Rabdoid:
22/22q
h) Congenital mesoblastic nephroma: t (12;15)(p12;q25), +11, +17, +20 ii. Bladder, papillary: del(9)(p21), 8p
, +7, +17 iii. Wilms’ tumor: 16q
, +1q, 1p
,
22, 17p
iv. Prostate: +17q31, 8p22
, +8q24, 10q
, 17p13
b. Gastrointestinal i. Liver a) Hepatoblastoma: +20, +2, +8, t (1q12q21) b) Hepatic mesenchymal hamartoma: t(11;19)(q13;q13.4), t(19q13.4) ii. Salivary gland a) Pleomorphic adenoma: t(3;8)(p21; q12) b) Mucoepidermoid cancer: t(11;19) (q21;p13) c) Warthin tumor: t(11;19)(q21;p13) c. Breast i. Invasive intraductal: dmin (double minute), hsr (homogeneously staining region) ii. Secretory breast: t(12;15)(p13;q25) d. CNS i. Astrocytic tumors: +7,
10/10q
, 9p21
, 19q
ii. Glioblastoma: +7, 10q
, 9p
iii. Anaplastic: 1p
, 19q
, der(1;19)(q10; p10) iv. Mixed oligoastocytoma: +7,
10/10q
, 15q
v. Oligoastrocytoma: 19q
, 1p


Chromosome Abnormalities in Pediatric Solid Tumors

e. Ependymoma i. Spinal: +7,
22q, 14q
ii. Intracranial: +1q, 6q
, +7, 9p
f. Mudulloblastoma: i(17q), 17p
,
10/10q
, +7 g. Supratentorial primitive neuroectodermal tumor +1q, 16q
, 19p
h. Atypical teratoid/rhabdoid tumor:
22 or del (22q11.23) i. Meningioma:
22 or del(22q11.2), 1p
,
14/ 14q
j. Choroid plexus tumors i. Carcinoma: loss 2, 3, 4, 5, 6, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 22 ii. Papilloma: gain 7, 8, 9, 12, 14, 15, 17, 18, 19, 20 k. Small round cell tumors i. Alveolar RMS: t(2;13)(q37;q14), t(1;13) (p36;q14), t(X;2)(q13lq35); t(2;2)(q35; p23) ii. Embryomal rhabdomyosarcoma: gain 2, 7, 8, 11, 12, 13, 20; loss 1p, 3p, 9q, 10q, 16q, 17p, 22 iii. Neuroblastoma: del(1p), del(11q) w/o MYCN amp, del(1p), +17q, MYCN amp, triploidy w/o above abnormalities iv. Ewing sarcoma/peripheral neuroectodermal tumor: t(11;22)(q24;q12) & variants, t(21;22)(q22;q12), del(9p), 17p
, der(1;16)(q10;p10) v. Desmoplastic small round cell tumor: t (11;22)(p13;q12) vi. Clear cell sarcoma: t(12;22)(q13;q12) vii. Retinoblastoma: del(13q14), gain 1q, 6p viii. Lymphomas: Specific translocations l. Bone, soft tissue i. Congenital fibrosarcoma/congenital mesoblastic nephroma: t(12;15)(p12; q25), +11, +17, +20 ii. Synovial sarcoma: t(X;18)(p11.2;q11.2) iii. Lipoma: t(3;12)(q27–28;q14–15), variants iv. Liposarcoma a) Myxoid, round cell: t(12;16)(q13;p11) b) Myxoid: t(12;22)(q13;q12), variant c) Well differentiated: rings, markers, dmin m. Leiomyoma: t(12;14)(q15;q24) i. Alveolar soft part sarcoma: der(17)t(X;17) (p11.2;q25)

367

n.

o. p. q.

ii. Extraskeletal myxoid chondrosarcoma: t (9;22)(q22;q12), t(9;17)(q22;q11.2), t (9;15)(q22;q21), t(3;9)(p11;q22) Dermal tumors i. Dermatofibrosarcoma protuberans: der (22)t(17;22)(q22;q13.1) or r(22)t(17;22) ii. Giant cell fibroblastoma: t(17;22)(q22; q13.1) iii. Bednar tumor: der (22)t(17;22) (q22; q13.1) or r(22)t(17;22) iv. Hidradenoma: t(11;19)(q21;p13) Non-small cell lung cancer: 3p
, +7, EGFR high copy number or amplification Dysgerminoma, ovary: i(12p), 12p overrepresentation Testicular germ cell tumors, seminoma, nonseminoma: i(12p), 12p amplification

Genetic Counseling 1. Recurrence risk a. Retinoblastoma i. Predisposition to retinoblastoma which is caused by germline mutations in the RB1 gene: transmitted in an autosomal dominant fashion ii. Use RB1 mutation analysis to clarify the genetic status of at-risk sibs and offspring when a previously characterized germline cancer-predisposing mutation is available iii. Use indirect testing using polymorphic loci linked to the RB1 gene in some families to clarify genetic status of at-risk family members if RB1 direct DNA testing is not available or is uninformative iv. Use empiric recurrence risk estimates in all families in which direct DNA testing of RB1 and linkage analysis are unavailable or uninformative v. Risk to patient’s siblings a) When there is an existing family history: a 45% chance for siblings of bilaterally affected cases and a 30% chance for siblings of unilaterally cases to develop disease b) When there is absence of any family history: 2% risk for siblings of bilaterally

368

affected cases and 1% for siblings of unilaterally affected cases to develop disease c) There is an additional risk to siblings in the absence of any family history or documented mutation in parental leukocyte DNA because of germline mosaicism. If neither parent has the cancerpredisposing RB1 germline mutation that was identified in the index case, germline mosaicism in one parent is possible and the risk to each sib of having retinoblastoma is 3–5%. d) If the index case has mosaicism for an RB1 cancer-predisposing mutation (the mutation arose as a post-zygotic event) and that neither parent has an RB1 germline mutation, the risk to the sibs is not increased and thus it is not warranted to test the sibs for the RB1 mutation identified in the index case. vi. Risk for patient’s offspring a) About 45% by the age 6 years (consistent with an autosomal dominant inheritance with 90% penetrance) for the offspring of survivors of hereditary (multifocal, bilateral) retinoblastoma b) About 2.5% for the offspring of survivors of unilateral retinoblastoma c) The low (1%), but not negligible, risk to the offspring of index cases with unifocal disease and a negative family history reflects the possibility of a germline RB1 mutation with low penetrance or mutational mosaicism. b. Genetic counseling for retinoblastoma in the presence of positive family history (Vogel 1979; Isidro et al. 2011) i. Multiplex disease (>2 affected members): The index patient had retinoblastoma and one or more close relatives are also affected a) Affected individuals definitely carry a germline mutation b) A 50% chance exists that a known carrier will pass the mutant copy of the retinoblastoma gene to each child and there is 50% penetrance, there is a 50%  90% ¼ 45% chance that each child will develop retinoblastoma

Chromosome Abnormalities in Pediatric Solid Tumors

ii. Multiplex disease (>2 affected members): The index patient did not develop retinoblastoma as a child but a parent is known to be a carrier a) Approximately 10% risk that an asymptomatic son or daughter of a known carrier is also a carrier b) The risk that his or her offspring will inherit a mutation is about 5% and the risk of the disease is 90%  5% ¼ 4.5% iii. Simplex disease (only one family member affected): The index patient had multifocal retinoblastoma a) The patient very likely has a germline mutation b) The risk to each offspring is 50% for being a carrier and 45% for developing the disease iv. Simplex disease (only one family member affected): The index patient had unifocal retinoblastoma (one tumor in one eye only) a) A 12% risk exists that the patient carries a germline mutation (i.e., has hereditary retinoblastoma) and an 88% risk that he or she does not (nonhereditary retinoblastoma) b) The risk for the first child of the index patient is 6% for being a carrier and 5.4% for developing the disease c) If the first child does not develop retinoblastoma, the risk for the next child is less d) If at least one child develops retinoblastoma, the index patient definitely has the hereditary type of the disease and risk for family members are as described for mutiplex families v. Simplex disease (only one family member affected): Two unaffected parents have one child with retinoblastoma a) The risk of the parents’ second child’s developing retinoblastoma is about 1% if the first child had unifocal disease and about 6% if the first child had multifocal disease b) These risks decrease with every unaffected child that passes the years of highest risk (year 0–5) without developing the disease

Chromosome Abnormalities in Pediatric Solid Tumors

vi. Simplex disease (only one family member affected): The index patient is an adult of childbearing age who did not develop retinoblastoma but a sibling had retinoblastoma a) A small risk exists that one of the parents is an asymptomatic carrier and the index patient is also an asymptomatic carrier b) The carrier risk for the index patient is 0.1% if the affected sibling had unilateral retinoblastoma and 0.6% if the affected sibling had bilateral retinoblastoma c) The risk that the first child of the index patient will develop retinoblastoma is approximately half of these numbers, i.e., 0.05% or 0.3%, respectively c. Neuroblastoma i. Risk for patient’s sibling: low unless a parent has hereditary form of neuroblastoma ii. Risk for patient’s offspring: 50% d. Wilms’ tumor i. Risk for patient’s sibling: low unless a parent has hereditary form of Wilms’ tumor ii. Risk for patient’s offspring: 50% 2. Prenatal diagnosis a. Retinoblastoma i. Prenatal testing possible if the germline RB1 mutation in the parent is known or if RB1 linkage analysis is informative in the family ii. Mutation analysis on fetal DNA obtained from amniocentesis or CVS iii. Use prenatal ultrasonography to detect intraocular tumors if the disease-causing RB1 mutation is identified in the fetus b. Adrenal neuroblastoma (Kesrouani et al. 1999) i. Prenatal diagnosis adrenal neuroblastoma by ultrasonography usually made in the 3rd trimester ii. Sonographic appearance of the adrenal neuroblastoma varies a) Solid b) Purely cystic (50%) c) Mixed echo pattern (related to necrosis, hemorrhage, or spontaneous tumoral involution) d) Fetal hydrops

369

e) Hydropic placenta with metastases in the placenta iii. Needle biopsy for selection of the group with favorable biological parameters (N-myc, DNA index) iv. Frequently producing catecholamines and hence maternal symptoms could aid the diagnosis v. Elevated catecholamines in the amniotic fluid c. Wilms’ tumor by prenatal ultrasonography i. A solid echogenic mass with a clearly defined capsule ii. Areas of hemorrhage and necrosis may be seen within the mass. 3. Management a. Surgeries for most solid tumors b. Determining the genetic changes present in the tumor of an individual patient: becoming increasingly important for managing the oncology patient c. Retinoblastoma (Chintagumpala et al. 2007) i. Goals of treatment: preservation of sight and life ii. Management of intraocular disease a) Enucleation b) External beam radiation (EBR) therapy c) Brachytherapy: involves the placement of a radioactive implant d) Thermotherapy e) Chemothermotherapy f) Laser photocoagulation g) Cryotherapy h) Chemotherapy iii. Management of extraocular disease: Patients with extraocular disease, having a very poor prognosis with respect to survival, may benefit from a combination of conventional chemotherapy and EBR and those with distant metastatic disease may benefit from high-dose chemotherapy and EBR in conjunction with bone marrow stem cell transplantation d. Neuroblastoma (Lee et al. 2003) i. Localized, low-risk disease: a) Primary curative surgery b) Minimal therapy: low-dose radiation or chemotherapy c) Supportive care with surveillance

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ii. Intermediate-risk patients: combination therapy with radiation, chemotherapy, and surgery iii. High-risk patients a) Combination of radiation, myeloablative chemotherapy, and surgery (delayed) b) Autologous bone marrow transplant c) Research protocols e. Wilms’ tumor: The usual approach in most patients is nephrectomy followed by chemotherapy with or without postoperative radiotherapy.

References Aerts, I., Lumbroso-Le Rouic, L., Gauthier-Villars, M., et al. (2006). Retinoblastoma. Orphanet Journal of Rare Diseases, 1, 31–41. Albertson, D. G., Collins, C., McCormick, F., et al. (2003). Chromosome aberrations in solid tumors. Nature Genetics, 34, 369–376. Barcus, M. E., Ferreira-Gonzalez, A., Buller, A. M., et al. (2000). Genetic changes in solid tumors. Seminars in Surgical Oncology, 18, 358–370. Bennicelli, J. L., & Barr, F. G. (1999). Genetics and the biologic basis of sarcomas. Current Opinion in Oncology, 11, 267–274. Brodeur, G. M., Maris, J. M., Yamashiro, D. J., et al. (1997). Biology and genetics of human neuroblastomas. Journal of Pediatric Hematology/Oncology, 19, 93–101. Carlson, E. A., & Desnick, R. J. (1979). Mutational mosaicism and genetic counseling in retinoblastoma. American Journal of Medical Genetics, 4, 365–381. Castel, V., Grau, E., Noguera, R., et al. (2007). Molecular biology of neuroblastoma. Clinical and Translational Oncology, 9, 478–483. Cavenee, W. K., Dryja, T. P., Phillips, R. A., et al. (1983). Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 305, 779–784. Chintagumpala, M., Chevez-Barrios, P., Paysse, E. A., et al. (2007). Retinoblastoma: Review of current management. The Oncologist, 12, 1237–1246. Clericuzio, C. L., & Johnson, C. (1995). Screening for Wilms tumor in high-risk individuals. Hematology/Oncology Clinics of North America, 9, 1253–1265. Cooley, L. D., Mascarello, J. T., Hirsch, B., et al. (2009). Section E6.5 of the ACMG technical standards and guidelines: Chromosome studies for solid tumor abnormalities. Genetics in Medicine, 11, 890–897. Cooper, C. S. (1996). Translocations in solid tumours. Current Opinion in Genetics and Development, 6, 71–75. Coppes, M. J., & Egeler, R. M. (1999). Genetics of Wilms tumor. Seminars in Urologic Oncology, 17, 2–10. Davidoff, A. M., & Hill, D. A. (2001). Molecular genetic aspects of solid tumors in childhood. Seminars in Pediatric Surgery, 10, 106–118.

Chromosome Abnormalities in Pediatric Solid Tumors Devesa, S. S. (1975). The incidence of retinoblastoma. American Journal of Ophthalmology, 80, 263–265. Draper, G. J., Sanders, B. M., Brownbill, P. A., et al. (1992). Patterns of risk of hereditary retinoblastoma and applications to genetic counseling. British Journal of Cancer, 66, 211–219. Esparza, S. D., Sakamoto, K. M., Mitton, B., et al. (2009). Childhood cancer, genetics. eMedicine from WebMD. Retrieved February 27, 2009. Available at: http:// emedicine.medscape.com/article/989983-overview Heim, S., & Mitelman, R. (1989). Primary chromosome abnormalities in human neoplasia. Advances in Cancer Research, 52, 1–43. Heim, S., & Mitelman, F. (1992). Cytogenetics of solid tumours. Recent Advances in Histopathology, 15, 37–66. Horsthemke, B. (1992). Genetics and cytogenetics of retinoblastoma. Cancer Genetics and Cytogenetics, 63, 1–7. Isidro, M. A., Roque, M. R., Aaberg, T. M. J., et al. (2011). Retinoblastoma. Medscape Reference. Updated April 29, 2011. Available at: http://emedicine.medscape.com/article/ 1222849-overview Karnes, P. S., Tran, T. N., Cui, M. Y., et al. (1992). Cytogenetic analysis of 39 pediatric central nervous system tumors. Cancer Genetics and Cytogenetics, 59, 12–19. Kesrouani, A., Duchatel, F., Seilanian, M., et al. (1999). Prenatal diagnosis of adrenal neuroblastoma by ultrasound: A report of two cases and review of the literature. Ultrasound in Obstetrics & Gynecology, 13, 446–449. Knudson, A. G. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proceedings of National Academy Science USA, 68, 82–823. Lee, K. L., Ma, J. F. & Shortliffe, L. D. (2003). Neuroblastoma: Management, recurrence, and follow-up. Urologic Clinics of North America, 30, 881. http://emedicine.medscape.com/ article/988284-overview Lohmann, D. R., & Gallie, B. L. (2010). Retinoblastoma. GeneReviews. Updated June 10, 2010. Available at: http:// www.ncbi.nlm.nih.gov/books/NBK1452/ Maris, J. M., & Matthay, K. K. (1999). Molecular biology of neuroblastoma. Journal of Clinical Oncology, 17, 2264–2279. Mertens, F., Mandahl, N., Mitelman, F., et al. (1994). Cytogenetic analysis in the examination of solid tumors in children. Pediatric Hematology and Oncology, 11, 361–377. Mitelman, F., Johansson, B., & Mertens, F. (Eds.) (2008). Mitelman database of chromosome aberrations in cancer. National Cancer Institute. Cancer Genome Anatomy Project. http://cgap.nci,nih.gov/Chromosomes/ Mitelman Pakakasama, S., & Tomlinson, G. E. (2002). Genetic predisposition and screening in pediatric cancer. Pediatric Clinics of North America, 49, 1393–1413. Palmer, A., Zografos, L., & Munier, F. (2006). Diagnosis and current management of retinoblastoma. Oncogene, 25, 5341–5349. Pappo, A. S., Rodriguez-Galindo, C., Dome, J. S., et al. (2000). Pediatric tumors. In: Abeloff: Clinical Oncology, (2nd ed., pp. 2346–2401), Chapter 80. Churchill Livingstone. Paulino, A. C., & Coppes, M. J. (2000). Wilms tumor. eMedicine from WebMD. Retrieved May 3, 2009. Available at: http:// emedicine.medscape.com/article/989398-overview

Chromosome Abnormalities in Pediatric Solid Tumors Quesnel, S., & Malkin, D. (1997). Genetic predisposition to cancer and familial cancer syndromes. Pediatric Clinics of North America, 47, 791–808. Rowland, J. M. (2002). Molecular genetic diagnosis of pediatric cancer: Current and emerging methods. Pediatric Clinics of North America, 49, 1415–1435. Sandberg, A. A. (1988). Chromosomal lesions and solid tumors. Hospital Practice October, 15, 93–106. Sandberg, A. A., & Turc-Carel, C. (1987). The cytogenetics of solid tumors. Relation to diagnosis, classification and pathology. Cancer, 59, 387–395. Schwab, M., Westermann, F., Hero, B., et al. (2003). Neuroblastoma: Biology and molecular and chromosomal pathology. The Lancet Oncology, 4, 472–480. Sippel, K. C., Faioli, R. E., Smith, G. D., et al. (1998). Frequency of somatic and germ-line mosaicism in retinoblastoma:

371 Implications for genetic counseling. American Journal of Human Genetics, 62, 610–619. Stanbridge, E. J. (1992). Functional evidence for human tumour suppressor genes: Chromosome and molecular genetic studies. Cancer Surveys, 12, 5–24. Vadeyar, S., Ramsay, M., James, D., et al. (2000). Prenatal diagnosis of congenital Wilms’ tumor (nephroblastoma) presenting as fetal hydrops. Ultrasound in Obstetrics & Gynecology, 16, 80–83. Varella-Garcia, M. (2003). Molecular cytogenetics in solid tumors: laboratorial tool for diagnosis, prognosis, and therapy. The Oncologist, 8, 45–58. Vogel, F. (1979). Genetics of retinoblastoma. Human Genetics, 1, 1–54.

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Fig. 1 Notice the white firm neoplasm (retinoblastoma) filling the vitreous space of the eye

Fig. 2 Large, well-circumscribed ovoid Wilms tumor in the upper pole of the kidney. Barely identifiable small areas of hemorrhage and necrosis are present

Chromosome Abnormalities in Pediatric Solid Tumors

Chromosome Abnormalities in Pediatric Solid Tumors Fig. 3 Karyotype of a patient with Wilms tumor showing 46, XY,der(11)(p11.2q13.5)del (11)(p13p15.1)

Fig. 4 Note a lobulated meningioma encroaching the brain at the inferior surface of left frontal lobe

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374 Fig. 5 (a, b) Karyotypes of two patients with meningioma showing 46,XX,del(22)(q12) (the first picture) and 44,XX, del(7)(q32q36),-11,der(14)t (11;14)(q12;p11),-22 (the second picture), respectively

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Fig. 6 Neuroblastoma smear. Note the anaplastic neuroblastic cells mixed with blood

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Fig. 7 N-MYC amplification in a patient with neuroblastoma. Gross copy number of the orange signal is noted (LSI® N-MYC (2p24.1) SpectrumOrange TM probe)

Cleft Lip and/or Cleft Palate

Cleft lip and/or palate (CL/CP) is the most common craniofacial malformation with an estimated incidence of approximately 1 in 700 to 1 in 1,000 live births among Caucasians. (Carinci et al. 2000). CL/CP may occur as an isolated finding or may be found in association with other congenital malformations.

Genetics/Basic Defects 1. Environmental agents (De La Pedraja et al. 2000) a. Cleft lip and cleft palate i. Alcohol ii. Anticonvulsants (phenytoin, sodium valproate) iii. Isotretinoin iv. Steroids v. Methotrexate vi. Maternal infections in the first trimester a) Rubella b) Toxoplasmosis vii. Maternal smoking b. Isolated clefts i. Little evidence linking to any single teratogenic agent, except anticonvulsant phenytoin ii. Use of phenytoin during pregnancy is associated with a tenfold increase in the incidence of cleft lip c. Cleft lip: Incidence of cleft lip in infants in mothers who smoke during pregnancy is twice that of those born to nonsmoking mothers 2. Genetic factors a. Syndromic clefts associated with malformations involving other developmental regions

i. About 25% of neonates with CL/CP show associated malformations, syndromes or aneuploidy (Berge et al. 2001) ii. Van der Woude syndrome: the most commonly recognized syndrome associated with CL/CP, an autosomal dominant disorder characterized by CL/CP and blind sinuses or pits of the lower lip iii. Microdeletion of chromosome 22q11.2 (velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome): currently the most common syndromic diagnoses among patients with clefts of the secondary palate alone iv. Other syndromes associated with clefts of the secondary palate alone: a) Stickler syndrome b) Ectrodactyly–ectodermal clefting (EEC) syndrome c) Popliteal pterygium syndrome b. Nonsyndromic cleft of the lip and/or palate (Carinci et al. 2000) i. An embryopathy derived from failure in fusion of the nasal process and/or palatal shelves ii. Genetic factors play an important role in the etiology of cleft lip and/or palate since one in five patients in different populations has a positive family history of CL/CP iii. Isolated CL/CP is considered multifactorial in origin and demonstrates strong familial aggregation with a significant genetic component iv. No evidence of classic Mendelian inheritance attributable to any single gene,

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although a number of genes or loci have been implicated, including transforming growth factor-alpha, retinoic acid receptor alpha, BCL3, MSX-1 and several regions on chromosome 6p23-24 (OFC1), 2q13 (OFC2), 19q13.2 (OFC3), and other loci such as 4q25–4q31.3 and 17q21 c. Molecular signaling events in embryonic palatal development (Yu et al. 2009) i. Failure of palatal shelf formation a) Recent studies have identified several molecular networks operating between the palatal shelf epithelium and mesenchyme during different steps of palatogenesis b) These networks include signaling molecules and growth factors such as sonic hedgehog (Shh), members of the transforming growth factor b (TGfb) super family, including bone morphogenetic proteins (Bmps) and Tgfbs, fibroblast growth factors (Fgfs) and their receptors (FgfR), effectors and targets ii. Fusion of the palatal shelf with the tongue or mandible a) Severe reduction of the expression of Jagged 2 (Jag2), thereby encoding a ligand for the Notch family receptors and ectopic Tgfb3 production in the nasal epithelia of mice b) Mutations in TBX22 have been reported in families with X-linked cleft palate and ankyloglossia iii. Failure of palatal elevation a) Mutations of Pax9, Pitx1, or Osr2 can lead to failed palatal shelf elevation and cleft palate defect b) The implication of GABA in palate development was demonstrated by genetic studies of mice lacking the b3 subunit of the GABA receptor that developed CP without other craniofacial malformations iv. Failure of palatal shelves to meet after elevation: Mutations in Msx1 and Lhx8 and conditional inactivation of Tgfbr2 in CNC cells or Shh in the epithelium all result in retarded palatal shelf development v. Persistence of middle edge epithelium: Mutations of CDH1/E cadherin, which

Cleft Lip and/or Cleft Palate

deletes the extracellular cadherin repeat domains required for cell-cell adhesion, have recently been associated with CL/CP in families with hereditary diffuse cancer

Clinical Features 1. Classification of different types of orofacial clefting a. Cleft lip with or without cleft palate (CL/CP) i. Unilateral cleft lip ii. Unilateral cleft lip and cleft palate iii. Bilateral cleft lip iv. Bilateral cleft lip and cleft palate b. Cleft palate only i. Cleft palate ii. Submucous cleft palate iii. Velopharyngeal insufficiency iv. Robin sequence and robin complexes c. Median clefts i. Median cleft lip ii. Persistent infranasal furrow iii. Median frenular cleft iv. Median mandibular cleft d. Alveolar clefts (oral-facial-digital syndromes) e. Tessier type clefts including lateral and oblique facial clefts 2. Racial difference in CL/CP (De La Pedraja et al. 2000) a. Whites: approximately 1 in 1,000 births b. African Americans: 0.41 per 1,000 births c. Asians: approximately twice of whites 3. Sex difference in CL/CP and isolated clefts of the secondary palate (De La Pedraja et al. 2000) a. Children born with CL/CP: 60–80% are males b. Isolated clefts of the secondary palate: more frequently in females 4. Sites of clefts a. Isolated cleft lip: 21% b. CL/CP: 46% c. Clefts of the secondary palate alone: 33% d. Unilateral clefts i. More common in the left than the right (2:1) ii. Much more common than bilateral (9:1) iii. Associated with palatal clefts in 68% of cases e. Bilateral clefts of the lip: associated with palatal clefts in 86% of cases

Cleft Lip and/or Cleft Palate

5. Types of cleft lip a. Microform i. Presence of a vertical groove and vermilion notching ii. Associated with varying degrees of lip shortening b. Unilateral incomplete cleft lip i. Present with varying degrees of lip disruption ii. Associated with an intact nasal sill or Simonart band (a band of fibrous tissue from the edge of the red lip to the nostril floor) c. Complete cleft lip: characterized by disruption of the lip, alveolus, and nasal sill 6. Incidence of cleft lip +/ palate (CL/CP) and cleft palate alone (CPA) (Robin et al. 2006) a. Overall incidence of CL/CP and CPA: 1–2/1,000 children b. CPA: about 1/1,500 i. More common if submucous CP/CA is included ii. Bifid uvula occurs in 1 of 80 patients and often occurs in isolation, with no clefting of the palatal muscles c. Incidence of CL/CP: varies by race i. Highest among American Indians, at 3.6 cases per 1,000 live births ii. Lowest among African Americans, with 0.3 cases per 1,000 live births iii. The incidence of CPA does not vary by race d. Of all CL/CP and CPA i. 20% of all clefts are isolated cleft lip (18% unilateral, 2% bilateral) ii. 50% are CL/CP (38% unilateral, 12% bilateral) iii. 30% are CPA e. CL/CP is twice as common in males; CPA is twice as common in females 7. Secondary medical problems with the presence of cleft plate a. Difficulty in sucking b. Inadequate intake of formula c. Aspiration d. Deviated nasal septum (airway obstruction) e. Hearing impairment f. Recurrent ear infections g. Malocclusion h. Abnormal craniofacial growth i. Inability to generate a pressure gradient between the oral and nasal chambers (hinders sucking in most infants)

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j. Speech dysfunction i. The most serious untoward consequence associated with cleft palate ii. Hypernasality or escape of sound into the nasal cavity associated with the production of many consonant phonemes and vowels in the English language except m, n, and ng k. Cosmetic disfigurement associated with orofacial clefting

Diagnostic Investigations 1. Speech and hearing evaluation 2. Echocardiography for associated cardiac anomalies 3. Karyotyping if indicated, especially to detect del (22)(q11.2) 4. Molecular genetic analysis for a known mutation in a syndromic CL/CP

Genetic Counseling 1. Recurrence risk (Chen 1988; Tolarova 1972) a. Recurrence risk for nonsyndromic CL +/ CP i. Unaffected parent a) No previously affected child: about 0.1% (general population risk) (Bonaiti-Pellie and Smith 1974; Kirschner and LaRossa 2000) b) With one previously affected child: about 4% c) With two previously affected children: about 14% ii. One affected parent a) No previously affected child: about 4% b) With one previously affected child: about 12% c) With two previously affected children: about 25% iii. Two affected parents a) No previously affected child: about 35% b) With one previously affected child: about 45% c) With two previously affected children: about 50% b. Recurrence risk for nonsyndromic CP i. Unaffected parent

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a) No previously affected child: about 0.04% (general population risk) (Kirschner and LaRossa 2000) b) With one previously affected child: about 3.5% c) With two previously affected children: about 13% ii. One affected parent a) No previously affected child: about 3.5% b) With one previously affected child: about 10% c) With two previously affected children: about 24% iii. Two affected parents a) No previously affected child: about 2.5% b) With one previously affected child: about 40% c) With two previously affected children: about 45% c. Presence of a microform such as a forme fruste cleft lip, submucous cleft palate, or bifid uvula suggest genetic factors within the family, which would alter the inheritance risks (e.g., striking association with lower-lip pits in the van der Woude syndrome). d. Recurrence risk for CL/CP with associated anomalies i. Mendelian diseases and syndromes a) Autosomal dominant inheritance (e.g., Apert syndrome) b) Autosomal recessive inheritance (e.g., Smith-Lemli-Opitz syndrome) c) X-linked inheritance (e.g., oto-palatodigital syndrome) ii. Chromosome disorders (e.g., trisomy 13) 2. Prenatal diagnosis a. Prenatal ultrasonography i. CL/CP not reliably diagnosed until the soft tissues of the fetal face become distinct by 13–14 weeks by transabdominal (TA) sonography and by transvaginal (TV) sonography slightly earlier ii. Fetal palate best seen in the axial plane iii. Fetal lips optimally visualized in the coronal view iv. To demonstrate isolated CL/CP v. To demonstrate associated anomalies (limb and spine anomalies, most common with 33%; cardiovascular anomalies, 24%)

Cleft Lip and/or Cleft Palate

b. Fetal echocardiography in case of fetal cardiac anomalies c. Fetal karyotyping in case of associated fetal anomalies 3. Management a. Medical i. A highly specialized multidisciplinary approach from birth to adulthood ii. Airway management iii. Establishment of feeding iv. Speech, hearing, and language therapies b. Surgical i. Primary surgery on the lip: usually carried out around the age of 3 months followed by palatal repair at around 6 months ii. Preventative and restorative dental care iii. Orthodontics iv. Secondary surgery in the form of alveolar bone grafting v. Pharyngeal flap or sphincter pharyngoplasty for velopharyngeal incompetence c. Psychological issues (Endrica and Kapp-Simon 1999) i. Parental stress ii. Parent-child relationship iii. Behavioral and emotional adjustment iv. Self-concept and personality v. Cosmetic disfigurement vi. Social functioning vii. Congnitive development and adjustment viii. Cleft Lip and Palate Association (CLAPA), a helpful source of support and information for both families and professionals d. Recent observation suggests beneficial effects of folic acid supplementation during pregnancy in the prevention of facial clefting

References Berge´, S. J., Plath, H., Van de Vondel, P. T., et al. (2001). Fetal cleft lip and palate: Sonographic diagnosis, chromosomal abnormalities, associated anomalies and postnatal outcome in 70 fetuses. Ultrasound in Obstetrics & Gynecology, 18, 422–431. Bonaiti-Pellie, C., Smith, C. (1974). Risk tables for genetic counselling in some common congenital malformations. Journal of Medical Genetics, 11, 374–377. Bonaiti-Pellie´, C., Briand, M. L., Feingold, J., et al. (1982). An epidemiological and genetic study of facial clefting

Cleft Lip and/or Cleft Palate in France. I. Epidemiological and frequency in relatives. Journal of Medical Genetics, 11, 374–377. Burdi, A. R. (1977). Epidemiology, etiology, and pathogenesis of cleft lip and palate. The Cleft Palate Journal, 14(14), 262–269. Carinci, F., Pezzetti, F., Scapoli, L., et al. (2000). Genetics of nonsyndromic cleft lip and palate: A review of international studies and data regarding the Italian population. The Cleft Palate-Craniofacial Journal, 37, 33–40. Chen, H. (1988). Medical genetics handbook (pp. 320–321). St Louis: Warren H Green. Cockell, A., & Lees, M. (2000). Prenatal diagnosis and management of orofacial clefts. Prenatal Diagnosis, 20, 149–151. Cohen, M. M., Jr. (2002). Craniofacial disorders. In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Emery and Rimoin’s principles and practice of medical genetics (4th ed., pp. 3689–3727). London: Churchill Livingstone. Chapter 142. Curtis, E., Fraser, F., & Warburton, D. (1961). Congenital cleft lip and palate: Risk figures for counselling. American Journal of Diseases of Children, 102, 853–857. De La Pedraja, J., Erbella, J., McDonald, W. S., et al. (2000). Approaches to cleft lip and palate repair. The Journal of Craniofacial Surgery, 11, 562–571. Endrica, M. C., & Kapp-Simon, K. A. (1999). Psychological issues in craniofacial care: State of the art. The Cleft Palate-Craniofacial Journal, 36, 3–11. Farrall, M., & Holder, S. (1992). Familial recurrence-pattern analysis of cleft lip with or without cleft palate. American Journal of Human Genetics, 50, 270–277. Fraser, F. C. (1970). The genetics of cleft lip and palate. American Journal of Human Genetics, 22, 336–352. Fraser, G. R., & Calnan, G. S. (1961). Cleft lip and palate: Seasonal incidence, birth weight, birth rank, sex, site, etc. Archives of Disease in Childhood, 36, 420. Habib, Z. (1978a). Factors determining occurrence of cleft lip and cleft palate. Surgery, Gynecology & Obstetrics, 146, 105–110. Habib, Z. (1978b). Genetic counseling and genetics of cleft lip and palate. Obstetrical and Gynecological Survey, 33, 441–447. Hartridge, T. (1999). The role of folic acid in oral clefting. British Journal of Orthodontics, 26, 115–120. Hibbert, S. A., & Field, J. K. (1996). Molecular basis of familial cleft lip and palate. Oral Diseases, 2, 238–241. Kirschner, R. E., & LaRossa, D. (2000). Cleft lip and palate. Otolaryngologic Clinics of North America, 33, 1191–1215. Lee, W., Kirk, J. S., Shaheen, K. W., et al. (2000). Fetal cleft lip and palate detection by three-dimensional ultrasonography. Ultrasound in Obstetrics & Gynecology, 16, 314–320. Lynch, H. A. T., & Kimberling, W. J. (1981). Genetic counseling in cleft lip and cleft palate. Plastic and Reconstructive Surgery, 68, 800–815. Matthews, M. S., Cohen, M., Viglione, M., et al. (1998). Prenatal counseling for cleft lip and palate. Plastic and Reconstructive Surgery, 101, 1–5.

381 Melnick, M., Bixler, D., Fogh-Anderson, P., et al. (1980). Cleft  cleft palate: An overview of the literature and an analysis of Danish cases born between 1941 and 1968. American Journal of Medical Genetics, 6, 83–97. Milerad, J., Larson, O., Hagberg, C., et al. (1997). Associated malformations in infants with cleft lip and palate: A prospective, population-based study. Pediatrics, 100, 180–186. Mitchell, L. E., & Risch, N. (1992). Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: A reanalysis. American Journal of Human Genetics, 51, 323–332. Mossey, P. A., Little, J., Munger, R. G., et al. (2009). Cleft lip and palate. Lancet, 374, 1773–1785. Mulliken, J. B., & Benacerraf, B. R. (2001). Prenatal diagnosis of cleft lip. What the sinologist needs to tell the surgeon. Journal of Ultrasound in Medicine, 20, 1159–1164. Murray, J. C. (2002). Gene/environment causes of cleft lip and/or palate. Clinical Genetics, 61, 248–256. Nyberg, D., Sickler, G., Hegge, F., et al. (1995). Fetal cleft lip with and without cleft palate: US classification and correlation with outcome. Radiology, 195, 677–684. Prescott, N. J., Winter, R. M., & Malcolm, S. (2001). Nonsyndromic cleft lip and palate: Complex genetics and environmental effects. Annals of Human Genetics, 65, 505–515. Robin, N. H., Baty, H., Franklin, J., et al. (2006). The multidisciplinary evaluation and management of cleft lip and palate. Southern Medical Journal, 99, 1111–1120. Stark, R. B. (1954). The pathogenesis of harelip and cleft palate. Plastic and Reconstructive Surgery, 13, 20–39. Stein, J., Mullikan, J. B., Stal, S., et al. (1995). Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 mutigenerational families. American Journal of Human Genetics, 57, 257–272. Tolarova, M. (1972). Empirical recurrence risk figures for genetic counseling of clefts. Annotation of results in research. Acta Chirurgiae Plasticae, 14, 234–235. Tolarova, M., & Cervenka, J. (1998). Classification and birth prevalence of orofacial clefts. American Journal of Medical Genetics, 75, 126–137. Tolarova, M., & Harris, J. (1995). Reduced occurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology, 51, 71–78. Wyszynski, D. F., & Beaty, T. H. (1996). Review of the role of potential teratogens in the origin of human non-syndromic oral clefts. Teratology, 53, 309–317. Wyszynski, D. F., Beaty, T. H., & Maestri, N. (1996). Genetics of nonsyndromic oral clefts revisited. The Cleft PalateCraniofacial Journal, 33, 406–417. Yu, W., Serrano, M., Miguel, S. S., et al. (2009). Cleft lip and palate genetics and application in early embryological development. Indian Journal of Plastic Surgery, 42(Suppl), S35–S50.

382 Fig. 1 (a, b) Two infants with bilateral cleft lips and cleft palate

Cleft Lip and/or Cleft Palate

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Cleft Lip and/or Cleft Palate Fig. 3 (a, b) An infant and a boy with cleft palate

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Fig. 5 An infant with bilateral CL/CP associated with trisomy 13 Fig. 4 A boy with high-arched palate

384 Fig. 6 A stillborn with CL/CP and other multiple congenital anomalies including massive cystic hygroma

Cleft Lip and/or Cleft Palate

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Cleidocranial Dysplasia

Cleidocranial dysplasia is a generalized skeletal dysplasia affecting not only the clavicles but almost the entire skeletal system. It is characterized by aplasia or hypoplasia of the clavicles, enlarged calvaria with frontal bossing, multiple Wormian bones, delayed tooth eruption, supernumerary unerupted teeth, distal phalanges with abnormally pointed tufts, hypoplasia of the pelvis, and numerous other abnormalities (Jensen 1990)

c. CBFA1 encodes a transcription factor that activates osteoblast differentiation and plays a role in differentiation of chondrocytes 4. Germline line mosaicism has been reported (Pai et al. 2007) 5. No significant genotype/phenotype correlations observed

Clinical Features Synonyms and Related Disorders Cleidocranial dysostosis

Genetics/Birth Defects 1. Inheritance: autosomal dominant 2. About 20–40% of cases represent new mutations (Martinez-Frias et al. 1988) 3. Cause a. Caused by mutations in CBFA1 (RUNX2) gene resulting in haploinsufficiency. Types of mutations identified are: i. Deletion ii. Insertion iii. Missense iv. Nonsense b. The gene for cleidocranial dysplasia called corebinding factor A1 (CBFA1) (a member of the runt family of transcription factors), mapped to 6p21. The alternative gene name is called RUNX2

1. Significant intra- and interfamilial variability of phenotypic expression (Mundlos 1999) 2. Abnormal craniofacial growth a. Head i. Abnormally large, wide-open fontanels at birth ii. A large brachycephalic head iii. A broad forehead with frontal bossing iv. Delayed closure of the fontanels and sutures v. Poorly developed midfrontal area showing a frontal groove owing to incomplete ossification of the metopic suture vi. Soft skull in infancy b. Face i. Frontal and parietal bossings, separated by a metopic groove ii. A depressed nasal bridge iii. Hypertelorism with possible exophthalmos iv. A small, flattened facial appearance (midface hypoplasia) with mandibular prognathism v. An anatomic pattern of dentofacial deformity consistent with the diagnosis of vertical maxillary deficiency (short face syndrome, type 2)

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8.

Cleidocranial Dysplasia

c. Oral/dental i. High arched palate ii. Clefts involving soft and hard palates iii. Persistence of the deciduous dentition with delayed eruption of the permanent teeth: a relatively constant finding iv. Impaction of supernumerary permanent teeth v. Crowding/malocclusion vi. Dentigerous cysts Otolaryngologic manifestations (Segal and Puterman 2007) a. Hypoplasia of the maxilla and zygoma resulting in small face and sometimes asymmetric b. Small or absent mastoid air cells c. A high rate of Eustachian tube dysfunction d. A higher prevalence of submucosal cleft palate e. Narrow external auditory canals f. Increase rates of recurrent childhood ear infections and various degrees of hearing loss g. Clumping of the ossicles, stapes fixation, and sclerosis of the footplate have been described (Hawkins et al. 1975) Shoulders and thorax a. Ability to bring shoulders together b. Dimplings in the skin secondary to mild hypoplasia of the clavicles c. Sloping, almost absent shoulders secondary to severe hypoplasia or absence of the clavicles d. Narrow thorax: may lead to respiratory distress during early infancy Mildly disproportionate short stature with short limbs comparing to the trunk and more apparent in the upper limbs than the lower Spine a. Scoliosis b. Kyphosis Hands a. Brachydactyly b. Short distal phalanges c. Tapering fingers d. Nail dysplasia/hypoplasia e. Short, broad thumbs f. Clinodactyly of the fifth fingers Other abnormalities a. Hearing loss b. Abnormal gait c. Joint hypermobility d. Muscular hypotonia

9. Intelligence: normal 10. Cesarean section often required in the pregnant female due to dysplastic pelvis

Diagnostic Investigations 1. Radiographic findings: generalized failure of midline ossification a. Skull i. Delayed closure of the anterior fontanel (open fontanel) and sagittal and metopic sutures, often open for life ii. Unossified areas of the skull becoming smaller with increasing age iii. Multiple Wormian bones formation, particularly around the lambdoid suture iv. Small or absent nasal bones v. Segmental calvarial thickening vi. Underdeveloped maxilla vii. Delayed union of the mandibular symphysis viii. Platybasia ix. Small cranial base x. A large foramen magnum xi. Hypoplastic sinuses (paranasal, frontal, mastoid) b. Clavicles i. Absent clavicles: rare ii. Pseudarthrosis of one or both clavicles iii. Hypoplasia of the acromial end: common iv. Two separate fragments v. Absent sternal end with presence of the acromial end vi. Bilaterality is the rule but not always the case c. Chest i. Small bell-shaped thoracic cage ii. Short, oblique ribs iii. Presence of cervical ribs iv. Scapula often hypoplastic with deficient supraspinatus fossae and acromial facets v. Associated deficiency in musculature d. Pelvis i. Widened pubis symphysis resulting from delay in ossification during adulthood ii. Hypoplasia and anterior rotation of the iliac wings iii. Wide sacroiliac joints iv. Delayed ossification of the pubic bone v. Large femoral epiphyses

Cleidocranial Dysplasia

vi. Unusual shape of femoral head reminiscent of a “chef’s hat” vii. Broad femoral necks viii. Frequent coxa vara e. Spine i. Hemivertebrae ii. Posterior wedging iii. Spondylolysis and spondylolisthesis iv. Syringomyelia v. Spina bifida occulta of the cervical, thoracic, or lumbar region f. Tubular bones i. Presence of both proximal and distal epiphyses in the second metacarpals and metatarsals leading to excessive growth and length ii. Frequent cone-shaped epiphyses and premature closure of epiphyseal growth plates leading to shortening of bones iii. Wide epiphyses iv. Unusually short distal phalanges and the middle phalanges of the second and fifth fingers v. Poorly developed terminal phalanges giving a tapered appearance to the digit vi. Occasional hypoplasia, dysplasia, and aplasia of nails g. Dentition: impacted, supernumerary teeth 2. Cytogenetic study: visible complex chromosome rearrangements occasionally seen (Purandare et al. 2008) 3. Molecular genetic studies of mutations involving RUNX2 (Mendoza-Londono and Lee 2009) a. Sequence analysis b. Deletion/duplication analysis

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected with the disorder or has germ line mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography (Stewart et al. 2000; Hermann et al. 2009) i. Hypoplastic clavicles ii. Less calcified cranium than expected for gestational age iii. Other craniofacial and skeletal anomalies

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b. Prenatal diagnosis and preimplantation genetic diagnosis: Direct DNA testing possible for those families with a known mutation in the RUNX2 3. Management (Cooper et al. 2001) a. Hearing evaluation b. Evaluate the presence of submucous cleft palate c. Evaluation of obstructive sleep apnea d. Medical and surgical therapy for upper airway obstruction, recurrent and chronic sinusitis and otitis e. Monitor skeletal and orthopedic complications f. Early surgical and orthodontic intervention of unerupted permanent teeth to induce eruption g. Orthognathic surgery to correct midface hypoplasia to reduce or correct significant upper respiratory complications and malocclusions h. Surgical and orthodontic management of vertical maxillary deficiency (Dann et al. 1980) i. Women with cleidocranial dysplasia at risk for a Cesarean section delivery

References Aktas, S., Wheeler, D., & Sussman, M. D. (2000). The ‘chef’s hat’ appearance of the femoral head in cleidocranial dysplasia. The Journal of Bone and Joint Surgery. British Volume, 82, 404–408. Chitayat, D., Hodgkinson, K. A., & Azouz, E. M. (1992). Intrafamilial variability in cleidocranial dysplasia: A three generation family. American Journal of Medical Genetics, 42, 298–303. Cohen, M. M., Jr. (2001). RUNX genes, neoplasia, and cleidocranial dysplasia. American Journal of Medical Genetics, 104, 185–188. Cole, W. R., & Levine, S. (1951). Cleidocranial dysplasia. The British Journal of Radiology, 24, 549–555. Cooper, S. C., Flaitz, C. M., Johnston, D. A., et al. (2001). A natural history of cleidocranial dysplasia. American Journal of Medical Genetics, 104, 1–6. Dann, J. J., III, Crump, P., & Ringenberg, Q. M. (1980). Vertical maxillary deficiency with cleidocranial dysplasia. Diagnostic findings and surgical-orthodontic correction. American Journal of Orthodontics, 78, 564–574. Dhooge, I., Lantsoght, B., Lemmerling, M., et al. (2001). Hearing loss as a presenting symptom of cleidocranial dysplasia. Otology & Neurotology, 22, 855–857. Ducy, P. (2000). Cbfa1: A molecular switch in osteoblast biology. Developmental Dynamics, 219, 461–471. Farrar, E. L., & Van Sickels, J. E. (1983). Early surgical management of cleidocranial dysplasia: A preliminary report. Journal of Oral and Maxillofacial Surgery, 41, 527–529. Feldman, G. J., Robin, N. H., Brueton, L. A., et al. (1995). A gene for cleidocranial dysplasia maps to the short arm of chromosome 6. American Journal of Human Genetics, 56, 938–943.

388 Gelb, B. D., Cooper, E., Shevell, M., et al. (1995). Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion. American Journal of Medical Genetics, 58, 200–205. Golan, I., Baumert, U., Held, P., et al. (2002). Radiological findings and molecular genetic confirmation of cleidocranial dysplasia. Clinical Radiology, 57, 525–529. Golan, I., Preising, M., Wagener, H., et al. (2000). A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplasia (CCD) and variable expressivity. Journal of Craniofacial Genetics and Developmental Biology, 20, 113–120. Hamner, L. H., III, Fabbri, E. L., & Browne, P. C. (1994). Prenatal diagnosis of cleidocranial dysostosis. Obstetrics and Gynecology, 83, 856–857. Hassan, J., Sepulveda, W., Teixeira, J., et al. (1997). Prenatal sonographic diagnosis of cleidocranial dysostosis. Prenatal Diagnosis, 17, 770–772. Hawkins, H. B., Shapiro, R., & Petrillo, C. J. (1975). The association of cleidocranial dysostosis with hearing loss. The American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine, 125, 944–947. Hermann, N. V., Hove, H. D., Jorgensen, C., et al. (2009). Prenatal 3D ultrasound diagnostics in cleidocranial dysplasia. Fetal Diagnosis and Therapy, 25, 36–39. International Working Group on Constitutional Diseases of Bone. (1998). International nomenclature and classification of the osteochondrodysplasias (1997). American Journal of Medical Genetics, 79, 376–382. Jarvis, J. L., & Keats, T. E. (1974). Cleidocranial dysplasia. A review of 40 new cases. American Journal of Roentgenology, 121, 5–16. Jensen, B. L. (1990). Somatic development in cleidocranial dysplasia. American Journal of Medical Genetics, 35, 69–74. Jensen, B. L., & Kreiborg, S. (1990). Development of the dentition in cleidocranial dysplasia. Journal of Oral Pathology & Medicine, 19, 89–93. Jensen, B. L., & Kreiborg, S. (1993a). Development of the skull in infants with cleidocranial dysplasia. Journal of Craniofacial Genetics and Developmental Biology, 13, 89–97. Jensen, B. L., & Kreiborg, S. (1993b). Craniofacial abnormalities in 52 school-age and adult patients with cleidocranial dysplasia. Journal of Craniofacial Genetics and Developmental Biology, 13, 98–108. Jensen, B. L., & Kreiborg, S. (1995). Craniofacial growth in cleidocranial dysplasia. A roentgenocephalometric study. Journal of Craniofacial Genetics and Developmental Biology, 15, 35–43. Komori, T., Yagi, H., Nomura, S., et al. (1997). Targeted disruption of CBFA1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell, 89, 755–764. Kreiborg, S., Jenson, B. L., Larsen, P., et al. (1999). Anomalies of craniofacial skeleton and teeth in cleidocranial dysplasia. Journal of Craniofacial Genetics and Developmental Biology, 19, 75–79. Lee, B., Thirunsvukkarasu, K., Zhou, I., et al. (1997). Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1. Nature Genetics, 16, 307–310.

Cleidocranial Dysplasia Martinez-Frias, M. L., Herranz, I., Salvador, J., et al. (1988). Prevalence of dominant mutations in Spain: Effect of changes in maternal age distribution. American Journal of Medical Genetics, 31, 845–852. Mendoza-Londono, R., & Lee, B. (2009). Cleidocranial dysplasia. GeneReviews. Updated June 25, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼ gene&part¼ccd Mundlos, S. (1999). Cleidocranial dysplasia: Clinical and molecular genetics. Journal of Medical Genetics, 36, 177–182. Mundlos, S., Otto, F., Mundlos, C., et al. (1997). Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell, 89, 773–779. Narahara, K., Tsuji, K., Yokoyama, Y., et al. (1995). Cleidocranial dysplasia associated with a t(6;18)(p12;q24) translocation. American Journal of Medical Genetics, 56, 119–120. Nienhaus, H., Mau, U., Zang, K. D., et al. (1993). Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia. American Journal of Medical Genetics, 46, 630–631. Otto, F., Thornell, A. P., Crompton, T., et al. (1997). CBFA1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell, 89, 765–771. Pai, T., Napierala, D., Becker, T. A., et al. (2007). The presence of germ line mosaicism of cleidocranial dysplasia. Clinical Genetics, 71, 589–591. Purandare, S. M., Mendoza-Londono, R., Yatsenko, S. A., et al. (2008). De novo three-way chromosome translocation 46, XY,t(4;6;21)(p16;p21.1;q21) in a male with Cleidocranial dysplasia. American Journal of Medical Genetics. Part A, 146A, 453–458. Quack, I., Vonderstrass, B., Stock, M., et al. (1999). Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia. American Journal of Human Genetics, 65, 1268–1278. Segal, N., & Puterman, M. (2007). cleidocranial dysplasia – Review with an emphasis otological and audiological manifestations. International Journal of Pediatric Otorhinolaryngology, 71, 523–526. Stewart, P. A., Wallerstein, R., Moran, E., et al. (2000). Early prenatal ultrasound diagnosis of cleidocranial dysplasia. Ultrasound in Obstetrics & Gynecology, 15, 154–156. Tesa, A., Salvi, S., Casali, C., et al. (2003). Six novel mutations of the RUNX2 gene in Italian patients with cleidocranial dysplasia. Hum Mutat mutation in Brief #626, 2003 online. Zackai, E. H., Robin, N. H., & McDonald-McGinn, D. M. (1997). Sibs with cleidocranial dysplasia born to normal parents: Germ line mosaicism? American Journal of Medical Genetics, 69, 348–351. Zhang, Y. W., Yasui, N., Kakazu, N., et al. (2000). PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene, 244, 21–28. Zhou, G., Chen, Y., Zhou, L., et al. (1999). CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Human Molecular Genetics, 8, 2311–2316.

Cleidocranial Dysplasia

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Fig. 1 (a–c) An infant and a child with cleidocranial dysplasia showing a large brachycephalic skull, frontal bossing, a large anterior fontanel, widely spaced eyes, flat nasal bridge, and easily proximated shoulders

390 Fig. 2 (a–c) A child with cleidocranial dysplasia showing prominent forehead, wide anterior fontanel and cranial sutures, wide eyes, depressed nasal bridge, and easily proximated shoulders. Radiographs show poorly ossified skull, wide fontanels, cone-shaped thorax, and absence of clavicles

Cleidocranial Dysplasia

a

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c

Cleidocranial Dysplasia

391

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Fig. 3 (a–c) A girl with cleidocranial dysplasia at different ages showing short stature, frontal bossing, wide cranial sutures, wide set eyes, depressed nasal bridge, and sloping and easily proximated shoulders

392 Fig. 4 (a–c) An adult with cleidocranial dysplasia showing widened cranial sutures, a characteristic face, and sloping and easily proximated shoulders. Radiograph showed a coneshaped thorax with absent clavicles

Cleidocranial Dysplasia

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Cleidocranial Dysplasia

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Fig. 5 (a–e) A father and a son with cleidocranial dysplasia showing characteristic clinical findings and a dysplastic left clavicle presenting as two separate fragments, illustrated by radiograph

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Cleidocranial Dysplasia

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Fig. 6 (a–d) Another adult patient with cleidocranial dysplasia, showing typical clinical and dental features (radiograph)

Cloacal Exstrophy

Cloacal exstrophy is a rare congenital malformation resulting in exstrophy of the urinary, intestinal, and genital systems and is associated with anomalies of other organ systems. The term OEIS complex (omphalocele, exstrophy of the bladder, imperforate anus, and spinal defects) are used to describe the spectrum of malformations in cloacal exstrophy (Kaya et al. 2000). The incidence of cloacal exstrophy is estimated to be 1/200,000–1/400,000 live births (Dick et al. 2001), although the true incidence may be as high as 1 in 10,000–50,000, taking into account lack of diagnosis in stillborn infants (Keppler-Noreuil 2001).

Synonyms and Related Disorders OEIS complex (omphalocele-exstrophy bladder-imperforate anus-spinal defects)

of

the

Genetics/Basic Defects 1. Genetics a. Recurrence of OEIS complex in siblings can be explained by the following mechanisms: i. Autosomal recessive inheritance ii. Multifactorial determination iii. Gonadal mosaicism for a dominant mutation iv. Environmental factors v. Subclinical maternal disorder vi. An unbalanced translocation between 9q and Y chromosome resulting in a 9q34.1qter deletion, as a potential cause (ThauvinRobinet et al. 2004)

vii. Mutations in a group of homeobox genes such as HLXB9 and HOX family which are involved in the development of embryonic mesoderm (Manner and Kluth 2005) b. Higher incidence of OEIS complex in monozygotic twins than in dizygotic twins suggests a possible genetic contribution to the occurrence of these defects. 2. Basic defects of OEIS complex (Lee et al. 1999) a. Resulting from a single localized defect in the early caudal mesoderm at approximately 29 days of development b. Resulting in the following sequence of events: i. Failure of cloacal septation leading to a persistence of the cloaca with a rudimentary mid-gut and imperforate anus ii. Failure of breakdown of the cloacal membrane leading to exstrophy of the cloaca, omphalocele, and lack of fusion of the pubic rami iii. The lumbosacral somites giving rise to abnormal vertebrae in which there is protrusion of the dilated spinal cord (hydromyelia) and a cystic, skin-covered mass in the lumbosacral region 3. Cloaca and cloacal exstrophy a. Cloaca i. A transient embryological structures ii. The term “cloaca” literally means “sewer” in Latin iii. The term used to represent the emptying of the gastrointestinal and urogenital tracts into a common sinus

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_45, # Springer Science+Business Media, LLC 2012

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396

iv. Defined as a common chamber (orifice) in the perineum into which the urinary, genital and intestinal tract drain b. Cloacal exstrophy: The common orifice empties onto the anterior abdominal wall

Clinical Features 1. Classic exstrophy of the cloaca (Lee et al. 1999) a. Lower abdominal defect b. Exposure of intestinal and bladder mucosa c. Accompanied by the following anomalies i. Omphalocele ii. Imperforate anus iii. Urogenital anomalies 2. Gastrointestinal malformations a. Omphalocele b. Imperforate anus c. Rectovestibular/rectovesical fistula d. Small bowel anomalies i. Foreshortened small bowel ii. Rotational anomalies e. Meckel diverticulum f. Inguinal hernias 3. CNS malformations a. Spina bifida: the most common CNS malformation i. Leptomeningocele ii. Myelomeningocele iii. Meningocele iv. Spina bifida occulta v. Cord tethering b. Craniosynostosis 4. Skeletal malformations a. Vertebral anomalies i. Presence of extra vertebrae ii. Hemivertebrae and associated scoliosis iii. Absent vertebrae b. Pubic diastasis c. Lower extremity anomalies i. Clubfoot deformities ii. Limb deficiencies 5. Genitourinary malformations a. Bladder anomaly i. Open ii. Separated into two halves iii. Flanking the exposed interior of the cecum

Cloacal Exstrophy

iv. Openings to the remainder of the hindgut v. Prolapse of the terminal ileum as a “trunk” of bowel onto the cecal plate b. Renal anomalies i. A single kidney ii. Rudimentary kidney iii. Pelvic ectopic kidney iv. Ureteropelvic junction obstruction v. Malrotation vi. Crossed renal ectopia c. Ureteral anomalies i. Duplication ii. Ectopic insertion iii. Distal stricture and megaureter d. Male genitalia anomalies i. Small and bifid penis ii. Hemiglans located caudal to each hemibladder e. Female genitalia anomalies i. Bifid clitoris ii. Uterine duplication iii. Vaginal duplication iv. Vaginal agenesis 6. Prognosis a. Used to be uniformly fatal malformation in its worst form b. Currently with an 80–100% survival rate due to early surgical repair but accompanied by lifelong severe morbidity

Diagnostic Investigations 1. Evaluation of associated malformations 2. Karyotyping for genetic sex 3. Renal ultrasonography for renal and upper urinary tract anomalies 4. Voiding cystourethrography to assess bladder capacity in early childhood in preparation for continence reconstruction 5. Radiographic studies to demonstrate spinal dysraphism (Dick et al. 2001) a. Plain spinal radiographs b. Myelography c. CT d. CT myelography e. Spinal MRI to identify occult abnormalities that predispose to symptomatic spinal cord tethering

Cloacal Exstrophy

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Genetic Counseling 1. Recurrence risk (Mathews et al. 1998) a. Patient’s sib: recurrence in subsequent pregnancies noted in one report b. Patient’s offspring: Lack of offspring from patients with cloacal exstrophy making the determination of inheritance difficult 2. Prenatal diagnosis by ultrasonography a. Elevated maternal serum a-fetoprotein (AFP) in OEIS complex. The open ventral wall defect likely results in AFP leakage. b. Ultrasonography (Austin et al. 1998) i. Major ultrasound criteria a) Non-visualization of the bladder (91%) b) A large midline infraumbilical anterior wall defect or cystic anterior wall structure (persistent cloacal membrane) (82%) c) Omphalocele (77%) d) Lumbosacral myelomeningocele (68%) ii. Minor (less frequent) ultrasound criteria a) Lower limb defects (23%) b) Renal anomalies (23%) c) Ascites (14%) d) Widened pubic arches (18%) e) A narrow thorax (9%) f) Hydrocephalus (9%) g) A single umbilical artery (9%) c. Early prenatal diagnosis with fetal MRI (Gobbi et al. 2008) 3. Management (Mathews et al. 1998) a. Appropriate parental counseling and referral to a center with significant expertise in the management of cloacal exstrophy when prenatal diagnosis is made b. Medical stabilization of the infant i. Fluid and electrolyte replacement ii. Parenteral nutrition iii. Moisten the exstrophied bladder and bowel with saline and cover them with a protective plastic dressing iv. Daily prophylactic antibiotics c. Gender assignment i. Evaluation of the genitalia ii. Decision limited to the genetic male patients with cloacal exstrophy

d.

e.

f.

g.

a) Male gender assignment appropriate for male patients with adequate bilateral or unilateral phallic structures b) Male neonates with minimal phallic structures: appropriate to raise as female subjects with early excision of the gonads c) Appropriate hormonal manipulation to improve psychosexual dysfunction d) Improvements in phallic reconstruction eventually allow most genetic male patients to be assigned male gender. iii. Initial sexual reassignment to be done in conjunction with extensive family counseling as well as continued counseling for the parents and children Management of gastrointestinal malformations i. Closure of omphalocele ii. Combined with gastrointestinal diversion or reconstruction a) Ileostomy with resection of the hindgut remnant b) Colostomy Management of genitourinary malformations i. Bladder closure ii. Initial bladder excision and urinary diversion iii. Further augmentation or urinary diversions to achieve continence Management of CNS malformations i. Closure of myelomeningocele ii. Cord untethering iii. Spinal fusion iv. Cranial expansion for craniosynostosis Management of orthopedic malformations i. Manage myelodysplasia ii. Pelvic osteotomies iii. Various orthopedic devices to assist with ambulation

References Austin, P. F., Homsy, Y. L., Gearhart, J. P., et al. (1998). The prenatal diagnosis of cloacal exstrophy. Journal of Urology, 160, 1179–1181. Baker Towell, D. M., & Towell, A. D. (2003). A preliminary investigation into quality of life, psychological distress and social competence in children with cloacal exstrophy. Journal of Urology, 169, 1850–1853.

398 Carey, J. C., & Greenbaum, B. (1978). Hall Arch Dermatol: The OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Birth Defects Original Article Series, XIV(6B), 253–263. Chitrit, Y., Zorn, B., Filidori, M., et al. (1993). Cloacal exstrophy in monozygotic twins detected through antenatal ultrasound scanning. Journal of Clinical Ultrasound, 21, 339–342. Davidoff, A. M., Hebra, A., Balmer, D., et al. (1996). Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy. Journal of Pediatric Surgery, 31, 771–773. Diamond, D. A., & Jeffs, R. D. (1985). Cloacal exstrophy: A 22-year experience. Journal of Urology, 133, 779–782. Dick, E. A., de Bruyn, R., Patel, K., et al. (2001). Spinal ultrasound in cloacal exstrophy. Clinical Radiology, 56, 289–294. Evans, J. A., & Chudley, A. E. (1999). Tibial agenesis, femoral duplication, and caudal midline anomalies. American Journal of Medical Genetics, 85, 13–19. Flanigan, R. C., Casale, A. J., & McRoberts, J. W. (1984). Cloacal exstrophy. Urology, 23, 227–233. Fujiyoshi, Y., Nakamura, Y., Cho, T., et al. (1987). Exstrophy of the cloacal membrane. A pathologic study of four cases. Archives of Pathology & Laboratory Medicine, 111, 157–160. Gobbi, D., Fascetti Leon, F., Tregnaghi, A., et al. (2008). Early prenatal diagnosis of cloacal exstrophy with fetal magnetic resonance imaging. Fetal Diagnosis and Therapy, 24, 437–439. Gosden, C., & Brock, D. J. H. (1981). Prenatal diagnosis of exstrophy of the cloaca. The Journal of the American Medical Association, 8, 95. Hurwitz, R. S., Manzoni, G. A., Ransley, P. G., et al. (1987). Cloacal exstrophy: A report of 34 cases. Journal of Urology, 138, 1060–1064. Jeffs, R. D. (1978). Exstrophy and cloacal exstrophy. The Urologic Clinics of North America, 5, 127–140. Kaya, H., Oral, B., Dittrich, R., et al. (2000). Prenatal diagnosis of cloacal exstrophy before rupture of the cloacal membrane. Archives of Gynecology and Obstetrics, 263, 142–144. Keppler-Noreuil, K. M. (2001). OEIS complex (omphaloceleexstrohy-imperforate anus-spinal defects): A review of 14 cases. American Journal of Medical Genetics, 99, 271–279. Keppler-Noreuil, K., et al. (2007). Prenatal ascertainment of OEIS complex/cloacal exstrophy – 15 new cases and literature review. American Journal of Medical Genetics Part A, 143A, 2122–2128. Kutzner, D. K., Wilson, W. G., & Hogge, W. A. (1988). OEIS complex (cloacal exstrophy): Prenatal diagnosis in the second trimester. Prenatal Diagnosis, 8, 247–253. Lee, D. H., Cottrell, J. R., Sanders, R. C., et al. (1999). OEIS complex (omphalocele-exstrophy-imperforate anus-spinal

Cloacal Exstrophy defects) in monozygotic twins. American Journal of Medical Genetics, 84, 29–33. Loder, R. T., & Dayioglu, M. M. (1990). Association of congenital vertebral malformations with bladder and cloacal exstrophy. Journal of Pediatric Orthopedics, 10, 389–393. Lund, D. P., & Hendren, W. H. (1993): Cloacal exstrophy: experience with 20 cases. Journal of Pediatric Surgery, 28, 1360–1368; discussion 1368–1369. Lund, D. P., & Hendren, W. H. (2001). Cloacal exstrophy: A 25-year experience with 50 cases. Journal of Pediatric Surgery, 36, 68–75. Manner, J., & Kluth, D. (2005). The morphogenesis of the exstrophy-epispadias complex: A new concept based on observations made in early embryonic cases of cloacal exstrophy. Anatomy and Embryology (Berlin), 210, 51–57. Mathews, R., Jeffs, R. D., Reiner, W. G., et al. (1998). Cloacal exstrophy–improving the quality of life: The Johns Hopkins experience. Journal of Urology, 160, 2452–2456. Meglin, A. J., Balotin, R. J., Jelinek, J. S., et al. (1990). Cloacal exstrophy: Radiologic findings in 13 patients. AJR, American Journal of Roentgenology, 155, 1267–1272. Mitchell, M. E., & Plaire, C. (2002). Management of cloacal exstrophy. Advances in Experimental Medicine and Biology, 511, 267–270; discussion 270–263. Molenaar, J. C. (1996). Cloacal exstrophy. Seminars in Pediatric Surgery, 5, 133–135. Reddy, R. A., Bharti, B., & Singhi, S. C. (2003). Cloacal exstrophy. Archives of Disease in Childhood, 88, 277. Schober, J. M., Carmichael, P. A., Hines, M., et al. (2002). The ultimate challenge of cloacal exstrophy. Journal of Urology, 167, 300–304. Smith, N. M., Chambers, H. M., Furness, M. E., et al. (1992). The OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): Recurrence in sibs. Journal of Medical Genetics, 29, 730–732. Smith, E. A., Woodard, J. R., Broecker, B. H., et al. (1997). Current urologic management of cloacal exstrophy: Experience with 11 patients. Journal of Pediatric Surgery, 32, 256–261; discussion 261–252. Thauvin-Robinet, C., Faivre, L., Cusin, V., et al. (2004). Cloacal exstrophy in an infant with 9q34.1-qter deletion resulting from a de novo unbalanced translocation between chromosome 9q and Yq. American Journal of Medical Genetics. Part A, 126A, 303–307. Woo, L. L., Thomas, J. C., & Brock, J. W. (2009). Cloacal exstrophy: A comprehensive review of an uncommon problem. Journal of Pediatric Urology, xx, 1–10.

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Fig. 1 Two infants (a–c) with cloacal exstrophy. The schematic diagram (d) illustrates the anatomy of various defects in the second infant (c)

Clubfoot

Clubfoot, or talipes equinovarus, is one of the most common congenital deformities affecting the lower limbs in approximately 1–2 in 1,000 live births. The incidence is higher in Hispanics and lower in Asians. Although clubfoot is recognizable at birth, the severity of the deformity can vary from mild to an extremely rigid foot that is resistant to manipulation (Dobbs and Gurnett 2009).

Synonyms and Related Disorders Talipes equinovarus

Genetics/Basic Defects 1. Pathogenesis a. Genetic cause: suggested because it tends to run in families (Lochmiller et al. 1998) b. Oligohydramnios: suggested as a cause from early amniocentesis data (CEMAT Group 1998) c. Osseous deformities (Shapiro and Glimcher 1979), muscle abnormalities (Herceg et al. 2006), and arrested fetal development (Fukuhara et al. 1994): hypothesized to play a role in pathogenesis 2. Etiology (Dobbs and Gurnett 2009) a. Most commonly as an isolated birth defect and considered idiopathic (Wynne-Davies 1964): various theories on etiologies include: i. Vascular deficiencies (Hootnick et al. 1982) ii. Environmental factors a) Early amniocentesis (75%) in which aldosterone production is inadequate and at risk of life-threatening salt-wasting crises b. Nonclassic “late onset” form of 21-hydroxylase deficiency i. Has only moderate enzyme deficiency ii. Present postnatally with signs of hyperandrogenism iii. Females with the nonclassic form: not virilized at birth 4. CAH due to 21-hydroxylase deficiency a. 21-hydroxylase i. A microsomal cytochrome P450 enzyme ii. Required to convert: a) 17-hydroxy-progesterone to 11deoxycortisol b) Progesterone to deoxycorticosterone b. 21-hydroxylase deficiency i. Impairs the metabolism of cholesterol to cortisol, generating excessive level of 17hydroxyprogesterone ii. Produces androstenedione and other androgens from the precursor (17-hydroxyprogesterone) via an alternative metabolic pathway iii. Aldosterone deficiency a) Inability to synthesize adequate amounts of aldosterone due to severely impaired 21-hydroxylation of progesterone in about 75% of patients b) Resulting in sodium loss via the kidney, colon, and sweat glands and excrete potassium from the renal tubules c. Cortisol deficiency i. Glucocorticoids a) Increase cardiac contractility b) Increase cardiac output

Congenital Adrenal Hyperplasia

c) Increase cardiac and vasculature sensitivity to the pressor effects of catecholamines and other pressor hormone ii. Absence of glucocorticoids a) Decrease in cardiac output b) Decrease in glomerular filtration leading to an inability to excrete free water and consequently to hyponatremia d. Shock and severe hyponatremia much more likely in 21-hydroxylase deficiency in which both cortisol and aldosterone biosynthesis are affected 5. Phenotype-genotype correlations (White 2001) a. Mutations in CYP21, such as deletions, frameshifts, or nonsense mutations i. Totally ablate enzyme activity ii. Most often associated with salt-wasting b. Mutations mainly consisting of the missense mutation Ile172Asn (Il72N) i. Yielding enzymes with 1–2% normal activity ii. Carried predominantly by patients with simple virilizing disease c. Mutations such as Val281Leu (V281L) and Pro30Leu (P30L) i. Producing enzymes with 20–60% of normal activity ii. Most often associated with the nonclassical disorder d. Two different CYP21 mutations i. Producing compound heterozygotes ii. Most often with a phenotype compatible with that of the less severe gene defects e. All patients homozygous or compound heterozygous for large deletions or gene conversions have a salt-wasting classic form. 6. Characteristics of other forms of CAH (Antal and Zhou 2009) a. 11-Beta Hydroxylase deficiency i. Incidence: 1:100,000 ii. Gene involved: CYP11B1 iii. Chromosome location: 8q24.3 b. 17-alpha-hydroxylase deficiency i. Incidence: rare ii. Gene involved: CYP17 iii. Chromosome location: 10q24.3 c. 3-beta-hydroxysteroid Dehydrogenase deficiency i. Incidence: rare ii. Gene involved: HSD3B2 iii. Chromosome location: 1p13.1

Congenital Adrenal Hyperplasia

d. Lipoid CAH i. Incidence: rare ii. Gene involved: steroidogenic acute regulatory protein (StAR) iii. Chromosome location: 8p11.2

Clinical Features 1. Typical signs and symptoms of acute adrenal crisis (Antal and Zhou 2009) a. Decreased activity/fatigue b. Altered sensorium/unresponsiveness c. Poor feeding/weak suck d. Dry mucous membranes e. Hyperpigmentation f. Abdominal pain g. Vomiting h. Hyponatremia i. Hyperkalemia j. Hypoglycemia k. Metabolic acidosis l. Hypothermia m. Hypotension n. Dehydration o. Lack of weight gain 2. Classic CAH phenotype (New 2002; White 2001) a. Simple virilizing form (about 25% of patients) b. Salt-wasting form (>75% of patients) i. Adrenal crises present at 1–4 weeks of age in severely affected patients a) Severe dehydration b) Hypotension c) Severe hyponatremia, hyperkalemia, and hyperreninemia d) Progressing to adrenal crisis (azotemia, vascular collapse, hypovolemic shock, and death) if adequate medical care is not provided e) Affected infant boys who are not detected in a newborn screening program are at high risk of a salt-wasting crisis since their normal genitalia fail to alert physicians to the diagnosis of congenital adrenal hyperplasia. ii. Non-specific symptoms a) Poor appetite/feeding b) Vomiting c) Hypotension

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d) Lethargy e) Failure to gain weight (weight loss) iii. Improved sodium balance and more efficient aldosterone synthesis with age in patients known to have severe slat-wasting episodes in infancy and early childhood iv. Siblings may be discordant for salt wasting v. The degree of salt wasting may vary in individuals carrying identical mutations. vi. Patients with 3b-hydroxysteroid hydrogenase deficiency, aldosterone synthase deficiency, or lipoid hyperplasia a) Unable to synthesize aldosterone b) May present with salt-wasting crises c. Children with classic CAH i. Lack of sufficient amounts of cortisol to mount a stress response and frequently succumb to minor illnesses ii. Premature closure of the epiphyses resulting in short stature even though these children grow at an accelerated rate when young d. Growth disturbances i. Accelerated skeletal maturation in untreated patients due to high levels of androgen ii. Growth retardation in patients treated with excessive doses of glucocorticoids iii. Final height, despite careful monitoring and good patient compliance, usually averaging one to two standard deviations below the population mean or the target height based on parental heights e. Reproductive problems in affected females (White 2001) i. Ambiguous genitalia typically present in the neonatal period a) Clitoromegaly (mild) b) With or without partial fusion of the labioscrotal folds (intermediate) c) Complete fusion of the labioscrotal folds with the appearance of a penile urethra (severe) ii. Internal genitalia a) Normal ovaries, fallopian tubes, and uteri b) Normal upper third of the vagina but urogenital sinus may be present distally with one opening on the perineum iii. Signs of androgen excess in affected females without glucocorticoid replacement therapy (New 2002)

418

Congenital Adrenal Hyperplasia

iv.

v.

vi.

vii.

viii.

a) Clitoral enlargement b) Excessive linear growth c) Advanced bone age d) Acne e) Early onset of pubic and axillary hair f) Hirsutism g) Male pattern baldness h) Menstrual abnormalities i) Reduced fertility Adolescence (White 2001) a) Late menarche in inadequately treated girls b) Sonographic finding of multiple ovarian cysts similar to patients with polycystic ovarian syndrome c) Anovulation d) Irregular bleeding e) Hyperandrogenic symptoms Pregnancy and live-birth rates a) Severely reduced in salt-wasting patients b) Mildly reduced in simple virilizing patients c) Normal in nonclassical patients Factors suggested responsible for the impaired fertility (Stikkelbroeek et al. 2003) a) Adrenal overproduction of androgens and progestins (17-hydroxyprogesterone, progesterone, and androstenedione) b) Ovarian hyperandrogenism c) Polycystic ovary syndrome d) Ovarian adrenal rest tumors e) Neuroendocrine factors f) Genital surgery g) Psychosocial factors (delayed psychosexual development, reduced sexual activity, low maternal feelings) No evidence of an excess of congenital malformations in offspring of women with 21-hydroxylase deficiency (White 2001) Other types of congenital adrenal hyperplasia (White 2001) a) 11b-hydroxylase deficiency: similar to 21-hydroxylase deficiency b) 17a-hydroxylase deficiency: remains sexually infantile due to inability to synthesize sex hormones unless supplemented with estrogen

c) 3b-hydroxysteroid hydrogenase deficiency: slightly virilized due to high levels of dehydroepiandrosterone f. Reproductive function and problems in affected males (New 2002; White 2001) i. Signs of androgen excess in affected males without glucocorticoid replacement therapy a) Penile enlargement b) Small testes c) Excessive linear growth d) Advanced bone age e) Acne f) Early onset of pubic and axillary hair ii. Ability to father children iii. Testicular adrenal rests a) Most often benign b) Manifest as testicular enlargement c) Seen most often in inadequately treated patients, particularly those with the saltwasting form of 21-hydroxylase deficiency iv. Other types of congenital adrenal hyperplasia a) Men with 11b-hydroxylase deficiency: similar to those with 21-hydroxylase deficiency b) Genetic males with 3b-hydroxysteroid hydrogenase deficiency, 17a-hydroxylase deficiency, or lipoid hyperplasia: usually raised as females and castrated during or before adolescence to prevent malignant transformation of abdominal testes g. Effects on gender role, sexual orientation, and identity (White 2001) i. Gender role a) Referring to gender-stereotyped behaviors such as choice of play toys by young children b) Girls with 21-hydroxylase deficiency may show low interest in maternal behavior, extending from lack of doll play in early childhood to lack of interest in childrearing in women. ii. Sexual orientation a) Referring to homosexual versus heterosexual preferences b) Heterosexuality in most adult women with 21-hydroxylase deficiency

Congenital Adrenal Hyperplasia

c) Homosexuality or bisexuality or increased tendency to homo-erotic fantasies in a small but significant proportion in women with 21-hydroxylase deficiency iii. Gender identity a) Referring to self-identification as male or female b) Self-reassignment to the male sex is unusual in women with 21-hydroxylase deficiency c) Severely virilized females are more likely to be raised as males in cultures that value boys more highly and/or in third world countries in which the diagnosis is likely to be delayed. 3. Nonclassic CAH phenotype (White 2001) a. Having only moderate enzyme deficiency b. Nonambiguous external genitalia, with normal or mild clitoromegaly, in females affected with mild, nonclassical form of 21-hydroxylase deficiency c. Signs of androgen excess i. Wide spectrum of symptoms and signs ii. Asymptomatic in many affected individuals iii. Children: premature pubarche iv. Young women a) Severe cystic acne b) Hirsutism c) Oligomenorrhea d. Signs and symptoms suggesting mild CAH (Deaton et al. 1999) i. Children a) Moderate to severe recurrent sinus or pulmonary infections b) Severe acne c) Hyperpigmentation, especially of the genitalia d) Tall for age e) Early onset of puberty ii. Adults a) Childhood history as described above b) Syncope or near-syncope c) Shortened stature compared with either parent d) Hypotension (21-hydroxylase deficiency) e) Hypertension (11b-hydroxylase deficiency) iii. Women a) Clitoromegaly b) Poorly developed labia

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c) Premature adrenarche d) Hirsutism e) Menstrual disturbances f) Infertility g) Polycystic ovary syndrome 4. Clinical characteristics of other forms of CAH (Antal and Zhou 2009) a. 11-Beta Hydroxylase deficiency i. Ambiguous genitalia in females ii. Rare adrenal crisis b. 17-alpha-hydroxylase deficiency i. Ambiguous genitalia in males ii. No adrenal crisis c. 3-beta-hydroxysteroid Dehydrogenase deficiency i. Ambiguous genitalia in males ii. Adrenal crisis present d. Lipoid CAH i. Ambiguous genitalia in males ii. Severe adrenal crisis

Diagnostic Investigations 1. Newborn screening (New 2002; White 2001, 2009) a. Objectives i. Detect a common and potentially fatal childhood disease (classic form of CAH) ii. Prevent serious morbidity and mortality by early recognition and treatment iii. Prevent incorrect male sex assignment of affected female infants with ambiguous genitalia iv. Detect most, but not all, cases of the nonclassic form of 21-hydroxylase deficiency b. Filter-paper blood spot sample (White 2001) i. Markedly elevated 17-hydroxyprogesterone by radioimmunoassay ii. False positives a) Samples taken in the first 24 h of life (elevated in all infants) b) Variation of weight adjusted cutoff values among newborn screening programs c) Infants with low birth weight or prematurity c. Diagnosis is based on elevated levels of 17hydroxyprogesterone, the preferred substrate for steroid 21-hydroxylase

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d. Initial testing usually involves dissociationenhanced lanthanide fluorescence immunoassay that has a low positive predictive value (about 1%), leading to many follow-up evaluations that have negative results e. Second level of screening based on detection of actual mutations on DNA extracted from the same dried blood spots or liquid chromatography followed by tandem mass spectrometry f. Main benefits of newborn screening i. Reduced morbidity and mortality ii. Reduced time to diagnosis of infants with 21-hydroxylase deficiency iii. Infants ascertained through screening a) Less severe hyponatremia b) Tend to be hospitalized for shorter periods of time 2. Diagnosis of CAH a. Female neonates i. With genital ambiguity a) Genital ambiguity highly distressing to the family b) Require urgent expert medical attention c) Need immediate comprehensive evaluation by a multidisciplinary team including specialists from pediatric endocrinology, psychosocial services, pediatric surgery/urology, and genetics ii. With or without salt loss iii. Presence of elevated concentration of serum 17-hydroxyprogesterone a) Only diagnostic of CAH when measured after the 3rd day of life b) Presence of relatively high concentrations in the immediate neonatal period in normal infants iv. Normal internal female genitalia on pelvic ultrasonography v. Normal female karyotype (46,XX) b. Male neonates i. Salt-losing crises ii. Presence of elevated 17-hydroxyprogesterone concentration 3. Clinical chemistry a. Important initial laboratory evaluation for patients suspected of experiencing adrenal crisis due to 21-hydroxylase deficiency (Antal and Zhou 2009)

Congenital Adrenal Hyperplasia

4.

5. 6. 7.

i. Glucose/dextrose stick at bedside ii. Chem-20 (including electrolytes and liver function panel): critical to assure that the potassium concentration is obtained from a nonhemolyzed sample to minimize the likelihood of a falsely elevated potassium value iii. Arterial blood gas/serum pH iv. Cortisol v. ACTH vi. 17-OHP vii. Pelvic ultrasonography viii. Karyotype b. ACTH stimulation test: necessary to evaluate adrenal function and differentiate among the various potential enzymatic defects (Antal and Zhou 2009) c. Comparison of baseline and cortrosyn-stimulated serum concentrations of the steroid precursor 17-hydroxyprogesterone (nonclassical) d. Increased serum levels of progesterone, 17-hydroxyprogesterone, and androstenedione in affected males and females with classic 21-hydroxylase deficiency e. Elevated serum levels of testosterone and adrenal androgen precursors in affected girls f. Salt losers i. Low serum bicarbonates, sodium, and chloride levels ii. Elevated levels of serum potassium and serum urea nitrogen iii. Hyponatremia and hyperkalemia usually not present before 7 days of age iv. Inappropriately increased urine sodium levels v. Elevated plasma rennin levels vi. Serum aldosterone level inappropriately low for the rennin level Karyotyping or fluorescence in situ hybridization for sex chromosome material a. 46,XX in females with 21-hydroxylase deficiency b. 46,XY in males with 21-hydroxylase deficiency Annual bone age radiography Careful monitoring of linear growth Transabdominal pelvic sonography a. Perform in patients with CAH undergoing vaginal reconstruction b. Provide adequate information about the anatomy of the vagina and urogenital sinus

Congenital Adrenal Hyperplasia

8. 9.

10. 11.

12.

13.

c. Demonstrate presence or absence of a uterus or associated renal anomalies Urogenitogram helpful to define the anatomy of the internal genitalia Adrenal ultrasonography to detect enlarged, lobulated adrenals with stippled echogenicity invariably associated with CAH Sonography or MRI for testicular adrenal rest tumors Carrier detection (New 2002) a. Carriers: asymptomatic individuals who have one normal allele and one mutant allele b. ACTH stimulation test i. Resulting in slightly elevated serum concentrations of deoxycortisol and 17hydroxyprogesterone ii. Overlap in serum concentration of 17hydroxyprogesterone between carriers and noncarriers iii. No longer the preferred method of carrier detection c. Molecular genetic testing i. Molecular genetic testing of the CYP21A2 gene available to at-risk relatives, given that the disease-causing mutation(s) have been identified in the proband ii. The preferred method of carrier detection Molecular genetic testing (New 2002) a. Molecular genetic analysis for CYP21A2 gene for a panel of 9 common mutations and gene deletions detect about 90–95% of diseasecausing alleles in affected individuals and carriers. b. Complete gene sequencing detects more rare alleles in affected individuals in whom the panel of nine mutations and deletions reveals only one or neither disease-causing allele c. Applications i. Primarily used in genetic counseling for carrier detection of at-risk relatives and for prenatal diagnosis ii. Can be used for diagnosis in newborns with slight to moderate elevations of 17hydroxyprogesterone Laboratory characteristics of other forms of CAH (Antal and Zhou 2009) a. 11-Beta Hydroxylase deficiency i. Glucocorticoid values; decreased ii. Mineralocorticoid values: elevated

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iii. iv. v. vi.

Androgens: elevated Sodium concentrations: elevated Potassium concentrations: decreased Elevated metabolites a) Deoxycorticosterone (DOC) b) 11-deoxycortisol b. 17-alpha-hydroxylase deficiency i. Glucocorticoid values: decreased ii. Mineralocorticoid values: elevated iii. Androgens: decreased iv. Sodium concentrations: increased v. Potassium concentrations: decreased vi. Elevated metabolites a) Deoxycorticosterone b) Corticosterone c. 3-beta-hydroxysteroid Dehydrogenase deficiency i. Glucocorticoid values: decreased ii. Mineralocorticoid values: decreased iii. Androgens a) Elevated in females b) Decreased in males iv. Sodium concentrations: decreased v. Potassium concentrations: elevated vi. Elevated metabolites a) Dehydroepiandrosterone (DHEA) b) 17-hydroxypregnenolone d. Lipoid CAH i. Glucocorticoid values: decreased ii. Mineralocorticoid values: decreased iii. Androgens: decreased iv. Sodium concentrations: decreased v. Potassium concentrations: elevated vi. Elevated metabolites: none

Genetic Counseling 1. Recurrence risk a. Genetic counseling according to autosomal recessive inheritance i. Most parents: heterozygotes with one normal allele and one mutated allele. ii. One percentage of probands having only one parent who is heterozygous since 1% of mutations occur de novo iii. In some instances, a parent, who was previously not known to be affected, was found to have the nonclassic form of 21-hydroxylase deficiency.

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b. Patient’s sib i. When the parents of a proband are both obligate heterozygotes a) Twenty-five percent risk of inheriting both altered alleles and being affected b) Fifty percent risk of inheriting one altered allele and being an unaffected carrier c) Twenty-five percent risk of inheriting both normal allele and being unaffected d) Two-third chance of unaffected sibs of a proband being a carrier ii. When a parent of a proband has 21-hydroxylase deficiency and the other is heterozygous a) Fifty percent risk of inheriting both mutant alleles and being affected b) Fifty percent risk of inheriting one mutant allele and being a carrier c. Patient’s offspring for a woman with classic 21-hydroxylase deficiency i. When the spouse status is unknown (Lo and Grumbach 2001) a) Risk of having an infant with the same disorder: approximately 1 in 120 births b) Risk of having an affected female infant: approximately 1 in 240 births c) Risk figures are based on an estimated 1 in 60 incidence of heterozygous individuals with a CYP21 mutation, derived from newborn screening data ii. When the spouse is not a carrier or not affected: risk is not increased iii. Appropriate to offer molecular genetic testing of the CYP21A2 gene to the spouse given the high carrier rate for 21-hydroxylase deficiency d. Patient’s offspring for a woman with nonclassic CAH and are compound heterozygotes with one severe CYP21A2 mutation: Risk of having an affected infant with classic CAH is 1 in 4 pregnancies (or 1 in 8 pregnancies for an affected female infant) when the spouse is a known carrier of the severe form of CYP21A2 deficiency. 2. Prenatal diagnosis a. Determination of amniotic fluid (AF) hormone levels i. Elevated 17a-hydroxyprogesterone ii. Elevated androstenedione

Congenital Adrenal Hyperplasia

b. Human leukocyte antigen (HLA) typing on cultured chorionic villus cells and cultured AF cells i. Basis for prenatal diagnosis: the gene for 21-hydroxylase has been linked to the HLA system on chromosome 6 ii. HLA type a) Fetus with an HLA type identical to that of the proband with 21-hydroxylase deficiency predicted to be affected b) Fetus sharing 1 parental haplotype with the proband predicted to be a heterozygous carrier c) Fetus with both haplotypes different from the index case predicted to be homozygous normal c. Molecular DNA diagnosis i. Molecular genetic testing of the proband and both parents should be undertaken prior to conception: a) To identify the two disease-causing mutations b) To confirm both parents are carriers ii. Analysis of both parents a) To determine the phase of different mutations (whether they lie on the same or opposite alleles) b) To distinguish homozygotes and hemizygotes (individuals who have a mutation on one chromosome and a deletion on the other) iii. De novo mutations, found in patients with CAH but not in parents, observed in 1% of disease-causing CYP21B mutations iv. Before 10 weeks of gestation and prior to any prenatal testing, administer dexamethasone to the pregnant mother to suppress excess fetal adrenal androgen secretion and to prevent virilization of an affected female v. Obtain fetal cells to determine fetal sex by chromosome analysis or FISH using Y-chromosome specific probes a) CVS in the 10th–12th week of gestation (preferable because of early result) b) Amniocentesis at 16–18 weeks of gestation vi. If the fetus is a female and if the two CYP21A2 disease-causing mutations have been identified in the proband:

Congenital Adrenal Hyperplasia

a) Perform molecular genetic testing to determine whether the fetus has inherited both disease-causing alleles b) Female fetus known to have 21hydroxylase deficiency by DNA analysis or having an indeterminant status: continue dexamethasone treatment to term vii. If the fetus is a male or unaffected female by DNA analysis: discontinue dexamethasone treatment 3. Management (White 2001) a. Replacement with glucocorticoids (hydrocortisone, prednisone, dexamethasone) i. Indicated in all patients with classic and symptomatic nonclassical patients with 21hydroxylase deficiency ii. To suppress the excessive secretion of CRH and ACTH by the hypothalamus and pituitary iii. To reduce the abnormal blood levels of adrenal sex steroids iv. Situations in which increase hydrocortisone dose is needed in patients with classic 21hydroxylase deficiency a) Febrile illness b) Surgery under general anesthesia v. Increase doe of hydrocortisone or prednisone in pregnancy due to pregnancy-induced alterations in steroid metabolism and clearance vi. Glucocorticoid replacement also required in patients with CAH caused by other enzymatic deficiencies b. Mineralocorticoid replacement i. Mineralocorticoid (fludrohydrocortisone) and sodium chloride supplements required in infants with the salt-wasting form of 21hydroxylase deficiency ii. Treat patients with simple virilizing form of the disease by fludrohydrocortisone to aid in adrenocortical suppression and reduce the dose of glucocorticoid required to maintain acceptable 17-hydroxyprogesterone levels iii. Signs of overtreatment with mineralocorticoid and sodium replacement a) Hypertension b) Tachycardia c) Suppressed plasma rennin activity

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iv. Other indications of fludrohydrocortisone replacement a) 3b-hydroxysteroid hydrogenase deficiency b) Aldosterone synthase deficiency c) Lipoid hyperplasia c. Other pharmacological approaches i. A novel 4-drug regimen for 21-hydroxylase deficiency a) Consisting of flutamide (an androgen receptor blocking drug), testolactone (an aromatase inhibitor), and low dose of hydrocortisone and fludrocortisone b) Benefit: produce less bone age advancement and attain more appropriate linear growth velocity than standard treatment c) Side effect: occurrence of central precocious puberty requiring treatment with gonadotrophin releasing hormone analog ii. Experimental treatment with carbenoxolone, an inhibitor of 11b-hydroxysteroid dehydrogenase d. Corrective surgery i. Decision about surgery a) Made by the parents, together with the clinical team b) After disclosure of all relevant clinical information and all available options c) Obtain informed consent ii. Objectives a) Genital appearance compatible with gender b) Unobstructed urinary emptying without incontinence or infections c) Good adult sexual and reproductive function iii. Clitoroplasty, rather than clitoridectomy, done in infancy iv. Vaginal reconstruction a) Often postponed until the age of expected sexual activity b) Single-stage corrective surgery in children e. Adrenalectomy i. Questionable therapeutic alternative ii. Likely to be used, if at all, in patients with severe 21-hydroxylase deficiency refractory to standard medical management

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f. Management of testicular adrenal rests i. Effective adrenal suppression with dexamethasone since many of these tumors are ACTH-responsive ii. Testis-sparing surgery for cases unresponsive to dexamethasone after imaging the tumor by sonography and/or MRI g. Management of adolescence with classical and nonclassical CAH (Clayton et al. 2002) i. Psychological assessment and support of the patient ii. Counseling a) Sexual function b) Future surgeries c) Gender role d) Issues related to living with a chronic disorder e) Low risk of women with CAH or nonclassic CAH having an affected fetus h. Management of pregnancy in women with classic 21-hydroxylase deficiency (Lo and Grumbach 2001) i. Factors contributing to lower fertility rates a) Masculinization of the external genitalia b) An inadequate introitus c) Factors relating to genital reconstructive surgery (poor surgical repair, vaginal stenosis, and clitoral dysfunction) d) Hormonal factors (increased levels of adrenal androgens and progestational steroid, and ovarian hyperandrogenism) ii. Recent improvement of fertility prognosis a) Earlier detection and treatment of 21hydroxylase deficiency b) Surgical advances in genital reconstruction c) Higher patient compliance rates iii. Preconception issues for all women with classic 21-hydroxylase deficiency who desire pregnancy a) Need for glucocorticoid treatment b) Careful endocrine monitoring throughout gestation c) Ovulation induction with clomiphene citrate or gonadotropin therapy or in vitro fertilization for patients who do not achieve normal ovulatory cycles and fertility despite effective glucocorticoid therapy d) Most pregnancies are successful in carrying to term with a healthy outcome.

Congenital Adrenal Hyperplasia

e) Preconceptional counseling about the risk of having a child affected with 21-hydroxylase deficiency iv. Gestational management (Lo Lo and Grumbach 2001) a) Regular assessment of maternal clinical status, serum electrolytes, and circulating adrenal androgen levels during gestation to determine the need for increased glucocorticoid or mineralocorticoid therapy b) Signs of adrenal steroid insufficiency (excessive nausea, slat craving, and poor weight gain) c) Monitor hypertension and fluid retention in patients receiving mineralocorticoid therapy, particularly in the third trimester v. Labor and delivery (Lo and Grumbach 2001) a) Require stress doses of glucocorticoid therapy during labor and delivery b) Elective cesarean section considered for pregnant women with virilizing CAH, for cephalopelvic disproportion due to android pelvic characteristics and especially for those who have had reconstructive surgery of the external genitalia vi. Evaluation of the infant (Lo and Grumbach 2001) a) Clinical signs of adrenal suppression (hypotension, hypoglycemia), particularly in cases in which dexamethasone was administered during pregnancy b) Sign of ambiguous external genitalia c) Female pseudohermaphroditism secondary to either maternal hyperandrogenism or fetal 21-hydroxylase deficiency (if the father is a carrier) i. Prenatal therapy i. Inclusion criteria (Clayton et al. 2002) a) A previously affected sibling or firstdegree relative with known mutations causing classic CAH, proven by DNA analysis b) Reasonable expectation that the father is the same as the father of the proband c) Availability of rapid, high-quality genetic analysis d) Therapy started less than 9 weeks after the last menstrual period

Congenital Adrenal Hyperplasia

ii.

iii.

iv.

v.

vi.

e) No plans for therapeutic abortion f) Reasonable expectation of patient compliance Dexamethasone a) No salt-retaining activity b) Not significantly metabolized by placental 11b-hydroxysteroid dehydrogenase c) Able to cross the placenta Administer oral dexamethasone to the mother in pregnancies at risk for a female child affected with virilizing adrenal hyperplasia a) To suppress fetal adrenal androgen production, beginning after conception and before the 7–8th week of gestation, to prevent ambiguity of the external genitalia in the female fetus with classic CAH b) To prevent progression of virilization on therapy after 7–8th week of gestation c) Chromosome analysis from fetal cells obtained from either CVS at 10–12 weeks of gestation or amniocentesis at 14–18 weeks of gestation d) If the fetus is a female, additional molecular genetic testing is performed on the sample to determine if she has 21hydroxylase deficiency (Antal and Zhou 2009) e) If the fetus is affected, maternal dexamethasone administration is continued to term; if not, it can be discontinued Outcome of prenatally treated females (American Academy of Pediatrics 2000) a) Approximately 70% born with normal or only slightly virilized genitalia with clitoromegaly, partial labial fusion, or both b) Approximately 30% born with marked genital virilization Disadvantage: 7 out of 8 fetuses unnecessarily treated since CAH is inherited as an autosomal recessive disease and only affected girls benefit from the treatment Prompt discontinuation of dexamethasone therapy to minimize potential risks of glucocorticoid toxicity if (White 2001): a) Male sex determination by prenatal genetic diagnosis b) CYP21 genotype indicating that the fetus is unaffected

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vii. Refer patient to centers with expertise in the prenatal management of pregnancies at risk for CAH. viii. Long-term follow-up studies still needed for prenatally treated children ix. Side effects of women treated to term (10%) a) Features of Cushing syndrome (excessive weight gain, severe striae, hypertension, hyperglycemia) b) Resolved when the treatment is discontinued x. Side effects of women treated for a shorter time (10–20%) a) Edema b) Gastrointestinal upset c) Mood fluctuations d) Acne e) Hirsutism xi. Similar therapeutic approaches: effective in families at risk for 11b-hydroxylase deficiency, in which affected female fetuses may also suffer severe prenatal virilization xii. Prenatal therapy not appropriate for nonclassic CAH xiii. Parents of affected girls a) Many opting for prenatal medical treatment because of severe psychological impact of ambiguous genitalia on the child and on the family b) Obtain informed consent as to the potential fetal and maternal risks, some of which may yet to be recognized

References Al-Alwan, I., Navarro, O., Daneman, D., et al. (1999). Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. Journal of Pediatrics, 135, 71–75. American Academy of Pediatrics Ad Hoc Writing Committee, 2000–2001. (2000). Technical Report: Congenital adrenal hyperplasia. Pediatrics 106, 1511–1518. Antal, Z., & Zhou, P. (2009). Congenital adrenal hyperplasia: Diagnosis, evaluation, and management. Pediatrics in Review, 30, e49–e57. Bose, H. S., Sugawara, T., Strauss, J. F., III, et al. (1996). The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. The New England Journal of Medicine, 355, 1970–1978.

426 Chen, H. (1986). Genetic disorders. In Paul I. Liu (Ed.), Blue book of diagnostic tests (pp. 421–462). Philadelphia, PA: W. B. Saunders. Chertin, B., Hadas-Halpern, I., Fridmans, A., et al. (2000). Transabdominal pelvic sonography in the preoperative evaluation of patients with congenital adrenal hyperplasia. Journal of Clinical Ultrasound, 28, 122–124. Clayton, P. E., Miller, W. L., & Oberfield, S. E. (2002). Concensus statement on 21-hydroxylase deficiency from the European Society of Pediatric Endocrinology and the lawson Wilkins Paediatric Endocrine Society. Hormone Research, 58, 188–195. Cutler, G. B., Jr., & Laue, L. (1990). Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The New England Journal of Medicine, 323, 1806–1813. David, M., & Forest, M. G. (1984). Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Journal of Pediatrics, 105, 799–803. Deaton, M. A., Glorioso, J. E., & Mclean, D. B. (1999). Congenital adrenal hyperplasia: Not really a zebra. American Family Physician, 59, 1190–1196. Deneux, C., Tardy, V., Dib, A., et al. (2001). Phenotypegenotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism, 86, 207–213. Forest, M. G., Morel, Y., & David, M. P. (1998). Prenatal treatment of congenital adrenal hyperplasia. Trends in Endocrinology and Metabolism, 9, 284–289. Garner, P. R. (1998). Congenital adrenal hyperplasia in pregnancy. Seminars in Perinatology, 22, 446–456. Hall, C. M., Jones, J. A., Meyer-Bahlburg, H. F., et al. (2004). Behavioral and physical masculinization are related to genotype in girls with congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism, 89, 419–424. Hoffman, W. H., Shin, M. Y., Donohoue, P. A., et al. (1996). Phenotypic evolution of classic 21-hydroxylase deficiency. Clinical Endocrinology, 45, 103–109. Hughes, I. A. (1986). Clinical aspects of congenital adrenal hyperplasia: Early diagnosis and prognosis. Journal of Inherited Metabolic Disease, 9(Suppl 1), 115–123. Hughes, I. A. (1988). Management of congenital adrenal hyperplasia. Archives of Disease in Childhood, 63, 1399–1404. Hughes, I. A. (2002a). Congenital adrenal hyperplasia: 21-hydroxylase deficiency in the newborn and during infancy. Seminars in Reproductive Medicine, 20, 229–242. Hughes, I. A. (2002b). Congenital adrenal hyperplasia: Phenotype and genotype. Journal of Pediatric Endocrinology & Metabolism, 15(Suppl 5), 1329–1340. Hughes, I. A. (2002c). Intersex. BJU International, 90, 769–776. Joint LWPES/ESPE CAH Working Group, Writing Committee. (2002). Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Journal of Clinical Endocrinology Metabolism 87, 4098–4053. Kuttenn, F., Couillin, P., Girard, F., et al. (1985). Late-onset adrenal hyperplasia in hirsutism. The New England Journal of Medicine, 313, 224–231.

Congenital Adrenal Hyperplasia Lajic, S., Wedell, A., Bui, T. H., et al. (1998). Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. Trends in Endocrinology and Metabolism, 9, 284–289. Levine, L. S. (2000). Congenital adrenal hyperplasia. Pediatrics in Review, 21, 159–170. Lo, J. C., & Grumbach, M. M. (2001). Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America, 30, 207–229. Merke, D. P., & Cutler, G. B. (1997). New approaches to the treatment of congenital adrenal hyperplasia. JAMA, 277, 1073–1076. Meyer-Bahlburg, H. F. (2001). Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America, 30, 155–171. Miller, W. L. (1998). Molecular biology of steroid hormone synthesis. Endocrine Reviews, 9, 295–318. Miller, W. L. (1999). Congenital adrenal hyperplasia in the adult patient. Advances in Internal Medicine, 44, 155–173. New, M. I. (1995). Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). The American Journal of Medicine, 98, 2S–8S. New, M. I. (2001a). Antenatal diagnosis and treatment of congenital adrenal hyperplasia. Current Urology Reports, 2, 11–18. New, M. I. (2001b). Prenatal treatment of congenital adrenal hyperplasia. The United States experience. Endocrinology and Metabolism Clinics of North America, 30, 1–13. New, M. I., Carlson, A., Obeid, J., et al. (2001). Extensive personal experience. Prenatal diagnosis for congenital adrenal hyperplasia. Journal of Clinical Endocrinology and Metabolism, 86, 5651–5657. New, M. I., & Wilson, R. C. (2002). Genetic disorders of the adrenal gland, chapter 84. In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Emery and Rimoin’s principles and practice of medical genetics (4th ed., Vol. 2, pp. 2277–2314). Nimkarn, S., & New, M. I. (2010). 21-hydroxylse deficient congenital adrenal hyperplasia. GeneReviews. Retrieved August 24, 2010. Available at: http://www.ncbi.nlm.nih. gov/books/NBK1171/ Pang, S. (1997). Congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics, 26, 853–891. Pang, S., & Shook, M. K. (1997). Current status of neonatal screening for congenital adrenal hyperplasia. Current Opinion in Pediatrics, 9, 419–423. Pang, S., Wallace, M. A., Hofman, L., et al. (1988). Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics, 81, 866–874. Ritze´n, E. M. (1998). Prenatal treatment of congenital adrenal hyperplasia: A commentary. Trends in Endocrinology and Metabolism, 9, 293–295. Ritze´n, E. M. (2001). Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: Benefits and concerns. Seminars in Neonatology, 6, 357–362. Schnitzer, J. J., & Donahoe, P. K. (2001). Surgical treatment of congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America, 30, 137–154.

Congenital Adrenal Hyperplasia Speiser, P. W. (2001). Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinology and Metabolism Clinics of North America, 30, 31–59. Speiser, P. W., Dupont, B., Rubinstein, P., et al. (1985). High frequency of nonclassical steroid 21-hydroxylase deficiency. American Journal of Human Genetics, 37, 650–667. Speiser, P. W., & New, M. I. (1994). Prenatal diagnosis and management of congenital adrenal hyperplasia. Clinics in Perinatology, 21, 631–645. Speiser, P. W., & White, P. C. (2003). Congenital adrenal hyperplasia. The New England Journal of Medicine, 349, 776–788. Stikkelbroeck, N. M., Hermus, A. R., Braat, D. D., et al. (2003). Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstetrical and Gynecological Survey, 58, 275–284. Therrell, B. L. (2001). Newborn screening for congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics, 30, 15–30. Therrell, B. L. J., Berenbaum, S. A., Manter-Kapanke, V., et al. (1998). Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics, 101, 583–590. Wedell, A. (1996). Molecular approaches for the diagnosis of 21-hydroxylase deficiency and congenital adrenal hyperplasia. Clinics in Laboratory Medicine, 16, 125–137.

427 Wedell, A. (1998). Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): Implications for diagnosis, prognosis and treatment. Acta Paediatrica, 87, 159–164. White, P. C. (2001). Congenital adrenal hyperplasias. Best Practice & Research. Clinical Endocrinology & Metabolism, 15, 17–41. White, P. C. (2009). Neonatal screening for congenital adrenal hyperplasia. Nature Review Endocrinology, 5, 490–498. White, P. C., New, M. I., & Dupont, B. (1987a). Congenital adrenal hyperplasia. (first of two parts). The New England Journal of Medicine, 316, 1519–1524. White, P. C., New, M. I., & Dupont, B. (1987b). Congenital adrenal hyperplasia (second of two parts). The New England Journal of Medicine, 316, 1580–1586. White, P. C., & Speiser, P. W. (2000). Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews, 21, 245–291. Wilson, T. (2004). Congenital adrenal hyperplasia. Emedicine. http://www.emedicine.com Woelfle, J., Hoepffner, W., Sippell, W. G., et al. (2002). Complete virilization in congenital adrenal hyperplasia: Clinical course, medical management and disease-related complications. Clinical Endocrinology, 56, 231–238.

428

Congenital Adrenal Hyperplasia

a

a

b b

c

Fig. 2 (a, b) A newborn with congenital adrenal hyperplasia showing ambiguous genitalia. Newborn screening from filter paper showed total 17OHP of >240 ng/mL (normal 20mu/L) should be confirmed by a venous sample (using age appropriate cutoffs) before initiating treatment a. Successful identification of infants with congenital hypothyroidism b. Enables early diagnosis and treatment of infants and prevention of mental retardation c. Newborn screening measures either TSH or T4 in neonatal blood placed on filter paper d. Confirmation with a serum sample if the filter paper result is abnormal i. Primary congenital hypothyroidism a) Low serum T4 levels b) Elevated serum TSH ii. Hypopituitary hypothyroidism a) Low total T4 levels b) Low or normal TSH iii. Thyroxine-binding globulin (TBG) deficiency a) Low total T4 but normal serum-free T4 levels b) Normal TSH e. Screening programs for congenital hypothyroidism in premature newborns (Kugelman et al. 2009) i. Sick premature infants may display transient hypothyroxinemia secondary to immaturity of the hypothalamic-pituitary axis. ii. Therefore, early screening programs of such infants may be misleading. iii. Recommendations a) Screening programs should report thyroid stimulating hormone (TSH) as well as thyroxin (T4) levels in premature infants, which will allow the treating physicians to be aware of possible abnormality that needs to be followed. b) Sick premature infants and other populations at risk should undergo a full serum thyroid function evaluation including free T4 and TSH beyond the screening program at discharge or at 30 days of age, whichever comes first.

2.

3. 4.

5.

c) Physicians should use their clinical judgment and experience even in the face of normal newborn thyroid screening test and reevaluate for hypothyroidism when there is a clinical suspicion. f. Pendred syndrome (Banghova et al. 2008) i. An autosomal recessive disorder characterized by sensorineural hearing loss and thyroid dyshormonogenesis ii. Caused by mutations in the PDS/SLC26A4 gene iii. Present from birth iv. Can be diagnosed by newborn screening Laboratory diagnosis a. Thyroid function tests i. Elevated serum TSH ii. Low serum T4 levels b. Determine antithyroglobulin and antithyroid peroxidase antibodies if indicated c. Determine TBG levels for suspected TBG deficiency Radiography for bone age Ultrasonography, considered as the best noninvasive method for the anatomical assessment of the thyroid gland Radionuclide scan (thyroid scintigraphy) using 99m Tc or 123I (DeLange 1997) a. To demonstrate the presence of ectopic thyroid tissue or thyroid aplasia b. Iodide transport defect i. Low or absent uptake of 123I ii. Response to therapeutic doses of potassium iodide c. Defective organification of iodide i. Rapid uptake of 123I ii. Marked decrease in thyroid radioactivity when perchlorate or thiocyanate is administered 2 h after administering radioiodine iii. Occasional sensorineural hearing loss (Pendred syndrome) d. Iodotyrosine-coupling defect i. Rapid uptake of 123I ii. No discharge by perchlorate iii. Very high thyroid gland content of monoiodotyrosine (MIT) and diiodotyrosine (DIT) iv. Virtually undetectable T4 and T3 v. Adequately iodinated thyroglobulin

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e. Defects in thyroglobulin gene expression and thyroglobulin secretion i. Elevated uptake of 123I ii. No discharge by perchlorate iii. Abnormal serum iodoproteins iv. Elevated protein-bound/T4 iodine ratio v. Low or borderline serum thyroglobulin f. Iodotyrosine deiodinase defect i. Rapid uptake and turnover of 123I ii. Elevated serum and urinary iodotyrosines (MIT, DIT) iii. Response to iodine supplementation 6. Intelligence quotient (IQ) measurement for testing neuropsychological progress and outcome 7. Molecular genetic diagnosis by sequencing of select exons to identify mutations

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: 25% iii. Autosomal dominant inheritance: low recurrence risk unless a parent is affected b. Patient’s offspring i. Sporadic cases: low recurrence risk ii. Autosomal recessive inheritance: low recurrence risk unless the spouse carries the recessive gene iii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis a. Ultrasonography and percutaneous fetal blood sampling i. Detection of fetal goiter a) A rare yet potentially dangerous condition b) A large goiter may cause hyperextension of the neck of the fetus caused by a large goiter, resulting in malpresentation and complicating labor and delivery c) Possibility of compressing the trachea and asphyxiating the neonate after birth ii. Fetal blood sample a) Elevated TSH b) Low T4 b. Amniocentesis i. Determination of TSH concentration (markedly elevated TSH level) in amniotic

Congenital Hypothyroidism

fluid in the second trimester for the offspring of a couple both known to have an iodide (iodothyronine synthesis) enzymatic organification defect ii. Affected fetus with markedly increased TSH level in the amniotic fluid sample for the trimester c. Molecular genetic diagnosis possible by sequencing of select exons on fetal DNA for previously identified mutations in a research laboratory 3. Management a. Sodium L-thyroxine i. The treatment of choice ii. Early therapy (within 14 days) with appropriate doses of thyroxine (about 10 mg/kg/ day) will prevent any brain damage even in case of evidence of fetal hypothyroidism, since thyroxine of maternal origin will reach and protect the fetus (DeLange 1997) iii. Avoid over treatment to prevent the following adverse effects (LaFranchi 1999): a) Premature cranial suture fusion b) Acceleration of growth and skeletal maturation c) Problems with temperament and behavior b. X-linked dominant thyroxine-binding globulin deficiency (causing a low total T4 but normal free T4): no need for thyroid hormone replacement c. Intrauterine treatment of fetus with a large goiter (Davidson et al. 1991) i. Indicated because of the morbidity associated with compression of the trachea and mechanical interferences during delivery ii. Intra-amniotic administration of levothyroxine presents the least invasive approach to fetal treatment a) Rapid decrease in the fetal goiter size b) Normalization of fetal thyroid function d. Intrauterine treatment of fetus affected with iodide organification defect with synthroid

References Abramowicz, M. J., Duprez, L., Parma, J., et al. (1997). Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of

Congenital Hypothyroidism the thyroid gland. Journal of Clinical Investigation, 99, 3018–3024. Abramowicz, M. J., Vassart, G., & Refetoff, S. (1997). Probing the cause of thyroid dysgenesis. Thyroid, 7, 325–336. Abuhamad, A. Z., Fisher, D. A., Worsof, S. L., et al. (1995). Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: Case report and review of the literature. Ultrasound in Obstetrics & Gynecology, 6, 368–371. Agrawal, P., Ogilvy-Stuart, A., & Lees, C. (2002). Intrauterine diagnosis and management of congenital goitrous hypothyroidism. Ultrasound in Obstetrics & Gynecology, 19, 501–505. Ambrugger, P., Stoeva, I., Biebermann, H., et al. (2001). Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism. European Journal of Endocrinology, 145, 19–24. American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health. (1993). Newborn screening for congenital hypothyroidism: Recommended guidelines. Pediatrics, 91, 1203–1209. Banghova, K., Al Taji, E., Cinek, O., et al. (2008). Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: Identification of two novel PDS/SLC26A4 mutations. European Journal of Pediatrics, 167, 777–783. Bargagna, S., Canepa, G., Costagli, C., et al. (2000). Neuropsychological follow-up in early-treated congenital hypothyroidism: A problem-oriented approach. Thyroid, 10, 243–249. Beltroy, E., Umpaichitra, V., Gordon, S., et al. (2003). Two infants who have coarse facial features and growth and developmental delay. Pediatrics in Review, 24, 16–21. Biebermann, H., Liesenkotter, K. P., Emeis, M., et al. (1999). Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene. Pediatric Research, 46, 170–173. Castanet, M., Polak, M., Bonaiti-Pellie, C., et al. (2001). Nineteen years of national screening for congenital hypothyroidism: Familial cases with thyroid dysgenesis suggest the involvement of genetic factors. Journal of Clinical Endocrinology and Metabolism, 86, 2009–2014. Clifton-Blight, R. J., Wentworth, J., Heinz, P., et al. (1998). Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nature Genetics, 18, 399–401. Coyle, B., Reardon, W., Herbrick, J. A., et al. (1998). Molecular analysis of the PDS gene in Pendred syndrome. Human Molecular Genetics, 7, 1105–1112. Davidson, K. M., Richards, D. A., Schatz, D. A., et al. (1991). Successful in utero treatment of fetal goiter and hypothyroidism. The New England Journal of Medicine, 234, 543–546. De Vijlder, J. J. M. (2003). Primary congenital hypothyroidism: Defects in iodine pathways. European Journal of Endocrinology, 149, 247–256. Delange, F. (1997). Neonatal screening for congenital hypothyroidism: Results and perspectives. Hormone Research, 48, 51–61. Fisher, D. A. (1997). Fetal thyroid function diagnosis and management of fetal thyroid disorders. Clinical Obstetrics and Gynecology, 40, 16–31.

475 Gr€ uters, A., Jenner, A., & Krude, H. (2002). Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Practice & Research. Clinical Endocrinology & Metabolism, 16, 369–382. Hirsch, M., Josefsberg, Z., Schoenfeld, A., et al. (1990). Congenital hereditary hypothyroidism–prenatal diagnosis and treatment. Prenatal Diagnosis, 10, 491–496. Jain, V., Agarwal, R., Deorari, A. K., et al. (2008). Congenital hypothyroidism. Indian Pediatrics, 75, 363–367. Kohn, L. D., Suzuki, K., Hoffman, W. H., et al. (1997). Characterization of monoclonal thyroid-stimulating and thyrotropin binding-inhibiting autoantibodies from a Hashimoto’s patients whose children had intrauterine and neonatal thyroid disease. The Journal of Clinical Endocrinology and Metabolism, 82, 3998–4004. Kopp, P. (2002). Perspective: Genetic defects in the etiology of congenital hypothyroidism. Endocrinology, 143, 2019–2024. Kreisner, E., Camargo-Neto, E., Maia, C. R., et al. (2003). Accuracy of ultrasonography to establish the diagnosis and aetiology of permanent primary congenital hypothyroidism. Clinical Endocrinology, 59, 361–365. Kugelman, A., Riskin, A., Bader, D., et al. (2009). Pitfalls in screening programs for congenital hypothyroidism in premature newborns. American Journal of Perinatology, 26, 383–385. LaFranchi, S. (1999). Congenital hypothyroidism: Etiologies, diagnosis, and management. Thyroid, 9, 735–740. Macchia, P. E. (2000). Recent advances in understanding the molecular basis of primary congenital hypothyroidism. Molecular Medicine Today, 6, 36–42. Macchia, P. E., De Felice, M., & Di Lauro, R. (1999). Molecular genetics of congenital hypothyroidism. Current Opinion in Genetics and Development, 9, 289–294. Macchia, P. E., Lapi, P., Krude, H., et al. (1998). PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genetics, 19, 83–86. Medeiros-Neto, G., Bunduki, V., Tomimori, E., et al. (1997). Prenatal diagnosis and treatment of dyshormonogenetic fetal goiter due to defective thryoglobulin synthesis. Journal of Clinical Endocrinology and Metabolism, 82, 4239–4242. Moreno, J. C., Bikker, H., Kempers, M. J., et al. (2002). Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. New England Journal of Medicine, 347, 95–102. Noia, G., De Santis, M., Tocci, A., et al. (1992). Early prenatal diagnosis and therapy of fetal hypothyroid goiter. Fetal Diagnosis and Therapy, 7, 138–143. Perelman, A. H., Johnson, R. L., Clemons, R. D., et al. (1990). Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 71, 618–621. Pfarr, N., Korsch, E., Kaspers, S., et al. (2006). Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene. Clinical Endocrinology, 65, 810–815. Postellon, D. C. (2011). Congenital hypothyroidism. eMedicine from WebMD. Updated May 16, 2011. Available at: http:// emedicine.medscape.com/article/919758-overview Schwingshandl, J., Donaghue, K., Luttrell, B., et al. (1993). Transient congenital hypothyroidism due to maternal

476 thyrotrophin binding inhibiting immunoglobulin. Journal of Paediatrics and Child Health, 29, 315–318. Smith, D. W., Klein, A. M., Henderson, J. R., et al. (1975). Congenital hypothyroidism–signs and symptoms in the newborn period. Journal of Pediatrics, 87, 958–962. Van Naarden Braun, K., Yeargin-Allsopp, M., Schendel, D., et al. (2003). Long-term developmental outcomes of children

Congenital Hypothyroidism identified through a newborn screening program with a metabolic or endocrine disorder: A population-based approach. Journal of Pediatrics, 143, 236–242. Vilain, C., Rydlewski, C., Duprez, L., et al. (2001). Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. Journal of Clinical Endocrinology and Metabolism, 86, 2345–238.

Congenital Hypothyroidism

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b

c

Fig. 1 (a–c) A neonate with congenital hypothyroidism showing coarse facial features, hypotonia, macroglossia, and umbilical hernia

Fig. 2 A twin affected with congenital hypothyroidism (left) shows coarse facial features. The normal co-twin is on the right

Congenital Muscular Dystrophy

Congenital muscular dystrophy (CMD) refers to a group of genetic disorders in which weakness and an abnormal muscle biopsy are present at birth.

Synonyms and Related Disorders Merosin-negative CMD; Merosin-positive CMD with mental retardation and neuronal migration defects (Fukuyama CMD, muscle-eye-brain disease, Walker-Warburg syndrome); Merosin-positive CMD (rigid spine disease, Ullrich disease, pure CMD)

Genetics/Basic Defects 1. Inheritance a. Genetic heterogeneity b. Most are autosomal recessive (Muntoni and Voit 2004) 2. Caused by genetic defects in proteins of the sarcolemmal membrane or its supporting structures. The proteins may also be expressed in the central nervous system, and many forms of CMD are associated with structural brain and eye anomalies 3. Classification of CMD according to biochemical defect (Cardamone et al. 2008) a. Extracellular matrix protein i. Merosin (lamin-a2) (LAMA2): Merosindeficient CMD (MDC1A) a) Demyelinating neuropathy b) White matter signal changes on brain MRI ii. Collagen VI (COL6A1, COL6A2, COL6A3): Ullrich CMD, Bethlem CMD

a) Proximal contractures b) Distal hyperextensibility c) Sandpaper rash iii. Integrin a7 (ITGA7): Merosin-positive CMD (mental retardation) b. Sarcolemmal protein (Plectin, PLEC1): CMD with epidermolysis bullosa (blistering skin rash from birth) c. Glycosyltransferases i. Fukutin (FCMD): Fukuyama CMD, Walker–Warburg syndrome a) Eye and structural brain anomalies b) Seizures c) Mental retardation d) Absent a-dystroglycan on muscle immunocytochemistry ii. Protein O-mannose b1.2 (N- acetylglucosaminyltransferase 1 (POMGnT1): Muscleeye-brain disease a) Eye and structural brain anomalies b) Absent a-dystroglycan on muscle immunocytochemistry iii. Protein O-mannosyltransferase 1 (POMT1): Walker–Warburg syndrome, Limb-girdle muscular dystrophy, type 2K a) Eye and structural brain anomalies b) Seizures c) Mental retardation d) Absent a-dystroglycan on muscle immunocytochemistry iv. Protein O-mannosyltransferase 2 (POMT2) a) Walker–Warburg syndrome: hydrocephalus b) Muscle-eye-brain disease: severe structural brain anomalies, absent

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_55, # Springer Science+Business Media, LLC 2012

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a-dystroglycan on muscle immunocytochemistry v. Unknown protein: Congenital muscular dystrophy type 1B (muscle hypertrophy, early respiratory failure) vi. Fukutin-related protein (FKRP): Limbgirdle muscular dystrophy type 21, congenital muscular dystrophy type 1C, Fukuyama congenital muscular dystrophy, muscle-eyebrain disease, Walker–Warburg syndrome a) Duchenne phenocopy b) Cardiomyopathy c) Absent a-dystroglycan on muscle immunocytochemistry vii. LARGE congenital muscular dystrophy (LARGE): congenital muscular dystrophy type 1D a) Severe mental retardation b) White matter signal changes on brain MRI viii. SIL1 (SIL1): Marinesco–Sjo¨gren syndrome a) Cerebellar ataxia b) Congenital cataracts d. Endoplasmic reticulum protein (Selenoprotein N, SEPN1) i. Rigid spine muscular dystrophy a) Thin habitus b) Spinal rigidity ii. Multicore myopathy: early respiratory failure iii. Congenital fiber-type disproportion iv. Myofibrillar myopathy e. Nuclear envelope protein (Lamin A/C, LMNA): variable phenotype i. Emery–Dreifuss MD ii. Limb-girdle muscular dystrophy type 1B iii. Congenital muscular dystrophy iv. Dilated cardiomyopathy v. Charcot–Marie–Tooth disease (CMT) type 2B1

Clinical Features 1. Typical features a. Present in the first year of life i. Hypotonia and weakness ii. Respiratory insufficiency iii. Bulbar dysfunction iv. Arthrogryposis

Congenital Muscular Dystrophy

b. Hypertrophy of the tongue and limb muscles, scoliosis, and contractures may develop with age c. Weakness is static or slowly progressive 2. Merosin-negative CMD a. Demonstrating clinical homogeneity i. Severe hypotonia ii. Multiple contractures iii. Delayed developmental milestones iv. Normal mentation v. Variable degrees of central hypomyelination seen on neuroimaging b. Patients with complete merosin deficiency i. Typically presenting as floppy infants ii. May or may not require ventilatory assistance iii. Most patients stabilize and able to continue developing without mechanical ventilation iv. Feeding difficulty leading to recurrent aspiration and poor nutrition in some patients v. The best motor milestone achieved: standing with support vi. Unable to ambulate vii. Cognitive development a) Generally normal b) Mental retardation in patients with brain anomalies viii. Epilepsy c. Patients with partial merosin deficiency i. Wide clinical spectrum a) Marked hypotonia at birth, contractures, and severely delayed motor milestones b) Limb-girdle muscular dystrophy-like presentation in the teen c) An adult-onset proximal limb-girdle weakness with elevated CK concentration ii. White matter abnormalities by MRI in all patients with documented merosin gene mutations 3. Merosin-positive CMD a. Rigid spine disease i. Onset in infancy ii. Axial muscle weakness iii. Early rigidity of the spine iv. Prominent nasal voice v. Nocturnal respiratory insufficiency vi. Early respiratory failure b. Ullrich disease i. Proximal contractures ii. Distal joint laxity

Congenital Muscular Dystrophy

iii. Delayed motor milestones a) Ability to walk in some cases b) Wheelchair dependent in majority of cases iv. Normal intelligence c. Pure CMD i. Normal intelligence ii. Normal brain imaging d. Other merosin-positive CMD 4. Merosin-positive CMD with mental retardation and neuronal migration defects a. Fukuyama CMD i. An autosomal recessive disorder ii. Prevalent in Japan iii. Early onset (before 9 months) iv. Muscle weakness v. Accompanied by joint contractures vi. Hypotonia/hypokinesia vii. Severe mental retardation viii. Epilepsy ix. Eye anomalies a) Myopia b) Congenital nystagmus c) Cortical blindness d) Optic atrophy e) Choreoretinal degeneration x. Brain anomalies (cobblestone lissencephaly; type 2 lissencephaly) a) Micropolygyria b) Pachygyria c) White matter lucency d) Minor cerebellar alterations (cortical dysplasia b. Muscle-eye-brain disease i. An autosomal recessive disorder ii. Mimics Walker–Warburg syndrome but overall changes tend to be much milder iii. Present as a floppy infant with suspected blindness iv. Severe mental retardation v. Extensive neuronal migration disorder a) Pachygyria and polymicrogyria b) Brain stem hypoplasia c) Cerebellar dysgenesis d) Hydrocephalus vi. Muscle involvement: typical features of muscular dystrophy with ongoing de- and regeneration vii. Normal expression of laminin a2

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c. Walker–Warburg syndrome i. An autosomal recessive disorder ii. Type II lissencephaly a) Micropolygyric “cobblestone” cortex b) Extensive white matter abnormalities c) Hydrocephaly with enlarged ventricles d) Brainstem hypoplasia e) Hypoplasia of the cerebellum, particularly the cerebellar vermis iii. Ocular dysgenesis a) Megacornea b) Buphthalmos c) Corneal clouding d) Cataracts e) Abnormal vitreous f) Retinal hypopigmentation g) Hypoplasia of the optic nerve h) Clinically blind iv. Muscular dystrophy a) Variable in severity: ranges from myopathy with increased variation of fiber size to severe, end-stage muscular dystrophy b) Well-preserved expression of laminin a2 v. Complete lack of psychomotor development (severe mental retardation) for those who survive for some years

Diagnostic Investigations 1. Markedly elevated serum creatine kinase (CPK) levels (Caramone et al. 2008). 2. Nerve conduction studies may show demyelinating neuropathy in merosin-deficient CMD (QuijanoRoy et al. 2004). 3. Electromyography (EMG) is myopathic. 4. Muscle biopsy shows typical dystrophic changes (degeneration and regeneration of muscle fibers, and proliferation of fatty and connective tissue). 5. Immunocytochemistry enables analysis of merosin, a-dystroglycan, collagen VI, and other muscle proteins (Jones and North 2003; Muntoni and Voit 2004). 6. Cerebral magnetic resonance imaging (MRI) may show abnormalities of neuronal migration and white matter signal. a. Pachygyria (with normal cognitive function) b. Cerebellar hypoplasia (with normal cognitive function but delay of speech development)

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c. Cerebellar cysts (in connection with pure CMD) d. Abnormal white matter signal (in connection with pure CMD of merosin-deficient type) e. Large lissencephalic changes f. Hydrocephalus 7. Molecular genetic analyses. a. Fukuyama CMD: Sequencing of entire coding region or select exons of FCMD gene b. Muscle-eye-brain disease: Sequencing of entire coding region or select exons or targeted mutation analysis of POMGnT1 gene c. Walker–Warburg syndrome: Sequencing of entire coding region or select exons or mutation scanning of POMT1 gene

Genetic Counseling 1. Recurrence risk (Sparks et al. 2011) a. Patient’s sib i. Autosomal recessive: a 25% recurrence risk ii. Autosomal dominant (Ullrich congenital muscular dystrophy): a low recurrence risk but greater than that of the general population if both parents are clinically unaffected or if the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, because of the possibility of germline mosaicism b. Patient’s offspring: i. Autosomal recessive a) Many individuals not living long enough to reproduce b) All offspring are carriers c) Recurrence risk to offspring probably less than 1% ii. Autosomal dominant: a 50% risk 2. Prenatal diagnosis a. Possible for pregnancies at 25% risk for complete merosin deficiency, provided complete merosin deficiency has been documented in the muscle of the proband. i. The diagnostic testing must be done on a sample of direct and flesh-frozen chorionic villi obtained at about 10–12 weeks of gestation by immunostaining ii. Using molecular testing for mutations that have been previously identified in the proband by CVS or amniocentesis

Congenital Muscular Dystrophy

b. Prenatal diagnosis by DNA mutation analysis is available for pregnancies at increased risk of Fukuyama MD, muscle-eye-brain disease, Walker–Warburg MD, congenital muscular dystrophy type 1C and 1D, and congenital muscular dystrophy with early spine rigidity by analysis of fetal DNA, obtained by amniocentesis or CVS, provided both disease-causing alleles of an affected family member have been identified. 3. Management (Sparks et al. 2011) a. No definitive treatment available b. General approaches i. Weight control to avoid obesity ii. Physical therapy and stretching exercises a) To promote mobility b) To prevent contractures iii. Using mechanical devices to help ambulation and mobility iv. Surgical interventions for scoliosis and foot deformity v. Medications for seizure control vi. Respiratory aids as needed vii. Social and emotional support

References Aida, N. (1998). Fukuyama congenital muscular dystrophy: A neuroradiologic review. Journal of Magnetic Resonance Imaging, 8, 317–326. Allamand, V., & Guicheney, P. (2002). Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). European Journal of Human Genetics, 10, 91–94. Brockington, M., Blake, D. J., Prandini, P., et al. (2001). Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. American Journal of Human Genetics, 69, 1198–1209. Brockington, M., Sewry, C. A., Herrmann, R., et al. (2000). Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. American Journal of Human Genetics, 66, 428–435. Brockington, M., Yuva, Y., Prandini, P., et al. (2001). Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Human Molecular Genetics, 10, 2851–2859. Cardamone, M., Darras, B. T., & Ryan, M. M. (2008). Inherited Myopathies and muscular dystrophies. Seminars in Neurology, 28, 250–259. Caro, P. A., Scavina, M., Hoffman, E., et al. (1999). MR imaging findings in children with merosin-deficient congenital

Congenital Muscular Dystrophy muscular dystrophy. AJNR. American Journal of Neuroradiology, 20, 324–326. Chijiiwa, T., Nishimura, M., Inomata, H., et al. (1983). Ocular manifestations of congenital muscular dystrophy (Fukuyama type). Annals of Ophthalmology, 15(921–923), 926–928. Cormand, B., Avela, K., Pihko, H., et al. (1999). Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and Homozygosity mapping. American Journal of Human Genetics, 64, 126–135. Cormand, B., Pihko, H., Baye´s, M., et al. (2001). Clinical and genetic distinction between Walker–Warburg syndrome and muscle-eye-brain disease. Neurology, 56, 1059–1069. De Stefano, N., Dotti, M. T., Villanova, M., et al. (1996). Merosin positive congenital muscular dystrophy with severe involvement of the central nervous system. Brain & Development, 18, 323–326. Donner, M., Rapola, J., & Somer, H. (1975). Congenital muscular dystrophy: A clinico-pathological and follow-up study of 15 patients. Neurop€ adiatrie, 6, 239–258. Dubowitz, V. (1999). 68th ENMC international workshop (5th international workshop): On congenital muscular dystrophy, 9–11 April 1999, Naarden, The Netherlands. Neuromuscular Disorders, 9, 446–454. Dubowitz, V. (2000). Congenital muscular dystrophy: An expanding clinical syndrome. Annals of Neurology, 47, 143–144. Echenne, B. (1988). Congenital muscular dystrophy of a non-Fukuyama type. Brain & Development, 10, 397. Eeg-Olofsson, K. E. (1999). Congenital muscular dystrophy. Care of children and families. Scandinavian Journal of Rehabilitation Medicine. Supplement, 39, 53–57. Farina, L., Morandi, L., Milanesi, I., et al. (1998). Congenital muscular dystrophy with merosin deficiency: MRI findings in five patients. Neuroradiology, 40, 807–811. Flanigan, K. M., Kerr, L., Bromberg, M. B., et al. (2000). Congenital muscular dystrophy with rigid spine syndrome: A clinical, pathological, radiological, and genetic study. Annals of Neurology, 47, 152–161. Fukuyama, Y., & Ohsawa, M. (1984). A genetic study of the Fukuyama type congenital muscular dystrophy. Brain & Development, 6, 373–390. Fukuyama, Y., Osawa, M., & Suzuki, H. (1981). Congenital progressive muscular dystrophy of the Fukuyama type – clinical, genetic and pathological considerations. Brain & Development, 3, 1–29. Guicheney, P., Vignier, N., Helbling-Leclerc, A., et al. (1997). Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: From identification of mutations to prenatal diagnosis. Neuromuscular Disorders, 7, 180–186. Guicheney, P., Vignier, N., Zhang, X., et al. (1998). PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): Application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy. Journal of Medical Genetics, 35, 211–217. Helbling-Leclerc, A., Zhang, X., Topaloglu, H., et al. (1995). Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nature Genetics, 11, 216–218. Hillaire, D., Leclerc, A., Faure, S., et al. (1994). Localization of merosin-negative congenital muscular dystrophy to

483 chromosome 6q2 by homozygosity mapping. Human Molecular Genetics, 3, 1657–1661. Jones, R., Khan, R., Hughes, S., et al. (1979). Congenital muscular dystrophy: The importance of early diagnosis and orthopaedic management in the long-term prognosis. Journal of Bone and Joint Surgery. British Volume, 61, 13–17. Jones, K., & North, K. (2003). The congenital muscular dystrophies. In H. R. Jones, D. C. De Vivo, & B. T. Darras (Eds.), Neuromuscular disorders of infancy, childhood, and adolescence: A clinician’s approach (pp. 633–634). Philadelphia: Butterworth Heinemann. Kobayashi, O., Hayashi, Y., Arahata, K., et al. (1996). Congenital muscular dystrophy: Clinical and pathologic study of 50 patients with the classical (Occidental) merosin-positive form. Neurology, 46, 815–818. Kondo, E., Saito, K., Toda, T., et al. (1996). Prenatal diagnosis of Fukuyama type congenital muscular dystrophy by polymorphism analysis. American Journal of Medical Genetics, 66, 169–174. Kondo-Iida, E., Kobayashi, K., Watanabe, M., et al. (1999). Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Human Molecular Genetics, 8, 2303–2309. Kondo-Iida, E., Saito, K., Tanaka, H., et al. (1997). Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy. Human Genetics, 99, 427–432. Leyten, Q. H., Gabreels, F. J., Joosten, E. M., et al. (1986). An autosomal dominant type of congenital muscular dystrophy. Brain & Development, 8, 533–537. Leyten, Q. H., Gabreels, F. J., Renier, W. O., et al. (1989). Congenital muscular dystrophy. Journal of Pediatrics, 115, 214–221. Leyten, Q. H., Gabreels, F. J., Renier, W. O., et al. (1996). Congenital muscular dystrophy: A review of the literature. Clinical Neurology and Neurosurgery, 98, 267–280. Lopate, G. (2009). Congenital muscular dystrophy. eMedicine from WebMD. Updated February 12, 2009. Available at: http://emedicine.medscape.com/article/1180214-overview McMenamin, J. B., Becker, L. E., & Murphy, E. G. (1982). Congenital muscular dystrophy: A clinicopathologic report of 24 cases. Journal of Pediatrics, 100, 692–697. Mendell, J. R. (2001). Congenital muscular dystrophy: Searching for a definition after 98 years. Neurology, 56, 993–994. Misugi, N. (1980). Light and electron microscopic studies of congenital muscular dystrophy. Brain & Development, 2, 191–199. Moghadaszadeh, B., Desguerre, I., Topaloglu, H., et al. (1998). Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35–36. American Journal of Human Genetics, 62, 1439–1445. Muntoni, F., & Guicheney, P. (2002). 85th ENMC international workshop on congenital muscular dystrophy. 6th international CMD workshop. 1st workshop of the Myo–Cluster project ‘GENRE’. 27–28th October 2000, Naarden, The Netherlands. Neuromuscular Disorders, 12, 69–78. Muntoni, F., & Voit, T. C. (2004). The congenital muscular dystrophies in 2004: A century of exciting progress. Neuromuscular Disorders, 14, 635–649.

484 Naom, I., Sewry, C., D’Alessandro, M., et al. (1997). Prenatal diagnosis in merosin-deficient congenital muscular dystrophy. Neuromuscular Disorders, 7, 176–179. Nass, D., Goldberg, I., & Sadeh, M. (1999). Laminin alpha2 deficient congenital muscular dystrophy: Prenatal diagnosis. Early Human Development, 55, 19–24. Nissinen, M., Helbling-Leclerc, A., Zhang, X., et al. (1996). Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein. American Journal of Human Genetics, 58, 1177–1184. Philpot, J., Sewry, C., Pennock, J., et al. (1995). Clinical phenotype in congenital muscular dystrophy: Correlation with expression of merosin in skeletal muscle. Neuromuscular Disorders, 5, 301–305. Quijano-Roy, S., Renault, F., Romero, N., et al. (2004). EMG and nerve conduction studies in children with congenital muscular dystrophy. Muscle & Nerve, 29, 292–299. Santavuori, P., Leisti, J., & Kruus, S. (1977). Muscle, eye, and brain disease: A new syndrome. Neuropediatrics, 8(suppl), 553–558. Sombekke, B. H., Molenaar, W. M., van Essen, A. J., et al. (1994). Lethal congenital muscular dystrophy with arthrogryposis multiplex congenita: Three new cases and review of the literature. Pediatric Pathology, 14, 277–285.

Congenital Muscular Dystrophy Sparks, S., Quijano-Roy, S., Harper, A., et al. (2011). Congenital muscular dystrophy overview. GeneReviews. Updated January 4, 2011. Available at: http://www.ncbi.nlm.nih.gov/ books/NBK1291/. Takai, Y., Tsutsumi, O., Harada, I., et al. (1998). Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis. Human Reproduction, 13, 320–323. Toda, T., Kobayashi, K., Kondo-Iida, E., et al. (2000). The Fukuyama congenital muscular dystrophy story. Neuromuscular Disorders, 10, 153–159. Toda, T., Segawa, M., Nomura, Y., et al. (1993). Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31–33. Nature Genetics, 5, 283–286. Tome´, F. M., Evangelista, T., Leclerc, A., et al. (1994). Congenital muscular dystrophy with merosin deficiency. Comptes Rendus de l’Acade´mie des Sciences. Se´rie III, 317, 351–357. Topaloglu, H., Renda, Y., Yalaz, K., et al. (1990). Classification of congenital muscular dystrophy. Journal of Pediatrics, 117, 166–167. Voit, T. (1998). Congenital muscular dystrophies: 1997 update. Brain & Development, 20, 65–74. Yoshioka, M., & Kuroki, S. (1994). Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. American Journal of Medical Genetics, 53, 245–250.

Congenital Muscular Dystrophy

Fig. 1 An infant with congenital muscular dystrophy showing hypotonic frog-leg posture, the chest deformity due to weakness of the intercostal muscles, and contractures of joints

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Congenital Toxoplasmosis

Acute infection in a pregnant woman with a parasite, Toxoplasma gondii, can have serious consequences on the fetus, ranging from fetal loss to severe neurologic or ocular lesions. In other cases, infected newborns are asymptomatic at birth, but are at risk for developing retinal diseases during childhood or adolescence on Toxoplasma reactivation (Wallon et al. 2004). In the United States, the incidence of congenital toxoplasmosis is estimated to be 1 in 1,000 to 1 in 10,000 births and approximately 400–4,000 cases of congenital toxoplasmosis occur each year.

3.

Synonyms and Related Disorders Toxoplasma gondii infection in pregnancy

Genetics/Basic Defects 1. Toxoplasma gondii (Beasley and Egerman 1998) a. A protozoan parasite b. The causative agent of toxoplasmosis, a common infection throughout the world with estimated one billion people infected worldwide c. Life cycle: exists in three forms i. The oocysts, or soil form ii. The tachyzoite, or active infectious form iii. The tissue cyst, or latent form 2. Hosts a. Cats i. The primary host ii. Maintain the intestinal–epithelial sexual cycle of Toxoplasma development with the production of oocysts

4. 5. 6.

b. All other animals (humans, birds, rodents, and domestic animals) i. The intermediate or secondary hosts ii. Have an extraintestinal asexual cycle with resultant parasitemia and the production of tissue cysts Routes by which Toxoplasma is transmitted to humans a. Principal routes i. Acquired a) Ingestion of raw or inadequately cooked infected meat (beef, pork, or lamb) b) Not washing hands thoroughly after handling raw meat or gardening c) Ingestion of oocysts, an environmentally resistant form of the organism that cats pass in their feces and human exposure to cat litter or contaminated soil (from gardening or unwashed fruits or vegetables) ii. Congenital: transplacental infection of unborn fetus by the newly infected mother b. Rare routes i. Blood and blood product transfusion ii. Organ transplant iii. Laboratory accident c. No evidence of direct human-to-human transmission other than from mother to fetus Seventy percent of the obstetric population with negative antibodies: at risk for transmission to the fetus Congenital toxoplasmosis usually occurs as a result of primary maternal infection Maternal–fetal transmission rate depends on gestational age at the time of maternal infection a. Less than five percent before fifth week of gestation

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_56, # Springer Science+Business Media, LLC 2012

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7.

8. 9.

10.

Congenital Toxoplasmosis

b. Twenty-five percent in the first trimester c. Seventy-five percent in the third trimester d. Greater than ninety percent in the last few weeks of pregnancy Severity of the fetal infection inversely related to gestational age: The earlier infections being the most severe Untreated maternal infections: About 50% of cases transmit to the fetus An immunocompetent woman previously infected is considered immune and will not transmit T. gondii to her offspring. Toxoplasma infection leads to life-long immunity with the presence of T. gondii-specific IgG antibodies. Acute toxoplasmosis in the adult is often asymptomatic and usually does not result in complications Reactivation can occur in immunocompromised pregnant woman (i.e., HIV) leading to parasitemia and fetal infection

Clinical Features 1. Unpredictable manifestations in the fetus and in the newborn 2. Maternal infections a. Generally asymptomatic in immunocompetent mothers b. Subtle symptoms in about 15–20% of infected mothers i. Cervical lymphadenopathy: the most common clinical manifestation ii. Fatigue iii. Flu-like symptoms c. In immunocompromised mothers i. Chorioretinitis ii. Encephalitis iii. Pneumonitis iv. Myocarditis d. Maternal infections early in pregnancy i. Less likely to be transmitted to the fetus than infections later in pregnancy ii. More likely to be severe than later infections 3. Fetal infections a. Usually resulting from a primary maternal infection with risk of developing congenital abnormalities. Reactivation of T gondii in an immunocompromised patient can render the fetus susceptible to infection.

b. Infectivity: The incidence and severity of the fetal infection depend on the gestational age at the time of the maternal infection. The later the gestation, the higher the infectivity. However, the postnatal sequelae are severer when infection occurs early in gestation. 4. Natural history of congenital toxoplasmosis a. Free of symptoms at birth in vast majority of cases with congenital infection (70–90% of cases) b. About 15% of the infected children with signs or symptoms at birth or neonatal period i. Maculopapular rash ii. Generalized lymphadenopathy iii. Hepatosplenomegaly iv. Jaundice v. Thrombocytopenia vi. Consequences of intrauterine meningoencephalitis a) CSF abnormalities b) Hydrocephalus c) Microcephaly d) Chorioretinitis e) Seizures vii. Signs of the “classic triad” (hydrocephalus, intracranial calcifications, and chorioretinitis) without systemic signs of disease c. Sequelae during childhood or early adult life in 50–90% of cases i. Learning disability ii. Visual impairment iii. Chorioretinitis: the most frequent congenital manifestation and is progressive in >80% of patients by 20 years of age iv. Mental retardation v. Hearing loss d. Ocular lesions: the most frequent manifestations of congenital toxoplasmosis (Metz 2001) i. Strabismus (33%) ii. Nystagmus (27%) iii. Microphthalmia (13%) iv. Phthisis (4%) v. Microcornea (19%) vi. Cataract (10%) vii. Active vitritis (11%) viii. Active retinitis (11%) ix. Chorioretinal scars (79%) x. Optic atrophy (20%)

Congenital Toxoplasmosis

e. Severely affected congenital infection i. Die in utero ii. Die within a few days of life

Diagnostic Investigations 1. Serological testing (Beasley and Egerman 1998; Lynfield and Eaton 1995) a. IgM anti-Toxoplasma antibodies i. Produced 1–2 weeks after an infection ii. Levels detectable for years after the acute infection b. IgG anti-Toxoplasma antibodies i. Levels peak approximately 2 months after the initial infection ii. Remain positive for life c. IgA anti-Toxoplasma antibodies i. Parallels IgM production ii. Peak levels occur approximately 2 months after the initial infection and then rapidly decline d. IgE anti-Toxoplasma antibodies i. Detected early after an acute infection ii. Usually present for 4–8 months iii. May provide useful information regarding the timing of an acute infection 2. Detection of antibodies to toxoplasmosis in the neonatal period a. Specific T. gondii IgM antibody i. A positive IgM antibody in the newborn: diagnostic of congenital toxoplasmosis ii. A negative IgM antibody in the newborn does not exclude the diagnosis and may be due to the following reasons: a) Lack of production of IgM b) Waning of the IgM response by the time of birth c) Insensitivity of the assay iii. A positive IgM antibody in the mother a) Associated with recent maternal infection b) Would support the diagnosis of congenital toxoplasmosis b. Specific T. gondii IgA antibody: more sensitive test than IgM antibodies c. Neonatal screening with IgM or IgA antibodies fails to detect majority of children with congenital toxoplasmosis when the maternal infection occurred before the 20 week of pregnancy

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3. Definitive postnatal diagnosis of congenital toxoplasmosis a. Detection of parasites in material collected from the newborn (blood, cerebrospinal fluid, or other clinical material) by inoculation into mice or tissue culture b. Detection of persisting specific IgG antibodies at the age of 1 year c. Reappearance of specific IgG antibodies in the child after cessation of postnatal antibiotic therapy d. Diffuse cerebral calcifications and hydrocephalus detected by radiography, ultrasonography, CT scan, or MRI of the brain 4. Other diagnostic evaluation of the infants a. Physical examination b. Dilated retinal examination c. Examination of the cerebrospinal fluid i. Protein ii. Glucose iii. Cell count iv. Antibody determination d. Audiologic screen e. Examination of the placenta i. Evidence of infection, although the gross appearance may not parallel the severity of fetal disease ii. Inoculation of the placental tissue into mice or tissue culture to attempt isolation of the parasite iii. The feasibility of placental analysis, in terms of sample recovery and rapid T. gondii detection by PCR, makes it a useful diagnostic tool for early monitoring and treatment of neonates at risk for congenital infection (Robert-Gangnex et al. 2010)

Genetic Counseling 1. Recurrence risk: women with previous infection not at risk for delivering a fetus with congenital toxoplasmosis unless immunosuppressed 2. Prenatal diagnosis a. Seroconversion during pregnancy i. Absence of specific Toxoplasma gondii IgG antibodies in the first serum sample obtained during gestation ii. Detection of specific IgG and IgM antibodies in the follow-up sample at a later prenatal visit or at birth

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b. Suggestive but not diagnostic signs by prenatal ultrasonography (Beasley and Egerman 1998) i. Ventriculomegaly: the most common sonographic finding in utero ii. Intracranial calcifications iii. Hydrops iv. Microcephaly v. Choroid plexus cysts vi. Growth retardation vii. Hepatomegaly viii. Splenomegaly ix. Ascites x. A thickened placenta c. Prenatal diagnosis of acute infection in the fetus i. Amniocentesis or cordocentesis a) Detection of parasites in amniotic fluid or in fetal blood by inoculation into tissue culture or mice b) Detection of anti-Toxoplasma gondii IgM, IgA, and IgE antibodies in the fetal blood. The diagnosis of fetal T. gondii infection before 22 weeks using cordocentesis is not possible because fetal IgM or IgA may not be produced before 22 weeks’ gestation c) Detection of T. gondii DNA (B1 gene) by gene amplification in amniotic fluid: more accurate and faster diagnosis of congenital toxoplasmosis ii. Chorionic villus sampling not helpful because it will show placental but not fetal infection 3. Management a. Prevention of Toxoplasma infection i. Cook meat to a safe temperature to kill Toxoplasma ii. Peel or thoroughly wash fruits and vegetables before eating iii. Clean cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables iv. Avoid changing cat litter during pregnancy or use gloves and wash hands thoroughly v. Do not feed raw or undercooked meat to cats and keep cats inside to prevent acquisition of Toxoplasma by eating infected prey vi. Avoid risk factors for T. gondii infection including careful adherence to simple hygienic measures during pregnancy (decrease Toxoplasma infection by 60%)

Congenital Toxoplasmosis

b. Treat Toxoplasma infection with spiramycin, pyrimethamine, sulfonamides, and folinic acid i. Reduce sequelae of congenital infection by treating the mother as soon as possible after the serologic screening program identifies the infection ii. Treat infected neonates: sooner the treatment, the better the outcome c. Newborn screening for Toxoplasma-specific IgM allows the identification and treatment of subclinical cases so that the sequelae of infection with toxoplasmosis may be prevented or attenuated

References Alford, C. A., Jr., Stagno, S., & Reynolds, D. W. (1974). Congenital toxoplasmosis: Clinical, laboratory, and therapeutic considerations with special reference to subclinical disease. Bulletin of the New York Academy of Medicine, 50, 160–181. American Academy of Pediatrics. (2000). Report of the Committee on Infectious Diseases: Toxoplasmosis. Red Book 2000, pp. 583–586. Elk Grove Village, IL. Antsaklis, A., Daskalakis, G., Papantoniou, N., et al. (2002). Prenatal diagnosis of congenital toxoplasmosis. Prenatal Diagnosis, 22, 1107–1111. Bale, J. F., Jr. (2002). Congenital infections. Neurologic Clinics, 20, 1039–1060. Beasley, D. M., & Egerman, R. S. (1998). Toxoplasmosis. Seminars in Perinatology, 22, 332–338. Black, M. W., & Boothroyd, J. C. (2000). Lytic cycle of Toxoplasma gondii. Microbiology and Molecular Biology Reviews, 64, 607–623. Daffos, F., Forestier, F., Capella-Pavlovsky, M., et al. (1988). Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. The New England Journal of Medicine, 318, 271–275. Desmonts, G., & Couvreur, J. (1974). Congenital toxoplasmosis: A prospective study of 378 pregnancies. The New England Journal of Medicine, 290, 1110–1116. Foulon, W., Pinon, J.-M., Stray-Pedersen, B., et al. (1999). Prenatal diagnosis of congenital Toxoplasmosis: A multicenter evaluation of different diagnostic parameter. American Journal of Obstetrics and Gynecology, 181, 843–847. Foulon, W., Villena, I., Stray-Pedersen, B., et al. (1999). Treatment of toxoplasmosis during pregnancy: A multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. American Journal of Obstetrics and Gynecology, 190, 410–415. Fricker-Hidalgo, H., Pelloux, H., Muet, F., et al. (1997). Prenatal diagnosis of congenital toxoplasmosis: Comparative value of fetal blood and amniotic fluid using serological techniques and cultures. Prenatal Diagnosis, 17, 831–835. Guerina, N. G., Hsu, H.-W., Meissner, H. C., et al. (1994). Neonatal serologic screening and early treatment for

Congenital Toxoplasmosis congenital Toxoplasma Gondii infection. The New England Journal of Medicine, 330, 1858–1863. Hall, S. M. (1992). Congenital toxoplasmosis. British Medical Journal, 305, 291–297. Hezard, N., Marx-Chemla, C., Foudrinier, F., et al. (1997). Prenatal diagnosis of congenital toxoplasmosis in 261 pregnancies. Prenatal Diagnosis, 17, 1047–1054. Hohlfeld, P., Daffos, F., Thulliez, P., et al. (1989). Fetal toxoplasmosis: Outcome of pregnancy and infant follow-up after in utero treatment. Journal of Pediatrics, 115, 765–769. Hohlfeld, P., Dafos, F., Costa, J. M., et al. (1994). Prenatal diagnosis of congenital toxoplasmosis with a polymerasechain-reaction test on amniotic fluid. The New England Journal of Medicine, 331, 695–699. Hovakimyan, A., & Cunningham, E. T., Jr. (2002). Ocular toxoplasmosis. Ophthalmology Clinics of North America, 15, 327–332. Jones, J., Lopez, A., & Wilson, M. (2000). Congenital toxoplasmosis. American Family Physician, 67, 2131–2138. Kuhlmann, R. S., & Autry, A. M. (2001). An approach to nonbacterial infections in pregnancy. Clinics in Family Practice, 3, 267–286. Lopez, A., Dietz, V. J., Wilson, M., et al. (2000). Preventing congenital toxoplasmosis. Morbidity Mortality Weekly Report, 49(RR-2), 57. Lynfield, R., & Eaton, R. B. (1995). Teratogen update: Congenital toxoplasmosis. Teratology, 52, 176–180. Melamed, J., Eckert, G., Spadoni, V. S., et al. (2010). Ocular manifestations of congenital toxoplasmosis. Eye, 24, 528–534. Metz, M. B. (2001). Eye manifestations of intrauterine infections. Ophthalmology Clinics of North America, 14, 521–531.

491 Naessens, A., Jenum, P. A., Pollak, A., et al. (1999). Diagnosis of congenital toxoplasmosis in the neonatal period: A multicenter evaluation. Journal of Pediatrics, 135, 714–719. Pataki, M., Meszner, Z., & Todorova, R. (2000). Congenital toxoplasmosis. International Pediatrics, 15, 33–36. Patel, D. V., Holfels, E. M., Vogel, N. P., et al. (1996). Resolution of intracranial calcifications in infants with treated congenital toxoplasmosis. Radiology, 199, 433–440. Rabilloud, M., Wallon, M., & Peyron, F. (2010). In utero and at birth diagnosis of congenital toxoplasmosis. Use of likelihood ratios for clinical management. The Pediatric Infectious Disease Journal, 29, 421–425. Remington, J. S. (1974). Toxoplasmosis in the adult. Bulletin of the New York Academy of Medicine, 50, 211–227. Robert-Gangnex, F., Dupretz, P., Yvenou, C., et al. (2010). Clinical relevance of placenta examination for the diagnosis of congenital toxoplasmosis. The Pediatric Infectious Disease Journal, 29, 33–38. Roizen, N., Swisher, C. N., Stein, M. A., et al. (1995). Neurologic and developmental outcome in treated congenital toxoplasmosis. Pediatrics, 95, 11–20. Sever, J. L., Ellenberg, J. H., Ley, A. C., et al. (1988). Toxoplasmosis: Maternal and pediatric findings in 23,000 pregnancies. Pediatrics, 82, 181–192. Wallon, M., Kodjikian, L., Binquet, C., et al. (2004). Long-term ocular prognosis in 327 children with congenital toxoplasmosis. Pediatrics, 113, 1567–1572. Wilson, C. B., & Remington, J. S. (1980). What can be done to prevent congenital toxoplasmosis? American Journal of Obstetrics and Gynecology, 138, 357–363.

492 Fig. 1 A newborn died of congenital generalized Toxoplasma infection. The heart showed myocarditis with presence of Toxoplasma cyst (arrow) (H and E, 400)

Fig. 2 Toxoplasma cyst seen in high magnification (arrow) (H and E, 1,000)

Fig. 3 Mild acute chorionitis associated with Toxoplasma infection. A Toxoplasma cyst was found in chorionic plate of the placental disc (H and E, 1,000)

Congenital Toxoplasmosis

Congenital Toxoplasmosis

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Fig. 6 Diffusely scattered punctate cerebral calcifications secondary to congenitally acquired toxoplasmosis Fig. 4 A small area of resolving acute toxoplasmic retinochoroiditis adjacent to a larger area of healed congenital toxoplasmosis scar

Fig. 5 Satellite lesions of acute exacerbation of toxoplasmic retinochoroiditis adjacent to a larger scar of healed congenital ocular toxoplasmosis

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a

Congenital Toxoplasmosis

b

Fig. 7 (a, b) An adult with congenital toxoplasmosis who had mental retardation, seizures, and chorioretinitis. CT of the brain showed scattered multiple foci of intracerebral calcifications

Conjoined Twins

Conjoined twins are incompletely separated monozygotic twins. They have long fascinated both medical profession and lay public. Such events are rare and occur in 1/50,000 to 1/100,000 births and 1 in 400 sets of monozygotic twins. Over 60% succumb in utero or are stillborn (Spitz 2005). It is a complication of monochorionic twinning at 13–15 days after conception.

Synonyms and Related Disorders Cephalopagus; Craniopagus; Dicephalus; Diprosopus; Epigastrius; Fetus-in-fetu; Ischiopagus; Omphalopagus; Pygoparus; Rachipagus; Thoracopagus

Genetics/Basic Defects 1. Conjoined twins a. Rare variants of monozygotic, monochorionic twins b. Two theories of conjoined twin formation i. Resulting from the secondary union of two originally separate monovular embryonic disks ii. Resulting from an incomplete separation of the inner cell mass at around 13–15 days of gestation of the monovular twins c. Twins can be conjoined at any site from the cranium downward to the sacrococcygeal region d. Approximately 60% are stillborn e. Female predominance: approximately 3:1 femaleto-male ratio

2. Embryologic classification of conjoined twins (Spencer 2000a; McHugh et al. 2006; Winkler et al. 2008): Greek word “pagus” is added to denote fixing to union site a. Ventral union (87%) i. Rostral (48%) a) Cephalopagus (11%): fusion from top of head to umbilicus; each twin has two arms and legs; separate lower abdomen and pelvis b) Thoracopagus (20–40%): position face to face, with fused thoraces and with a shared heart or single interatrial vessel c) Omphalopagus (18–33%): similar fusion to thoracopagus without shared heart or interatrial vessel ii. Caudal (11%) (ischiopagus): a large, conjoined pelvis, more commonly joined end to end; can be face to face with a conjoined abdomen; always shared external genitalia and anus b. Dorsal union (13%) i. Craniopagus (5%): joined by any portion of the skull except the face and foramen magnum, shared cranium, meninges, and occasionally, the brain ii. Rachipagus(2%): dorsal fusion above the sacrum iii. Pygopagus (6%): fused sacrococcygeal and perineal regions, typically with shared anus but separate rectums; spinal cord may be shared

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_57, # Springer Science+Business Media, LLC 2012

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c. Lateral union (28%): Parapagus (side-to-side connection with shared pelvis and variable cephalad sharing), defined as follows: i. Dithoracic parapagus (separate thoraces and heads) ii. Dicephalic parapagus (separate head with fused thoraces) iii. Diprosopus parapagus (two faces on the same side of single head) 3. Anatomic classifications of conjoined twins, based on how the body axes of the twins are mutually oriented in the embryonic disk a. Notochordal axes facing each other i. Ventro-ventral a) Thoracopagus b) Xiphopagus c) Omphalopagus ii. Cranial ventro-ventral (cephalothoracopagus) iii. Caudal ventro-ventral (ischiopagus) iv. Cranial end to end (craniopagus) v. Caudal end to end (pygopagus) b. Notochordal axes facing side by side i. Dicephalus ii. Diprosopus 4. Anatomic classifications of conjoined twins, based on how the subsequent events of migration, growth, and body folding result in different types of conjoined twins a. Dipygus b. Fetus-in-fetu i. A fetiform mass located within a basically normal fetus (Spencer 2001) ii. Inclusion of a monozygotic diamniotic twin within the bearer is the best explanation 5. Duplicitas symmetros (symmetrical conjoined twins resulting from incomplete fission of the uniovum) (Gilbert-Barness et al. 2003) a. Terata katadidyma (twins joined at the lower part of the body and double above) i. Dicephalus (twins with two separate heads and necks side by side with one body; lateral conjugation) ii. Diprosopus (twins with two faces side by side, one head, and one body) iii. Ischiopagus (twins joined by the inferior margins of the coccyx and sacrum with two completely separate spinal columns; caudal conjugation)

Conjoined Twins

iv. Pygopagus (twins joined by posterior surfaces of the coccyx and sacrum, back to back; posterior conjugation) v. Craniothoracopagus vi. Ileothoracopagus b. Terata anadidyma (twins joined at the upper part of the body and double below) i. Craniopagus (twins joined at the top of cranial vaults; cephalic conjugation) ii. Dipygus (twins with one head, one thorax, one abdomen, and double pelvis with or without two sets of external genitalia and up to four legs; lateral conjugation) iii. Syncephalus (twins joined by the face; the faces turn laterally) c. Terata anakatadidyma (twins joined by the midportion of the body) i. Omphalopaus (twins joined from the umbilicus to xiphoid cartilage; anterior conjugation) ii. Xiphopagus (twins joined at xiphoid process) iii. Rachipagus (twins joint by the vertebral column; back to back) iv. Thoracopagus (twins joined at the chest wall; anterior conjugation) 6. Duplicatas asymmetros (asymmetrical conjoined twins resulting from unequal and incomplete fission of the uniovum and unequal placental circulation to twins) a. Cephalic conjugation i. Craniopagus parasiticus ii. Janus parasiticus iii. Epignathus heteropagus b. Anterior conjugation i. Thoracopagus parasiticus ii. Epigastrius c. Posterior conjugation i. Ischiopagus parasiticus ii. Pyopagus parasiticus iii. Sacral parasiticus

Clinical Features 1. Thoracopagus twins a. Represents 40% of conjoined twins b. Conjoined at the thoracic region c. Face to face

Conjoined Twins

d. Associated congenital heart defects i. Present in 75% of cases ii. Presence of varying degree of pericardial sac fusion iii. A conjoined heart with two ventricles and a varying number of atria (most frequent abnormality) iv. Ventricular septal defect in virtually all patients 2. Omphalopagus twins (fused umbilical region)/ Xiphopagus twins (fused xiphoid process of sternum) a. Constitutes one third of all types of conjoined twins b. The most readily separable conjoined twins since their union may involve only skin and portions of the liver, occasionally including portions of the sternum c. Most omphalopagus twins joined by a skin bridge that contains liver and bowel d. Conjoined liver in 81% e. Conjoined sternal cartilage in 26% f. Conjoined diaphragm in 17% g. Conjoined genitourinary tract in 3% h. Malformations of the abdominal wall (usually omphalocele) in at least one of the twins in 33% i. Congenital heart defects in at least one of the twins in 25% i. Ventricular septal defects ii. Tetralogy of Fallot j. Concordant congenital heart defects in only one out of nine sets of twins 3. Pygopagus twins a. Constitutes 19% of conjoined twins b. Conjoined at sacrum (buttocks and lower spine) c. Most commonly back to back (face away from each other) d. May share part of the sacral spinal canal e. May share common rectum and anus f. Often with fused genitalia 4. Ischiopagus twins a. Constitutes 6% of conjoined twins b. Conjoined back to back at the coccyx c. Often with a common large pelvic ring formed by the union of the two pelvic girdles d. May have four legs (ischiopagus tetrapus) e. May have three legs (ischiopagus tripus) f. Frequently share the lower gastrointestinal tract i. Intestines joined at the terminal ileum ii. Emptying into a single colon

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5.

6. 7. 8.

9. 10.

11. 12. 13. 14.

15.

g. May have a single bladder and urethra h. Displaced anus i. Common vaginal anomalies j. Common rectovaginal communications Craniopagus twins (fused at the cranial vault) (2%) a. Classification according to the area of junction i. Frontal craniopagus ii. Parietal craniopagus (most common) iii. Temporal craniopagus iv. Occipital craniopagus b. Classification based on surgical and prognostic purposes i. Partial type (brains separated by bone or dura with each brain having separate leptomeninges) ii. Complete type (presence of cerebral connection) Rachiopagus twins (fused upper spinal column; back to back) Pygodidymus twins (fused cephalothoracic region; duplicate pelves and lower extremities) Pygopagus twins/pygomelus twins (joined back to back at the sacrum; additional limb or limbs at or near buttock) Iniopagus twins/craniopagus occipitalis twins (fused head, at parasitic occipital region) Epicomus twins/craniopagus parasiticus twins (smaller, parasitic twin joined to larger autosite at occiput) Monocephalus twins (single head with two bodies) Diprosopus twins (single body with two faces) Dicephalus twins (symmetric body with two heads) Dipygus parasiticus twins (head and thorax completely merged; pelvis and lower extremities duplicated) Cephalopagus conjoined twins a. The rarest type of conjoined twins b. Fused from the top of the head to the umbilicus c. Presence of two faces on the opposite sides of the head with one face usually being rudimentary d. Separation of the lower abdomen e. With four arms and four legs f. Prognosis dismal dependent on the following factors i. Presence of associated anomalies ii. Degree of fusion of the intracranial, intrathoracic, and/or intra-abdominal structures iii. Extent of venous connections

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16. Epigastric heteropagus twins a. A rare type of conjoined twinning b. Resulting from an ischemic atrophy of one fetus at an early stage of gestation c. Pelvis and lower limbs of the ischemic fetus (incomplete parasitic twin; heteropagus) attached to the epigastrium of the well-developed fetus (the autosite) 17. Fetus-in-fetu a. The parasites embodied in the autosite, usually within cranial, thoracic, and abdominal cavities during the developmental process of the asymmetrical conjoined twins b. Most likely arise from inclusion of a monochorionic, diamniotic, monozygotic twin within the bearer due to anastomoses of vitelline circulation (Nastanski and Downey 2001) 18. Prognosis a. A high mortality rate i. Nearly 40% are stillborn. ii. One third die within 24 h of birth. iii. No prospect of survival when complex cardiac union is present. b. Causes of death i. Severely abnormal conjoined heart ii. Pulmonary hypoplasia due to distortion of fused thoracic cages 19. Examples of historically famous conjoined twins (Sills et al. 2001; Gilbert-Barness et al. 2003; Spitz 2005) a. So-called Biddenden Maids (1100–1134) in England i. Probably pyopagus twins ii. Their famous image imprinted on the “cakes” iii. Walks with their arms around each other iv. They lived together for 34 years and died within 6 h b. Chang and Eng Bunker (1811–1874) from Bangkok and settled in the USA (“Siamese twins”) i. Born on a river boat in Siam ii. Joined at the xiphisternum by a short bank that stretched so they were eventually able to stand side by side iii. Taken by Hunter, a traveling Scottish merchant, to the USA where they were exhibited by the showman iv. Later married to twin sisters

Conjoined Twins

v. Fathered 22 children vi. Lived together for 63 years and one died shortly from other twin c. Blazˇek sisters (1878–1922) from Bohemia i. Two heads ii. Four arms iii. Four legs iv. Partially fused torso v. Combined reproductive organs vi. Delivered an infant through a single vagina but the gestation had occurred in the uterus of one of the twins

Diagnostic Investigations 1. Prenatal echocardiography a. Presence and extent of cardiac conjunction b. Associated cardiac defects 2. Prenatal radiography 3. Prenatal ultrasonography (including transvaginal two-dimensional sonography), especially threedimensional sonographic examinations (The surface-rendered image of the conjoined twin and its demonstration on an axially rotating cine loop facilitates explanation of the precise nature of the abnormalities, especially in the case of cephalothoracopagus conjoining) 4. CAT scan and MRI of the abdomen and the chest a. Anatomy of the heart b. Anatomy of the livers c. Anatomy of the genitourinary systems 5. Gastrointestinal contrast studies to demonstrate the presence and level of conjunction of the intestinal tract 6. Ventrally fused conjoined twins a. Prenatal radiography/ultrasonography i. Fetal body parts on the same level ii. Constant relative fetal position iii. Fetal extremities in unusual proximity iv. Face-to-face fetal position v. Bibreech, less commonly bicephalic presentation vi. Hyperextension of one or both cervical spines b. Prenatal ultrasonography i. Nonseparable continuous external skin contour ii. Single heart sound by Doppler

Conjoined Twins

iii. Solitary large liver and heart iv. Multiple shared omenta v. Solitary umbilical cord with >3 vessels 7. Cephalothoracopagus a. Prenatal radiographic criteria i. Both fetal heads at the same level ii. Backward fusion of the cervical spines iii. A narrow space between lower cervical and upper thoracic spines iv. No change in fetal relative positions after maternal movement b. Prenatal sonographic criteria i. Fusion of the skulls, face, thorax, and upper abdomen ii. Fetal body parts at the same level iii. Constant relative fetal motion iv. Fetal extremities in unusual positions v. Breech position vi. Hyperextension of both cervical spines vii. Nonseparable external skin contour viii. A solitary umbilical cord with multiple vessels ix. Polyhydramnios x. Two actively beating hearts xi. Two sets of pelves, limbs, and spine

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not higher according to family study b. Patient’s offspring: report of delivery of a healthy male infant to the pygopagus Blazˇek sisters 2. Prenatal diagnosis a. Radiography b. 2D/3D ultrasonography: prenatal diagnosis made as early as 10–12 weeks’ gestation c. Transcervical embryoscopy for first trimester embryonic evaluation of conjoined twins after a missed abortion 3. Management a. Early prenatal diagnosis: highly desirable, given the extremely poor prognosis of some types of conjoined twins b. Psychological and prognosis counseling c. Accurate preoperative investigation d. A team approach

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e. Previous experience f. Meticulous operative and postoperative management g. Substantial mortality rate related to the underlying conditions h. High likelihood of success if major associated anomalies are absent i. Options of obstetrical management i. Continue the vaginal delivery and deliver the twins intact ii. Deliver the twins vaginally after intrauterine separation or a destructive procedure iii. Cesarean section and deliver the twins intact iv. Cesarean section and deliver the twins after intrauterine separation or destruction j. Anesthetic management for separating operations i. Extensive cross circulation a) Through a liver bridge b) Common cerebral venous sinus ii. Mechanical problems a) One anesthetist required for each infant b) A third anesthetist to look after intravenous infusions and monitors c) A fourth anesthetist to look after massive blood loss, circulatory collapse, or other catastrophic occurrence iii. Anticipate complex congenital heart defects that was not diagnosed preoperatively k. Four separate time frames of management (Spitz 2005) i. Prenatal a) Define the anatomy of the union once the diagnosis of conjoined twins is suspected b) Termination can be considered in the event of complex cardiac fusion in thoracopagus twins or extensive cerebral fusion in craniopagus twins: required detailed echocardiography and accurate ultrasonography complemented as necessary with MRI scanning c) Obtain informed decision as to either terminate or proceed with the pregnancy d) Delivery by cesarean section at 36–38 weeks of gestation ii. Nonoperative treatment a) In the presence of complex cardiac fusion b) Where a severe unacceptable deformity would follow separation

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Conjoined Twins

iii. Emergency separation a) When one twin is dead or dying, threatening the survival of the remaining twin b) Presence of a life-threatening correctable congenital abnormality (e.g., intestinal atresia, malrotation with or without volvulus, ruptured omphalocele, or anorectal agenesis) c) Emergency separation carries a significantly higher mortality rate compared with elective procedures iv. Elective separation a) Normally takes place between 2 and 4 months b) Allows time to stabilize, thrive, carry out detailed investigation to define the nature and the extent of union, and detailed planning of the operative procedure with all members of the operating team c) Survival rate: approaches 80%

References Awashi, M., Narlawar, R., Hira, P., et al. (2001). Fetus in fetu. Rare cause of a lump in an adult’s abdomen. Australasian Radiology, 45, 354–356. Bega, G., Wapner, R., Lev-Toaff, A., et al. (2000). Diagnosis of conjoined twins at 10 weeks using three-dimensional ultrasound: A case report. Ultrasound in Obstetrics & Gynecology, 16, 388–390. Benirschke, K. (1998). Sonographic diagnosis of conjoined twinning. Ultrasound in Obstetrics & Gynecology, 11, 241. Benirschke, K., Temple, W. W., & Bloor, C. M. (1978). Conjoined twin: Nosologic and congenital malformation. Birth Defects Original Article Series, 15, 179–192. Biswas, A., Chia, D., & Wong, Y. C. (2001). Three-dimensional sonographic diagnosis of cephalothoracopagus janiceps twins at 13 weeks. Ultrasound in Obstetrics & Gynecology, 18, 289. Bonilla-Musoles, F., Machado, L. E., Osborne, N. G., et al. (2002). Two-dimensional and three-dimensional sonography of conjoined twins. Journal of Clinical Ultrasound, 30, 68–75. Chen, C.-P., Lee, C.-C., Liu, F.-F., et al. (1997). Prenatal diagnosis of cephalothoracopagus janiceps monosymmetros. Prenatal Diagnosis, 17, 384–388. Chou, S. Y., Liang, S. J., Wu, C. F., et al. (2001). Sacral parasite conjoined twin. Obstetrics and Gynecology, 98, 938–940. Edmonds, L. D., & Layde, P. M. (1982). Conjoined twins in the United States. 1970–1977. Teratology, 25, 301–308. Gilbert-Barness, E., Debich-Spicer, D., & Opitz, J. M. (2003). Conjoined twins: Morphogenesis of the heart and a review. American Journal of Medical Genetics, 120A, 568–582. Gore, R. M., Filly, R. A., & Parer, J. T. (1982). Sonographic antepartum diagnosis of conjoined twins. Its impact on

obstetric management. Journal of the American Medical Association, 247, 3351–3353. Guttmacher, A. F. (1967). Biographical notes on some famous conjoined twins. Birth Defects Original Article Series, III(1), 10–17. Guttmacher, A. F., & Nichols, B. L. (1967). Teratology of conjoined twins. Birth Defects Original Article Series, 3(1), 3–9. Harper, R. G., Kenigsberg, K., Sia, C. G., et al. (1980). Xiphopagus conjoined twin: A 300-year review of the obstetric, morphopathologic, neonatal, and surgical parameters. American Journal of Obstetrics and Gynecology, 137, 617–629. Herbert, W. N. P., Cefalo, R. C., & Koontz, W. L. (1983). Perinatal management of conjoined twins. American Journal of Perinatology, 1, 58–63. Keats, A. S., Cave, P. E., Slataper, E. L., et al. (1967). Conjoined twins-A review of anesthetic management for separating operations. Birth Defects Original Article Series, III(1), 80–88. Knox, J. S., & Webb, A. J. (1975). The clinical features and treatment of fetus in fetu: Two case reports and review of literature. Journal of Pediatric Surgery, 10, 483–489. Kuroda, K., Kamei, Y., Kozuma, S., et al. (2000). Prenatal evaluation of cephalopagus conjoined twins by means of three-dimensional ultrasound at 13 weeks of pregnancy. Ultrasound in Obstetrics & Gynecology, 16, 264–266. Lam, Y. H., Sin, S. Y., Lam, C., et al. (1998). Prenatal sonographic diagnosis of conjoined twins in the first trimester: Two case reports. Ultrasound in Obstetrics & Gynecology, 11, 289–291. Machin, G. A. (1997). Multiple pregnancies and conjoined twins, Ch 9. In E. Gilbert-Barness (Ed.), Potter’s pathology of the fetus and infant (pp. 281–321). St. Louis: Mosby. Maymon, R., Halperin, R., Weinraub, Z., et al. (1998). Threedimensional transvaginal sonography of conjoined twins at 10 weeks: A case report. Ultrasound in Obstetrics & Gynecology, 11, 292–294. McHugh, K., Kiely, E. M., & Spitz, L. (2006). Imaging of conjoined twins. Pediatric Radiology, 36, 899–910. Nastanski, F., & Downey, E. C. (2001). Fetus in fetu: A rare cause of a neonatal mass. Ultrasound in Obstetrics & Gynecology, 18, 72–75. Petit, T., Raynal, P., Ravasse, P., et al. (2001). Prenatal sonographic diagnosis of a twinning Epigastric heteropagus. Ultrasound in Obstetrics & Gynecology, 17, 534–535. Rudolph, A. J., Michaels, J. P., & Nichols, B. L. (1967). Obstetric management of conjoined twins. Birth Defects Original Article Series, III(1), 28–37. Sanders, S. P., Chin, A. J., Parness, I. A., et al. (1985). Prenatal diagnosis of congenital heart defects in thoracoabdominally conjoined twins. The New England Journal of Medicine, 313, 370–374. Sills, E. S., Vrbikova, J., & Kastratovic-Kotlica, B. (2001). Conjoined twins, conception, pregnancy, and delivery: A reproductive history of the pygopagus Blazˇek sisters (1878–1922). American Journal of Obstetrics and Gynecology, 185, 1396–1402. Spencer, R. (1996). Anatomic description of conjoined twins: A plea for standardized terminology. Journal of Pediatric Surgery, 31, 941944.

Conjoined Twins Spencer, R. (2000a). Theoretical and analytical embryology of conjoined twins: Part I: Embryogenesis. Clinical Anatomy, 13, 36–53. Spencer, R. (2000b). Theoretical and analytical embryology of conjoined twins: Part II: Adjustments to union. Clinical Anatomy, 13, 97–120. Spencer, R. (2001). Parasitic conjoined twins: External, internal (fetuses in fetu and teratomas), and detached (acardiacs). Clinical Anatomy, 14, 428–444. Spitz, L. (2005). Conjoined twins (Review). Prenatal Diagnosis, 25, 814–819. Spitz, L., & Kiely, E. M. (2002). Experience in the management of conjoined twins. The British Journal of Surgery, 89, 1188–1192. Tan, A., & Lee, S.-L. (2002). Prenatal diagnosis of parasitic twins using three-dimensional ultrasound: A case report. Ultrasound in Obstetrics & Gynecology, 20, 192–193. Tongsong, T., Chanprapaph, P., & Pongsatha, S. (1999). First-trimester diagnosis of conjoined twins: A report of

501 three cases. Ultrasound in Obstetrics & Gynecology, 14, 434–437. Van Den Brand, S. F., Nijhuis, J. G., & Van Dongen, P. W. (1994). Prenatal ultrasound diagnosis of conjoined twins. Obstetrical and Gynecological Survey, 49, 656–662. Weingast, G. R., Johnson, M. L., Pretorius, D. H., et al. (1984). Difficulty in sonographic diagnosis of cephalothoracopagus. Journal of Ultrasound in Medicine, 3, 421–423. Wilcox, D. T., Quinn, F. M., Spitz, L., et al. (1998). Urological problems in conjoined twins. British Journal of Urology, 81, 905–910. Winkler, N., Kennedy, A., Byrne, J., et al. (2008). The imaging spectrum of conjoined twins. Ultrasound Quarterly, 24, 249–255. Yin, C. S., Chen, W.-H., Wei, R. Y.-C., et al. (1998). Transcervical embryoscopic diagnosis of conjoined twins in a ten-week missed abortion. Prenatal Diagnosis, 18, 626–628. Zimmermann, A. A. (1967). Embryological and anatomic considerations of conjoined twins. Birth Defects, 3, 18–27.

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Fig. 1 The conjoined twins are joined at the level of abdomen from umbilicus to the xiphoid cartilage (xiphoomphalopagus). This type of conjoined twins is the one most amenable to successful surgical correction because the incidence of complex anatomical anomalies is low. Left twin was successfully separated from the right twin who succumbed shortly after surgery to multiple congenital anomalies including exstrophy of the cloaca, left Bochdalek hernia, hypoplastic kidney, hypoplastic lungs, imperforate anus, and a large sacral meningomyelocele

a

Fig. 2 Prenatal ultrasound (a) detected the above conjoined twins with a shared liver (CAB) and separate hearts, stomach, pelvis, and extremities. One fetus was noted to have

b

a meningomyelocele (M). The magnified view (b) shows part of the shared liver and meningomyelocele

Conjoined Twins

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Fig. 5 Dicephalic conjoined twins. Two separate heads, two separate necks, and only one body are evident. The twins shared a common pericardium with complex cardiac anomalies, a common aorta at the level of iliac arteries, a common small intestine and other GI tract distally, a common bladder and urethra drained from a single kidney from each twin, and single normal female genitalia with normally placed fallopian tubes and ovaries. Surgical separation of the twins was deemed impossible and was not attempted

Fig. 3 These twins are thoraco-omphalopagus, connected at the thorax and upper abdomen. The heart showed complex anomalies with a common atrium and a single ventricle. Therefore, separation of the twins was not attempted

Fig. 4 The radiograph of the twins in Fig. 3 showing the connection at the thorax and the upper abdomen

Fig. 6 Prenatal ultrasound study showed lateral view of the dicephalic twins with two heads side by side, one trunk with two overlapping vertebral columns, and two upper extremities

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Fig. 7 Prenatal ultrasound study showed two separate vertebral columns

Fig. 8 Prenatal radiographic study showed dicephalic twins with two separate heads and two separate vertebral columns

Conjoined Twins

Fig. 9 The postnatal radiograph of the above conjoined twins showing separate heads, separate vertebrae, and separate upper GI tract. There is one pericardium sac and a fused liver

Fig. 10 A stillbirth with dicephalic conjoined twins

Conjoined Twins

Fig. 11 A set of dicephalic conjoined twin embryos at 6–7 weeks of gestation

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Corpus Callosum Agenesis/Dysgenesis

The corpus callosum is an interhemispheric structure that permits the integration of motor, sensory, and cognitive performance between the two cerebral hemispheres. Agenesis/dysgenesis of the corpus callosum is among the most common brain developmental malformation with a wide spectrum of associated clinical and pathologic abnormalities. The prevalence and clinical significance are uncertain. It is estimated to be 0.3–0.7% in the general population and 2–3% in the developmentally disabled (Jeret et al. 1985).

Synonyms and Related Disorders Agenesis of corpus callosum; Dysgenesis of corpus callosum

Genetics/Basic Defects 1. Markedly heterogeneous etiology of agenesis/ dysgenesis of the corpus callosum (Dobyns 1996) a. Sporadic in most cases b. Environmental factors i. Alcoholism ii. Maternal rubella iii. Maternal diabetes c. A multifactorial trait d. As a part of autosomal dominant syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Apert syndrome iii. Basal cell nevus syndrome iv. Miller–Dieker syndrome v. Rubinstein–Taybi syndrome vi. Tuberous sclerosis

e. As a part of autosomal recessive syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with thrombocytopenia iii. Acrocallosal syndrome iv. Andermann syndrome a) Agenesis/dysgenesis of the corpus callosum with peripheral neuropathy b) Mapping of the gene to a 5-cM region in chromosome 15q13-15 v. Cerebro-oculo-facio-skeletal (COFS) syndrome vi. Cogan syndrome (ocular motor apraxia) vii. Craniotelencephalic dysplasia viii. Dincsoy syndrome a) Multiple midline malformations b) Limb abnormalities c) Hypopituitarism ix. Fukuyama congenital muscular dystrophy x. Hydrolethalis syndrome xi. Joubert syndrome (cerebellar vermis agenesis) xii. Leprechaunism xiii. Lowry–Wood syndrome a) Epiphyseal dysplasia b) Microcephaly c) Nystagmus xiv. Meckel–Gruber syndrome xv. Microcephalic osteodysplastic primordial dwarfism type I/III xvi. Neu–Laxova syndrome xvii. Opitz G syndrome xviii. Peters plus syndrome a) Peters anomaly b) Short-limb dwarfism

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xix. Shapiro syndrome (recurrent hypothermia) xx. Smith–Lemli–Opitz syndrome xxi. Toriello–Carey syndrome a) Agenesis/dysgenesis of the corpus callosum b) Facial anomalies c) Robin sequence xxii. Vici syndrome a) Agenesis/dysgenesis of the corpus callosum b) Immunodeficiency c) Cleft lip/palate d) Cataract e) Hypopigmentation xxiii. Walker–Warburg syndrome a) Hydrocephalus b) Agyria c) Retinal dysplasia xxiv. Warburg micro syndrome a) Microcephaly b) Microphthalmia c) Cerebral malformations d) Other anomalies f. As a part of X-linked syndrome i. Agenesis/dysgenesis of the corpus callosum ii. Agenesis/dysgenesis of the corpus callosum with Hirschsprung disease iii. Agenesis/dysgenesis of the corpus callosum with hypohidrotic ectodermal dysplasia iv. Aicardi syndrome (retinovertebral anomalies in females) v. ATR-X syndrome (X-linked alpha thalassemia mental retardation syndrome) vi. Craniofrontonasal syndrome vii. Curatolo syndrome a) Agenesis/dysgenesis of the corpus callosum b) Chorioretinal abnormality viii. FG syndrome a) Mental retardation b) Large head c) Imperforate anus d) Congenital hypotonia e) Partial agenesis/dysgenesis of the corpus callosum ix. HSAS syndrome (hydrocephalus due to congenital stenosis of aqueduct of Sylvius)

Corpus Callosum Agenesis/Dysgenesis

x. Lenz dysplasia a) Microphthalmia/anophthalmia b) Associated anomalies xi. Lujan–Fryns syndrome a) X-linked mental retardation b) Marfanoid habitus xii. MASA syndrome a) Mental retardation b) Aphasia c) Shuffling gait d) Adducted thumbs xiii. MLS syndrome a) Microphthalmia b) Linear skin defects xiv. Opitz G syndrome xv. OFD I xvi. Proud syndrome a) X-linked syndrome b) Seizures c) Acquired micrencephaly d) Agenesis/dysgenesis of the corpus callosum xvii. XLIS syndrome (X-linked lissencephaly) g. As a part of unknown-genesis syndrome i. Calloso-genital dysplasia ii. Delleman (oculocerebrocutaneous) syndrome iii. Frontonasal dysplasia iv. Opitz C trigonocephaly syndrome v. Sebaceous nevus syndrome h. As a part of metabolic disorders i. Adenylosuccinase deficiency ii. Adipsic hypernatremia iii. b-hydroxyisobutyryl coenzyme A deacyclase deficiency iv. Glutaric aciduria type II v. Histidinemia vi. Hurler syndrome vii. Leigh syndrome viii. Menkes syndrome ix. Neonatal adrenoleukodystrophy x. Nonketotic hyperglycinemia xi. Pyruvate dehydrogenase deficiency xii. Zellweger syndrome i. Associated chromosome abnormalities i. Trisomy 18 ii. Trisomy 8 iii. Trisomy 21 iv. Trisomy 22 v. Other trisomies

Corpus Callosum Agenesis/Dysgenesis

vi. Deletions vii. Translocations viii. Duplications j. Agenesis of the corpus callosum with interhemispheric cyst: a heterogeneous group of disorders that have in common callosal agenesis and extraparenchymal cysts, both of which are among the commonest CNS malformations (Barkovich et al. 2001) k. Incidental finding in normal individuals (isolated dysgenesis of the corpus callosum) 2. Embryogenesis of the corpus callosum a. Development of the corpus callosum i. A late event in cerebral ontogenesis ii. Taking place between 12 and 18 weeks of gestation b. An important brain commissure connecting the cerebral hemispheres (Achiron and Achiron 2001) c. Essential for efficient cognitive function (Achiron and Achiron 2001) d. Failure of development of the commissural fibers connecting the cerebral hemispheres produces dysgenesis or agenesis of the corpus callosum e. Diagnosis of agenesis: a challenge even for expert sonologists, particularly prior to 20 weeks of gestation 3. Types of agenesis a. Complete agenesis: commonly regarded as a malformation deriving from faulty embryogenesis b. Type I agenesis i. Not associated with other disorders ii. Usually absent or associated with mild neurologic manifestations c. Type II agenesis i. Associated with other migrational, genetic, and chromosomal disorders ii. Usually associated with severe neurologic manifestations d. Partial agenesis i. Referred to as dysgenesis ii. Either a true malformation or a disruptive event occurring at any time during pregnancy iii. Missing caudad portion (splenium and body) to varying degrees 4. Agenesis/dysgenesis of the corpus callosum (da-Silva 1988) a. Without other associated brain anomalies

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b. Frequently associated with other brain anomalies i. Defects of septum pellucidum and fornix ii. Hydrocephalus iii. Dandy–Walker malformation iv. Interhemispheric cyst v. Holoprosencephaly vi. Porencephaly vii. Polymicrogyria viii. Macrogyria ix. Cortical heterotopia and atrophy x. Lipoma xi. Encephalocele xii. Hypoplasia of cerebellum c. Frequently associated other anatomical anomalies i. Congenital heart defects ii. Costovertebral defects iii. Gastrointestinal anomalies iv. Genitourinary anomalies

Clinical Features 1. Craniofacial abnormalities a. Microcephaly b. Macrocephaly 2. Developmental anomalies a. Nonspecific mental retardation b. Developmental delay c. Learning disabilities d. Behavioral disorder e. Mental retardation f. Failure to thrive 3. Infantile spasms/seizures 4. Signs and symptoms related to type I and type II agenesis a. Type I i. Variable intelligence: normal to mild or moderate mental retardation ii. Seizure disorder iii. Impaired visual, motor, and/or bimanual coordination iv. Mild impairment of crossed tactile localization and skills requiring matching of visual patterns b. Type II i. Mental retardation ii. Seizures iii. Hydrocephaly

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Corpus Callosum Agenesis/Dysgenesis

iv. v. vi. vii. viii.

Microcephaly Hemiparesis Diplegia Spasticity Failure to thrive

Diagnostic Investigations 1. Psychometric tests (Finlay et al. 2000) a. Difficulties in motor coordination b. Difficulties in interhemispheric transfer of tactile information c. Difficulties in some areas of memory d. A marked difference in verbal IQ and performance IQ in children 2. EEG for seizure activities 3. CT and/or ultrasound of the brain (Gupta and Lilford 1995) a. Absence of the corpus callosum b. Absence of septum pellucidum c. Increased separation of the lateral ventricles d. Marked separation of the slit-like anterior horns of the lateral ventricles and dilatation of the occipital horns creating the typical “rabbit’s ear” or “tear drop” appearance e. Upward displacement of the third ventricle f. Evidence of other migration disorders 4. Coronal radiographs showing a pathognomonic batwing ventricular pattern 5. Karyotyping for underlying chromosomal disorder 6. Metabolic studies for underlying inborn error of metabolism

Genetic Counseling 1. Recurrence risk a. Patient’s sib: depending on the etiology and the mode of inheritance i. Isolated agenesis/dysgenesis of the corpus callosum: recurrence risk not increased ii. Environmental factor: recurrence risk not increased by avoiding the environmental factor iii. Autosomal recessive inheritance: 25% of siblings affected, 50% siblings carriers, and 25% of siblings normal

iv. Autosomal dominant inheritance: recurrence risk not increased unless a parent is affected in which case the recurrence risk is 50% v. X-linked recessive inheritance a) Carrier mother (50% of brothers affected; 50% of sisters carriers) b) Affected father (all brothers normal, all sisters carriers) v. X-linked dominant inheritance a) Affected mother (50% of brothers and sisters affected) b) Affected father (all brothers normal; all sisters affected) vi. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation b. Patient’s offspring i. Environmental factor: recurrence risk not increased by avoiding the environmental factor ii. Autosomal recessive inheritance: recurrence risk not increased unless the spouse is also a carrier in which case the recurrence risk is 50% iii. Autosomal dominant inheritance: 50% iv. X-linked recessive inheritance a) Carrier female (50% of sons affected, 50% of daughters carriers) b) Affected male (all sons normal, all daughters carriers) v. X-linked dominant inheritance a) Affected female (50% of sons and daughters affected) b) Affected male (all sons normal, all daughters affected) vi. Chromosomal disorder: recurrence risk increased, especially if a parent carries a balanced translocation 2. Prenatal diagnosis a. Ultrasonography i. Prenatal detection of the agenesis of the corpus callosum usually not possible before 22 weeks of gestation (Bennett et al. 1996) ii. Direct demonstration of the absence or partial absence of the corpus callosum

Corpus Callosum Agenesis/Dysgenesis

iii. Failure to visualize the cavum septum pellucidum iv. Third ventricle lying between widely separated lateral ventricles due to absent corpus callosum v. Lateral ventricles more parallel to the midline than usual vi. A cyst arising from the superior aspect of the third ventricle communicating with the lateral ventricles vii. Vertical orientation of the gyri with agenesis instead of normal horizontal alignment viii. Colpocephaly (locally dilated occipital horns of the lateral ventricle) forming an appearance on axial views similar to bulls’ horns ix. Absence of pericallosal artery x. Up to 50% of cases with other associated anatomic defects xi. Variable developmental outcome on prenatal detection of an isolated agenesis of the corpus callosum b. MRI i. Allows more detailed visualization of the fetal brain than ultrasonography ii. Constitutes a useful additional procedure after ultrasonographic diagnosis or suspicion of corpus callosum agenesis c. Amniocentesis recommended for karyotyping as there is 10–20% risk of aneuploidy associated with the agenesis of the corpus callosum d. Prenatal counseling for ultrasonically diagnosed fetal agenesis of the corpus callosum remains very difficult, as giving precise information on outcome is impossible. (Moutard et al. 2003) The following observation, however, may be of help in prenatal counseling: (Gupta 1995) i. Isolated agenesis/dysgenesis of the corpus callosum (in the absence of other sonographically detectable anomalies) carrying apparent excellent prognosis a) 85% chance of a normal developmental outcome b) 15% risk of handicap ii. Agenesis/dysgenesis of the corpus callosum with other associated anomalies: poor outcome

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3. Management a. Identification of actual deficits resulting from the absence of such a major structure (corpus callosum): clearly an issue b. Multidisciplinary team approach to intervention programs c. Anticonvulsants for seizures d. Management based on the underlying etiology

References Achiron, R., & Achiron, A. (2001). Development of the human fetal corpus callosum: A high-resolution, cross-sectional sonographic study. Ultrasound in Obstetrics & Gynecology, 18, 343–347. Barkovich, A. J., Simon, E. M., & Walsh, C. A. (2001). Callosal agenesis with cyst. A better understanding and new classification. Neurology, 56, 220–227. Bennett, G. L., Bromley, B., & Benacerraf, B. R. (1996). Agenesis of the corpus callosum: Prenatal detection usually is not possible before 22 weeks of gestation. Radiology, 199, 447–450. Casaubon, L. K., Melanson, M., Lopes-Cendes, I., et al. (1996). The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. American Journal of Human Genetics, 58, 28–34. D’Ercole, C., Girard, N., Cravello, L., et al. (1998). Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenatal Diagnosis, 18, 247–253. da-Silva, E. O. (1988). Callosal defect, microcephaly, severe mental retardation, and other anomalies in three sibs. American Journal of Medical Genetics, 29, 837–843. Dobyns, W. B. (1996). Absence makes the search grow longer (Editorial). American Journal of Medical Genetics, 58, 7–16. Finlay, D. C., Peto, T., Payling, J., et al. (2000). A study of three cases of familial related agenesis of the corpus callosum. Journal of Clinical and Experimental Neuropsychology, 22, 731–742. Gupta, J. K., & Lilford, R. J. (1995). Assessment and management of fetal agenesis of the corpus callosum. Prenatal Diagnosis, 15, 301–312. Jeret, J. S., Serur, D., Wisniewski, K., et al. (1985). Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatric Neuroscience, 12, 101–103. Lacey, D. J. (1985). Agenesis of the corpus callosum. Clinical features in 40 children. American Journal of Diseases of Children, 139, 953–955. Loeser, J. D., & Alvord, E. C. (1968). Agenesis of the corpus callosum. Brain, 91, 553–570. Moutard, M.-L., Kieffer, V., Feingold, J., et al. (2003). Agenesis of corpus callosum: Prenatal diagnosis and prognosis. Child Nerv Syst, 19, 471–476.

512 Pilu, G., & Hobbins, J. C. (2002). Sonography of fetal cerebrospinal anomalies. Prenatal Diagnosis, 22, 321–330. Pilu, G. L., Sandri, F., Perolo, A., et al. (1993). Sonography of fetal agenesis of the corpus callosum: A survey of 35 cases. Ultrasound in Obstetrics & Gynecology, 3, 318–329. Probst, F. P. (1973). Agenesis of the corpus callosum. Acta Radiologica, 331(Suppl), 1–150.

Corpus Callosum Agenesis/Dysgenesis Serur, D., Jeret, J. S., Wisniewski, K., et al. (1988). Agenesis of the corpus callosum: Clinical, neuroradiological and cytogenetic studies. Neuropediatrics, 19, 87–91. Vergani, P., Ghidini, A., Strobelt, N., et al. (1994). Prognostic indicators in the prenatal diagnosis of agenesis of the corpus callosum. American Journal of Obstetrics and Gynecology, 170, 753–758.

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a

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b

c d

e

Fig. 1 (a–e) An infant (ages 3 months and 16 months) with agenesis of the corpus callosum and interhemispheric cyst, illustrated by MRI

Craniometaphyseal Dysplasia

In 1954, Jackson et al. coined the term “craniometaphyseal dysplasia” for a hereditary bone disease with metaphyseal widening of the tubular bones and bony overgrowth of the facial and skull bones (leonteasis ossea).

Genetics/Basic Defects 1. Genetic heterogeneity (Beighton 1995) a. Autosomal dominant form [also called CMD, Jackson type (CMDJ)]: i. CMDJ locus mapped to 5p15.2-p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene ii. Mutations in ANKH have been associated in craniometaphyseal dysplasia in some families (N€ urnberg et al. 2001; Reichenberger et al. 2001) iii. ANKH mutations that cause CMD most likely entail a loss of function (Kornak et al. 2010) or a loss of ANKH protein expression and activity in the plasma membrane as a result of aberrant intracellular protein trafficking (Zajac et al. 2010) b. Autosomal dominant form cosegregating with chondrocalcinosis i. Mutations in ANKH have been associated with familial chondrocalcinosis (OCAL2) in some families (Pendleton et al. 2002; Williams et al. 2003) ii. A family was reported with an ANKH mutations in which these conditions cosegregated in some affected family members (Baynam et al. 2009)

c. Autosomal recessive form i. Rare ii. Ill-defined iii. Probably heterogeneous iv. Often difficult to diagnose with precision v. Autosomal recessive CMD locus mapped to 6q21-22 2. Basic defects a. Autosomal dominant form: caused by mutations in the human homolog of the mouse progressive ankylosis gene (ANKH) (Reichenberger et al. 2001) b. Autosomal recessive form (Beighton 1995) i. May involve dysfunctional osteoclasts because reported metabolic responses of affected children to therapy with calcitonin and clacitrol ii. Osteoclast-like cells derived from the bone marrow shown to lack expression of the osteoclast vacuolar proton pump

Clinical Features 1. Autosomal dominant form a. General features i. Good general health ii. Normal intelligence iii. Normal stature b. Bony overgrowth of the facial bone resulting in the typical facies: i. Frontal bossing ii. Hypertelorism iii. Paranasal bossing (30% of cases in childhood) a) May be present during infancy b) Tends to regress with age

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c) Virtually absent by adolescence and early adulthood d) May be associated with some degree of nasal obstruction and frequent mouth breathing iv. Mild to moderate mandibular prognathism v. An open mouth secondary to bony encroachment of the nasal passages vi. Malalignment of the teeth vii. Grotesque hyperostosis of the facial bones viii. Decreased facial movement c. Bony overgrowth of the cranial foramina resulting in the following features: i. Cranial nerve paralysis ii. Nystagmus iii. Optic atrophy iv. Facial palsy (30% of cases) a) Common but variable b) May be unilateral or bilateral c) May occur at any age d) The involvement often fluctuant in early childhood e) May be permanent in adulthood v. Deafness (50% of cases) a) Due to compromised auditory nerve and inner ear by bone overgrowth b) May be unilateral or bilateral c) Often “mixed” in type due to chronic otitis media and upper respiratory tract infection secondary to minor anatomical abnormalities of the airway and sinuses d) Usually partial and rarely profound vi. Less commonly reported conditions (Kietzer and Paparella 1969) a) Compression of the cerebellar tonsils and medulla secondary to a narrowed foramen magnum b) Obstruction of Eustachian tube c) Obstruction of nasolacrimal duct d) Obstruction of nasal passages e) Raised intracranial pressure: rare instances of a potentially lethal rise in intracranial pressure due to hyperostosis of the calvarium d. Abnormal modeling of the metaphyses of the long bones i. Metaphyseal widening of the long and short tubular bones

Craniometaphyseal Dysplasia

ii. Thin cortical layer iii. Coarse trabeculations e. Clinical and radiographic features improved in later childhood in the dominant form 2. Autosomal recessive form a. Similar to, but more severe than, those seen in the dominant form b. An increasing severity with age c. Progressive overgrowth and craniofacial deformity i. Very severe facial distortion ii. A thick bony wedge over the bridge of the nose iii. Dystopia canthorum iv. Ocular hypertelorism v. Enlarged malar prominences and mandible (marked prognathism) vi. Wide alveolar ridge vii. Narrowed nasal passages leading to mouth breathing viii. Dental abnormalities ix. Blindness x. Facial palsy xi. Deafness d. Abnormal modeling of the metaphyses of the long bones i. Gradual, club-shaped widening of the metaphyses ii. Thin cortex and undermineralized medullary bone 3. Differential diagnosis (Cole and Cohen 1988) a. Pyle disease (metaphyseal dysplasia) i. Frequently confused with craniometaphyseal dysplasia. In Pyle disease, metaphyseal flaring occurs but there is minimal involvement of the skull ii. Autosomal recessive inheritance b. Craniodiaphyseal dysplasia (Cole and Cohen 1988) i. Most severe thickening, distortion, and enlargement of the craniofacial region ii. Characterized by diaphyseal endostosis iii. Does not exhibit metaphyseal flaring iv. Inheritance likely autosomal recessive c. Frontometaphyseal dysplasia (Cooper 1974) i. A pronounced bony supraorbital ridge ii. Hirsutism iii. Long-bone alterations iv. Conductive deafness

Craniometaphyseal Dysplasia

d. Camurati–Engelmann disease (progressive diaphyseal dysplasia) (Cooper 1974) i. Presence of excess subperiosteal bone in the diaphyses of the long bone ii. Normal metaphyses iii. Rare craniofacial involvement e. Van Buchem disease (hyperostosis corticalis generalisata) (Cooper 1974) i. Dense and thickened craniofacial skeleton ii. Generalized cortical thickening of the long bones mainly due to endosteal bone apposition

Diagnostic Investigations 1. Normal serum calcium, phosphorous, and alkaline phosphatase 2. Radiographic features (Beighton 1995) a. Autosomal dominant form: age-related radiographic features i. Characteristic hyperostosis and sclerosis of the skull ii. Paranasal bony bossing, most evident in early childhood iii. May be present with prognathism and asymmetry iv. Characteristic non-sclerotic widening of the metaphyses of the tubular bones: a major radiographic feature a) Most obvious at the lower end of the femur b) An “Erlenmeyer flask” configuration in childhood c) A “club” shape in adulthood b. Autosomal recessive form: severe radiographic manifestations (Penchaszadeh et al. 1980) i. Increasing severity with age ii. Sclerosis and hyperostosis of the calvarium, the base of the skull, and the facial bones and mandible iii. Increased bone deposition on the walls of the paranasal sinuses iv. Underpneumatization of mastoid cells v. Gradual, club-shaped widening of the metaphyses vi. Thin cortex and undermineralized medullary bone

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3. Gross pathological features (Kietzer and Paparella 1969) a. Thickened “ivory-hard” facial and cranial bones b. Narrow cranial foramina c. Narrowing of the nasal chambers and posterior choanae 4. Histological features (Kietzer and Paparella 1969) a. Compact laminar cortical bone with dilated Haversian canals containing osteoblasts b. No osteoclasts identified in the periosteal or endosteal layers c. An increased amount of ground substance and excessive formation of subperiosteal and subendosteal bone 5. Molecular genetic analysis for human ankylosis gene (ANKH): Sequence analysis detects mutations in about 90% of individuals meeting the diagnostic criteria for CMD (Reichenberger and Chen 2010)

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant form: 50% risk if one parent is affected, otherwise risk not increased ii. Autosomal recessive form: 25% b. Patient’s offspring i. Autosomal dominant form: 50% ii. Autosomal recessive form: not increased unless the spouse is also a carrier in which case there is 50% recurrence risk 2. Prenatal diagnosis for pregnancies at risk may be available through laboratories offering custom prenatal testing if the disease-causing mutations in the family is known (Reichenberger and Chen 2010) 3. Management a. Medical treatment attempted with the following two hormones i. Calcitonin: has an inhibitory effect on bone formation ii. Calcitriol (Key et al. 1988) a) Stimulates resorption of bone by promoting osteoclast formation b) Partial resolution of facial nerve paralysis, increased size of the cranial nerve foramina, and demineralization of the

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cranial base during treatment of one patient with high doses of calcitriol b. Hearing aids for hearing loss c. Psychological support for facial disfigurement d. Surgical treatment with mixed results (Day et al. 1997) i. Resection of dysplastic bone arduous because it is highly mineralized with a consistency like thick ivory ii. Craniofacial reduction performed with some difficulty iii. Optic canal decompression for progressive visual loss iv. Facial nerve decompression v. Middle ear exploration and implantation of total ossicular replacement prosthesis for conductive hearing loss vi. Foramen magnum decompression for cervicomedullary encroachment

References Baynam, G., Goldblatt, J., & Schofield, L. (2009). Craniometaphyseal dysplasia and chondrocalcinosis cosegregating in a family with an ANKH mutation. American Journal of Medical Genetics. Part A, 149A, 1331–1333. Beighton, P. (1995). Craniometaphyseal dysplasia (CMD), autosomal dominant form. Journal of Medical Genetics, 32, 370–374. Beighton, P., Hamersma, H., & Horan, F. (1979). Craniometaphyseal dysplasia–variability of expression within a large family. Clinical Genetics, 15, 252–258. Boltshauser, E., Schmitt, B., Wichmann, W., et al. (1996). Cerebellomedullary compression in recessive craniometaphyseal dysplasia. Neuroradiology, 38(Suppl 1), S193–S195. Bricker, S. L., Langlais, R. P., & van Dis, M. L. (1983). Dominant craniometaphyseal dysplasia. Literature review and case report. Dento Maxillo Facial Radiology, 12, 95–100. Carnevale, A., Grether, P., del Castillo, V., et al. (1983). Autosomal dominant craniometaphyseal dysplasia. Clinical variability. Clinical Genetics, 23, 17–22. Chandler, D., Tinschert, S., Lohan, K., et al. (2001). Refinement of the chromosome 5p locus for craniometaphyseal dysplasia. Human Genetics, 108, 394–397. Cheung, V. G., Boechat, M. I., & Barrett, C. T. (1997). Bilateral choanal narrowing as a presentation of craniometaphyseal dysplasia. Journal of Perinatology, 17, 241–243. Cole, D. E., & Cohen, M. M., Jr. (1988). A new look at craniometaphyseal dysplasia. Journal of Pediatrics, 112, 577–579. Cooper, J. C. (1974). Craniometaphyseal dysplasia: A case report and review of the literature. The British Journal of Oral Surgery, 12, 196–204. Day, R. A., Park, T. S., Ojemann, J. G., et al. (1997). Foramen magnum decompression for cervicomedullary encroachment

Craniometaphyseal Dysplasia in craniometaphyseal dysplasia: Case report. Neurosurgery, 41, 960–964. Fanconi, S., Fischer, J. A., Wieland, P., et al. (1988). Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: Therapeutic effect of calcitonin. Journal of Pediatrics, 112, 587–591. Gorlin, R. J., Koszalka, M. F., & Spranger, J. (1970). Pyle’s disease (familial metaphyseal dysplasia). A presentation of two cases and argument for its separation from craniometaphyseal dysplasia. Journal of Bone and Joint Surgery. American Volume, 52, 347–354. Gorlin, R. J., Spranger, J., & Koszalka, M. F. (1969). Genetic craniotubular bone dysplasias and hyperostoses: A critical analysis. Birth Defects Original Article Series, V(4), 79–95. Iughetti, P., Alonso, L. G., Wilcox, W., et al. (2000). Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. American Journal of Medical Genetics, 95, 482–491. Jackson, W. P. U., Albright, F., Drewry, G., et al. (1954). Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions I. Familial metaphyseal dysplasia and craniometaphyseal dysplasia: Their relation to leontiasis ossea and osteopetrosis: Disorders of “bone remodeling”. Archives of Internal Medicine, 94, 871–885. Key, L. L., Jr., Volberg, F., Baron, R., et al. (1988). Treatment of craniometaphyseal dysplasia with calcitriol. Journal of Pediatrics, 112, 583–587. Kietzer, G., & Paparella, M. M. (1969). Otolaryngological disorders in craniometaphyseal dysplasia. The Laryngoscope, 79, 921–941. Kornak, U., Brancati, F., Le Merrer, M., et al. (2010). Three novel mutations in the ANK membrane protein cause craniometaphyseal dysplasia with variable conductive hearing loss. American Journal of Medical Genetics. Part A, 152A, 870–874. Martin, F. W. (1979). Otorhinological aspects of craniometaphyseal dysplasia. Clinical Otolaryngology, 4, 67–76. Millard, D. R., Jr., Maisels, D. O., Batstone, J. H., et al. (1967). Craniofacial surgery in craniometaphyseal dysplasia. American Journal of Surgery, 113, 615–621. N€ urnberg, P., Thiele, H., Chandler, D., et al. (2001). Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nature Genetics, 28, 37–41. N€ urnberg, P., Tinschert, S., Mrug, M., et al. (1997). The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5p and is distinct from the growth hormone-receptor gene. American Journal of Human Genetics, 61, 918–923. Penchaszadeh, V. B., Gutierrez, E. R., & Figueroa, E. (1980). Autosomal recessive craniometaphyseal dysplasia. American Journal of Medical Genetics, 5, 43–55. Pendleton, A., Johnson, M. D., Hughes, A., et al. (2002). Mutations in ANKH cause chondrocalcinosis. American Journal of Human Genetics, 71, 933–940. Puri, P., & Chan, J. (2003). Craniometaphyseal dysplasia: Ophthalmic features and management. Journal of Pediatric Ophthalmology and Strabismus, 40, 228–231. Reichenberger, E., Chen, I. -P. (2010). Craniometaphyseal dysplasia. GeneReviews. Retrieved November 2, 2010. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1461/

Craniometaphyseal Dysplasia Reichenberger, E., Tiziani, V., Watanabe, S., et al. (2001). Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. American Journal of Human Genetics, 68, 1321–1326. Shea, J., Gerbe, R., & Ayani, N. (1981). Craniometaphyseal dysplasia: The first successful surgical treatment for associated hearing loss. The Laryngoscope, 91, 1369–1374. Sun, G. H., Samy, R. N., Tinkle, B. T., et al. (2011). Craniometaphyseal dysplasia-induced hearing loss. Otology & Neurotology, 32(2), e9–e10. Williams, C. J., Pendleton, A., Bonavita, G., et al. (2003). Mutations in the amino terminus of ANKH in two US families

519 with calcium pyrophosphate dihydrate crystal deposition disease. Arthritis and Rheumatism, 48, 2627–2631. Yamamoto, T., Kurihara, N., Yamaoka, K., et al. (1993). Bone marrow-derived osteoclast-like cells from a patient with craniometaphyseal dysplasia lack expression of osteoclastreactive vacuolar proton pump. Journal of Clinical Investigation, 91, 362–367. Zajac, A., Baek, S. H., Salhab, I., et al. (2010). Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia. American Journal of Medical Genetics. Part A, 152A, 770–776.

520 Fig. 1 (a–d) A girl with craniometaphyseal dysplasia showing characteristic craniofacial features consisting of hypertelorism, broadening nasal base with paranasal bossing, short nose, and prominent facial bones

Craniometaphyseal Dysplasia

a

c

b

d

Cri-Du-Chat Syndrome

Cri-du-chat syndrome is a chromosome 5p deletion syndrome first described by Lejeune et al. in 1963. The name of the syndrome refers to the most characteristic clinical feature, a high-pitched crying similar to the mewing of a cat, which usually disappears in the first years of life. The incidence is estimated to be approximately 1 in 15,000 (Higurashi et al. 1990) to 1 in 50,000 births (Niebuhr 1978). The prevalence among mentally retarded individuals is approximately 1.5 in 1,000.

Synonyms and Related Disorders Cat cry syndrome; Chromosome 5p deletion syndrome

Genetics/Basic Defects 1. Cause a. Caused by deletion of short arm of chromosome 5: The size of the deletion ranges from the entire short arm to the region 5p15 (Overhauser et al. 1994) and a deletion size ranging from 5 to 40 Mb (Simmons et al. 1995) i. De novo deletion (80%): paternally derived deletions in 80% of cases ii. Familial rearrangement (12%) iii. Mosaicism (3%) iv. Rings (2.4%) v. De novo translocation (3%) b. A high-resolution physical and transcription map generated a 3.5-Mb region of 5p15.2 that is associated with the Cri-du-chat syndrome region (Church et al. 1997)

2. Genotype–phenotype correlation (Gersh et al. 1997) a. Deletion of 5p15.3 results in a cat-like cry and speech delay (Gersh et al. 1995; Church et al. 1995) b. Deletion of 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay 3. Hemizygosity of d-catenin (CTNND2, mapped to 5p15.2), reported to be associated with severe mental retardation in cri-du-chat syndrome (Medina et al. 2000) 4. Deletion of the telomerase reverse transcriptase (hTERT) gene (mapped at 5p15.33) and haploinsufficiency of telomere maintenance is probably a genetic element contributing to the phenotypic changes in cri-du-chat syndrome (Zhang et al. 2003)

Clinical Features 1. Characteristic mewing cry (Niebuhr 1978) a. A high-pitched monochromatic cry with subtle dysmorphism and neonatal complications: commonly observed in infants with this syndrome b. Observed in many infants with cri-du-chat syndrome c. Not associated with other aneuploidies d. Usually considered diagnostic e. Loss of the characteristic cry by age 2 years in one third of children 2. Clinical findings during infancy a. Low birth weight b. Hypotonia

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c. d. e. f. g. h. i. j. k. l. m.

n.

o. p. q.

Microcephaly Poor sucking/swallowing difficulties Need for incubator care Respiratory distress Jaundice Pneumonia Dehydration Failure to thrive/growth retardation Early ear infections Severe cognitive, speech, and motor delays Facial features i. Round face with full cheek ii. Hypertelorism iii. Epicanthal folds iv. Down-slanting palpebral fissures v. Strabismus vi. Flat nasal bridge vii. Down-turned mouth viii. Micrognathia ix. Low-set ears Cardiac defects i. VSD ii. ASD iii. PDA iv. Tetralogy of Fallot Short fingers Single palmar creases Less frequent features i. Cleft lip and palate ii. Preauricular tags and fistulas iii. Thymic dysplasia iv. Gut malrotation v. Megacolon vi. Inguinal hernia vii. Dislocated hips viii. Cryptorchidism ix. Hypospadias x. Rare renal malformations a) Horseshoe kidneys b) Renal ectopia or agenesis c) Hydronephrosis x. Clinodactyly of the fifth fingers xi. Talipes equinovarus xii. Pes planus xiii. Syndactyly of the second and third fingers and toes xiv. Oligosyndactyly xv. Hyperextensible joints

3. Clinical findings in childhood a. Severe mental retardation b. Developmental delay c. Microcephaly d. Hypertonicity e. Premature graying of the hair f. Small, narrow, and often asymmetric face g. Dropped-jaw h. Open-mouth expression secondary to facial laxity i. Short philtrum j. Malocclusion of the teeth k. Scoliosis l. Short third-fifth metacarpals m. Chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation iv. Hyperactivity 4. Clinical findings in late childhood and adolescence a. Coarsening of facial features b. Prominent supraorbital ridges c. Deep-set eyes d. Hypoplastic nasal bridge e. Affected females reaching puberty and developing secondary sex characteristics and menstruate at the usual time (Martinez et al. 1993) f. Small testis and normal spermatogenesis in males 5. Dermatoglyphics a. Transverse flexion creases b. Distal axial triradius c. Increased whorls and arches on digits 6. Behavioral profile a. Hyperactivity b. Aggression c. Tantrums d. Stereotypic and self-injurious behavior e. Repetitive movements f. Hypersensitivity to sound g. Clumsiness h. Obsessive attachments to objects i. Able to communicate needs and interact socially with others j. Autistic-like features and social withdrawal: more characteristic of individuals who have a 5p deletion as the result of an unbalanced segregation of a parental translocation

Cri-Du-Chat Syndrome

7. Prognosis a. Ability of many children to develop some language and motor skills b. Ability of these children to attain developmental and social skills observed in 5- to 6-year-old children, although their linguistic abilities are seldom as advanced c. Older, home-reared children i. Usually ambulatory ii. Able to communicate verbally or through gestural sign language iii. Independent in self-care skills

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6. Echocardiography to rule out structural cardiac malformations 7. MRI of the brain (Kjaer and Niebuhr 1999) a. Atrophic brainstem, middle cerebellar peduncles, and cerebellar white matter b. Possible hypoplasia of cerebellar vermis with enlargement of the cisterna magna and fourth ventricle 8. Swallowing study for feeding difficulty 9. Comprehensive evaluation for receptive and expressive language. Most children have better receptive language than expressive language 10. Developmental testing and referral to early intervention and appropriate school placement

Diagnostic Investigations 1. Conventional cytogenetic studies once the suspected diagnosis is established. The size of the 5p deletion may vary from the entire short arm to only 5p15. A small deletion of 5p may be missed by a conventional cytogenetic technique 2. High-resolution cytogenetic studies are required for a smaller 5p deletion 3. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH) a. Allow the diagnosis to be made in the patients with very small deletions b. Use genetic markers that have been precisely localized to the area of interest c. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions: indicative of monosomy for that chromosomal region 4. Comparative genomic hybridization (CGH) especially the CGH method based on DNA microarray and quantitative PCR (Mainardi et al. 2001; Rodriguez-Caballero et al. 2010) 5. Skeletal radiographs a. Microcephaly b. Retromicrognathia c. Cranial base malformations i. Reduced cranial base angle ii. Malformed sella turcica and clivus d. Disproportionately short third, fourth, and fifth metacarpals and disproportionately long second, third, fourth, and fifth proximal phalanges (frequent) (Fenger and Niebuhr 1978)

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Recurrence risk for a de novo case is 1% or less (possibility of gonadal mosaicism in one of the parents cannot be ruled out) ii. Rare recurrences in chromosomally normal parents: most likely the result of gonadal mosaicism for the 5p deletion in one of the parents iii. The risk is substantially high if a parent is a balanced carrier of a structural rearrangement. Risk should be assessed based on the type of structural rearrangement and its pattern of segregation b. Patient’s offspring: Female patients are fertile and can deliver viable affected offspring, with an estimated recurrence risk of 50% 2. Prenatal diagnosis by amniocentesis, CVS, and PUBS for chromosome analysis to detect 5p deletion 3. Management a. Supportive care: No treatment exists for the underlying disorder b. Appropriate treatment for chronic medical problems i. Upper respiratory tract infections ii. Otitis media iii. Severe constipation c. Using the relatively good receptive skills to encourage language and communicative development rather than relying on traditional verbal methods (Cornish and Munir 1988)

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d. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy e. Introduction to sign language, an effective means of developing communication skills (>50% of children are able to use sign language to communicate) (Cornish and Munir 1988) f. Behavior modification programs to successfully manage hyperactivity, short attention span, low threshold for frustration, and self-stimulatory behaviors (e.g., head-banging, hand-waving) g. Surgical interventions i. Correction of congenital heart defects if indicated ii. Medical problems involving minor malformations such as strabismus and clubfoot iii. Gastrostomy in infancy to protect airway of patients with major feeding difficulties iv. Orchiopexy for undescended testes v. Issues important to anesthetic plan a) Anatomical abnormalities of the airway b) Congenital heart disease c) Hypotonia d) Mental retardation e) Temperature maintenance

References Aoki, S., Hata, T., Hata, K., et al. (1999). Antenatal sonographic features of cri-du-chat syndrome. Ultrasound in Obstetrics & Gynecology, 13, 216–217. Baccichetti, S. E., Lenzini, L., Artifoni, D., et al. (1988). Terminal deletion of the short arm of chromosome 5. Clinical Genetics, 34, 219–223. Brislin, R. P., Stayer, S. A., & Schwartz, R. E. (1995). Anaesthetic considerations for the patient with cri du chat syndrome. Paediatric Anaesthesia, 5, 139–141. Chen, H. (2009). Cri-du-chat syndrome. eMedicine from WebMD. Updated May 13, 2009. Available at: http:// emedicine.medscape.com/article/942897-overview Church, D. M., Bengtsson, U., Nielsen, K. V., et al. (1995). Molecular definition of deletions of different segments of distal 5p that results in distinct phenotypic features. American Journal of Human Genetics, 56, 1162–1172. Church, D. M., Yang, J., Bocian, M., et al. (1997). A highresolution physical and transcript map of the cri du chat region of human chromosome 5p. Genome Research, 7, 787–801. Clarke, D. J., & Boer, H. (1998). Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and cri du chat

syndrome. American Journal of Mental Retardation, 103, 264–271. Collins, M. S., & Cornish, K. (2002). A survey of the prevalence of stereotypy, self-injury and aggression in children and young adults with cri du chat syndrome. Journal of Intellectual Disability Research, 46, 133–140. Cornish, K. M., & Munir, F. (1988). Receptive and expressive language skills in children with cri-du-chat syndrome. Journal of Communication Disorders, 31, 73–80 quiz 80–81. Cornish, K. M., & Pigram, J. (1996). Developmental and behavioural characteristics of cri du chat syndrome. Archives of Disease in Childhood, 75, 448–450. Dykens, E. M., & Clark, D. J. (1997). Correlates of maladaptive behavior in individuals with 5p- (cri du chat) syndrome. Developmental Medicine and Child Neurology, 39, 752–756. Fankhauser, L., Brundler, A. M., & Dahoun, S. (1998). Cri-duchat syndrome diagnosed by amniocentesis performed due to abnormal maternal serum test. Prenatal Diagnosis, 18, 1099–1100. Fenger, K., & Niebuhr, E. (1978). Measurements of hand radiographs from 32 cri-du-chat probands. Radiology, 129, 137–141. Gersh, M., Goodart, S. A., & Pasztor, L. M. (1995). Evidence for a distinct region causing a cat-like cry in patients with 5p deletions. American Journal of Human Genetics, 56, 1404–1410. Gersh, M., Grady, D., & Rojas, K. (1997). Development of diagnostic tools for the analysis of 5p deletions using interphase FISH. Cytogenetics and Cell Genetics, 77, 246–251. Goodart, S. A., Simmons, A. D., Grady, D., et al. (1994). A yeast artificial chromosome contig of the critical region for cri-duchat syndrome. Genomics, 24, 63–68. Higurashi, M., Oda, M., Iijima, K., et al. (1990). Livebirths prevalence and follow-up of malformation syndromes in 27,472 newborns. Brain & Development, 12, 770–773. Hodapp, R. M., Wijma, C. A., & Masino, L. L. (1997). Families of children with 5p- (cri du chat) syndrome: Familial stress and sibling reactions. Developmental Medicine and Child Neurology, 39, 757–761. Kjaer, I., & Niebuhr, E. (1999). Studies of the cranial base in 23 patients with cri-du-chat syndrome suggest a cranial developmental field involved in the condition. American Journal of Medical Genetics, 82, 6–14. Lejeune, J., Lafourcade, J., Berger, R., et al. (1963). 3 Cases of partial deletion of the short arm of a 5 chromosome. Comptes Rendus Hebdomadaires des Se´ances de l’Acade´mie des Sciences, 257, 3098–3102. Mainardi, P. C. (2006). Cri du chat syndrome (Review). Orphanet Journal of Rare Diseases, 1, 33–41. Mainardi, C. P., Guala, A., Pastore, G., et al. (2000). Psychomotor development in cri du chat syndrome. Clinical Genetics, 57, 459–461. Mainardi, P. C., Perfumo, C., Cali, A., et al. (2001). Clinical and molecular characterization of 80 patients with 5p deletion: Genotype-phenotype correlation. Journal of Medical Genetics, 38, 151–158. Manning, K. P. (1977). The larynx in the cri du chat syndrome. Journal of Laryngology and Otology, 91, 887–892. Marinescu, R. C., Johnson, E. I., Dykens, E. M., et al. (1999). No relationship between the size of the deletion and the level of

Cri-Du-Chat Syndrome developmental delay in cri-du-chat syndrome. American Journal of Medical Genetics, 86, 66–70. Marinescu, R. C., Johnson, E. I., Grady, D., et al. (1999). FISH analysis of terminal deletions in patients diagnosed with cridu-chat syndrome. Clinical Genetics, 56, 282–288. Martinez, J. E., Tuck-Muller, C. M., & Superneau, D. (1993). Fertility and the cri du chat syndrome. Clinical Genetics, 43, 212–214. Medina, M., Marinescu, R. C., Overhauser, J., et al. (2000). Hemizygosity of d-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics, 63, 157–164. Niebuhr, E. (1971). The cat cry syndrome (5p-) in adolescents and adults. Journal of Mental Deficiency Research, 15(Pt 4), 277–291. Niebuhr, E. (1978). The Cri du Chat syndrome: Epidemiology, cytogenetics, and clinical features. Human Genetics, 44, 227–275. Overhauser, J., Huang, X., & Gersh, M. (1994). Molecular and phenotypic mapping of the short arm of chromosome 5: Sublocalization of the critical region for the cri-du-chat syndrome. Human Molecular Genetics, 3, 247–252. Overhauser, J., McMahon, J., & Oberlender, S. (1990). Parental origin of chromosome 5 deletions in the cri-du-chat syndrome. American Journal of Medical Genetics, 37, 83–86. Perfumo, C., Mainardi, P. C., Cali, A., et al. (2000). The first three mosaic cri du chat syndrome patients with two rearranged cell lines. Journal of Medical Genetics, 37, 967–972. Rodriguez-Caballero, A., Torres-Lagares, D., Rodriguez-Perez, A., et al. (2010). Cri du chat syndrome: A critical review. Medicina Oral, Patologı´a Oral y Cirugı´a Bucal, 15(3), e473–e478.

525 Romano, C., Ragusa, R. M., Scillato, F., et al. (1991). Phenotypic and phoniatric findings in mosaic cri du chat syndrome. American Journal of Medical Genetics, 39, 391–395. Saito, N., Ebara, S., Fukushima, Y., et al. (2001). Progressive scoliosis in cri-du-chat syndrome over a 20-year follow-up period: A case report. Spine, 26, 835–837. Simmons, A. D., Goodard, S. A., Gallardo, T. D., et al. (1995). Five novel genes from the cri-du-chat critical region isolated by direct selection. Human Molecular Genetics, 4, 295–302. Stefanou, E. G., Hanna, G., Foakes, A., et al. (2002). Prenatal diagnosis of cri du chat (5p-) syndrome in association with isolated moderate bilateral ventriculomegaly. Prenatal Diagnosis, 22, 64–66. Tullu, M. S., Muranjan, M. N., Sharma, S. V., et al. (1998). Cridu-chat syndrome: Clinical profile and prenatal diagnosis. Journal of Postgraduate Medicine, 44, 101–104. Van Buggenhout, G. J., Pijkels, E., Holvoet, M., et al. (2000). Cri du chat syndrome: Changing phenotype in older patients. American Journal of Medical Genetics, 90, 203–215. Wilkins, L. E., Brown, J. A., & Nance, W. E. (1983). Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. Journal of Pediatrics, 102, 528–533. Wilkins, L. E., Brown, J. A., & Wolf, B. (1980). Psychomotor development in 65 home-reared children with cri-du-chat syndrome. Journal of Pediatrics, 97, 401–405. Zhang, A., Zheng, C., Hou, M., et al. (2003). Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in cri du chat syndrome. American Journal of Human Genetics, 72, 940–948.

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Fig. 1 (a, b) Two infants with cri-du-chat syndrome. Note a round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears

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Fig. 2 (a, b) Cri-du-chat syndrome in an older child and a teenager showing a long and narrow face

Cri-Du-Chat Syndrome Fig. 3 (a, b) FISH of an interphase cell and a metaphase spread with two orange signals (LSI SpectrumOrange, D5S721) and one green signal (LSI SpectrumGreen, D5S23 chromosome 5p15.2-specific probe) indicating deletion of 5p15.2

Fig. 4 (a–c) The 16-year-old boy was evaluated for developmental delay. He was noted to have unusual cry during early infancy, poor muscle control, and unable to hold his head up until 6 months of age. FISH using a locus specific for 5p11.2 cri-du-chat syndrome region showed 5p11.2 deletion (illustrated by a metaphase chromosome spread and interphase cells)

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Cri-Du-Chat Syndrome

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Fig. 5 (a–c) A blond-haired 60-year-old female with cri-du-chat syndrome, showing microcephaly with severe mental retardation. The karyotypes showed deletion of most of the short arm of a chromosome 4

Crouzon Syndrome

In 1912, Crouzon described the hereditary syndrome of craniofacial dysostosis in a mother and son. He described the triad of calvarial deformities, facial anomalies, and exophthalmos. Crouzon syndrome is characterized by premature closure of calvarial and cranial base sutures as well as those of the orbit and maxillary complex (craniosynostosis). Other clinical features include hypertelorism, exophthalmos, strabismus, beaked nose, short upper lip, hypoplastic maxilla, and relative mandibular prognathism. Prevalence is 1 per 60,000 (approximately 16.5 per 1,000,000) live births (Cohen and Kreiborg 1992). Crouzon syndrome makes up approximately 4.8% of all cases of craniosynostosis.

Synonyms and Related Disorders Craniofacial dysostosis type I; Crouzon craniofacial dysostosis

Genetics/Basic Defects 1. Inheritance a. An autosomal dominant disorder with i. Complete penetrance ii. Variable expressivity b. Sporadic in 50% of patients resulting from new mutations 2. Cause a. Mutations in the fibroblast growth factor receptor-2 (FGFR2) gene which is mapped to 10q25-q26

b. Mutations reported in the third immunoglobulins-like domain (Meyers et al. 1996) c. Different mutations detected in both exon IIIa and exon IIIc. Most of these mutations are missense, although several different mutations leading to alternative splicing have been recognized (Meyers et al. 1996) d. Crouzon syndrome exhibits locus heterogeneity with causal mutations in FGFR2 and FGFR3 in different affected individuals e. Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome) i. Described as a separate entity from Crouzon syndrome (Cohen 1999) ii. Caused by the GAG to GCG transversion mutation in the FGFR3 gene, leading to Ala391Glu substitution (Wilkes et al. 1996) 3. Pathophysiology a. Premature synostosis of the coronal, sagittal, and occasional lambdoidal sutures i. Begins in the first year of life ii. Completed by the second or third year b. Degree of deformity and disability determined by the order and rate of suture fusion c. After fusion of a suture i. Growth perpendicular to that suture becoming restricted ii. Fused bones acting as a single bony structure. d. Compensatory growth occurring at the remaining open sutures to allow continued brain growth e. Multiple sutural synostoses often extend to premature fusion of the skull base sutures causing the following effects i. Midfacial hypoplasia ii. Shallow orbit

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Crouzon Syndrome

iii. A foreshortened nasal dorsum iv. Maxillary hypoplasia v. Occasional upper airway obstruction.

Clinical Features 1. History a. Presence of mildly affected individuals in the family b. Craniofacial abnormalities often present at birth and may progress with time c. Decreased mental function in approximately 12% of the patients d. Headaches (29%) and failing vision due to elevated intracranial pressure e. Visual disturbance results from corneal injury due to exposed conjunctivitis and keratitis f. Conductive deafness common due to ear canal stenosis or atresia g. Causes of upper airway obstruction i. Septal deviation ii. Mid-nasal abnormalities iii. Choanal abnormalities iv. Nasopharyngeal narrowing h. Meniere disease i. Seizures (12%) 2. Skull and face a. Craniosynostosis i. Onset: commonly seen during the first year ii. Usually completing by the second or third year iii. Coronal suture most commonly involved iv. Acrocephaly v. Brachycephaly vi. Turricephaly vii. Oxycephaly viii. Flat occiput ix. High prominent forehead with or without frontal bossing x. Ridging of the skull usually palpable b. Cloverleaf skull i. Rare ii. Occurring in most severely affected individuals iii. Flattened sphenoid bone iv. Shallow orbits v. Hydrocephalus (progressive in 30%) vi. Midface (maxillary) hypoplasia

3. Eyes a. Exophthalmos (proptosis) (100%) secondary to shallow orbits resulting in frequent exposure conjunctivitis or keratitis b. Ocular hypertelorism (100%) c. Divergent strabismus d. Rare occurrence i. Nystagmus ii. Iris coloboma iii. Aniridia iv. Anisocoria v. Microcornea vi. Megalocornea vii. Cataract viii. Ectopia lentis ix. Blue sclera x. Glaucoma xi. Luxation of the eye globes xii. Blindness from optic atrophy 4. Nose a. Beaked appearance (parrot-like nose) b. Compressed nasal passage c. Choanal atresia or stenosis d. Deviated nasal septum 5. Mouth a. Mandibular prognathism b. Overcrowding of upper teeth c. Malocclusions d. V-shaped maxillary dental arch e. Narrow, high, or cleft palate and bifid uvula f. Oligodontia g. Macrodontia h. Peg-shaped i. Widely spaced teeth 6. Ears a. Narrow or absent ear canals b. Deformed middle ears c. Mild-to-moderate hearing losses 7. Other skeletal a. Cervical fusion (18%), C2–C3 and C5–C6 b. Block fusions involving multiple vertebrae c. Subluxation of the radial heads d. Ankylosis of the elbows 8. Acanthosis nigricans (5%) a. Velvety, light-brown to black darkened, thickened skin with accentuated markings that occur in areas including the neck, axillae, groin, and breasts b. Usual age of onset: first decade (80%)

Crouzon Syndrome

c. Only one case reported at birth (Koizumi et al. 1992) d. Typical presentation (Arnaud-Lopez et al. 2007; Sharda et al. 2010) i. Crouzonoid facies ii. Acanthosis nigricans with atypical distribution iii. Choanal atresia iv. Hydrocephalus v. Oral abnormalities vi. Melanocytic nevi vii. Less frequent findings: vertebral abnormalities and deafness 9. CNS a. Chronic tonsillar herniation (approximately 73%). Of these, 47% have progressive hydrocephalus (Cinalli et al. 1995) b. Syringomyelia c. Mental retardation (3%)

Diagnostic Investigations 1. Skull radiographs a. Synostosis: The coronal, sagittal, lambdoidal, and metopic sutures may be involved. b. Craniofacial deformities c. Digital markings of skull d. Basilar kyphosis e. Widening of hypophyseal fossa f. Small paranasal sinuses g. Maxillary hypoplasia with shallow orbits 2. Cervical radiographs (Anderson 1997b) a. Butterfly vertebrae b. Fusions of the vertebral bodies and the posterior elements i. Cervical fusions in approximately 18% of patients ii. C2–C3 and C5–C6 affected equally iii. Block fusions may involve multiple vertebrae. 3. Limb radiographs a. Metacarpophalangeal analysis b. Subluxation of the radial head 4. Computed tomography (CT) scan: Comparative 3-D reconstruction analysis of the calvaria and cranial bases to precisely define the pathologic anatomy and to permit specific operative planning

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5. Magnetic resonance imaging (MRI): Used to demonstrate occasional corpus callosum agenesis and optic atrophy 6. Molecular analysis a. FGFR2 mutations in more than 50% of patients (FGFR2 mutations also observed in Apert syndrome, Pfeiffer syndrome, and Jackson-Weiss syndrome) b. FGFR3 ala391-to-glu mutation in all patients with associated acanthosis nigricans: Finding of acanthosis nigricans in a young child with Crouzon syndrome should prompt testing for the Ala391Gln substitution in FGFR3 before testing for FGFR2 mutations (Sharda et al. 2010)

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected or with germinal mosaicism (Navarrete et al. 1991) b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Prenatal ultrasonography i. Exophthalmos ii. Ocular hypertelorism b. Identification of the disease-causing FGFR2 mutation using i. CVS in the first trimester ii. Amniocentesis in the second trimester iii. Preimplantation genetic diagnosis (Harper et al. 2002) 3. Management a. Medical care i. No specific medical therapy available ii. Nasal continuous positive airway pressure device to relieve airway obstruction iii. Management of speech b. Surgical care i. Stage reconstruction to coincide with facial growth patterns, visceral function, and psychosocial development. ii. Early craniectomy with frontal bone advancement most often indicated to prevent or treat increased intracranial pressure because newborns with Crouzon syndrome develop multiple suture synostosis and fused synchondrosis.

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Crouzon Syndrome

iii. Fronto-orbital and midfacial advancements to help in the cosmetic reconstruction of facial dysmorphisms. iv. A new technique, craniofacial disjunction, followed by gradual bone distraction (Ilizarov procedure) has been reported to produce complete correction of exophthalmos and improvement in the functional and esthetic aspects of the middle third of the face without the need for bone graft in patients aged 6–11 years. v. Shunting procedures for hydrocephalus. vi. Tracheostomy for airway compromise. vii. Myringotomy to drain middle ear secretions secondary to distorted nasopharynx. viii. Orthodontic management.

References Anderson, P. J., & Evans, R. D. (1998). Metacarpophalangeal analysis in Crouzon syndrome. American Journal of Medical Genetics, 80, 439. Anderson, P. J., Hall, C., & Evans, R. D. (1997a). The cervical spine in Crouzon syndrome. Spine, 22, 402–405. Anderson, P. J., et al. (1997b). Hand anomalies in Crouzon syndrome. Skeletal Radiology, 26, 113–115. Arnaud-Lopez, L., Fragoso, R., Mantilla-Capacho, J., et al. (2007). Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clinical Genetics, 72, 405–410. Beck, R., Sertie, A. L., Brik, R., et al. (2002). Crouzon syndrome: Association with absent pulmonary valve syndrome and severe tracheobronchomalacia. Pediatric Pulmonology, 34, 478–481. Bobertson, M. M., & Reynolds, H. T. (1975). Crouzon’s disease (craniofacial dysostosis). A neuropsychiatric presentation. South African Medical Journal, 49, 7–10. Bresnick, S., & Schendel, S. (1995). Crouzon’s disease correlates with low fibroblastic growth factor receptor activity in stenosed cranial sutures. The Journal of Craniofacial Surgery, 6, 245–248. Chen, H. (2009). Crouzon syndrome. eMedicine from WebMD. Updated September 10, 2009. Available at: http://emedicine. medscape.com/article/942989-overview Cinalli, G., Renier, D., & Sebag, G. (1995). Chronic tonsillar herniation in Crouzon’s and Apert’s syndromes: The role of premature synostosis of the lambdoid suture. Journal of Neurosurgery, 83, 575–782. Cohen, M. M. (1975). An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Original Article Series, 11(2), 137–189. Cohen, M. M., Jr. (1986). Craniosynostosis: Diagnosis, evaluation, and management. Raven Press: New York. Cohen, M. M., Jr. (1988). Craniosynostosis update 1987. American Journal of Medical Genetics. Supplement, 4, 99–148.

Cohen, M. M., Jr. (1995). Craniosynostoses: Phenotypic/molecular correlations (editorial) (see comments). American Journal of Medical Genetics, 56, 334–339. Cohen, M. M., Jr. (1999). Let’s call it “Crouzonodermoskeletal syndrome” so we won’t be prisoners of our own conventional terminology. American Journal of Medical Genetics, 84, 74. Cohen, M. M., Jr., & Kreiborg, S. (1992). Birth prevalence studies of the Crouzon syndrome: Comparison of direct and indirect methods. Clinical Genetics, 41, 12–15. Cohen, M. M., Jr., & MacLean, R. E. (1999). Craniosynostosis: Diagnosis, evaluation, and management (2nd ed.). New York: Oxford University Press. Crouzon, O. (1912). Dysostose cranio-faciale hereditaire. Bulletins et me´moires de la Socie´te´ des Me´decins des Hoˆpitaux de Paris, 33, 545–555. David, D. J., & Sheen, R. (1990). Surgical correction of Crouzon syndrome. Plastic and Reconstructive Surgery, 85, 344–354. Dodge, H. W., et al. (1959). Craniofacial dysostosis: Crouzon’s disease. Pediatrics, 23, 98–106. Glaser, R. L., et al. (2000). Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. American Journal of Human Genetics, 66, 768–777. Golabi, M., et al. (1984). Radiographic abnormalities of Crouzon syndrome. A survey of 23 cases. Proceedings of the Greenwood Genetic Center, 3, 102. Gorry, M. C., Preston, R. A., & White, G. J. (1995). Crouzon syndrome: Mutations in two splice forms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. Human Molecular Genetics, 4, 1387–1390. Harper, J. C., Wells, D., Piyamongkol, W., et al. (2002). Preimplantation genetic diagnosis for single gene disorders: Experience with five single gene disorders. Prenatal Diagnosis, 22, 525–533. Hollway, G. E., Suthers, G. K., & Haan, E. A. (1997). Mutation detection in FGFR2 craniosynostosis syndromes. Human Genetics, 99, 251–255. Jabs, E. W., Li, X., & Scott, A. F. (1994). Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2 [published erratum appears in Nature Genetics 9, 451, 1995]. Nature Genetics, 8, 275–279. Jarund, M., & Lauritzen, C. (1996). Craniofacial dysostosis: Airway obstruction and craniofacial surgery. Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, 30, 275–279. Kaler, S. G., et al. (1982). Radiologic hand abnormalities in fifteen cases of Crouzon syndrome. Journal of Craniofacial Genetics and Developmental Biology, 2, 205–214. Koizumi, H., Tomoyori, T., Sato, K. C., et al. (1992). An association of acanthosis nigricans and Crouzon syndrome. Journal of Dermatology, 19, 122–126. Kreiborg, S. (1981). Crouzon syndrome: A clinical and roentgencephalometric study. Scandinavian Journal of Plastic and Reconstructive Surgery, 18(Suppl), 1–198. Leo, M. V., Suslak, L., Ganesh, V. L., et al. (1991). Crouzon syndrome: Prenatal ultrasound diagnosis by binocular diameters. Obstetrics and Gynecology, 78, 906–908. Liptak, G. S., & Serletti, J. M. (1998). Pediatric approach to craniosynostosis [published erratum appears in Pediatrics in Review 20, 20 (1999)]. Pediatrics in Review 19, 352; quiz 359.

Crouzon Syndrome Menashe, Y., et al. (1989). Exophthalmus – prenatal ultrasonic features for diagnosis of Crouzon syndrome. Prenatal Diagnosis, 9, 805–808. Meyers, G. A., Day, D., & Goldberg, R. (1996). FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. American Journal of Human Genetics, 58, 491–498. Meyers, G. A., Orlow, S. J., & Munro, I. R. (1995a). Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature Genetics, 11, 462–464. Meyers, G. A., et al. (1995b). Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature Genetics, 11, 462–464. Navarrete, C., et al. (1991). Germinal mosaicism in Crouzon syndrome. A family with three affected siblings of normal parents. Clinical Genetics, 40, 29–34. Oldridge, M., et al. (1995). Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome. Human Molecular Genetics, 4(6), 1077–1082. Park, W. J., Meyers, G. A., & Li, X. (1995). Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. Human Molecular Genetics, 4, 1229–1233. Preston, R. A., et al. (1994). A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10. Nature Genetics, 7, 149–153. Reardon, W., Winter, R. M., & Rutland, P. (1994). Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature Genetics, 8, 98–103.

533 Robin, N. H., Falk, M. J., & Haldeman-Englert, C. R. (2007). FGFR-related craniosynostosis syndromes. GeneReviews. Updated September 27, 2007. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼gene &part¼craniosynostosis Rollnick, B. R., et al. (1988). Germinal mosaicism in Crouzon syndrome. Clinical Genetics, 33, 145–150. Rutland, P., Pulleyn, L. J., & Reardon, W. (1995). Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes (see comments). Nature Genetics, 9, 173–176. Schwartz, M., Kreiborg, S., & Skovby, F. (1996). First-trimester prenatal diagnosis of Crouzon syndrome. Prenatal Diagnosis, 16, 155–158. Sharda, S., Panigrahi, I., Gupta, K., et al. (2010). A newborn with acanthosis nigricans: Can it be Crouzon syndrome with acanthosis nigricans? Pediatric Dermatology, 27, 43–47. Tessier, P. (1971). The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis: Crouzon’s and Apert’s disease. Plastic and Reconstructive Surgery, 48, 419–442. Turvy, T. A., et al. (1979). Multidisciplinary management of Crouzon syndrome. The Journal of the American Dental Association, 99, 205–209. Wilkie, A. O., Slaney, S. F., & Oldridge, M. (1995). Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome (see comments). Nature Genetics, 9, 165–172. Wilkes, D., Rutland, P., & Pulleyn, L. J. (1996). A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. Journal of Medical Genetics, 33, 744–748.

534 Fig. 1 (a–d) Two children with Crouzon syndrome showing proptosis secondary to shallow obits and hypertelorism

Crouzon Syndrome

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Crouzon Syndrome

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Fig. 2 A neonate with Crouzon syndrome showing typical craniofacial features with tracheostomy in place for the respiratory problem

Fig. 3 (a, b) A father and a daughter with Crouzon syndrome showing characteristic craniofacial features

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Cutis Marmorata Telangiectatica Congenita

In 1922, van Lohuizen1 first described cutis marmorata telangiectatica congenita (CMTC) as a pattern of reticulate erythema and telangiectasia, skin atrophy and ⁄or ulceration.

Genetics/Basic Defects 1. Pathogenesis a. Unknown b. Most cases are sporadic 2. Hypothesis a. Environmental factors b. Multifactorial cause c. A nerve conduction defect (Bormann et al. 2001) d. A lethal gene surviving by mosaicism suggested by segmental distribution often with a sharp midline separation (Rogers and Poyzer 1982) e. Autosomal dominant inheritance with low or variable penetrance i. An affected parent showing more limited involvement than his offspring (Kurczynski 1982) ii. Two siblings with one having CMTC alone and the other showing associated anomalies (hypertension and acrocyanosis) (Andreev and Pramatarov 1979)

Clinical Features 1. Onset (Garzon and Schweiger 2004) a. Congenital: common b. Later onset (Way et al. 1974)

2. Reticulated vascular pattern a. Finely reticular or coarse pattern: will not resolve completely with warming of the skin b. Broad streaks of discolored skin in a “traintrack-like” pattern c. Relatively fixed and discernable at rest d. Pallor of the skin between the vascular network pattern: often reported (Ben-Amitai et al. 2000) e. Often accompanied by: i. Phlebectasia (prominent veins) ii. Telangiectasias iii. Cutaneous and subcutaneous tissue atrophy: may manifest as hypoplasia of the affected limb (an inconsistent feature) (South and Jacobs 1978) iv. Ulceration of the affected skin, particularly involving the skin overlying the elbows and knees (Picascia and Esterly 1989) v. Hyperkeratosis f. The presence of atrophy and ulceration helps to differentiate CMTC from physiologic cutis marmorata g. Localized lesions i. Most commonly affecting the trunk and extremities ii. Sharp segmental pattern: easy to differentiate from physiologic cutis marmorata h. Generalized lesions i. Often unilateral ii. May involve face but mucosal involvement uncommon (Ben-Amitai et al. 2000) iii. Do not occur on the entire body surface (Devillers et al. 1999)

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_62, # Springer Science+Business Media, LLC 2012

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3. Associated anomalies (27–80%) (Picascia and Esterly 1989; Devillers et al. 1999) a. Relatively high associated defects i. May represent true associations or coincidental ii. May represent a bias toward reporting cases with more severe anomalies iii. Inconsistency among authors regarding diagnostic criteria b. Asymmetry i. Limb asymmetry (hyperplasia or hypoplasia of a limb) a) The most common associated anomaly b) Cutaneous atrophy may be noted concomitantly with asymmetry ii. Facial asymmetry may occur c. Skeletal defects i. Syndactyly ii. Tendinitis stenosans iii. Hip dysplasia iv. Clubfoot v. Scoliosis vi. Macrocephaly vii. Skull asymmetry viii. Scaphoid scapula ix. Micrognathia x. Generalized osteoporosis xi. Consider Adams–Oliver syndrome and macrocephaly-CMTC if limb defects are present d. Other vascular anomalies i. May occur distant to the area of CMTC or within the same affected area (Picascia and Esterly 1989) ii. Capillary malformations (port-wine stains): the most commonly associated vascular birthmark occurring in 20% of patient (Ben-Amitai et al. 2000) iii. Sturge–Weber syndrome (Petrozzi et al. 1970) iv. Hemangiomas of infancy v. Multiple angiokeratomas e. Ocular anomalies i. Glaucoma ii. Infrequent anomalies a) Persistent arterial hyaloidia (an embryonic vessel that typically regresses) b) Granular retinal pigmentation

Cutis Marmorata Telangiectatica Congenita

c) Small optic disks d) Optic nerve atrophy f. Neurologic anomalies i. Macrocephaly: diagnostic feature of macrocephaly-CMTC syndrome ii. Hydrocephaly iii. Psychomotor retardation iv. Seizures v. Cerebral atrophy vi. Agenesis of the corpus callosum vii. Dilated ventricles g. Other cutaneous anomalies (may be coincidental) (Ben-Amitai et al. 2000) i. Congenital melanocytic nevi ii. Cafe´ au lait macules iii. Mongolian spots h. Other systemic anomalies (uncommon) i. Hypothyroidism ii. Cardiac defects iii. Genitourinary tract anomalies (Del Guidice and Nydorl 1986; Ben-Amitai et al. 2001; Sills et al. 2002; Fujita et al. 2003) a) Hypospadias b) Renal cysts c) Duplication of the renal collecting system d) Rectovaginal and ureterovaginal fistulae e) Absent clitoris f) Imperforate anus g) Unilateral ovarian agenesis h) Septate uterus i) Premature gonadal failure associated with de novo balance translocation affecting chromosomes 8 and 9 4. Suggested diagnostic criteria for cutis marmorata telangiectatica congenita (Kienast and Hoeger 2009) a. Major criteria i. Congenital reticulate (marmorated) erythema (27%) ii. Absence of venectasia (27%) iii. Unresponsiveness to local warming (27%) b. Minor criteria i. Fading of erythema within 2 years (18%) ii. Telangiectasia (5%) iii. Port-wine stain outside the area affected by CMTC (2%) iv. Ulceration (2%) v. Atrophy (2%)

Cutis Marmorata Telangiectatica Congenita

5. Differential diagnosis a. Cutis marmorata (physiologic) b. Cutis marmorata (associated with genetic syndrome) i. Cornelia de Lange syndrome ii. Down syndrome iii. Homocystinuria iv. Divry and Van Bogaert syndrome a) A rare disorder b) Corticomeningeal angiomatosis c) Visual field defects d) Seizures e) “Marble” skin c. Reticulated capillary malformations i. A diffuse, generalized form of a “livedoid” capillary malformation involving the entire skin ii. Not associated with atrophy, ulceration or limb hypoplasia iii. Associated with a significant risk of associated visceral vascular anomalies (eye, brain, kidneys, and heart) and requires evaluation and follow-up (Enjolras and Garzon 2001) d. Bockenheimer syndrome (diffuse phlebectasia): i. A very rare disorder ii. Onset in infancy iii. Characterized by progressive venous varicosity e. Neonatal lupus erythematosus f. CMTC “syndrome” i. CMTC-macrocephaly syndrome ii. Adams–Oliver syndrome iii. CMTC phakomatosis pigmentovascularis

Diagnostic Investigations 1. Physical evaluation (Garzon and Schweiger 2004) a. Reticulated vascular pattern b. Limb length and girth c. Limb defects d. Scalp defects e. Head circumference f. Other associated anomalies g. Facial lesions 2. Ophthalmologic evaluation

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Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Sporadic cases: a low recurrence risk ii. A 50% risk if one of the parents is affected b. Patient’s offspring: a 50% risk in autosomal dominant transmission, otherwise a low recurrence risk 2. Prenatal diagnosis: not reported 3. Management a. Careful physical examination to assess for other congenital anomalies b. Measurement of limb length and girth at the time of evaluation c. Baseline and follow-up ophthalmologic examinations should be performed when the vascular lesions affect the periocular skin d. Local supportive care including application of hydrocolloid dressings for ulcerations

References Akcar, N., Adapinar, B., Dinleyici, C., et al. (2004). A case of macrocephaly-cutis marmorata telangiectatica congenita and review of neuroradiologic features. Annales de Genetique, 47, 261–265. Andreev, V. C., & Pramatarov, K. (1979). Cutis marmorata telangiectatica congenital in two sisters. British Journal of Dermatology, 101, 345–350. Ben-Amitai, D., Fichman, S., Merlob, P., et al. (2000). Cutis marmorata telangiectatica congenita: Clinical findings in 85 patients. Pediatric Dermatology, 17, 100–104. Ben-Amitai, D., Merlob, P., & Metzker, A. (2001). Cutis marmorata telangiectatica congenital and hypospadias: Report of 4 cases. Journal of the American Academy of Dermatology, 45, 131–132. Bormann, G., Wohlrab, J., Fischer, M., et al. (2001). Cutis marmorata telangiectatica congenital: Laser Doppler fluxmetry evidence for a functional nervous defect. Pediatric Dermatology, 18, 110–113. Clayton-Smith, J., Kerr, B., Brunner, H., et al. (1997). Macrocephaly with cutis marmorata, haemangioma and syndactyly – a distinctive overgrowth syndrome. Clinical Dysmorphology, 6, 291–302. Del Guidice, S. M., & Nydorf, E. D. (1986). Cutis marmorata telangiectatica congenita with multiple congenital anomalies. Archives of Dermatology, 122, 1060–1061. Devillers, A. C., de Waard-van der Spek, F. B., & Oranje, A. P. (1999). Cutis marmorata telangiectatica congenita: Clinical features in 35 cases. Archives of Dermatology, 135, 34–38.

540 Enjolras, O., & Garzon, M. C. (2001). Vascular stains, malformations and tumors. In L. F. Eichenfield, I. J. Frieden, & N. B. Esterly (Eds.), Textbook of neonatal dermatology (pp. 324–352). Philadelphia, PA: Saunders. Fujita, M., Darmstadt, G. L., & Dinulos, J. G. (2003). Cutis marmorata telangiectatica congenita with hemangiomatous histopathologic features. Journal of the American Academy of Dermatology, 48, 950–954. Garavelli, L., Leask, K., Zanacca, C., et al. (2005). MRI and neurological findings in macrocephaly-cutis marmorata telangiectatica congenita syndrome: Report of ten cases and review of the literature. Genetic Counseling, 16, 117–128. Garzon, M. C., & Schweiger, E. (2004). Cutis marmorata telangiectatica congenita (Review). Seminars in Cutaneous Medicine and Surgery, 23, 99–106. Gerritsen, M. J. P., Steijlen, P. M., Brunner, H. G., et al. (2000). Cutis marmorata telangiectatica congenita: Report of 18 cases. British Journal of Dermatology, 142, 366–369. Giuliano, F., David, A., Edery, P., et al. (2004). Macrocephalycutis marmorata telangiectatica congenita: Seven cases including two with unusual cerebral manifestations. American Journal of Medical Genetics. Part A, 126, 99–103. Kienast, A. K., & Hoeger, P. H. (2009). Cutis marmorata telangiectatica congenita: A prospective study of 27 cases and review of the literature with proposal of diagnostic criteria. Clinical and Experimental Dermatology, 34, 319–323. Kurczynski, T. W. (1982). Hereditary cutis marmorata telangiectatica congenita. Pediatrics, 70, 52–53. Lapunzina, P., Gairi, A., Delicado, A., et al. (2004). Macrocephaly-cutis marmorata telangiectatica congenita: Report of six new patients and a review. American Journal of Medical Genetics. Part A, 130, 45–51.

Cutis Marmorata Telangiectatica Congenita Moore, C. A., Toriello, H. V., Abuelo, D. N., et al. (1997). Macrocephaly-cutis marmorata telangiectatica congenita: A distinct disorder with developmental delay and connective tissue abnormalities. American Journal of Medical Genetics, 70, 67–73. Petrozzi, J. W., Rahn, E. K., Mofenson, H., et al. (1970). Cutis marmorata telangiectatica congenita. Archives of Dermatology, 101, 74–77. Picascia, D. D., & Esterly, N. B. (1989). Cutis marmorata telangiectatica congenita: Report of 22 cases. Journal of the American Academy of Dermatology, 20, 1098–1104. Rekate, H. L. (2007). Macrocephaly-cutis marmorata telangiectatica congenita. Journal of Neurosurgery, 106, 292–295. Robertson, S. P., Gattas, M., Rogers, M., et al. (2000). Macrocephaly-cutis marmorata telangiectatica congenita: Report of five patients and a review of the literature. Clinical Dysmorphology, 9, 1–9. Rogers, M., & Poyzer, K. G. (1982). Cutis marmorata telangiectatica congenita. Archives of Dermatology, 118, 895–899. Sills, E. S., Harmon, K. E., & Tucker, M. J. (2002). First reported convergence of premature ovarian failure and cutis marmorata telangiectatica congenital. Fertility and Sterility, 78, 1314–1316. South, D. A., & Jacobs, A. H. (1978). Cutis marmorata telangiectatica congenita (congenital generalized phlebectasia). Journal of Pediatrics, 93, 944–949. € Van Lohuizen, C. H. J. (1922). Uber eine seltene angeborene Hautanomalie [Cutis marmorata telangiectatica congenita]. Acta Dermato-Venereologica, 3, 202–211. Way, B. H., Herrmann, J., Gilbert, E. F., et al. (1974). Cutis marmorata telangiectatica congenita. Journal of Cutaneous Pathology, 1, 10–25.

Cutis Marmorata Telangiectatica Congenita

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Fig. 1 (a, b) A 2-month-old infant with cutis marmorata telangiectatica congenita showing a reticular vascular pattern which was present from birth

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Fig. 2 (a, b) The same infant at 14 months of age

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542 Fig. 3 (a, b) The same patient at 26 months of age showing development of a large diffuse vascular lesion extending from the whole left anterior chest to the left neck

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Cutis Marmorata Telangiectatica Congenita

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Fig. 4 (a–c) A 3-month-old infant boy with cutis marmorata telangiectatica congenita. Cutaneous vascular lesions consist of a 4  4  2 cm soft vascular lesion of the upper posterior back

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and diffuse bluish vascular lesions on front chest, shoulders, arms, trunk, buttock, and legs. The right leg is larger than the left

Cutis Marmorata Telangiectatica Congenita

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Fig. 5 Another infant with a reticular vascular pattern on the right leg

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Fig. 6 (a–f) A child with cutis marmorata telangiectatica congenita at different ages (newborn, 4 months, and 4 years of age)

Cystic Fibrosis

Cystic fibrosis (CF) is the most common Caucasian lethal genetic disorder (with gene frequency of 1 in 25) in the United States, where 4–5% of population have at least one CF allele. CF affects approximately 1 in 2,500 live births among Caucasians, 1 in 17,000 among African-Americans, and 1 in 90,000 among Asians. (Ruzal-Shapiro 1998)

Synonyms and Related Disorders CFTR-related disorders; Congenital absence of vas deferens; Mucoviscidosis

Genetics/Basic Defects 1. Inheritance a. Autosomal recessive b. CF gene mapped to chromosome 7q31.2 2. Molecular defect (Moskowitz et al. 2008) a. Caused by a single gene defect on chromosome 7 that encodes a cAMP-regulated chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR) i. CFTR usually resides in the apical membrane of epithelial cells lining the airway, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts. ii. Insufficient fluid secretion secondary to inability of CFTR to transport chloride ion at the above sites causes higher viscidity of the protein portions of the secretions and

obstructing the ducts, leading to plugging and dysfunction at the organ level. iii. CFTR also regulates the activity of other proteins that conduct ions and affects intracellular regulatory processes at the cellular level. b. Presence of close to 1,500 different diseasecausing mutations of the CFTR gene (RuzalShapiro 1998; O’Sullivan and Freedman 2009) i. Deletion mutations including delta F508 which, observed in over 70% of patients with CF, have a deletion of three contiguous base pairs resulting in the loss of a single amino acid, phenylalanine at codon 508) ii. Missense mutation (single base pair exchange within a normal length CFTR protein) iii. Nonsense mutations (exchange of a single base pair resulting in premature termination of the protein) iv. Frameshift mutations (the deletions or insertion of a single base pair) c. Classification of CFTR mutations (Culling and Ogle 2010) i. Class I mutations a) Introduce a stop codon prematurely b) Produce either an unstable mRNA with no detectable protein being made or an unstable protein that is rapidly degraded or has no functional capability c) No CFTR protein in the cell membrane d) E.g., G542X, 394delTT, 1717-1 G ! A ii. Class II mutations a) Block the processing of the protein due to aberrant folding and subsequent

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_63, # Springer Science+Business Media, LLC 2012

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degradation when recognized as abnormal by cellular “quality control” mechanisms b) No CFTR protein at the apical cell membrane c) E.g., N1303K, DF508, 3905insT iii. Class III mutations: a) Produce a CFTR protein that does not function as a chloride channel due to a block in regulation, despite being fully processed and correctly located b) Within this class there are mutations that have very little function (G551D), those where ATP is less potent at stimulating activity (S1255P) and those with reduced absolute activity (G551S, G1244E and G1349D). iv. Class IV mutations a) Produce a fully processed and correctly located CFTR protein b) However, the conductance and/or gating properties of the channel have been altered by mutations in the membrane spanning domains c) Extent to which conduction is affected varies between mutations d) E.g., R117H, R347P v. Class V mutations a) Result in a reduction in the synthesis of CFTR protein b) Include promoter mutations, the promotion of alternative splicing and inefficient protein maturation c) E.g., A455E, 2789 + 5G ! A, IVS8-5T vi. Class VI mutations a) Presence of functional but unstable CFTR protein at the apical membrane b) Decreased stability on CFTR protein c) E.g., Q1412X, 4326delTC, 4279insA d. Genotype-phenotype correlations (RuzalShapiro 1998) i. Phenotypic presentation of the disease: probably related to the underlying genetic abnormality ii. Patients with homozygous delta F508 typically have respiratory distress and malabsorption. iii. Patients with less severe variations of the disease or typical CF with borderline normal sweat tests may have other haplotypes

Cystic Fibrosis

Clinical Features 1. Signs and symptoms of cystic fibrosis (O’Sullivan and Freedman 2009) a. General (any age) i. Family history of cystic fibrosis ii. Salty-tasting skin iii. Clubbing fingers and toes iv. Cough with sputum production v. Mucoid Pseudomonas aeruginosa isolated from airway secretions vi. Hypochloremic metabolic alkalosis b. Neonatal i. Meconium ileus ii. Protracted jaundice iii. Abdominal or scrotal calcifications iv. Intestinal atresia c. Infancy i. Persistent infiltrates on chest radiographs ii. Failure to thrive iii. Anasarca or hypoproteinemia iv. Chronic diarrhea v. Abdominal distention vi. Cholestasis vii. Staphylococcus aureus pneumonia viii. Idiopathic intracranial hypertension (vitamin A deficiency) ix. Hemolytic anemia (vitamin E deficiency causes anemia by increasing fragility and reducing lifespan of red blood cells) d. Childhood i. Chronic pansinusitis or nasal polyposis ii. Steatorrhea iii. Rectal prolapse iv. Distal intestinal obstruction syndrome or intussusceptions v. Idiopathic recurrent or chronic pancreatitis vi. Liver disease e. Adolescence and adulthood i. Allergic bronchopulmonary aspergillosis ii. Chronic pansinusitis or nasal polyposis iii. Bronchiectasis iv. Hemoptysis v. Idiopathic recurrent pancreatitis vi. Portal hypertension vii. Delayed puberty viii. Azoospermia secondary to congenital bilateral absence of the vas deferens

Cystic Fibrosis

2. Classic clinical triad a. Exocrine pancreatic insufficiency b. Chronic obstructive pulmonary disease c. Elevation of sodium and chloride concentration in sweat 3. Chronic sino-pulmonary disease a. Varying widely in age of onset and rate of progression b. Clinical course i. Newborn with CF with histologically normal respiratory systems ii. First few months of age a) Epithelial chloride channel defect, leading to abnormal respiratory secretions, bronchopulmonary infections, and airway obstruction b) Clinical manifestations including cough, wheezing, retractions, and tachypnea c. Persistent endobronchial infection and inflammation with typical CF pathogens (RuzalShapiro, 1998) i. Staphylococcus aureus a) Responsible for the majority of lung disease when CF was first described b) Commonly isolated in the first year of life from the sputum of patients with CF c) Typically controlled by antibiotic therapy d) Currently only 10% of adult patients with CF are chronically colonized by the pathogen. ii. Mucoid and non-mucoid Pseudomonas aeruginosa a) The most prevalent of the pathogens in CF, causing chronic infection in up to 90% of adults and 80% of children b) Initial colonization with non-mucoid forms c) Subsequent conversion to mucoid variants iii. Hemophilus influenzae a) Commonly seen in babies b) Rarely encountered in the adults iv. Other pulmonary pathogens a) Burkholderia cepacia b) Aspergillus c) Mycobacteria d) Respiratory viruses

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d. Upper airway disease i. Opacified or maldeveloped sinuses ii. Nasal polyps (up to 26% of patients) iii. Sinusitis a) Facial pain b) Swelling c) Tenderness d) Air-fluid levels on radiograph e. Pulmonary exacerbations i. Persistent cough and sputum production ii. Increased dyspnea iii. Reduction in pulmonary function iv. Increased hemoptysis: a life-threatening complication but fatal hemoptysis is rare v. Digital clubbing vi. Changes in chest radiographic findings vii. Bronchiolitis viii. Increased rales or rhonchi ix. Decreased air exchange x. Increased use of accessory muscles of respiration xi. Spontaneous pneumothorax (5–8%), a lifethreatening complication xii. Obstructive airway disease, leading to respiratory insufficiency associated with bronchiectasis 4. Gastrointestinal abnormalities a. Intestine i. Meconium ileus at birth a) An obstruction of the distal ileum or proximal colon with thickened, viscous meconium in 15–20% of CF patients developed in utero in the second trimester b) Virtually diagnostic of CF ii. Meconium peritonitis (rupture of the intestine secondary to complete obstruction) iii. Meconium plug syndrome in the newborn infants, a more benign condition characterized by blockage of the colon iv. Distal intestinal obstruction syndrome later in childhood, adolescence, or adulthood (10%), presenting as crampy abdominal pain, usually with decreased stooling v. Rectal prolapse occurring in less than 1% of patients but may be the presenting symptom, particularly in infants vi. Occasional intussusception vii. Gastroesophageal reflux

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b. Pancreas i. Pancreatic exocrine insufficiency a) Failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein b) Obstruction of the pancreatic duct in utero with resultant progressive loss of exocrine pancreatic acini and their function c) A hallmark of the disease, occurring in 90% of patients by 1 year of age d) Leads to frequent, bulky, foul-smelling, oily stools e) Steatorrhea (presence of excessive undigested fat in the stool) f) Failure to thrive is commonly in the patients with CF ii. Recurrent pancreatitis in few patients iii. CF-related diabetes mellitus (Nathan et al. 2010) a) Affect approximately one third of all CF patients b) Rare before 10 years of age c) Resulting from a loss of functional pancreatic b cells and a state of relative insulin deficiency d) Oral glucose tolerance test as a screening tool e) HbA1c, an accepted diagnostic test for diabetes in the general population (International Expert Report 2009), cannot be used as screening tool because levels are often falsely low (Holl et al. 2000). c. Liver i. Prolonged obstructive jaundice in a few affected infants, presumably secondary to obstruction of extrahepatic bile ducts by thick bile along with intrahepatic bile stasis ii. Chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis or multi-lobular cirrhosis 5. Genitourinary manifestations (Ruzal-Shapiro 1998) a. Congenital bilateral absence of the vas deferens in most males i. Leading to azoospermia ii. A significant cause of infertility

Cystic Fibrosis

6.

7.

8.

9.

b. Infertility common in women i. Due to increased amounts of thick mucus in the cervical canal ii. An increased incidence of amenorrhea iii. Occasional patients carrying pregnancies to term without significant respiratory deterioration Skeletal manifestations (Ruzal-Shapiro 1998) a. Hypertrophic pulmonary osteoarthropathy i. Rarely seen in children with CF ii. Increasing frequency with increasing age and severity of disease b. Triad of skeletal manifestations i. Clubbing of fingers and toes ii. Arthritis iii. Periosteal new bone formation Nutritional abnormalities a. Failure to thrive, a common manifestation during infancy and beyond b. Poor appetite c. Weight loss d. Fatigue e. Prone to heat prostration f. Hypoproteinemia with or without edema, anemia, and deficient fat-soluble vitamins A, D, E, and K g. Peripheral neuropathy secondary to deficient vitamin E h. Delayed puberty largely due to nutritional factors i. Potentially lethal protein-energy malnutrition in some infants j. Development of some degree of malabsorption by 4 years of age in roughly 85% of patients Salt losing syndromes a. Acute salt depletion b. Chronic hypochloremic or hyponatremic alkalosis c. Excessive salt loss in the sweat potentially fatal for patients exposed to moderate heat or during prolonged hot weather Prognosis a. Respiratory failure: the leading cause of death in CF and occurs eventually in nearly all patients b. Current median survival: approximately 35 years in the United States c. Current data suggesting a lifespan exceeding 50 years for those diagnosed and treated early

Cystic Fibrosis

Diagnostic Investigations 1. Newborn screening a. Measuring blood immunoreactive trypsinogen in dried blood spots i. Elevated levels in most CF infants (85–90% sensitive) ii. Associated with a relatively large number of false positive results iii. Diagnosis must be confirmed by sweat tests or genotyping (CF multimutational analysis) b. Use DNA-based testing on dried blood spots by CFTR multimutational analysis 2. Sweat test a. The traditional method of CF diagnosis b. Remains the most readily available and clinically useful way of making the diagnosis of CF, provided it is done according to strict guidelines with pilocarpine iontophoresis and a quantitative determination of chloride concentration (LeGrys et al. 2007) c. Reliably identifies the vast majority of patients with CF who have multiorgan involvement including the lungs and pancreas d. Using pilocarpine iontophoresis technique to produce sweat for chloride analysis e. Sweat chloride concentrations i. >60 mEq/L, observed in: a) CF patients with clinical manifestation of chronic pulmonary disease and/or pancreatic insufficiency b) CF patients with positive family history c) Untreated Addison disease d) Ectodermal dysplasia e) Certain types of glycogen storage diseases f) Untreated hypothyroidism g) A few normal adults ii. 90%): painful swelling or stiffness of the neck in most patients vi. Spine a) Leading to complete fusion b) Mimicking ankylosing spondylitis c) Pain and stiffness of the spine present in most patients vii. Muscles of mastication a) Leading to limited mouth opening b) Inability to feed orally c) Poor oral hygiene d) Subsequent cachexia h. Severe restrictive pulmonary disease i. Causes a) Scoliosis of the thoracolumbar spine b) Ankylosis of costovertebral joints c) Ossification of the chest wall with resultant dependence on diaphragm for respiration ii. Severely reduced lung volume iii. Constrictive airway dysfunction developing over time iv. Recurrent pulmonary infections secondary to ineffective cough: a common cause of death in the third or fourth decade i. Eventual confinement to wheelchair 3. Congenital malformation (microdactylia) of the great toes (>95%) and thumbs (50%) a. Association with congenital great toe malformation i. Mainly short big toes with single phalanx (a cartilaginous anlage of the first metatarsal and proximal phalanx) present at birth ii. An important early diagnostic clue b. Shortened thumbs c. Clinodactyly of the fifth fingers 4. Other features a. Patients with FOP are prone to fractures with poor outcome b. Occasional baldness c. Conductive hearing loss (50%) secondary to calcification and fusion of the ligaments, tendons, and bones of the middle ear d. Markedly reduced reproductive fitness

Fibrodysplasia Ossificans Progressiva

e. Life-threatening complications caused by thoracic insufficiency syndrome (95%) due to: i. Costovertebral malformations with orthotopic ankylosis of the costovertebral joints ii. Ossification of intercostals muscles, paravertebral muscles, and aponeuroses iii. Progressive spinal deformity a) Kyphoscoliosis b) Thoracic kyphosis iv. Pneumonia v. Right-sided congestive heart failure f. Reduced life span but most patients survive to adulthood 5. Natural history a. Mobility becomes more restricted as the disease advances. b. A life-long rigid immobility caused by the progressive metamorphosis of skeletal muscle and soft connective tissue into a second skeleton of heterotopic bone. c. Typically confined to bed or wheelchair by early 30s. 6. Diagnostic criteria (Kartal-Kaess et al. 2010) a. Major characteristics i. Congenital malformation of the great toes (earliest phenotypic feature) ii. Progressive extraskeletal bone formation (episodic, begin during childhood) iii. Heterozygous ACVR1 mutation b. Other features i. Early stage lesions associated with soft tissue swellings and inflammation in characteristic anatomic patterns ii. Predictable regional pattern of heterotopic ossification iii. Cervical spine fusions iv. Short/broad femoral necks v. Osteochondromas vi. Conductive hearing loss 7. Differential diagnosis of heterotopic ossification (Kartal-Kaess et al. 2010) a. Progressive osseous heteroplasia (Shore and Kaplan 2005) i. Presence of cutaneous ossification ii. Absence of congenital malformations of the skeleton iii. Absence of inflammatory tumor-like swellings

837

b. c.

d. e.

f.

g.

iv. Asymmetric mosaic distribution of lesions v. Absence of predictable regional patterns of heterotopic ossification vi. Presence of dominance of intramembranous rather than endochondral ossification vii. Inherited only paternally viii. Carries inactivating mutations of the GNAS gene, a gene that is regulated through genomic imprinting and allele-specific gene expression Posttraumatic: myositis ossificans circumscripta Neurogenic i. After head trauma or spinal cord injury ii. After long coma Postsurgical: after total joint arthroplasties Reactive i. Bizarre parosteal osteochondromatous proliferation ii. Florid reactive periostitis iii. Subungual exostosis Neoplasms i. Sarcoma ii. Malignant fibrous histiocytoma Degenerative processes

Diagnostic Investigations 1. Radiography (Bridges et al. 1994) a. Extraskeletal ossification i. Progressive widespread heterotopic ossification of muscles, tendons, ligaments, and fascia ii. Ankylosis a) Shoulder joints b) Elbow joints c) Hip joints: prevent ability to ambulate d) Knee joints e) Muscles of mastication b. Phalangeal abnormalities i. Characteristically affecting the great toes a) Shortened first digits b) Delta-shaped proximal phalanges c) Often monophalangism with absence of the interphalangeal joint of the great toes ii. Shortened thumbs iii. Clinodactyly of the fifth fingers

838

2.

3.

4. 5. 6. 7.

c. Less common congenital malformations i. Small vertebral bodies and enlarged pedicles in early childhood ii. Variable degrees of vertebral fusion, especially apophysial joint fusion in late childhood iii. Short, broad femoral necks iv. Ossification of ligamentous insertions producing exostoses of the proximal tibia v. Delay in skeletal maturation vi. Enchondroma formation vii. Association with synovial chondromatosis Bone scintigraphy (radionuclide imaging) (Tulchinsky 2007) a. A very sensitive technique for new bone formation in FOP b. Reveals multiple foci of increased uptake in connective tissue at characteristic locations, in combination with pathognomonic microdactyly of the great toes (or thumbs): highly specific CT scan a. Useful for diagnosis because CT scan is very sensitive for calcification. b. Soft tissue swelling in the fascial planes and muscle in the early course of FOP. c. Evidence of soft tissue calcification, typically in the form of shell seen within days to a few weeks. d. Calcification appearing as spicules in the soft tissue or in thin planes along the fascia often encircling muscle. e. Able to delineate the presence or absence of bone destruction, differentiating FOP from invasive processes such as infection and tumor. MRI: a sensitive imaging technique for soft tissue abnormalities but not particularly useful for diagnosis Ultrasonography to demonstrate echogenic and shadowing mass Audiography: mixed-type hearing loss with prominent conductive component Histopathology (Mahboubi et al. 2001) a. Earliest finding: an intense perivascular lymphocytic infiltration b. Followed by death of skeletal muscle and replacement by a highly vascular fibroproliferative soft tissue, which rapidly progresses through an endochondral process to form heterotopic bone

Fibrodysplasia Ossificans Progressiva

8. Molecular genetic diagnosis: mutational screening of ACVR1 gene a. Detection of a specific heterozygous mutation (c.617G>A; p.R206H) in the activin A type I receptor gene (ACVR1) in all classically affected individuals b. Detection of a variant FOP phenotype (c.983G>A; p.G328E) (Carvalho et al. 2010)

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected or has gonadal mosaicism b. Patient’s offspring: 50% 2. Prenatal diagnosis: possible by molecular genetic testing of the ACVR1 gene on fetal DNA obtained from amniocentesis or CVS for fetuses at 50% risk for FOP if a clinically diagnosed relative has an identified disease-causing ACVR1 gene alteration 3. Management (Kocyigit et al. 2001) a. No effective treatment available b. FOP can often be recognized in children with or without previously affected family members at birth or in early years before the onset of heterotopic ossifications because of the presence of shortening of the great toe and short thumbs c. Early recognition allows protection of the child from injuries i. Avoid multiple biopsies, trauma, intramuscular injections, and dysfunctional IV catheters to prevent precipitating the heterotopic ossification and exacerbating the disease ii. Prevention of influenza-like illnesses iii. Minimal soft tissue trauma during routine dental care may precipitate permanent ankylosis of the jaw d. Physical therapy in general not recommended as stretching of the soft tissues around a joint can lead to a painful flare-up e. Steroids, nonsteroid anti-inflammatory agents, disodium etidronate, warfarin, and radiotherapy i. Used to halt the progression of disease ii. Without proven benefit f. Isotretinoin i. Principle based on its ability to inhibit differentiation of mesenchymal tissue into cartilage and bone

Fibrodysplasia Ossificans Progressiva

g.

h.

i.

j.

ii. Questionable benefit to decrease the incidence of heterotopic ossification at uninvolved anatomical sites Etidronate (aminobisphosphonates) i. Blocks ectopic calcification and is approved by Food and Drug Administration for treatment of postoperative heterotopic ossification ii. Short-term effect of bone metabolism shows diminished bone turnover rate iii. Long-term effect on ectopic calcification is unchanged in most cases with few exceptions Primary therapy for the debilitating disease: supportive care i. Active range-of-motion exercises encouraged if the movements are comfortable ii. Available adaptations or modifications prescribed to a disabled patient with FOP to achieve functional independence in the home and community a) Shoes b) Canes c) Wheelchairs Surgery i. Nearly always contraindicated since new heterotopic ossification occurs at the operative site ii. Surgical removal of heterotopic bone a) Ineffective b) Leading to catastrophic exacerbation of the disease iii. Existence of intercurrent problems occasionally requiring surgery Anesthesia i. Presenting numerous difficulties to the anesthesiologist including cervical spine ankylosis and restrictive pulmonary disease ii. Avoid tissue trauma in the form of local anesthetic injections iii. Presence of anatomical airway abnormalities iv. Alternative methods preferred a) Nebulized lidocaine b) IV sedation c) Nasotracheal intubation v. Proper positioning and padding perioperatively vi. Vigorous chest physiotherapy and pulmonary toilet postoperatively

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References Ahn, J., Feldman, G., Terry, L., et al. (2003). Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva. Clinical Orthopaedics and Related Research, 406, 205–213. Blaszczyk, M., Majewski, S., Brzezinska-Wcislo, L., et al. (2003). Fibrodysplasia ossificans progressiva. European Journal of Dermatology, 13, 234–237. Brantus, J. F., & Meunier, P. J. (1998). Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clinical Orthopaedics, 346, 117–120. Bridges, A. J., Hsu, K. C., Singh, A., et al. (1994). Fibrodysplasia (myositis) ossificans progressiva. Seminars in Arthritis and Rheumatism, 24, 155–164. Carter, S. R., Davies, A. M., Evans, N., et al. (1989). Value of bone scanning and computed tomography in fibrodysplasia ossificans progressiva. British Journal of Radiology, 62, 269–272. Carvalho, D. R., Navarro, M. M. M., Martins, M. J. A. F., et al. (2010). Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients. Clinical Genetics, 77, 171–176. Cohen, M. M., Jr. (2002). Bone morphogenetic proteins with some comments on fibrodysplasia ossificans progressiva and NOGGIN. American Journal of Medical Genetics, 109, 87–92. Cohen, R. B., Hahn, G. V., Tabas, J. A., et al. (1993). The natural history of heterotopic ossification in patients who have Fibrodysplasia ossificans progressive. A study of forty-four patients. Journal of Bone and Joint Surgery (America), 75, 215–219. Connor, J. M., & Evans, D. A. (1982a). Extra-articular ankylosis in fibrodysplasia ossificans progressiva. The British Journal of Oral Surgery, 20, 117–121. Connor, J. M., & Evans, D. A. (1982b). Genetic aspects of fibrodysplasia ossificans progressiva. Journal of Medical Genetics, 19, 35–39. Connor, J. M., & Evans, D. A. (1982c). Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. Journal of Bone and Joint Surgery British, 64, 76–83. Connor, J. M., Skirton, H., & Lunt, P. W. (1993). A three generation family with fibrodysplasia ossificans progressiva. Journal of Medical Genetics, 30, 687–689. Connor, J. M., & Smith, R. (1982). The cervical spine in fibrodysplasia ossificans progressiva. British Journal of Radiology, 55, 492–496. Cramer, S. F., Ruehl, A., & Mandel, M. A. (1981). Fibrodysplasia ossificans progressiva: A distinctive boneforming lesion of the soft tissue. Cancer, 48, 1016–1021. Cremin, B., Connor, J. M., & Beighton, P. (1982). The radiological spectrum of fibrodysplasia ossificans progressiva. Clinical Radiology, 33, 499–508. Delatycki, M., & Rogers, J. G. (1998). The genetics of fibrodysplasia ossificans progressiva. Clinical Orthopaedics and Related Research, 346, 15–18. Groppe, J. C., Shore, E. M., & Kaplan, F. S. (2007). Functional modeling of the ACVR1 (R206H) mutation in FOP. Clinical Orthopaedics and Related Research, 462, 87–89.

840 Hall, J. G., Schaller, J. G., Worsham, N. G., et al. (1979). Fibrodysplasia ossificans progressiva (myositis ossificans progressiva) treatment with disodium etidronate. Journal of Pediatrics, 94, 679–680. Janoff, H. B., Muenke, M., Johnson, L. O., et al. (1996). Fibrodysplasia ossificans progressiva in two half-sisters: Evidence for maternal mosaicism. American Journal of Medical Genetics, 61, 320–324. Kaplan, F. S., & Glaser, D. L. (2005). Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism, 3, 213–216. Kaplan, F. S., Glaser, D. L., Pignolo, R. J., et al. (2007). A new era for fibrodysplasia ossificans progressive: A druggable target for the second skeleton. Expert Opinion on Biological Therapy, 7, 705–712. Kaplan, F. S., Glaser, D. L., Shore, E. M., et al. (2005). The phenotype of: Fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism, 3, 183–188. Kaplan, F. S., McCluskey, W., Hahn, G., et al. (1993). Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family. Journal of Bone and Joint Surgery America, 75, 1214–1220. Kaplan, F. S., Shen, Q., Lounev, V., et al. (2008). Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP). Journal of Bone and Mineral Metabolism, 26, 521–530. Kartal-Kaess, M., Shore, E. M., Xu, M., et al. (2010). Fibrodysplasia ossificans progressiva (FOP): Watch the great toes! European Journal of Pediatrics, 169(11), 1417–1421. Kocyigit, H., Hizli, N., Memis, A., et al. (2001). A severely disabling disorder: Fibrodysplasia ossificans progressiva. Clinical Rheumatology, 20, 273–275. Levy, C., Berner, T. F., Sandhu, P. S., et al. (1999). Mobility challenges and solutions for fibrodysplasia ossificans progressiva. Archives of Physical Medicine and Rehabilitation, 80, 1349–1353. Lucotte, G., Bathelier, C., Mercier, G., et al. (2000). Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21-22. Genetic Counseling, 11, 329–334. Lucotte, G., Semonin, O., & Lutz, P. (1999). A de novo heterozygous deletion of 42 base-pairs in the noggin gene of a fibrodysplasia ossificans progressiva patient. Clinical Genetics, 56, 469–470.

Fibrodysplasia Ossificans Progressiva Mahboubi, S., Glaser, D. L., Shore, E. M., et al. (2001). Fibrodysplasia ossificans progressiva. Pediatric Radiology, 31, 307–314. Rocke, D. M., Zasloff, M. A., Peeper, J., et al. (1994). Age and joint-specific risk of initial heterotopic ossification in patients who have Fibrodysplasia ossificans progressive. Clinical Orthopaedics and Related Research, 301, 243–248. Rogers, J. G., & Geho, W. B. (1979). Fibrodysplasia ossificans progressiva. A survey of forty-two cases. Journal of Bone and Joint Surgery America, 61, 909–914. Schroeder, H. W., Jr., & Zasloff, M. (1980). The hand and foot malformations in fibrodysplasia ossificans progressiva. The Johns Hopkins Medical Journal, 147, 73–78. Se´monin, O., Fontaine, K., Daviaud, C., et al. (2001). Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. American Journal of Medical Genetics, 102, 314–317. Shafritz, A. B., Shore, E. M., Gannon, F. H., et al. (1996). Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. The New England Journal of Medicine, 335, 555–561. Shore, E. M., & Kaplan, F. S. (2005). Fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. Clinical Reviews in Bone and Mineral Metabolism, 3, 257–259. Shore, E. M., Xu, M., Feldman, G. J., et al. (2006). A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics, 38, 525–527. Smith, R. (1998). Fibrodysplasia (myositis) ossificans progressiva. Clinical lessons from a rare disease. Clinical Orthopaedics and Related Research, 346, 7–14. Thornton, Y. S., Birnbaun, S. J., & Liebowitz, N. (1987). A viable pregnancy in a patient with myositis ossificans progressive. American Journal of Obstetrics and Gynecology, 156, 577–578. Tulchinsky, M. (2007). Diagnostic features of fibrodysplasia (myositis) ossificans progressiva on bone scan. Clinical Nuclear Medicine, 32, 616–619. Xu, M. Q., Feldman, G., Le Merrer, M., et al. (2000). Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP). Clinical Genetics, 58, 291–298. Xu, M., & Shore, E. M. (1998). Mutational screening of the bone morphogenetic protein 4 gene in a family with fibrodysplasia ossificans progressiva. Clinical Orthopaedics, 346, 53–58.

Fibrodysplasia Ossificans Progressiva

a

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c

b

d

e

f

Fig. 1 (a–h) A boy with fibrodysplasia ossificans progressiva showing a stiff neck, a narrow chest, and inability to raise arms upward due to ossification of the soft tissues on the back of the neck, the lateral chest wall, and the axillary region, illustrated by the neck, chest, and pelvic radiographs. The radiographs of both

g

h

feet showed shortened first toes and hallux valgus with deltashaped proximal phalanges, monophalangism with absence of the interphalangeal joint of the great toes. The radiographs of both hands showed shortening of the first metacarpals and the middle phalanx of the fifth fingers with clinodactyly

842 Fig. 2 A 14-year-old girl was seen because of swelling and pain on the upper thigh, especially on the left. The pelvic radiograph showed extensive heterotopic calcifications on the inner upper thighs, worse on the left. Her father was also affected

Fibrodysplasia Ossificans Progressiva

Finlay–Marks Syndrome

In 1978, Finlay and Marks described the association of scalp defect, malformed ears, and absence of nipples in a family. The association is also known as scalp-earnipple syndrome.

Synonyms and Related Disorders Scalp-ear-nipple syndrome

Genetics/Basic Defects 1. Inheritance a. Autosomal dominant in most reports b. Severe autosomal recessive form: two children from an inbred Arab family with features suggestive of scalp-ear-nipple syndrome (Al-Gazali et al. 2007) 2. Lymphoid enhancer factor-1 (Lef-1), identified as a candidate gene for scalp-ear-nipple syndrome (van Steensel et al. 1999) a. Lef-1: an HMG-domain DNA-binding protein expressed in the neural crest, mesencephalon, tooth germs, and other sites during embryogenesis b. Homozygous deficiency of this gene causing postnatal lethality in mice c. Mutant mice lacking teeth, mammary glands, whiskers, and hair d. Lack of hair, missing teeth, and aplasia of breast tissue suggest that Lef-1 may be a candidate gene for scalp-ear-nipple syndrome

Clinical Features 1. Scalp abnormalities (Edwards et al. 1994; Taniai et al. 2004) a. Raised firm nodules over the scalp in the occipital region, not covered by hairs b. The areas: raw at birth and heal during childhood c. Crumpled scalp over occipital region 2. External ear abnormalities a. Hypoplastic tragus, antitragus, and lobule b. Over-folding of the superior helix c. Flattening of the antihelix 3. Athelia (absent breasts and nipples) a. Rudimentary or absent nipples b. Breast hypoplasia or aplasia 4. Other reported features a. Ectodermal dysplasia features i. Dental anomalies a) Widely spaced teeth b) Missing secondary teeth c) Neonatal teeth ii. Reduction of axillary apocrine secretion and axillary hair growth iii. Hypohidrosis iv. Nail dysplasia b. Aplasia cutis vertices c. Renal hypoplasia d. Hypospadias e. Pyeloureteral duplication f. Cataract g. Coloboma of the iris h. Hypertension i. Diabetes mellitus j. Partial syndactyly

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5. Hypotonia and developmental delay in severe autosomal recessive form

Diagnostic Investigations 1. No specific laboratory tests available 2. Histology of scalp defect resembling aplasia cutis congenita (Finlay and Marks 1978) a. An excess of normal-appearing connective tissue b. Lack pilosebaceous elements 3. Renal sonography for renal hypoplasia 4. Diagnosis primarily by clinical features

Genetic Counseling 1. Recurrence risk a. Autosomal dominant i. Patient’s sib: low unless a parent is affected ii. Patient’s offspring: 50% b. Autosomal recessive i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis: not been reported 3. Management: primarily supportive

References Aase, J. M., & Wilroy, S. R. (1988). The Finlay-Marks (S.E.N.) syndrome: Report of a new case and review of the literature. Proceedings of the Greenwood Genetic Center, 7, 247–250.

Finlay–Marks Syndrome Al-Gazali, L., Nath, R., Iram, D., et al. (2007). Hypotonia, developmental delay and features of scalp-ear-nipple syndrome in an inbred Arab family. Clinical Dysmorphology, 16, 105–107. Berman, D. S., & Silverstone, L. M. (1975). Natal and neonatal teeth. A clinical and histological study. British Dental Journal, 139, 361–364. De Macena Sobreira, N. L., Brunoni, D., Cernach, M. C. S. P., et al. (2006). Finlay-marks (SEN) syndrome. American Journal of Medical Genetics, 140A, 300–302. Edwards, M. J., McDonald, D., Moore, P., et al. (1994). Scalpear-nipple syndrome: Additional manifestations. American Journal of Medical Genetics, 50, 247–250. Finlay, A. Y., & Marks, R. (1978). A hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples. British Journal of Dermatology, 99, 423–430. Le Merrer, M., Renier, D., & Briard, M. L. (1991). Scalp defect, nipples absence and ears abnormalities: Another case of Finlay syndrome. Genetic Counseling, 2, 233–236. Milatovich, A., Travis, A., Grosschedl, R., et al. (1991). Gene for lymphoid enhancer-binding factor 1 (LEF1) mapped to human chromosome 4 (q23-q25) and mouse chromosome 3 near EGF. Genomics, 11, 1040–1048. Picard, C., Couderc, S., Skojaei, T., et al. (1999). Scalp-earnipple (Finlay-Marks) syndrome: A familial case with renal involvement. Clinical Genetics, 56, 170–172. Plessis, G., Le Treust, M., & Le Merrer, M. (1997). Scalp defect, absence of nipples, ear anomalies, renal hypoplasia: Another case of Finlay-Marks syndrome. Clinical Genetics, 52, 231–234. Taniai, H., Chen, H., & Ursin, S. (2004). Finlay-Marks syndrome: Another sporadic case and additional manifestations. International Pediatrics, 46, 353–355. Tawil, H. M., & Najjar, S. S. (1968). Congenital absence of the breasts. Journal of Pediatrics, 73, 751–753. van Steensel, M. A., Celli, J., van Bokhoven, J. H., et al. (1999). Probing the gene expression database for candidate genes. European Journal of Human Genetics, 7, 910–919.

Finlay–Marks Syndrome

Fig. 1 A 7-month-old boy with Finlay–Marks syndrome showing absence of nipples and abnormal ears. He also had scanty eyebrows and eyelashes, neonatal teeth, which were extracted, nasolacrimal duct stenosis, and lumpy scalp on the occiput region

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Floppy Infant

A floppy infant is an infant with poor muscle tone affecting the limbs, trunk, and the craniofacial musculature. The causes are numerous (heterogeneous etiologies) and the workup in many instances can be complex. The task of evaluating infants with hypotonia is difficult and complex.

Synonyms and Related Disorders Congenital hypotonia

Genetics/Basic Defects 1. Heterogeneous causes of hypotonia (Prasad and Prasad 2003; Igarash 2004) a. Chromosome disorders: central hypotonia i. Aneuploidy: e.g., Down syndrome (one of the most frequently encountered cause of neonatal hypotonia) ii. Microdeletions: e.g., Prader–Willi syndrome (neonatal hypotonia, feeding problems, and failure to thrive with later onset of hyperphagia and obesity) iii. Subtelomeric cryptic deletions (relatively new category of disorders that account for unexplained mental retardation): e.g., terminal 22q13.3 deletion syndrome (neonatal hypotonia can be a prominent feature) b. CNS malformations/encephalopathies (associated with profound neonatal hypotonia) i. Congenital CNS malformations a) Lissencephaly b) Holoprosencephaly

ii. Acquired CNS disorders a) Birth trauma b) Hypoxic–ischemic encephalopathy c) Spinal cord injury c. Disorders affecting anterior horn cells and peripheral nerves i. Spinal muscular atrophy (SMA1) (Werdnig–Hoffman disease): generalized weakness, often spares the diaphragm, facial muscles, pelvis, and sphincters ii. Charcot–Marie–Tooth disease a) CMT1A b) CMT4E (congenital hypomyelination syndrome) c) Dejerine–Sottas syndrome (CMT3) d. Neuromuscular junction disorders i. Transient myasthenic syndrome ii. Hypermagnesemia of the newborn iii. Infantile botulism iv. Congenital myasthenic syndromes (neuromuscular junction disorders): bulbar, oculomotor muscles exhibit greater degree of involvement (neonatal hypotonia, easy fatigability, recurrent aspiration, feeding difficulty, cyanosis, and apnea) a) Congenital myasthenic with episodic apnea b) Slow-channel and fast-channel syndromes c) Endplate cholinesterase deficiency e. Congenital muscular dystrophies (CMD) and myopathies: hypoactive reflexes. For example, i. Classical congenital muscular dystrophy ii. Fukuyama muscular dystrophy iii. Walker–Warburg syndrome

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iv. v. vi. vii.

f.

g.

h.

i.

j.

k.

Muscle-eye-brain disease Ullrich congenital muscular dystrophy Bethlem myopathy Rigid spine-muscular dystrophy (SEPN1 selenoprotein deficiency) viii. Congenital myotonic dystrophy a) Triplet repeat CTG expansion of the DMPK and SIX5 genes b) Abnormal splicing of chloride channels mRNA leading to the myotonia Congenital myopathies: prominent weakness. For example, i. Central core myopathy ii. Nemaline myopathy iii. Myotubular (centronuclear) myopathy iv. Multicore myopathy v. Congenital myopathy with fiber type disproportion Metabolic disorders/myopathies: proximal musculature weakness. For example, i. Acid maltase deficiency (Pompe disease) ii. Pyruvate dehydrogenase complex deficiency iii. Pyruvate carboxylase deficiency iv. Respiratory chain defects (mitochondrial disorder) v. Zellweger syndrome vi. Smith–Lemli–Opitz syndrome vii. Congenital disorders of glycosylation viii. Phosphomannomutase-2 deficiency Combined CNS and motor unit disorder i. Metachromatic leukodystrophy ii. Giant axonal neuropathy iii. Familial dysautonomia iv. Mitochondrial encephalopathy v. Congenital muscular dystrophies Congenital hypotonia with a favorable outcome (benign congenital hypotonia): characterized by an early neonatal onset and a benign clinical course: No longer considered as a specific diagnostic entity Acute and systemic diseases especially in the newborn period i. Sepsis ii. Congestive heart failure Chronic i. Hypothyroidism ii. Connective tissue disorder

2. Localization of hypotonia in the floppy infant (Bodensteiner 2008) a. Supraspinal/suprasegmental hypotonia in which deep tendon reflexes are preserved: i. Central hypotonia caused by brain lesions a) Sepsis b) Congenital heart failure c) Hypoxic–ischemic encephalopathy ii. Syndromic central hypotonia caused by brainstem lesions (extensive list of etiologic possibilities associated with constellation of dysmorphic features) iii. Nonsyndromic central hypotonia a) Cerebral dysgenesis (developmental anomalies of the brain). b) Grossly normal brain by MRI includes myelination within normal range, normal development (essential hypotonia), delayed myelination, motor delay only (usually catch up to peers in tone and development by school age), developmental delay (may later be diagnosed as nonsyndromic mental retardation, frequently labeled as autistic), or global developmental delay (usually do not catch up intellectually and cognitively to peer by school age). iv. Central hypotonia caused by craniocervical junction lesions a) Spinal cord injury (critically ill infant with severe hypotonia at first and the nature of the injury is not usually suspected until the development of the hyperactive reflexes and the lack of the expected maturation of the corticospinal tract influences on the motor unit). b) Chiari I malformation (may be an isolated finding that may cause hypotonia early on by compression of the lower brainstem at the level of the foramen magnum). c) Chiari II malformation (usually associated with spina bifida and easily suspected). b. Segmental or motor unit hypotonia in which deep tendon reflexes are depressed or lost i. Anterior horn cell (spinal muscular atrophy) ii. Peripheral nerve (hereditary motor sensory neuropathy)

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iii. Neuromuscular junction a) Myasthenia gravis b) Congenital myasthenic syndromes c) Botulism iv. Muscle a) Congenital myopathies b) Metabolic myopathies c) Neonatal presentation of muscular dystrophy

Clinical Features 1. Hypotonia (decreased or loss of muscle tone) a. Full abduction and external rotation of the legs. b. Flaccid extension of the arms. c. Prominent head lag on pull to sit (normally diminished or absent by about 2 months of age): “Pull to sit” maneuver tests axial tone of the neck and back and appendicular tone of the shoulder and arms and also tests strength to some extent. Normal response from the infant being tested is to resist the pull on the arms and shoulder. d. Scarf sign: produced by grasping the supine infant’s hand and pulling it across the chest and bring the baby’s elbow well beyond the baby’s chin and the midline of the chest before encountering the resistance. The maneuver tests the appendicular tone in the shoulder and is somewhat sensitive to the gestational age of the infant, the degree of laxity of the ligaments, and the state of alertness of the child. e. Shoulder suspension test: produced by picking the infant up holding under the infant’s arms and observe the tendency of the hypotonic infant to slip through the examiner’s hands. The maneuver tests the appendicular tone but also gives some indication of head control (axial) as well as strength. f. Ventral suspension test: produced by lifting off the infant from the table by examiner’s one hand under the infant’s chest and abdomen and observe the hypotonic infant unable to lift the head above the horizontal plane and unable to flex the arms and legs. 2. Central hypotonia (disorders of central nervous system that cause decreased tone by interrupting

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pathways involved in the modulation) with following general characteristics: a. Hypotonia b. Obtundation c. Neonatal seizures d. Hyperactive deep tendon reflexes e. Neonatal encephalopathy f. Clinical or neuroimaging evidence for hypoxia–ischemia 3. Peripheral hypotonia (disorders of the motor unit) a. General characteristics i. Hypotonia (absence of features of central hypotonia) ii. Areflexia or diminished reflexes iii. Convincing weakness iv. Decreased antigravity limb movements v. Weak cry vi. Weak suck vii. Fasciculations viii. External ophthalmoplegia ix. Alert look x. Arthrogryposis b. Anterior horn cell disease i. SMA: the most common serious cause of hypotonia in the infant and child ii. Very few conditions other than SMA that would result in widespread denervation on EMG in the clinical setting of hypotonia and weakness in infancy iii. Muscle biopsy no longer necessary to make the diagnosis of SMA in the clinical situation c. Peripheral nerve diseases, such as CMT, rarely cause hypotonia in infancy d. Neuromuscular junction disease i. Not a common cause of hypotonia in infancy ii. The only category of motor unit disease in which the reflexes may be preserved iii. Neonatal myasthenia gravis a) Uncommon cause of hypotonia in infancy in recent years b) Caused by antibodies to the acetylcholine receptor (AchR) which are passively transferred to the infant by the mother who has autoimmune myasthenia gravis iv. Congenital myasthenic syndromes a) Much more common cause of hypotonia in infancy

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b) Caused by genetic defects of neuromuscular transmission resulting in a decrease in the safety margin in neuromuscular transmission c) Manifest clinically by easy fatigability and weakness to variable degree depending on the severity of the defect in transmission d) Diagnosis based on fatigue with exercise e) Affected infants may be very sensitive to neuromuscular blocking agents and may respond to AchE antagonists v. Selected congenital myasthenic syndromes a) AchR deficiency: early onset, variable severity, ptosis, extraocular palsy, and involvement of bulbar, arm, and legs. b) Slow-channel syndrome: selective severe weakness of neck, wrist, and finger extensor, variable onset and severity, and common, often progressive ventilatory problems. c) Fast-channel syndrome: variable onset and severity and may respond to AchE inhibitors. d) Endplate rapsyn deficiency: early onset with hypotonia, respiratory failure, apnea, and arthrogryposis. e) Congenital myasthenia syndrome with episodic apnea: early respiratory failure, episodic apnea, improvement with age, and may respond to AchE inhibitors. f) Endplate acetylcholinesterase deficiency: ophthalmoparesis, severe axial musculature weakness, slow papillary responses. e. Abnormalities of muscle structure or function i. A major cause of motor unit hypotonia, second only to SMA in overall frequency ii. Congenital myopathies a) More likely than Duchenne muscular dystrophy as a cause of hypotonia in the first year b) Comprised of a group of muscle diseases that typically only slowly progressive over time, although present at birth with variable severity c) Classical congenital myopathies (central core disease, nemaline myopathy, centronuclear myopathy)

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iii.

iv.

v.

vi.

d) Other well-established congenital myopathies (multicore, congenital myopathy with fiber-type disproportion (CFTD, reducing body, fingerprint, cytoplasmic body) e) Congenital muscular dystrophies (CMD): CMD is an important subgroup of congenital myopathies. The conditions are usually present at birth, often quite severe with muscle weakness, wasting, respiratory difficulty, and contractures, with variable involvement of brain, eyes, and other tissues. Muscle biopsies show dystrophic muscle with muscle fiber necrosis and regeneration with replacement of muscle with fibrous and fatty connective tissue. The CMD is typically subdivided into two categories: those with brain involvement (syndromic CMD, comprised of merosin-deficient CMD, CMD with partial merosin deficiency, CMD 1C, CMD with ITGA7 mutations, CMD with spine rigidity) and those without brain involvement (nonsyndromic CMD, comprised of Fukuyama CMD, muscle-eye-brain disease, Walker–Warburg syndrome 2, congenital muscular dystrophy) Central core disease a) Variable presentation b) Somatic abnormalities c) Characteristic malignant hyperthermia d) Occasional cardiomyopathy Nemaline myopathy a) Variable presentation b) Somatic abnormalities (infantile) c) Muscle wasting d) Ocular muscle weakness e) Adult onset of pain/cramp f) Rare cardiomyopathy Centronuclear (myotubular) myopathy a) Variable presentation b) Somatic abnormalities (infantile) c) Muscle wasting d) Ocular muscle weakness with ptosis Multicore myopathy a) Mild early presentation b) Somatic abnormalities

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vii.

viii.

ix.

x.

xi.

xii.

xiii.

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c) Ocular muscle weakness with ptosis d) Malignant hyperthermia reported e) Cardiomyopathy reported Congenital myopathy with fiber-type disproportion (CFTD) a) Variable presentation b) Muscle wasting c) Somatic abnormalities d) Stiffness e) Mental retardation Reducing body myopathy (X-linked) a) Variable presentation b) Somatic abnormalities c) Ocular muscle weakness with ptosis d) Cardiomyopathy reported Fingerprint body myopathy a) Mild early presentation b) Muscle wasting c) Somatic abnormalities d) Mental retardation Cytoplasmic inclusion body myopathy a) Early, moderate to severe onset b) Somatic abnormalities c) Cardiomyopathy Merosin-deficient DMD a) Severe manifestation b) Hypotonia c) Global weakness d) Contractures e) Scoliosis f) Inability to walk g) Normal intelligence h) Abnormal white matter signal (MRI) CMD with partial merosin deficiency a) Milder manifestation b) Ability to walk in most cases c) Cardiomyopathy d) Contractures of elbow, knees, and fingers e) Normal intelligence f) Normal MRI of the brain CMD type 1C a) Severe weakness b) Global involvement c) Contractures of elbow, knees, fingers d) Cardiomyopathy e) Normal intelligence f) Normal MRI of the brain

xiv. CMD with ITGA7 mutation a) Proximal muscle weakness b) Torticolis c) Congenital hip dislocation xv. CMD with spine rigidity a) Rigid spine, elbows, hips, and ankles b) Progressive sleep hypoventilation xvi. Ullrich CMD a) Global weakness with contractures b) Distal hyperextensibility c) Calf atrophy d) Normal intelligence xvii. Fukuyama CMD a) Severe generalized weakness b) Contractures c) Cobblestone lissencephaly xviii. Muscle-eye-brain disease a) Mild presentation early (ability to walk in some cases but lose walking by age 20) b) Eye malformations (without cataracts) c) Hydrocephalus d) White matter abnormality (MRI) e) Cobblestone lissencephaly xix. Walker–Warburg syndrome a) Severe generalized weakness b) Contractures at elbows only c) Lissencephaly d) Dandy–Walker malformation or cerebellar hypoplasia, flat pons (MRI) e) Early demise xx. CMD 1D a) Global delay b) Proximal weakness greater than distal weakness c) Muscle hypertrophy d) Facial sparing e) White matter changes (MRI) 4. Differentiating congenital hypotonia of central versus peripheral origin (Harris 2008) a. Weakness i. Central: mild to moderate ii. Peripheral: significant (“paralytic”) b. Deep tendon reflexes i. Central: decreased or increased ii. Peripheral: absent c. Placing reactions i. Central: sluggish or slow ii. Peripheral: absent

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d. Motor delays i. Central: present ii. Peripheral: present e. Antigravity movements in prone and supine i. Central: some but less than a typical infant ii. Peripheral: often absent f. Pull to sit i. Central: some head lag (more so than typical infant) ii. Peripheral: marked head lag g. Cognition/affect i. Central: delayed ii. Peripheral: typical h. Ability to “build up” tone, e.g., tapping under knees with infant in supine to assist them in holding hips in adduction i. Central: present ii. Peripheral: absent 5. Pattern of muscle weakness and localization in the floppy infant (Prasad and Prasad 2003) a. Central nervous system i. Corresponding disorders a) Chromosome disorders b) Inborn errors of metabolism c) Cerebral dysgenesis d) Cerebral/spinal cord trauma ii. Pattern of weakness and involvement a) Central hypotonia b) More prominent axial weakness c) Hyperactive reflexes b. Motor neuron i. Corresponding disorders (SMA) ii. Pattern of weakness and involvement (generalized weakness, often sparing diaphragm, facial muscles, pelvis, and sphincters) c. Nerve i. Corresponding disorders: peripheral neuropathies ii. Pattern of weakness and involvement (weakness with wasting involving distal muscle) d. Neuromuscular junction i. Corresponding disorders a) Myasthenia syndrome b) Infantile botulism ii. Pattern of weakness and involvement (weakness with greater involvement of bulbar and oculomotor muscles)

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e. Muscle i. Corresponding disorders a) Congenital myopathies b) Metabolic myopathies c) CMD d) Congenital myotonic dystrophy ii. Pattern of weakness and involvement a) Prominent weakness b) Proximal musculature c) Hypoactive reflexes d) Joint contractures 6. Congenital hypotonia with a favorable outcome (benign congenital hypotonia) a. No longer considered as a specific diagnostic entity b. The term applied to a group of patients in whom a specific diagnosis cannot be made despite best effort in workup c. Common features i. Generalized hypotonia since birth ii. Mild delayed or normal developmental milestones iii. Active movement with preserved reflexes iv. Significant joint laxity or hypermobility v. Normal investigations (muscle enzymes, EMG, nerve conduction studies, muscle biopsy) vi. Favorable outcome common 7. Other diagnostic features a. Areflexia, decreased limb movement, and demonstration of denervation on EMG suggest anterior horn cell disorders such as SMA type I. b. Decreased conduction velocities on nerve conduction test suggest a demyelinating neuropathies such as Charcot–Marie–Tooth (CMT) type 2 (also known as Dejerine–Sottas disease), congenital hypomyelinating neuropathy (CMT 4E), other subtypes of CMT4. c. Demonstration of cerebral myelin abnormalities and peripheral demyelination suggest Pelizaeus–Merzbacher disease or other known leukodystrophies such as Krabbe disease. d. Pompe disease (acid maltase deficiency). i. Can easily mistaken for a primary myopathy in the first year ii. Major differential clinical features a) A large heart b) Firm skeletal muscles secondary to glycogen stored in the muscle fibers c) Distinctive EMG findings

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8. Differential diagnosis of hypotonia based on specific associated features (Dubowitz 1985) a. Hypotonia and respiratory difficulties i. Muscular disorders a) Spinal muscular atrophy b) Myotonic dystrophy c) Myotubular myopathy (especially X-linked form) d) Nemaline myopathy e) Congenital muscular dystrophy f) Other ii. Nonmuscular disorders a) Intracranial hemorrhage b) Intracranial ischemia b. Hypotonia and facial weakness: muscular disorders i. Congenital myotonic dystrophy ii. Myotubular myopathy iii. Congenital muscular dystrophy iv. Congenital facial diplegia syndrome c. Hypotonia and swallowing difficulty i. Muscular disorders a) Spinal muscular atrophy b) Myotubular myopathy c) Myotonic dystrophy d) Myasthenia gravis (neonatal) ii. Nonmuscular disorders a) Prader–Willi syndrome b) Intracranial hemorrhage c) Intracranial ischemia d. Hypotonia and ptosis/ophthalmoplegia: muscular disorders i. Myotubular myopathy ii. Mitochondrial myopathy iii. Myotonic dystrophy iv. Congenital muscular dystrophy v. Myasthenia gravis e. Hypotonia and arthrogryposis i. Muscular disorders a) Congenital muscular dystrophy b) Myotonic dystrophy c) Congenital fiber-type disproportion d) Denervation syndromes ii. Nonmuscular disorders a) Oligohydramnios b) Bicornuate uterus c) Renal agenesis f. Hypotonia and CNS dysfunction/convulsions i. Hypoxic–ischemic encephalopathy ii. Intracranial hemorrhage

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iii. iv. v. vi. vii.

Intracranial ischemia Organic acidurias Mitochondrial encephalopathies Zellweger disease Other rare metabolic disorders

Diagnostic Investigations 1. A stepwise approach to the evaluation of a neonate with hypotonia (modified from Paro-Panjan and Neubauer 2004) a. Step 1 comprised of history taking and physical examination i. Family history a) Drug or teratogen exposure b) Breech presentation c) Reduced fetal movements d) Polyhydramnios e) Maternal diseases such as diabetes and epilepsy f) Parental age g) Neuromuscular disease h) Affected siblings ii. Prenatal history a) Decreased fetal movement b) Abnormal ultrasonographic findings such as hydrocephalus or polyhydramnios c) Possible evidence for hypoxic–ischemic insult, either in utero or during birth: detail perinatal birth trauma, birth anoxia, delivery complications, low APGAR scores (lower scores for tone, reflexes, and respiratory effort) and onset of hypotonia iii. Neonatal history a) A shortened umbilical cord and abnormal fetal presentation: reflects poor fetal movement or immobility. b) Infants requiring ventilator assistance soon after birth to maintain respiration in addition to hypotonia: suggest the presence of significant muscle weakness. c) In addition to hypotonia, infants with severe CNS abnormalities develop signs of impairment in level of consciousness, feeding difficulties, seizures, apneas, abnormal posturing,

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abnormalities of ocular movements and of brain stem reflexes. d) Presence of congenital malformations in other organ systems, deformations, and craniofacial dysmorphic features: need to establish a syndromic diagnosis. iv. Postnatal history v. Clinical and neurological examinations b. Step 2 comprised of neurological imaging tests: important to determine whether there is evidence for a cerebral lesion contributing to hypotonia i. Computed tomography (CT) ii. Magnetic resonance imaging (MRI) c. Step 3 comprised careful search of dysmorphology databases d. Step 4 comprised of karyotyping with fluorescence in situ hybridization (FISH) for chromosome anomalies e. Step 5 comprised of biochemical investigations for inborn errors of metabolism f. Step 6 comprised of other specific studies i. Specific nerve and muscle investigations a) Serum kinase levels b) Electromyography c) Nerve conduction velocities ii. DNA markers a) Spinal muscular atrophy b) Congenital myotonic dystrophy c) Duchenne muscular dystrophy iii. Muscle and nerve biopsy with mitochondrial enzymes 2. Initial workup of the floppy infant based on clinical presentation, localization, and diagnostic yield (Prasad and Prasad 2003) a. Clinical history and physical examination i. Central hypotonia a) Hypotonia b) Obtundation c) Seizures d) Hyperactive deep tendon reflexes ii. Disorders of the lower motor unit a) Hypotonia b) Weakness c) Areflexia d) Fasciculations e) Weak cry f) Weak suck g) External ophthalmoplegia

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h) Alert look i) Arthrogryposis b. Multidisciplinary assessment including pedigree/family history and targeted investigations i. CT/MRI, EEG, infection screen (CSF, blood) a) Birth trauma b) Hypoxic–ischemic encephalopathy c) Sepsis d) Cerebral dysgenesis ii. Genetic studies (karyotyping, FISH, methylation studies, mutation analysis) a) Chromosomal rearrangements b) Prader–Willi syndrome c) Congenital myotonic dystrophy d) Subtelomeric deletions iii. Creatine kinase assay, electrophysiology, nerve conduction studies, EMG a) Nerve biopsy and/or direct mutation analysis (inherited neuropathies, disorders of neuromuscular junction) b) Muscle biopsy followed by DNA-based mutation analysis when available (congenital muscular dystrophy, congenital myopathies) 3. Investigation scheme in the floppy infant with multisystem involvement (Prasad and Prasad 2003) a. Cranial MRI, echocardiography, abdominal ultrasound, ophthalmic examinations for infants with hypotonia plus manifestations. i. CNS obtundation ii. Abnormal odors iii. Seizures iv. Craniofacial dysmorphisms v. Cataracts vi. Hepatomegaly vii. Renal cysts viii. Retinopathy ix. Arthrogryposis x. Lipodystrophy b. Plasma lactate levels, mt DNA mutations, DNA depletion studies, respiratory chain analysis (muscle), DNA-based mutation analysis for mitochondrial and “energy deficient” encephalopathies (e.g., congenital lactic acidosis). c. Plasma ammonia, amino acids (blood, urine), urine organic acids, blood acylcarnitine profile, plasma uric acid, urinary sulfites, enzyme assays in skin fibroblasts for

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aminoacidopathies, organic acidemias, sulfite oxidate/molybdenum cofactor deficiency. d. Lysosomal enzyme assay in WBC, skin biopsy (EM for inclusion), skin fibroblast culture + enzyme assays for lysosomal disorders (e.g., Pompe disease). e. Phytanic acid, plasma VLCFA for peroxisomal disorders (e.g., Zellweger syndrome). f. Isoimmune electrophoresis for transferrin for congenital disorders of glycosylation. g. 7-dehydrocholesterol for Smith–Lemli–Opitz syndrome. 4. Cytogenetic analyses: for floppy infants with dysmorphic features and/or multiple congenital anomalies a. Aneuploidy disorders such as Down syndrome b. Microdeletion disorders such as Prader–Willi syndrome i. Methylation patterns study to determine the presence of PWS ii. FISH and mutation analysis to identify the class of mutation c. Subtelomeric deletion disorders: easily detected using in situ hybridization using chromosomal telomeric probes 5. Molecular analyses: genetic testing aid significantly in timely diagnosis for a critically ill newborn and allow for anticipation of medical interventions by the multidisciplinary team caring for the infant a. Chromosomal microarray studies b. Mutation or deletion analysis of the survival motor neuron gene (SMN) for SMA i. All patients with SMA have deletions or mutations of SMN1 (also known as SMNt, the telomeric copy of SMN gene). Homozygous deletion of exon 7 in the telomeric survival motor neuron gene found in 95% of SMA type I patients ii. The major phenotype determinant is the presence of the number of copies of SMN2 (also known as SMNc, the centromeric copy of SMN gene) a) One copy: likely to produce SMA1 b) No copy of SMA1: likely results in spontaneous abortion or fetal wastage c) Five or six copies: likely allow normal survival with little or no progressive weakness

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c. Mutation analysis in CMT hereditary motor sensory neuropathies i. CMT 1A: mutations in the peripheral myelin protein-22 gene ii. CMT 1B: mutation in the myelin protein zero gene iii. CMT 2B: mutation in the RAS-associated protein RAB7 iv. CMT 4A: mutation in the gangliosideinduced differentiation-associated protein1 gene v. CMT-X1: mutation in the connexin-32 gene d. Mutation analysis for disorders of neuromuscular junction (congenital myasthenic syndromes) i. Congenital myasthenia with episodic apnea ii. Slow-channel and fast-channel syndrome iii. Endplate cholinesterase deficiency e. Mutation analysis for disorders with prominent muscle involvement i. Bethlem myopathy ii. Triplet repeat CTG expansion of the DM protein kinase mutations (>37) iii. Congenital DM protein kinase repeat expansion (>750) f. Gene sequencing, mutation analysis, or mutation scanning i. Dystrophinopathies ii. Muscular dystrophies iii. Myopathies g. mtDNA mutation analysis or mutation analysis in nuclear gene for mitochondrial disorders 6. Electrophysiological studies a. Needle electromyogram (EMG) i. Neurogenic changes a) Spontaneous fibrillation at rest b) Long duration polyphasic motor unit potentials c) Decreased interference pattern ii. Myopathic changes: consider muscle biopsy a) Low amplitude, short duration polyphasic b) Normal interference pattern iii. Myopathy plus muscle irritability (large amplitude of CMAPs, increased insertional activity) should consider Pompe disease (acid maltase enzyme assay) iv. Demonstration of denervation on EMG (large amplitude of CMAPs, fasciculation, positive sharp wave) should prompt

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investigation for anterior horn cell disorders (proceed to SMA genetic test, SMN type I and type II copy number) b. Motor and sensory nerve conduction studies (NCS): Decreased nerve conduction velocities on NCS suggest a demyelinating neuropathy 7. Pathologic studies of muscles (muscle biopsy): a. The most useful test in the diagnosis of motor unit hypotonia b. Used much less often today with the availability of specific gene test for many of the conditions under consideration c. A sequential scheme for the proper use of the muscle biopsy i. Nonspecific myopathy: consider myotonic, dystrophinopathy, and other congenital myopathy ii. Characteristic pathology a) Central core disease b) Nemaline rod myopathy c) Centronuclear myopathy iii. Dystrophic muscle a) Brain involvement: consider muscleeye-brain disease, Fukuyama congenital muscular dystrophy, and Walker–Warberg syndrome b) Without brain involvement: consider histoimmunological stain for merosindeficient and merosin-positive muscular dystrophies d. SMA: extensive large grouped atrophy involving both type I and type II fibers and scattered clusters of enlarged type I fibers e. Congenital muscular dystrophy: considerable variations in fiber size with extensive fatty infiltration f. Glycogen storage disease: vacuolar myopathy with muscle fibers containing type vacuoles of varying sizes g. Central nuclear myopathy: presence of central nucleus in the majority of muscle h. Central core myopathy: deficient oxidative enzyme in the center of many fibers i. Nemaline myopathy: muscle fibers with thickened striations and aggregates of rod bodies j. Congenital fiber-type disproportions: increased number of small lightly stained type I fibers and reduced number of larger darkly stained type II fibers

Floppy Infant

8. Biochemical studies a. Muscle enzymes (creatine kinase) i. Rarely helpful in workup of a floppy infant ii. Elevated in: a) Congenital muscular dystrophies b) Some forms of congenital myopathies b. Inborn errors of metabolism screening i. Categories of biochemical defects a) Toxic encephalopathies b) Energy deficient encephalopathies c) Disorders affecting intracellular processing of complex molecules ii. Blood ammonia a) Urea cycle defects b) Organic acidemias c) Fatty acid oxidation disorders iii. Lactate (blood, urine, CSF) a) Carbohydrate metabolism disorders b) Mitochondrial disease iv. Blood and urine quantitative analysis of amino acids for aminoacidopathies v. Blood organic acid and acylcarnitine profiles using tandem mass spectrometry a) Organic acidemias b) Fatty acid oxidation defects vi. Plasma very long chain fatty acids (VLCFA) for peroxisomal disorders vii. Transferrin (low in glycosylation disorders) viii. Blood 7-dehydrocholesterol (elevated in Smith–Lemli–Opitz syndrome) 9. Cranial ultrasound or CT studies (Rumack 1985): to detect CNS lesions causing infantile hypotonia a. Hypoxic–ischemic encephalopathy i. Fetal or neonatal hypoxia ii. Sudden infant death syndrome iii. Infarction from other causes b. Neonatal intracranial hemorrhage i. Subependymal hemorrhage (premature infants) ii. Subarachnoid hemorrhage or atypical intracranial hemorrhage (term infants) c. Intracranial infection i. Prenatal a) Cytomegalovirus b) Toxoplasmosis c) Herpes d) Rubella ii. Neonatal and infant: bacterial

Floppy Infant

d. Trauma i. Subdural hematoma ii. Epidural hematoma iii. Parenchymal hemorrhage or edema 10. Cranial CT/MRI studies a. Structural malformations b. Altered signals i. White matter: Laminin deficiency ii. Basal ganglia: mitochondrial cytopathies iii. Brain stem and cerebellar abnormalities a) Joubert syndrome b) Pontocerebellar hypoplasia

Genetic Counseling 1. Recurrence risk: depends on underline etiology a. Patient’s sib i. Autosomal recessive (e.g., spinal muscular atrophy, congenital muscular dystrophy): 25% ii. Autosomal dominant (e.g., congenital myotonic dystrophy): not increased unless a parent is affected iii. X-linked recessive (e.g., severe infantile form of myotubular myopathy): 50% of male sibs affected if the mother is a carrier iv. Mitochondrial: All sibs are at risk of being affected if the mother has the mitochondrial DNA mutation v. Chromosomal: increased risk, especially a parent is a translocation carrier b. Patient’s offspring i. Autosomal recessive: not increased unless the spouse is also a carrier ii. Autosomal dominant: 50% iii. X-linked recessive: All daughters of affected males will be carriers. All sons of an affected male will be normal iv. Mitochondrial: a) Offspring of males with a mtDNA mutation are not at risk b) All offspring of females with a mtDNA mutation are at risk of inheriting the mutation c) A female harboring a heteroplasmic mtDNA point mutation may transmit a variable amount of mutant mtDNA to her offspring, resulting in considerable clinical variability among sibs within

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the same nuclear family (Poulton and Turnbull 2000; Chinnery 2006) v. Chromosomal: an increased risk 2. Prenatal diagnosis: not reported to date 3. Management (Pediatric Care Online 2008) a. Supportive treatment in most causes of hypotonia b. Multidisciplinary team approach for coordination of interventions c. Infantile progressive spinal muscular atrophy i. Physical therapy ii. Respiratory therapy iii. Nutritional support as needed iv. Scoliosis treatments: e.g., a) Body jacket b) Molded back support c) Surgery d) Motorized wheelchair for children with type II at approximately 2–3 years of age d. Peripheral nerve disorders: bracing for children with foot drop e. Neuromuscular junction disorders: hospitalization, with respiratory and nutritional support as needed i. Passively acquired autoimmune myasthenia gravis (transient neonatal myasthenia): give pyridostigmine until asymptomatic, then taper over 1–2 weeks ii. Acquired autoimmune myasthenia gravis ( juvenile myasthenia) a) Anticholinesterase drugs b) Immunosuppressive treatment c) Intravenous g-globulin d) Corticosteroids e) Thymectomy iii. Nonautoimmune myasthenic syndromes (congenital myasthenia gravis) a) Anticholinesterase inhibitors b) Corticosteroids c) Diaminopyridine (experimental) iv. Infantile botulism: antibotulism immune globulin may be therapeutic f. Myopathies i. Infantile form of myotonic dystrophy–type hypotonia a) Assisted ventilation as indicated b) Gastrostomy tube feedings as indicated

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ii. Glycogen storage disease: consider enzyme replacement therapy (prognosis dismal without such therapy)

References Bodensteiner, J. B. (2008). The evaluation of the hypotonic infant. Seminars in Pediatric Neurology, 15, 10–20. Brown, R. H., Grant, P. E., & Pierson, C. R. (2006). Case 35–2006; a newborn boy with hypotonia. The New England Journal of Medicine, 355, 2132–2142. Carboni, P., Pistani, F., Crescenzi, A., et al. (2002). Congenital hypotonia with favorable outcome. Pediatric Neurology, 26, 383–386. Chinnery, D. F. (2006). Mitochondrial disorders overview. GeneReviews. Updated February 21, 2006. Available at UTP: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? book¼gene&part¼mt-overview Darras, B. T., & Jones, H. R., Jr. (2000). Diagnosis of pediatric neuromuscular disorders in the era of DNA analysis. Pediatric Neurology, 23, 289–300. Dubowitz, V. (1985). Evaluation and differential diagnosis of the hypotonic infant. Pediatrics in Review, 6, 237–243. Harris, S. R. (2008). Congenital hypotonia: Clinical and developmental assessment [Review]. Developmental Medicine and Child Neurology, 50, 889–892. Howell, R. R., Byrne, B., Darras, B. T., et al. (2006). Diagnostic challenges for Pompe disease: An under-recognized cause of floppy baby syndrome. Genetics in Medicine, 8, 289–296. Igarash, M. (2004). Floppy infant syndrome (Review). Journal of Clinical & Neuromuscular Disorders, 6, 69–90. Jaradeh, S. S., & Ho, H. (2004). Muscle, nerve, and skin biopsy. Neurologic Clinics, 22, 539–561. Johnston, H. M. (2003). The floppy weak infant revisited. Brain & Development, 25, 155–158. Krajewski, K. M., & Shy, M. E. (2004). Genetic testing in neuromuscular disease. Neurologic Clinics, 22, 481–508. Paro-Panjan, D., & Neubauer, D. (2004). Congenital hypotonia: Is there an algorithm? Journal of Child Neurology, 10, 439–442.

Parush, S., Yehezhehel, I., Tenenbaum, A., et al. (1998). Developmental correlates of school-age children with a history of benign congenital hypotonia. Developmental Medicine and Child Neurology, 40, 448–452. Pediatric Care Online. (2008). Hypotonia. Updated July 25, 2008. Available at http://www.pediatriccareonline.org/pco/ub/view/ Point-of-Care-Quick-Reference/397087/all/hypotonia Poulton, J., Turnbull, D. M. (2000). 74th ENMC international workshop: mitochondrial diseases 19–20, November 1999. Naarden, the Netherlands. Neuromuscul Disordorders, 10, 460–462, 2000 Prasad, A. N., & Prasad, C. (2003). The floppy infant: Contribution of genetic and metabolic disorders. Brain & Development, 17, 457–476. Premasiri, M. K., & Lee, Y.-S. (2003). The myopathology of floppy and hypotonic infants in Singapore. Pathology, 35, 409–413. Richer, L. P., Shevell, M. I., & Miller, S. P. (2001). Diagnostic profile of neonatal hypotonia: An 11-year study. Pediatric Neurology, 25, 32–37. Riggs, J. E., Bodensteiner, J. B., & Schochet, S. S., Jr. (2003). Congenital myopathies/dystrophies. Neurologics Clinics of North America, 21, 779–794. Rumack, C. M. (1985). Diagnostic value of ultrasonic and computed tomographic imaging in infants with hypotonia. Pediatrics in Review, 6, 282–286. Shuper, A., Wietz, R., Varsano, I., et al. (1987). Benign congenital hypotonia. A clinical study in 43 children. European Journal of Pediatrics, 146, 360–362. Simon, D. K., & Johns, D. R. (1999). Mitochondrial disorders: Clinical and genetic features. Annual Review of Medicine, 50, 111–127. Stiefel, L. (1996). Hypotonia in infants. Pediatrics in Review, 17, 104–105. Taratuto, A. L. (2002). Congenital myopathies and related disorders. Current Opinion in Neurology, 15, 553–561. Tubridy, N., Fontaine, B., & Eymard, B. (2001). Congenital myopathies and congenital muscular dystrophies. Current Opinion in Neurology, 14, 575–582. Zand, D. J., & Zackai, E. H. (2004). Cytogenetic and molecular diagnoses of hypotonia in the newborn. NeoReviews, 5, e296–e300.

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a

Fig. 1 (a–b) An infant boy with hypotonia

Fig. 2 The same boy with hypotonia at 6 years of age

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860 Fig. 3 (a–b) Hypotonia associated with cerebellum and optic nerve hypoplasia in an infant at 9 months of age

Fig. 4 (a–c) Hypotonia associated with Down syndrome in an infant

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a

b

a

b

c

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Fig. 5 (a–b) Hypotonia associated with Prader–Willi syndrome in a 7-month-old boy

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Fig. 6 (a–b) Hypotonia associated with dysmorphic facies (ocular hypertelorism, slightly upslanted palpebral fissures, bulbous nose, micro/retrognathia, and small ears) secondary to microdeletion of 15q demonstrated by chromosome microarray analysis [arr cgh l5q11.2q13.1 n19,623,685 ! 26,605,469)  1]. Regular chromosome analysis was normal

a

b

b

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a

b

Fig. 7 A 28-month-old infant with metachromatic leukodystrophy with hypotonia

Fig. 8 (a–b) “Congenital benign hypotonia” in a 7-month-old infant

Fragile X Syndrome

Fragile X syndrome is the most common form of heritable mental retardation affecting approximately 1 in 1,250 males and 1 in 2,000 females (Webb 1989). The prevalence appears to be 1 in 4,000–6,000 males and 1 in 8,000–10,000 females. Martin and Bell first documented X-linked mental retardation in 1943. Subsequent identification of a fragile site on the long arm of the X chromosome (Lubs 1969), discovery of cell culture medium-dependent fragile site, and recognition of a unique constellation of physical features served to distinguish fragile X syndrome from other X-linked mental retardation syndromes. In Verkerk et al. (1991) identified a single gene that was associated with symptoms of the disorder. The gene, known as fragile X mental retardation gene 1 (FMR1), exhibited a novel form of mutation, a sequence of three nucleotides (CGG) that was repeated many times in patients with fragile X syndrome.

Synonyms and Related Disorders Fragile X mental retardation syndrome; Marker X syndrome; Martin-Bell syndrome; X-linked mental retardation and macroorchidism

Genetics/Basic Defects 1. Inheritance not conforming to usual rules governing X-linked traits a. Presence of asymptomatic transmitting males b. Presence of affected female carriers who inherited the gene

2. Caused by mutations in a trinucleotide (CGG)n repeat found in the coding region of the FMR1 gene, mapped to Xq27.3 a. Expanded CGG repeats >200 (full mutation): associated with fragile X syndrome. b. High repeat number (full mutation) leads to hypermethylation of an upstream promoter region and subsequent silencing (inactivating) of the FMR1 gene. c. A small expansion (premutation) with approximately 50–200 CGG repeats: usually not associated with cognitive deficits. d. Expansion to a full mutation from the premutation in normal carriers occurs only when it is transmitted by a female. e. Presence of anticipation phenomenon. 3. The Sherman paradox (Laxova 1994) a. A perplexing and confusing fragile X pedigree pattern was discovered during mid-1980s by Sherman et al. who discovered the large discrepancy in risks for mental retardation within fragile X families containing transmitting males. This phenomenon was termed the “Sherman paradox” by Opitz (1986). i. 20% of males within fragile X families who carried the mutation are unaffected clinically and intellectually and became known as transmitting males. ii. An increasing risk of mental retardation in grandsons of normal transmitting males: a special form of genetic anticipation (the increase in disease severity through successive generations). iii. About a third of obligate carrier females are mentally impaired.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_96, # Springer Science+Business Media, LLC 2012

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iv. More than half of known carrier females are either mildly impaired or expressed the fragile site on one of their X chromosomes. b. Possible explanations of the Sherman paradox. i. An unaffected transmitting male who inherits a premutation from his unaffected carrier mother, who has 50–200 repeats but probably a number closer to the lower end of the premutation range. ii. Offspring of a carrier mother with the number of repeats still within the premutation range, even if amplification occurs during oogenesis. iii. Transmission of the premutation to the daughters by the transmitting male. No amplification has occurred during spermatogenesis; hence, the daughters also have a premutation and are unaffected. iv. Amplification to more than 200 repeats occurs during oogenesis of the transmitting male’s daughters whose sons will receive a ull mutation and be affected and their daughters may or may not be affected. 4. Genotypic–phenotypic correlations (Kaufmann and Reiss 1999) a. Fragile X full mutation and mental retardation with a wide spectrum of phenotypic effects in both sexes i. Mental retardation in 100% of males ii. Usually a milder form of retardation in 60% of females b. Large CGG amplification i. Associated with hypermethylation ii. Almost invariably correlated with the most severe fragile X phenotype iii. Seen in males with the full mutation pattern c. Premutation expansions that are not usually accompanied by methylation: minimal or no neurologic repercussion d. Correlation of methylation in FMR1 expression and cognitive function i. Individuals with full mutation without methylation scored better than those with full mutation and complete methylation ii. Individuals with full mutation and partial methylation showed intermediate values

Fragile X Syndrome

e. Presence of the FMR1 protein (FMRP) responsible for: i. Lack of neurologic abnormalities in individuals with premutation ii. Milder phenotype of males having full mutation without full methylation 5. Pathogenesis a. A consequence of the absence or deficit of the FMRP b. Absence of FMRP in the brain: the likely cause of mental retardation in patients with fragile X syndrome

Clinical Features 1. Affected males (Hagerman and Cronister 1996) a. CNS involvement i. Delayed developmental milestones ii. Mild to severe mental retardation iii. Difficulty with abstract thinking, sequential processing, mathematics, short-term memory, and visual motor coordination iv. Seizures b. Connective tissue dysplasia i. Hyperextensible finger joints ii. Double-jointed thumbs iii. Flat feet iv. High-arched palate v. Mitral valve prolapse (55%, diagnosed by echocardiography) vi. Dilatation of the ascending aorta vii. Inguinal hernia viii. Soft and velvet-like skin c. Typical facial features i. Long face ii. Prominent forehead iii. Prominent/long ears iv. Prominent jaw d. Other features i. Macroorchidism present in over 80% of adult fra(X) males ii. Pectus excavatum iii. Scoliosis iv. Strabismus v. Recurrent otitis media in early childhood vi. Reproduction documented but rare because of significant mental retardation

Fragile X Syndrome

e. Behavior abnormalities i. Stereotyped with odd mannerisms (hand flapping/biting) ii. Tactile defensiveness iii. Poor eye contact (excessive shyness) iv. Attention-deficit/hyperactivity disorder a) Hyperactivity b) Temper tantrums c) Distractibility d) Mood lability v. Speech disorder a) Perseveration b) Litany speech c) Echolalia vi. Autism vii. Autistic-like features viii. Schizotypal personality disorder ix. Anxiety disorder 2. Females heterozygous for full mutation alleles a. Fifty percentage with cognitive deficits with learning disabilities, borderline IQ, or mental retardation b. Fifty percentage with normal intellectual function 3. Females heterozygous for premutation alleles (carriers) at risk for premature ovarian failure (early onset of menopause before age 40 years) (FMR1-related premature ovarian failure 4. Fragile X-associated tremor/ataxia syndrome (FXTAS) (Saul and Tarleton 2010) a. A definite diagnosis based on the following three observations i. Presence of FMR1 premutation ii. White matter lesions on MRI in the middle cerebellar peduncles and/or brain stem (the major neuroradiologic sign) iii. Presence of two major clinical signs a) Intention tremor b) Gait ataxia b. Other minor clinical criteria i. Parkinsonism ii. Moderate to severe working memory deficits iii. Executive cognitive function deficits c. A probable diagnosis: requires either one major neuroradiologic sign and one minor clinical sign or two major clinical signs d. A possible diagnosis: based on one minor neuroradiologic sign and one major clinical sign

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Diagnostic Investigations 1. Pedigree analysis 2. Karyotyping of cells grown in folate- or thymidinedepleted cell culture media a. A “fragile” site on one of the X chromosomes (Xq27.3) that appeared as a constriction on the distal long arm in many patients b. Cells exhibiting fragile X chromosome: 5–50% c. Cytogenetic studies now rendered obsolete by direct DNA testing 3. Indications for molecular genetic testing (Park et al. 1994) a. Individuals of either sex with mental retardation, developmental delay, or autism i. Any physical or behavioral characteristics of fragile X syndrome ii. A family history of fragile X syndrome iii. Male or female relatives with undiagnosed mental retardation b. Individuals seeking reproductive counseling who have a family history of fragile X syndrome or undiagnosed mental retardation c. Fetus of a known carrier mother d. Patients with cytogenetic fragile X test result discordant with phenotype i. Patients with a strong clinical impression of being affected with or carrier of fragile X syndrome but had a negative or ambiguous cytogenetic test result ii. Patients with an atypical phenotype of fragile X syndrome but had a positive cytogenetic test result 4. Direct DNA analysis for point mutation or deletion in FMR1 gene. Mutation analysis to determine the CGG repeat size by Southern blot hybridization and polymerase chain reaction (PCR): mutation detection rate >99% (commercially available) 5. Methylation analysis by Southern blot analysis to determine the FMR1 methylation status 6. Types of FMR1 repeat expansion mutations (Tarleton and Saul 1993; Saul and Tarleton 2010) a. Normal alleles: 5–40 CGG repeats i. Stably transmitted without any increase or decrease in repeat number

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Fragile X Syndrome

ii. In stable normal alleles, the CGG region is interrupted by an AGG triplet after every nine or ten CGG repeats. These AGG triplets are believed to maintain repeat integrity by preventing DNA strand slippage during replication iii. Normal alleles with more than 35 CGG repeats are associated with increased risk of FMR1-related premature ovarian failure Mutable normal alleles (intermediate alleles, also termed “gray zone”): broadly defined as 41–58 repeats (no consensus exists regarding the precise size) Premutation alleles i. 59–200 CGG repeats ii. Methylation status of FMR1: Premutation alleles are usually unmethylated and FMRP production is normal iii. Therefore, individuals (males or females) with permutation are clinically unaffected iv. Do convey increased risk for FXTAS and POF, because of: a) Potential repeat instability upon transmission of premutation alleles b) Women with alleles in this range are considered to be at risk of having children affected with fragile X syndrome Full mutation alleles i. >200 CGG (several hundreds to several thousands) repeats. Expansion of the repeat more than 200 generally results in hypermethylation of both the CpG island and the CGG repeat within the FMR1 gene ii. Methylation status of FMR1: completely methylated iii. Males: affected iv. Females: affected in about 50% of cases; unaffected in about 50% of cases Mosaicism i. Number of CGG repeats varies between premutation and full mutation in different cell lines. ii. Methylation status of FMR1: partially methylated (unmethylated in the premutation cell line and methylated in the full mutation cell line)

iii. Males: affected but may function higher than individuals with full mutation iv. Females: highly variable clinical expression ranging from normal intellect to affected f. Methylation mosaicism i. Number of CGG repeats >200 ii. Methylation status of FMR1 gene: partially methylated (mixture of methylated and unmethylated cell lines) iii. Males: affected but may function higher than individuals with full mutation iv. Females: highly variable clinical expression ranging from normal intellect to affected g. Unmethylated full mutation i. Number of CGG repeats >200 ii. Methylation status of FMR1 gene: unmethylated iii. Males: Nearly all are affected but may have high functioning mental retardation to low normal intellect iv. Females: highly variable clinical expression ranging from normal intellect to affected 7. Immunocytochemical tests based on the direct detection of FMRP using monospecific antibodies. This FMRP detection assay is based on the presence of FMRP in cells from unaffected individuals and its absence in cells from patients with fragile X syndrome. This assay is proven to be a reliable alternative method to identify male patients with fragile X syndrome. The new test on hair roots is suitable for use in large screening programs among males. The immunocytochemical tests can also be used in patients with mosaic pattern, affected premutation males, and intragenic mutations 8. Molecular genetic testing a. Targeted mutation analysis i. PCR analysis ii. Southern blot analysis b. Methylation status c. Sequence analysis d. Deletion/duplication analysis e. FISH analysis f. X-chromosome inactivation

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Genetic Counseling 1. Recurrence risk: Adequate genetic counseling depends on accurate diagnosis at the molecular level a. Individuals identified as noncarriers: The zero risk of transmitting fragile X syndrome to the next generation. b. Individuals identified as carriers: The risk of having children with fragile X syndrome depending on the sex of the carrier parent, the sex of the child, and the size of the CGG repeats. i. Premutation carrier males: considered “transmitting males.” All daughters of transmitting males are unaffected premutation carriers. However, the grandsons and granddaughters of a transmitting male are at risk for developing fragile X syndrome. ii. All mothers of a child with FMR1 full mutation (expansion >200 CGG trinucleotide repeats), considered carriers of an FMR1 gene expansion (either full mutation or premutation and may be affected). iii. Females with premutation: an increased risk of passing on the full mutation and having offspring with the fragile X phenotype (the fragile X premutation can expand to the full mutation during maternal meiosis). iv. Carrier males who may reproduce: essentially zero risk of having male offspring with fragile X syndrome, since all their sons receive their Y chromosome [except in the rare instance of the fragile X chromosome coming into the family from the other source (mother)]. All the daughters of male carriers will have premutations regardless of the size of paternal amplifications and will not have fragile X syndrome. Only a few reports with premutation males have full mutation daughters. c. Females with full mutation: Her offspring, if they inherit the fragile X locus, all will have full mutation. i. All her sons will have fragile X syndrome.

2.

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ii. About 50–60% of her daughters will have fragile X syndrome, exceeding the 35% applicable to all female carriers of the fragile X chromosome. Affected females generally have less severe intellectual disability than found in affected males. d. Males with full mutations. i. Mentally retarded ii. Generally do not reproduce Risks to pregnant women with an expanded FMR1 gene a. A repeat size of 40–59: safe (0% risk) with no fetal full mutations b. A repeat size of 60–80: low risk (14%) of full mutation in the fetus c. A repeat size of over 80–100: a significant increase in risk (89%) of developing full mutation in the fetus d. A repeat size of 100–200: 100% risk of developing full mutation in the fetus Prenatal diagnosis by amniocentesis or CVS a. Available to at-risk pregnancies: requires prior confirmation of the presence of an expanded (or altered) FMR1 allele in the family b. Prenatal diagnosis using direct DNA analysis to women discovered to be premutation carriers c. The limitation: inability to accurately predict phenotype in female fetuses with full mutation d. CVS: follow-up amniocentesis or testing using PCR, necessary to determine the size of the FMR1 alleles in a methylation-independent manner Preimplantation genetic diagnosis: available to atrisk pregnancies in which prior confirmation of the presence of an expanded (or altered) FMR1 allele was identified in the family Management a. Early intervention programs for developmental delay including speech and language therapies, physical therapy, and occupational therapy b. Behavioral interventions including psychopharmacological therapy c. Special educations d. Vocational planning e. Anticonvulsants for seizure control

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f. Prophylactic antibiotics for surgical or dental procedures in patients with mitral valve prolapse g. Orthopedic care for joint dislocations, flat feet, and scoliosis

References American Academy of Pediatrics. (1996). Health supervision for children with fragile X syndrome. Pediatrics, 98, 297–300. Bardoni, B., Mandel, J. L., & Fisch, G. S. (2000). FMR1 gene and fragile X syndrome. American Journal of Medical Genetics (Seminars in Medical Genetics), 97, 153–163. Brown, W. T. (1990). The fragile X: Progress toward solving the puzzle. American Journal of Human Genetics, 47, 175–180. Brown, W. T. (1995). Perspectives and molecular diagnosis of the fragile X syndrome. Clinics in Laboratory Medicine, 15, 859–875. Caskey, C. T. (1994). Fragile X syndrome: Improving understanding and diagnosis. Journal of the American Medical Association, 271, 552–553. Caskey, C. T., Pizzuti, A., Fu, Y.-H., et al. (1992). Triplet repeat mutations in human disease. Science, 256, 784–789. Crawford, D. C., Acuna, J. M., & Sherman, S. L. (2001). FMR1 and the fragile X syndrome: Human genome epidemiology review. Genetics in Medicine, 3, 359–371. Das, S., Kubota, T., Song, M., et al. (1997). Methylation analysis of the fragile X syndrome by PCR. Genetic Testing, 1, 151–155. Davids, J. R., Hagerman, R. J., & Eilert, R. E. (1990). Orthopaedic aspects of fragile-X syndrome. Journal of Bone and Joint Surgery (America), 72, 889–896. De Boulle, K., Verkerk, A. J. M. H., Reyniers, E., et al. (1993). A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genetics, 3, 31–35. De Vries, B. B., Halley, D. J., Oostra, B. A., et al. (1998). The fragile X syndrome. Journal of Medical Genetics, 35, 579–589. Dyer-Friedman, J., Glaser, B., & Hessl, D. (2002). Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 237–244. Dykens, E. M., Hodapp, R. M., & Leckman, J. F. (1994). Behavior and development in Fragile X syndrome. Thousand Oaks: Sage. Feng, Y., Lakkis, D., & Warren, S. T. (1995). Quantitative comparison of FMR1 gene expression in normal and permutation alleles. American Journal of Human Genetics, 56, 106–113. Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., et al. (1991). Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell, 67, 1047–1058. Goldson, E., & Hagerman, R. J. (1992). The fragile X syndrome. Developmental Medicine and Child Neurology, 34, 822–832. Hagerman, R. J. (2001). Fragile X syndrome. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. New York: Wiley-Liss.

Fragile X Syndrome Hagerman, R. J., Amiri, K., & Cronister, A. (1991). Fragile X checklist. American Journal of Medical Genetics, 38, 283–287. Hagerman, R. J., & Cronister, A. (Eds.). (1996). Fragile X syndrome: Diagnosis, Treatment, and Research. Baltimore: Johns Hopkins University Press. Hagerman, R. J., Hull, C. E., Safanda, J. F., et al. (1994). High functioning fragile X males: Demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. American Journal of Medical Genetics, 51, 298–308. Hagerman, R. J., Jackson, C., Amiri, K., et al. (1992). Girls with fragile X syndrome: Physical and neurocognitive status and outcome. Pediatrics, 89, 395–400. Hagerman, R. J., Kimbro, L. T., & Taylor, A. K. (1998). Fragile X syndrome: A common cause of mental retardation and premature menopause. Contemporary OB/GYN, 43, 47–70. Hagerman, R. J., & Silverman, A. C. (1991). Fragile X syndrome. Diagnosis, treatment, and research. Baltimore: Johns Hopkins University Press. Hansen, R. S., Gartler, S. M., Scott, C. R., et al. (1992). Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Human Molecular Genetics, 1, 571–578. Holden, J. J. A., Percy, M., Allingham-Hawkins, D., et al. (1999). Eighth international workshop on the fragile X syndrome and X-linked mental retardation. American Journal of Medical Genetics, 83, 221–236. August 16–22, 1997. Kallinen, J., Heinonen, S., Mannermaa, A., et al. (2000). Prenatal diagnosis of fragile X syndrome and the risk of expansion of a permutation. Clinical Genetics, 58, 111–115. Kau, A. S. M., Meyer, W. A., & Kaufmann, W. E. (2002). Early development in males with fragile X syndrome: A review of the literature. Microscopy Research and Technique, 57, 174–178. Kaufmann, W. E., & Reiss, A. L. (1999). Molecular and cellular genetics of fragile X syndrome. American Journal of Medical Genetics, 88, 11–24. Kenneson, A., & Warren, S. T. (2001). The female and the fragile X reviewed. Seminars in Reproductive Medicine, 19, 159–165. Laxova, R. (1994). Fragile X syndrome. Advances in Pediatrics, 41, 305–342. Lubs, H. A. (1969). A marker X chromosome. American Journal of Human Genetics, 21, 231–244. Mulley, J. C., & Sutherland, G. R. (1994). Diagnosis of fragile X syndrome. Fetal and Maternal Medicine Review, 6, 1–15. Naber, S. P. (1995). Molecular diagnosis of fragile X syndrome. Diagnostic Molecular Pathology, 4, 158–161. Nelson, D. L. (1993). Fragile X syndrome: Review and current status. Growth Genetics Hormone, 9, 1–4. Nolin, S. L., Brown, W. T., Glicksman, A., et al. (2003). Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. American Journal of Human Genetics, 72, 454–464. Noline, S. L., Lewis, F. A., II, Ye, L. L., et al. (1996). Familial transmission of the FMR1 CGG repeat. American Journal of Human Genetics, 59, 1252–1261. Oostra, B. A., Jacky, P. B., Brown, W. T., et al. (1993). Guidelines for the diagnosis of fragile X syndrome. Journal of Medical Genetics, 30, 410–413.

Fragile X Syndrome Oostra, B. A., & Willemsen, R. (2001). Diagnostic tests for fragile X syndrome. Expert Review of Molecular Diagnostics, 1, 226–232. Opitz, J. M. (1986). On the gates of hell and a most unusual gene (editorial). American Journal of Medical Genetics, 23, 1–10. Park, V., Howard-Peebles, P., Sherman, S., et al. (1994). Fragile X syndrome: Diagnostic and carrier testing. American Journal of Medical Genetics, 53, 380–381. Rousseau, F., Heitz, D., Biancalana, V., et al. (1991). Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. The New England Journal of Medicine, 325, 1673–1681. Saul, R. A., Tarleton, J. C. (2010). FMR1-related disorders. GeneReviews. Updated May 18, 2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼ gene&part¼fragilex Sherman, S. L., Jacobs, P. A., Morton, N. E., et al. (1985). Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Human Genetics, 69, 289–299. Sherman, S. L., Morton, N. E., Jacobs, P. A., et al. (1984). The marker (X) syndrome: A cytogenetic and genetic analysis. Annals of Human Genetics, 48, 21–37. Simensen, R. J., & Rogers, R. C. (1989). Fragile-X syndrome. American Family Physician, 39, 185–193. Sutherland, G. R. (1979). Heritable fragile sites on human chromosomes. I. Factors affecting expression in lymphocyte culture. American Journal of Human Genetics, 31, 125–135. Sutherland, G. R., Brown, W. T., Hagerman, R., et al. (1994). Sixth international workshop on the fragile X and X-linked

869 mental retardation. American Journal of Medical Genetics, 51, 281–293. Sutherland, G. R., Gecz, J., & Mulley, J. C. (2002). Fragile X syndrome and other causes of X-linked mental handicap. In D. L. Rimoin, J. M. Connor, R. E. Pyeritz, & B. R. Korf (Eds.), Principles and practice of medical genetics (4th ed., pp. 2801–2826). New York: Long Churchill Livingstone. Tarleton, J. C., & Saul, R. A. (1993). Molecular genetic advances in fragile X syndrome. Journal of Pediatrics, 122, 169–185. Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., et al. (1991). Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65, 905–914. Warren, S. T., & Nelson, D. L. (1994). Advances in molecular analysis of fragile X syndrome. Journal of the American Medical Association, 271, 536–542. Warren, S. T., & Sherman, S. L. (2001). The fragile X syndrome. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic and molecular bases of inherited disease (8th ed., pp. 1257–1289). New York: McGraw-Hill. Chapter 179. Webb, T. (1989). The epidemiology of the Fragile X syndrome. In K. E. Davis (Ed.), The Fragile X syndrome (pp. 40–55). Oxford: Oxford University Press. Willemsen, R., Oosterwijk, J. C., Los, F. J., et al. (1997). Prenatal diagnosis of fragile X syndrome. Lancet, 348, 967–968. Willemsen, R., & Oostra, B. A. (2000). FMRP detection assay for the diagnosis of the fragile X syndrome. American Journal of Medical Genetics (Seminars in Medical Genetics), 97, 183–188.

870 Fig. 1 Two brothers with fragile X syndrome showing large ears, accompanied by their mother

Fig. 2 A pair of brothers with fragile X syndrome showing a long face with large ears

Fragile X Syndrome

Fragile X Syndrome Fig. 3 Another pair of male siblings with fragile X syndrome

Fig. 4 A chromosome spread showing a fragile X chromosome (arrow)

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a

b

Fragile X Syndrome

c

d

Fig. 5 A large family affected by fragile X syndrome. The first boy (a, age 15) is the most affected one with CGG repeats of >1,500. He was not toilet trained until age 5 or 6 years. He never spoke until after auditory training. He may watch TV for 6–8 h straight and get agitated if someone approaches him. The brother (b, age 10) and sister (c, age 16) have CGG repeats of 1,200 and 600 respectively. Another sister (d) is a carrier with CGG repeats of 110 who has four children. The daughter (age 3, the first one

from the left) has CGG repeats of 700. She has a long face with prominent ears, a high-arched palate, and flat feet. She suffers from hyperactivity, tactile/oral/olfactory defensiveness, gaze aversion, poor postural alignment, food cramming, hand biting, excessive drooling, poor self-regulation, and speech difficulties including echolalia. The other three children are normal with normal CGG repeats. The maternal grandmother has CGG repeats of 126

Fragile X Syndrome

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Fig. 7 A 46-year-old male with methylation mosaic fragile X syndrome (mixture of methylated full mutation allele of approximately 450 repeats in some cells and unmethylated premutation size allele of approximately 200 repeats in some cells). He is tall and has mental retardation, a long narrow face, slightly large ears, and macroorchidism Fig. 6 A 66-year-old male with fragile X syndrome. The patient has mental retardation, a long face with large ears, and macroorchidism. Molecular analysis revealed CGG repeats of about 400

Fraser Syndrome

Fraser syndrome is a malformation syndrome characterized by cryptophthalmos (“hidden eye,” a term coined by Zehender et al. 1872), cutaneous syndactyly, and anomalies of the genitourinary system. It was first described by Fraser in 1962. It is also known as cryptophthalmos-syndactyly syndrome, cryptophthalmos syndrome, or Fraser cryptophthalmos syndrome. Fraser syndrome occurs with a minimal estimated frequency of 0.43 per 100,000 liveborn infants and 11.06 per 1,000,000 stillbirths (Martı´nezFrı´as et al. 1998).

Synonyms and Related Disorders Cryptophthalmos with other malformations; Cryptophthalmos-syndactyly syndrome

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. Caused by mutations in FRAS1 and FRAS1related extracellular matrix protein 2 (FREM2) genes a. FRAS1 gene, encoding a putative extracellular matrix (ECM) protein, located on the long arm of chromosome 4 (4q21) b. FREM2 gene located on the long arm of chromosome 13 (13q13.3) 3. Genotype–phenotype correlations (van Haelst et al. 2008) a. Patients with an FRAS1 mutation i. More frequently skull ossification defects ii. Low insertion of the umbilical cord

b. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for Fraser syndrome as well 4. Familial cases (56%) a. Presence of consanguinity, estimated to be as high as 15% b. Multiple affected sibs born to the same parents (Slavotinek and Tifft 2002; Singh et al. 2007) 5. Three forms of cryptophthalmos, classified based on ophthalmic findings (Francois 1969) a. Complete (typical) cryptophthalmos i. The eyelids replaced by a sheet of skin running from forehead to cheek with absence or poor development of the eyebrow ii. Absence of the eyelashes or the gland structures iii. The elevated skin covering the globe moves when eye movements occur iv. The skin adherent to the underlying cornea v. Absence of the conjunctival sac vi. Microphthalmia usually present vii. Often associated with numerous congenital abnormalities, including anomalies of the head, ears, nose and genitalia, and syndactyly. This pattern of anomalies is termed Fraser syndrome (Ferri and Harvey 1999) b. Incomplete (atypical) cryptophthalmos i. Presence of rudimentary eyelids ii. Lateral placement of a small conjunctival sac iii. The palpebral aperture about one-third of normal length iv. Usually small globe, covered almost completely by the skin

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_97, # Springer Science+Business Media, LLC 2012

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c. Abortive form or congenital symblepharon i. The upper eyelids, without a defined margin, covers and adherent to up to 75% of the upper cornea ii. Absence of punctum in the eyelid iii. Absence of the upper conjunctival fornix iv. Free part of the cornea often keratinized or opaque v. Globes: usually normal or small size 6. Pathogenesis (Ferri and Harvey 1999) a. Primary failure of differentiation during embryogenesis b. Compression of the amniochorionic band c. Intrauterine inflammation d. Failure of lid fold development e. Inactivation of glutamate receptor interacting protein 1 (GRIP1), a cytoplasmic multi-PDZ scaffolding protein, leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly, and permanent fusion of eyelids (cryptophthalmos), Fraser syndrome-like defects in mice (Takamiya et al. 2004)

Fraser Syndrome

5.

6.

7. 8. 9.

10.

Clinical Features 1. Intrafamilial clinical heterogeneity (Chattopadhyay et al. 1993; Slavotinek and Tifft 2002) 2. Eyes a. Cryptophthalmos (a developmental anomaly in which the skin is continuous over the eyeballs without any indication of the formation of eyelids): the most common feature of Fraser syndrome (84–93%) i. Bilateral (more common) or unilateral ii. Total or partial b. Microphthalmia c. Absent or malformed lacrimal ducts d. Ocular hypertelorism e. Coloboma of the upper eyelid f. Supernumerary eyebrows g. Blindness 3. Head: unusually low lateral hairline on temples extending to lateral eyebrow 4. Nose a. Hypoplastic and notched nares b. Broad nasal bridge

11.

12.

c. Midline nasal cleavage d. Choanal atresia Mouth a. Cleft lip b. Cleft palate c. High-arched palate d. Crowding of the teeth Ears a. Malformation of middle and external ears (cup shaped and low set) b. Microtia c. Low-set ears d. Absent pinna e. Skin of the upper helix contiguous with scalp f. Conductive hearing loss Laryngeal stenosis/atresia Chest: widely spaced nipples Lungs a. Lung hyperplasia (Stevens et al. 1994) b. Lung hypoplasia Cardiac anomalies (Thapa and Bhattachakya 2008) a. Hypertrophy of the left ventricle b. A variant of Ebstein anomaly c. Coarctation of the aorta d. Atrial septal defect e. Interventricular communication f. Truncus arteriosus g. Ventricular septal defect h. Complex heart disease i. PDA j. Patent foramen ovale k. Dextrocardia l. Transposition of the great vessels m. Partial anomalous pulmonary venous connection Gastrointestinal anomalies (Slavotinek and Tifft 2002) a. Imperforate anus b. Anal atresia and anal stenosis c. Rectal atresia d. Displaced anus e. Umbilical hernia f. Intestinal malrotation g. Colonic atresia Urogenital anomalies a. Renal agenesis/hypoplasia i. Unilateral ii. Bilateral iii. Hypoplastic bladder

Fraser Syndrome

13. 14.

15.

16.

17.

b. Male genital anomalies i. Small penis ii. Hypospadias iii. Cryptorchidism c. Female genital anomalies i. Bicornuate uterus ii. Hypoplastic uterus iii. Vaginal atresia iv. Hypoplastic labia majora v. Clitoral enlargement Limbs: syndactyly of the fingers (cutaneous in 54% of cases) and toes CNS involvement a. Mental retardation b. Microcephaly c. Meningomyelocele d. Encephalocele Natural history a. Stillborn: 25% of affected infants b. Additional 20% of affected infants die before 1 year of age c. Survival to 96 years of age reported (Impallomeni et al. 2006) d. Commonest causes of death i. CNS malformations ii. Laryngeal stenosis or atresia iii. Respiratory insufficiency iv. Obstructive uropathy or bilateral renal agenesis Diagnostic criteria (Thomas et al. 1986): requires at least two major and one minor, or one major and four minor criteria for the diagnosis a. Major criteria i. Cryptophthalmos ii. Syndactyly iii. Abnormal genitalia iv. Sib with Fraser syndrome b. Minor criteria i. Congenital malformation of nose ii. Congenital malformation of ears iii. Congenital malformation of larynx iv. Cleft lip/palate v. Skeletal defects vi. Umbilical hernia vii. Renal agenesis viii. Mental retardation Revised diagnostic criteria for Fraser syndrome (van Haelst et al. 2007): requires either three

877

major, or two major and two minor, or one major and three minor diagnostic criteria present in a patient a. Major criteria i. Syndactyly ii. Cryptophthalmos spectrum iii. Urinary tract abnormalities iv. Ambiguous genitalia v. Laryngeal and tracheal anomalies vi. Positive family history b. Minor criteria i. Anorectal defects ii. Dysplastic ears iii. Skull ossification defects iv. Umbilical abnormalities v. Nasal anomalies

Diagnostic Investigations 1. Radiography a. Poor ossification of the calvarium b. Orbital structures c. Pulmonary hypoplasia d. Diastasis of the symphysis pubis e. Syndactyly 2. Renal ultrasound for renal anomalies 3. Hearing test 4. Molecular genetic testing (van Haelst et al. 2008; Shafeghati et al. 2008) a. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases b. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation

Genetic Counseling 1. Recurrence risk a. Patient’s sibs: 25% b. Patient’s offspring: recurrence risk not increased unless the spouse is a carrier or affected 2. Prenatal diagnosis a. Prenatal diagnosis made in the follow-up of a pregnancy with a previous sibling having had the same syndrome (Feldman et al. 1985; Ramsing et al. 1990; Schauer et al. 1990; Fryns

878

et al. 1997; Berg et al. 2001; Rousseau et al. 2002; Vijayaraghavan et al. 2005) b. Prenatal diagnosis made in families with a negative history (Boyd et al. 1988; Serville et al. 1989; Maruotti et al. 2004) c. Prenatal ultrasonography i. Major findings a) Microphthalmia b) Syndactyly c) Ambiguous genitalia ii. Other findings a) Oligohydramnios b) Ear defects c) Renal abnormalities d) Uropathy e) Hyperechogenic lungs f) Laryngeal stenosis/atresia g) Ascites h) Intrauterine growth retardation i) Polyhydramnios d. Fetoscopy (Kabra et al. 2000) 3. Management a. Immediate ocular management: frequent use of artificial tears to maintain corneal luster and clarity (Dinno et al. 1974) b. Intubation or tracheotomy to provide an adequate airway when laryngeal atresia/stenosis is present. Final repair of the laryngeal stenosis is deferred until about 1–2 years of age when adequate thyroid cartilage development has occurred (Karas and Respler 1995) c. Surgical correction of associated anomalies d. Goals of reconstruction, considering the poor probability of restoring visual function (Ferri and Harvey 1999) i. To protect the cornea (if present) from infection and ulceration ii. To enhance cosmetic appearance iii. To preserve the globe e. Surgical treatment at a later age (Dibben et al. 1997) i. Reconstruction in partial cryptophthalmos a) Dissection of the eyelids from the cornea b) Reconstruction of the conjunctival fornices with buccal mucosa c) Repair the upper lid coloboma in a flap reconstruction using the inferior eyelid margin

Fraser Syndrome

ii. Reconstruction without grafting in complete cryptophthalmos (Ferri and Harvey 1999) f. Surgical strategy for correction of cryptophthalmos (Saleh et al. 2009) i. The main indication for early surgery: presence or risk of corneal exposure in eyes with visual potential, as may occur in abortive cryptophthalmos ii. Surgery deferred for painless eyes with no potential for vision and where there is a low risk of corneal exposure. These include: a) Complete cryptophthalmos b) Incomplete cryptophthalmos with completely keratinized corneas c) Patients without corneal exposure

References Andiran, F., Tanyel, F. C., & Hicsonmez, A. (1999). Fraser syndrome associated with anterior urethral atresia. American Journal of Medical Genetics, 82, 359–361. Azevedo, E. S., Biondi, J., & Ramalho, M. (1973). Cryptophthalmos in two families from Bahia, Brazil. Journal of Medical Genetics, 10, 389–392. Balci, S. (1999). Laryngeal atresia presenting as fetal Ascites, oligohydramnios and lung appearance mimicking cystic adenomatoid malformation in a 25-week-old fetus with Fraser syndrome. Prenatal Diagnosis, 19, 856–858. Berg, C., Geipel, A., Germer, U., et al. (2001). Prenatal detection of Fraser syndrome without cryptophthalmos: Case report and review of the literature. Ultrasound in Obstetrics & Gynecology, 18, 76–80. Bialer, M. G., & Wilson, W. G. (1988). Syndromic cryptophthalmos. American Journal of Medical Genetics, 30, 835–837. Bieber, F. R., Page, D. V., & Holmes, L. B. (1982). Variation in the expression of the cryptophthalmia syndrome. American Journal of Human Genetics, 34, 812. Boyd, P. A., Keeling, J. W., & Lindenbaum, R. H. (1988). Fraser syndrome (cryptophthalmos-syndactyly syndrome): A review of eleven cases with postmortem findings. American Journal of Medical Genetics, 31, 159–168. Brazier, D. J., Hardman-Lea, S. J., & Collin, J. R. O. (1986). Cryptophthalmos: Surgical treatment of the congenital Symblepharon variant. British Journal of Ophthalmology, 70, 391–395. Burn, J., & Marwood, R. P. (1982). Fraser syndrome presenting as bilateral renal agenesis in three sibs. Journal of Medical Genetics, 19, 360–361. Chattopadhyay, A., Kher, A. S., Udwadia, A. D., et al. (1993). Fraser syndrome. Journal of Postgraduate Medicine, 39, 228–230.

Fraser Syndrome Codere, F., Brownstein, S., & Chen, M. F. (1981). Cryptophthalmos syndrome with bilateral renal agenesis. American Journal of Ophthalmology, 91, 737–742. Dibben, K., Rabinowitz, Y. S., Shorr, N., et al. (1997). Surgical correction of incomplete cryptophthalmos in Fraser syndrome. American Journal of Ophthalmology, 124, 107–109. Dinno, N. D., Edwards, W. C., & Weiskopf, B. (1974). The cryptophthalmos-syndactyly syndrome. Description, manner of inheritance, and notes on the eye lesions. Clinical Pediatrics, 13, 219–224. Feldman, E., Shalev, E., Weiner, E., et al. (1985). Microphthalmia prenatal ultrasonic diagnosis. Prenatal Diagnosis, 5, 205. Ferri, M., & Harvey, J. T. (1999). Surgical correction for complete cryptophthalmos: Case report and review of the literature. Canadian Journal of Ophthalmology, 34, 233–236. Francannet, C., Lefrancois, P., Dechelotte, P., et al. (1990). Fraser syndrome with renal agenesis in two consanguineous Turkish families. American Journal of Medical Genetics, 36, 477–479. Francois, J. (1969). Syndrome malformatif avec cryptophtalmie. Acta geneticae medicae et gemellologiae (Roma), 18, 18–50. Fraser, G. R. (1962). Our genetic load: a review of some aspects of genetical variation. Annals of Human Genetics, 25, 387–405. Fryns, J. P., Schoubroeck, D. V., Vanderberche, K., et al. (1997). Diagnostic echographic findings in cryptophthalmos syndrome (Fraser syndrome). Prenatal Diagnosis, 17, 582–584. Gattuso, J., Patton, M. A., & Baraitser, M. (1987). The clinical spectrum of the Fraser syndrome: Report of three new cases and review. Journal of Medical Genetics, 24, 549–555. Greenberg, F., Keenan, B., De Yanis, V., et al. (1986). Gonadal dysgenesis and gonadoblastoma in situ in a female with Fraser (Cryptophthalmos) syndrome. Journal of Pediatrics, 108, 952–954. Gupta, S. P., & Saxena, R. C. (1962). Cryptophthalmos. British Journal of Ophthalmology, 46, 629–632. Howard, R. O., Fineman, R. M., Anderson, B., Jr., et al. (1979). Unilateral cryptophthalmia. American Journal of Ophthalmology, 87, 556. Ide, C. H., & Wollschlaeger, P. B. (1969). Multiple congenital abnormalities associated with cryptophthalmos. Archives of Ophthalmology, 81, 638–644. Impallomeni, M., Subramanian, D., Mahmood, N., et al. (2006). Fraser syndrome in a 96-year-old female. Age and Ageing, 35, 642–643. Kabra, M., Gulati, S., Ghosh, M., et al. (2000). Frasercryptophthalmos syndrome. Indian Journal of Pediatrics, 67, 775–778. Kantaputra, P. (2001). Cryptophthalmos, dental and oral abnormalities, and brachymesophalangy of second toes: New syndrome or Fraser syndrome? American Journal of Medical Genetics, 98, 263–268. Karas, D. E., & Respler, D. S. (1995). Fraser syndrome: A case report and review of the otolaryngologic manifestations. International Journal of Pediatric Otorhinolaryngology, 31, 85–90. Koenig, R., & Spranger, J. (1986). Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clinical Genetics, 29, 413–416.

879 Lurie, I. W., & Cherstvoy, E. D. (1984). Renal agenesis as a diagnostic feature of the cryptophthalmos-syndactyly syndrome. Clinical Genetics, 25, 528. Martı´nez-Frı´as, M. L., Bermejo Sa´nchez, E., Fe´lix, V., et al. (1998). Fraser syndrome: Frequency in our environment and clinical-epidemiological aspects of a consecutive series of cases (in Spanish). Anales Espan˜oles de Pediatrı´a, 48, 634–638. Maruotti, G. M., Paladini, D., Agangi, A., et al. (2004). Prospective prenatal diagnosis of Fraser syndrome variant in a family with negative history. Prenatal Diagnosis, 24, 69–70. Meinecke, P. (1986). Cryptophthalmos-syndactyly syndrome without cryptophthalmos. Clinical Genetics, 30, 527. Narrang, M., Kumar, M., & Shah, D. (2007). Frasercryptophthalmos syndrome. Indian Journal of Pediatrics, 75, 189–191. Pankau, R., Partsch, C. J., Janig, U., et al. (1994). Fraser (Cryptophthalmos-syndactyly) syndrome: A case with bilateral anophthalmia but presence of normal eyelids. Genetic Counseling, 5, 191–194. Ramsing, M., Rehder, H., Holzgreve, W., et al. (1990). Fraser syndrome (Cryptophthalmos with syndactyly) in the fetus and newborn. Clinical Genetics, 37, 84–96. Rousseau, T., Laurent, N., Thauvin-Robinet, C., et al. (2002). Prenatal diagnosis and intrafamilial clinical heterogeneity of Fraser syndrome. Prenatal Diagnosis, 22, 692–696. Saleh, G. M., Hussain, B., Verity, D. H., et al. (2009). A surgical strategy for the correction of Fraser syndrome cryptophthalmos. Ophthalmology, 116, 1707–1712. Schauer, G. M., Dunn, L. K., Godmilow, L., et al. (1990). Prenatal diagnosis of Fraser syndrome at 18.5 weeks gestation, with autopsy findings at 19 weeks. American Journal of Medical Genetics, 37, 583–591. Serville, F., Carles, D., & Broussin, B. (1989). Fraser syndrome: Prenatal ultrasonic detection. American Journal of Medical Genetics, 32, 561–563. Shafeghati, Y., Kniepert, A., Vakili, G., et al. (2008). Fraser syndrome due to homozygosity for a splice site mutation of FREM2. American Journal of Medical Genetics. Part A, 146A, 529–531. Singh, R., Tandon, I., & Deo, S. (2007). Fraser syndrome: recurrence in a family. Indian Pediatrics, 44, 929–930. Slavotinek, A. M., & Tifft, C. J. (2002). Fraser syndrome and cryptophthalmos: Review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. Journal of Medical Genetics, 39, 623–633. Stevens, C. A., McClanahan, C., Steck, A., et al. (1994). Pulmonary hyperplasia in the Fraser cryptophthalmos syndrome. American Journal of Medical Genetics, 52, 427–431. Takamiya, K., Kostourou, V., Adams, S., et al. (2004). A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome proteinRfas1. Nature Genetics, 36, 172–177. Thapa, R., & Bhattachakya, A. (2008). Fraser syndrome with partial anomalous pulmonary venous connection. Indian Pediatrics, 45, 510–511. Thomas, I. T., Frias, J. L., Felix, V., et al. (1986). Isolated and syndromic cryptophthalmos. American Journal of Medical Genetics, 25, 85–98.

880 Van Haelst, M. M., Maiburg, M., Baujat, G., et al. (2008). Molecular study of 33 families with Fraser syndrome. New data and mutation review. American Journal of Medical Genetics. Part A, 146A, 2252–2257. Van Haelst, M. M., Scambler, P. J., Fraser Syndrome Collaboration Group, et al. (2007). Fraser syndrome: A clinical study of 59 cases and evaluation of diagnostic criteria. American Journal of Medical Genetics. Part A, 143A, 3194–3203.

Fraser Syndrome Vijayaraghavan, S. B., Suma, N., Lata, S., et al. (2005). Prenatal sonographic appearance of cryptophthalmos in Fraser syndrome. Ultrasound in Obstetrics & Gynecology, 25, 629–630. Weng, C.-J. (1998). Surgical reconstruction in cryptophthalmos. British Journal of Plastic Surgery, 51, 17–21. Zehender, W., Ackermann, E., & Manz, E. (1872). Eine Mibbildung mit haut€ uberwachsenen Augen oder Kryptophthalmos. Klin Mbl Augenheilk, 10, 225–249.

Fraser Syndrome

881

a

d

b

c

e

Fig. 1 (a–e) An infant with Fraser cryptophthalmos showing fused eyelids, lateral hair extending to lateral eyebrows, ocular hypertelorism, notched nares, and a tracheostomy site for

management of laryngeal stenosis. Postmortem photos show lung hypoplasia, a small uterus, and clitoral hypertrophy. The skull radiographs show poorly ossified calvarium

882 Fig. 2 (a–c) The sibling of the previous infant with Fraser syndrome showing microphthalmia, partial fusions of eyelids, ocular hypertelorism, genitourinary anomalies, and partial syndactyly of the toes. Variability of expression is illustrated in these two sibs

Fraser Syndrome

a

b

c

Freeman–Sheldon Syndrome

In 1938, Freeman and Sheldon described a syndrome characterized by a whistling face with a long philtrum, a puckered mouth, microstomia, H-shaped cutaneous dimpling on the chin, multiple joint contractures with camptodactyly, ulnar deviation of the fingers, bilateral talipes equinovarus, and kyphoscoliosis. Freeman–Sheldon syndrome (FSS) is the most severe of the distal arthrogryposes with the striking contractures of the orofacial muscles. The syndrome is also known as distal arthrogryposis (DA) type 2A, craniocarpotarsal dysplasia, or “whistling face” syndrome (Lev et al. 2000).

Synonyms and Related Disorders Craniocarpotarsal syndrome

dysplasia;

“Whistling

Face”

Genetics/Basic Defects 1. Caused by mutations in embryonic myosin heavy chain gene (MYH3) (Toydemir et al. 2006). Sheldon–Hall syndrome (SHS) is known to be caused by mutations in either MYH3, TNNT2, or TNNT3 (Toydemir and Bamshad 2009) 2. Genetic heterogeneity (Lev et al. 2000) a. Autosomal dominant inheritance i. Usually with normal psychomotor development, although mild motor delay attributable to joint anomalies might be present ii. A variant of autosomal dominant inheritance, mapped to chromosome 11p15.5-pter (Krakowiak 1997)

b. Autosomal recessive inheritance: severe developmental retardation reported in a few patients 3. Pathogenesis a. Considered a form of distal arthrogryposis i. Closely related to distal arthrogryposis type 1 a) Similar limb phenotypes but distinguished only by differences in facial morphology b) Reports of families in which different individuals were diagnosed with distal arthrogryposis type 1 or Freeman–Sheldon syndrome ii. Proposed to classify Freeman–Sheldon syndrome as distal arthrogryposis type 2 (a distinct disorder from distal arthrogryposis type 1 with overlapping phenotypes) in a revised classification of distal arthrogryposis b. Primary brain anomalies suggested to explain many manifestations of the syndrome c. Also considered possibly a nonprogressive or slowly progressive myopathy (Vaneˇk et al. 1986) 4. Overlap of clinical characteristics of FSS with other DA syndromes suggests a shared etiology and/or pathogenesis (Stevenson et al. 2006) a. Several DAs can be caused by mutations in four genes that encode proteins of the troponin-tropomyosin complex of fast-twitch myofibers. b. Specifically, mutations in TPM2, TNNT2 or TNNT3, and MYH8 cause DA1, SHS, and trismus-pseudocamptodactyly (i.e., DA7), respectively.

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Clinical Features 1. Variable clinical severity and phenotypic abnormalities (Marasovich et al. 1989) 2. Normal intelligence 3. “Whistling face” appearance a. Long philtrum b. Microstomia c. Puckered mouth d. Pursed lips e. H-shaped cutaneous dimpling on the chin 4. Musculoskeletal anomalies a. Multiple joint contractures b. Camptodactyly c. Ulnar deviation of fingers d. Windmill vane hand (bilateral ulnar deviation and contracture of fingers two to five at the metacarpophalangeal joints with adduction of thumbs) e. Normal hands in a few reports f. Bilateral talipes equinovarus g. Kyphoscoliosis 5. Growth retardation 6. Other craniofacial features a. Masklike rigid face b. Flat midface c. Deep-sunken eyes with hypertelorism d. Antimongoloid slant of the palpebral fissures e. Blepharophimosis f. Convergent strabismus g. Full cheeks h. Small nose i. Coloboma alae of the nose j. Micrognathia k. Cleft palate or high-arched palate l. Choanal atresia m. Low-set and malformed ears n. Hearing loss 7. Other features a. Nasal speech b. Short neck c. Inguinal hernia d. Cryptorchidism e. Spina bifida occulta 8. Complications a. Difficulty in swallowing attributed to the mouth deformity

Freeman–Sheldon Syndrome

b. Pulmonary problems due to decreased thoracic expansion 9. Diagnostic criteria of Freeman–Sheldon syndrome (Stevenson et al. 2006) a. Presence of 2 of the major clinical manifestations of distal arthrogryposis (DA) plus the presence of a small pinched mouth, prominent nasolabial folds, and H-shaped dimpling of the chin b. Major manifestations of DA of the upper limbs i. Ulnar deviation of the wrists and fingers ii. Camptodactyly iii. Hypoplastic, and/or absent flexion creases, and/or overriding fingers at birth c. Major manifestations of DA of the lower limbs i. Talipes equinovarus ii. Calcaneovalgus deformities iii. A vertical talus iv. Metatarsus varus 10. Differential diagnosis of Sheldon–Hall syndrome (SHS) (Stevenson et al. 2006): Diagnostic criteria of SHS include: a. 2 of the major clinical manifestations of DA b. Deep nasolabial folds c. A small oral opening (but a larger oral opening than that of FSS) d. A small but protuberant chin (but lack an H-shaped dimpling of the chin) e. Webbing of the neck

Diagnostic Investigations 1. Radiography a. Skull i. Shallow anterior cranial fossa ii. Hypoplastic mandible iii. Small malar bones b. Ulnar deviation and flexion contractures of the fingers c. Talipes equinovarus d. Kyphoscoliosis 2. Polysomnography for sleep-disordered breathing 3. Muscle biopsy findings: structural changes predominantly involving type I fibers suggesting that the muscle lesion is a form of congenital fiber type disproportion (Duggar et al. 1989) 4. Molecular genetic testing of MHY3 mutations

Freeman–Sheldon Syndrome

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Genetic Counseling

References

1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: low unless a parent is affected ii. Autosomal recessive inheritance: 25% iii. Empirical risks for sibs of sporadic cases: 7% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: low unless the spouse is affected iii. Empirical risk for children of sporadic case: 37% 2. Prenatal diagnosis a. Ultrasonography at 20 weeks of gestation in a fetus with a positive family history (RobbinsFurman et al. 1995) i. Bilateral equinovarus and abnormally positioned toes ii. Clenched hands with overlapping thumbs iii. An abnormally appearing mouth with pursing of the lips b. Molecular genetic diagnosis: If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible by direct molecular testing of fetal DNA sample obtained from chorionic villus or amniotic fluid. 3. Management a. Tracheostomy required for severe upper airway narrowing (Robinson 1997) b. Management of anesthetic risks (Duggar et al. 1989) i. Risks primarily related to severe microstomia ii. Combinations of myopathic and skeletal abnormalities predisposing affected patients to significant postoperative respiratory difficulty iii. Awake endotracheal intubation or fiberoptic nasotracheal intubation in infants before induction of general anesthesia c. Functional and cosmetic correction of microstomia (Neumann and Coetzee 2009) d. Functional hand reconstruction for hand deformities e. Orthopedic correction of clubfeet and scoliosis

Alves, A. F., & Azevedo, E. S. (1977). Recessive form of Freeman–Sheldon’s syndrome or “whistling face”. Journal of Medical Genetics, 14, 139–141. Burzynski, N. J., Podruch, P. E., Howell, J., et al. (1975). Craniocarpotarsal dysplasia syndrome (whistling face syndrome). Case reports and survey of clinical findings. Oral Surgery, Oral Medicine, and Oral Pathology, 39, 893–900. Dallapiccola, B., Giannotti, A., Lembo, A., et al. (1989). Autosomal recessive form of whistling face syndrome in sibs. American Journal of Medical Genetics, 33, 542–544. Duggar, R. G., Jr., DeMars, P. D., & Bolton, V. E. (1989). Whistling face syndrome: General anesthesia and early postoperative caudal analgesia. Anesthesiology, 70, 545–547. Fitzsimmons, J. S., Zaldua, V., & Chrispin, A. R. (1984). Genetic heterogeneity in the Freeman–Sheldon syndrome: Two adults with probable autosomal recessive inheritance. Journal of Medical Genetics, 21, 364–368. Freeman, E., & Sheldon, J. (1938). Cranio-carpotarsal dystrophy: Undescribed congenital malformation. Archives of Disease in Childhood, 13, 277–283. Gross-Kieselstein, E., Abrahamov, A., & Ben-Hur, N. (1971). Familial occurrence of the Freeman–Sheldon syndrome: Cranio-carpotarsal dysplasia. Pediatrics, 47, 1064–1067. Hall, J. G., Reed, S. D., & Greene, G. (1982). The distal arthrogryposes: Delineation of new entities-review and nosologic discussion. American Journal of Medical Genetics, 11, 185–239. Kousseff, B. G., McConnachie, P., & Hadro, T. A. (1982). Autosomal recessive type of whistling face syndrome in twins. Pediatrics, 69, 328–331. Krakowiak, P. A., O’Quinn, J. R., Bohnsack, J. F., et al. (1997). A variant of Freeman-Sheldon syndrome maps to 11p15.5pter. American Journal of Human Genetics, 80, 426–432. Lev, D., Yanoov, M., Weintraub, S., et al. (2000). Progressive neurological deterioration in a child with distal arthrogryposis and whistling face. Journal of Medical Genetics, 37, 231–233. Malkawi, H., & Tarawneh, M. (1983). The whistling face syndrome, or craniocarpotarsal dysplasia. Report of two cases in a father and son and review of the literature. Journal of Pediatric Orthopaedics, 3, 364–369. Marasovich, W. A., Mazaheri, M., & Stool, S. E. (1989). Otolaryngologic findings in whistling face syndrome. Archives of Otolaryngology – Head & Neck Surgery, 115, 1373–1380. Mustacchi, Z., Richieri-Costa, A., & Frota-Pessoa, O. (1979). The Freeman–Sheldon syndrome. Review Brasil Genetics II, 4, 259–266. Neumann, A., & Coetzee, P. F. (2009). Freeman–Sheldon syndrome: A functional and cosmetic correction of microstomia. Journal of Plastic, Reconstructive & Aesthetic Surgery, 62, e123–e124. O’Connell, D. J., & Hall, C. M. (1977). Cranio-carpo-tarsal dysplasia: A report of seven cases. Radiology, 123, 719–722.

886 Robbins-Furman, P., Hecht, J. T., Rocklin, M., et al. (1995). Prenatal diagnosis of Freeman–Sheldon syndrome (whistling face). Prenatal Diagnosis, 15, 179–182. Robinson, P. J. (1997). Freeman–Sheldon syndrome: Severe upper airway obstruction requiring neonatal tracheostomy. Pediatric Pulmonology, 23, 457–459. Sa´nchez, J. M., & Kaminker, C. P. (1986). New evidence for genetic heterogeneity of the Freeman–Sheldon syndrome. American Journal of Medical Genetics, 25, 507–511. Stevenson, D. A., Carey, J. C., Palumbos, J., et al. (2006). Clinical characteristics and natural history of Freeman–Sheldon syndrome. Pediatrics, 117, 754–762. Toydemir, R. M., & Bamshad, M. J. (2009). Sheldon-Hall syndrome. Orphanet Journal of Rare Diseases, 4, 11. Toydemir, R. M., Rutherford, A., Whitby, R. G., et al. (2006). Mutations in embryonic myosin heavy chain (MYH3) cause

Freeman–Sheldon Syndrome Freeman–Sheldon syndrome and Sheldon–Hall syndrome. Nature Genetics, 38, 561–565. Vaneˇk, J., Janda, J., Amblerova´, V., et al. (1986). Freeman–Sheldon syndrome: A disorder of congenital myopathic origin? Journal of Medical Genetics, 23, 231–236. Weinstein, S., & Gorlin, R. J. (1969). Cranio-carpo-tarsal dysplasia or the whistling face syndrome. I. Clinical considerations. American Journal of Disease of Children, 117, 427–433. Wettstein, A., Buchinger, G., Braun, A., et al. (1980). A family with whistling-face-syndrome. Human Genetics, 55, 177–189. Zampino, G., Conti, G., Balducci, F., et al. (1996). Severe form of Freeman–Sheldon syndrome associated with brain anomalies and hearing loss. American Journal of Medical Genetics, 62, 293–296.

Freeman–Sheldon Syndrome

a

887

d

e

b f

c

Fig. 1 (a–f) Freeman–Sheldon syndrome in a father and son showing whistling face appearance of the face and ulnar deviation of fingers and fixed position of the thumbs illustrated by radiographs

888

Freeman–Sheldon Syndrome

a

b

Fig. 2 (a, b) Freeman–Sheldon syndrome in a neonate showing characteristic “whistling face,” ulnar deviation of the fingers with contractures, and talipes equinovarus

a

b

Fig. 3 (a, b) Another neonate showing characteristic “whistling face” with H-shaped cutaneous dimpling on the chin and ulnar deviation and contractures of the fingers

Freeman–Sheldon Syndrome

Fig. 4 A newborn with Freeman–Sheldon syndrome showing whistling appearance of the face, tight mouth opening, hypoplastic nasal alae, arthrogryposis of the hands and fingers with

889

contractures and ulnar deviation of the wrists, and metatarsus adductus. Intrauterine growth retardation and Dandy–Walker malformation were detected prenatally by ultrasound

Friedreich Ataxia

During the period 1863–1877, Friedreich described the condition, now called Friedreich ataxia (FRDA), in nine members of three families. His initial report noted the following characteristics: age of onset around puberty and ataxia, dysarthria, sensory loss, muscle weakness, scoliosis, foot deformity, and cardiac symptoms. FRDA is the commonest inherited ataxia (Harding 1984). Recent study based on molecular data suggests a carrier rate of 1 in 85 with a disease prevalence of 1 in 29,000 (Cossee et al. 1997).

Genetics/Basic Defects 1. An autosomal recessive disorder 2. The gene mutated in FRDA (FXN), mapped to 9q13-21.1, was initially called X25 and later changed to FRDA a. FRDA: unique among trinucleotide repeat disorders in that it is autosomal recessive b. The repeat is intronic c. It is the only disease known to be the result of expansion of a GAA trinucleotide repeat 3. Frataxin, the encoded protein, is predicted to contain 210 amino acids. Frataxin has an N-terminal leader peptide that directs its subcellular localization to mitochondria 4. Intergenerational instability, premutations, and origin of mutations a. GAA repeat underlying FRDA: unstable in its transmission from parent to offspring as in other trinucleotide repeat disorders (Timchenko and Caskey 1996).

b. Maternal transmission may result in a larger or smaller allele in offspring while paternal transmission always results in smaller allele (Monros et al. 1997; Pianese et al. 1997; Delatycki et al. 1998; De Michele et al. 1998). The size of the triplet repeat influences the direction of instability with smaller alleles more prone to increase in size and larger ones to decrease. c. Premutation alleles are prone to large expansion in one generation. d. Normal-sized alleles have a bimodal distribution. i. Small normal alleles (about 83%): between 6 and 12 repeats ii. Large normal alleles (about 17%): between 14 and 34 repeats 5. Genotype-phenotype correlation: not possible to predict the specific clinical outcome in any individual based on genotype (Bidichandani and Delatycki 2009) a. Variability in individuals with FRDA may be caused by: i. Genetic background (e.g., Acadian individuals) ii. Somatic heterogeneity of the GAA expansion iii. Other unidentified factors b. GAA repeat size in homozygotes for pathogenic GAA repeat expansions i. Statistically significant correlations with: a) Age of onset b) Presence of leg muscle weakness and/or wasting c) Duration until wheelchair use d) Prevalence of cardiomyopathy, pes cavus, and scoliosis

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ii. Individuals with late-onset FRDA (LOFA): frequently exhibit fewer than 500 GAA repeats in at least one of the expanded alleles iii. Individuals with very-late-onset FRDA (VLOFA): usually have fewer than 300 GAA repeats in at least one of the expanded alleles iv. Cardiomyopathy: more frequently seen with longer GAA repeat alleles v. Diabetes mellitus or abnormal glucose tolerance: does not show a clear-cut correlation with the size of the GAA expansion c. Spastic paraparesis without ataxia: may be seen in those with smaller expanded alleles or in association with the G130V missense mutation d. Compound heterozygotes for an expansion and a point mutation i. Most compound heterozygotes are clinically indistinguishable from typical individuals with FRDA with homozygous GAA expansions. ii. Compound heterozygotes for an expansion and a borderline “mutable” allele. Individuals with somatically unstable borderline alleles present with LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia. 6. Pathophysiology (Chawla 2008) a. Major pathophysiologic finding: “dying back phenomena” of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis b. Primary sites of changes in spinal cord and spinal roots resulting in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration c. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared

Friedreich Ataxia

2.

3.

4.

5.

v. Absent tendon reflexes in the legs vi. Muscle weakness b. Secondary i. Extensor plantar responses ii. Pes cavus iii. Scoliosis iv. Cardiomyopathy Diagnostic criteria for FRDA (Harding 1981) a. Primary (essential for diagnosis) i. Age of onset of symptoms before the age of 25 years ii. Progressive unremitting ataxia of limbs and of gait iii. Absence of knee and ankle jerks b. Secondary i. Dysarthria ii. Extensor plantar responses c. Additional: If secondary criteria are absent, the following have to be present: i. An affected sib fulfilling primary and secondary criteria ii. Median motor nerve conduction velocities of greater than 40 m/s thus excluding cases of type I hereditary motor and sensory neuropathy Typical and atypical FRDA (Harding 1981) a. Typical: cases meeting above criteria b. Atypical: cases not meeting above criteria Cardinal features a. Progressive gait and limb ataxia b. Absent lower limb reflexes c. Extensor plantar responses d. Dysarthria e. Reduction in or loss of vibration sense and proprioception (sensory modalities mediated by posterior column neurons) Common but nonessential features a. Cardiomyopathy b. Scoliosis c. Foot deformity

Clinical Features 1. Diagnostic criteria for FRDA (Geoffroy et al. 1976) a. Primary (essential for diagnosis) i. Onset before the end of puberty (never after the age of 20 years) ii. Progressive ataxia of gait iii. Dysarthria iv. Loss of joint position or vibration sense

Diagnostic Investigations 1. Molecular genetic testing (Chawla 2008; Bidichandani and Delatycki 2009) a. GAA triplet repeat expansion in intron 1 of the FXN gene with four classes of alleles (Sharma et al. 2004)

Friedreich Ataxia

2.

3.

4.

5.

6.

7.

i. Normal alleles: 5–33 GAA repeats a) Short normal: 80%) b) Long normal: 12–33 GAA repeats (approximately 15%) ii. Premutation (mutable normal) alleles: 34–65 pure, uninterrupted, GAA repeats a) Not associated with FRDA but may expand during parental transmission, resulting in disease-causing alleles. b) Expansion of premutation alleles, sometimes more than tenfold the original size, has been observed in both paternal and maternal transmission. iii. Disease-causing expanded (full penetrance) alleles: 66–1,700 GAA repeats iv. Borderline alleles: 44–66 uninterrupted GAA repeats Clinical laboratory testing i. Targeted mutation analysis a) Homozygous GAA expansion in FXN (96%) b) Heterozygous GAA expansion in FXN ii. Sequence analysis: heterozygous point mutation in FXN a) Approximately 4% of patients are compound heterozygotes for a GAA expansion in the disease-causing range in one FXN allele and another inactivating FXN gene mutation in the other allele. b) No affected individuals with inactivating point mutations in both FXN alleles reported to date Echocardiography: reveals symmetric, concentric ventricular hypertrophy, although asymmetric septal hypertrophy may be present Brainstem auditory evoked responses: typically displaying absent waves III and IV with preservation of wave I, suggestive of involvement of central auditory pathways Visual evoked potentials: absent or delayed latency and reduced amplitude of the p100 wave in two thirds of patients Somatosensory evoked potentials a. Delayed central conduction time (N13a/N20, N13b/N20) b. Dispersed potentials at the sensory cortex c. Abnormal central motor conduction Magnetic resonance imaging of the brain and spinal cord: consistently shows atrophy of the cervical

893

spinal cord with minimal evidence of cerebellar atrophy 8. Nerve conduction studies a. Absent sensory nerve action potentials b. Absent spinal somatosensory evoked potentials, although these may be reduced or even normal early in the disease course (Harding 1984) c. Motor nerve conduction velocities are reduced to a lesser extent than sensory nerve action potentials. 9. Histological studies a. Loss of myelinated fibers of the dorsal columns and the corticospinal tracts in lower cervical cord (Weil stain) b. Milder involvement of spinocerebellar tracts c. Compact fibrillary gliosis in the affected tract on hematoxylin and eosin (H&E) stain but no breakdown products or macrophages, reflecting the very slow rate of degeneration and death of fibers d. Shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells in the dorsal spinal ganglia (H&E) e. Nearly devoid of large myelinated fibers in the posterior roots f. Degeneration and loss of cells of the Clarke column within the thoracic spinal cord

Genetic Counseling 1. Ability to diagnose FRDA by molecular means with a high sensitivity and specificity a. Clinically typical patients i. A specific and rapid diagnosis can be made in most patients and in the 4% compound heterozygous for a point mutation. ii. The presence of one expanded allele indicates that the diagnosis is likely. b. Clinically atypical patients can be diagnosed to have or not to have FRDA by: i. GAA repeat study ii. Mutation analysis for point mutations c. Carrier testing i. Available for relatives of affected and their partners ii. There is a small possibility that a point mutation may be present.

894

d. For a subject with FRDA who has a carrier partner, there is a 1:2 risk of having an affected child. The a priori risk for a person with FRDA having a child with the condition is approximately 1:200 unless there is consanguinity. e. If the partner of a carrier does not have an expanded allele, the chance that they carry a point mutation is about 1:5,000 (taking a FRDA carrier rate of 1:100 and that 2% of mutations are point mutations). Therefore, the risk of this couple having a child with FRDA is about 1:20,000 which is only about twice the background risk of the general population. 2. Recurrence risk (Bidichandani and Delatycki 2009) a. Patient’s sib i. Both parents carry a full penetrance allele, or one parent carries a full penetrance allele, and the other parent carries another deleterious FXN gene mutation. a) At conception: each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. b) Once an at-risk sib is known to be clinically unaffected, the risk of his/her being a carrier is 2/3. c) The wide range in age of onset and variable intergenerational instability of the GAA expansion dictate the use of caution in diagnosing an at-risk sib as unaffected. ii. One parent carries a full penetrance allele or another deleterious FXN gene mutation, and the other parent carries a mutable normal (premutation) allele. a) At conception: each sib of a proband whose parent is a carrier of a mutable normal (premutation) allele has a 25% chance of inheriting both parental mutations. b) Since the mutable normal (premutation) allele may remain unchanged or undergo minimal change (i.e., not expand to produce a full penetrance allele), the sibs have less than 25% chance of being affected. c) Each sib also has a 50% chance of being an asymptomatic carrier of one of the

Friedreich Ataxia

parental alleles and a 25% chance of being unaffected and having two normal alleles. b. Patient’s offspring i. All offspring inherit one mutant allele from the affected parent. ii. Offspring have a 50% chance of being affected only if the reproductive partner of the proband is a carrier of a full penetrance allele or another deleterious FXN gene mutation. iii. If the reproductive partner of the proband carries a mutable normal (premutation) allele, the risk to each offspring of developing FRDA is less than 50%. 3. Prenatal diagnosis (Bidichandani and Delatycki 2009) a. Possible for pregnancies at 25% risk provided both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed i. Amniocentesis ii. Chorionic villus sampling b. Preimplantation genetic diagnosis: available for families in which the disease-causing mutations have been identified in an affected family member 4. Management a. Supporting measures (Bidichandani and Delatycki 2009) i. Prostheses, walking aids, and wheelchairs for mobility ii. Orthopedic interventions for scoliosis and foot deformities iii. Speech, occupational, and physical therapy iv. Hearing aids v. Pharmacologic agents for spasticity vi. Dietary modifications and placement of a nasogastric tube or gastrostomy for dysphagia vii. Antiarrhythmic agents viii. Anti–cardiac failure medications ix. Anticoagulants and pacemaker insertion for cardiac disease x. Oral hypoglycemic agents or insulin for diabetes mellitus xi. Antispasmodics for bladder dysfunction xii. Psychological support b. Currently, no treatments have been proven to delay, prevent, or reverse the inexorable decline that occurs in this condition. However, several

Friedreich Ataxia

pharmaceutical agents are undergoing clinical assessment (Delatycki 2009). c. Treatment with intermediate- and high-dose idebenone had beneficial effects on neurological symptoms (Schulz et al. 2009). d. Improvement in both cardiac hypertrophy and neurological symptoms among patients with FRDA treated with idebenone (Meier and Buyse 2009)

References Bidichandani, S. I., & Delatycki, M. B. (2009) Friedreich ataxia. GeneReview. Retrieved June 25, 2009. Available at: http:// www.ncbi.nlm.nih.gov/books/NBK1281/ Chawla J. (2010). Friedreich ataxia. eMedicine from WebMD. Retrieved August 18, 2010. Available at: http://emedicine. medscape.com/article/1150420-overview Cossee, M., Schmitt, M., Campuzano, V., et al. (1997). Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutation. Proceedings of the National Academy of Sciences United States of America, 94, 7452–7457. De Michele, G., Cavalcanti, F., Criscuolo, C., et al. (1998). Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: Pedigree studies and analysis of sperm from patients with Friedreich’s ataxia. Human Molecular Genetics, 7, 1901–1906. Delatycki, M. B. (2009). Evaluating the progression of Friedreich ataxia and its treatment. Journal of Neurology, 256(Suppl 1), 36–41. Delatycki, M., Paris, D., Gardner, R., et al. (1998). Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene. Journal of Medical Genetics, 53, 713–716.

895 Delatycki, M. B., Williamson, R., & Forrest, S. M. (2000). Friedreich ataxia: An overview. Journal of Medical Genetics, 37, 1–8. Friedreich, N. (1863). Uber degenerative Atrophie der spinalen Hinterstrange. Virchow’s Archives on Pathological Anatomy, 26, 391–419. Geoffroy, G., Barbeau, A., Breton, G., et al. (1976). Clinical description and roentgenologic evaluation of patients with Friedreich’s ataxia. Canadian Journal of Neurological Sciences, 3, 279–286. Harding, A. E. (1981). Friedreich’s ataxia: A clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain, 104, 589–620. Harding, A. (1984). The hereditary ataxias and related disorders. Edinburgh: Churchill Livingstone. Meier, T., & Buyse, G. (2009). Idebenone: An emerging therapy for Friedreich ataxia. Journal of Neurology, 256(Suppl 1), 25–30. Monros, E., Molto, M. D., Martinez, F., et al. (1997). Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. American Journal of Human Genetics, 61, 101–110. Pandolfo, M. (2009). Friedreich ataxia: The clinical picture. Journal of Neurology, 256(Suppl 1), 3–8. Pandolfo, M., & Montermini, L. (1998). Prenatal diagnosis of Friedreich ataxia. Prenatal Diagnosis, 18, 831–833. Pianese, L., Cavalcanti, F., De Michele, G., et al. (1997). The effect of parental gender on the GAA dynamic mutation in the FRDA gene. American Journal of Human Genetics, 60, 460–463. Schulz, J. B., Di Prospero, N. A., et al. (2009). Clinical experience with high-dose idebenone in Friedreich ataxia. Journal of Neurology, 256(Suppl 1), 42–45. Sharma, R., De Biase, I., Gomez, M., et al. (2004). Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Annals of Neurology, 56, 898–901. Timchenko, L. T., & Caskey, C. T. (1996). Trinucleotide repeat disorders in humans: Discussions of mechanisms and medical issues. The FASEB Journal, 10, 1589–1597.

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Fig. 1 This 22-year-old man was seen for progressive muscle weakness and progressive ataxia. The patient began noticing the problem while running during football practice in high school. In the last 6 months, he has had trouble swallowing, especially liquids, and trouble speaking. At present, he walks with a cane with ataxic gait. There was a significant thigh muscle mass loss. His deep tendon reflexes are absent. Friedreich ataxia DNA test showed that the patient is homozygous for the GAA repeat expansion mutation which confirms the clinical diagnosis of Friedreich ataxia type I (FRDA1) with X25 allele 1 of 400 GAA repeats and X25 allele 2 of 400 GAA repeats

Friedreich Ataxia

Fig. 2 The patient stands with a cane and need to support standing with hand support on the wall

Frontonasal Dysplasia

Frontonasal dysplasia is a developmental field defect of craniofacial region characterized by hypertelorism and varying degrees of median nasal clefting. In 1967, DeMeyer first described the malformation complex “median cleft face syndrome” to emphasize the key midface defects. Since then, several terms have been introduced: frontonasal dysplasia, frontonasal syndrome, frontonasal dysostosis, and craniofrontonasal dysplasia (currently recognized as a syndrome distinct from frontonasal dysplasia) (Dubey and Garap 2000).

Synonyms and Related Disorders Frontonasal malformation; Frontorhiny; Median facial cleft syndrome

Genetics/Basic Defects 1. Inheritance a. Sporadic in most cases. b. Rare autosomal dominant inheritance with variable expression. c. Recessive mutations in the homeobox gene ALX3 cause a recurrent pattern of frontonasal malformation (Twigg et al. 2009). d. Rare autosomal recessive inheritance: disruption of ALX1 causes autosomal-recessive ALX-related frontonasal dysplasia (Uz et al. 2010). e. Rare X-linked dominant inheritance. 2. Rare association with chromosome anomalies a. Partial trisomy 2q and partial monosomy 7q from a balanced maternal t(2;7)(q31;q36) (Chen et al. 1992)

3. 4. 5. 6.

b. 22q11 microdeletion (Stratton and Payne 1997) c. Reciprocal translocation t(15;22)(q22;q13) (Fryns et al. 1993) d. Complex translocation involving chromosomes 3, 7, and 11 (Stevens and Qumsiyeh 1995) Rare variants of frontonasal dysplasia/malformation with variable inheritance patterns Embryologically classified as a developmental field defect (Sedano and Gorlin 1986) Extreme variable phenotypic expression Pathogenesis (Twigg et al. 2009) a. Formation of the human face is an exquisitely orchestrated developmental process involving multiple tissue swellings (the frontonasal, medial and lateral nasal, and maxillary and mandibular prominences) derived from the neural crest (Moore and Persaud 2007). b. During a critical period between 4 and 8 weeks of human fetal development, these processes must undergo cell proliferation and tissue fusion to form the orbital, nasal, and oral structures (Yoon et al. 2000; Moore and Persaud 2007). c. Disturbance to this developmental sequence causes frontonasal malformation, a very heterogeneous group of disorders characterized by combinations of hypertelorism, abnormal nasal configuration, and oral, palatal, or facial clefting, sometimes associated with facial asymmetry, skin tags, ocular or cerebral malformations, widow’s peak, and anterior cranium bifidum (DeMeyer 1967; Sedano et al. 1970; Sedano and Gorlin 1986; van der Meulen and Vaandrager 1989; Guinon-Almeida et al. 1996; Tan and Mulliken 1997; Losee et al. 2004).

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Clinical Features 1. Pure frontonasal dysplasia (Dubey and Garap 2000) a. Variable mental retardation b. Inheritance pattern i. Sporadic in majority of cases ii. Familial transmission in few cases c. Cranium bifidum occultum d. CNS anomalies i. Frontal cephalocele ii. Meningocele/meningoencephalocele iii. Agenesis of the corpus callosum iv. Mild holoprosencephaly v. Hydrocephalus e. Nasal anomalies i. Mild colobomas of the nostril ii. Flattening of the nose with widely separated nares iii. A broad nasal root iv. Broad nasal tip v. Notching or clefting of alae nasi (cleft nose) vi. Nasal tag f. Ocular anomalies i. Hypertelorism ii. Epicanthal folds iii. Narrowing of the palpebral fissures iv. Accessory nasal eyelid tissue with secondary displacement of inferior puncti colobomas v. Epibulbar dermoids vi. Upper eyelid colobomas vii. Microphthalmia viii. Vitreoretinal degeneration with retinal detachment ix. Congenital cataracts g. Facial anomalies i. Widow’s peak configuration of the anterior hairline in the forehead ii. Median cleft of upper lip iii. Median cleft palate iv. Preauricular tag v. Absent tragus vi. Low-set ears h. Other anomalies i. Conductive deafness ii. Hypoplastic frontal sinuses iii. Cardiac anomalies, especially tetralogy of Fallot

Frontonasal Dysplasia

iv. Limb anomalies a) Clinodactyly b) Polydactyly c) Syndactyly d) Tibial hypoplasia v. Umbilical hernia vi. Cryptorchidism 2. Autosomal-recessive frontonasal dysplasia in two distinct families (Uz et al. 2010) a. Bilateral extreme microphthalmia b. Bilateral oblique facial cleft c. Complete cleft palate d. Hypertelorism e. Wide nasal bridge with hypoplasia of the ala nasi f. Low-set, posteriorly rotated ears 3. Other syndromes associated with frontonasal dysplasia or frontonasal malformation (Martinelli et al. 2002) a. Autosomal dominant form of frontonasal dysplasia with vertebral anomalies b. Acromelic frontonasal dysplasia i. Autosomal recessive disorder ii. Similar frontonasal “dysplasia” iii. Rare agenesis of the corpus callosum iv. Tibial hypoplasia v. Polydactyly (duplicated hallux) c. Craniofrontonasal dysplasia i. Possible X-linked disorder ii. Rare mental retardation iii. Hypertelorism iv. Craniosynostosis v. Facial asymmetry vi. Broad nasal root vii. Bifid nasal tip viii. Syndactyly of toes and fingers ix. Split nails x. Broad first toe d. Acrocallosal syndrome i. Autosomal dominant or autosomal recessive disorder ii. Severe mental retardation iii. Hypertelorism iv. Hypoplastic or absent corpus callosum v. Prominent forehead vi. Small nose vii. Broad nasal bridge viii. Normal nasal tip ix. Cardiac defects x. Postaxial polydactyly of hands and feet

Frontonasal Dysplasia

xi. Preaxial polydactyly of feet xii. Syndactyly of toes xiii. Clinodactyly e. Oral-facial-digital syndrome i. X-linked disorder ii. Variable mental retardation iii. Agenesis of the corpus callosum iv. Median cleft lip and palate v. Lobated/bifid tongue vi. Clinodactyly vii. Syndactyly viii. Polydactyly f. Oculo-auriculo-frontonasal dysplasia i. Frontonasal dysplasia ii. Ocular dermoids iii. Eyelid colobomata iv. Preauricular tags g. Fronto-facio-nasal dysplasia i. Autosomal recessive disorder ii. Frontonasal dysplasia iii. Ocular dermoids iv. Preauricular tags v. Cerebral lipoma h. Acro-fronto-facio-nasal dysplasia I i. Autosomal recessive disorder ii. Frontonasal dysplasia iii. Macrostomia iv. Broad and notched nasal tip v. Fibular hypoplasia vi. Polydactyly vii. Short stature i. Acro-fronto-facio-nasal dysplasia II i. Autosomal recessive disorder ii. Frontonasal dysplasia iii. Microcephaly iv. Nasal midline groove with blind dimples v. Broad thumbs vi. Syndactyly j. Greig acrocephalopolysyndactyly i. Autosomal dominant disorder ii. Mild mental retardation iii. Mild features of frontonasal dysplasia iv. Macrocephaly v. Broad nasal root vi. Normal nasal tip vii. Postaxial polydactyly of hands viii. Preaxial polysyndactyly of feet ix. Broad thumbs and halluces x. Syndactyly

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k. Meinecke frontonasal dysplasia-cardiac defects i. Frontonasal dysplasia ii. Microcephaly iii. Cardiac defects, especially tetralogy of Fallot 4. Prognosis depending on severity of defects a. Normal intelligence in most patients b. Mental retardation affecting 12% of cases without CNS abnormalities c. Up to 50% of cases with mental retardation complicated by agenesis of the corpus callosum

Diagnostic Investigations 1. Radiography, CT, and MRI of the brain a. Anterior cranium bifidum b. Agenesis of the corpus callosum c. Lipoma of the corpus callosum d. Arhinencephaly e. Hydrocephalus 2. Chromosome analysis for chromosome etiology 3. Molecular genetic diagnosis of ALX1 and ALX3 mutations: not available clinically

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant disorder: not increased in de novo case unless a parent is affected ii. Autosomal recessive disorder: 25% iii. X-linked dominant disorder: 50% when the mother is a carrier iv. Chromosome disorder: not increased in a de novo case; risk of unbalanced segregation from a carrier parent b. Patient’s offspring i. Autosomal dominant disorder: 50% ii. Autosomal recessive disorder: not increased unless the spouse is a carrier iii. X-linked dominant disorder: 50% iv. Chromosome disorder: not surviving to reproductive age 2. Prenatal diagnosis a. Ultrasonography (Martinelli et al. 2002) i. Hypertelorism ii. Frontonasal cephalocele

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iii. Agenesis of the corpus callosum iv. Median cleft lip b. 3-D ultrasonography: increasingly helpful in identifying facial features (Johnstone et al. 2008) c. Amniocentesis for associated chromosome anomaly 3. Management a. Speech therapy b. Maxillofacial surgeries for functional and cosmetic improvement i. Cleft lip/palate ii. Hypertelorism iii. Nose c. Psychosocial and/or psychiatric support

References Chen, H., Rightmire, D., Zapata, C., et al. (1992). Frontonasal dysplasia and arrhinencephaly resulting from unbalanced segregation of a maternal t(2;7)(q31;q36). Dysmorphology Clinical Genetics, 6, 99–106. Chervenak, F. A., Tortora, M., Mayden, K., et al. (1984). Antenatal diagnosis of median cleft syndrome: Sonographic demonstration of cleft lip and hypertelorism. American Journal of Obstetrics and Gynecology, 149, 94–97. Cohen, M. M., Jr. (1979). Craniofrontonasal dysplasia. Birth Defects Original Article Series, 15(5B), 85–89. Cohen, M. M., Jr., Sedano, H. O., Gorlin, R. J., et al. (1971). Frontonasal dysplasia (median cleft face syndrome): Comments on etiology and pathogenesis. Birth Defects Original Article Series, 7, 117–119. DeMeyer, W. (1967). The median cleft face syndrome: Differential diagnosis of cranium bifidum occultum, hypertelorism and median cleft nose, face and palate. Neurology, 17, 961–971. Dubey, S. P., & Garap, J. P. (2000). The syndrome of frontonasal dysplasia, spastic paraplegia, mental retardation and blindness: A case report with CT scan findings and review of literature. International Journal of Pediatric Otorhinolaryngology, 54, 51–57. Edwards, W. C., et al. (1971). Median cleft face syndrome. American Journal of Ophthalmology, 72, 202–205. Fox, F. W., et al. (1976). Frontonasal dysplasia with alar clefts in two sisters. Plastic and Reconstructive Surgery, 57, 553–561. Frattarelli, J. L., Boley, T. H., & Miller, R. A. (1996). Prenatal diagnosis of frontonasal dysplasia (median cleft syndrome). Journal of Ultrasound in Medicine, 1, 81–83. Fryburg, J. S., Persing, J. A., & Lin, K. Y. (1993). Frontonasal dysplasia in two successive generations. American Journal of Medical Genetics, 46, 712–714. Fryns, J. P., Kleczkowska, A., & Van den Berghe, H. (1993). Frontonasal malformation and reciprocal translocation t(15;22)(q22;q13). Clinical Genetics, 44,46–47. Fuenmayor, H. M. (1980). The spectrum of frontonasal dysplasia in an inbred pedigree. Clinical Genetics, 17, 137.

Frontonasal Dysplasia Gollop, T. R. (1981). Fronto-facio-nasal dysostosis. A new autosomal recessive syndrome. American Journal of Medical Genetics, 10, 409–412. Guinon-Almeida, M. L., Richieri-Costa, A., Saavedra, D., et al. (1996). Frontonasal dysplasia: Analysis of 21 cases and literature review. International Journal of Oral Surgery, 25, 91–97. Johnstone, E., Glanville, T., Pilling, J., et al. (2008). Prenatal diagnosis of frontonasal dysplasia using 3D ultrasound. Prenatal Diagnosis, 28, 1075–1076. Kinsey, J. A., & Streeten, B. W. (1977). Ocular abnormalities in the median cleft face syndrome. American Journal of Ophthalmology, 83, 261–266. Kurlander, G. J., et al. (1967). Roentgenology of the median cleft face syndrome. Radiology, 88, 473. Losee, J. E., Kirschner, R. E., Whitaker, L. A., et al. (2004). Congenital nasal anomalies: A classification scheme. Plastic and Reconstructive Surgery, 113, 676–689. Martinelli, P., Russo, R., Agangi, A., et al. (2002). Prenatal ultrasound diagnosis of frontonasal dysplasia. Prenatal Diagnosis, 22, 375–379. Moore, K. L., & Persaud, T. V. N. (2007). The Developing Human. Philadelphia: WB Saunders. Moreno Fuenmayor, H. (1980). The spectrum of frontonasal dysplasia in an inbred pedigree. Clinical Genetics, 17, 137–142. Nelson, M. M., & Thomson, A. J. (1982). The acrocallosal syndrome. American Journal of Medical Genetics, 12, 195–199. Nevin, N. C., Leonard, A. G., & Jones, B. (1999). Frontonasal dysostosis in two successive generations. American Journal of Medical Genetics, 87, 251–253. Orr, D. J., Slaney, S., Ashworth, G. J., et al. (1997). Craniofrontonasal dysplasia. British Journal of Plastic Surgery, 50, 153–161. Qureshi, I. L., & Naeem-uz-Zfar, K. (1996). Experience with frontonasal dysplasia of varying severity. Journal of Pediatric Surgery, 7, 885–889. Reich, E. W., et al. (1981). A clinical investigation into the etiology of frontonasal dysplasia. American Journal of Human Genetics, 33, 88A. Rohasco, S. A., & Massa, J. L. (1968). Frontonasal syndrome. British Journal of Plastic Surgery, 21, 244–249. Roubicek, M., et al. (1981). Frontonasal dysplasia as an expression of holoprosencephaly. European Journal of Pediatrics, 137, 229–231. Sedano, H. O., Cohen, M. M., Jirasek, J., et al. (1970). Frontonasal dysplasia. Journal of Pediatrics, 6, 906–913. Sedano, H. O., & Gorlin, R. J. (1986). Frontonasal malformation as a field defect and in syndromic associations. Oral Surgery, Oral Medicine, and Oral Pathology, 65, 704–710. Slaney, S. F., Goodman, F. R., Eilers-Walsman, B. L. C., et al. (1999). Acromelic frontonasal dysostosis. American Journal of Medical Genetics, 83, 109–116. Smith, D. W., & Cohen, M. M., Jr. (1973). Widow’s peak, scalphair anomaly and its relation to ocular hypertelorism. Lancet, 2, 1127–1128. Stevens, C. A., & Qumsiyeh, M. B. (1995). Syndromal frontonasal dysostosis in a child with a complex translocations involving chromosomes 3, 7, 11. American Journal of Medical Genetics, 55, 494–497.

Frontonasal Dysplasia Stratton, R. F., & Payne, R. M. (1997). Frontonasal malformation with tetralogy of Fallot associated with a submicroscopic deletion of 22q11. American Journal of Medical Genetics, 69, 287–289. Tan, S. T., & Mulliken, J. B. (1997). Hypertelorism: Nosologic analysis of 90 patients. Plastic and Reconstructive Surgery, 99, 317–327. Temple, I. K., Brunner, H., Jones, B., et al. (1990). Midline facial defects with ocular colobomata. American Journal of Medical Genetics, 37, 23–27. Tommerup, N., & Nielsen, F. (1983). A familial reciprocal translocation t(3;7)(p21.1;p13) associated with the Greig polysyndactyly-craniofacial anomalies syndrome. American Journal of Medical Genetics, 16, 313–321. Toriello, H. V. (1993). Oral-facial-digital syndromes. Clinical Dysmorphology, 2, 95–105. Toriello, H. V., Higgins, J. V., & Mann, R. (1995). Oculoauriculofrontonasal syndrome: Report of another case and review of differential diagnosis. Clinical Dysmorphology, 4, 338–346.

901 Toriello, H. V., et al. (1985). Familial occurrence of a developmental defect of the medial nasal process. American Journal of Medical Genetics, 21, 131–135. Twigg, S. R. F., Versnel, S. L., N€ urnberg, G., et al. (2009). Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. American Journal of Human Genetics, 84, 698–705. Uz, E., Alanay, Y., Aktas, D., et al. (2010). Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: Expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. American Journal of Human Genetics, 86, 789–796. van der Meulen, J. C. H., & Vaandrager, J. M. (1989). Facial clefts. World Journal of Surgery, 13, 373–383. Warkany, J., Bofinger, M. K., & Benton, D. (1973). Median facial cleft syndrome in half sisters: Dilemmas in genetic counselling. Teratology, 8, 273–285. Yoon, H., Chung, I. S., Seol, E. Y., et al. (2000). Development of the lip and palate in staged human embryos and early fetuses. Yonsei Medical Journal, 41, 477–484.

902 Fig. 1 (a, b) A newborn with frontonasal dysplasia showing ocular hypertelorism, cephalocele, hydrocephalus, and cranium bifidum

Frontonasal Dysplasia

a

b

Frontonasal Dysplasia Fig. 2 (a–g) A newborn with frontonasal dysplasia and arrhinencephaly resulting from unbalanced segregation of a maternal t(2;7)(q31;q36). The patient had partial trisomy 2q and partial monosomy 7q, iris coloboma, tetralogy of Fallot, and limb anomalies

903

a

c

b

e d

f

g

904

Frontonasal Dysplasia

a

b

Fig. 3 (a, b) A mother and a child with frontonasal dysplasia showing hypertelorism and broad and notched nasal tip

Fig. 4 A 2-year-old girl with frontonasal dysplasia

Galactosemia

Classic galactosemia (G/G) is an autosomal recessive disorder of galactose metabolism, caused by a deficiency of galactose-1-phosphate uridyl transferase. The incidence is estimated to be 1 in 30,000–1 in 60,000 births, based on the results of newborn screening programs.

Synonyms and Related Disorders Classic galactosemia; uridyltransferase deficiency

Galactose-1-phosphate

Genetics/Basic Defects 1. Inheritance: autosomal recessive. (Leslie 2003) 2. Cause: deficiency of galactose-1-phosphate uridyl transferase (GALT) 3. Galactose metabolism (Arn 2003) a. D-galactose i. Galactose: an important sugar in human nutrition, especially during childhood. ii. Milk: major source of galactose, which contains lactose, a disaccharide of glucose and galactose. iii. Liver: the primary site of galactose metabolism. iv. Individuals have the capacity to metabolize large quantities of galactose under normal circumstances. b. Normal individuals i. Lactase (present in the small intestine): metabolizes galactose to glucose and galactose. ii. The resulting glucose and galactose is then absorbed via the portal system to the liver.

iii. In the liver, a series of four reactions converts galactose to glucose-1-phosphate. iv. Glucose-1-phosphate can be metabolized to glucose, CO2, pyruvate, or glycogen depending on prevailing metabolic conditions. v. Inborn errors have been described in all of the enzymes of the pathway. c. Affected individuals: Deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT) causes classic galactosemia. 4. Galactose-1-phosphate uridyl transferase a. The gene for GALT is mapped on chromosome 9p13. b. GALT is second enzyme in the Leloir pathway, catalyzing conversion of galactose-1-phosphate and UDP glucose to UDP galactose and glucose1-phosphate. c. Essential in human infants who consume lactose as their primary carbohydrate source. d. Near total absence of GALT activity in infants with classical galactosemia. e. A deficiency causes elevated levels of galactose1-phosphate and galactitol in body tissues. 5. Endogenous production of galactose may be responsible for the long-term effects, such as cognitive dysfunction and gonadal dysfunction in female patients 6. Duarte (D) allele (Beutler 1991) a. Very common b. Defined biochemically by: i. Reduced enzyme activity ii. An isoform distinguishable by gel electrophoresis and isoelectric focusing c. Heterozygous Duarte variants (D/N) i. Observed in about 11% of Caucasian subjects ii. Have about 75% of normal GALT activity

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d. Homozygotes for the Duarte variant (D/D) i. Have approximately one half (50%) of normal transferase activity ii. Mimic carriers for galactosemia e. Infants with a galactosemia allele and a Duarte allele (D/G) i. Have 1 quarter (25%) of normal enzyme activity ii. Have reduced capacity to metabolize galactose with abnormal accumulation of galactose-1-phsphate in the red cells iii. Phenotypically normal with no ill effect 7. Genotype–phenotype correlations (Elsas II 2003). a. Q188R mutations (prevalent in 70% of Caucasians): a poorer outcome in homozygous state associated with essentially no enzyme activity (Elsas et al. 1995) b. Duarte variant (N314D) i. Homozygous state (D/D or N314D/N314D) with erythrocyte GALT enzyme activity reduced by only 50% ii. Compound heterozygotes (D/G or N314D/ Q188R) a) Relatively benign in most infants b) May or may not require dietary intervention c. Los Angels (LA) variant with identical N314D missense mutation but has normal erythrocyte GALT activity d. S135L allele i. Prevalent in Africa ii. A good prognosis if therapy is initiated in the neonatal period without neonatal hepatotoxicity and chronic problems e. K285N allele i. Prevalent in Southern Germany, Austria, and Croatia ii. A poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R

Clinical Features 1. Onset of symptoms a. May present by the end of the first week of life b. May die or develop cataracts, hepatomegaly, cirrhosis, and mental retardation in late-detected cases

Galactosemia

2. Neonatal toxicity syndrome a. Exposure to dietary galactose in infants with classical galactosemia results in acute deterioration of multiple organ systems, including the following: i. Liver dysfunction a) Jaundice b) Hepatomegaly ii. Coagulopathy iii. Poor feeding and weight loss iv. Vomiting and diarrhea v. Lethargy and hypotonia vi. Renal tubular dysfunction vii. Cerebral edema (encephalopathy) viii. Vitreous hemorrhage ix. Escherichia coli (or other gram-negative) sepsis: consider diagnosis of galactosemia since a high frequency of neonatal death appears to be caused by E. coli sepsis (Levy et al. 1977) b. Withdrawal of dietary galactose results in reversal of neonatal toxicity syndrome and reducing mortality and morbidity in the early weeks of life. 3. Cataracts a. Resulting from accumulation of galactitol within the lens b. Seen in infants with classical GALT-deficient galactosemia (and also in galactokinase deficiency) i. The ocular hallmark of untreated or latedetected patients ii. Severity of lens involvement dependent on the severity of galactosemia and the age at commencement of therapy c. Reoccur in older patients who have poor dietary compliance d. May be prevented by dietary restriction of galactose 4. Premature ovarian failure a. Despite the high prevalence of premature ovarian failure and subsequent infertility in galactosemic women, spontaneous pregnancies occur and may not be as rare as is generally assumed (Gubbels et al. 2008) b. Hypergonadotropic hypogonadism occurring almost universally (>90%) in females with classical GALT deficiency c. The rapidity and severity of the ovarian failure vary widely among individuals

Galactosemia

d. Clinical manifestations i. Delayed puberty ii. Primary amenorrhea iii. Secondary amenorrhea iv. Oligomenorrhea 5. Chronic brain effects a. Specific deficits i. Developmental speech dyspraxia and tremor ii. Globally decreased IQ and/or learning disability b. Uncertainty as to: i. Whether these deficits are initiated in early development, perhaps even prenatally, and unmasked, as more complex brain function is required ii. Whether these deficits represent true neurodegenerative processes compounded by dietary exposure and endogenous production of “intoxicants” iii. Longitudinal assessment of intellectual achievement in patients with classic galactosemia (Schadewaldt et al. 2010): a) Confirms the presence of reduced cognitive ability in classical galactosemia b) Presents evidence for an absence of substantial galactosemia-induced aggravation of this impairment with increasing age, at least in patients from 4 to 40 years of age c) Remains to be clarified whether a reduction of cognitive function in galactosemia may be initiated by an in utero toxicity of endogenously formed galactose and which role such a process may play in the development of intellectual deficiencies that are later maintained throughout life 6. Prognosis a. A life-threatening disorder if untreated. b. Currently, affected infants are treated before becoming ill because of newborn screening in most states. 7. Differential diagnosis (Elsas II 2003) a. Galactokinase (GALK) deficiency i. An autosomal recessive disorder ii. Considered in patients with cataracts and galactosemia but otherwise healthy iii. Cataracts a) The main clinical feature b) Due to accumulation of galactitol

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iv. Pseudotumor cerebri a) Described in several cases b) Considered to be a true consequence of the disorder v. These features resolve when a galactoserestricted diet is introduced vi. Diagnosis made by detection of reduced galactokinase activity vii. Caused by mutations in the GALK1 gene b. UDP-galactose 4-epimerase (GALE) deficiency i. An autosomal recessive disorder ii. Considered in patients with liver disease, sensorineural deafness, failure to thrive, and elevated galactose-1-phosphate but normal GALT activity iii. Response to the removal of galactose from their diets iv. Diagnosis made by detection of reduced UDP-galactose 4-epimerase activity v. Caused by mutations in the GALE gene c. Neonatal hepatotoxicity i. Infectious diseases (sepsis) ii. Obstructive biliary disease a) Progressive familial intrahepatic cholestasis (Byler disease) b) Metabolic diseases such as Niemann–Pick disease, type C and Wilson disease

Diagnostic Investigations 1. Newborn screening programs in most states (Leslie 2003) a. An almost 100% detection of affected infants in states that include testing for galactosemia in their newborn screening programs b. Prevention of needless deaths associated with galactosemia, resulting from limiting diagnostic measures to infants who develop symptoms c. A positive (i.e., abnormal) screening, followed by a quantitative erythrocyte GALT analysis 2. Liver dysfunction a. Bilirubin determination. i. Initial unconjugated hyperbilirubinemia ii. Later conjugated hyperbilirubinemia b. Abnormal liver function tests. c. Abnormal clotting. d. Raised plasma amino acids, particularly phenylalanine, tyrosine, and methionine. Raised

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3.

4.

5. 6. 7. 8.

9.

10. 11.

Galactosemia

phenylalanine may result in a false positive neonatal screening test for phenylketonuria. Renal tubular dysfunction a. Metabolic acidosis b. Urinalysis i. Galactosuria a) The presence of reducing substances or galactose in the urine is neither sensitive nor specific. b) Small quantities of galactose commonly found in the urine of any patient with liver disease. ii. Albuminuria a) Present in the initial stage b) Quick disappearance of albuminuria after eliminating lactose-containing formula from the diet iii. Aminoaciduria in the later stage Abnormal carbohydrate metabolism a. Increased plasma galactose b. Increased red cell galactose-1-phosphate c. Increased urine and blood galactitol Testing for hemolytic anemia Study for septicemia, especially Escherichia coli Slit lamp examination for cataract assessment Computerized tomography and magnetic resonance imaging a. Abnormalities on brain imaging: common in classical galactosemia b. Patients with late neurologic disease i. Abnormal white matter ii. Ventricular enlargement iii. Diffuse cortical atrophy with basal ganglia and brainstem involvement iv. Cerebellar atrophy v. Failure of normal myelination Endocrine investigations for hypergonadotropic hypogonadism a. Raised follicle-stimulating hormone b. Raised luteinizing hormone c. Initially normal estradiol concentration with high gonadotropin levels, indicating continued follicular development, but fall as ovarian failure progresses Increased urinary galactitol excretion Beutler test a. A fluorescent spot test for galactose1-phosphate uridyl transferase activity

b. Now widely used for the diagnosis of galactosemia c. False negative resulting from recent blood transfusions (within 3 months) d. False positive resulting from glucose6-phosphate dehydrogenase deficiency 12. Red blood cell galactose-1-phosphate a. Concentration always raised in classical galactosemia b. Not significantly affected by blood transfusions 13. Biochemical confirmation of the diagnosis a. Red blood cell galactose-1-phosphate uridyl transferase assay i. A quantitative assay to confirm the diagnosis (virtual absence of the enzyme activity in classical (G/G) galactosemia) ii. Also identifies variants with residual enzyme activity iii. False negative results due to blood transfusion within 3 months b. A GALT isoelectric-focusing electrophoresis test to distinguish variant forms such as the Duarte defect 14. DNA analysis: GALT genotyping for providing specific molecular diagnosis a. Classic (G/G) galactosemia i. Mutation analysis for the six common GALT galactosemia (G) mutations a) Q188R mutation: the most common GALT allele in whites b) S135L: the most common allele in blacks c) K285N d) L195P e) Y209C f) F171S ii. GALT sequence analysis to detect private mutations under the following two conditions: a) Both disease-causing mutations not detected by mutation analysis b) Diagnosis of galactosemia confirmed by biochemical testing b. Mutation analysis for Duarte variant (D/G) galactosemia identified by biochemical testing of the patient and both parents i. Identification of Duarte allele (N314D) by mutation analysis ii. Identification of G allele by mutation analysis or sequence analysis

Galactosemia

15. Carrier testing a. Measuring GALT activity: about 50% of control values in carriers b. Molecular genetic testing for carriers available to family members, provided GALT mutation(s) has/have been identified in the proband

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. A proband with G/G galactosemia a) Given the parents are G/N and G/N: a 25% chance of being affected with G/G galactosemia for each sib b) Given the parents are D/G and G/N: a 25% chance of being affected with G/G galactosemia and a 25% chance of being affected with D/G galactosemia for each sib ii. A proband with D/G galactosemia, given the parents are D/N and G/N: a 25% chance of being affected with D/G galactosemia for each sib b. Patient’s offspring: i. Patient with G/G galactosemia and the normal spouse with N/N: All offspring are carriers. ii. Patient with G/G galactosemia and the carrier spouse for a G allele (N/G): a 50% chance of having G/G galactosemia. iii. Patient with G/G galactosemia and the carrier spouse for a G allele (D/G): a 50% chance of having G/G galactosemia and a 50% chance of having D/G galactosemia. 2. Prenatal diagnosis possible for fetuses at a 25% risk for classical galactosemia a. Galactose-1-phosphate uridyl transferase assay in cultured amniotic fluid cells or in chorionic villus biopsies. b. Galactitol estimation in amniotic fluid supernatant. c. Mutation analysis of DNA extracted from amniocytes or chorionic villus samples if the genotype of the index case has been characterized. d. Prenatal diagnosis of a treatable condition, such as classic galactosemia, may be controversial if

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the prenatal testing is being considered for the purpose of pregnancy termination rather than early diagnosis. e. Preimplantation genetic diagnosis: may be available for families in which the disease-causing mutations have been identified. 3. Management (Arn 2003; Elsas II 2003) a. Dietary intervention. i. Lactose-galactose-restricted diet a) Restrict milk, the principal source of lactose, and products made from milk b) Breast milk and cows’ milk contraindicated ii. Milk substitutes a) Use a formula free of bioavailable lactose (e.g., Isomil or Prosobee) b) Casein hydrolysate (Alimentum, Nutramigen, and Pregestimil): not recommended because they contain small amounts of bioavailable lactose iii. Difficult to totally eliminate galactose since it is present in a wide variety of food, such as infant foods, fruits, and vegetables iv. Older patients tolerating lactose much better than children, but recommend restrict milk intake throughout life v. Calcium supplements if calcium intake does not meet the recommended daily allowance vi. May prevent cataracts, hepatomegaly, liver cirrhosis, mental retardation, and other symptoms vii. Effect of dietary restrictions during pregnancy on the long-term complications of an affected fetus: unknown viii. Individuals with homozygous Duarte variant without symptoms: do not require treatment (Ficicioglu et al. 2008) ix. Management of D/G or N344D/Q188R compound heterozygotes a) Decision to treat should be based on the demonstration of abnormal biochemical indices. b) No dietary therapy is instituted if the blood galactose and/or galactose-1phosphate do not rise above 12 mg/dL within 4 h following such ingestion, and there are no clinical signs associated with galactosemia.

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Galactosemia

b. c.

d.

e.

f.

g.

h.

c) Dietary therapy should probably be given if there is a greater accumulation of galactose or of galactose-1-phosphate. d) There is possible benefit of dietary intervention to individuals with variant forms of galactosemia with residual GALT activity in the range of 5–20%: for prevention of cataracts, ataxia, dyspraxic speech, and cognitive deficits. Vitamin K and fresh-frozen plasma to correct clotting abnormalities. Pharmacologic treatment. i. An appropriate intravenous antibiotic for gram-negative sepsis. ii. Many medications, particularly tablets, contain lactose, and this should be considered when prescribing; however, the amount of galactose is often insignificant when given over a short period. Treat unconjugated hyperbilirubinemia with phototherapy or exchange transfusion to infants who may be at an increased risk of kernicterus if albumin levels are particularly low secondary to liver disease. Parental feeding if the infant is too sick to tolerate enteral feeding for more than 1 or 2 days, unless there is significant liver disease or thrombocytopenia. Treat the following long-term problems in older children and adults with classical galactosemia, despite early and adequate therapy. i. Cataracts ii. Speech defects iii. Poor growth iv. Poor intellectual function v. Neurological deficits, predominantly extrapyramidal findings with ataxia vi. Ovarian failure Physical/speech therapy. i. Speech therapy for speech delay or verbal dyspraxia (Nelson 1995) ii. Regular assessment of development and cognitive function using standardized tests recommended (Walter et al. 1999) Other therapies/evaluations. i. Monitoring of red cell galactose1-phosphate available for assessing dietary compliance, though despite dietary adherence, these levels never decline to normal

ii. Ophthalmologic examination for cataract assessment to be made at the time of diagnosis, every 6 months until age 3 years, and then annually (Walter et al. 1999) iii. Referral to a pediatric endocrinologist by the time a female patient is 10 years (Walter et al. 1999) i. Emerging therapies. i. None with trial data. ii. Environment, GALT genotype, and epigenetic pathway of galactose metabolism probably all contribute to outcome. iii. In the absence of new therapies emerging from pathogenetic studies, attempts to enhance GALT activities may prove of value (Holton 1996; Elsas and Lai 1998).

References Arn, P. H. (2003). Galactosemia. Current Treatment Options in Neurology, 5, 343–345. Berry, G. T., Anadiotis, G. A. (2008) Galactose-1-phosphate uridyltransferase deficiency (galactosemia). eMedicine from WebMD. Updated 10 Oct, 2008. Available at: http:// emedicine.medscape.com/article/944069-overview Beutler, E. (1991). Galactosemia: Screening and diagnosis. Clinical Biochemistry, 24, 293–300. Burke, J. P., O’Keefe, M., Bowell, R., et al. (1989). Ophthalmic findings in classical galactosemia–a screened population. Journal of Pediatric Ophthalmology and Strabismus, 26, 165–168. Elsas, L. J. (2001). Prenatal diagnosis of galactose-1-phosphate uridyltransferase (GALT)-deficient galactosemia. Prenatal Diagnosis, 21, 302–303. Elsas, L. J., II (2003). Galactosemia. GeneReviews. Updated October 26, 2010. Available at: http://www.ncbi.nlm.nih. gov/books/NBK1518/ Elsas, L. J., II (2010). Galactosemia. GeneReviews. Updated October 26, 2010. Available at: http://www.ncbi.nlm.nih. gov/books/NBK/ Elsas, L. J., Dembure, P. P., Langley, S., et al. (1994). A common mutation associated with the Duarte galactosemia allele. American Journal of Human Genetics, 54, 1030–1036. Elsas, L. J., II, Langley, S., & Paulk, E. M. (1995). A molecular approach to galactosemia. European Journal of Pediatrics (7 suppl 2), S21–S27. Elsas, L. J., II, & Lai, K. (1998). The molecular biology of galactosemia. Genetics in Medicine, 1, 40–48. Elsas, L. J., Lai, K., Saunders, C. J., et al. (2001). Functional analysis of the human galactose-1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia. Molecular Genetics and Metabolism, 72, 297–305. Ficicioglu, C., Thomas, N., Yager, C., et al. (2008). Duarte (DG) galactosemia: A pilot study of biochemical and

Galactosemia neurodevelopmental assessment in children detected by newborn screening. Molecular Genetics and Metabolism, 95, 206–212. Gubbels, G. S., Land, J. A., & Rubio-Gonzalbo, M. E. (2008). Fertility and impact of pregnancies on the mother and child in classic galactosemia. Obstetrics and Gynecology, 63, 334–342. Holton, J. B. (1995). Effects of galactosemia in utero. European Journal of Pediatrics, 154, S77–S81. Holton, J. B. (1996). Galactosaemia: Pathogenesis and treatment. Journal of Inherited Metabolic Disease, 19, 3–7. Holton, J. B., Walter, J. H., & Tyfield, L. A. (2001). Galactosemia. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The Metabolic & Molecular Bases of Inherited Disease (8th ed.). New York: McGraw-Hill. Jakobs, C., Kleijer, W. J., Allen, J., et al. (1995). Prenatal diagnosis of galactosemia. European Journal of Pediatrics, 154, S33–S36. Lai, K., & Elsas, L. J. (2001). Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosemia. Molecular Genetics and Metabolism, 74, 264–272. Lai, K., Langley, S. D., Singh, R. H., et al. (1996). A prevalent mutation for galactosemia among black Americans. Journal of Pediatrics, 128, 89–95. Langley, S. D., Lai, K., Dembure, P. P., et al. (1997). Molecular basis for Duarte and Los Angeles variant galactosemia. American Journal of Human Genetics, 60, 366–372.

911 Leslie, N. D. (2003). Insights into the pathogenesis of galactosemia. Annual Review of Nutrition, 23, 59–80. Levy, H. L., Sepe, S. J., Shih, V. E., et al. (1977). Sepsis due to Escherichia coli in neonates with galactosemia. The New England Journal of Medicine, 297, 823–825. Nelson, D. (1995). Verbal dyspraxia in children with galactosemia. European Journal of Pediatrics, 154(Suppl), S6–S7. Nelson, M. D., Jr., Wolff, J. A., Cross, C. A., et al. (1992). Galactosemia: Evaluation with MR imaging. Radiology, 184, 255–261. Ng, W. G., Xu, Y. K., Kaufman, F. R., et al. (1994). Biochemical and molecular studies of 132 patients with galactosemia. Human Genetics, 94, 359–363. Schadewaldt, P., Hoffmann, B., Hammen, H.-W., et al. (2010). Longitudinal assessment of intellectual achievement in patients with classical galactosemia. Pediatrics, 125, e374–e381. Waggoner, D. D., Buist, N. R., & Donnell, G. N. (1990). Long-term prognosis in galactosaemia: Results of a survey of 350 cases. Journal of Inherited Metabolic Disease, 13, 802–818. Waisbren, S. E., Norman, T. R., Schnell, R. R., et al. (1983). Speech and language deficits in early-treated children with galactosemia. Journal of Pediatrics, 102, 75–77. Walter, J. H., Collins, J. E., & Leonard, J. V. (1999). Recommendations for the management of galactosaemia (UK Galactosaemia Steering Group). Archives of Disease in Childhood, 80, 93–96.

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Fig. 1 A 5-year-old boy with classical galactosemia. The initial clinical presentation was at 12 days of age with unconjugated hyperbilirubinemia, presence of reducing substance in the urine, and E. coli sepsis. The patient was found to have posterior stellate lens opacities OU. He was found to have deficient galactose-1-phosphate uridyl transferase activity of 0.3 (normal range: 17–37 UMOL/HR/G HGB). Galactokinase was within normal limits. The patient was put on galactose-free diet and has been growing well

Galactosemia

Fig. 2 A 2-month-old girl with D/G compound heterozygote. The newborn screening revealed total blood galactose (Gal + Gal-1-phosphate) level of 33.4 mg/dL (normal, 40.0). DNA analysis showed one copy of the N314D (Duarte galactosemia) variant and one copy of the Q188R (classical galactosemia) mutation. The patient is currently on Isomil and growing well

Gastroschisis

Gastroschisis (Greek for belly cleft) is a congenital paraumbilical wall defect characterized by the protrusion of the intestines uncovered by the peritoneum. It represents one of the most common congenital malformations requiring multidisciplinary neonatal intensive care, with an incidence of approximately 1 in 3,300 births that seems to be increasing (Alvarez and Burd 2007).

Genetics/Basic Defects 1. Precise etiology unknown 2. Inheritance a. Isolated occurrence in most cases b. Rare autosomal dominant inheritance 3. Pathogenesis and risk factors Sharp et al. (2000); Fillingham and Rankin 2008; Lammer et al. 2008; Rasmussen and Frias 2008) a. Pathogenesis i. Most commonly quoted: Hoyme’s vascular disruption theory with disruption occurring in the omphalomesenteric artery (Hoyme et al. 1983) ii. More recent proposed pathogenesis a) Consequence of abnormal folding of the body wall (Feldkamp et al. 2007) b) Disruption of endothelial oxide synthase pathway (its relationship to vasculogenesis) by environmental exposures or by genetic variation may represent one pathogenetic model for gastroschisis (Lammer et al. 2008).

b. Risk factors i. Vascular insult a) Association of maternal smoking and maternal cocaine use with an increased incidence of gastroschisis b) The association of intestinal atresia and gastroschisis ii. Premature atrophy or abnormal persistence of the right umbilical vein iii. In utero rupture of a hernia of the umbilical cord iv. Young maternal age (97 percentile (macrocephaly), with frontal bossing iii. Cardiac or ovarian fibromas iv. Childhood medulloblastoma (primitive neuroectodermal tumor) v. Lymphomesenteric or pleural cysts vi. Congenital malformation: cleft lip and/or palate, polydactyly, eye anomaly (cataract, coloboma, microphthalmia)

Diagnostic Investigations 1. Family history: a. Brain tumors b. Female organ tumors 2. Medical and dental history: a. Removal of jaw cysts b. Abscesses c. Skin lesions 3. Physical examination: a. Mandibular and maxillary swelling b. Head circumference c. Head shape d. Skin basal cell nevi e. Pits on the palms and soles 4. Radiographic studies: a. Skull radiography for detection of calcified cerebral falx b. Jaw radiography for detection of maxillary and mandibular cystic lesions c. Chest radiography for rib and vertebral anomalies 5. MRI of the brain to detect meningiomas or medulloblastomas at an early age 6. Ovarian ultrasonography for detection of ovarian cysts or fibromas 7. Echocardiograms to evaluate cardiac fibromas 8. Cytogenetic analysis to detect rare interstitial 9q deletion associated with clinical features of NBCCS and additional features such as severe developmental delay or short stature 9. Molecular genetic testing (Evans and Farndon 2010): a. Sequence analysis of exons 2-23 with intronexon junctions and one of the splice forms of exon 1 to detect PTCH1 gene mutation (Marsh et al. 2005; Klein et al. 2005) b. Deletion testing to detect exonic and whole PTCH1 gene deletions

981

Genetic Counseling 1. Recurrence risk: a. Patient’s sib: i. An affected parent: a 50% risk ii. Unaffected parents: a low risk b. Patient’s offspring: a 50% risk 2. Prenatal diagnosis: a. Ultrasonography: i. Hydrocephalus ii. Macrocephaly iii. Cleft lip and palate iv. Intracardiac tumor v. Fetal hydrops vi. Fetal chylothorax b. Molecular genetic testing available, provided the disease-causing allele of an affected family member has been identified, by analyzing DNA extracted from fetal cells obtained by: i. CVS ii. Amniocentesis 3. Management: a. Surgical excision of keratocysts identified early in life b. Basal cell carcinomas: i. Complete eradication of aggressive BCCs; surgical excision supplemented by cryotherapy, laser treatment for early lesion, and photodynamic therapy ii. Preserve normal tissue to prevent disfigurement c. Surgical excision of ovarian fibromas

References Agaram, N. P., Collins, R. M., Barnes, L., et al. (2004). Molecular analysis to demonstrate that odontogenic keratocysts are neoplastic. Archives of Pathology & Laboratory Medicine, 128, 313–317. Ahn, S. G., Lim, Y. S., Kim, D. K., et al. (2004). Nevoid basal cell carcinoma syndrome: A retrospective analysis of 33 affected Korean individuals. International Journal of Oral and Maxillofacial Surgery, 33, 458–462. Bak, M., Hansen, C., Tommerup, N., et al. (2003). The Hedgehog signaling pathway-implications for drug targets in cancer and neurodegenerative disorders. Pharmacogenomics, 4, 411–429. Bale, A. E., & Yu, K. (2001). The Hedgehog pathway and basal cell carcinomas. Human Molecular Genetics, 10, 757–762.

982 Bare, J. W., Chen, M. A., Rothman, A. L., et al. (1992). Basal cell nevus syndrome: linkage studies at 9q. The American Society of Human Genetics 42nd annual meeting. American Journal of Human Genetics 51(4 Suppl), A57–A62. Bitar, G. J., Herman, C. K., Dahman, M. I., et al. (2002). Basal cell nevus syndrome: Guideline for early detection. American Family Physician, 65, 2501–2504. Bonifas, J. M., Bare, J. W., Kerschmann, R. L., et al. (1994). Parental origin of chromosome 9q22.3-q31 lost in basal cell carcinomas from basal cell nevus syndrome patients. Human Molecular Genetics, 3, 477–478. Boonen, S. E., Stahl, D., Kreiborg, S., et al. (2005). Delineation of an interstitial 9q22 deletion in basal cell nevus syndrome. American Journal of Medical Genetics, 132A, 324–328. Chen, C.-P., Lin, S.-P., Wang, T.-H., et al. (2006). Perinatal findings and molecular cytogenetic analyses of de novo interstitial deletion of 9q (9q22.3 ! q31.3) associated with Gorlin syndrome. Prenatal Diagnosis, 26, 725–729. Cohen, M. M., Jr. (1999). Nevoid basal cell carcinoma syndrome: Molecular biology and new hypotheses. International Journal of Oral and Maxillofacial Surgery, 28, 216–223. Compton, J. G., Goldstein, A. M., Turner, M., et al. (1994). Fine mapping of the locus for nevoid basal cell carcinoma syndrome on chromosome 9q. The Journal of Investigative Dermatology, 103, 178–181. Dahl, E., Kreiborg, S., & Jensen, B. L. (1976). Craniofacial morphology in the nevoid basal cell carcinoma syndrome. International Journal of Oral Surgery, 5, 300–310. Debeer, P., & Devriendt, K. (2005). Early recognition of basal cell naevus syndrome. European Journal of Pediatrics, 164, 123–125. Donatsky, O., Hjorting-Hansen, E., et al. (1976). Clinical, radiologic, and histopathologic aspects of 13 cases of nevoid basal cell carcinoma syndrome. International Journal of Oral Surgery, 5, 19–28. Evans, D. G., Birch, J. M., & Orton, C. I. (1991). Brain tumours and the occurrence of severe invasive basal cell carcinoma in first degree relatives with Gorlin syndrome. British Journal of Neurosurgery, 5, 643–646. Evans, D. G., & Farndon, P. A. (2010). Nevoid basal cell carcinoma syndrome [review]. GeneReviews. Updated July 22, 2010. Available at: http://www.ncbi.nlm.nih.gov/books/ NBK1151/. Evans, D. G., Farndon, P. A., Burnell, L. D., et al. (1991). The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. British Journal of Cancer, 64, 959–961. Evans, D. G., Ladusans, E. J., Rimmer, S., et al. (1993). Complications of the naevoid basal cell carcinoma syndrome: Results of a population based study. Journal of Medical Genetics, 30, 460–464. Farndon, P. A. (2004). Gorlin (naevoid basal cell carcinoma) syndrome. In R. Eeles, D. F. Easton, B. A. J. Ponder, & C. Eng (Eds.), Genetic predisposition to cancer (pp. 193–213). London: Hodder Arnold. Farndon, P. A., Del Mastro, R. G., Evans, D. G., et al. (1992). Location of gene for Gorlin syndrome. Lancet, 339, 581–582. Gorlin, R. J. (2004). Nevoid basal cell carcinoma (Gorlin) syndrome. Genetics in Medicine, 6, 530–539.

Gorlin Syndrome Gorlin, R. J., & Goltz, R. W. (1960). Multiple nevoid basal cell epithelioma, jaw cysts and bifid rib: A syndrome. The New England Journal of Medicine, 262, 908–912. Hahn, H., Wicking, C., Zaphiropoulous, P. G., et al. (1996). Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell, 85, 841–851. Howell, J., & Caro, M. R. (1959). The basal cell nevus. Its relationship to multiple cutaneous cancer and associated anomalies of development. Archives of Dermatology, 79, 67. Itkin, A., & Gilchrest, B. A. (2004). delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatologic Surgery, 30, 1054–1061. Johnson, R. L., Rothman, A. L., Xie, J., et al. (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science, 272, 1668–1671. Kagy, M. K., & Amonette, R. (2000). The use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas in a basal cell nevus syndrome patient. Dermatologic Surgery, 26, 577–578. Kimonis, V. E., Goldstein, A. M., Pastakia, B., et al. (1997). Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. American Journal of Medical Genetics, 69, 299–308. Kimonis, V. E., Mehta, S. G., Digiovanna, J. J., et al. (2004). Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genetics in Medicine, 6, 495–502. Klein, R. D., Dykas, D. J., & Bale, A. E. (2005). Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory. Genetics in Medicine, 7, 611–619. Lo Muzio, L. (2008). Nevoid basal cell carcinoma syndrome (Review). Orphanet Journal of Rare Diseases, 3, 32–48. Manfredi, M., Vescovi, P., Bonanini, M., et al. (2004). nevoid basal cell carcinoma syndrome: A review of the literature (Review). International Journal of Oral and Maxillofacial Surgery, 33, 117–124. Marks, R., Gebauer, K., Shumack, S., et al. (2001). Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: Results of a multicenter 6-week dose-response trial. Journal of the American Academy of Dermatology, 44, 807–813. Marsh, A., Wicking, C., Wainwright, B., et al. (2005). DHPLC analysis of patients with nevoid basal cell carcinoma syndrome reveals novel PTCH missense mutations in the sterolsensing domain. Human Mutation, 26, 283. Midro, A., Panasiuk, B., Tumer, Z., et al. (2004). Interstitial deletion 9q22.32-q33.2 associated with additional familial translocation t(9;17)(q34.11;p11.2) in a patient with GorlinGoltz syndrome and features of nail-patella syndrome. American Journal of Medical Genetics, 124A, 179–191. Olivieri, C., Maraschio, P., Caselli, D., et al. (2003). Interstitial deletion of chromosome 9, int del(9)(9q22.31–q31.2), including the genes causing multiple basal cell nevus syndrome and Robinow/brachydactyly 1 syndrome. European Journal of Pediatrics, 162, 100–103. Oseroff, A. R., Shieh, S., Frawley, N. P., et al. (2005). Treatment of diffuse basal cell carcinomas and basaloid follicular

Gorlin Syndrome hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Archives of Dermatology, 141, 60–67. Pastorino, L., Ghiorzo, P., Nasti, S., et al. (2009). identification of a SUFU germline mutation in a family with Gorlin syndrome. American Journal of Medical Genetics. Part A, 149A, 1539–1543. Ragge, N. K., Salt, A., Collin, J. R., et al. (2005). Gorlin syndrome: The PTCH gene links ocular developmental defects and tumour formation. British Journal of Ophthalmology, 89, 988–991. Ratcliffe, J. F., Shanley, S., & Chenevix-Trench, G. (1995). The prevalence of cervical and thoracic congenital skeletal abnormalities in basal cell naevus syndrome; a review of cervical and chest radiographs in 80 patients with BCNS. British Journal of Radiology, 68, 596–599. Sasaki, K., Yoshimoto, T., Nakao, T., et al. (2000). A nevoid basal cell carcinoma syndrome with chromosomal aberration. No To Hattatsu, 32, 49–55. Shanley, S., Ratcliffe, J., Hockey, A., et al. (1994). Nevoid basal cell carcinoma syndrome: Review of 118 affected individuals. American Journal of Medical Genetics, 50, 282–290. Shimkets, R., Gailani, M. R., Siu, V. M., et al. (1996). Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients. American Journal of Human Genetics, 59, 417–422. Smyth, I., Narang, M. A., Evans, T., et al. (1999). Isolation and characterization of human patched 2 (PTCH2), a putative

983 tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Human Molecular Genetics, 8, 291–297. Stockfleth, E., Ulrich, C., Hauschild, A., et al. (2002). Successful treatment of basal cell carcinomas in a nevoid basal cell carcinoma syndrome with topical 5% imiquimod. European Journal of Dermatology, 12, 569–572. Van der Geer, S., Krekels, G. A. M., & Verhaegh, M. E. (2009). treatment of the patient with nevoid basal cell carcinoma syndrome in a megasession. Dermatologic Surgery, 35, 709–713. Veenstra-Knol, H. E., Scheewe, J. H., van der Vlist, G. J., et al. (2005). Early recognition of basal cell naevus syndrome. European Journal of Pediatrics, 164, 126–130. Wicking, C., Shanley, S., Smyth, I., et al. (1997). Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. American Journal of Human Genetics, 60, 21–26. Yamamoto, K., Yoshihashi, H., Furuya, N., et al. (2009). Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: Report of two cases and review of the literature. Congenital anomalies, 49, 8–14. Zurada, J., & Ratner, D. (2005). Diagnosis and treatment of basal cell nevus syndrome. Skinmed, 4, 107–110.

984 Fig. 1 (a, b) An 11-year-old boy and his father both have Gorlin syndrome. The boy had multiple odontogenic cysts removed from his jaw. Craniofacial CT scan showed extensive dural and choroid plexus calcifications and abnormal enlargement of subarachnoid space in the left frontal and anterior temporal regions. He was noted to have macrocephaly, forehead bossing, and plantar pits. His father had his multiple odontogenic cysts removed at 16 years of age. In addition, he has several soft subcutaneous tissue masses in his fingers and his right foot. The patient is heterozygous for a duplication of a single “A” nucleotide in exon 2 of the PTCH gene. The normal sequence with the base that is duplicated in braces is “TTGTT(A)CATTCA.” This mutation is denoted c.278dupA at the cDNA level or p Tyr93Stop (Y93X). The c.278DupA mutation results in the replacement of a Tyrosine codon with a Stop codon at position 93

Gorlin Syndrome

a

b

Gorlin Syndrome

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Fig. 2 CT scan of jaw shows multiple odontogenic cysts

Fig. 4 A small subcutaneous nodule seen in the dorsal aspect of the foot of the father

Fig. 3 A small subcutaneous nodule seen in the index fingers of the father

Greig Cephalopolysyndactyly Syndrome

Greig cephalopolysyndactyly (GCPS) syndrome is named after David Middleton Greig for his 1926 description of a patient with unusual head shape, hypertelorism, and limb anomalies. It is a rare, pleiotropic, multiple congenital anomaly syndrome characterized by the primary clinical triad of polysyndactyly, macrocephaly, and hypertelorism.

Synonyms and Related Disorders Cephalopolysyndactyly; Polysyndactyly with peculiar skull shape

Genetics/Basic Defects 1. Inheritance: Autosomal dominant with high penetrance in majority of cases. 2. Caused by mutations in the transcription factor GLI3 on chromosome 7p13 resulting in functional haploinsufficiency of GLI3. The mutations include: a. Point mutations b. Frameshift mutations c. Translocation mutations d. Deletion mutations e. Insertion mutations 3. Allelic to the Pallister-Hall syndrome (PHS) and one form of the acrocallosal syndrome: a. Severe GCPS phenotype is likely caused by deletion of contiguous genes and substantially overlaps with the mild end of the acrocallosal syndrome (an autosomal recessive disorder characterized by pre- or postaxial polydactyly, syndactyly, agenesis corpus callosum, ocular

hypertelorism, macrocephaly, moderate to severe mental retardation, intracerebral cysts, seizures, and umbilical and inguinal hernias). b. GLI3 mutations can also cause PHS, postaxial polydactyly type A, and other GLI3 morphopathies. GCPS and PHS are likely allelic with distinct modes of pathogenesis. 4. Phenotypes caused by mutations in GLI3 are diverse, discrete, variable, and pleiotropic. The mutations in GLI3 that cause PHS and GCPS correlate with the phenotypes on two levels: a. Many types of inactivating mutations cause GCPS. b. Whereas PHS is caused almost exclusively by truncation mutations in the middle third of the gene. 5. Mutations in genes other than GLI: possible in some patients with a GCPS phenotype.

Clinical Features 1. The primary clinical triad. a. Macrocephaly b. Hypertelorism c. Polysyndactyly 2. Variable clinical manifestations 3. Developmental history: a. Feeding problems/failure to thrive b. Developmental delay, seizures, and psychomotor retardation: more likely in a child with rare CNS malformations or uncommon hydrocephalus and more common in individuals with large (>300 kb) deletions that encompass GLI3

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4. Craniofacial features: highly variable a. Significant hypertelorism (increased interpupillary distance) with or without telecanthus (increased inner canthal distance) in some patients b. Macrocephaly, not typically associated with CNS anomalies, such as hydrocephalus and seizures 5. Digital anomalies: a. Polydactyly: i. Classically described as preaxial. ii. May occur in any limb. iii. Postaxial may be more common than preaxial. iv. Most common finding: postaxial polydactyly of the hands and preaxial polydactyly of the feet. v. Severity varies widely among individuals and among limbs in the same individual. This can vary from an apparently normal extremity, through subtle broadening of the thumb or hallux, tiny postaxial nubbins, to partially bifid digits, hypoplastic supernumerary digits, fully formed supernumerary digits, and higher order polydactyly. b. Cutaneous syndactyly: highly variable. i. Absent in many patients ii. Mild partial cutaneous syndactyly of a few digits in some patients iii. The spectrum continues through to complete cutaneous syndactyly of all digits, not unlike that seen in patients with Apert syndrome. 6. Less common anomalies: a. Craniosynostosis: very few patients. b. Mental retardation: not common. c. Agenesis of the corpus callosum. d. Umbilical and diaphragmatic hernias. e. Risk of cognitive impairment appears to be associated with the GCPS-contiguous gene syndrome. 7. Diagnostic criteria (Johnston et al. 2005): a. Presumptive diagnosis: a proband with: i. Preaxial polydactyly ii. Syndactyly of toes 1–3 or fingers 3–4 iii. Ocular hypertelorism iv. Macrocephaly b. Firm diagnosis: i. Presence of an affected first-degree relative whom the diagnosis has been independently established

Greig Cephalopolysyndactyly Syndrome

8.

9.

10.

11.

ii. A proband who has features of GCPS and a mutation in GLI3 c. Cautions in applying above diagnostic criteria: i. Clinical criteria: useful but not sufficiently specific to warrant a “firm” diagnosis on clinical grounds alone ii. A small but significant fraction of individuals with features of GCPS do not have mutations in GLI3. iii. Features of GCPS are seen in many other syndromes. Diagnostic criteria (combined clinical-molecular definition for the syndrome) (Biesecker 2008) a. A presumptive diagnosis with the classic triad: i. Preaxial polydactyly with cutaneous syndactyly of at least one limb ii. Hypertelorism iii. Macrocephaly b. Definitive diagnosis: i. A phenotype consistent with GCPS but which may not manifest all three attributes listed above ii. Presence of a GLI3 mutation Additional definitive diagnostic criteria: persons with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance Prognosis: a. A mild form: excellent general health and normal longevity reported in several large families b. Slight increase in the incidence of developmental delay or cognitive impairment c. Worse prognosis in patients with large deletions that include GLI3 Differential diagnosis: a. Preaxial polydactyly type IV b. GCPS contiguous gene syndrome c. Acrocallosal syndrome (ACLS): i. Inherited in an autosomal recessive manner. ii. Pre- or postaxial polydactyly. iii. Syndactyly. iv. Agenesis of the corpus callosum (rare in GCPS). v. Ocular hypertelorism. vi. Macrocephaly. vii. Moderate to severe mental retardation. viii. Intracerebral cysts.

Greig Cephalopolysyndactyly Syndrome

ix. Seizures. x. Umbilical and inguinal hernias. xi. The milder end of the ACLS phenotype can overlap with the severe end of the GCPS phenotype caused by interstitial deletions of 7p13 that delete GLI3 and additional neighboring genes. xii. Frequency of consanguinity, sibling recurrences with unaffected parents, and preliminary mapping data suggest that ACLS can be a disorder distinct from severe GCPS. d. Gorlin syndrome e. Carpenter syndrome f. Teebi syndrome

Diagnostic Investigations 1. Radiographic studies of digital anomalies 2. CNS imaging studies: a. For individuals showing signs of increased intracranial pressure, developmental delay, loss of milestones, or seizures b. To evaluate hydrocephalus or other CNS abnormalities 3. Chromosome analysis: performed either as a first test, or in all patients who have GCPS but no mutation was found by sequencing: a. Detection of visible pure chromosomal deletions involving 7p13 or a deletion combined with a translocation b. Detection of familial translocation: a risk for offspring with unbalanced translocations in addition to their risk of having a child with GCPS 4. Molecular genetic testing: a. Indications: i. Confirmatory diagnostic testing ii. Prenatal diagnosis b. FISH analysis: Using hybridization of the labeled BAC clone to metaphase spreads detects deletions in the estimated 5–10% of individuals with large deletions. c. Comparative genomic hybridization (CGH): i. An array of GLI3 is available on a limited clinical basis. ii. CGH array would be expected to detect a deletion that encompasses more than one target on the array.

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d. Other methodologies: i. Loss-of-heterozygosity (LOH) analysis to detect large deletions ii. Sequencing of the GLI3 coding exons or scanning with denaturing high-performance liquid chromatography (DHPLC), single-strand conformation polymorphism (SSCP), or other conformation detection methods: an appropriate first screen for patients with typical GCPS iii. Quantitative PCR

Genetic Counseling 1. Recurrence risk: a. Patient’s sib: i. De novo cases: recurrence risk low ii. Fifty percent of siblings affected if one of the parents is affected iii. No instances of germline mosaicism reported, but it remains a possibility iv. Proband with an unbalanced structural chromosome constitution: a) Neither parents with a structural chromosome rearrangement: risk to sibs negligible b) A parent with a balanced structural chromosome rearrangement: risk to sibs increases and depends upon the specific chromosome rearrangement b. Patient’s offspring i. Fifty percent risk of inheriting the mutation and having an affected offspring: Since intrafamilial variability is generally low, affected offspring are expected to have clinical findings similar to those of the parent. ii. Offspring of an individual with a balanced or unbalanced chromosomal rearrangement: at risk of having a similar or related rearrangement. 2. Prenatal diagnosis: a. Ultrasound studies in pregnancies at 50% risk may detect the following findings: i. Polydactyly ii. Ma iii. CNS malformations such as hydrocephalus b. Chromosome analysis of fetal cells in at-risk families with a parent having a cytogenetically visible 7p13 deletion or a balanced chromosomal rearrangement.

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c. Molecular genetic testing: Antenatal molecular diagnosis is technically straightforward to perform. d. Preimplantation genetic diagnosis (PGD): may be available for families in which the diseasecausing mutation or chromosome abnormality has been identified in an affected family. 3. Management: a. Symptomatic treatment with plastic or orthopedic surgery indicated for significant limb malformations b. Surgical repair: i. Preaxial polydactyly of the thumbs: a higher priority for surgical correction than postaxial polydactyly of the hand or polydactyly of the foot because of the importance of the thumbs for prehensile grasp ii. Severe syndactyly of the fingers iii. Surgical correction of the feet for orthopedic complications, cosmetic benefits, and easier fitting of shoes

References Balk, K., & Biesecker, L. G. (2008). The clinical atlas of Greig cephalopolysyndactyly syndrome. American Journal of Medical Genetics. Part A, 146, 548–557. Baraitser, M., Winter, R. M., & Brett, E. M. (1983). Greig cephalopolysyndactyly: Report of 13 affected individuals in three families. Clinical Genetics, 24, 257–265. Biesecker, L. G. (2002). Polydactyly: How many disorders and how many genes? American Journal of Medical Genetics, 112, 279–283. Biesecker, L. G. (2006). What you can learn from one gene: GLI3. Journal of Medical Genetics, 43, 465–469. Biesecker, L. G. (2008). The Greig cephalopolysyndactyly (Review). Orphanet Journal of Rare Diseases, 3, 10–15. Biesecker, L. G. (2009). Greig cephalopolysyndactyly syndrome. Gene Reviews. Updated April 30, 2009. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1446/. Debeer, P., Peeters, H., Driess, S., et al. (2003). Variable phenotype in Greig cephalopolysyndactyly syndrome: Clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. American Journal of Medical Genetics, 120A, 49–58.

Greig Cephalopolysyndactyly Syndrome Driess, S., Freese, K., Bornholdt, D., et al. (2003). Gene symbol: GLI3. Disease: Greig cephalopolysyndactyly syndrome. Human Genetics, 112, 103. Duncan, P. A., Klein, R. M., Wilmot, P. L., et al. (1979). Greig cephalopolysyndactyly syndrome. American Journal of Diseases of Children, 133, 818–821. Greig, D. M. (1926). Oxycephaly. Edinburgh Medical Journal, 33, 189–218. Johnston, J. J., Olivos-Glander, I., Killoran, C., et al. (2005). Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: Robust phenotype prediction from the type and position of GLI3 mutations. American Journal of Human Genetics, 76, 609–622. Johnston, J. J., Olivos-Glander, I., Turner, J., et al. (2003). Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and its distinction from acrocallosal syndrome. American Journal of Medical Genetics, 123A, 236–242. Johnston, J., Walker, R., Davis, S., et al. (2007). Zoom-in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes. Journal of Medical Genetics, 44, e59. Kalff-Suske, M. (2000). Gene symbol: GLI3. Disease: Greig cephalopolysyndactyly syndrome. Human Genetics, 107, 203. Kalff-Suske, M., Wild, A., Topp, J., et al. (1999). Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Human Molecular Genetics, 8, 1769–1777. Kroisel, P. M., Petek, E., & Wagner, K. (2001). Phenotype of five patients with Greig syndrome and microdeletion of 7p13. American Journal of Medical Genetics, 102, 243–249. Mendoza-Londono, R., Kashork, C. D., Shaffer, L. G., et al. (2005). Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes. Genes, Chromosomes & Cancer, 42, 82–86. Pettigrew, A. L., Greenberg, F., Caskey, C. T., et al. (1991). Greig syndrome associated with an interstitial deletion of 7p: Confirmation of the localization of Greig syndrome to 7p13. Human Genetics, 87, 452–456. Radhakrishna, U., Bornholdt, D., Scott, H. S., et al. (1999). The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations. American Journal of Human Genetics, 65, 645–655. Wild, A., Kalff-Suske, M., Vortkamp, A., et al. (1997). Point mutations in human GLI3 cause Greig syndrome. Human Molecular Genetics, 6, 1979–1984. Williams, P. G., Hersh, J. H., Yen, F. F., et al. (1997). Greig cephalopolysyndactyly syndrome: Altered phenotype of a microdeletion syndrome due to the presence of a cytogenetic abnormality. Clinical Genetics, 52, 436–441.

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Fig. 1 (a, b) A 34-year-old patient with typical facial features characterized by macrocephaly and hypertelorism. He also has mental retardation and seizure disorder. The hands show

a

postaxial polydactyly and complete cutaneous syndactyly of digits 2–5 with fusion of nails. The feet show a partially duplicated hallux with cutaneous syndactyly of several digits

b

Fig. 2 (a, b) Radiographs of the same patient. The hands show six phalanges with partial fusion of the third and fourth metacarpals and partial fusion of the fourth and fifth proximal phalanges. The feet shows a partially duplicated hallux

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a

Greig Cephalopolysyndactyly Syndrome

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Fig. 3 (a–c) Another patient with macrocephaly, ocular hypertelorism, and a partially duplicated great hallux

Hallermann-Streiff Syndrome

Hallermann-Streiff syndrome was independently described by Hallermann in 1948 and Streiff in 1950. The syndrome is characterized by proportionate short stature, craniofacial dysostoses consisting of skeletal, ophthalmologic, and cutaneous defects.

Synonyms and Related Disorders Francois dyscephalic syndrome

Genetics/Basic Defects 1. Sporadic in virtually all cases 2. Inheritance pattern unknown

Clinical Features 1. Characteristic craniofacial features a. Dyscephaly (malformation of the cranium and bones of the face) (89–90%) i. Calvarium a) Brachycephaly b) Thin calvarium c) Delayed closure of fontanelles d) Wide cranial sutures ii. Cranial base a) Platybasia b) Depressed sella c) Elevated anterior cranial fossa iii. Parrotlike face a) A beaked nose b) Hypoplastic mandible

b. Hypotrichosis (80–82%) i. Alopecia a) Characteristic sutural alopecia (hair loss following the lines of the cranial sutures) b) Frontal alopecia c) Alopecia at the scalp margins ii. Hypotrichosis involving the eye-brows and eyelashes iii. Brittle and sparse scalp hair c. Cutaneous atrophy (68–70%) i. Face ii. Scalp d. Ocular abnormalities i. Congenital cataracts (81–90%) ii. Microphthalmos (78–83%) iii. Nystagmus iv. Strabismus v. Glaucoma vi. Blue sclerae vii. Fundal anomalies viii. Conjunctival defects ix. Corneal abnormalities x. Down slanting palpebral fissures xi. Intraocular hypertension xii. Lower lid coloboma xiii. Iris atrophy xiv. Persistent pupillary membrane xv. Enophthalmos xvi. Bilateral retinal detachments (Haque et al. 2009) xvii. Epicanthal folds e. Mouth i. Microstomia ii. Narrow/high-arched palate

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iii. Dental abnormalities (80–85%) a) Natal teeth b) Partial anodontia/hypoplasia c) Persistent deciduous teeth d) Irregular implantation of the teeth e) Anterior open bite 2. Musculoskeletal abnormalities a. Proportionate short stature (45–69%) b. Syndactyly c. Lordosis d. Scoliosis e. Spina bifida f. Winged scapulae g. Hyperextensible joints including temporomandibular joints h. Hip dislocation i. Periodic osteoporosis 3. Other abnormalities a. Mild to severe mental retardation (15%) b. Calcified falx cerebri c. Neurologic abnormalities i. Neurofibromatosis ii. Epilepsy d. Genital anomalies (10–12%) i. Hypogenitalism ii. Cryptorchidism iii. Hypospadias iv. Subseptate uterus v. Clitoral hypertrophy e. Cardiac defects (2–9%) i. Pulmonic stenosis ii. Atrial septal defect iii. Ventricular septal defect iv. Patent ductus arteriosus v. Tetralogy of Fallot f. Endocrinological abnormalities i. Immune deficiency ii. Hypoparathyroidism iii. Hypothyroidism iv. Hypopituitarism g. Ear anomalies (9%) h. Hematopoietic abnormalities (7%) i. Pulmonary anomalies (3%) i. Obstructive sleep apnea ii. Tracheomalacia iii. Recurrent pulmonary infections iv. Cor pulmonale j. Gastrointestinal abnormalities (3%)

Hallermann-Streiff Syndrome

k. Muscular hypotrophy (3%) l. Hepatic anomalies (2%) m. Renal anomalies (1–2%): bilateral duplication of renal collecting system 4. Prognosis a. Some patients succumb in infancy to respiratory infections and pulmonary insufficiency, possibly related to airway obstruction and abnormal compliance b. Majority of patients with a normal life span 5. Diagnostic criteria a. Major features i. Dyscephaly with beak nose and mandibular hypoplasia ii. Dental abnormalities iii. Proportional short stature iv. Hypotrichosis v. Cutaneous atrophy vi. Microphthalmia vii. Congenital cataracts b. Minor features i. Narrow/high-arched palate ii. Ocular features a) Blue sclera b) Antimongoloid palpebral fissures c) Synechiae irides d) Choroid atrophy iii. Hypoplastic genitalia iv. Musculoskeletal features a) Elevated scapulae b) Scoliosis c) Lordosis d) Hyperextensible joints v. Mental retardation

Diagnostic Investigations 1. Radiography (Christian et al. 1991) a. Skull i. A large, poorly ossified skull ii. Delayed closure of fontanelles with persistent wide sutures iii. Presence of Wormian bones iv. Brachycephaly v. Platybasia vi. Depressed sella turcica

Hallermann-Streiff Syndrome

vii. Frontal or parietal bossing viii. Small orbits ix. Disproportion between the large cranial vault and the small facial skeleton x. Midfacial hypoplasia a) Hypoplastic mandibular ramus b) Possible absent condyles c) Anteriorly displaced temporomandibular joint d) Hypoplastic malar bones xi. A birdlike nose xii. Micrognathia xiii. Dental anomalies a) Presence of natal teeth b) Retained decidual teeth c) Partial anodontia d) Supernumerary and hypoplastic teeth e) Anterior open bite malocclusion b. Long bones i. Thin/gracile ii. Retarded bone age c. Other skeletal anomalies i. Scaphocephaly ii. Cervical vertebral anomalies iii. Mild platyspondyly iv. Scoliosis v. Lordosis vi. Elevated scapulae vii. Hip dislocation viii. Spina bifida ix. Syndactyly 2. Overnight polysomnography to confirm obstructive sleep apnea 3. Endocrine evaluation for hypothyroidism, hypoparathyroidism, or hypopituitarism 4. Chromosome study: no diagnostic cytogenetic characteristics

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased 2. Prenatal diagnosis: not been reported 3. Management a. Surgery i. Repair of cardiovascular defect

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ii. Ophthalmological procedure (cataracts removal) iii. Rhinoplasty iv. Facial augmentation v. Dental surgery (Patterson et al. 1982) a) General restorative dentistry b) Orthodontic palatal expansion c) Realignment of the dental arches vi. Mandibular advancement b. General anesthesia and airway management i. Difficult laryngoscopy and endotracheal intubation secondary to micrognathia, microstomia, and serious upper airway compromise ii. Brittle and easily broken natal teeth during laryngoscopy iii. Orotracheal intubation precluded by anterior placement or absence of the temporomandibular joints iv. Difficult nasotracheal intubation secondary to hypoplastic nose and deviated nasal septum v. Consider preoperative tracheotomy or prepare for emergency tracheotomy c. Long-term nasal continuous positive airway pressure therapy for obstructive sleep apnea (Ryan et al. 1990) d. Management for endocrine problem if present

References Aracena, T., & Sangueza, P. (1977). Hallermann-StreiffFrancois syndrome. Journal of Pediatric Ophthalmology, 14, 373–378. Christian, C. L., Lachman, R. S., Aylsworth, A. S., et al. (1991). Radiological findings in Hallermann-Streiff syndrome: Report of five cases and a review of the literature. American Journal of Medical Genetics, 41, 508–514. Cohen, M. M., Jr. (1991). Hallermann-Streiff syndrome: A review. American Journal of Medical Genetics, 41, 488–499. Colomb, R. S., & Porter, P. S. (1975). A distinct hair shaft abnormality in the Hallermann-Streiff syndrome. Cutis, 16, 122–128. David, L. R., Finlon, M., Genecov, D., et al. (1999). HallermannStreiff syndrome: Experience with 15 patients and review of the literature. The Journal of Craniofacial Surgery, 10, 160–168. Dinwiddie, R., Gewitz, M., & Taylor, J. F. N. (1978). Cardiac defects in the Hallermann-Streiff syndrome. Journal of Pediatrics, 92, 77–78.

996 Franc¸ois, J. (1982). Francois dysencephalic syndrome. Birth Defects, 18(6), 595–619. Franc¸ois, J., & Pierard, J. (1971). The Francois dysencephalic syndrome and skin manifestations. American Journal of Ophthalmology, 71, 1241–1250. Friede, H., Lopata, M., Fisher, E., et al. (1985). Cardiorespiratory disease associated with Hallermann-Streiff syndrome: Analysis of craniofacial morphology by cephalometric roentgenograms. Journal of Craniofacial Genetics and Developmental Biology. Supplement, 1, 189–198. Golomb, R. S., & Porter, P. S. (1975). A distinct hair shaft abnormality in the Hallermann-Streiff syndrome. Cutis, 16, 122–128. Haberman, H., & Clement, P. A. (1979). The value of anthropometrical measurements in a case of Hallermann-Streiff syndrome. Rhinology, 17, 179–184. Haque, M., Goldenberg, D. T., Walsh, M. K., et al. (2009). Retinal detachments involving the posterior pole in HallermannStreiff syndrome. Retinal Cases & Brief Reports, X, 1–3. Hendrix, S. L., & Sauer, H. J. (1991). Successful pregnancy in a patient with Hallermann-Streiff syndrome. American Journal of Obstetrics and Gynecology, 164, 1102–1104. Hutchinson, D. (1971). Oral manifestations of oculomandibulodyscephaly with hypotrichosis (Hallermann-Streiff syndrome). Oral Surgery, Oral Medicine, and Oral Pathology, 31, 234–244. Malde, A. D., Jagtap, S. R., & Pantvaidya, S. H. (1994). Hallermann-Streiff syndrome: Airway problems during anaesthesia. Journal of Postgraduate Medicine, 40, 216–218. Nevin, N. C., Scally, B. G., Thomas, P., et al. (1974). The Hallermann-Streiff syndrome. Journal of Mental Deficiency Research, 18, 145–151. Ohishi, M., Murakami, E., Haita, T., et al. (1986). HallermannStreiff syndrome and its oral implications. ASDC Journal of Dentistry for Children, 53, 32–37. Patterson, G. T., Braun, T. W., & Sotereanos, G. C. (1982). Surgical correction of the dentofacial abnormality in

Hallermann-Streiff Syndrome Hallermann-Streiff syndrome. Journal of Oral and Maxillofacial Surgery, 40, 380–384. Ryan, C. F., Lowe, A. A., & Fleetham, J. A. (1990). Nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea in Hallermann-Streiff syndrome. Clinical Pediatrics (Philadelphia), 29, 122–124. Salbert, B. A., Stevens, C. A., & Spence, J. E. (1991). Tracheomalacia in Hallermann-Streiff syndrome. American Journal of Medical Genetics, 41, 521–523. Sataloff, R. T., & Roberts, B. R. (1984). Airway management in Hallermann-Streiff syndrome. American Journal of Otolaryngology, 5, 64–67. Scheuerle, A. (1999). Commentary on Hallermann-Streiff Syndrome: Experience with 15 patients and review of the literature. The Journal of Craniofacial Surgery, 10, 225. Sclaroff, A., & Eppley, B. L. (1987). Evaluation and surgical correction of the facial skeletal deformity in HallermannStreiff syndrome. International Journal of Oral and Maxillofacial Surgery, 16, 738–744. Slootweg, P. J., & Huber, J. (1984). Dento-alveolar abnormalities in oculomandibulodyscephaly (Hallermann-Streiff syndrome). Journal of Oral Pathology, 13, 147–154. Spaepen, A., Schrander-Stumpel, C., Fryns, J. P., et al. (1991). Hallermann-Streiff syndrome: Clinical and psychological findings in children. Nosologic overlap with oculodentodigital dysplasia? American Journal of Medical Genetics, 41, 517–520. Steele, R. W., & Bass, J. W. (1970). Hallermann-Streiff syndrome. Clinical and prognostic considerations. American Journal of Diseases of Children, 120, 462–465. Sugar, A., Bigger, J. F., & Podos, S. M. (1971). HallermannStreiff-Francois syndrome. Journal of Pediatric Ophthalmology, 8, 234–238. Suzuki, Y., Fujii, T., & Fukuyama, Y. (1970). HallermannStreiff syndrome. Developmental Medicine and Child Neurology, 12, 496–506.

Hallermann-Streiff Syndrome

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Fig. 2 (a, b) A male infant with Hallermann-Streiff syndrome showing frontal bossing, microphthalmia, thin nose, mandibular hypoplasia, hypotrichosis involving eyelashes and eyebrows, and genital hypoplasia Fig. 1 (a, b) An infant with Hallermann-Streiff syndrome showing brachycephaly, frontal and parietal bossing, microphthalmia, thin, pointed nose, mandibular hypoplasia, and hypotrichosis

998 Fig. 3 (a, b) An adult with Hallermann-Streiff syndrome with mental retardation, short stature, alopecia, scanty eyelashes, a beaked nose, and scoliosis

Hallermann-Streiff Syndrome

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b

Harlequin Ichthyosis

Harlequin ichthyosis is a rare severe scaling disorder and the most devastating congenital ichthyosis, which manifests in utero and is often fatal early in life.

Synonyms and Related Disorders Congenital ichthyosis of harlequin type; Harlequin fetus

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. ABCA12 gene a. Located on chromosome 2q34 b. Consists of 53 exons and codes a 2595 amino acid protein member of the adenosine triphosphate (ATP)–binding cassette transporter family (Lefe´vre et al. 2003; Akiyama et al. 2005; Kelsell et al. 2005) 3. Caused by loss-of-function mutations in ABCA12 (Akiyama and Shimizu 2008; Akiyama 2010) a. Truncation mutations: most mutations i. Nonsense mutations ii. Frameshift mutations (deletion/insertion mutations) iii. Splice site mutations b. Missense mutations c. Exon deletion d. Single amino acid deletions 4. Novel homozygous mutation p.R287X resulted from complete paternal isodisomy (Castiglia et al. 2009)

a. Non-mosaic chromosome 2 trisomy from chorionic villus karyotyping while postnatal peripheral blood karyotype was normal female. b. These findings indicate that trisomic rescue is one step of the mutational cascade leading to reduction to homozygosity for the ABCA12 mutation in the embryo. 5. Pathomechanisms of ichthyosis involving ABCA12 mutations (Akiyama 2010): several morphologic abnormalities including abnormal lamellar granules in the keratinocyte granular layer and a lack of extracellular lipid lamellae within the stratum corneum observed in harlequin ichthyosis (Akiyama et al. 2005) a. Lack of ABCA12 function subsequently leads to disruption of lamellar granule lipid transport in the upper keratinizing epidermal cells resulting in malformation of the intercellular lipid layers of the stratum corneum. b. Cultured epidermal keratinocytes from an harlequin ichthyosis patient carrying ABCA12 mutations demonstrated defective glucosylceramide transport and this phenotype was recoverable by in vitro ABCA12 corrective gene transfer. c. To date, intracytoplasmic glucosylceramide transport has been studied using cultured keratinocytes from a total of three patients harboring ABCA12 mutations (Akiyama et al. 2005, 2006, 2007). i. One patient was a homozygote for a splice site mutation c.3295-2A > G. ii. Another patient was a compound heterozygote for p.Ser387Asn and p.Thr1387del. iii. Only one heterozygous mutation p.Ile1494Thr was identified in the other patient.

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iv. Cultured keratinocytes from all the three patients showed apparently disturbed glucosylceramide transport, although this assay is not quantitative. 6. Report of a male with harlequin ichthyosis with a de novo deletion of the long arm of chromosome 18 [46,XY,del(18)(q21.3)] suggesting the possible gene localization within the deleted region

Harlequin Ichthyosis

iv. Dehydration v. Malnutrition vi. Severe anemia vii. Renal failure d. Rare survivals i. Variable neurologic impairment ii. Short stature iii. Failure to thrive iv. At risk for severe keratitis due to ectropion of all eyelids

Clinical Features 1. Major clinical features a. Large, thick, and yellowish armor-like plaques (platelike scales) with reddish, moist, oozing fissures and cracks, covering the whole body b. Severe ectropion (complete eversion of the nonkeratinizing mucosa of the eyelids with occlusion of the eyes) c. Eclabium (eversion of the non-keratinizing mucosa of the lips) d. “Frog-like” grostesque appearance of the face e. Crumpled and flattened ears f. Flattened nasal tip with anteversion of the nares (nasal hypoplasia) g. Permanently opened mouth unable to suck properly h. Swollen extremities secondary to tight sausagelike encasement by the thickened stratum corneum i. Semiflexed rigid extremities (allowing little limb movement) with hypoplastic fingers 2. Minor clinical features a. Absent eyebrows and eyelashes b. Absent scalp hair 3. Associate anomalies a. Renal tubular defects b. Altered thymic structures c. Pulmonary hypoplasia 4. Natural history a. Restricted fetal movement caused by dense masses of hyperkeratotic scale b. Prematurity in most cases c. Perinatal death (usually in the first few weeks) secondary to: i. Respiratory compromise due to mechanical limitation of ribcage excursion ii. Sepsis iii. Hypothermia

Diagnostic Investigations 1. Light microscopy findings a. Extraordinary compact orthohyperkeratosis (thickened orthokeratotic stratum corneum) b. Keratin plugs in hair follicles and sweat ducts c. Absent lamellar bodies and abundant vesicles in both the stratum granulosum and stratum corneum d. Abnormal lipid droplets and vacuoles in the cytoplasm of keratinized cells in the thick stratum corneum 2. Ultrastructural findings a. Abnormal lipid droplets and vacuoles in the cytoplasm of keratinized cells in the thick stratum corneum b. Absent normal lamellar granules in the cytoplasm of granular layer keratinocytes c. Lack of lamellar structure in the extracellular space between the first cornified cell and the granular cell 3. Biochemical analysis of skin samples: a defect of conversion from profilaggrin to filaggrin 4. Family history for evidence of consanguinity 5. Molecular genetic diagnosis by gene sequencing or deletion/duplication analysis of ABCA12

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: patient not surviving to reproductive age 2. Prenatal diagnosis possible in families at risk a. Ultrasonography (2D, 3D and 4D) at 18–24 weeks (Kudla and Timmerman, 2010).

Harlequin Ichthyosis

i. Minimal fetal movement with stiff limbs in a semiflexed position ii. Swollen limbs with hypoplastic fingers and toes and short phalanges iii. Shriveled hands that do not open iv. Characteristic facial features a) Flat face profile b) Open eyes c) Ectropion d) Cataracts e) Flat nose f) Thick lips g) Eclabium h) Absence of typical ear morphology (hypoplasia of the ears) i) Large open mouth j) Micrognathia k) Partitioned cystic formations in front of the eyes v. Short neck vi. Thick skin vii. Choroid plexus cysts viii. Short umbilical cord ix. Hyperechogenic amniotic fluid x. Absence of associated visceral anomalies b. Amniocentesis: demonstration of clumping of keratinocyte cells in the amniotic fluid containing lipid droplets and amorphous electron dense material. c. Electron microscopy of the fetal skin biopsy specimen from fetoscopy at 20–22 weeks. i. Abnormal vacuoles in keratinized cells ii. Abnormal lamellar granules in the hair canal d. Molecular genetic testing: After identification of ABCA12 as the causative gene for harlequin ichthyosis, it is feasible to perform DNA-based prenatal diagnosis for harlequin ichthyosis by chorionic villus or amniotic fluid sampling (Akiyama et al. 2007; Yanagi et al. 2008) or preimplantation genetic diagnosis. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. 3. Management a. Temperature control. b. Electrolyte and fluid balance. c. Adequate caloric intake. d. Prevention of infection with antibiotics. e. Topical steroids to reduce secondary inflammation.

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f. Tretinoin creams or ointments or oral retinoid treatment to reduce the amount of scale. Early use of systemic retinoids promotes accelerated shedding of the hyperkeratotic plates, whereas continued use reduces scale and improves ectropion and eclabium (Harvey et al. 2010). g. Pain management with anti-inflammatory drugs and morphine sulfate if necessary. h. Ocular management. i. Intensive topical eye ointment ii. Treat keratitis promptly iii. Surgical management of the ectropion by skin-release surgery with autologous skin grafting in patients with severe exposure keratitis or cosmetically unacceptable ectropion i. Careful handling to avoid hard friction and physical contract for prevention of blistering.

References Akiyama, M. (1998). Severe congenital ichthyosis of the neonate. International Journal of Dermatology, 37, 722–728. Akiyama, M. (2006). Pathomechanisms of harlequin ichthyosis and ABCA transporters in human diseases. Archives of Dermatology, 142, 914–918. Akiyama, M. (2010). ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutation, 31, 1090–1096. Akiyama, M., & Shimizu, H. (2008). An update on molecular aspects of the nonsyndromic ichthyoses. Experimental Dermatology, 17, 373–382. Akiyama, M., Suzumori, K., & Shimizu, H. (1999). Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks’ estimated gestational age. Prenatal Diagnosis, 19, 167–171. Akiyama, M., Dale, B. A., Smith, L. T., et al. (1998). Regional difference in expression of characteristic abnormality of harlequin ichthyosis in affected fetuses. Prenatal Diagnosis, 18, 425–436. Akiyama, M., Sugryama-Nakagini, Y., Sakai, K., et al. (2005). Mutations in ABCA12 in harlequin ichthyosis and fictional rescue by corrective gene transfer. The Journal of Clinical Investigation, 115, 1777–1784. Akiyama, M., Sakai, K., Sugiyama-Nakagiri, Y., et al. (2006). Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity. The Journal of Investigative Dermatology, 126, 1518–1523. Akiyama, M., Titeux, M., Sakai, K., et al. (2007). DNA-based prenatal diagnosis of harlequin ichthyosis and characterization of ABCA12 mutation consequences. The Journal of Investigative Dermatology, 127, 568–573.

1002 Anton-Lamprecht, I. (1983). Genetically induced abnormalities of epidermal differentiation and ultrastructure in ichthyoses and epidermolyses: pathogenesis, heterogeneity, fetal manifestation, and prenatal diagnosis. J Inv Dermatol, 81(suppl), 149S–156S. Badden, H. P., Kubilus, J., Rosenbaum, K., et al. (1982). Keratinization in the harlequin fetus. Archives of Dermatology, 118, 14–18. Bale, S. J., Richards, G (2009) Autosomal recessive congenital ichthyosis. GeneReviews. Updated November 19, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br. fcgi?book¼gene&part¼li-ar Blanchet-Bardon, S., Dumez, Y., Labbe, F., et al. (1983). Prenatal diagnosis of a harlequin fetus using EM. Annales de Pathologie, 3, 321–325. Bongain, A., Benoit, B., Ejnes, L., et al. (2002). Harlequin fetus: three-dimensional sonographic findings and new diagnostic approach. Ultrasound in Obstetrics & Gynecology, 20, 82–85. Buxman, M. M., Goodkin, P. E., Fahrenback, W. H., et al. (1979). Harlequin ichthyosis with an epidermal lipid abnormality. Archives of Dermatology, 115, 189–193. Castiglia, D., Castori, M., Pisaneschi, E., et al. (2009). Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis. Clinical Genetics, 76, 392–397. Craig, J. M., Goldsmith, L. A., & Baden, H. P. (1970). An abnormality of keratin in the harlequin fetus. Pediatrics, 46, 437–440. Dale, B. A., Holbrook, K. A., Fleckman, P., et al. (1990). Heterogeneity in Harlequin ichthyosis, an inborn error of epidermal keratinization: variable morphology and structural protein expression and a defect in lamellar granules. J Inv Dermatol, 94, 6–18. Dale, B. A., & Kam, E. (1993). Harlequin ichthyosis. Variability in expression and hypothesis for disease mechanism. Archives of Dermatology, 129, 1471–1477. Harvey, H. B., Shaw, M. G., & Morrell, D. S. (2010). Perinatal management of harlequin ichthyosis: A case report and literature review. Journal of Perinatology, 30, 66–72. Hashimoto, K., & Khan, S. (1992). Harlequin fetus with abnormal lamellar granules and giant mitochondria. Journal of Cutaneous Pathology, 19, 247–252. Haftek, M., Cambazard, F., Dhouailly, D., et al. (1996). A longitudinal study of a harlequin infant presenting clinically as non-bullous congenital ichthyosiform erythroderma. British Journal of Dermatology, 135, 448–453.

Harlequin Ichthyosis Kelsell, D. P., Norgett, E. E., Unsworth, H., et al. (2005). Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. American Journal of Human Genetics, 76, 794–803. Kudla, M. J., & Timmerman, D. (2010). Prenatal diagnosis of harlequin ichthyosis using 3- and 4-dimensional sonography. Journal of Ultrasound in Medicine, 29, 317–319. Lefe´vre, C., Audebert, S., Jobard, F., et al. (2003). Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Human Molecular Genetics, 12, 2369–2378. Moreau, S., & Salame, E. (1999). Goullet de Rugy M, et al: Harlequin fetus: A case report. Surgical and Radiologic Anatomy, 21, 215–216. Multani, A. S., Sheth, F. J., Shah, V. C., et al. (1996). Three siblings with harlequin ichthyosis in an Indian family. Early Human Development, 45, 229–233. Prasad, R. S., Pejaver, R. K., Hassan, A., et al. (1994). Management and follow-up of harlequin siblings. British Journal of Dermatology, 130, 650–653. Roberts, L. J. (1989). Long-term survival of a harlequin fetus. Journal of the American Academy of Dermatology, 21, 335–339. Sarkar, R., Sharma, R. C., Sethi, S., et al. (2000). Three unusual siblings with harlequin ichthyosis in an Indian family. Journal of Dermatology, 27, 609–611. Singh, S., Bhura, M., Maheshwari, A., et al. (2001). Successful treatment of harlequin ichthyosis with acitretin. International Journal of Dermatology, 40, 472–473. Stewart, H., Smith, P. T., Gaunt, L., et al. (2001). De novo deletion of chromosome 18q in a baby with harlequin ichthyosis. American Journal of Medical Genetics, 102, 342–345. Sybert, V. P. (1997). Genetic skin disorders (pp. 13–16). New York: Oxford University Press. Unamuno, P., Pierola, J. M., Fernandez, E., et al. (1987). Harlequin foetus in four siblings. British Journal of Dermatology, 116, 569–572. Watson, W. J., & Mabee, L. M., Jr. (1995). Prenatal diagnosis of severe congenital ichthyosis (harlequin fetus) by ultrasonography. Journal of Ultrasound in Medicine, 14, 241–243. Yanagi, T., Akiyama, M., Sakai, K., et al. (2008). DNA-based prenatal exclusion of harlequin ichthyosis. Journal of the American Academy of Dermatology, 58, 653–656.

Harlequin Ichthyosis

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Fig. 1 (a–d) A newborn with harlequin ichthyosis, covered with yellowish plaques (severe hyperkeratosis) with moist fissures and cracks and grostesque appearance of face with ectropion, eclabium, a flat nose, crumpled/flat ears, and swollen/semiflexed rigid limbs

Hemophilia A

Hemophilia A is a congenital X chromosome–linked coagulation disorder characterized by deficiency in factor VIII clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery and delayed or recurrent bleeding prior to complete wound healing. It affects approximately 1 in 5,000–1 in 10,000 male births.

Synonyms and Related Disorders Classic hemophilia

Genetics/Basic Defects 1. Inheritance (Hedner et al. 2000) a. An X-linked recessive disorder b. New mutations in approximately one third of patients c. Hemophilia A in females i. Rarely reported ii. Possible explanation a) Extreme skewing of X chromosome inactivation resulting in unusually low factor VIII levels in female hemophilia A carriers b) Rare individuals carrying a hemophilia A mutation associated with an X chromosome–autosome translocation or other cytogenetic abnormality, which may result in exclusive inactivation of the normal X chromosome c) Rare individuals carrying a hemophilia A mutation in the rearranged X-chromosome

2. Molecular genetics (Hedner et al. 2000) a. Caused by absent or decreased factor VIII (FVIII) procoagulant function, resulting from mutations in FVIII (F8) gene, mapped on chromosome Xq28. b. A unique rearrangement within the FVIII gene (intron 22 gene inversion), recently identified as a common, recurrent mechanism for hemophilia A. i. Accounting for approximately 45% of all severe hemophilia A patients. ii. The mutation almost always arises during a male meiosis. iii. The mother of an apparently new mutation patient with an identified gene inversion can generally be assumed to be a carrier, with the recombination event often identified in the maternal grandfather’s allele. c. The remaining 55% of severe hemophilia patients are shown to have a more conventional molecular defect in the FVIII gene. i. Approximately 50% of patients with specific point mutations in exons or at splice junctions within the FVIII gene ii. Approximately 5% of patients with deletions which remove varying-sized segments of the FVIII gene iii. Rare small insertions and deletions d. Nearly all patients with mild or moderately severe hemophilia A have some residual level of FVIII activity, shown to have a point mutation within the FVIII coding sequence, resulting in a single amino acid substitution. e. Clinical severity of the hemophilia A phenotype correlates very closely with the amount of residual factor VIII activity.

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Hemophilia A

Clinical Features 1. Clinical features suspecting a coagulation disorder (Hedner et al. 2000) a. Hemarthrosis, especially with mild or no antecedent trauma b. Deep muscle hematomas c. Intracranial bleeding in the absence of major trauma d. Cephalohematoma or intracranial bleeding at birth e. Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision f. Prolonged bleeding or renewed bleeding following surgery or trauma g. Unexplained gastrointestinal bleeding or hematuria h. Menorrhagia, especially at menarche i. Prolonged nosebleeds, especially recurrent and bilateral j. Excessive bruising, especially with firm, subcutaneous hematomas 2. Severe hemophilia A (43% of hemophiliacs) a. Spontaneous bleeding i. Joints: the most frequent symptom ii. Other sites a) Kidneys b) Gastrointestinal tract c) Brain b. Without treatment i. Bleeding from minor mouth injuries and large “goose eggs” from minor head bumps during the toddler period ii. Rare intracranial bleeding resulting from head injuries iii. Almost always with subcutaneous hematomas iv. Frequency of bleeding a) Relating to the FVIII clotting activity b) Varying from two to five spontaneous bleeding episodes each month c) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Age of diagnosis i. Usually diagnosed during the first year of life ii. Relating to the FVIII clotting activity 3. Moderately severe hemophilia A (26% of hemophiliacs) a. Seldom with spontaneous bleeding

4.

5.

6.

7. 8.

b. Without treatment i. Prolonged or delayed oozing after relatively minor trauma ii. Frequency of bleeding a) Varying from once a month to once a year b) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Usually diagnosed before the age of 5–6 years Mild hemophilia A (31% of hemophiliacs) a. Absent spontaneous bleeding b. Without treatment i. Occurrence of abnormal bleeding with surgery, tooth extraction, and major injuries ii. Frequency of bleeding a) Varying from once a year to once every 10 years b) Bleeding episodes more frequent in childhood and adolescence than in adulthood c. Often not diagnosed until later in life Carrier females a. Risk of bleeding in approximately 10% of carrier females b. Mild symptoms Complications of untreated bleeding a. Intracranial hemorrhage: the leading cause of death b. Chronic joint disease: the major cause of disability Life expectancy: 60–70 years Differential diagnosis a. Inherited bleeding disorders associated with a low factor VIII clotting activity i. Type 1 vWD (mild von Willebrand disease) a) An autosomal dominant disorder b) Predominant feature: mucous membrane bleeding c) Quantitative deficiency of von Willebrand factor (low vWF antigen, factor VIII clotting activity, and ristocetin cofactor activity) in 80% of patients ii. Type 2 vWD a) Quantitative deficiency of vWF with a decrease of the high molecular weight multimers b) Low normal to mildly decreased vWF antigen and factor VIII clotting activity c) Low functional vWF level in a ristocetin cofactor assay

Hemophilia A

iii. Type 2 N (Normandy) vWD a) An uncommon variant due to several missense mutations in the amino terminus of the vWF protein, resulting in defective binding of factor VIII to vWF b) Low factor VIII clotting activity usually showing autosomal recessive inheritance c) Indistinguishable clinically from mild hemophilia A, which can be differentiated with molecular genetic testing of the FVIII gene, molecular genetic testing of the vWF gene, or measuring binding of factor VIII to vWF using ELISA or column chromatography iv. Type 3 vWD (severe von Willebrand disease) a) An autosomal recessive disorder b) Frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to hemophilia A c) G)

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Recurrence risk: 25% ii. Unaffected sibs of a proband: two thirds chance of being heterozygotes b. Patient’s offspring: a lethal entity not surviving to reproduction 2. Prenatal diagnosis a. Possible by prenatal ultrasonography in at-risk families b. Possible for pregnancies at risk when the disease-causing mutation in the family is known 3. Management a. Supporting care b. No treatment available for the underlying lethal disorder

References Adetoro, O. O., Komolafe, F., & Anjorin, A. (1984). Hydrolethalus syndrome in consecutive African siblings. Pediatric Radiology, 14, 422–424. Ammala, P., & Salonen, R. (1995). First-trimester diagnosis of hydrolethalus syndrome. Ultrasound in Obstetrics & Gynecology, 5, 60–62. Anyane-Yeboa, K., Collins, M., Kupsky, W., et al. (1987). Hydrolethalus (Salonen-Herva-Norio) syndrome: Further clinicopathological delineation. American Journal of Medical Genetics, 26, 899–907. Aughton, D. (1994). Sonographic detection of hydrolethalus syndrome. Journal of Clinical Ultrasound, 22, 286–287. Aughton, D. J., & Cassidy, S. B. (1987). Hydrolethalus syndrome: Report of an apparent mild case, literature review, and differential diagnosis. American Journal of Medical Genetics, 27, 935–942. Bachman, H., Clark, R. D., & Salahi, W. (1990). Holoprosencephaly and polydactyly: A possible expression of the hydrolethalus syndrome. Journal of Medical Genetics, 27, 50–52.

Hydrolethalus Syndrome Chan, B. C., Shek, T. W., & Lee, C. P. (2004). First-trimester diagnosis of hydrolethalus syndrome in a Chinese family. Prenatal Diagnosis, 24, 587–590. Christensen, B., Blaas, H. G., Isaksen, C. V., et al. (2000). Sibs with anencephaly, anophthalmia, clefts, omphalocele, and polydactyly: Hydrolethalus or acrocallosal syndrome? American Journal of Medical Genetics, 91, 231–234. de Ravel, T. J., van der Griendt, M. C., Evan, P., et al. (1999). Hydrolethalus syndrome in a non-Finnish family: Confirmation of the entity and early prenatal diagnosis. Prenatal Diagnosis, 19, 279–281. Dincsoy, M. Y., Salih, M. A., al-Jurayyan, N., et al. (1995). Multiple congenital malformations in two sibs reminiscent of hydrolethalus and pseudotrisomy 13 syndromes. American Journal of Medical Genetics, 56, 317–321. Hartikainen-Sorri, A. L., Kirkinen, P., & Herva, R. (1983). Prenatal detection of hydrolethalus syndrome. Prenatal Diagnosis, 3, 219–224. Herva, R., & Seppanen, U. (1984). Roentgenologic findings of the hydrolethalus syndrome. Pediatric Radiology, 14, 41–43. Kivela, T., Salonen, R., & Paetau, A. (1996). Hydrolethalus: A midline malformation syndrome with optic nerve coloboma and hypoplasia. Acta Neuropathologica (Berlin), 91, 511–518. Krassikoff, N., Konick, L., & Gilbert, E. F. (1987). The hydrolethalus syndrome. Birth Defects Original Article Series, 23, 411–419. Mee, L., Honkala, H., Kopra, O., et al. (2005). Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Human Molecular Genetics, 14, 1475–1488. Morava, E., Adamovich, K., & Czeizel, A. E. (1996). DandyWalker malformation and polydactyly: A possible expression of hydrolethalus syndrome. Clinical Genetics, 49, 211–215. Muenke, M., Ruchelli, E. D., Rorke, L. B., et al. (1991). On lumping and splitting: A fetus with clinical findings of the oral-facial-digital syndrome type VI, the hydrolethalus syndrome, and the pallister-hall syndrome. American Journal of Medical Genetics, 41, 548–556. Norgard, M., Yankowitz, J., Rhead, W., et al. (1996). Prenatal ultrasound findings in hydrolethalus: Continuing difficulties in diagnosis. Prenatal Diagnosis, 16, 173–179.

1083 Pryde, P. G., Qureshi, F., Hallak, M., et al. (1993). Two consecutive hydrolethalus syndrome-affected pregnancies in a nonconsanguinous black couple: Discussion of problems in prenatal differential diagnosis of midline malformation syndromes. American Journal of Medical Genetics, 46, 537–541. Rakheja, D., Cimo, M. L., Ramus, R. M., et al. (2004). Hydrolethalus syndrome, in contrast to Smith-Lemli-Opitz syndrome, is not due to a defect in post-squalene cholesterol biosynthesis: A case report. American Journal of Medical Genetics, 129A, 212–213. Salonen, R., & Herva, R. (1990). Hydrolethalus syndrome. Journal of Medical Genetics, 27, 756–759. Salonen, R., Herva, R., & Norio, R. (1981). The hydrolethalus syndrome: Delineation of a “new”, lethal malformation syndrome based on 28 patients. Clinical Genetics, 19, 321–330. Sharma, A. K., Phadke, S., Chandra, K., et al. (1992). Overlap between Majewski and hydrolethalus syndromes: A report of two cases. American Journal of Medical Genetics, 43, 949–953. Shotelersuk, V., Punyavoravud, V., Phudhichareonrat, S., et al. (2001). An Asian girl with a ‘milder’ form of the hydrolethalus syndrome. Clinical Dysmorphology, 10, 51–55. Siffring, P. A., Forrest, T. S., & Frick, M. P. (1991). Sonographic detection of hydrolethalus syndrome. Journal of Clinical Ultrasound, 19, 43–47. Toriello, H. V., & Bauserman, S. C. (1985). Bilateral pulmonary agenesis: Association with the hydrolethalus syndrome and review of the literature from a developmental field perspective. American Journal of Medical Genetics, 21, 93–103. Verloes, A., Ayme, S., Gambarelli, D., et al. (1991). Holoprosencephaly-polydactyly (‘pseudotrisomy 13’) syndrome: A syndrome with features of hydrolethalus and Smith-Lemli-Opitz syndromes. A collaborative multicentre study. Journal of Medical Genetics, 28, 297–303. Visapaa, I., Salonen, R., Varilo, T., et al. (1999). Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25. American Journal of Human Genetics, 65, 1086–1095.

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a d

b

e

c

Fig. 1 (a–e) A neonate with hydrolethalus syndrome showing malformed skull, microcephaly, ocular hypertelorism, anomalous nose, micrognathia, left cleft lip and palate, a small tongue,

low-set and malformed ears, short neck, postaxial polydactyly of the hands, and preaxial polydactyly of the feet

Hydrops Fetalis

Hydrops fetalis is a condition in which fluid accumulates in the serous cavities and/or in the soft tissues of the fetus. It is classified as immune if there is an indication of a fetomaternal blood group incompatibility, otherwise classified as nonimmune. The incidence of nonimmune hydrops fetalis is estimated to be approximately 1 in 2,500 to 1 in 3,500 neonates.

Synonyms and Related Disorders Hydrops fetalis syndrome; Immune hydrops; Nonimmune hydrops

Genetics/Basic Defects 1. Causes of immune hydrops (IH) a. Rh-D disease (approximately 90% of immune hydrops) i. Prior to 1960s, this is the most common cause (up to 80%) of all cases with hydrops fetalis. The incidence of rhesus isoimmunization has declined steadily because of the widespread use of anti-D gamma globulin. The majority of hydrops is now of the nonimmune type (Holzgreve et al. 1985). ii. Mother (Rh ), father (Rh+), and fetus (Rh+) iii. After sensitization, maternal Rh antibody (IgG anti-D) crosses the placenta and destroys the Rh-positive fetal red blood cells. It results in fetal anemia.

iv. Previous pregnancy, including maternalfetal blood mixing v. Previous abortion (spontaneous, missed, therapeutic) vi. First trimester bleeding vii. Trauma viii. Blood transfusion b. ABO incompatibility (rare, overall incidence about 1%) i. ABO incompatible pregnancies (about 20%) in which only 5% of these cases lead to hydrops ii. Mother (nearly always O+ with antibodies to A, B, or both) iii. Fetus (A, B, or AB) c. Other autoimmune causes (targeting other RBC antigens) i. Anti-Lewis antibodies: benign (“Lewis lives”) ii. Anti-Kell antibodies (the second most common type accounting for about 10% of antibody mediated severe fetal anemia): mild to severe hydrops (“Kell kills”) iii. Anti-Duffy antibodies: mild to severe hydrops (“Duffy dies”) 2. Pathophysiology of immune hydrops a. Sensitization of the mother to an antigen (usually Rh-D) i. Presence of antigen on fetal RBC but not on mother’s RBC ii. Primary response generally a maternal IgM anti-RBC response b. Production of IgG antibodies by the mother on the secondary exposure. The IgG antibodies can cross the placenta.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_123, # Springer Science+Business Media, LLC 2012

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c. Destruction of fetal RBC by maternal anti-fetal RBC antibodies i. A Coombs’ positive process ii. Destruction most likely mediated by complement and macrophages iii. Jaundice frequently observed secondary to increased bilirubin production d. Compensatory increase in fetal cardiac output due to decreased fetal hematocrit e. Heart failure resulting from high cardiac output by the fetal heart i. Edema ii. Ascites iii. Circulatory failure with fetal death in utero 3. Conditions associated with nonimmune hydrops fetalis (NIHF). Nonimmune type now represents majority of hydrops fetalis after the practice of anti-D gammaglobulin prophylaxis since 1960s (Holzgreve et al. 1985). a. Cardiovascular disorders (5.3–26%, the most frequent underlying cause of NIHF) (Bukowski and Saade 2000) i. Tachyarrhythmia (supraventricular tachycardia, atrial flutter) ii. Bradyarrhythmias (complete heart block) iii. Congenital heart block iv. Hypoplastic left heart syndrome (31%) v. Endocardial cushion defects (13%) vi. Agenesis of the ductus venosus vii. Other anatomic defects of the heart viii. Premature closure of the ductus arteriosus ix. Generalized arterial calcification x. Cardiomyopathy xi. Myocarditis (Coxsackie virus or CMV) xii. Cardiac rhabdomyoma xiii. Intracardiac teratoma b. Chromosome abnormalities (7.5–77.8%, the second most frequent underlying causes of NIH) i. Trisomies a) Trisomy 21 b) Trisomy 18 c) Trisomy 13 ii. Turner syndrome (most common chromosome anomaly) iii. Triploidies iv. Deletions v. Others

Hydrops Fetalis

c. Recognizable syndromes (2.2–27.6%) i. Skeletal dysplasias a) Thanatophoric dysplasia b) Arthrogryposis multiplex congenita c) Asphyxiating thoracic dystrophy d) Hypophosphatasia e) Osteogenesis imperfecta f) Achondrogenesis g) Saldino–Noonan syndrome h) McKusick–Kaufman syndrome i) Klippel–Trenaunay–Weber syndrome j) Conradi syndrome k) Other types of skeletal dysplasias ii. Metabolic diseases a) Mucopolysaccharidosis type IV Morquio disease (b-galactosidase deficiency) b) Mucopolysaccharidosis Type VII (bglucuronidase deficiency) c) I-cell disease d) Niemann–Pick disease e) Gaucher disease f) Sialidosis g) Galactosialidosis h) Salla disease (Finnish type sialuria) i) Wolman disease j) Farber disease k) Carnitine deficiency l) Disorder of glycosylation (Le´tice´e et al. 2010) iii. Other genetic syndromes a) Pena–Shokeir syndrome b) Neu–Laxova syndrome c) Recessive cystic hygroma d) Multiple pterygium syndrome e) Meckel syndrome f) Caudal regression syndrome g) Noonan syndrome h) Tuberous sclerosis i) Myotonic dystrophy j) X-linked dominant disorders with male lethality (e.g., hypomelanosis of Ito) k) Other single gene disorders d. Twin pregnancy (twin-twin transfusion syndrome) (3–8%) e. Hematologic disorders (10–27%) i. Intrinsic hemolysis a) a-thalassemia syndromes (Homozygous a-thalassemia-1 is the most common

Hydrops Fetalis

f.

g.

h.

i.

cause of hydrops fetalis in Southeast Asia) (Lam et al. 1999) b) G6PD deficiency c) Pyruvate kinase deficiency d) Glucosephosphate isomerase deficiency e) Spectin abnormalities ii. Extrinsic hemolysis (Kasabach–Merritt syndrome) iii. Hemorrhage a) Fetomaternal hemorrhage b) Twin-twin transfusion syndrome c) Fetal hemorrhage iv. Fetal liver and bone marrow replacement syndromes a) Transient myeloproliferative disorder b) Congenital leukemia v. Red cell aplasia and dyserythropoiesis a) Parvovirus B19 infection b) Blackfan–Diamond syndrome c) Congenital dyserythropoiesis Thoracic abnormalities (2.5–13%) i. Diaphragmatic hernia ii. Congenital cystic adenomatous malformation of the lung iii. Extralobar pulmonary sequestration iv. Congenital hydrothorax or chylothorax v. Mediastinal teratoma vi. Laryngeal atresia vii. Pulmonary hypoplasia Genitourinary malformations (2.5–3.5%) i. Urethral obstruction ii. Posterior urethral valves iii. Neurogenic bladder with reflux iv. Ureterocele v. Prune-belly syndrome vi. Upper urinary tract obstruction vii. Renal dysplasia viii. Cloacal malformations Gastrointestinal anomalies i. Jejunal atresia ii. Midgut volvulus iii. Malrotation of the intestine iv. Duplication of the intestinal tract v. Meconium peritonitis vi. Gastroschisis vii. Tracheoesophageal fistula Hepatic diseases i. Polycystic disease of the liver ii. Hepatic fibrosis

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k.

l.

m.

iii. Cholestasis iv. Biliary atresia v. Hepatic vascular malformations vi. Familial cirrhosis Neurological abnormalities i. Encephalocele ii. Intracranial hemorrhage iii. Cerebral aneurysm iv. Intracranial arteriovenous malformation Maternal diseases/complications i. Medications (indomethacin taken to stop premature labor causing fetal ductus closure and secondary nonimmune hydrops fetalis) ii. Mirror syndrome a) Maternal edema b) Preeclampsia iii. Systemic diseases a) Severe diabetes mellitus b) Severe anemia c) Hypoproteinemia iv. Antepartum/postpartum hemorrhage v. Theca lutein cysts development Placenta-umbilical cord abnormalities i. Chorioangioma ii. Chorionic vein thrombosis iii. Fetomaternal transfusion iv. Placental and umbilical vein thrombosis v. Umbilical cord torsion vi. True cord knots vii. Angiomyxoma of the umbilical cord viii. Aneurysm of umbilical artery Intrauterine infections (2–17.5%) i. Viruses a) Parvovirus B19 b) CMV c) Rubella d) Adenovirus e) Enteroviruses f) Coxsackie virus g) Polio h) Influenza B i) Respiratory syncytial virus j) Congenital hepatitis k) Herpes simplex, type I ii. Bacteria/spirochetes a) Treponema pallidum b) Listeria monocytogenes c) Leptospira interogans

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iii. Parasites a) Toxoplasma gondii b) Trypanosoma cruzii iv. Other a) Chlamydia b) Ureaplasma urealyticum n. Miscellaneous conditions i. Congenital lymphedema ii. Congenital hydrothorax or chylothorax iii. Polysplenia syndrome iv. Amniotic band syndrome v. Congenital neuroblastoma vi. Tuberous sclerosis vii. Ovarian cyst torsion viii. Fetal trauma ix. Large fetal angioma x. Sacrococcygeal teratoma xi. Cloacal malformation o. Idiopathic (without an identifiable cause) 4. Pathophysiology of nonimmune fetal hydrops a. Cardiac failure directly involving the heart i. Arrhythmias ii. Malformations iii. Myocarditis iv. Infarction v. Cardiomyopathy b. Abnormal vascularization causing high output cardiac failure i. Twin-twin transfusion syndrome ii. Acardiac twinning iii. Tumors iv. AV fistulas v. Placental vascular anomalies c. Profound anemia i. Hemolytic anemias ii. Parvovirus B19 (fifth disease) iii. Fetal-maternal hemorrhage iv. Alpha-thalassemia, hemoglobin Bart’s v. G6PD deficiency vi. Glucose-6-phosphate isomerase deficiency vii. Pyruvate kinase deficiency viii. Defects of red cell membrane d. Decreased plasma oncotic pressure i. Congenital nephrosis ii. Hepatic necrosis e. Fetal infections i. Increased capillary permeability (anoxia due to congenital infection)

Hydrops Fetalis

ii. Infection of erythroid progenitor cells (e.g., parvovirus B19) iii. Myocarditis (e.g., adenovirus, Coxsackie virus) iv. Hepatic destruction (e.g., syphilis) f. Obstruction of venous return i. Congenital cystic adenomatoid malformation ii. Fetal closure or restriction in the size of the ductus arteriosus, foramen ovale or ductus venosus iii. Diaphragmatic hernia iv. Pulmonary sequestration v. Tumors of the heart, lungs, abdomen or pelvis vi. Umbilical cord lesions g. Obstruction of lymphatic flow (e.g., Turner syndrome)

Clinical Features 1. Maternal history associated with hydropic infants a. Previous history of hydrops b. Severe maternal anemia c. Associated polyhydramnios in at least 50% of hydropic fetuses d. Size-date discrepancy e. Twin gestation f. Maternal diabetes mellitus g. Maternal pregnancy induced hypertension/ preeclampsia h. Fetal arrhythmia i. Placentomegaly j. Positive antibody screen k. Syphilis or other TORCH infections 2. Edema due to right-sided heart failure a. Circulatory failure b. Ascites i. First sign of fetal hydrops caused by anemia ii. Hypertension iii. Hypoalbuminemia iv. Prune belly secondary to marked fetal ascites c. Pleural effusions d. Pericardial effusions e. Jaundice (hyperbilirubinemia) 3. Hemolysis with extramedullary hematopoiesis

Hydrops Fetalis

4. Hepatosplenomegaly a. A hallmark for immune hydrops b. Absent in nonimmune hydrops fetalis 5. Fetal prognosis: presence of fetal hydrops often indicating fetal compromise with a significant risk of mobility and death a. Cardiovascular disorders i. Best prognosis among abnormalities underlying nonimmune hydrops ii. Cumulative survival rate: 29% iii. Treatment of tachycardia improves prognosis. b. Chromosome abnormalities: 2% survival rate c. Syndromes: 5% survival rate d. Fetal infections: 19% cumulative survival rate e. Thoracic lesions: one of the best cumulative prognosis, 26% f. Fetofetal transfusion syndrome: 20% survival rate g. Extremely poor prognosis i. Anemia secondary to parvovirus infection ii. Anemia resulting from fetomaternal hemorrhage iii. a-thalassemia: All fetuses with the Hb Bart’s hydrops fetalis syndrome succumb to severe fetal hypoxia in utero during the third trimester of gestation or within hours after birth (Chui and Waye 1998). h. Good prognosis for psychomotor development in survivors with nonimmune hydrops fetalis (Haverkamp et al. 2000) 6. Morbidity (Bukowski and Saade 2000) a. Morbidity depending on the underlying disorder b. Short-term morbidity high (neonate requires difficult resuscitation, long and intensive hospitalization, and multiple invasive procedures) c. Relatively low long-term morbidity in NIHF in children diagnosed prenatally 7. Mortality a. Mortality rate: 50–98% b. Contribute to 3% of perinatal mortality c. Mortality depending on the underlying disorder

Diagnostic Investigations 1. Diagnostic evaluation of immune hydrops a. ABO and Rh typing and a serum antibody screen (positive indirect Coombs’ test) for every pregnant woman as early as possible during each pregnancy

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b. Spectrophotometric estimation of bilirubin pigments in the amniotic fluid, obtained by amniocentesis in selected patients, to estimate the risk of severe hemolytic disease while the fetus is still in utero c. Direct Coombs’ test on cord blood i. Nearly always positive in Rh-induced hemolytic disease of newborns (HDN) ii. Frequently but not always positive in ABOinduced HDN d. Usually increased cord blood bilirubin and decreased cord blood hemoglobin in severe HDN 2. Diagnostic evaluation of newborn babies with nonimmune hydrops (Carlton et al. 1989) a. Cardiovascular disorders i. Echocardiogram ii. Electrocardiogram b. Thoracic abnormalities i. Chest radiographs ii. Pleural fluid examination c. Hematologic disorders i. Complete blood cell count ii. Differential iii. Platelet count iv. Blood type v. Coombs’ test vi. Blood smear for morphology vii. Hemoglobin electrophoresis d. Gastrointestinal abnormalities i. Abdominal radiographs ii. Abdominal ultrasound iii. Liver function tests iv. Peritoneal fluid examination v. Total protein vi. Albumin e. Renal malformations i. Urinalysis ii. BUN iii. Creatinine f. Genetics i. Chromosome analysis ii. Skeletal radiographs g. Congenital infections viral cultures or serology (Barron and Pass 1995) i. Parvovirus B19 a) Maternal infection: specific IgM and IgG b) Fetal/neonatal infection: specific IgM, virus detection by PCR

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ii. Syphilis a) Maternal infection: RPR or VDRL b) Fetal/neonatal infection: RPR or VDRL, dark-field examination of material from lesions iii. CMV a) Maternal infection: CMV-IgM or IgG seroconversion b) Fetal/neonatal infection: isolation of virus from amniotic fluid, fetal, or neonatal body fluid iv. HSV a) Maternal infection: HSV culture of lesion b) Fetal/neonatal infection: HSV culture of amniotic fluid, fetal tissue, or neonate v. Toxoplasmosis a) Maternal infection: capture IgM, specific IgG b) Fetal/neonatal infection: capture IgM ELISA vi. Rubella a) Maternal infection: specific IgM and IgG or proven exposure plus compatible illness b) Fetal/neonatal infection: isolation of virus from fetal or neonatal body fluid, rubella IgM h. Autopsy indicated for stillbirth or perinatal death including examination of the placenta and babygram

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Immune hydrops fetalis: will be affected unless sensitization is prevented ii. Nonimmune hydrops fetalis a) Sporadic: no increased risk b) Autosomal recessive disorder: 25% c) Autosomal dominant disorder: not increased unless a parent is affected d) Chromosome disorder: increased especially when a parent is a translocation carrier b. Patient’s offspring i. Immune hydrops fetalis: recurrence risk not increased ii. Nonimmune hydrops fetalis a) Sporadic: no increased risk

Hydrops Fetalis

b) Autosomal recessive disorder: not increased unless the spouse is a carrier c) Autosomal dominant disorder: 50% d) Chromosome disorder: increased if the patient survives to reproductive age 2. Prenatal evaluation of immune hydrops fetalis a. Rh testing and ABO typing indicated for all pregnancies b. Positive maternal antibody screen (indirect Coombs test) c. Suspicious for immune hydrops i. Cord blood for testing of hemolysis and hematocrit ii. Amniocentesis for bilirubin d. Specific testing for antibodies in women with previous pregnancy losses e. Doppler ultrasonography i. Used to measure peak velocity of systolic blood flow in fetus ii. Increased peak systolic blood flow velocity in fetuses with anemia iii. Increased systolic velocity: 100% sensitive to fetal anemia f. Prenatal diagnosis of fetal Rh-D status by molecular analysis 3. Maternal evaluation of nonimmune hydrops fetalis (Holzgreve et al. 1985) a. Complete blood count and indices for hematological disorders b. Hemoglobin electrophoresis (a-thalassemia) c. Kleihauer–Betke stain for evidence of fetomaternal hemorrhage d. Maternal blood chemistry for fetal red cell enzyme deficiency i. Glucose-6-phosphate deficiency screen ii. Pyruvate kinase carrier status e. Infection screening i. Syphilis by VDRL ii. TORCH titers iii. Parvovirus titers iv. Group B streptococcus v. Listeria monocytogenes f. Autoantibody screen i. Systemic lupus erythematosus ii. Anti-Ro (anti-SS-A) and Anti-La (anti-SS-B) antibody titers for Sjogren syndrome g. Fetal echocardiography for presence of congenital heart defects

Hydrops Fetalis

4. Prenatal ultrasonography a. Immune hydrops secondary to a-thalassemia (Tongsong et al. 1996) i. Hepatosplenomegaly (>95%) ii. Cardiomegaly (>95%) iii. Edematous placenta (>95%) iv. Ascites (>95%) v. Oligohydramnios (82%) vi. Subcutaneous edema (75%) vii. Decreased fetal movement (74%) viii. Cord edema (63%) ix. Enlarged umbilical vessel (62%) x. Pericardial/pleural effusion (15%) b. Nonimmune hydrops i. Fetal ascites ii. Fetal pleural effusion iii. Fetal pericardial effusion (the earliest finding) iv. Fetal skin thickening v. Maternal polyhydramnios vi. Placentomegaly, especially Rh disease or chorioangioma vii. Cystic hygroma as early as 13 weeks of gestation 5. Fetal evaluation of nonimmune hydrops fetalis a. Fetal echocardiography, M-mode, pulsed, and color flow Doppler i. Congenital heart defects ii. Fetal rhythmic abnormalities iii. Cardiac biometry b. Doppler flow velocity studies i. Umbilical artery ii. Middle cerebral artery iii. Tricuspid ejection velocity c. Amniocentesis i. Amniotic fluid index ii. Fetal karyotype (chromosome abnormality) iii. Amniotic fluid viral cultures iv. Alpha-fetoprotein (congenital nephrosis, sacrococcygeal teratomas) v. Isolation of CMV virus for identification of CMV DNA by PCR vi. Specific metabolic tests a) Tay–Sachs disease b) Gaucher disease c) GM1 gangliosidosis vii. Metabolic disease screening panel a) Acid sphingomyelinase deficiency b) Deficient cholesterol esterification

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Acid b-glucosidase deficiency Acid b-galactosidase deficiency Acid sialidase deficiency Sialidase deficiency b-galactosidase deficiency Ceramidase deficiency Glucose phosphate isomerase deficiency N-acetylglucosamine phosphotransferase deficiency viii. Restriction endonucleases tests (e.g., thalassemias) d. Fetal blood sampling i. Rapid karyotype (chromosome abnormality) ii. Fetal complete blood count (fetal anemia) iii. Blood group and Coombs’ test iv. Hemoglobin electrophoresis (a-thalassemia) v. Fetal plasma analysis for specific IgM (e.g., CMV-specific IgM antibody, PCR) vi. G6PD in male fetuses vii. Fetal plasma albumin (fetal hypoalbuminemia) viii. Metabolic testing a) Tay–Sachs disease b) Gaucher disease c) GM1 gangliosidosis e. Fluid aspirated for biochemistry and viral screen i. Pleural effusion ii. Ascites iii. Amniotic fluid f. Placenta i. Morphology ii. Thickness 6. Management a. Immune hydrops fetalis i. Prevent sensitization by Rhogam or Rh immune globulin ii. Prevent fetal heart failure when mother has sensitization reaction iii. Fetal transfusion for fetal anemia via cordocentesis iv. Induction of labor v. Postpartum exchange blood transfusion to prevent kernicterus, the most feared complication of Rh-induced HDN b. Nonimmune hydrops fetalis i. Screen tests to detect couples at risk for having a fetus with the Hb Bart’s hydrops fetalis by simple blood counts and hemoglobin electrophoresis c) d) e) f) g) h) i) j)

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ii. Neonatal resuscitation iii. Intrauterine or immediate post-delivery transfusions to babies (e.g., homozygous a-thalassemia, Parvovirus B19 infection) iv. Fetal cardiac arrhythmias treated by transplacental antiarrhythmic therapy v. Flecainide acetate for fetal supraventricular tachycardia with hydrops fetalis vi. Continuous arteriovenous hemodilution for fluid overload in newborns with hydrops fetalis vii. Pleurocentesis in utero to drain pleural effusion to minimize pulmonary hypoplasia viii. Treatment of maternal infection (Barron and Pass 1995) a) Parvovirus B19: intrauterine transfusion b) Syphilis: IV penicillin c) CMV: No pharmaceutic regimens available for treatment of maternal and fetal CMV infections. Treatment with antiviral agents (ganciclovir, foscarnet) is limited to severe infections (CMV retinitis) in immunocompromised patients and not currently used in pregnancy. d) HSV: acyclovir warranted in disseminated disease; fetal effect unknown e) Toxoplasmosis: spiramycin and/or pyrimethamine, sulfadiazine, and folinic acid ix. Fetal surgery attempted for congenital cystic adenomatoid malformation, pulmonary sequestration, fetal pleural effusions, and sacrococcygeal teratoma

References Anandakumar, C., Biswas, A., Wong, Y. C., et al. (1996). Management of non-immune hydrops: 8 years’ experience. Ultrasound in Obstetrics & Gynecology, 8, 196–200. Arcasoy, M. O., & Gallagher, P. G. (1995). Hematologic disorders and nonimmune hydrops fetalis. Seminars in Perinatology, 19, 502–515. Barron, S. D., & Pass, R. F. (1995). Infectious causes of hydrops fetalis. Seminars in Perinatology, 19, 493–501. Bukowski, R., & Saade, G. R. (2000). Hydrops fetalis. Clinics in Perinatology, 27, 1007–1031. Bullard, K. M., & Harrison, M. R. (1995). Before the horse is out of the barn: Fetal surgery for hydrops. Seminars in Perinatology, 19, 462–473. Carlton, D. P., McGillivray, B. C., & Schreiber, M. D. (1989). Nonimmune hydrops fetalis: A multidisciplinary approach. Clinics in Perinatology, 16, 839–851.

Chui, D. H., & Waye, J. S. (1998). Hydrops fetalis caused by alpha-thalassemia: An emerging health care problem. Blood, 91, 2213–2222. Forouzan, I. (1997). Hydrops fetalis: Recent advances. Obstetrical & Gynecological Survey, 52, 130–138. Haverkamp, F., Noeker, M., Gerresheim, G., et al. (2000). Good prognosis for psychomotor development in survivors with nonimmune hydrops fetalis. British Journal of Obstetrics and Gynaecology, 107, 282–284. Heinonen, S., Ryynanen, M., & Kirkinen, P. (2000). Etiology and outcome of second trimester non-immunologic fetal hydrops. Acta Obstetricia et Gynecologica Scandinavica, 79, 15–18. Holzgreve, W., Curry, C. J., Golbus, M. S., et al. (1984). Investigation of nonimmune hydrops fetalis. American Journal of Obstetrics and Gynecology, 150, 805–812. Holzgreve, W., Holzgreve, B., & Curry, C. J. (1985). Nonimmune hydrops fetalis: Diagnosis and management. Seminars in Perinatology, 9, 52–67. Hutchinson, A. A., Drew, J. H., Yu, V. Y., et al. (1982). Nonimmune hydrops fetalis: A review of 61 cases. Obstetrics and Gynecology, 59, 347–352. Iskaros, J., Jauniaux, E., & Rodeck, C. (1997). Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstetrics and Gynecology, 90, 321–325. Iskarps, K., Jauniaux, E., & Rodeck, C. (1997). Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstetrics and Gynecology, 90, 321–325. Ismail, K. M., Martin, W. L., Ghosh, S., et al. (2001). Etiology and outcome of hydrops fetalis. The Journal of MaternalFetal Medicine, 10, 175–181. Jauniaux, E. (1997). Diagnosis and management of early nonimmune hydrops fetalis. Prenatal Diagnosis, 17, 1261–1268. Jauniaux, E., Van Maldergem, L., De Munter, C., et al. (1990). Nonimmune hydrops fetalis associated with genetic abnormalities. Obstetrics and Gynecology, 75, 568–572. Jones, D. C. (1995). Nonimmune fetal hydrops: Diagnosis and obstetrical management. Seminars in Perinatology, 19, 447–461. Knilans, T. K. (1995). Cardiac abnormalities associated with hydrops fetalis. Seminars in Perinatology, 19, 483–492. Knisely, A. S. (1995). The pathologist and the hydropic placenta, fetus, or infant. Seminars in Perinatology, 19, 525–531. Lam, Y. H., Tang, M. H., Lee, C. P., et al. (1999). Prenatal ultrasonographic prediction of homozygous type 1 alpha thalassemia at 12 to 13 weeks of gestation. American Journal of obstetrics and Gynecology, 180, 148–150. Le´tice´e, N., Bessie`res-Grattagliano, B., Dupre´, T., et al. (2010). Should PMM2-deficiency (CDG Ia) be searched in every case of unexplained hydrops fetalis? Molecular Genetics and Metabolism, 101(2–3), 253–257. Lo, Y. M. D., Hjelm, N. M., Fidler, C., et al. (1998). Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. The New England Journal of Medicine, 339, 17341738. Machin, G. A. (1989). Hydrops revisited: Literature review of 1,414 cases published in the 1980s. American Journal of Medical Genetics, 34, 366–390. Mari, G., et al. (2000). Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell

Hydrops Fetalis alloimmunization Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. The New England Journal of Medicine, 342, 9. McGillivray, B. C., & Hall, J. G. (1987). Nonimmune hydrops fetalis. Pediatrics in Review, 9, 197–202. McMahan, M. J., & Donovan, E. F. (1995). The delivery room resuscitation of the hydropic neonate. Seminars in Perinatology, 19, 474–482. Norton, M. E. (1994). Nonimmune hydrops fetalis. Seminars in Perinatology, 18, 321–332. Poeschmann, R. P., Verheijen, R. H., & Van Dongen, P. W. (1991). Differential diagnosis and causes of nonimmunological hydrops fetalis: A review. Obstetrical & Gynecological Survey, 46, 223–231. Rodriguez, M. M., Chaves, F., Romaguera, R. L., et al. (2002). Value of autopsy in nonimmune hydrops fetalis: Series of 51 stillborn fetuses. Pediatric and Developmental Pathology, 5, 365–374. Salzman, D. H., Frigoletto, F. D., Jr., Harlow, B. L., et al. (1989). Sonographic evaluation of hydrops fetalis. Obstetrics and Gynecology, 74, 106–111. Santolaya, J., Alley, D., Jaffe, R., et al. (1992). Antenatal classification of hydrops fetalis. Obstetrics and Gynecology, 79, 256–259.

1093 Socol, M. L., MacGregor, S. N., Pielet, B. W., et al. (1987). Percutaneous umbilical transfusion in severe rhesus isoimmunization: Resolution of fetal Hydrops. American Journal of Obstetrics and Gynecology, 157, 1369–1375. Sosa, M. E. (1999). Nonimmune hydrops fetalis. The Journal of Perinatal & Neonatal Nursing, 13, 33–44. Steiner, R. D. (1995). hydrops fetalis: Role of the geneticist. Seminars in Perinatology, 19, 516–524. Stone, D. L., & Sidransky, E. (1999). Hydrops fetalis: Lysosomal storage disorders in extremis. Advances in Pediatrics, 46, 409–440. Swain, S., Cameron, A. D., McNay, M. B., et al. (1999). Prenatal diagnosis and management of nonimmune hydrops fetalis. The Australian and New Zealand Journal of Obstetrics and Gynaecology, 39, 285–290. Tongsong, T., Wanapirak, C., Srisomboon, J., et al. (1996). Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. Journal of Clinical Ultrasound, 24, 73–77. Van Maldergem, L., Jauniaux, E., Fourneau, C., et al. (1992). Genetic causes of hydrops fetalis. Pediatrics, 89, 81–86. Watson, J., & Camphell, S. (1986). Antenatal evaluation and management of nonimmune hydrops fetalis. Obstetrics and Gynecology, 67, 589–593.

1094 Fig. 1 An 18-week gestation fetus with hydropic change of the scalp and chest

Fig. 2 A fetus showing hydropic change of the abdominal wall

Hydrops Fetalis

Hydrops Fetalis Fig. 3 (a–c) A macerated fetus, a newborn, and an infant with nonimmune hydrops fetalis

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Hyper-IgE Syndrome

Hyper-IgE syndrome (HIES) is a rare, hereditary multisystem disorder characterized clinically by hyperimmunoglobulinemia E, recurrent infections, and eczematoid dermatitis. In 1966, Job reported two patients with eczematous dermatitis, recurrent staphylococcal boils, hyperextensible joints, and distinctive coarse facies. In 1972, Buckley et al. expanded the clinical picture by adding elevated immunoglobulin E (IgE).

Synonyms and Related Disorders Job syndrome

Genetics/Basic Defects 1. Inheritance (Erlewyn-Lajeunnesse 2000) a. Autosomal dominant with variable penetrance and expressivity b. Linkage to a region on chromosome 4q21demonstrated in several affected families c. An upregulating mutation in the interleukin-4 receptor gene on chromosome 16, demonstrated in some patients with hyper-IgE syndrome d. Autosomal recessive hyper-IgE syndrome: a similar but distinct syndrome reported by Renner et al. (2004) 2. Autosomal dominant hyper-IgE syndrome (AD-HIES): caused by dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3) in most cases of autosomal dominant HIES

(Holland et al. 2007; Minegishi et al. 2007; Jiao et al. 2008; Renner et al. 2008) a. Most cases are sporadic. b. When familial, all individuals carrying the mutation have the HIES phenotype. 3. Autosomal recessive hyper-IgE syndrome (AR-HIES) (Freeman and Holland 2009; Engelhardt et al. 2009) a. Homozygous mutation of Tyk2 with a four nucleotide deletion resulting in a premature stop codon reported in one patient (Minegishi et al. 2006). This patient had the following common features of AR-HIES: i. Eczema ii. Viral infections iii. Recurrent sinopulmonary infections iv. Bacille Calmette–Guerin and Salmonella infections, classic for IL-12/IFN-gamma defects b. Mutations of Tyk2 have been absent in the other reported cases of AR-HIES (Woellner et al. 2007). c. Homozygous mutations (large deletions and point mutations) in the dedicator of cytokinesis 8 (DOCK8) identified recently in most patients with AR-HIES (Engelhardt et al. 2009)

Clinical Features 1. Classic triad (77%) (Grimbacher et al. 1999a; Erlewyn-Lajeunnesse 2000) a. Abscesses b. Pneumonia c. An elevated IgE

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2. Skin manifestations a. Onset with distinctive neonatal rash i. Typically pruritic, secondary to intradermal mast cell histamine release triggered by the elevation of available IgE ii. Often lichenified iii. A distribution atypical for true atopic dermatitis b. Chronic eczema and dermatitis c. Skin infections i. Frequent presentation in infancy a) Furuncles b) Occasional “cold” abscesses c) Cellulitis ii. Multiple staphylococcal abscesses on the skin (furunculosis) a) Most common around the face b) Tender and warm to touch iii. Cold abscesses a) A large fluctuant mass that feels like a tumor or cyst b) Neither hot or tender c) Not associated with systemic symptoms, fever, or other signs of local or generalized inflammation d) Filled with pus that always grows Staphylococcus aureus e) Pathognomic to hyper-IgE syndrome f) Not essential to the diagnosis d. Skin abscesses e. Candidiasis 3. Infections a. Pulmonary infections i. Recurrent and severe ii. Most common infecting organism: Staphylococcus aureus iii. Chronic infections a) Sinusitis b) Discharging otitis media c) Otitis externa d) Mastoiditis iv. Long-term complications a) Bronchiectasis b) Bronchopleural fistulae c) Pneumatocele secondary to staphylococcal pneumonia b. Mucocutaneous candidiasis and fungal infection i. Chronic candidiasis (83%) a) Mucosa sites (oral moniliasis)

Hyper-IgE Syndrome

b) Nail fungal infection and dystrophy secondary to Candida albicans ii. Aspergillus infection iii. Cryptococcal infection c. Other serious infections i. Skin, sinopulmonary, and bone infections: most common ii. Staphylococcus: the most frequently infecting organisms iii. Encapsulated organisms a) Haemophilus b) Streptococcus pneumoniae iv. Opportunistic infections: Pneumocystis carinii 4. Facial and dental abnormalities a. Characteristic coarse facies i. Frontal bossing ii. Wide alar base of the nose iii. Wide outer canthal distance iv. Rare craniosynostosis v. Midline facial defects vi. High-arched palate b. Red hair: uncommon finding c. Retained primary teeth (72%): failure or delay of shedding of the primary teeth secondary to lack of root resorption 5. Skeletal abnormalities a. Scoliosis (76%) b. Pathological fractures i. Secondary to minor trauma ii. Associated with osteopenia iii. Frequent recurrent fractures (57%) iv. Systemic infections at fracture sites a) Recurrent bacterial arthritis b) Staphylococcal osteomyelitis c. Generalized joint hyperextensibility (68%) i. Fingers ii. Wrists iii. Shoulders iv. Hips v. Knees vi. Genu valgum 6. Vascular features (Yavuz and Chee 2009): constitute one of the major clinical characteristics in HIES a. Types of vascular abnormalities i. Aneurysms (coronary, aortic, carotid, and cerebral) ii. Pseudoaneurysms iii. Congenital patent ductus venosus

Hyper-IgE Syndrome

iv. Superior vena cava syndrome v. Vasculitides vi. Vascular ectasia vii. Thrombosis viii. Others b. May be congenital or acquired, in the veins and arteries, affecting both sexes c. Can be seen in all subtypes of HIES d. Can be fatal in children and adults e. Limited pathological investigations revealed the presence of vasculitis. f. Presence of hypereosinophilia, vasculitis, and defective angiogenesis in HIES may contribute to the formation of vascular abnormalities in HIES. 7. Association with isolated reports of autoimmune disease a. Systemic lupus erythematosus b. Dermatomyositis c. Membranoproliferative glomerulonephritis 8. Malignant changes a. Hodgkin disease b. Lymphoma c. Leukemias d. Cancers of the vulva, liver, and lung 9. Autosomal recessive hyper-IgE syndrome (AR-HIES) (Renner et al. 2004) a. Similar features i. Extremely elevated serum IgE ii. Severe eczema iii. Recurrent skin bacterial and viral infections as well as sinopulmonary infection b. Distinctive features i. Lack the somatic features, such as the characteristic facies, scoliosis, and the failure of baby teeth to exfoliate ii. Although pneumonias occur in AR-HIES, pneumatoceles do not form. iii. Has a much higher rate of cutaneous viral infections such as Molluscum contagiosum, Herpes simplex, and varicella infections iv. Has frequent neurologic disease, ranging from facial paralysis to hemiplegia, in some cases due to CNS vasculitis v. Mortality: high at a young age in AR-HIES with sepsis more frequent than in AD-HIES vi. Eosinophilia and elevated serum IgE: the most consistent laboratory findings and may be more dramatic than in AD-HIES vii. Autoimmune cytopenias may occur.

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Diagnostic Investigations 1. Routine laboratory workup a. Grossly elevated serum polyclonal IgE: at least ten times normal (peak serum IgE >2,000 IU/mL) b. Accompanying eosinophilia 2. Radiographs, CT scan, and MRI imaging a. Pulmonary abnormalities i. Recurrent alveolar lung infections ii. Pneumatoceles iii. Occasional pneumothorax b. Skeletal abnormalities i. Full evaluations and monitor vigilantly for fractures after even minor trauma ii. Scoliosis c. CNS abnormalities on brain MRI (Freeman et al. 2007) i. Remarkably common and previously unrecognized aspect of HIES ii. Several patients with lacunar infarcts in addition to focal hyperintensities suggest possible small vessel disease. 3. Skin biopsy (Chamlin et al. 2002) a. An eosinophilic infiltrate similar to that seen in eosinophilic pustular folliculitis b. Spongiosis c. Perivascular dermatitis 4. Molecular genetic diagnosis a. AD-HIES: investigate STAT3 mutations b. AR-HIES: investigate DOCK8 mutations in patients with a phenotype of elevated IgE, eosinophilia, and recurrent skin boils, pneumonia, and viral infections (especially molluscum contagiosum and herpes) (Engelhardt et al. 2009)

Genetic Counseling 1. Recurrence risk a. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is a carrier b. Autosomal dominant inheritance i. Patient’s sib: not increased unless one of the parents is affected, in which case, there will be 50% risk of sibling affected ii. Patient’s offspring: 50%

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2. Prenatal diagnosis for AD-HIES (Freeman et al. 2010) a. Possible for pregnancies at increased risk by analysis of DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling (CVS):The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. b. Preimplantation genetic diagnosis (PGD) may be available for families in which the diseasecausing mutation has been identified previously. 3. Management (Erlewyn-Lajeunnesse 2000; Freeman and Holland 2009) a. Largely supportive b. Prompt treatment of infection with prolonged intravenous antibiotics c. Treatment of eczema and prevention of S. aureus abscesses are most successfully accomplished with antiseptics such as bathing in bleach (120 mL of bleach in tub of water for 15 min three times weekly) or swimming in chlorinated pools. d. Active suspicion of pneumonia is necessary because systemic symptoms of illness are often lacking. e. Antimicrobial prophylaxis i. Prevents recurrent sinopulmonary infections with trimethoprim–sulfamethoxazole, a frequent choice ii. Pneumonias should be treated aggressively to try to prevent parenchymal damage. iii. If pneumatocoeles and bronchiectasis are present, antimicrobial prophylaxis often needs to be broadened to cover Gramnegative bacteria and fungi. iv. Management of pneumatocoeles is complex, as these cysts when secondarily infected carry significant risk for morbidity and mortality; however, surgery is not without risk, as HIES patients may have trouble re-expanding their lungs and soilage of the pleural space can occur. f. Cimetidine, the histamine receptor-2 (H2) antagonist i. Shown to reverse the hyper-IgE syndrome neutrophil chemotactic defect in vitro ii. A single patient showed a clinical improvement on treatment with improved neutrophil chemotaxis in spite of a clinical relapse.

Hyper-IgE Syndrome

g. h. i. j. k. l. m.

n. o.

p.

q. r.

s.

iii. Another seven patients treated with H2 antagonist with benefit. Cyclosporine may be helpful. Bronchoscopy may help isolate causative pathogens and clear pus. Dental extraction of primary teeth Surgical intervention by incision and drainage of abscesses Chest tube drainage and lobectomy for complications of pneumonias Orthopedic cares for fractures and scoliosis Dermatitis i. Topical steroid ii. Topical antifungals iii. Emollient creams Isotretinoin used to improve dermatitis High-dose intravenous g-globulin for patients with aberrant humoral immunity: Intravenous immunoglobulin (IVIG) may decrease the number of infections for some individuals and is the most frequent immunomodulator used. Invasive approach with plasmapheresis with temporary improvement of skin condition and free of infections Bone marrow transplantation: only hope of cure at present, likely not fully corrective A single report of a peripheral stem cell transplantation i. Serum IgE returned to normal ii. Disappearance of symptoms iii. Unfortunately, patient died of interstitial pneumonia Hematopoietic cell transplantation (Gatz et al. 2010) i. Curative in patients with AR-HIES ii. Should be considered early before lifethreatening complications develop, which include malignancies

References Buckley, R. H. (2001). The hyper-IgE syndrome. Clinical Reviews in Allergy & Immunology, 20, 139–154. Buckley, R. H., Wray, B. B., & Belmaker, E. Z. (1972). Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics, 49, 59–70.

Hyper-IgE Syndrome Chamlin, S. L., McCalmont, T. H., Cunningham, B. B., et al. (2002). Cutaneous manifestations of hyper-IgE syndrome in infants and children. Journal of Pediatrics, 141, 572–575. Chehimi, J., Elder, M., Greene, J., et al. (2001). Cytokine and chemokine dysregulation in hyper-IgE syndrome. Clinical Immunology, 100, 49–56. Dahl, M. V. (2002). Hyper-IgE syndrome revisited. International Journal of Dermatology, 41, 618–619. Dau, P. C. (1988). Remission of hyper-IgE treated with plasmapheresis and cytotoxic immunosuppression. Journal of Clinical Apheresis, 4, 8–12. Davis, S. D., Schaller, J., & Wedgwood, R. J. (1966). Job’s syndrome: Recurrent, “cold,” staphylococcal abscesses. Lancet, 1, 1013–1015. Donabedian, H., & Gallin, J. I. (1983). The hyperimmunoglobulin E recurrent –infection (Job’s) syndrome: a review of the NIH experience and the literature. Medicine, 62, 195–208. Engelhardt, K. R., McGhee, S., Winkler, S., et al. (2009). Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. The Journal of Allergy and Clinical Immunology, 124, 1289–1302. Erlewyn-Lajeunesse, M. D. S. (2000). Hyperimmunoglobulin-E syndrome with recurrent infection: A review of current opinion and treatment. Pediatric Allergy and Immunology, 11, 133–141. Freeman, A. F., Collura-burke, C. J., Patronas, N. J., et al. (2007). Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics, 119, e1121–e1125. Freeman, A.F., Davis, J., Hsu, A.P., et al (2010). Autosomal dominant IgE syndrome. GeneReviews. Initial posting February 23, 2010. Available at: http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book¼gene&part¼higes Freeman, A., & Holland, S. M. (2009). Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndrome. Pediatric Research, 65, 32R–37R. Gatz, S. A., Benninghoff, U., & Sch€ utz, C. (2010). Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplantation, 46, 552–554. Gennery, A. R., Flood, T. J., Abinun, M., et al. (2000). Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplantation, 25, 1303–1305. Grimbacher, B., Holland, S. M., Gallin, J. I., et al. (1999a). Hyper-IgE syndrome with recurrent infections–an autosomal dominant multisystem disorder. The New England Journal of Medicine, 340, 692–702. Grimbacher, B., Schaffer, A. A., Holland, S. M., et al. (1999b). Genetic linkage of hyper-IgE syndrome to chromosome 4. The American Journal of Human Genetics, 65, 735–744. Holland, S. M., DeLeo, F. R., Elloumi, H. Z., et al. (2007). STAT3 mutations in the hyper-IgE syndrome. The New England Journal of Medicine, 357, 1608–1619. Jhaveri, K. S., Sahani, D. V., Shetty, P. G., et al. (2000). Hyperimmunoglobulinaemia E syndrome: Pulmonary imaging features. Australasian Radiology, 44, 328–330. Jiao, H., Toth, B., Fransson, I., et al. (2008). Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Molecular Immunology, 46, 202–206.

1101 Khurana-Hershey, G. K., Friedrich, M. F., Esswein, L. A., et al. (1997). The association of atopy with a gain of function mutation in the alpha subunit of the interleukin-4 receptor. The New England Journal of Medicine, 337, 1720–1725. Kikkawa, Y., Kamimura, K., Hamajima, T., et al. (1973). Thymic alymphoplasia with hyper-IgE-globulinemia. Pediatrics, 51, 690–696. Kimata, H. (1995). High-dose intravenous gamma-globulin treatment for hyperimmunoglobulin E syndrome. The Journal of Allergy and Clinical Immunology, 95, 771–774. Mawhinney, H., Killen, M., Fleming, W. A., et al. (1980). The hyperimmunoglobulin E syndrome-a neutrophil chemotactic defect reversible by histamine H2 receptor blockade? Clinical Immunology and Immunopathology, 17, 483–491. Minegishi, Y., Saito, M., Morio, T., et al. (2006). Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25, 745–755. Minegishi, Y., Saito, M., & Tsuchiya, S. (2007). Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature, 448, 1058–1062. Nester, T. A., Wagnon, A. H., Reilly, W. F., et al. (1998). Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinemia E and recurrent infections. The American Journal of Medicine, 105, 162–164. Ochs, H. D., Kraemer, M. J., Lindgren, C. G., et al. (1983). Immune regulation in the hyper-IgE/Job syndrome. Birth Defects Original Article Series, 19, 57–61. Ohga, S., Nomura, A., Ihara, K., et al. (2003). Cytokine imbalance in hyper-IgE syndrome: Reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells. British Journal of Haematology, 121, 324–331. Paganelli, R., Quinti, I., Carbonari, M., et al. (1986). IgG antiIgE in circulating immune complexes in the hyper-IgE syndrome. Clinical Allergy, 16, 513–521. Renner, E. D., Puck, J. M., Holland, S. M., et al. (2004). Autosomal recessive hyperimmunoglobulin E syndrome: A distinct disease entity. Journal of Pediatrics, 144, 93–99. Renner, E. D., Ryalaarsdam, S., Anover-Sombke, S., et al. (2008). Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and STAT3 phosphorylation in hyper-IgE syndrome. The Journal of Allergy and Clinical Immunology, 122, 181–187. Ring, J., & Landthaler, M. (1989). Hyper-IgE syndromes. Current Problems in Dermatology, 18, 79–88. Shemer, A., Weiss, G., Confino, Y., et al. (2001). The hyper-IgE syndrome. Two cases and review of the literature. International Journal of Dermatology, 40, 622–628. Thompson, R. A., & Kumararatne, D. S. (1989). Hyper-IgE syndrome and H2-recptor blockade. Lancet, 2, 630. Vercelli, D., Jabara, H. H., Cunningham-Rundles, C., et al. (1990). Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. The Journal of Clinical Investigation, 85, 1666–1671.

1102 Wakim, M., Alazard, M., Yajima, A., et al. (1998). High dose intravenous immunoglobulin in atopic dermatitis and hyperIgE syndrome. Annals of Allergy, Asthma & Immunology, 81, 153–158. Woellner, C., Schaffer, A. A., Puck, J. M., et al. (2007). The hyper IgE syndrome and mutations in Tyk2. Immunity, 26, 535.

Hyper-IgE Syndrome Yavuz, H., & Chee, R. (2009). A review on the vascular features of the hyperimmunoglobulin E syndrome. Clinical and Experimental Immunology, 159, 238–244. Yokota, S., Mitsuda, T., Shimizu, H., et al. (1990). Cromoglycate treatment of a patient with Hyperimmunoglobulin E syndrome. Lancet, 335, 857–858.

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a

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Fig. 1 (a–d) A 3-year-9-month-old patient with hyperimmunoglobulin E syndrome showing skin scars on his arm and bowing of the legs. Facial features included frontal bossing, wide alar basis of the nose, and wide outer canthal distance. He had history

of recurrent pneumonias, otitis media, asthma, and fractures of the leg bones. At 2 years and 10 months of age, IgE was 15,610 (93 KU/L). He is currently on intravenous immunoglobulin therapy with antibiotic prophylaxis

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Fig. 2 A 13-year-old boy had a history of recurrent pneumonias, a right hip infection, and significant atopic dermatitis. Facial features included frontal bossing, wide alar basis of the nose, and wide outer canthal distance. Laboratory tests showed hyperimmunoglobulin E

Hyper-IgE Syndrome

Hypochondroplasia

Hypochondroplasia is a disproportionate short stature disorder resembling achondroplasia but with less severe phenotype.

Genetics/Basic Defects 1. Inheritance (Le Merrer et al. 1994). a. Autosomal dominant with full penetrance b. Sporadic in 90% of cases c. Observation of an increased paternal age effect at the time of conception, suggesting involvement of de novo mutations of paternal origin d. Presence of locus heterogeneity 2. Evidence supporting the view that hypochondroplasia and achondroplasia are allelic disorders (McKusick et al. 1973; Le Merrer et al. 1994) a. A remarkable inter- and intrafamilial variation in expression of hypochondroplasia with some cases resembling minor forms of achondroplasia b. Offspring of an achondroplastic parent and hypochondroplastic parent with severe neonatal achondroplasia resembling homozygous achondroplasia c. Similar histopathological aspects of the growth cartilage for the two disorders 3. Molecular defect. a. About 70% of affected individuals who are heterozygous for a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which is mapped on chromosome 4p16.3 (Francomano 2005)

b. FGFR3 mutations reported in hypochondroplasia i. 1620C-A (Asn540Lys): two thirds of cases ii. 1620C-G (Asn540Lys): one third of cases iii. 1658A-C (Asn540Thr) and other FGFR3 mutations: rare c. FGFR3 mutation reported in hypochondroplasia association with acanthosis nigricans (CastroFeijo´o et al. 2008) and acanthosis nigricans and hyperinsulinemia (Blomberg et al. 2010): p.Lys650Thr mutation 4. Hypochondroplasia-achondroplasia compound heterozygote a. Born to a hypochondroplastic parent and an achondroplastic parent b. The severity of the child: clinical and radiographic findings more severe than achondroplasia or hypochondroplasia alone but less severe than homozygous achondroplasia (Huggins et al. 1999) c. Demonstration of both the hypochondroplasia (Asn540Lys) and achondroplasia (Gly380Arg) mutations at the FGFR3 locus in a patient with the genetic compound

Clinical Features 1. Short stature (Francomano 2005) a. Evident by school age b. Adult height: 128–165 cm 2. Stocky build 3. Facial appearance a. Usually normal b. Mild macrocephaly may be present.

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4. Skeletal features a. General features: usually similar but milder to achondroplasia b. Limbs i. Disproportionately short compared with the length of the trunk ii. Shortening of the proximal (rhizomelia) or middle (mesomelia) segments of the extremities iii. Mild limitation of elbow extension iv. Broad and short hands and feet (brachydactyly) v. Absence of trident hand deformity vi. Bow legs (genu varum): usually mild vii. Adult onset osteoarthritis: less common c. Spine i. Scoliosis ii. Slight lumbar lordosis with a sacral tilt 5. Rare association with acanthosis nigricans 6. Medical complication a. Following complications: less frequent compared to achondroplasia i. Spinal stenosis with neurologic complications ii. Tibial bowing iii. Obstructive apnea b. Deficits in mental capacity and/or function: may be more prevalent than achondroplasia

Diagnostic Investigations 1. Radiography (Francomano 2005) a. The most common features i. Short proximal (rhizomelic) and/or middle (mesomelic) segments of the long bones with mild metaphyseal flare, especially femora and tibiae ii. Caudal narrowing or unchanged lumbar interpedicular distance iii. Mild to moderate brachydactyly iv. Short and broad femoral neck v. Squared and shortened ilia b. The less common but significant features i. Elongation of the distal fibula ii. Anterior-posterior shortening of the lumbar vertebrae iii. Dorsal concavity of the lumbar vertebral bodies

Hypochondroplasia

iv. Shortening of the distal ulna v. Long ulnar styloid in adults vi. Prominence of muscle insertions on the long bones vii. Shallow “chevron” deformity of distal femur metaphysis viii. Low articulation of sacrum on pelvis with a horizontal orientation ix. Flattened acetabular roof 2. Molecular genetic testing a. Mutation analysis i. 1620C-A (Asn540Lys) ii. 1620C-G (Asn540Lys) iii. Other FGFR3 mutations b. Sequence analysis of mutations in FGFR3 exons 10, 13, and 15

Genetic Counseling 1. Recurrence risk (Francomano 2005) a. Patient’s sib: an extremely low risk ( A transversion at nucleotide 1620 (c.1620 C > A) of the fibroblast growth factor receptor 3 (FGFR3) gene. The presence of this mutation is consistent with a clinical diagnosis of hypochondroplasia Fig. 6 (a, b) Radiographs of the spine (AP and lateral views) show caudal narrowing of lumbar interpedicular distance and the dorsal convexity of the lumbar vertebral bodies

a

b

Hypoglossia-Hypodactylia Syndrome

Hypoglossia-hypodactylia syndrome is an extremely rare condition characterized by a small tongue associated with distal limb deficiency. The syndrome is also called aglossia-adactylia syndrome, which is a misnomer since the tongue is never completely absent and the term “adactylia” does not convey the variation in limb defects of affected individuals. The syndrome is also known as oromandibular limb hypogenesis syndrome, a spectrum of congenital anomalies that affect the tongue, oromandibular region, and the limbs.

Synonyms and Related Disorders Aglossia-adactylia syndrome; Oromandibular limb hypogenesis syndrome

Genetics/Basic Defects 1. Inheritance a. Sporadic in all reported cases. b. Autosomal dominant inheritance cannot be ruled out. 2. Pathogenesis (Yasuda et al. 2003) a. Impairments or insults to fetus during the early fetal life (fourth to seventh week) may be responsible for the findings of tongue and limb abnormalities seen in hypoglossia-hypodactylia syndrome because of the close chronological relationship between the development of the tongue and the limbs. b. A hypoplastic mandible with concurrent hypoglossia could be explained by the fact that

the mandible originates from the same visceral arch as the tongue. c. Vascular mechanism (either hemorrhage or vasoocclusion) may be responsible for defects that are asymmetric and always distal.

Clinical Features 1. Mouth a. Mandible i. Micro-/retrognathia a) Minor feeding problems in infancy b) Minor speech impairment ii. Oligodontia iii. Absent mandibular incisors with concomitant hypoplasia of the associated alveolar ridge iv. Other features a) Mild lower lip defect b) Microstomia (markedly reduced mouth opening) c) Intraoral bands d) Oral frenula e) Oral syngnathia b. Tongue i. Varying degrees of hypoglossia ii. Ankyloglossia iii. Marked enlargement of the sublingual muscular ridges iv. Hypertrophy of the sublingual and submandibular glands 2. Variable limb anomalies a. May involve any limb

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4. 5.

6.

b. Distal reduction anomalies i. Oligodactyly (absence of some fingers and toes) ii. Adactylia (congenital absence of the fingers and toes) iii. Peromelia (severe congenital malformation of the extremity, including absence of hand and foot) c. Syndactyly Other associated anomalies a. Moebius syndrome b. Fused labia majora c. Unilateral renal agenesis d. Imperforate anus Normal intelligence Classification of syndromes of oromandibular and limb hypogenesis (Hall 1971) a. Type I i. Hypoglossia ii. Aglossia b. Type II i. Hypoglossia-hypodactylia ii. Hypoglossia-hypomelia (peromelia) iii. Hypoglossia-hypodactylomelia c. Type III i. Glossopalatine ankylosis ii. With hypoglossia iii. With hypoglossia-hypodactylia iv. With hypoglossia-hypomelia v. With hypoglossia-hypodactylomelia d. Type IV i. Intraoral bands and fusion ii. With hypoglossia iii. With hypoglossia-hypodactylia iv. With hypoglossia-hypomelia v. With hypoglossia-hypodactylomelia e. Type V i. The Hanhart syndrome ii. Charlie M syndrome iii. Pierre Robin syndrome iv. Moebius syndrome v. Amniotic band syndrome Differential diagnosis with other oromandibular limb hypogenesis syndromes (Bonneau et al. 1999) a. Hanhart syndrome i. Micrognathia a) Microglossia b) Hypodontia

Hypoglossia-Hypodactylia Syndrome

ii. Limb anomalies a) Ranging from stunted digits, oligodactyly, to more severe peromelia b) May affect any limb b. Glossopalatine and ankylosis syndrome i. Tongue. a) Usually attached to the hard palate b) May adhere to the maxillary alveolar ridge c) Mildly cleft tongue tip ii. High-arched or cleft palate. iii. Hypoplastic mandible. iv. Hypodontia principally affects the incisor teeth. v. Ankylosis of the temporomandibular joint. vi. Facial paralysis. vii. Extremely variable limb anomalies. a) Oligodactyly b) Syndactyly c) Polydactyly d) Peromelia c. Limb deficiency-splenogonadal fusion syndrome (Bonneau et al. 1999) i. Splenogonadal fusion a) A rare malformation in which the spleen is abnormally connected to the gonad, or, more rarely, to a derivative of the mesonephros b) May occur as a rare malformation ii. Association with other malformations, especially with terminal limb defects d. Moebius syndrome (please refer to the chapter of Moebius Syndrome)

Diagnostic Investigations 1. Radiography a. Fusion of the temporomandibular joints b. Micro-/retrognathia c. Hypodontia d. Limb defects i. Variable distal limb deficiency ii. Asymmetric reduction deformities of the distal extremities iii. Severity ranging from hypoplastic digits to peromelia

Hypoglossia-Hypodactylia Syndrome

e. Other rare anomalies i. Dextrocardia ii. Transposition of abdominal organs iii. Jejunal atresia iv. Short bowel v. “Apple peel” bowel 2. Reconstructed 3D CT imaging of the craniofacial skeletal structures (Yasuda et al. 2003) a. Retruded and reduced mandible b. Steep inclination of the anterior surface of the mandible in relation to the lower mandibular plane c. Bone defect of the alveolar ridge at the midline area of the mandible 3. MRI of the tongue and the floor of the mouth (Yasuda et al. 2003) a. Degree of the hypoglossia b. Space between the tongue and the inferior surface of the palate c. Hypertrophy of the floor of the mouth

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: not increased unless the condition represents an autosomal dominant inheritance, in which case there will be 50% risk to have an affected offspring 2. Prenatal diagnosis: not been reported 3. Management (Yasuda et al. 2003) a. Early surgical intervention for presence of severe anomalies that are life-threatening and interfere swallowing, breathing, and eating b. Extraction of the supernumerary tooth c. Orthodontic expansion appliance for widening the mandibular dental arch d. Distraction osteogenesis to improve the size and shape of the hypoplastic mandible e. Mandibular advancement

References Alexander, R., Friedman, J. S., Eichen, M. M., et al. (1992). Oromandibular-limb hypogenesis syndrome: Type II A,

1115 hypoglossia-hypodactylia–report of a case. The British Journal of Oral & Maxillofacial Surgery, 30, 404–406. Alvarez, G. E. (1976). The aglossia-adactylia syndrome. British Journal of Plastic Surgery, 29, 175–178. Bersu, E. T., Pettersen, J. C., Charboneau, W. J., et al. (1976). Studies of malformation syndromes of man XXXXIA: Anatomical studies in the Hanhart syndrome–a pathogenetic hypothesis. European Journal of Pediatrics, 122, 1–17. Bonneau, D., Roume, J., Gonzalez, M., et al. (1999). Splenogonadal fusion limb defect syndrome: Report of five new cases and review. American Journal of Medical Genetics, 86, 347–358. Cohen, M. M., Jr., Pantke, H., & Siris, E. (1971). Nosologic and genetic considerations in the aglossy-adactyly syndrome. Birth Defects Original Article Series, 7(7), 237–240. Coskunfirat, O. K., Velidedeoglu, H. V., Demir, Z., et al. (1999). An unusual case of hypoglossia-hypodactyly syndrome. Annals of Plastic Surgery, 42, 333–336. David, A., Roze, J. C., Remond, S., et al. (1992). Hypoglossiahypodactylia syndrome with jejunal atresia in an infant of a diabetic mother. American Journal of Medical Genetics, 43, 882–884. Dellagrammaticas, H., Tzaki, M., Kapiki, A., et al. (1982). Hanhart syndrome: Possibility of autosomal recessive inheritance. Progress in Clinical and Biological Research, 104, 299–305. Elalaoui, S. C., Ratbi, I., Malih, M., et al. (2010). Severe form of hypoglossia–hypodactylia syndrome associated with complex cardiopathy: A case report. International Journal of Pediatric Otorhinolaryngol, 74(9), 1092–1094. Gorlin, R. J., Cohen, M. M., Jr., & Hennekam, R. C. M. (2001). Syndromes of the head and neck (4th ed.). New York: Oxford University Press. Grippaudo, F. R., & Kennedy, D. C. (1998). Oromandibularlimb hypogenesis syndromes: A case of aglossia with an intraoral band. British Journal of Plastic Surgery, 51, 480–483. Hall, B. D. (1971). Aglossia-adactylia. Birth Defects Original Article Series, 7(7), 233–236. Harwin, S. M., & Lorinsky, L. C. (1970). Picture of the month: Aglossia-adactylia syndrome. American Journal of Diseases of Children, 119, 255–256. Herrmann, J., Pallister, P. D., Gilbert, E. F., et al. (1976). Studies of malformation syndromes of man XXXXI B: Nosologic studies in the Hanhart and the Mobius syndrome. European Journal of Pediatrics, 122, 19–55. Johnson, G. F., & Robinow, M. (1978). Aglossia-adactylia. Radiology, 128, 127–132. Kelln, E. E., Bennett, C. G., & Klingberg, W. G. (1968). Aglossia-adactylia syndrome. American Journal of Diseases of Children, 116, 549–552. Lustmann, J., Lurie, R., Struthers, P., et al. (1981). The hypoglossia–hypodactylia syndrome. Report of 2 cases. Oral Surgery, Oral Medicine, and Oral Pathology, 51, 403–408. McPherson, F., Frias, J. L., Spicer, D., et al. (2003). Splenogonadal fusion-limb defect “syndrome” and associated malformations. American Journal of Medical Genetics, 120A, 518–522.

1116 Mishima, K., Sugahara, T., Mori, Y., et al. (1996). Case report: Hypoglossia-hypodactylia syndrome. Journal of CranioMaxillo-Facial Surgery, 24, 36–39. Nevin, N. C., Burrows, D., Allen, G., et al. (1975). Aglossiaadactylia syndrome. Journal of Medical Genetics, 12, 89–93. Nevin, N. C., Dodge, J. A., & Kernohan, D. C. (1970). Aglossiaadactylia syndrome. Oral Surgery, Oral Medicine, and Oral Pathology, 29, 443–446. Pauli, R. M., & Greenlaw, A. (1982). Limb deficiency and splenogonadal fusion. American Journal of Medical Genetics, 13, 81–90. Qaisi, M., Chen, H., Ghali, G. E. (2010). Oromandibular limb hypogenesis syndrome with a unique presentation of hemimandibular agenesis. Personal communication. Robertson, S. P., & Bankier, A. (1999). Oromandibular limb hypogenesis complex (Hanhart syndrome): A severe adult phenotype. American Journal of Medical Genetics, 83, 427–429. Robinow, M., Marsh, J. L., Edgerton, M. T., et al. (1978). Discordance in monozygotic twins for aglossia-adactylia,

Hypoglossia-Hypodactylia Syndrome and possible clues to the pathogenesis of the syndrome. Birth Defects Original Article Series, 14, 223–230. Scott, C. I., Jr. (1971). Aglossia-adactylia syndrome. Birth Defects Original Article Series, 7, 281. Stallard, M. C., & Saad, M. N. (1976). Aglossia-adactylia syndrome. Case reports. Plastic and Reconstructive Surgery, 57, 92–95. Steigner, M., Stewart, R. E., & Setoguchi, Y. (1975). Combined limb deficiencies and cranial nerve dysfunction: Report of six cases. Birth Defects Original Article Series, 11(5), 133–141. Tuncbilek, E., Yalcin, C., & Atasu, M. (1977). Aglossiaadactylia syndrome (special emphasis on the inheritance pattern). Clinical Genetics, 11, 421–423. Wada, T., Inoue, K., Fukuda, T., et al. (1980). Hypoglossiahypodactylia syndrome: Report of a case. The Journal of Osaka University Dental School, 20, 297–304. Yasuda, Y., Kitai, N., Fujii, Y., et al. (2003). Report of a patient with hypoglossia-hypodactylia syndrome and a review of the literature. The Cleft Palate-Craniofacial Journal, 40, 196–202.

Hypoglossia-Hypodactylia Syndrome Fig. 1 (a–c) A 2-month-old female infant with hypoglossia-hypodactylia syndrome showing antimongoloid slant of the palpebral fissures, facial palsy, micro-/retrognathia, microstomia, hypoglossia, and limb anomalies with adactylia of the right hand and both feet and oligodactyly of the left hand

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Fig. 2 (a, b) Another infant with hypoglossia-hypodactylia syndrome showing extreme micro-/retrognathia, hypoglossia, microstomia, and adactylia of both hands

Hypoglossia-Hypodactylia Syndrome Fig. 3 (a–c) A 3-month-old girl with hypoglossiahypodactylia syndrome showing extreme micro-/ retrognathia, hypoglossia, microstomia, and adactylia of both hands (right upper extremity showed a transverse growth arrest beyond the wrist and left upper extremity showed a transverse arrest beyond the proximal one third of the forearm)

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1120 Fig. 4 (a, b) CT of the face (AP and lateral views) show left hemimandibular agenesis (complete absence of the body, angle, ramus, and condyle) and a significant aplasia of posterior maxilla on the left

Fig. 5 (a, b) Plain radiographs show transverse growth arrest past the proximal one third of the left forearm and V-shaped formation of the radius and ulna with growth arrest past the right wrist

Hypoglossia-Hypodactylia Syndrome

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Hypoglossia-Hypodactylia Syndrome

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Fig. 6 The previous girl was seen at 3 years of age

Fig. 7 (a, b) Preoperative photos at 5 years of age

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Fig. 10 Titanium mesh used as a crib for BMP at the inferior border of the rib graft

Fig. 8 Preoperative CT at the age of 5

Fig. 9 Intraoperative photo. Costochondral graft fixated to the adjacent mandible. Cartilaginous cap seated in the glenoid fossa

Hypoglossia-Hypodactylia Syndrome

a

Fig. 11 (a, b) Postoperative photos at age 5. She was reconstructed with a right costochondral rib graft to replace the condyle and ramus region and established continuity of her mandible. This was combined with the use of a titanium mesh crib and some bone morphogenetic proteins (BMP) at the

Fig. 12 Three-month postoperative cone beam CT. Cartilaginous cap not apparent on this view

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junction of the native mandible and the costochondral graft. Note the improved facial profile on the left. Despite improved result, the patient will require further surgery as she grows to correct her facial profile

Fig. 13 Note the broad intraoral band extending from the left subglossal region to the soft palate. This band also attaches to the left lower lip causing retraction of the lip

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Fig. 14 The patient protruding her tongue past the intraoral band. Maximum protrusion. Based on the hypoglossia, the oral band extending from the floor of mouth and left cheek to the soft palate, and the limb abnormalities (hypodactylomelia), the patient would fit best as Hall’s type IVD (intraoral bands and fusion with hypoglossia-hypodactylomelia. Thus, the patient is classified as a type IVD with hemimandibular agenesis (Qaisi et al. 2010)

Hypoglossia-Hypodactylia Syndrome

Hypohidrotic Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia (HED) is a common form of ectodermal dysplasia characterized by a defect in the hair, in the teeth, and in mucosal and sweat glands. It is also known as anhidrotic ectodermal dysplasia. The incidence is estimated to be 1 in 10,000 to 1 in 100,000 male live births (Crawford et al. 1991).

Synonyms and Related Disorders Anhidrotic ectodermal dysplasia; Christ-SiemensTouraine syndrome

Genetics/Basic Defects 1. Inheritance: genetically heterogeneous a. X-linked recessive type: the most common form of over 170 different ectodermal dysplasias b. Autosomal dominant type: less common c. Autosomal recessive type: less common 2. X-linked HED: the most common form a. Caused by mutations in the ectodysplasin-A gene (EDA1) which (Doffinger et al. 2001): i. Codes for the tumor necrosis factor (TNF) family member ectodysplasin-A (EDA) ii. Maps to chromosome Xq12-q13.1 by X autosome translocations of female EDA patients iii. Affects a transmembrane protein expressed by keratinocytes, hair follicles, and sweat glands iv. Possibly has a key role in epithelialmesenchymal signaling b. Over 94% of patients with X-linked HED carry mutations in the EDA1 gene.

c. Tabby phenotype is caused by mutation in mouse homolog of the human EDA gene (Priolo et al. 2000). d. Hemizygous males show severe forms of the disease while heterozygous females often manifest mild to moderate symptoms because of X-chromosome inactivation. 3. Autosomal dominant form and some familial cases of autosomal recessive form of HED caused by at least two genes: a. EDAR (EDA receptor) gene (2q11-q13) i. Cause either dominant or recessive forms ii. Mutated in approximately 25% of non-EDArelated HED b. EDARADD (EDAR-associated death domain) gene (1q42-q43) i. Encodes a protein that interacts with the EDA receptor ii. Known to cause either autosomal recessive or dominant HED iii. Implicated in a very small number of HED patients (Chassaing et al. 2010)

Clinical Features 1. General features a. Characterized by a triad of symptoms i. Atrichosis or hypotrichosis (missing or sparse hair) ii. Anodontia, hypodontia, or misshapen teeth iii. Absent or reduced sweating b. Variable clinical features c. Short stature

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d. Recurrent benign infectious disease seen in most patients with HED e. Unusually severe infections observed in: i. Anhidrotic ectodermal dysplasia with immunodeficiency: a distinct syndrome ii. Ectodermal dysplasia with cleft lip/palate iii. Ectrodactyly-ectodermal dysplasia-cleft lip/palate f. Otitis media g. Infantile fever of unknown etiology h. Hyperthermia i. Hoarse voice 2. Clinical features in X-linked recessive hypohidrotic ectodermal dysplasia a. Affected individuals i. Hemizygous males: affected ii. Heterozygous female carriers: variable clinical symptoms (normal, or mild or partially affected) a) Dental abnormalities, such as hypodontia b) Mild hypohidrosis c) Mild hypotrichosis b. Clinical evidence of the distribution of normal and abnormal skin along Blaschko lines in heterozygous and postzygotic mutation carriers of X-linked hypohidrotic ectodermal dysplasia i. Presence of two different cell lines in a female heterozygous for the XHED due to random inactivation of one of the two X chromosomes during embryogenesis, reflected by the presence of different skin areas, some normal and some showing the result of the genetic abnormality. ii. These abnormal areas, disposed along Blaschko lines, reflect the lines of embryonal development of the epidermis and epidermal derivatives. iii. This clonal inactivation (“lyonization”) of the X chromosome results in variable degree of clinical expression of the disorder. c. Clinically differentiating X-linked HED from autosomal forms of HED i. Finding heterozygous females with XHED ii. Finding parents with partial manifestations of the disorder due to a postzygotic mutation d. Clinical features i. Scalp hair a) Sparse b) Thin

Hypohidrotic Ectodermal Dysplasia

c) Light pigmented d) Slow growing e) Excessive fragility of the shafts, breaking easily with the usual wear and tear of childhood ii. Body hair a) Sparse b) Normal sexual hair (beard, pubic hair) iii. Sweating a) Greatly deficient sweating (hypohidrosis) b) Leading to hyperthermia iv. Teeth a) Congenital absence of teeth (hypodontia) b) Teeth that are present (smaller than average and have conical crowns) v. Facial features a) Frontal bossing b) A saddle nose (depressed nasal bridge) c) Thick lips d) Periorbital hyperpigmentation vi. Other features a) Normal growth and psychomotor development b) Atopic dermatitis c) Bronchial asthma d) Fever of unknown reason e) Sudden death during infancy and early childhood 3. Clinical features in autosomal recessive hypohidrotic ectodermal dysplasia a. Similar to (but indistinguishable from) the hemizygous form of X-linked hypohidrotic ectodermal dysplasia i. Decreased sweating ii. Hypodontia iii. Conical teeth iv. Hypotrichosis of the scalp v. Sparse or absent eyebrows and eyelashes vi. Sparse or absent body hair vii. Dry skin or eczema viii. Hypoplastic nails ix. Hypoplastic breasts x. Atrophic rhinitis xi. Depressed nasal bridge xii. Hyperpigmented and wrinkled periorbital skin b. Males and females equally affected

Hypohidrotic Ectodermal Dysplasia

4. Clinical features in autosomal dominant hypohidrotic ectodermal dysplasia: milder in expression a. Hypodontia, anodontia, microdontia, or other dental anomalies (100%) b. Sparse eyelashes (100%) c. Sparse eyebrows (96%) d. Sparse, fine, slow-growing hair (89%) e. Decreased sweating (85%) f. Thin skin (78%) g. Sparse body hair (62%) h. Decrease heat tolerance (50%) i. Onychodysplasia (39%)

Diagnostic Investigations 1. Radiography a. Hypodontia and adontia i. Essential to determine the extent of hypodontia and adontia ii. Useful in the diagnosis of mildly affected individuals b. Recurrent respiratory infections 2. Normal hair morphology under electron microscopy 3. Starch-iodine test to confirm a mosaic distribution of functional sweat glands in a heterozygous female carrier of X-linked HED (Cambiaghi et al. 2000) 4. Molecular analysis: clinically available a. Sequence analysis i. Mutation in EDA gene for the X-linked form ii. Mutations in EDAR and EDARADD genes for the autosomal dominant or recessive forms b. Duplication/deletion testing: to detect exonic, multiexonic, or whole gene deletions in females which sequence analysis of EDA cannot detect

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. X-linked recessive: 50% of affected brothers if the mother is a carrier, otherwise the risk to sibs is low ii. Autosomal dominant: not increased unless a parent is affected, in which case the risk to the sibs is 50% iii. Autosomal recessive: 25% of the sibs affected

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b. Patient’s offspring i. X-linked recessive a) Offspring of a male proband: none of the sons will be affected; 50% of the daughters will be carriers b) Offspring of a female proband: 50% of her son will be affected and 50% of her daughters will be carriers and may show minimal manifestations ii. Autosomal dominant: 50% risk to each child iii. Autosomal recessive: not increased unless the spouse is also a carrier, in which case the risk to offspring is 50% 2. Prenatal diagnosis a. Analysis of fetal skin obtained from fetoscopy-guided skin biopsy in the second trimester b. Three-dimensional ultrasonography to identify the distinct facial features during the third trimester c. Identification of the disease-causing mutation in the fetus d. Preimplantation genetic diagnosis for at-risk pregnancies is possible, provided diseasecausing mutations have been identified 3. Management a. Environmental modification to control temperature i. Air condition for home, school, and work ii. Adequate supply of water during the hot weather b. Control body temperature i. Tepid sponging ii. Showers iii. Cold drink iv. Antipyretics v. Wet clothing c. Use moisturizers to prevent xerosis or eczema for dry skin d. Use artificial tears (eye drops) to prevent damage to the cornea in patients with defective tearing e. Remove nasal and aural concretions with suction devices or forceps and humidification of the ambient air to prevent their formation f. Treatment and prophylaxis for infections

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g. Dental evaluation and intervention i. Early dental treatment a) Simple restoration b) Dentures c) Orthodontics ii. Dental implants iii. Orthodontic treatment h. Wear wigs to improve appearance for patients with severe alopecia i. Avoid vigorous physical activities for patients with hypohidrosis j. Monitor growth

References Aswegan, A. L., Josephson, K. D., Mowbray, R., et al. (1997). Autosomal dominant hypohidrotic ectodermal dysplasia in a large family. American Journal of Medical Genetics, 72, 462–467. Baala, L., Hadj Rabia, S., Zlogotora, J., et al. (1999). Both recessive and autosomal dominant forms of anhidrotic/ hypohidrotic ectodermal dysplasia map to chromosome 2q11-q13. American Journal of Human Genetics, 64, 651–653. Cambiaghi, S., Restano, L., P€a€akko¨nen, K., et al. (2000). Clinical findings in mosaic carriers of hypohidrotic ectodermal dysplasia. Archives of Dermatology, 136, 217–224. Chassaing, N., Cluzeau, C., Bal, E., et al. (2010). Mutations in EDARADD account for a small proportion of hypohidrotic ectodermal dysplasia cases. British Journal of Dermatology, 162, 1044–1048. Clarke, A. (1987). Hypohidrotic ectodermal dysplasia. Journal of Medical Genetics, 24, 659–663. Clarke, A., & Burn, J. (1991). Sweat testing to identify female carriers of X linked hypohidrotic ectodermal dysplasia. Journal of Medical Genetics, 28, 330–333. Clarke, A., Phillips, D. I., Brown, R., et al. (1987). Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Archives of Disease in Childhood, 62, 989–996. Crawford, P. J. M., Alder, J. M., & Clarke, A. (1991). Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. Journal of Medical Genetics, 28, 181–185. Dhanrajani, P. J., & Jiffry, A. O. (1998). Management of ectodermal dysplasia: A literature review. Dental Update, 25, 73–75. Doffinger, R., Smahi, A., Bessia, C., et al. (2001). X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kB signaling. Nature Genetics, 27, 277–285.

Ho, L., Williams, M. S., & Spritz, R. A. (1998). A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13. American Journal of Human Genetics, 62, 1102–1106. Monreal, A. W., Ferguson, B. M., Headon, D. J., et al. (1999). Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nature Genetics, 22, 366–369. Monreal, A. W., Zonana, J., & Ferguson, B. (1998). Identification of a new spice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. American Journal of Human Genetics, 63, 380–389. Munoz, F., Lestringant, G., Sybert, V., et al. (1997). Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder. American Journal of Human Genetics, 61, 94–100. Passarge, E., et al. (1966). Anhidrotic ectodermal dysplasia as autosomal recessive trait in an inbred kindred. Humangenetik, 3, 181–185. Pinheiro, M., & Freire-Maia, N. (1994). Ectodermal dysplasia: A clinical classification and a causal review. American Journal of Medical Genetics, 53, 153–162. Priolo, M., Silengo, M., Lerone, M., et al. (2000). Ectodermal dysplasias: not only “skin” deep. Clinical Genetics, 58, 415–430. Rossman, R. E., & Johnson, W. P., Jr. (1966). Anhidrotic ectodermal dysplasia; a surgical problem. American Journal of Medical Association, 195, 494–495. Sepulveda, W., Sandoval, R., Carstens, E., et al. (2003). Hypohidrotic ectodermal dysplasia: Prenatal diagnosis by three-dimensional ultrasonography. Journal of Ultrasound in Medicine, 22, 731–735. Srivastava, A. K., Montonen, O., Saarialho-Kere, U., et al. (1996). Fine mapping of the EDA gene: A translocation breakpoint is associated with a CpG island that is transcribed. American Journal of Human Genetics, 58, 126–132. Tanner, B. A. (1988). Psychological aspects of hypohidrotic ectodermal dysplasia. Birth Defects Original Article Series, 24, 263–275. Wright, J.T., Grange, D. K., Richter, M. K. (2009) Hypohidrotic ectodermal dysplasia. GeneReviews. Updated July 23, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br. fcgi?book¼gene&part¼x-hed Zonana, J., Schinzel, A., Upadhyaya, M., et al. (1990). Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis. American Journal of Medical Genetics, 35, 132–135. Zonana, J., et al. (1988). Recognition and reanalysis of a cell line from a manifesting female with X linked hypohidrotic ectodermal dysplasia and an X;autosome balanced translocation. Journal of Medical Genetics, 25, 383–386.

Hypohidrotic Ectodermal Dysplasia Fig. 1 Three boys (a–d) with X-linked hypohidrotic ectodermal dysplasia showing sparse scalp hair, frontal bossing, sparse eyebrows and eyelashes, saddle nose, hypodontia, and irregularly shaped conical and pointed primary incisors

Fig. 2 Two brothers with X-linked hypohidrotic ectodermal dysplasia showing sparse eyebrows, hypodontia, and conical permanent teeth

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a

b

c

d

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Hypohidrotic Ectodermal Dysplasia

Fig. 3 (a, b) A boy with hypohidrotic ectodermal dysplasia showing sparse scalp hairs and eyebrows, hypodontia, and conical permanent teeth

a

Fig. 4 (a, b) A boy with hypohidrotic ectodermal dysplasia showing sparse scalp hairs and eyebrows, hypodontia, and nail hypoplasia of the thumbs

a

Fig. 5 A 15-year-old girl with hypohidrotic ectodermal dysplasia showing sparse eyebrows and ocular hypertelorism

b

b

Hypomelanosis of Ito

In 1952, Ito reported a female patient with a widespread, symmetric pattern of depigmented whorls and streaks, naming it incontinentia pigmenti achromians because the distribution of the depigmented lesions is the negative image of the hyperpigmented streaks of incontinentia pigment. Hypomelanosis of Ito (HI) is a relatively common disorder with a frequency of 1 in 8,000–10,000 patients in a general pediatric hospital and 1 in 1,000 patients in a pediatric neurology service (K€ uster and Konig 1999).

Synonyms and Related Disorders Incontinentia pigmenti achromians

Genetics/Basic Defects 1. Inheritance a. Sporadic occurrence in nearly all cases with no affected sibs or parents (K€ uster and Konig 1999) i. Result of a de novo postzygotic mutation ii. Mutation can only survive in a mosaic state b. Only a few cases with possible genetic inheritance reported i. X-linked dominant inheritance ii. Autosomal dominant iii. Autosomal recessive 2. Pathogenesis a. Chromosome abnormalities (52%) i. Mosaicism leading to generation of two cell lineages producing patterns of hypopigmented and hyperpigmented skin ii. Balanced X/autosome translocations

iii. Supernumerary X chromosome/ring fragment iv. Ring chromosomes (10, 14, 22) v. Mosaic triploidy vi. Mosaic diploidy/tetraploidy vii. Mosaic trisomies (2, 8, 13, 14, 18, 20, 22) viii. Mosaic tetrasomy 13q ix. Mosaic translocations x. Mosaic deletions xi. Autosomal deletions and duplications involving chromosomes 7, 12, 13, 14, 15, and 18 xii. Dup(Xp) b. X chromosome abnormalities i. Inactivation ii. Activation iii. Mosaicism 3. “Pigmentary mosaicism” (Taibjee et al. 2004) a. Hypomelanosis of Ito and related disorders such as linear and whorled nevoid hypermelanosis are due to mosaicism for a variety of chromosomal abnormalities. b. Classification of chromosome mosaicism i. Mosaicism with two or more different karyotypes, involving structural abnormalities of chromosomes ii. Mosaicism involving structural abnormalities of chromosomes, where the chromosome was undetermined iii. Chromosomal abnormality apparently affecting all cells, but where undetected mosaicism remains a possibility iv. Balanced X/autosome translocations affecting all cells, with functional mosaicism due to lionization

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v. Polyploidy mosaicism (cells having different multiples of 23 chromosomes): can be associated with mosaic trisomy such as chromosome18 vi. Chimaerism 4. A descriptive term rather than a true syndrome a. Suggested by the pattern of chromosomal aberrations and the polymorphic nature of the disease b. A term used for a phenotype i. Presence of linear streaks lighter than the patient’s background skin color, extending around the trunk and down the long axes of the extremities, roughly following the lines of Blaschko ii. Association with systemic findings

Clinical Features 1. Cutaneous symptoms (K€ uster and Konig 1999) a. Onset i. Recognizable at birth (54%) ii. Visible during childhood (70%) b. No signs of inflammation or verrucous changes characteristically seen in incontinentia pigmenti c. Hypopigmented lesions i. Typical phenotype a) Cutaneous pattern: essentially the reverse of the third stage of incontinentia pigmenti b) Bilateral or unilateral whirls, patches, and streaks corresponding to the lines of Blaschko, often showing a midline cutoff c) Eruption not preceded by any inflammatory lesions (unlike incontinentia pigmenti) ii. Unilateral skin lesions contralateral to the side of brain malformation in patients with HI and hemimegalencephaly iii. Wood lamp useful in demonstrating hypopigmented lesions in persons with fair skin iv. Atypical phenotype: checkerboard pattern zosteriform, dermatomal, or plaque-like arrangement d. Nonspecific skin lesions (20–40%) i. cafe´-au-lait spots ii. Persistent Mongolian blue spots

Hypomelanosis of Ito

iii. Nevus of Ota iv. Nevus marmoratus and angiomatous nevi v. Soft fibroma vi. Pilomatrixoma vii. Aplasia cutis viii. Atopic dermatitis 2. Hair/nail/sweat gland anomalies a. Focal hypertrichosis b. Slow growth c. Diffuse alopecia d. Coarse, curly hair e. Trichorrhexis f. Widow’s peak g. Generalized hirsutism h. Facial hypertrichosis i. Low hairline j. Ungual hypoplasia k. Hypohidrosis corresponding to hypopigmented areas 3. Associated extracutaneous anomalies (75%) a. CNS anomalies i. Mental retardation (50–75%) ii. Seizures (50%) iii. Autistic behavior (11%) iv. Microcephaly v. Hypotonia vi. Hyperkinesia vii. Ataxia viii. Deafness ix. Hemimegalencephaly x. Brain tumors (medulloblastoma, choroid plexus papilloma) b. Ophthalmological abnormalities (20%) i. Microphthalmia ii. Ptosis iii. Nonclosure of the upper lid iv. Symblepharon v. Dacryostenosis vi. Strabismus vii. Nystagmus viii. Myopia ix. Hyperopia x. Astigmatism xi. Amblyopia xii. Megalocornea xiii. Corneal opacification xiv. Cataracts xv. Iridal heterochromia xvi. Scleral melanosis

Hypomelanosis of Ito

xvii. Heterochromia of the iris xviii. Optic atrophy xix. Striated patchy hypopigmented fundi xx. Retinal detachment c. Dental abnormalities i. Defective dental implantation ii. Conical teeth iii. Partial anodontia iv. Dental dysplasia/hypoplasia v. Defective enamel vi. Hamartomatous dental cusps d. Skeletal defects i. Short stature ii. Facial and limb asymmetry (hemihypertrophy) iii. Pectus carinatum or excavatum iv. Scoliosis v. Syndactyly vi. Polydactyly vii. Brachydactyly viii. Clinodactyly e. Congenital heart defect i. Tetralogy of Fallot ii. Pulmonary stenosis iii. Ventricular septal defect iv. Atrial septal defect v. Incomplete right bundle branch block vi. Cardiomegaly of unknown etiology f. Abdomen/gastrointestinal anomalies i. Diastasis recti ii. Hepatomegaly iii. Segmental dilation of the colon iv. Diaphragmatic, umbilical, and inguinal hernias g. Genitourinary anomalies i. Hypospadias ii. Micropenis iii. Single kidney iv. Urethral duplication v. Cryptorchidism vi. Precocious puberty vii. Gynecomastia viii. Asymmetrical breasts ix. Nephritis 4. Diagnostic criteria (Ruiz-Maldonado et al. 1992) a. Sine qua non criterion: congenital or early acquired nonhereditary cutaneous hypopigmentation in linear streaks or patches involving more than two body segments

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b. Major criterion i. One or more nervous system anomalies ii. One or more musculoskeletal anomalies c. Minor criterion i. Two or more congenital malformations other than nervous system or musculoskeletal anomalies ii. Chromosomal anomalies d. Definitive diagnosis: sine qua non criterion plus one or more major criteria or two or more minor criteria e. Presumptive diagnosis: sine qua non criterion alone or in association with one minor criterion 5. Classification of linear pigmentary disorders distributed along the Blaschko lines (Di Lernia 2007) a. Linear and whorled hypermelanosis i. Hyperpigmentation ii. Diffuse distribution iii. Presence of mosaicism iv. Associated abnormalities (30%) b. Hypomelanosis of Ito i. Hypopigmentation ii. Diffuse distribution iii. Presence of mosaicism iv. Associated abnormalities (30%) c. Progressive cribriform and zosteriform hyperpigmentation i. Hyperpigmentation ii. Segmental distribution iii. Associated abnormalities: very low incidence d. Segmental nevus depigmentosus i. Hyperpigmentation ii. Segmental distribution iii. Associated abnormalities: very low incidence

Diagnostic Investigations 1. Cytogenetic investigation a. Peripheral blood karyotyping indicated especially when systemic manifestations are present b. Fibroblast karyotyping by sampling the dark and light skin for demonstrating mosaicism or chromosomal abnormalities c. Presence of a wide variety of karyotypic abnormalities

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2. Histopathology a. Decreased numbers of melanocytes b. Decreased numbers and size of pigmented melanosomes c. Neuropathological features i. Polymicrogyria ii. Disarray of cortical lamination iii. Heterotopic neurons in the white matter iv. Giant cells 3. CT and MRI of the brain a. White matter abnormalities somewhat predictive of a poor neurological outcome b. Neuroblast migration i. Heterotopia ii. Pachygyria iii. Polymicrogyria c. Localized or generalized cerebral atrophy d. Cerebral hemiatrophy e. Hemimegalencephaly f. Other rare anomalies i. Noncommunicating hydrocephalus ii. Megacisterna magna iii. Arteriovenous malformation iv. Cerebellar hypoplasia (hemispheres and vermis) v. Brainstem hypoplasia vi. Brain tumors 4. Radiography for musculoskeletal anomalies 5. EEG for seizures

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent shows chromosomal abnormalities b. Patient’s offspring i. Not increased unless the patient has chromosomal abnormalities ii. Guarded counseling in women with a phenotype similar to HI who have nonmosaic balanced X/autosome translocations 2. Prenatal diagnosis: undetermined for affected mother who has a specific type of chromosome abnormality 3. Management a. Early intervention programs including physical, occupational, and speech therapies b. Special education

Hypomelanosis of Ito

c. Seizure control d. Surgical treatment of cataracts and retinal detachment

References Di Lernia, V. (2007). Linear and whorled hypermelanosis. Pediatric Dermatology, 24, 205–210. Flannery, D. B. (1990). Pigmentary dysplasias, hypomelanosis of Ito, and genetic mosaicism. American Journal of Medical Genetics, 35, 18–21. Fryburg, J. S., Lin, K. Y., & Matsumoto, J. (1996). Abnormal head MRI in a neurologically normal boy with hypomelanosis of Ito. American Journal of Medical Genetics, 66, 200–203. Glover, M. T., Brett, E. M., & Atherton, D. J. (1989). Hypomelanosis of Ito: Spectrum of the disease. Journal of Pediatrics, 115, 75–80. Gordon, N. (1994). Hypomelanosis of Ito (incontinentia pigmenti achromians). Developmental Medicine and Child Neurology, 36, 271–274. Happle, R. (1993a). Mosaicism in human skin: Understanding the patterns and mechanisms. Archives of Dermatology, 129, 1460–1470. Happle, R. (1993b). Pigmentary patterns associated with human mosaicism: A proposed classification. European Journal of Dermatology, 3, 170–184. Harre, J., & Millikan, L. E. (1994). Linear and whorled pigmentation. International Journal of Dermatology, 33, 529–537. Hatchwell, E., Robinson, D., Crolla, J. A., et al. (1996). X inactivation analysis in a female with hypomelanosis of Ito associated with a balanced X;17 translocation: Evidence for functional disomy of Xp. Journal of Medical Genetics, 33, 216–220. Ishikawa, T., Kanayama, M., Sugiyama, K., et al. (1985). Hypomelanosis of Ito associated with benign tumors and chromosomal abnormalities: A neurocutaneous syndrome. Brain & Development, 7, 45–49. Ito, M. (1951). A singular case of naevus depigmentosus systematicus bilateralis. Japan Journal of Dermatology, 61, 31–32. Janniger, C. K., de Menezes, M. S. (2010). Hypomelanosis of Ito. eMedicine from WebMD. Updated 10 March 2010. Available at: http://emedicine.medscape.com/article/ 909996-overview Koiffmann, C. P., de Souza, D. H., Diament, A., et al. (1993). Incontinentia pigmenti achromians (hypomelanosis of Ito, MIM 146150): Further evidence of Localization at Xp11. American Journal of Medical Genetics, 46, 529–533. K€ uster, W., & Konig, A. (1999). Hypomelanosis of Ito: No entity, but a cutaneous sign of mosaicism. American Journal of Medical Genetics, 85, 346–350. Metzker, A., Morag, C., & Weitz, R. (1982). Segmental pigmentation disorder. Acta Dermato Venereologica (Stockh), 63, 167–169. Moss, C., & Burn, J. (1988). Genetic counselling in hypomelanosis of Ito: Case report and review. Clinical Genetics, 34, 109–115.

Hypomelanosis of Ito Nehal, K. S., PeBenito, R., & Orlow, S. J. (1996). Analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of Blaschko. Archives of Dermatology, 132, 1167–1170. Ohashi, H., Tsukahara, M., Murano, I., et al. (1992). Pigmentary dysplasias and chromosomal mosaicism: Report of 9 cases. American Journal of Medical Genetics, 43, 716–721. Ono, J., Harada, K., Kodaka, R., et al. (1997). Regional cortical dysplasia associated with suspected hypomelanosis of Ito. Pediatric Neurology, 17, 252–254. Pascual-Castroviejo, I., Lopez-Rodriguez, L., de la Cruz, M. M., et al. (1988). Hypomelanosis of Ito. Neurological complications in 34 cases. Canadian Journal of Neurological Sciences, 15, 124–129. Pascual-Castroviejo, I., Roche, C., Martinez-Bermejo, A., et al. (1998). Hypomelanosis of ITO. A study of 76 infantile cases. Brain Development, 20, 36–43. Ratz, J., Gross, N. (2009) Hypomelanosis of Ito. eMedicine from WebMD. Updated 31 August 2009. Available at: http:// emedicine.medscape.com/article/1068339-overview Ritter, C. L., Steele, M. W., Wenger, S. L., et al. (1990). Chromosome mosaicism in hypomelanosis of Ito. American Journal of Medical Genetics, 35, 14–17. Ross, D. L., Liwnicz, B. H., Chun, R. W., & Gilbert, E. (1982). Hypomelanosis of Ito (incontinentia pigmenti achromians) – a clinicopathologic study: macrocephaly and gray matter heterotopias. Neurology, 32, 1013–1016. Rott, H.-D., Lang, G. E., Huk, L. W., et al. (1990). Hypomelanosis of Ito (incontinentia pigmenti achromians). Ophthalmological evidence for somatic mosaicism. Ophthalmic Paediatrics Genetics, 11, 273–279. Rubin, M. B. (1972). Incontinentia pigmenti achromians. Multiple cases within a family. Archives of Dermatology, 105, 424–425. Ruggieri, M. (2000). Familial hypomelanosis of Ito: Implications for genetic counselling. American Journal of Medical Genetics, 95, 82–84. Ruggieri, M., & Pavone, L. (2000). Hypomelanosis of Ito: Clinical syndrome or just phenotype? Journal of Child Neurology, 15, 635–644.

1135 Ruggieri, M., Tigano, G., Mazzone, D., et al. (1996). Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromians). Neurology, 46, 485–492. Ruiz-Maldonado, R., Toussaint, S., Tamayo, L., et al. (1992). Hypomelanosis of Ito: Diagnostic criteria and report of 41 cases. Pediatric Dermatology, 9, 1–10. Steiner, J., Adamsbaum, C., Desguerres, I., et al. (1996). Hypomelanosis of Ito and brain abnormalities: MRI findings and literature review. Pediatric Radiology, 26, 763–768. Sybert, V. P. (1994). Hypomelanosis of Ito: A description, not a diagnosis. The Journal of Investigative Dermatology, 103(5 Suppl), 141S–143S. Sybert, V. P., & Pagon, R. A. (1994). Hypomelanosis of Ito in a girl with plexus papilloma and translocation (X;17) [letter]. Human Genetics, 93, 227. Sybert, V. P., Pagon, R. A., Donlan, M., & Bradley, C. M. (1990). Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito. Journal of Pediatrics, 116, 581–586. Tagawa, T., Futagi, Y., & Arai, H. (1997). Hypomelanosis of Ito associated with hemimegalencephaly: A clinicopathological study. Pediatric Neurology, 17, 180–184. Taibjee, S. M., Bennett, D. C., & Moss, C. (2004). Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: The role of pigmentary genes. British Journal of Dermatology, 151, 269–282. Urgelles, E., Pascual-Castroviejo, I., Roche, C., et al. (1996). Arteriovenous malformation in hypomelanosis of Ito. Brain & Development, 18, 78–80. Weaver, R. G., Jr., Martin, T., & Zanolli, M. D. (1991). The ocular changes of incontinentia pigmenti achromians (hypomelanosis of Ito). Journal of Pediatric Ophthalmology and Strabismus, 28, 160–163. Zajac, V., Kirchhoff, T., Levy, E. R., et al. (1997). Characterisation of X;17(q12;p13) translocation breakpoints in a female patient with hypomelanosis of Ito and choroid plexus papilloma. European Journal of Human Genetics, 5, 61–68.

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Hypomelanosis of Ito

a

b

c

Fig. 1 (a–c) Three children with hypomelanosis of Ito showing hypopigmented skin lesions in a characteristic distribution of whirls and streaks on the trunk and limbs. The first patient has 49,XXXXY

Hypophosphatasia

Hypophosphatasia is a heritable metabolic disease, characterized by impaired ossification of the bones, reduction in tissue and plasma levels of alkaline phosphatase, and the presence of phosphoethanolamine in the urine. The incidence is estimated to be about 1 in 100,000 live births (Fraser 1957). The incidence of severe disease is especially high in Canadian Mennonites (1 in 2,500 newborns) (Gehring et al. 1999).

Synonyms and Related Disorders Adult hypophosphatasia (mild hypophosphatasia, odontohypophosphatasia); Childhood hypophosphatasia; Perinatal lethal hypophosphatasia; Phosphoethanolaminuria

Genetics/Basic Defects 1. Genetic heterogeneity a. Perinatal lethal hypophosphatasia form: autosomal recessive b. Prenatal benign hypophosphatasia form: autosomal dominant c. Infantile hypophosphatasia form: autosomal recessive d. Childhood hypophosphatasia form: autosomal recessive (frequent) and dominant (rare) e. Adult hypophosphatasia form: autosomal recessive and dominant with variable penetrance f. Odontohypophosphatasia form: autosomal recessive and dominant

2. Cause a. Caused by mutations in the alkaline phosphatase gene (ALPL) which (Barcia et al. 1997): i. Codes for tissue nonspecific (“liver/bone/ kidney”) alkaline phosphatase (TNSALP) ii. Is mapped on chromosome 1p36.1–p34 b. Typically, the other isoenzymes (placental and intestinal forms) are not affected (Gehring et al. 1999). 3. Pathophysiology a. Defects in mineralization. i. Caused by deficiency in TNSALP ii. Resulting in increased urinary excretion of phosphoethanolamine and inorganic pyrophosphate and an increase in serum pyridoxal 5’-phosphate b. Osteoclasts, although morphologically normal, lack membrane-associated alkaline phosphatase activity on histochemical analysis (Barcia et al. 1997). i. Impede the proper incorporation of calcium into newly formed bone matrix ii. Result in bone demineralization and hypercalcemia when the impaired matrix calcification process occurs with a rapid rate of bone resorption 4. Genotype-phenotype correlations a. A number of different mutations account for the clinical heterogeneity. i. Individuals with recessive hypophosphatasia with both defective TNSALP alleles. a) In general, manifest more severe symptoms, with many of those affected being stillborn or expiring shortly after birth.

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b.

c.

d. e.

Hypophosphatasia

b) Exception when consanguineous marriage is a factor: the two defective alleles tend to have distinct point mutations resulting in different amino acid substitutions in the alkaline phosphatase protein. ii. Individuals with dominant hypophosphatasia with only one defective TNSALP allele: usually manifest moderate symptoms, such as the premature exfoliation of fully rooted primary teeth. iii. Division between dominant and recessive hypophosphatasia sometimes is not well defined because the heterozygous siblings with one defective TNSALP allele in kindreds with recessive hypophosphatasia may show mild or moderate symptoms of the disease. Missense mutations in the TNSALP gene have been observed in some hypophosphatasia kindreds, particularly those families with the more severe perinatal and infantile forms of the disease. Autosomal recessive inheritance has been observed in most cases of hypophosphatasia with affected individuals being compound heterozygotes for two different mutant hypophosphatasia alleles. Autosomal dominant alleles cause a few relatively mild cases of hypophosphatasia. Mild hypophosphatasia (Fauvert et al. 2009). i. Can result from either compound heterozygosity for severe and moderate mutations but also in a large part from heterozygous mutations with a dominant negative effect. ii. A sequence variation in linkage disequilibrium with haplotype E could in addition play the role of an aggravating factor resulting in loss of haplosufficiency.

Clinical Features 1. Presence of a wide phenotypic variability ranging from intrauterine death and extreme hypomineralization of the skeleton to lifelong absence of clinical symptoms (Gehring et al. 1999) a. The following four different forms of the hypophosphatasia have been defined: i. Perinatal lethal form ii. Infantile form

iii. Childhood form iv. Adult form b. In general, the earlier the age of presentation, the more severe the presenting features. 2. Perinatal lethal form a. Often stillborn b. Skeletal deformities: presenting features i. A profound lack of skeletal mineralization in utero. ii. Skin-covered spurs extending from the forearms or legs (skin dimples) (Shohat et al. 1991): these spurs are often diagnostic for hypophosphatasia. iii. Markedly shortening and bowing of the long bones (short-limbed dwarfism). iv. Fractures (perinatal). v. Rickety rosary. vi. Metaphyseal swelling. vii. Soft, pliable cranial bones (“vault like a balloon”). viii. Bulging anterior fontanelle. c. Respiratory distress due to hypoplastic lungs and rachitic deformities of the chest d. Other features i. Hypotonia ii. High-pitched cry iii. Vomiting iv. Constipation v. Unexplained fever vi. Apnea vii. Cyanosis viii. Irritability ix. Seizures e. Prognosis i. Lethal in utero or within a few days of birth. ii. In the rare prenatal benign form, despite prenatal symptoms, there is a spontaneous improvement of skeletal defects (Pauli et al. 1999; Moore et al. 1999; Wenkert et al. 2007). 3. Infantile form a. Appears normal at birth b. Onset of symptoms i. Before 6 months of age ii. Poor feeding iii. Failure to thrive (growth failure) iv. Hypotonia v. Convulsions

Hypophosphatasia

c. Associated with progressive bony demineralization i. Abnormal skull with apparent wide separation of the cranial sutures and a wide, bulging anterior fontanelle ii. Tendency toward developing craniosynostosis a) Formation of a sagittal ridge b) A bony prominence at the position of the anterior fontanelle iii. Rachitic skeletal deformities manifesting by age 6 months iv. Flail chest v. Pulmonary insufficiency d. Late in walking e. Development of genu valgum f. Short stature g. Complications i. Recurrent pneumonia ii. Increased intracranial pressure iii. Renal compromise secondary to: a) Hypercalcemia b) Hypercalcinuria c) Nephrocalcinosis h. Prognosis: i. Fatal in approximately 50% of cases by the age of 1 year ii. Survivors a) Tend to improve symptomatically. b) Deformities persist and often become worse. 4. Childhood form a. Appears normal at birth. b. Often present after 6 months of age. c. History of delayed walking and waddling gait. d. Early loss of deciduous teeth (before age of 5 years): the most consistent clinical sign. e. Frequent bone pain. f. Defective bone mineralization presenting clinically as rickets in children. g. Respiratory complications due to rachitic deformities of the chest. h. Premature craniosynostosis despite open fontanelle resulting in increased intracranial pressure. i. Dolichocephalic skull. j. Enlarged joints. k. Short stature. l. Bone fractures.

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m. Presence of hypercalcemia causes increased excretion of calcium resulting in renal damage. n. Prognosis: improving both clinically and radiographically with age in some childhood hypophosphatasia patients. 5. Adult form a. Variable age of onset and severity. b. Onset usually during middle age. c. Defective bone mineralization presents clinically as osteomalacia in adults. d. Premature loss of deciduous teeth. e. Usually presents clinically with loss of adult teeth. f. Multiple fractures secondary to osteomalacia, often after minimal fractures. g. Foot pain due to stress fractures of the metatarsals. h. Thigh pain due to pseudofractures of the femur. i. Delay in healing after a fracture. j. Joint pain due to deposition of calcium pyrophosphate dihydrate (chondrocalcinosis). 6. Odontohypophosphatasic form: premature loss of adult teeth; the only physical finding in this form 7. Craniosynostosis a. Considered a known feature in the infantile and childhood types of hypophosphatasia (Whyte 1995; Mornet 2007; Collmann et al. 2009), while it is missed in the adult and odontohypophosphatasia forms b. Often progressively involves all cranial sutures and poses significant functional risks to the optic nerves, as well as the spinal cord

Diagnostic Investigations 1. Laboratory tests. a. Low serum alkaline phosphatase levels in all types of hypophosphatasia b. Increased levels of urinary phosphoethanolamine levels c. Elevated plasma levels of pyridoxal 5’phosphate d. Normal serum calcium, except in infantile cases where hypercalcemia can be seen due to renal failure e. Normal serum phosphate: hyperphosphatemia in various forms of hypophosphatasia reported

1140

2. Skeletal survey (Kozlowski et al. 1976). a. Lethal perinatal form i. Near absence of skeletal mineralization ii. Skull: tiny ossification of occipital and/or frontal bones or complete absence of ossification iii. Teeth: very poorly formed iv. Spine a) Some vertebrae frequently unossified b) Occasionally unossified vertebrae c) Abnormally shaped vertebrae: rectangular, round, flattened, sagittally cleft, or butterfly-shaped vertebrae v. Shortening and bowing of the long and tubular bones vi. Diaphyseal spurs vii. Skin-covered spurs extending from the medial and lateral aspects of the knee and elbow joints viii. Fractures ix. Rachitic changes a) Pathology most evident at metaphyses as in rickets where growth is most rapid, namely the wrists, knees, hips, and proximal humeri. b) Defective, irregular ossification of the metaphysis: the most diagnostic feature of the disease. c) Nearly absent provisional zone of calcification. d) Irregular widening of the epiphyseal plate. e) Grossly irregular ossification of metaphysis giving a “frayed” or “tufted” appearance: a distinguished feature in hypophosphatasia. In rickets, the decalcification is usually regular and may give a “ground glass” effect to the affected metaphysis (metaphyseal cupping). b. Infantile form i. Deficient skeletal mineralization. ii. Congenital bowing of the long bones. iii. Bands of decreased density in metaphyses. iv. Widened cranial sutures. v. Later craniosynostosis: premature craniosynostosis occurs despite an open fontanelle.

Hypophosphatasia

vi. Asymmetrical, moderate to severe ricketslike metaphyseal changes. vii. Metaphyseal and epiphyseal ossification defects. viii. Distorted bone trabeculation with areas of decreased and increased transradiancy. ix. Thin cortical bone. x. Diaphyseal spurs. c. Childhood form i. Mild, asymmetrical, metaphyseal changes resembling rickets or metaphyseal dysplasia ii. Distorted bone trabeculation with areas of decreased and increased transradiancy iii. Thin cortical bone iv. Hypotubulation and bowing of long bones v. Stress fractures vi. Radiolucent projections from the epiphyseal plate into the metaphysis d. Adult form i. Pseudofractures often occur in the lateral aspect of the proximal femur: a hallmark of this form ii. Osteomalacia iii. An increased incidence of poorly healing stress fractures, especially of the metatarsals e. Odontohypophosphatasic form: normal radiographic findings 3. Radiography and ultrasound screening for nephrocalcinosis. 4. Histology. a. Growth plates i. Rachitic abnormalities ii. Poorly mineralized and ossified columns with broad osteoid seams in metaphysis iii. Osteoblasts lacking membrane-associated alkaline phosphatase activity on histochemical testing, disrupting incorporation of calcium into the matrix b. Teeth i. A decrease in cementum ii. Enlarged pulp chamber iii. Incisors tend to be affected 5. Molecular genetic diagnosis: ALPL, the geneencoding alkaline phosphatase, tissue nonspecific isozyme (TNASALP), is the only gene known to be associated with hypophosphatasia. a. Targeted mutation analysis b. Sequence analysis

Hypophosphatasia

Genetic Counseling 1. Recurrence risk: genetic counseling is complicated by the inheritance that may be autosomal dominant or autosomal recessive, the existence of the uncommon prenatal benign form, and the variable expression of the disease (Simon-Bouy et al. 2008). a. Patient’s sib i. Autosomal recessive: 25% ii. Autosomal dominant: not increased unless a parent is affected in which case the recurrence risk is 50% b. Patient’s offspring i. Autosomal recessive: not increased unless a spouse is a carrier in which case the recurrence risk is 50% ii. Autosomal dominant: 50% 2. Prenatal diagnosis. a. Fetal radiography b. Prenatal ultrasonography i. 2D-ultrasonography a) Failure to visualize a well-defined skull b) Other fetal skeletal structures not readily discernable ii. 3D-ultrasonography: can demonstrate specific osseous spurs in a lethal form (Sinico et al. 2007) c. Assay of the alkaline phosphatase activity: a useful complementary and independent method, especially when a mutation is unidentified and DNA from the index case is unavailable i. Assay of the tissue nonspecific alkaline phosphatase activity in chorionic villus samples in the first trimester ii. Absent alkaline phosphatase activity in the amniotic fluid and cultured amniotic fluid cells in the second trimester d. Prenatal diagnosis and preimplantation genetic diagnosis: mutation analysis of fetal DNA from amniocentesis or CVS where the disease-causing mutation has been identified in the family 3. Management. a. No specific treatment available: efforts to effect improved mineralization in patients with hypophosphatasia have not been successful (Barcia et al. 1997). i. Nonsteroidal anti-inflammatory drugs for control of the bone pain.

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ii. Dietary phosphate restriction may be helpful (Wenkert et al. 2007). iii. Large dose of vitamin D: reversal of improvement in the bony architecture upon withdrawal of the drug (Anderton 1979). iv. Oral cortisone: reversal of improvement in serum alkaline phosphatase level and radiographic appearance of the bones upon withdrawal of the drug (Anderton 1979). v. Avoid saline solution, furosemide diuresis, steroid therapy, or a low-calcium diet because these approaches may actually worsen bone mineralization and nephrocalcinosis. vi. Inhibition of osteoclastic activity with calcitonin: continued demineralization despite returning of normal serum calcium concentration. vii. Plasma infusions designed to supplement alkaline phosphatase activity or induce alkaline phosphatase production: not consistently improve bone mineralization. viii. Pyridoxine and/or pyridoxal phosphate in neonates with intractable seizures (Balasubramaniam et al. 2010). b. A clinical trial of marrow cell transplantation for infantile hypophosphatasia. i. A significant, prolonged clinical and radiographic improvement followed soon after receiving a boost of donor marrow cells. ii. Biochemical features of hypophosphatasia, however, remain unchanged to date. iii. The most plausible hypothesis for the patient’s survival and progress: transient and long-term engraftment of sufficient numbers of donor marrow mesenchymal cells forms functional osteoblasts and perhaps chondrocytes, to ameliorate the skeletal disease. c. Surgical care. i. Rachitic deformities ii. Gait abnormalities iii. Adult form a) Rod placement for pseudofractures of the adult type results in the union and relief of the pain. b) Primary bone grafting and plating for midshaft fractures. c) Anticipate delayed union of fractures.

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References Anderton, J. M. (1979). Orthopaedic problems in adult hypophosphatasia: A report of two cases. Journal of Bone and Joint Surgery (British), 61, 82–84. Balasubramaniam, S., Bowling, F., Carpenter K., et al. (2010). Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-50 -phosphate availability. Journal of Inherited Metabolic Disease Published Online January 5, 2010. Barcia, J. P., Strife, C. F., & Langman, C. B. (1997). Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. Journal of Pediatrics, 130, 825–828. Brock, D. J., & Barron, L. (1991). First-trimester prenatal diagnosis of hypophosphatasia: Experience with 16 cases. Prenatal Diagnosis, 11, 387–391. Collmann, H., Mornet, E., Gattenlo¨hner, S., et al. (2009). Neurosurgical aspects of childhood hypophosphatasia. Child’s Nervous System, 25, 217–223. Fallon, M. D., Teitelbaum, S. L., Weinstein, R. S., et al. (1984). Hypophosphatasia: Clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine (Baltimore), 63, 12–24. Fauvert, D., Brun-Heath, I., Lia-Baldini, A. S., et al. (2009). Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Medical Genetics, 10, 51–58. Fraser, D. (1957). Hypophosphatasia. The American Journal of Medicine, 22, 730–746. Gehring, B., Mornet, E., Plath, H., et al. (1999). Perinatal hypophosphatasia: Diagnosis and detection of heterozygote carriers within the family. Clinical Genetics, 56, 313–317. Henthorn, P. S., & Whyte, M. P. (1992). Missense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia. Clinical Chemistry, 38, 2501–2505. Hornet, E., & Nunes, M. E. (2010). Hypophosphatasia. GeneReviews. Updated August 5, 2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼gene& part¼hops. Hu, J. C., Plaetke, R., Mornet, E., et al. (2000). Characterization of a family with dominant hypophosphatasia. European Journal of Oral Sciences, 108, 189–194. James, W., & Moule, B. (1966). Hypophosphatasia. Clinical Radiology, 17, 368–376. Kozlowski, K., Sutcliffe, J., Barylak, A., et al. (1976). Hypophosphatasia. Review of 24 cases. Pediatric Radiology, 5, 103–117. Leroy, J. G., Vanneuville, F. J., De Schepper, A. M., et al. (1982). Prenatal diagnosis of congenital hypophosphatasia: Challenge met most adequately by fetal radiography. Progress in Clinical and Biological Research, 104, 525–539. Maxwell, D. J., Blau, K., Johnson, R. D., et al. (1985). Activities of alkaline phosphatase in first trimester chorion biopsy tissue. Prenatal Diagnosis, 5, 283–286. Moore, C. A., Curry, C. J., Henthorn, P. S., et al. (1999). Mild autosomal dominant hypophosphatasia: In utero presentation

Hypophosphatasia in two families. American Journal of Medical Genetics, 86, 410–415. Mornet, E. (2007). Hypophosphatasia. Orphanet Journal of Rare Diseases, 2, 40–47. Mornet, E., Muller, F., Ngo, S., et al. (1999). Correlation of alkaline phosphatase (ALP) determination and analysis of the tissue non-specific ALP gene in prenatal diagnosis of severe hypophosphatasia. Prenatal Diagnosis, 19, 755–757. Mulivor, R. A., Mennuti, M., Zackai, E. H., et al. (1978). Prenatal diagnosis of hypophosphatasia; genetic, biochemical, and clinical studies. American Journal of Human Genetics, 30, 271–282. Pauli, R. M., Modaff, P., Sipes, S. L., et al. (1999). Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: Bent but not broken. American Journal of Medical Genetics, 86, 434–438. Plotkin, H., & Anadiotis, G. A. (2010) Hypophosphatasia. eMedicine from WebMD. Updated May 6, 2010. Available at: http://emedicine.medscape.com/article/945375-overview. Rathbun, J. C. (1948). “Hypophosphatasia”, a new developmental anomaly. American Journal of Diseases of Children, 75, 822–831. Shohat, M., Rimoin, D. L., Gruber, H. E., et al. (1991). Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings. Pediatric Radiology, 21, 421–427. Simon-Bouy, B., Taillandier, A., Fauvert, D., et al. (2008). Hypophosphatasia: Molecular testing of 19 prenatal cases and discussion about genetic counseling. Prenatal Diagnosis, 28, 993–998. Sinico, M., Levaillant, J. M., Vergnaud, A., et al. (2007). Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images. Prenatal Diagnosis, 27, 222–227. Tongsong, T., & Pongsatha, S. (2000). Early prenatal sonographic diagnosis of congenital hypophosphatasia. Ultrasound in Obstetrics & Gynecology, 15, 252–255. Wendling, D., Jeannin-Louys, L., Kremer, P., et al. (2001). Adult hypophosphatasia. Current aspects. Joint Bone Spine, 68, 120–124. Wenkert, D., McAlister, W. H., Coburn, S., et al. (2007). Non-lethal hypophosphatasia interpreted as severe skeletal dysplasia in utero. In: Understanding alkaline phosphatase function-Pathophysiology and treatment of Hypophosphatasia and other AP-related diseases, Fifth International Alkaline Phosphatase Symposium, Huningue, France. Whyte, M. P. (1994). Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocrine Reviews, 15, 439–461. Whyte, M. P. (1995). Hypophosphatasia. In J. D. Jeffers, G. Gavert, M. R. Englis, & P. McGurdy (Eds.), The metabolic and molecular bases of inherited diseases (7th ed., pp. 4095–4111). New York: McGraw-Hill. Whyte, M. P., Kurtzberg, J., McAlister, W. H., et al. (2003). Marrow cell transplantation for infantile hypophosphatasia. Journal of Bone and Mineral Research, 18, 624–636. Whyte, M. P., McAlister, W. H., Patton, L. S., et al. (1984). Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphataserich Paget plasma: Results in three additional patients. Journal of Pediatrics, 105, 926–933.

Hypophosphatasia

a

1143

b

c

Fig. 1 (a–c) A neonate with perinatal lethal form of hypophosphatasia showing severe shortening of limbs. Radiograph shows markedly deficient ossification and abnormal bone development similar to achondrogenesis type I

Fig. 2 Radiograph of another neonate with hypophosphatasia shows rickets-like metaphyseal cupping (spurs) and poor mineralization of cranial bones

Fig. 3 Photomicrograph of a rib. Broad columns of hypertrophic chondrocytes with osteoid seams are present in the metaphysis. These columns are poorly mineralized and ossified

1144 Fig. 4 (a–d) Radiographs of another neonate with perinatal lethal form of hypophosphatasia showing marked deficient skeletal mineralization, prenatal fracture of the left femur, and abnormal metaphyseal ossification of the proximal femurs

Hypophosphatasia

a

c

b

d

Hypophosphatasia

Fig. 5 Childhood hypophosphatasia in two brothers showing short stature and bowed legs

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Hypopituitarism

Hypopituitarism is a term used to describe the deficiency of one or more of the hormones of the anterior or posterior pituitary gland. It can vary in severity and age at presentation. These hormonal deficits can also be present as part of a syndrome, with patients manifesting extrapituitary abnormalities such as in the eye and forebrain. In clinical practice, panhypopituitarism is used to describe patients deficient in growth hormone (GH), gonadotropins, corticotropin, and thyrotropin in whom posterior pituitary function remains intact. Hypopituitarism is rare, with an estimated annual incidence rate of 4.2 cases per 100,000 and with a prevalence rate of 45.5 per 100,000 (Regal et al. 2001).

Synonyms and Related Disorders Adrenocorticotropin deficiency; Gonadotropin deficiency; Growth hormone deficiency; Pituitary hormone deficiency; Prolactin deficiency; Thyrotropin deficiency

Genetics/Basic Defects 1. Heterogeneous causes (Schneider et al. 2007; Kelberman and Dattani 2007; Toogood and Stewart 2008) a. Brain damage i. Traumatic brain injury (trauma to hypophysis) ii. Subarachnoid hemorrhage iii. Neurosurgery iv. Radiation v. Stroke

b. Pituitary tumors i. Adenomas ii. Others c. Non-pituitary tumors i. Craniopharyngiomas ii. Meningiomas iii. Gliomas iv. Chordomas v. Ependymomas vi. Metastases d. Infections i. Abscess ii. Hypophysitis iii. Meningitis iv. Encephalitis v. Tuberculosis vi. Syphilis e. Infarction i. Anoplexia ii. Sheehan syndrome f. Autoimmune disorders: lymphocytic hypophysitis g. Infiltrative processes i. Hemochromatosis ii. Granulomatous diseases iii. Histiocytosis X h. Empty sella syndrome i. Perinatal insults j. Pituitary hypoplasia or aplasia k. Genetic causes l. Idiopathic causes 2. Genetic causes (mutations) of multiple pituitary hormone deficiencies a. POU1F1 (PIT-1) (Andersen and Rosenfeld 2001): genetic combined pituitary hormone

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_130, # Springer Science+Business Media, LLC 2012

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deficiency (CPHD) caused by mutations within the pituitary-specific transcription factor 1 i. Hormone deficiencies a) GH b) Thyrotropin (TSH) c) Prolactin ii. Inheritance a) Autosomal dominant b) Autosomal recessive iii. Phenotypes a) Hormone deficiencies: severe b) Thyrotropin secretion: initially normal, but secondary hypothyroidism inevitable c) Pituitary size: variable b. PROP1 (Sornson et al. 1996): the most common cause of CPHD caused by mutations of Prophet of PIT1 i. Hormone deficiencies a) GH b) TSH c) LH d) FSH e) Prolactin f ) Occasionally adrenocorticotropic hormone (ACTH) ii. Inheritance: autosomal recessive (AR) iii. Phenotypes a) Deficiencies tend to be milder than in POU1F1 mutations b) Evolving corticotropin deficiency with increasing age c) Enlarged pituitary size with later involution d) Can be associated with a mass lesion (Turton et al. 2005) c. HESX1 (Dattani et al. 1998) i. Hormone deficiencies: range from isolated GH deficiency to panhypopituitarism, including diabetes insipidus ii. Inheritance: autosomal dominant (AD), AR iii. Phenotypes a) May be associated with septo-optic dysplasia, combined pituitary hormone deficiency (CPHD), and isolated growth hormone deficiency. b) Mutations result in a variable phenotype: anterior pituitary hypoplasia, ectopic posterior pituitary, and midline forebrain abnormalities.

Hypopituitarism

c) Environmental factors, such as drugs and alcohol, are implicated. d. LHX3 (Netchine et al. 2000) i. Hormone deficiencies a) GH b) TSH c) LH d) FSH e) Prolactin ii. Inheritance: AR iii. Phenotypes a) Elevated and anteverted shoulders giving the appearance of a stubby neck with limited rotation of the head (short rigid cervical spine) b) Hypoplasia of anterior pituitary gland c) Preservation of corticotropin secretion (e) LHX4 (Machinis et al. 2001) i. Hormone deficiencies a) GH b) TSH c) Cortisol ii. Inheritance: AD iii. Phenotypes (MRI of the brain) a) Small sella b) Persistent craniopharyngeal canal c) Hypoplastic anterior pituitary and ectopic posterior pituitary d) Pointed cerebellar tonsils 3. Genetic causes (mutations) of isolated pituitary hormone deficiencies a. TBX19 (TPIT) (Pulichino et al. 2003) i. Hormone deficiencies: corticotropin ii. Inheritance: AR iii. Phenotypes a) Presentation in neonatal period with severe hypoglycemia and prolonged cholestatic jaundice b) Undetectable corticotropin and cortisol levels c) Failure to respond to corticotropinreleasing hormone d) High incidence of neonatal death in affected families b. SOX2 (Maheshwari et al. 1998) i. Hormone deficiencies: hypogonadotropic hypogonadism ii. Inheritance: de novo mutation reported iii. Phenotypes

Hypopituitarism

c.

d.

e.

f.

g.

a) Anophthalmia or microphthalmia b) Learning difficulties c) Developmental delay d) Genital abnormalities e) Esophageal atresia f ) Sensorineural hearing loss SOX3 (Hamel et al. 1996; Laumonnier et al. 2002) i. Hormone deficiencies: isolated growth hormone deficiency ii. Inheritance: XL recessive iii. Phenotypes a) Mental retardation b) Anterior pituitary hypoplasia c) Infandibular hypoplasia d) Midline abnormalities GHRHR (Maheshwari et al. 1998) i. Hormone deficiencies: GH ii. Inheritance: AR iii. Phenotypes a) Short stature b) Proportionate growth c) Anterior pituitary hypoplasia GH1 (Cogan et al. 1993) i. Hormone deficiencies: GH ii. Inheritance: AR iii. Phenotypes a) Short stature b) Abnormal facies c) Respond to exogenous GH treatment, but may develop antibodies KAL-1 (Legouis et al. 1991; Franco et al. 1991) i. Hormone deficiencies a) GnRH b) FSH c) LH ii. Inheritance: X-linked iii. Phenotypes a) Failed or arrested puberty b) Anosmia c) Synkinesis d) Unilateral renal agenesis FGFR-1 (KAL-2) (Dode et al. 2003) i. Hormone deficiencies a) GnRH b) FSH c) LH ii. Inheritance: AD iii. Phenotypes: failed or arrested puberty

1149

h. GNRHR1 (Beranova et al. 2001) i. Hormone deficiencies a) FSH b) LH ii. Inheritance: AR iii. Phenotypes: variable, determined by the sensitivity of the mutant receptor to GnRH i. DAX1 (Lin et al. 2006) i. Hormone deficiencies a) FSH b) LH ii. Inheritance: AR, X-linked iii. Phenotypes a) Presents initially with severe neonatal hypoadrenalism b) Subsequently fail to enter puberty or suffer delayed or arrested puberty j. GPR54 (de Roux et al. 2003) i. Hormone deficiencies a) FSH b) LH ii. Inheritance: AR iii. Phenotypes: presents with absent or delayed puberty k. POMC (Krude et al. 1998) i. Hormone deficiencies: corticotropin ii. Inheritance: AR iii. Phenotypes (clinical triad) a) Early-onset obesity b) Adrenal hypoplasia c) Cortisol deficiency l. Thyrotropin-b (Vuissoz et al. 2001) i. Hormone deficiencies: thyrotropin ii. Inheritance: AR iii. Phenotypes: severe congenital hypothyroidism if not detected and treated early on

Clinical Features 1. Nonspecific symptoms (Toogood and Stewart 2008) a. Feeling of general ill health b. Being abnormally tired c. Increased lethargy d. Feeling cold e. Weight loss f. Reduced appetite g. Abdominal pain

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2. Symptoms related to local effects of any underlying tumor a. Headaches b. Visual disturbance (typically a bitemporal hemianopia) c. Cerebrospinal fluid rhinorrhea 3. GH deficiency a. Neonates with congenital GH deficiency (or hypopituitarism) i. Severe neonatal hypoglycemia often associated with convulsions, presenting most frequently in the first 24 h of life (birth trauma) ii. Prolonged conjugated hyperbilirubinemia iii. Hypothermia iv. Possibly a micropenis (Ogilvy-Stuart 2003) b. Neonates with midline birth defects should be considered at risk for isolated or multiple pituitary hormone deficiencies c. Older babies who escape early diagnosis may present with failure to thrive and poor weight gain d. Older children i. Proportional short stature with height more than 2–3 standard deviations (SD) below the mean for the age ii. Reduced growth velocity for their age iii. Delayed bone maturation in the absence of an inherited skeletal dysplasia or chronic disease iv. Characteristic craniofacial appearance in patients with severe GH deficiency: a prominent forehead and depressed midface development caused by the lack of GH effect on endochondrial growth at the base of the skull, occiput, and sphenoid v. Delayed dentition vi. Presence of other features attributable to the underlying etiology of the GH deficiency e. Adults i. Multiple symptoms and pathophysiologic changes affecting a variety of biologic systems (none are pathognomonic) are attributed to GH deficiency in adult life (Molitch et al. 2006). ii. Impaired quality of life (Burman et al. 1995; Holmes and Shalet 1995) a) Complaining of tiredness b) Lack of energy

Hypopituitarism

c) Emotional lability d) Reduced sleep quality e) A degree of disability consistent with psychiatric illness requiring treatment (up to 30% of patients) (McGauley et al. 1990) f) Patients who have childhood-onset GH deficiency do not seem to suffer the same degree of impairment in quality of life as those who have adult-onset GH deficiency (Attanasio et al. 1997) 4. Gonadotropin (LH, FSH) deficiency a. Male infants with congenital hypogonadotropic hypogonadism: effect of relative androgen deficiency occurring during the third trimester i. Unilateral or bilateral cryptorchidism ii. Microphallus b. Adolescent boys i. Pubertal development a) Fail to initiate, or abnormal with failure to progress normally b) Testicular volumes vary between prepubertal boys (0.5 cm/year) c) Abdominal aorta >4.0 cm or expanding rapidly (>0.5 cm/year) d) Rapid expansion of peripheral aneurysms ii. Children a) Severe craniofacial features: aortic root z-score >3.0 or expanding rapidly (>0.5 cm/year), or mild craniofacial features: aortic root z-score >4.0 or expanding rapidly (>0.5 cm/year) b) Effort should be made to delay surgery until the annulus reaches 1.8 cm, allowing placement of a valve-sparing graft of sufficient size to accommodate growth. c) Large size or rapid expansion of the descending aorta or other vessels Situations and agents to avoid i. Contact sports ii. Competitive sports iii. Isometric exercise iv. Agents that stimulate the cardiovascular system including routine use of decongestants v. Activities that cause joint injury or pain

Loeys–Dietz Syndrome

References Aalberts, J. J. J., van den Berg, M. P., Bergman, J. E. H., et al. (2008). The many faces of aggressive aortic pathology: Loeys–Dietz syndrome. Netherlands Heart Journal, 16, 299–304. Ade`s, L. C. (2008). Evolution of the face in Loeys–Dietz syndrome type II: Longitudinal observations from infancy in seven cases. Clinical Dysmorphology, 17, 243–248. Akutsu, K., Morisaki, H., Takeshita, S., et al. (2007). Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factorbeta genes. Circulation Journal, 71, 1305–1309. Augoustides, J. G., Plappert, T., Bavaria, J. E., et al. (2009). Aortic decision–making in the Loeys–Dietz syndrome: Aortic root aneurysm and a normal-caliber ascending aorta and aortic arch. The Journal of Thoracic and Cardiovascular Surgery, 138, 502–503. Dietz, H. C., Loeys, B., Carta, L., et al. (2005). Recent Progress Towards a Molecular Understanding of Marfan Syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 139 C, 4–9. Dreraa, B., Tadinib, G., Barlatia, S., et al. (2008). Identification of a novel TGFBR1 mutation in a Loeys–Dietz syndrome type II patient with vascular Ehlers–Danlos syndrome phenotype. Clinical Genetics, 73, 290–293. Johnson, P. T., Chen, J. K., Loeys, B. L., et al. (2007). Loeys–Dietz syndrome: MDCT angiography findings. American Journal of Roentgenology, 189, W29–W35. LeMaire, S. A., Pannu, H., Tran-Fadulu, V., et al. (2007). Severe aortic and arterial aneurysms associated with a TGFBR2 mutation. Nature Clinical Practice. Cardiovascular Medicine, 4, 167–171. Loeys, B. L., Chen, J., Neptune, E. R., et al. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37, 275–281. Loeys, B. L., Schwarze, U., Holm, T., et al. (2006). Aneurysm syndromes caused by mutations in the TGF-beta receptor. The New England Journal of Medicine, 355, 788–798. Mizuguchi, T., & Matsumoto, N. (2007). Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. Journal of Human Genetics, 52, 1–12.

1299 Oderich, G. S., Pannenton, J. M., Bower, T. C., et al. (2005). The spectrum, management and clinical outcome of Ehlers–Danlos syndrome type IV: A 30-year experience. Journal of Vascular Surgery, 42, 98–106. Pearson, G. D., Devereux, R., Bart Loeys, B., et al. (2008). Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on research in Marfan Syndrome and related disorders. Circulation, 118, 785–791. Sakai, H., Visser, R., Ikegawa, S., et al. (2006). Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. American Journal of Medical Genetics. Part A, 140A, 1719–1725. Singh, K. K., Rommel, K., Mishra, A., et al. (2006). TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys–Dietz syndrome. Human Mutation, 27, 770–777. Soylen, B., Singh, K. K., Abuzainin, A., et al. (2009). Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys–Dietz syndrome and report of 22 novel FBN1 mutations. Clinical Genetics, 75(3), 265–270. Stheneur, C., Collod-Beroud, G., Faivre, L., et al. (2008). Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys–Dietz syndrome and related disorders. Human Mutation, 29, E284–E295. Viassolo, V., Lituania, M., Marasini, M., et al. (2006). Fetal aortic root dilation: A prenatal feature of the Loeys–Dietz syndrome. Prenatal Diagnosis, 26, 1081–1083. Watanabe, Y., Sakai, H., Nishimura, A., et al. (2008). Paternal somatic mosaicism of a TGFBR2 mutation transmitting to an affected son with Loeys–Dietz syndrome. American Journal of Medical Genetics. Part A, 146A, 3070–3074. Williams, J. A., Loeys, B. L., Nwakanma, L. U., et al. (2007). Early surgical experience with Loeys–Dietz: A new syndrome of aggressive thoracic aortic aneurysm disease. The Annals of Thoracic Surgery, 83, S757–S763. Yetman A. T., Beroukhim, R. S., Ivy, D. D., et al. (2007). Importance of the clinical recognition of Loeys–Dietz syndrome in the neonatal period. Pediatrics, 119, e1199–e1202.

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Loeys–Dietz Syndrome

Fig. 2 Note the large incisional umbilical hernia

Fig. 3 Note the marked hypotonia and long and slender extremities

Fig. 1 A 5-month-old infant girl with molecularly confirmed Loeys–Dietz syndrome with TGFBR1 exon 4 mutation c.722C>T (Ser241Leu). She was evaluated initially for possible neonatal Marfan syndrome because of very long fingers and toes. At 3 weeks of age, she was diagnosed to have intestinal malrotation which was surgically repaired and a Nissen fundoplication was performed. She had seizures since birth (eyes rolling up, occasional twitching and head pulling back for a very short period). MRI of the brain showed bilateral caudal thalamic groove cyst. At 3 months of age, she was noted to be abnormally pale and was found to have bleeding due to a ruptured wandering spleen in the pelvis which was surgically removed. She had a surgical incision hernia at the site of the first surgery in addition to her original inguinal hernia. Multiple echocardiograms showed no aortic root dilatation but the patient was put on b-blocker for aortic root dilatation prevention. Family history was noncontributory. Note the ocular hypertelorism, dolichostenomelia, and arachnodactyly

Fig. 4 Note the long toes

Lowe Syndrome

Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare X-linked recessive disorder. It was initially recognized in 1952 by Lowe and colleagues who described the triad of congenital cataracts, mental retardation, and generalized aminoaciduria. In 1954, a renal Fanconi syndrome was recognized as being associated with the syndrome (Bickel & ThurshbyPelnam 1954) and in 1965, an X-linked recessive pattern of inheritance was determined (Richards et al. 1965). Its prevalence is estimated to be several cases per 100,000 males.

3.

Synonyms and Related Disorders Dent-2 disease; Oculocerebrorenal syndrome

Genetics/Basic Defects 1. Inheritance a. X-linked recessive disorder predominantly affecting males, although several affected females have been reported b. New mutations in 31.6% of affected males c. Germline mosaicism in 4.5% 2. The gene involved (OCRL1) a. Map locus: Xq26.1, based on i. Balanced X-autosome translocations with a break-point in band Xq25-q26 in two unrelated female patients ii. Linkage analysis with RLFP in families with multiple affected individuals b. Mapped in 1977 c. Cloned in 1992

4. 5.

6.

d. Encoding OCRL1, a 105-kD enzyme with phosphatidylinositol 4,5-bisphosphate 5phosphatase (PtdIns-4,5-P2) activity localized to the Golgi complex i. Loss or reduction of the enzyme demonstrated in affected males ii. Carrier status of OCRL in females not readily determined by assays of the enzyme due to the X-linked nature of OCRL1 and random X inactivation Mutations of OCRL1 gene responsible for Lowe syndrome a. Nonsense mutations and deletions causing frameshifts and premature termination b. Deletions c. Missense mutations in domains conserved among all the known PtdIns(4,5)P2 5-phosphatases Carrier females with typical lens opacities Affected females as a result of a. Unfavorable lyonization b. Turner syndrome c. X-autosome translocation through the relevant gene Dent-2 disease (a mild variant of Lowe syndrome (Bo¨kenkamp et al. 2009) a. Dent disease i. An X-linked tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, and nephrolithiasis/ nephrocalcinosis (1) ii. In more than half the patients, Dent disease is caused by mutations affecting the voltagegated chloride channel and chloride/proton antiporter (ClC-5).

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b. Dent-2 disease i. In approximately 15% of patients with a Dent phenotype, mutations in the oculocerebrorenal syndrome of Lowe gene (OCRL) encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase, have been found (Hoopes et al. 2005; Utsch et al. 2006; Sekine et al. 2007; Cho et al. 2008). ii. These patients are classified as having “Dent disease-2” to distinguish them from most patients with an OCRL mutation who have the more severe oculocerebrorenal syndrome of Lowe phenotype (Charnas et al. 1991) which is characterized by a proximal tubulopathy (Bo¨ckenhauer et al. 2008; Kleta 2008), congenital cataract, severe mental retardation, and behavioral disturbances.

Clinical Features 1. Variable age of onset and severity of clinical manifestations 2. Eye abnormalities a. Congenital cataracts (the hallmark of the disease) i. Developed prenatally ii. Always present prior to birth b. Congenital glaucoma with or without buphthalmos (50–60%) c. Microphthalmos d. Nystagmus e. Decreased visual acuity (blindness) f. Corneal scarring and keloid formation i. Develops spontaneously without trauma ii. Onset usually after age 5 iii. Causes significant visual impairment 3. Renal abnormalities a. Fanconi syndrome of renal tubules (the cardinal features) i. Bicarbonaturia ii. Proximal tubular acidosis iii. Generalized aminoaciduria iv. Hyperphosphaturia leading to osteomalacia, renal rickets, and pathologic fractures v. Hypercalciuria vi. Proteinuria vii. Glycosuria (not a feature of the renal tubular dysfunction)

Lowe Syndrome

viii. Impairment in urine-concentration (polyuria) ix. Carnitine wasting b. Variable age of onset and severity of the tubular dysfunction i. Failure to thrive ii. Recurrent infections iii. Metabolic collapse iv. Severe hypokalemia or hypocalcemia requiring replacement therapy in a minority of patients. This is probably a part of preterminal exacerbation of tubular dysfunction. v. Slowly progressive renal failure may occur in the second to fourth decade of life. 4. CNS (prominently involved organ) and behavioral abnormalities a. Cardinal features i. Neonatal/infantile hypotonia ii. Delay in motor milestones iii. Cognitive impairment iv. Areflexia by 1 year of age b. Mental retardation (common but not cardinal feature) c. Seizures d. Neuropathologic and neuroimaging abnormalities e. Stereotypic behaviors i. Temper tantrum (Lowe tantrum) ii. Aggression iii. Irritability iv. Stubbornness v. Rigidity of thought vi. Self injury vii. Repetitive nonpurposeful movements 5. Musculoskeletal abnormalities a. Secondary consequences of hypotonia, renal tubular acidosis, and/or hypophosphatemia i. Short stature ii. Joint hypermobility iii. Dislocated hips iv. Genu valgum v. Scoliosis vi. Kyphosis vii. Platyspondylia viii. Fractures b. Primary abnormality of excessive connective tissue growth i. Nontender joint swelling ii. Subcutaneous nodules

Lowe Syndrome

6. Typical facies a. Frontal bossing b. Characteristic deep-set eyes c. Inattentiveness 7. Other features a. Increased hemorrhagic risk (Lane et al. 2010) b. Cryptorchidism 8. Natural history a. Succumb to either severe renal insufficiency and dehydration or infection b. Survival to adulthood if metabolic abnormalities are adequately treated 9. Manifestation in the carriers a. Lens involvement i. Micropunctate cataracts clustered in a radial wedge pattern ii. Occasional dense posterior cortical cataract b. Sensitivity of carrier detection by slit-lamp examination (>90%), due to random inactivation of Lowe syndrome allele in the proportion of cells in the lens of female carriers c. Germ line or somatic mosaicism documented d. Positive family history of early cataracts in mother, maternal female relatives, and institutionalized maternal uncles

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3.

4.

5.

6.

Diagnostic Investigations 1. Blood chemistry a. Blood gas for metabolic acidosis b. Electrolyte disturbances (likely absent in neonates and young infants) 2. Urine a. Aminoaciduria b. Hyperphosphaturia c. Low-molecular-weight (LMV) proteinuria: characterized by the excretion of proteins such as retinal binding protein and N-acetyl glucosaminidase, is seen in i. Lowe syndrome: LMW proteinuria can be seen early in life even in the absence of clinically significant aminoaciduria or other renal tubular abnormalities (Laube et al. 2004) ii. The allelic disorder Dent disease iii. Many other diseases associated with the Fanconi syndrome d. Glycosuria

7.

e. Low urine osmolality f. Elevated 24-h volume Serum enzyme values a. Elevated CK b. Elevated SGOT c. Elevated LDH d. Elevated a2-globulin Measurement of inositol polyphosphate 5-phosphatase OCRL1 activity in cultured skin fibroblasts (Lewis et al. 2008) a. Males: to confirm the diagnosis in affected males (Suchy et al. 1995; Zhang et al. 1995) i. Affected males have less than 10% normal activity of the enzyme. ii. Such testing is abnormal in more than 99% of affected males. b. Carrier females. The activity is not accurate for carrier detection because of lyonization (random X-chromosome inactivation), which results in a wide range of “normal” activity in females (Lin et al. 1999). Karyotype. Translocations between an autosome and an X chromosome with a breakpoint through the OCRL locus (Xq26.1) have been observed (Hodgson et al. 1986; Mueller et al. 1991) Radiography a. Rickets/osteoporosis b. Pathological fractures c. Frontal bossing d. Kyphoscoliosis e. Cervical spine anomalies f. Platyspondyly g. Hip subluxations/dislocation Neuroimaging a. Cranial MRI i. Mild ventriculomegaly (33%) ii. Multiple tiny periventricular cysts (no clinical significance) iii. Two patterns of brain lesions (de CarvalhoNeto et al. 2009) a) Hyperintensities on T2-weighted images b) Periventricular cystic lesions b. Neuropathologic examination of the brain i. Normal in some cases ii. Diffuse or focal myelin pallor without myelin breakdown iii. Ventriculomegaly iv. Mild cerebral abnormalities

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Lowe Syndrome

v. vi. vii. viii. ix. x. xi. xii.

Isolated cases of subependymal cysts Mesencephalic porencephaly Postencephalitic changes Blunted and foreshortened frontal lobes Acute pontine necrosis Cerebellar hypoplasia Aberrant neuronal migration Multiple tiny cysts without inflammatory changes 8. Affected male patients a. Biochemical assay of reduced activity ( A, m.11778G > A (a point mutation within the mitochondrial genome known to cause the first human disease, LHON) (Wallace et al. 1988), and m.14484T > C, which all involve genes encoding complex I subunits of the mitochondrial respiratory chain (Mackey et al. 1996). b. Mitochondrial genetic factors i. Homoplasmy: In most LHON pedigrees, the primary mutation is homoplasmic (every mtDNA molecule harbors the mutant allele, i.e., only one type of mtDNA exists within an individual). ii. Heteroplasmy (both mutant and wild-type mtDNA coexist within an individual) a) Cells can contain anywhere between 100 and 10,000 mitochondria depending on their metabolic demands. With 2–10 mtDNA molecules in each

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mitochondrion, this results in a very high copy number per cell. b) Ten to fifteen percentage of LHON carriers are thought to be heteroplasmic (one mtDNA subpopulation carrying the wildtype allele) (Smith et al. 1993; Harding et al. 1995; Man et al. 2003). c) Available data suggest that heteroplasmy contributes to incomplete penetrance, with the risk of blindness being minimal if the mutational load is A and m.14484T > C mutations but not for m.3460G > A (Hudson et al. 2005). iii. The possibility of other autosomal nuclear modifier genes in LHON has not been excluded, and the genetic etiology of LHON might prove even more complex, with epistatic interaction of these multiple nuclear susceptibility loci and genetic heterogeneity. d. Environmental factors i. Existence of discordant monozygotic twins strongly suggests that environmental factors also contribute to penetrance. ii. Anecdotal reports of nutritional deprivation, exposure to industrial toxins, antiretroviral drugs, psychological stress, or acute illness precipitating the onset of blindness in LHON (Mackey et al. 2003; Sanchez et al. 2006; Carelli et al. 2007) iii. The role of environmental triggers in LHON remains largely unanswered, and more robust epidemiological data are needed, which will necessitate a multicenter collaborative effort in order to collect sufficient number of subjects for analysis. 2. DOA: caused by mutations in the OPA1 gene, a gene encoding for a dynamin-like mitochondrial GTPase, an inner mitochondrial membrane protein critical for mtDNA maintenance and oxidative phosphorylation, in the majority of DOA families 3. Pathology for both LHON and DOA: limited in the majority of cases to the retinal ganglion cells (RGCs), a highly specialized group of cells within the eye 4. Expanding phenotype associated with LHON and DOA: providing important insights into possible disease pathways leading to optic nerve degeneration and visual failure

Clinical Features 1. LHON (Yu-Wai-Man et al. 2009; Milea et al. 2010) a. Presymptomatic phase i. Fundal abnormalities such as telangiectatic vessels around the optic discs and variable degrees of retinal nerve fiber layer edema a) Documented in some asymptomatic carriers b) Can fluctuate with time

Mitochondrial Leber Hereditary Optic Neuropathy

ii. Thickening of the temporal retinal nerve fiber layer found in a proportion of unaffected carriers by using optical coherence tomography imaging: provides further evidence that the papillomacular bundle is particularly vulnerable in this disorder (Savini et al. 2005; Quiros et al. 2006) iii. Subtle impairment of optic nerve function in some individuals on detailed psychophysical testing (Sadun et al. 2006) a) Loss of color vision affecting mostly the red–green system b) Reduced contrast sensitivity c) Subnormal visual electrophysiological parameters b. Acute phase i. Experiencing blurring or clouding of vision in one eye ii. Subacute presentation in the vast majority of an early age of onset (95% in untreated patients) ii. Unilateral or bilateral pheochromocytoma iii. Other hyperplasia and/or neoplasia of different endocrine tissues b. Signs and symptoms (Richards 2010) i. Hypertension if a pheochromocytoma presents ii. Chronic constipation: constant finding in MEN2B patients resulting from hyperplasia of the intrinsic autonomic ganglia in the intestinal wall iii. A neck mass or dominant thyroid nodule with nontender anterior neck lymph nodes arising insidiously with progressive enlargement: may signify regional metastasis iv. MEN2B patients a) Marfanoid habitus (high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis) b) Neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips c) Prominent hypertrophied lips leading to a characteristic facies. c. Presence of three clinical subtypes i. MEN2A ii. MEN2B iii. Familial MTC (FMTC) 3. MEN2A a. The most common subtype. b. Associated with MTC. c. Risk of developing pheochromocytoma (approximately 50%). d. Risk of developing primary hyperparathyroidism (30–40%). e. Typical age at onset of biochemical evidence of MTC in untreated patients with MEN2A: 15–20 years. However, MTC is frequent in children ages 10 years and younger (Lips et al.

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1994; Machens et al. 2003; O’Riordain et al. 1994). f. Rare variants of MEN2A can be associated with paraneoplastic syndromes. i. Cutaneous lichen amyloidosis ii. Excessive production of corticotrophin iii. Hirschsprung disease 4. MEN2B a. The rarest and most aggressive subtype i. Associated with the earliest onset (usually 10 years earlier than that for MEN2A) and most aggressive type of MTC ii. Pheochromocytomas (40–50% of patients) iii. Multiple neuromas and/or diffuse ganglioneuromatosis of the gastro-enteric mucosa (approximately 40% of patients) b. Characteristic facial appearance: resulting from mucosal neuromas in the tongue, lips, and eyelids (Schimke et al. 1968) i. Enlarged lips ii. A “bumpy” tongue iii. Eversion of the eyelids c. Often with a thin and lanky (Marfanoid) habitus with increased joint mobility, and with decreased subcutaneous fat d. Frequently with thickening of the corneal nerves or ganglioneuromatosis of the gastrointestinal tract, which can result in abdominal distention, megacolon, constipation, or diarrhea e. The physical traits: usually evident in early childhood f. Without prophylactic thyroidectomy at a young age (before 1 year of age), most patients with MEN2B develop metastatic MTC in childhood or adolescence (O’Riordain et al. 1994) g. Patients with MEN2B do not develop primary hyperparathyroidism 5. Familial medullary thyroid carcinoma (FMTC) a. MTC is the only clinical feature b. Refers to occurrence of medullary thyroid cancer in at least four affected members within the same family with documented absence of other endocrinopathies c. Clinical course of MTC i. More benign than that of MEN2A and MEN2B ii. Prognosis: relatively good in most cases

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6. Differential diagnosis of other category of MEN (Callender et al. 2008) a. Von Hippel–Lindau syndrome (VHL) i. Mutated gene: VHL ii. Manifestations a) Pheochromocytoma b) Retinal and central nervous system hemangioblastoma c) Renal cysts and clear cell carcinoma d) Pancreatic cysts and islet cell tumors e) Endolymphatic sac tumors f) Papillary cystadenomas of the epididymis and broad ligament b. Familial pheochromocytoma/paraganglioma syndrome i. Mutated gene: SDHB, SDHC, SDHD ii. Manifestations: multiple paragangliomas and pheochromocytoma c. Cowden syndrome i. Mutated gene: PTEN ii. Manifestations a) Nonmedullary thyroid cancer (usually follicular rather than papillary) b) Benign and malignant tumors of skin, oral mucosa, breast, and uterus d. Carney complex i. Mutated gene: PRKAR1A ii. Manifestations a) Endocrine tumors (including thyroid, pituitary, and primary pigmented nodular adrenocortical diseases) b) Characteristic skin pigmentation c) Myxomas d) Melanotic schwannomas e. Familial isolated hyperparathyroidism i. Mutated gene: MEN1, HRPT2, CASR, others ii. Manifestations: nonsyndromic primary hyperparathyroidism f. Hyperparathyroidism-jaw tumor syndrome i. Mutated gene: HRPT2 ii. Manifestations a) Primary hyperparathyroidism (usually single adenoma) b) Ossifying fibromas of maxilla or mandible c) Renal cysts and hamartomas d) Fifteen percent risk of parathyroid carcinoma g. Familial hypocalciuric hypercalcemia i. Mutated gene: CASR

Multiple Endocrine Neoplasia Syndromes

ii. Manifestations a) Benign hypercalcemia. b) Hypocalciuria. c) Low to normal parathyroid hormone levels. d) Renal calcium-to-creatinine clearance ratio 200 pg/mL by a secretin stimulation test confirms the diagnosis c) Tumors localized by a combination of octreotide scan, CT, and endoscopic ultrasonography ii. Insulinomas presents as “Whipple’s triad”: a) Fasting or exercise-induced hypoglycemia b) Plasma glucose level 1,000 pg/mL b) A secretin stimulation test may be useful c) Localized with an octreotide scan, CT, and endoscopic ultrasonography iv. Vasoactive intestinal peptide tumors (VIPomas) a) Fasting plasma vasoactive intestinal peptide (VIP) levels >200 pg/mL b) VIPomas: usually located in the body and tail of the pancreas and are localized by an octreotide scan, CT, and endoscopic ultrasonography v. Somatostatinoma a) A fasting somatostatin level of >100 pg/mL b) Localized with an octreotide scan, CT, and endoscopic ultrasonography vi. Nonfunctioning MEN1-associated pancreatic endocrine tumors: localized by an octreotide scan, CT, and endoscopic ultrasonography d. Other tumor types: not part of the diagnostic criteria for MEN1, but their presence helps to support a diagnosis of MEN1 i. Foregut (thymic, bronchial, or gastric) carcinoid tumors ii. Adrenal cortex tumors (adenomas, pheochromocytoma, adrenocortical carcinomas) iii. Thyroid tumors (follicular adenomas, goiters, nonmedullary thyroid carcinoma) iv. Benign facial angiomas

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v. Collagenomas of the neck, upper limbs and chest vi. Subcutaneous or visceral lipomas vii. Uterine or esophageal leiomyomas viii. Meningiomas ix. Spinal ependymomas 2. Diagnosis of component tumors in MEN2 (Falchetti et al. 2008). a. Medullary thyroid carcinoma i. Pentagastrin or calcium stimulation to evaluate calcitonin secretion: earlier detection of MTC ii. Ultrasonography, CT, or MRI: localize tumor extension and possible distant metastases b. Pheochromocytoma i. 24-h measurement of urinary excretion of catecholamines and their metabolites to assess adrenal gland function: recommended on an annual basis ii. CT and MRI to localize the tumor c. Primary hyperparathyroidism: diagnosis made by elevated serum PTH and calcium concentrations 3. Routine surveillance of presymptomatic patients and treated patients who are currently without evidence of disease (Brandi et al. 2001). a. Annual biochemical testing for all tumor types i. Parathyroid: serum calcium, parathyroid hormone (starts to screen at age of 8 years) ii. Gastrinoma: serum gastrin (starting at age of 20 years) iii. Insulinoma: fasting serum glucose, insulin (starting at age of 5 years) iv. Other enteropancreatic: chromogranin A, glucagons, proinsulin (starting at age of 20 years) v. Anterior pituitary: prolactin, insulin-like growth factor 1 (starting at age of 5 years) b. Imaging studies (CT or MRI) every 3 years i. Other enteropancreatic: octreotide scan, CT, or MRI (starting at age of 20 years) ii. Anterior pituitary: MRI of the brain (starting at age of 5 years) iii. Foregut carcinoid: CT (starting at age 30 years) 4. Molecular genetic testing for MEN1 a. Should be offered to patients in whom a diagnosis of MEN1 is being considered. b. The benefit of offering genetic testing: a diagnosis of MEN1 at an early age allows

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patients to be monitored for the development of subsequent MEN1-related tumors c. Sensitivity of genetic testing: varies, depending on the combination of affected organs and whether the patient is an index or familial case d. Mutations can be identified in only 75–90% of patients with a clinical diagnosis of MEN1. i. A negative test result cannot definitively rule out the risk for further MEN1-related tumors ii. Follow-up screening recommendations in such cases are controversial and require careful consideration of the index of suspicion of MEN1 based on the patient’s personal and family history. 5. Molecular genetic testing for MEN2 (Moline and Eng 2010) a. MEN2A i. Approximately 95% of families with MEN 2A have a RET mutation in exon 10 or 11. ii. Other rare mutations, including codon 804 alterations, have been reported in a few cases b. MEN2B i. Approximately 95% of individuals with the MEN2B phenotype have a single point mutation in the tyrosine kinase domain of the RET gene at codon 918 in exon 16 (M918T). ii. Other rare mutations include second mutation at codon 883 in exon 15 (A883F) and two mutations (V804M and Y806C) in cis configuration 6. Molecular genetic testing for FMTC (Moline and Eng 2010): approximately 88% of families with FMTC have an identifiable RET mutation.

Genetic Counseling 1. Recurrence risk a. Patient’s sib: a 50% risk if a parent is affected or has a disease-causing mutation b. Patient’s offspring: a 50% risk of inheriting the mutation 2. Prenatal diagnosis: possible for pregnancies at increased risk by analysis of DNA extracted from fetal cells by amniocentesis or CVS, provided the disease-causing allele of an affected family member must be identified or linkage established in the family

Multiple Endocrine Neoplasia Syndromes

3. Management a. MEN1 (Callender et al. 2008) i. Parathyroidectomy for parathyroid tumors ii. Transcervical thymectomy because there is an increased risk of supernumerary parathyroid glands and developing carcinoid tumors in the thymus iii. Pituitary tumors a) Surgery (usually from a minimally invasive transsphenoidal approach) b) Medication for patients with prolactin- or growth hormone–producing tumors with dopamine agonists, such as bromocriptine or cabergoline, and a GH receptor antagonist, respectively c) Radiation iv. Gastrinomas a) Proton pump inhibitors for medical control of acid hypersecretion b) Surgical approaches: no consensus v. Insulinomas a) Manage surgically b) Treat unresectable tumors with diazoxide (Proglycem) vi. VIPoma a) Manage surgically b) Octreotide (Sandostatin) for diarrhea control b. MEN2 (Falchetti et al. 2008) i. Medullary thyroid carcinoma a) Total thyroidectomy with lymph node dissection of at least the central compartment. b) An elevated serum calcitonin level after surgery can be a sign of persistent, recurrent or generalized MTC. c) Total thyroidectomy within the first month of life should be performed in patients with the highest risk mutations (MEN2B, codons 883 and 918) (Lewis and Yeh 2008). ii. Pheochromocytoma a) Surgical laparoscopy excision. b) Recommend lifelong follow-up after surgery. c) Long-term drug treatment with a and b adrenergic blockers should only be considered in those patients in whom the tumor is unresectable.

Multiple Endocrine Neoplasia Syndromes

iii. Primary hyperparathyroidism a) Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation of normal fresh or cryopreserved tissue in the forearm. b) All individuals who have undergone partial or total parathyroidectomy with autotransplantation need to be monitored for possible recurrences.

References Brandi, M. L., Gagel, R. F., Angeli, A., et al. (2001). Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism, 86, 5658–5671. Callender, G. G., Rich, T. A., & Perrier, N. D. (2008). Multiple endocrine neoplasia syndromes [Review]. Surgical Clinics of North America, 88, 863–895. Da Silva, A. M., Maciel, R. M., Da Silva, M. R., et al. (2003). A novel germ-line point mutation in RET exon 8 (Gly(533) Cys) in a large kindred with familial medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism, 88, 5438–5443. Darling, T. N. (2010). Multiple endocrine neoplasia type 1. Medscape Reference. Updated March 2, 2010. Available at: http://emedicine.medscape.com/article/1093723-overview. Dean, P. G., van Heerden, J. A., Farley, D. R., et al. (2000). Are patients with multiple endocrine neoplasia type 1 prone to premature death? World Journal of Surgery, 24, 1437–1441. DeLellis, R. A., Lloyd, R. V., Heitz, P. U., et al. (2004). Pathology and genetics: Tumours of the endocrine organs. In P. Kleihues & L. H. Sobin (Eds.), World Health Organization classification of tumours (Vol. 10, p. 257). Lyon, France: IARC Press. Doherty, G. M. (2005). Multiple endocrine neoplasia type 1. Journal of Surgical Oncology, 89(2005), 143–150. Doherty, G. M., Olson, J. A., Frisella, M. M., et al. (1998). Lethality of multiple endocrine neoplasia type I. World Journal of Surgery, 22, 581–586. Dvorakova, S., Vaclavikova, E., Duskova, J., et al. (2005). Exon 5 of the RET proto-oncogene: A newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. Journal of Endocrinological Investigation, 28, 905–909. Falchetti, A. F., Marini, F., Brandi, M. L. (2010). GeneReviews. Updated March 2, 2010. Available at: http://www.ncbi.nlm. nih.gov/books/NBK1538/. Falchetti, A., Marini, F., Luzi, E., et al. (2008). Multiple endocrine neoplasms [Review]. Best Practice & Research. Clinical Rheumatology, 22, 149–163. Gagel, R. F., & Marx, S. J. (2007). Multiple endocrine neoplasia. In P. R., Larsen, H., Kronenburg, S., Melmed, & K. Polonsky, (Eds.). Williams Textbook of Endocrinology, 11th edn. Orlando: W. B. Saunders & Company, November (Section X, Chapter 40). Gimm, O., Marsh, D. J., Andrew, S. D., et al. (1997). Germline dinucleotide mutation in codon 883 of the RET proto-

1463 oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. Journal of Clinical Endocrinology and Metabolism, 82, 3902–3904. Hoff, A. O., Cote, G. J., & Gagel, R. F. (2000). Multiple endocrine neoplasias. Annual Review of Physiology, 62, 377–411. Jerry R. J. Jr. (2011). Pediatric multiple endocrine neoplasia. Medscape Reference. Updated August 11, 2011. Available at: http://emedicine.medscape.com/article/923269-overview. Lewis, C. E., & Yeh, M. W. (2008). Inherited endocrinopathies: An update [Minireview]. Molecular Genetics and Metabolism, 94, 271–282. Lips, C. J., Landsvater, R. M., Hoppener, J. W., et al. (1994). Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type2A. The New England Journal of Medicine, 331, 828–835. Machens, A., Niccoli-Sire, P., Hoegel, J., et al. (2003). Early malignant progression of hereditary medullary thyroid cancer. The New England Journal of Medicine, 349, 1517–1525. Marini, F., Falehetti, A., Del Monte, F., et al. (2006a). Multiple endocrine enoplasia type I. Orphanet Journal of Rare Diseases, 1, 38–46. Marini, F., Falchetti, A., Del Monte, F., et al. (2006b). Multiple endocrine neoplasia type 2 [Review]. Orphanet Journal of Rare Diseases, 1, 45–50. Moline, J., & Eng, C. (2010). Multiple endocrine neoplasia type 2. GeneReviews. Updated May 4, 2010. Available at: http:// www.ncbi.nlm.nih.gov/books/NBK1257/. Mulligan, L. M., Eng, C., Healey, C. S., et al. (1994). Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genetics, 6, 70–74. Mulligan, L. M., Marsh, D. J., Robinson, B. G., et al. (1995). Genotype-phenotype correlation in multiple endocrine neoplasia type 2: Report of the International RET Mutation Consortium. Journal of Internal Medicine, 238, 343–346. O’Riordain, D. S., O’Brien, T., Weaver, A. L., et al. (1994). Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery, 116, 1017–1023. Pack, S., Turner, M. L., Zhuang, Z., et al. (1998). Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene. The Journal of Investigative Dermatology, 110, 438–440. Richards, M. L. (2010). Multiple endocrine neoplasia, type 2. Medscape Reference. Updated February 19, 2010. Available at: http://emedicine.medscape.com/article/123447-overview. Santoro, M., Carlomagno, F., Melillo, R. M., et al. (2004). Dysfunction of the RET receptor in human cancer. Cellular and Molecular Life Sciences, 61, 2954–2964. Schimke, R. N., Hartmann, W. H., Prout, T. E., et al. (1968). Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue. The New England Journal of Medicine, 279, 1–7. Schuffenecker, I., Billaud, M., Calender, A., et al. (1994). RET proto-oncogene mutations in French MEN 2A and FMTC families. Human Molecular Genetics, 3, 1939–1943. Schussheim, D. H., Skarulis, M. C., Agarwal, S. K., et al. (2001). Multiple endocrine neoplasia type 1: New clinical and basic findings. Trends in Endocrinology and Metabolism, 12, 173–178.

1464 Thakker, R. V. (2001). Multiple endocrine neoplasia. Hormone Research, 56, 67–72. Vortmeyer, A. O., Bo¨ni, R., Pack, S. D., et al. (1999). Perivascular cells harboring multiple endocrine neoplasia type 1 alterations are neoplastic cells in angiofibromas. Cancer Research, 59, 274–278.

Multiple Endocrine Neoplasia Syndromes Wilkinson, S., Teh, B. T., Davey, K. R., et al. (1993). Cause of death in multiple endocrine neoplasia type 1. Archives of Surgery, 128, 683–690. Wray, C. J., Rich, T. A., Waguespack, S. G., et al. (2008). Failure to recognize multiple endocrine neoplasia: More common than we think? Annals of Surgical Oncology, 15, 293–301.

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a

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b

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Fig. 1 (a–c) The patient, a 13-year-old Caucasian female, was seen initially because of a history of weight loss of approximately 17 lb over a period of 4–6 weeks and a mass in her neck. The biopsy of the neck mass revealed a medullary thyroid carcinoma. She has a long history of developmental delay and an unusual appearance with a thin body habitus, long face, and

full kips. MEN2 mutation screening revealed a sequence change in exon 16 of 2,753T > C (ATG > ACG) with an amino acid change of M918T (Met918Thr). The presence of this mutation in codon 918 of the RET proto-oncogene is consistent with a clinical diagnosis of MEN2B

Multiple Epiphyseal Dysplasia

In 1945, Fairbank first described multiple epiphyseal dysplasia (MED). MED is a type of short-limbed dwarfism characterized by impaired endochondral ossification affecting multiple epiphyses and premature degenerative joint disease.

Synonyms and Related Disorders Autosomal dominant multiple epiphyseal dysplasia (Fairbank type, Ribbling type); Autosomal recessive multiple epiphyseal dysplasia (with bilayered patellae, with clubfoot)

Genetics/Basic Defects 1. Inheritance: genetically heterogeneous a. Autosomal dominant (Briggs et al. 2011) i. Multiple epiphyseal dysplasia type I (EDM1) ii. Multiple epiphyseal dysplasia type II (EDM2) iii. Multiple epiphyseal dysplasia type III (EDM3) iv. Multiple epiphyseal dysplasia type V (EDM5) v. Multiple epiphyseal dysplasia type VI (EDM6) b. Autosomal recessive: multiple epiphyseal dysplasia type IV (EDM4) 2. Causes a. EDM1: mutations in the gene (COMP) encoding cartilage oligomeric matrix protein (COMP) on the centromeric region of 19p (19p13.1-p12), same locus as (allelic to) pseudoachondroplasia (the disease that shares some clinical features with multiple epiphyseal dysplasia) b. EDM2: mutations in the type IX collagen, alpha-1 polypeptide gene (COL9A1) on 6q13

c. EDM3: mutations in the type IX collagen, alpha-2 polypeptide gene (COL9A2) on 1p33-p32.2 d. EDM4 i. Mutations in the diastrophic dysplasia sulfate transporter gene (DTDST) on 5q32-q33.1 ii. Recessive mutations in the DTDST gene also cause a spectrum of osteochondrodysplasias, including achondrogenesis type IB, atelosteogenesis type II, and diastrophic dysplasia e. EDM5: mutations in the gene (MATN3) encoding matrilin-3 on 2p24-p23 f. EDM6: mutations in the type IX collagen, alpha-3 polypeptide gene (COL9A3) on 20q13.3 3. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3 a. Produce a spectrum of mild to severe chondrodysplasias characterized by epiphyseal and vertebral abnormalities b. Disrupt protein processing and excessive accumulation of some of these proteins in the rER that appears to compromise cellular function 4. Genotype-phenotype correlations (Briggs et al. 2011) a. Patients with COMP mutations i. Significant involvement at the capital femoral epiphyses ii. Irregular acetabuli b. Patients with type IX collagen defects i. More severe involvement of the knees ii. Relative sparing of the hips c. Patients with MATN3 mutations i. Abnormalities similar to those in patients with COL9A2 mutations: more severe hip abnormalities ii. More intrafamilial/interfamilial variability

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Clinical Features 1. Broad historical classification: has not proved useful a. Ribbing: milder form with flat epiphyses and minimal involvement of the hands and feet b. Fairbank: more severe form with late appearing epiphyses and greater involvement of the hands and feet 2. Onset usually in childhood: as a rule, not recognizable at birth or during the first 1–2 years of life a. Joint pain after exercise initially: a common presenting sign b. Limp, pain, and stiffness in hip, knee, and ankle joints c. Waddling gait d. Easy fatigue 3. Mild to moderate short stature with normal body proportion 4. Mild short-limbed dwarfism 5. Stubby hands and feet 6. Osteoarthritis: severe osteoarthritis of the hip develops in early childhood. 7. Limited joint motions 8. Proximal muscle weakness with mild variability in muscle fiber size in EDM3 9. Association with diabetes mellitus in early infancy (Wolcott-Rallison syndrome) 10. Consider MED (Unger et al. 2008) in: a. Any child with bilateral Perthes disease b. Any child with noninflammatory joint pain, especially involving the knees c. Family history of early joint replacement 11. Prognosis a. Normal life expectancy b. Joint deformities resulting from abnormal epiphyseal ossification frequently leading to early degenerative arthroses 12. Distinctive features of the different forms of MED (Unger et al. 2008) a. EDM1 (COMP-MED) i. Distinctive clinical features a) Muscular hypotonia b) Pseudomyopathy c) Joint laxity d) Mild genu vara

b.

c.

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e.

f.

ii. Distinctive radiographic features a) Hand: carpal bones more delayed than phalangeal epiphyses; ragged carpal bones, small, rounded phalangeal epiphyses b) Proximal femoral epiphyses: round and small c) Knee: small epiphyses with lateral thinning, additional ossification centers with “glacier crevice” sign before puberty EDM4 (rMED) i. Homozygous and compound heterozygous mutations in the DTDST gene lead to a relatively mild phenotype that seems to be clinically dominated by a tendency to recurrent dislocation of a bilateral multilayered patella and by early-onset osteoarthritis of the hip joints (Miyake et al. 2008; Cho et al. 2010; Hinrichs et al. 2010). ii. Distinctive clinical features a) Club feet at birth b) Genu valga rather than genu vara c) Joint contractures d) Mild to moderate brachydactyly iii. Distinctive radiographic features a) Hand: phalangeal epiphyses delayed, but maturation of carpal bones normal or advanced; flat epiphyses or phalanges and radius; “snow cap” sign of metacarpals b) Proximal femoral epiphyses: small and flat c) Knee: double-layered patella EDM5 (MATN3-MED) i. Distinctive clinical features: not specific ii. Distinctive radiographic features a) Hand: unspecific changes at the hands b) Proximal femoral epiphyses: small but not as rounded as in COMP-MED c) Knee: small epiphyses with “harlequin hat” appearance; metaphyseal striations EDM2 (COL9A2) i. Rare but may be under reported ii. Knee epiphyses: more affected than proximal femoral epiphyses EDM3 (COL9A3) i. Rare but may be under reported ii. Knee epiphyses: more affected than proximal femoral epiphyses EDM6 (COL9A1): Very rare (only single family reported)

Multiple Epiphyseal Dysplasia

Diagnostic Investigations 1. Radiography a. Radiographic abnormalities may be present before the onset of physical symptoms. b. Predominantly epiphyseal involvement i. Initial stage: delayed appearance of epiphyseal ossification ii. Later stage in the appearance of epiphysis a) Usually small ossification centers b) Sometimes fragmented ossification centers with irregular contours c) Adjacent metaphyseal borders may be slightly abnormal. iii. Adulthood a) Flattened and dysplastic articular surfaces b) Presence of early features of osteoarthrosis iv. Characteristic epiphyseal involvement a) Epiphyses of the hips and knees: most affected b) Ivory epiphyses in the hands c) Schmorl nodes in the spine d) Double-layered patella c. Vertebrae i. Ovoid vertebral bodies ii. Mildly irregular vertebral endplates d. Limbs i. Late ossifying epiphyses ii. Small, irregular, fragmented, and in some cases flattened epiphyses iii. Osteoarthritis iv. Short femoral neck v. Markedly dysplastic capital femoral epiphyses vi. Often initially diagnosed as Legg-Perthes disease (avascular necrosis of femoral head) vii. Genu varum or valgum viii. Short metacarpals and phalanges with irregular epiphyses ix. Small, irregular carpal and tarsal bones x. Normal metaphyses e. Irregular acetabuli f. Patella i. Doubled-layered ii. Dislocation or subluxation

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g. Absence of severe spinal involvement and minimal metaphyseal defects allows differentiating multiple epiphyseal dysplasia from other disorders with similar clinical features such as spondyloepimetaphyseal dysplasia and spondyloepiphyseal dysplasia. 2. Histology: chondrocytic inclusion (ultrastructurally, a dilated rER containing accumulated material) 3. Molecular genetic diagnosis is important for accurate prognosis and genetic counseling: mutation analyses are available on clinical basis a. Mutations in the COMP gene b. Mutations in the COL9A1 gene c. Mutations in the COL9A2 gene d. Mutations in the COL9A3 gene e. Mutations in the MATN3 gene f. Mutations in the DTDST gene

Genetic Counseling 1. Recurrence risk a. Autosomal dominant inheritance i. Patient’s sib a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50% b. Autosomal recessive inheritance i. Patient’s sib: 25% ii. Patient’s offspring: not increased unless the spouse is also carrying the gene 2. Prenatal diagnosis for pregnancies at risk for COMP and other mutations is possible if the diseasecausing allele of an affected family member has been identified. a. Amniocentesis b. CVS 3. Management (Briggs et al. 2011) a. Initial aims of management i. Control pain a) Can be difficult b) Combination of analgesics and physiotherapy including hydrotherapy ii. Limit joint destruction and the development of osteoarthritis b. Weight control c. Avoid exercise that causes repetitive strain on affected joints

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d. Realignment osteotomy and/or acetabular osteotomy to slow the progression of symptoms e. Total joint arthroplasty in some cases f. Psychosocial support to address issues of short stature, disability, and employment

References Ballo, R., Briggs, M. D., Cohn, D. H., et al. (1997). Multiple epiphyseal dysplasia. Ribbing type: A novel point mutation in the COMP gene in a South African family. American Journal of Medical Genetics, 68, 396–400. Berg, P. K. (1966). Dysplasia epiphysialis multiplex: A case report and review of the literature. American Journal of Roentgenology, 97, 31–38. Bonafe´, L., Mittaz-Crettol, L., & Ballhausen, D. (2010). Multiple epiphyseal dysplasia, recessive. GeneReviews. Retrieved March 18, 2010. http://www.ncbi.nlm.nih.gov/books/ NBK1306/ Briggs, M. D., Hoffman, S. M. G., King, L. M., et al. (1995). Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genetics, 10, 330–336. Briggs, M. D., Mortier, G. R., Cole, W. G., et al. (1998). Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. American Journal of Human Genetics, 62, 311–319. Briggs, M. D., Wright, M. J., & Mortier, G. R. (2011). Multiple epiphyseal dysplasia, dominant. GeneReviews. Retrieved February 1, 2011. Available at: http://www.ncbi.nlm.nih. gov/books/NBK1123/ Chapman, K. L., Briggs, M. D., & Mortier, G. R. (2003). Review: Clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia. Pediatric Pathology & Molecular Medicine, 22, 53–75. Cho, T.-J., Kim, O.-H., Lee, H.-R., et al. (2010). Autosomal recessive multiple epiphyseal dysplasia in a Korean girl caused by novel compound heterozygous mutations in the DTDST (SLC26A2) gene. Journal of Korean Medical Science, 25, 1105–1108. Czarny-Ratajczak, M., Lohiniva, J., Rogala, P., et al. (2001). A mutation in COL9A1 causes multiple epiphyseal dysplasia. Further evidence for locus heterogeneity in MED. American Journal of Human Genetics, 69, 969–980. Deere, M., Blanton, S. H., Scott, C. I., et al. (1995). Genetic heterogeneity in multiple epiphyseal dysplasia. American Journal of Human Genetics, 56, 698–704. Deere, M., Sanford, T., Francomano, C., et al. (1999). Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia. American Journal of Medical Genetics, 85, 486–490. Fairbank, H. A. T. (1945). Dysplasia epiphysealis multiplex. Proceedings of the Royal Society of Medicine, 39, 315–317. Hinrichs, T., Superti-Furga, A., Scheiderer, W.-D., et al. (2010). Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene –

Multiple Epiphyseal Dysplasia Phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: Case report. BMC Musculoskeletal Disorders, 11, 110–115. Hoefnagel, D., Sycamore, L. K., Russell, S. W., et al. (1967). Hereditary multiple epiphysial dysplasia. Annals of Human Genetics, 30, 201–210. Hunt, D. D., Ponseti, I. V., Pedrini-Mille, A., et al. (1967). Multiple epiphyseal dysplasia in two siblings. Journal of Bone and Joint Surgery, 49A, 1611–1627. Ikegawa, S., Ohashi, H., Nishimura, G., et al. (1998). Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple metaphyseal dysplasia. Human Genetics, 103, 633–638. Jacobs, P. A. (1968). Dysplasia epiphysialis multiplex. Clinical Orthopaedics, 58, 117–128. Leeds, N. E. (1960). Epiphysial dysplasia multiplex. American Journal of Roentgenology, 84, 506–510. M€akitie, O., Mortier, G. R., Czarny-Ratajczak, M., et al. (2004). Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: Description of 12 patients. American Journal of Medical Genetics, 125A, 278–284. Maudsley, R. H. (1955). Dysplasia epiphysialis multiplex: A report of fourteen cases in three families. Journal of Bone and Joint Surgery, 37B, 228–240. Miyake, A., Nishimura, G., Futami, T., et al. (2008). A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia. Journal of Human Genetics, 53, 764–768. Mortier, G. R., Chapman, K., Leroy, J. L., et al. (2001). Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. European Journal of Human Genetics, 9, 606–612. Muragaki, Y., Mariman, E. C. M., van Beersum, S. E. C., et al. (1996). A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nature Genetics, 12, 103–105. Murphy, M. C., Shine, I., & Stevens, D. B. (1973). Multiple epiphyseal dysplasia: Report of a pedigree. Journal of Bone and Joint Surgery, 55A, 814–820. Oehlmann, R., Summerville, G. P., Yeh, G., et al. (1994). Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19. American Journal of Human Genetics, 54, 3–10. Paassilta, P., Lohiniva, J., Annunen, S., et al. (1999). COL9A3: A third locus for multiple epiphyseal dysplasia. American Journal of Human Genetics, 64, 1036–1044. Sheffield, E. G. (1998). Double-layered patella in multiple epiphyseal dysplasia: A valuable clue in the diagnosis. Journal of Pediatric Orthopedics, 18, 123–128. Stanescu, R., Stanescu, V., Muriel, M.-P., et al. (1993). Multiple epiphyseal dysplasia, Fairbank type: Morphologic and biochemical study of cartilage. American Journal of Medical Genetics, 45, 501–507. Superti-Furga, A., Neumann, L., Riebel, T., et al. (1999). Recessively inherited multiple epiphyseal dysplasia with normal stature, clubfoot, and double layered patella caused by a DTDST mutation. Journal of Medical Genetics, 36, 621–624.

Multiple Epiphyseal Dysplasia Superti-Furga, A., Spbetzko, D., Hecht, J. T., et al. (2000). Recessive multiple epiphyseal dysplasia (rMED: MIM 226900): Phenotype delineation in twelve individuals homozygous for DTST mutation R279W. American Journal of Human Genetics, 67(Suppl. 2), 379. Thornton, C. M., Carson, D. J., & Stewart, F. J. (1997). Autopsy findings in the Wolcott–Rallison syndrome. Pediatric Pathology & Laboratory Medicine, 17, 487–496. Unger, S., Bonafe´, L., & Superti-Furga, A. (2008). Multiple epiphyseal dysplasia: Clinical and radiographic features, differential diagnosis and molecular basis. Best Practice & Research. Clinical Rheumatology, 22, 19–32. Unger, S. L., Briggs, M. D., Holden, P., et al. (2001). Multiple epiphyseal dysplasia: Radiographic abnormalities correlated with genotype. Pediatric Radiology, 31, 10–18.

1471 Unger, S., & Hecht, J. T. (2001). Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 106, 244–250. Villarreal, T., Carnevale, A., Mayen, D. G., et al. (1992). Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia. American Journal of Medical Genetics, 42, 415–419. Watt, J. K. (1952). Multiple epiphyseal dysplasia: Report of four cases. British Journal of Surgery, 39, 533–535. Waugh, W. (1952). Dysplasia epiphysialis multiplex in three sisters. Journal of Bone and Joint Surgery, 34B, 82–87.

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Fig. 1 (a–e) A boy with multiple epiphyseal dysplasia showing short stature and epiphyseal dysplasia in the wrists, hips, and knee joints

Multiple Epiphyseal Dysplasia Fig. 2 (a, b) A girl and an adult female with multiple epiphyseal dysplasia showing mild short stature with normal body proportion

Fig. 3 Radiograph of the pelvis of a 12-year-old boy with multiple epiphyseal dysplasia showing poorly developed acetabular fossae and flat, fragmented femoral heads

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Fig. 4 (a–c) Radiographs of another patient with multiple epiphyseal dysplasia showing poorly formed acetabular fossae, poorly ossified femoral heads, and flattened epiphyses of the knees and ankles

Multiple Epiphyseal Dysplasia

Multiple Epiphyseal Dysplasia Fig. 5 (a, b) A 13 year old boy with multiple epiphyseal dysplasia has been complaining pain in knees, legs, and feet since 4 years of age. He was also noted to have limp, joint stiffness, and worsening waddling gait. Mutation analysis showed a heterozygous G > A nucleotide substitution in exon 16, resulting in the replacement of an aspartic acid codon (GAC) with an asparagine codon (AAC) at amino acid position 605 (c.1813G > A or p.Asp605Asn (D605N)). The D605N missense mutation in the COMP gene has been reported previously in association with multiple epiphyseal dysplasia and is consistent with the diagnosis of this patient

Fig. 6 Radiographs of the same patient showing epiphyseal dysplasias at the distal femoral epiphyses and the proximal tibial epiphyses causing weakness and pains at the knees

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Multiple Epiphyseal Dysplasia

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Fig. 8 A 10-year old girl was seen because of short stature. The radiographs were consistent with multiple epiphyseal dysplasia. DNA sequencing revealed a c.1445A > G transition in exon 13 of the COMP gene. This change converts a codon for aspartic acid (GAC) to a codon for glycine (GGC). The patient is heterozygous for the mutation. The mutation confirms the diagnosis of multiple epiphyseal dysplasia. She was also diagnosed to have growth hormone deficiency and was receiving daily Humatrope injection

Fig. 7 (a, b) A 12-year-old boy with multiple epiphyseal dysplasia. Radiograph of the pelvis at 8 years of age showed poorly developed acetabular fossae and flat femoral heads

Multiple Epiphyseal Dysplasia

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Fig. 11 Note short and stubby toes

Fig. 9 Note the short upper arms with short fingers

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Fig. 12 Hip radiograph 6 months earlier shows poorly developed acetabular fossae and flat fragmented femoral heads

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Fig. 10 (a, b) Note the short and stubby fingers

Fig. 13 Knee radiograph shows flattened epiphyses of the knees

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Fig. 14 Hand radiograph shows short and broad phalanges

Fig. 15 Radiograph of left upper extremity shows relatively short tubular bones with small proximal epiphysis of the left humerus

Multiple Epiphyseal Dysplasia

Fig. 16 Radiograph of feet shows short and stubby phalanges

Multiple Pterygium Syndrome

Multiple pterygium syndrome is a distinct syndrome consisting of a constellation of congenital anomalies characterized by pterygia of the neck, antecubital, popliteal and intercrural areas, numerous flexion contractures of the joints, growth retardation, ptosis, antimongoloid slant with or without epicanthal folds, cleft palate, scoliosis, vertebral anomalies, rockerbottom deformity of the feet, and genital anomalies.

Synonyms and Related Disorders Escobar syndrome

Genetics/Basic Defects 1. Inheritance: genetic heterogeneity (Chen 2009) a. Autosomal recessive inheritance in most cases i. Recessive forms of MPS: clinically and genetically heterogeneous. a) May result from early-onset fetal akinesia b) Traditionally classified into prenatally lethal MPS and nonlethal Escobar variant-MPS ii. Escobar syndrome: Mutations in CHRNG gene, which encodes the acetylcholine receptor g-subunit cause the autosomal recessive Escobar syndrome, one of the most common types of MPS, although other genes may be involved (Hoffmann et al. 2006; Morgan et al. 2006; Prontera et al. 2007). iii. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes

of the neuromuscular junction (CHRNG, CHRNA1, CHRNB1, CHRND, and RAPSN) (Hoffmann et al. 2006; Morgan et al. 2006; Michalk et al. 2008; Vogt et al. 2008). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. iv. The first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements (Monnier et al. 2009). v. Clinical features. a) Multiple joint contractures with marked pterygia b) Dysmorphic facies (flat, sad, motionless facial appearance) c) Cervical vertebral anomalies b. Autosomal dominant inheritance in some cases (Mckeown and Harris 1988) i. Great variation in severity between affected individuals ii. Characterized by multiple pterygia with or without mental retardation c. X-linked inheritance (MacArthur and Pereira 1996) d. Sporadic occurrence (Ramer et al. 1988; Spranger et al. 1995; Aslani et al. 2002) 2. Phenotypic analysis a. Multiple congenital pterygia, joint contractures, and severe foot defects: deformation sequence secondary to reduced frequency of fetal movement b. Micrognathia: resulting from reduced use and represents “disuse hypotrophy”

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c. Cleft palate: a mechanical disruption due to presumed interposition of tongue between palatine shelves d. Neck pterygia i. Able to exert a downward pull on facial structures ii. Responsible for the following effects: a) Down-turned angles of the mouth b) Long philtrum c) Antimongoloid slant of palpebral fissures d) Low posterior hairline e) Anteversion and apparently low-set position of auricles f) Often with strikingly abnormal directional hair patterning in posterior and posterior-lateral areas of scalp iii. Short neck due to: a) Lateral cervical pterygia b) Secondary fusion of upper vertebrae e. Congenital scoliosis: secondary to abnormal prenatal position, movement, and/or muscle pull f. Genital anomalies i. Small scrotum and apparently absent or hypoplastic labia majora: resulting from the pull of the intercrural pterygia which affects a flattening of these structures ii. Cryptorchidism: representing mechanical obstruction of the processus vaginalis from pull of intercrural web or some intrinsic defect of the gubernaculums testis which is unable to effect descent of the gonads 3. Pathogenesis a. The underlying pathogenesis of the secondary deformities and distortions, hypotrophies, disruptions, bony fusions, and incomplete or impeded morphogenetic movements is unknown b. A neuromuscular disease causing fetal akinesia (Chen et al. 1980; Bhargava et al. 2002) is suspected. c. Intrauterine crowding and oligohydramnios are contributory factors to joint contractures associated with MPS (Chen 2009).

Multiple Pterygium Syndrome

i. Neck ii. Axillary iii. Antecubital iv. Popliteal v. Digital vi. Intercrural b. Multiple joint contractures c. Rib or vertebral anomalies d. Scoliosis/lordosis e. Rocker-bottom feet with vertical talus 3. Standing with a crouching or semi-crouching stance 4. Orofacial features a. A flat, sad, motionless facial appearance b. Epicanthal folds c. Ptosis d. Antimongoloid palpebral fissure e. Long philtrum f. Pointed, receding chin g. Down-turned angles of the mouth h. Cleft lip+/ palate i. Apparent low-set ears 5. Genitalia a. Males i. Small penis and scrotum ii. Cryptorchidism b. Females i. Apparent aplasia of the labia majora ii. A small clitoris

Diagnostic Investigations 1. Radiography a. Multiple joint contractures b. Fusion of cervical vertebrae c. Scoliosis/lordosis d. Flexion contractures of fingers e. Rocker-bottom feet with vertical talus 2. Pathological evaluations of muscle and nerve tissue: no consistent abnormality

Genetic Counseling Clinical Features 1. Short stature 2. Cutaneous and musculoskeletal a. Pterygia involving the following areas:

1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. Autosomal dominant inheritance: not increased unless a parent is also affected

Multiple Pterygium Syndrome

b. Patient’s offspring i. Autosomal recessive inheritance: not increased unless the spouse is a carrier ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis possible by ultrasonography for the family at risk a. Micrognathia b. Low-set ears c. Hypertelorism d. Cystic hygroma colli e. Rocker-bottom feet 3. Management (McCall and Budden 1992) a. Correction of the hand deformities i. Attention given to any deformities in the shoulder and elbow to maximize function of the limb before initiating correction of hand deformities ii. Intensive physiotherapy and occupational therapy preferable to surgery for management of the upper extremity and hand anomalies b. Correction of mild hip flexion contractures of 50) ii. Characterized by cataracts and baldness with little or no muscle involvement iii. CTG repeats: 50–100 iv. Occasionally difficult to diagnose: The pleomorphic manifestations, due to a dynamic mutation in the length of CTG repeat, lead to difficulty in clinical identification of asymptomatic or mildly affected patients. b. The classic (juvenile or adult) form i. The more common form ii. Usually becoming evident between the ages of 15 and 35 years iii. CTG repeats: 100–1,000 iv. Phenotypically variable v. Characteristic clinical features a) Myotonia b) Muscle weakness c) Cardiac arrhythmias d) Male balding e) Hypogonadism f) Psychocognitive dysfunction g) Glucose intolerance c. The childhood form i. Age at onset: 1–10 ii. CTG repeats: 500–>2,000 iii. Clinical manifestations a) Hypotonia b) Learning difficulties c) Limited motor skills d. The most severe (congenital) form i. Recognized at birth or in the neonatal period

ii. Pregnancy a) Maternal polyhydramnios b) Reduced fetal movement c) Breech presentation d) Prematurity iii. Associated with generalized muscular hypotonia iv. Respiratory distress a) Aspiration pneumonia b) Recurrent bronchitis c) Hypoventilation d) Sleep apnea e) Bronchiectasis v. Feeding difficulties vi. Dysphagia vii. Nasal regurgitation viii. Facial diplegia with a “tented-shaped” mouth ix. Delayed motor development x. Joint deformities xi. Mental retardation xii. High neonatal mortality xiii. Those survived invariably exhibiting the classical form of the disease in late childhood or adolescence xiv. Almost all congenital cases are exclusively maternally transmitted xv. CTG repeats: 1,000–5,000 xvi. The phenomenon of anticipation often most strikingly manifested in a family producing a congenitally affected child 2. Neurologic manifestations a. Myotonia (100%) (Miller 2008) i. Delayed relaxation of muscles after an initial voluntary contraction or percussion. ii. Muscle stiffness that improves with repeated use of the muscle, the so-called warm-up phenomenon. iii. On examination, myotonia may be apparent from the first handshake, presenting with a delayed release of the hand. This can also be appreciated by asking the patient to repeatedly grip and release the examiner’s fingers. Another helpful maneuver is to ask the patient to repeatedly close the eyes tightly. After the first closure, there may be lag in opening the eyes, but this will improve with repeated efforts.

Myotonic Dystrophy Type I

iv. Myotonia may be provoked by percussion of muscle, e.g., by percussion of the thenar eminence. The muscle stiffens, often adducting the thumb. b. Muscle weakness and atrophy i. Muscles most prominently affected a) Superficial facial muscles b) Levator palpebrae superioris c) Temporalis d) Sternocleidomastoids e) Distal muscles of forearm f) Dorsiflexors of foot ii. Other muscles commonly affected a) Quadriceps b) Diaphragm and intercostals c) Intrinsic muscles of hand and feet d) Palate and pharyngeal muscles e) Tongue f) External ocular muscles c. Percussion myotonia and voluntary myotonia aggravated by cold d. Dysarthria e. Slow nasal indistinct speech f. Foot drop g. Step page gait h. Contractures of the Achilles tendon i. Diminished deep tendon reflexes j. Cognitive and behavioral abnormalities 3. Craniofacial appearance a. Long thin face b. Flat, sagging, sad, and expressionless face c. Frontal bossing d. Hollow temple secondary to atrophy of temporalis e. Bilateral facial weakness (facial diplegia) f. Tented mouth g. Micrognathia h. Swan neck appearance (sternocleidomastoid muscle wasting) 4. Ocular findings a. Cataracts (>85%) b. Ptosis c. Extraocular weakness d. Peripheral retinal changes e. Coloboma of retina/choroid f. Optic atrophy g. Blepharospasms h. Decreased ocular pressure

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5. Cardiac involvement (76%) a. An integral part of myotonic dystrophy targeting i. Almost selectively the conduction system ii. Less specifically the myocardium b. Electrocardiographic conduction abnormalities i. Manifesting with or without ventricular tachyarrhythmias or bradyarrhythmias ii. The first-degree atrioventricular (AV) block (most common) iii. Intraventricular conduction abnormalities (premature ventricular complexes like couplets and triplets) iv. Atrial arrhythmias (atrial fibrillation and flutter) c. A high incidence of sudden death d. Possible cardiomyopathy e. Congestive heart failure (6%) 6. Gastrointestinal findings a. Achalasia b. Gastroparesis c. Constipation d. Megacolon e. Gallstones 7. Genitourinary findings a. Dysuria b. Urinary retention c. Polycystic kidneys d. Testicular atrophy 8. Endocrine findings a. Hypogonadism b. Male infertility secondary to testicular atrophy c. Hypothyroidism d. Goiter/hyperparathyroidism e. Multiple endocrine neoplasia type 2A (pheochromocytoma and amyloid-producing medullary thyroid carcinoma) f. Dysmenorrhea g. Postprandial hyperinsulinemia 9. Orthopedic problems a. Arthrogryposis b. Talipes c. Kyphoscoliosis 10. Female patients a. Decreased total reproductive rate b. Obstetrical complications (Rudnik-Scho¨neborn and Zerres 2004) i. Higher rate of spontaneous abortions

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ii. Ectopic pregnancies iii. Abnormal placentation iv. Urinary tract infections 11. Occasional accompanying benign or malignant neoplasms a. Pilomatrixoma b. Parathyroid adenoma c. Small bowel carcinoma d. Neurofibromatosis e. Thymoma f. Pleomorphic adenoma of the parotid gland g. Pituitary adenoma h. Ovarian cancer i. Ovarian cyst j. Laryngeal cancer not previously reported 12. Natural history a. Usually progressive b. Usually leading to severe disability within 15–20 years c. Greatly reduced life expectancy, particularly in the case of an early disease onset and proximal muscle involvement d. The high mortality rate reflecting an increase in deaths due to i. Respiratory diseases ii. Cardiovascular diseases iii. Neoplasms iv. Sudden deaths induced by cardiac arrhythmias 13. Differential diagnosis of myotonic disorders (Meola 2000; Miller 2008) a. Myotonic dystrophy type 2 (DM2) i. Clinical characteristics similar to those of DM1: an adult-onset muscular dystrophy associated with a) Myotonia (clinically and on EMG) b) Proximal weakness c) Frontal balding d) Polychromatic cataracts e) Cardiac arrhythmias f) Facial and respiratory muscles: relatively spared g) Insulin resistance h) Infertility i) Absence of congenital form of DM2 comparable with DM1 ii. Molecular basis: DM2: caused by an expansion of a cytosine-cytosine-thymine-

Myotonic Dystrophy Type I

guanine (CCTG) repeat in the zinc finger protein 9 (ZNF9) gene on chromosome 3 (Liquori et al. 2001) b. Myotonia congenita i. Myotonia: prominent clinical symptom. a) Stiffness especially when first starting an activity in severe classic myotonia b) Perform activities at a normal or advanced level, including competitive sports, once warmed up c) Presents in early childhood, described by the parents as weakness and clumsiness in addition to or instead of stiffness d) Despite the reported difficulties, affected children appear “athletic,” with increased muscle bulk, presumably because of the sustained muscle activity. e) The myotonic symptoms often improve with age but do not completely disappear. ii. Caused by a mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1) (Renner and Ptacek 2002). The chloride channel defect leads to an elevation of the resting membrane potential and thus a tendency toward repeated muscle contractions. iii. Inheritance: either autosomal dominant (Thomsen myotonia congenita) or autosomal recessive (Becker myotonia congenita). c. Schwartz-Jampel syndrome (chondrodystrophic myotonia) i. Caused by loss-of-function mutation in the HSPG2 gene, which encodes perlecan, a heparan sulfate proteoglycans secreted into basement membranes (Nicole et al. 2000) ii. Clinical manifestations a) Severe myotonia: one of the first symptoms present in childhood. No warm-up phenomenon for the myotonia b) Short stature c) Muscular hypertrophy d) Diffuse bone disease e) Ocular and facial abnormalities f) Joint contractures

Myotonic Dystrophy Type I

Diagnostic Investigations 1. Clinical examination to search muscle and nonmuscle manifestations (Meola 2000) 2. Lab: mildly elevated serum creatine kinase 3. Electromyography to identify subclinical myotonia 4. Slit-lamp examination to detect characteristic cataracts 5. Muscle biopsy a. Diagnostic but not indicated or useful for routine clinical evaluation b. Atrophic small type I fibers c. An increase in central nuclei d. Ringed fibers 6. Radiography a. Kyphosis of cervical spine b. Thin ribs observed in neonates suffering from myotonic dystrophy 7. Electrocardiogram abnormalities (60–70%) (Finsterer et al. 2001) a. ST abnormalities b. AV block I c. Increased QTc interval d. Tall R and/or S waves e. Left anterior hemiblock f. Supraventricular ectopic beats g. T wave abnormalities h. Pacemaker i. Missing R progression j. Abnormal U wave k. Left bundle branch block 8. Echocardiography (Finsterer et al. 2001) a. Septal thickness >11 mm b. Posterior wall thickness >11 mm c. Fractional shortening 1 e. Left ventricular end-diastolic diameter >57 mm f. Valve abnormalities 9. DNA testing for CTG repeat size: detects mutations in nearly 100% of affected individuals and is clinically available (Bird 2007) a. Gold standard for the diagnosis of DM1 b. CTG repeat size i. Normal alleles: 5–34 CTG repeats ii. Premutation (mutable normal alleles): 35–49 CTG repeats

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iii. Full penetrance alleles (associated with disease manifestations): >50 CTG repeats c. Clinical testing by targeted mutation analysis 10. Presymptomatic carrier testing a. Leukocyte DNA analysis: provides an earlier opportunity to diagnose DM1 in family members at risk who are clinically asymptomatic b. Providing more aggressive monitoring program to detect i. Early cardiac conduction disturbance ii. Cataract formation iii. Respiratory difficulties iv. At risk of developing anesthetic complications, especially delayed-onset apnea

Genetic Counseling 1. Recurrence risk (Bird 2007) a. General principle for genetic counseling i. A normal molecular analysis excludes the risk of developing or transmitting myotonic dystrophy in essentially all situations. ii. For women who have had a child with congenital myotonic dystrophy, almost all subsequently affected pregnancies are likely to be severely affected. iii. Clinically affected women, in general, have around a 30% chance that an affected child would have congenital or severe childhood myotonic dystrophy. The risk of a congenitally affected child is related to maternal repeat size. iv. The risk for the healthy sib of a congenitally affected patient developing the disorder after childhood is low. v. For the adult healthy sib of an adult-onset case, the risk of carrying the mutation is also low (around 10%), with about half of this developing clinically significant disease. b. Patient’s sib: recurrence risk depending on the genetic status of the parents i. Not increased if both parents are normal ii. Fifty percent risk if one parent has an expanded DMPK allele

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c. Patient’s offspring i. Offspring of an individual with an expanded allele (>34 CTG repeats) have a 50% chance of inheriting the mutant allele. ii. Disease-causing alleles may expand in length during gametogenesis, resulting in the transmission of longer CTG trinucleotide repeat alleles that may be associated with earlier onset and more severe disease than that observed in the parent. 2. Prenatal diagnosis a. Prenatal ultrasonography in congenital myotonic dystrophy i. Polyhydramnios ii. Talipes iii. Decreased fetal movements reflecting the neuromuscular failure of swallowing and movement b. Prenatal diagnosis possible by using mutation analysis (requires prior confirmation of the diagnosis of DM1 by molecular genetic testing of DMPK in an affected family member) and detection of the CTG repeat expansion with the DMPK gene in amniocytes or chorionic villi c. More challenging by using the CTG repeat test to determine whether the fetus is at risk for the severe form of myotonic dystrophy i. Generally, in amniocytes, congenital myotonic dystrophy is associated with CTG repeat expansion larger than that of the affected mother. ii. CTG repeat size may change over time in CVS or amniocentesis, providing different CTG repeat size at different gestational ages. d. Counseling of pregnant patients affected with myotonic dystrophy i. An explanation of the risk associated with anticipation, which is the tendency toward large intergenerational expansion of the CTG repeat during maternal transmission, resulting in offspring with congenital myotonic dystrophy ii. CTG repeat number provides only an approximate guide to prognosis or to pregnancy outcome. Most cases with over 2,000 repeats will have congenital or severe childhood-onset disease; most individuals with 50–100 repeats will not have significant neuromuscular disease.

Myotonic Dystrophy Type I

iii. An intergenerational contraction of the CTG fragment observed in approximately 7% of cases. Clinical anticipation was seen despite the reduced CTG repeat size, resulting in congenital myotonic dystrophy in the offspring. iv. Prenatal diagnosis (PND) is available; however, the decision to terminate affected pregnancies is difficult as the extent of disability is hard to predict from the size of the expansion. e. Preimplantation genetic diagnosis (PGD) genetic analysis: available and is carried out before the establishment of pregnancy (Kakourou et al. 2008) 3. Management a. No specific treatment available for the progressive weakness that is responsible for most of the disability in patients with myotonic dystrophy b. Patients with myotonic dystrophy usually do not seek treatment for the myotonia per se, or they are not compliant with medication regimens to treat it, either because myotonia is much milder than their other symptoms or because they avoid medical treatment as part of their personality (Conravey and Santana-Gould 2010). c. To alleviate myotonia by drugs i. Quinine, quinidine, dilantin, carbamazepine, procainamide, diamox to alleviate myopia not universally successful ii. Encouraging results with mexiletine (Logigian et al. 2010) and tocainide d. Avoid cold which may induce myotonia e. Prescription for orthoses, wheelchairs, or other assisted devices f. Treat cataracts, diabetes mellitus, hypothyroidism, and sleep apnea g. Avoid surgery and anesthesia (sensitive to narcotics and sedatives)

References Amorosi, B., Giustini, S., Rossi, A., et al. (1999). Myotonic dystrophy (Steinert disease): a morphologic and biochemical hair study. International Journal of Dermatology, 38, 434–438. Bird TD (2007) Myotonic dystrophy type 1. GeneReviews. Updated November 15, 2007. Available at: http://www.ncbi. nlm.nih.gov/bookshelf/br.fcgi?book¼gene&part¼myotonic-d

Myotonic Dystrophy Type I Brook, J. D., McCurrach, M. E., Genet, H. H., et al. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 30 end of a transcript encoding a protein kinase family member. Cell, 68, 799–808. Bundley, S. (1982). Clinical evidence for heterogeneity in myotonic dystrophy. Journal of Medical Genetics, 19, 341–348. Conravey, A., & Santana-Gould, L. (2010). Myotonia congenita and myotonic dystrophy surveillance and management. Current Treatment Options in Neurology, 12, 16–28. Dalton JC, Ranum LPW, Day JW (2007) Myotonic dystrophy type 2. GeneReviews. Updated April 23, 2007. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼ gene&part¼myotonic-d2 Day, J. W., Roelofs, R., Leroy, B., et al. (1999). Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscular Disorders, 9, 19–27. Day, J. W., Ricker, K., Jacobsen, J. F., et al. (2003). Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology, 60, 657–664. Delaporte, C. (1998). Personality patterns in patients with myotonic dystrophy. Archives of Neurology, 55, 635–640. Dufour, P., Berard, J., Vinatier, D., et al. (1997). Myotonic dystrophy and pregnancy. A report of two cases and a review of the literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 72, 159–164. Finsterer, J., Gharehbaghi-Schnell, E., Korschineck, I., et al. (1999). Phenotype and CTG-repeat size in myotonic dystrophy: a study of 26 patients and 55 relatives. Journal of Neurogenetics, 13, 181–190. Finsterer, J., Gharehbaghi-Schnell, E. G., Sto¨llberger, C., et al. (2001). Relation of cardiac abnormalities and CTGrepeat size in myotonic dystrophy. Clinical Genetics, 59, 350–355. Geifman-Holtzman, O., & Fay, K. (1998). Prenatal diagnosis of congenital myotonic dystrophy and counseling of the pregnant mother: Case report and literature review. American Journal of Medical Genetics, 78, 250–253. Gennarelli, M., Novella, G., Andreasi Bassi, F., et al. (1996). Prediction of myotonic dystrophy clinical severity based on the number of intragenic (CTG)n trinucleotide repeats. American Journal of Medical Genetics, 65, 342–347. Gharehbaghi-Schnell, E., Finsterer, J., Korschineck, I., et al. (1998). Genotype-phenotype correlation in myotonic dystrophy. Clinical Genetics, 53, 20–26. Hageman, A. T., Gabreels, F. J., Liem, K. D., et al. (1993). Congenital myotonic dystrophy; a report on thirteen cases and a review of the literature. Journal of Neurological Sciences, 115, 95–101. Harley, H. G., Rundle, S. A., Mc Millan, J. C., et al. (1993). Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. The American Journal of Human Genetics, 52, 1164–1174. Harper, P. S. (1975a). Congenital myotonic dystrophy in Britain. I. Clinical aspects. Archives of Disease in Childhood, 50, 505–513. Harper, P. S. (1975b). Congenital myotonic dystrophy in Britain. II. Genetic aspects. Archives of Disease in Childhood, 50, 514–521.

1493 Harper, P. S. (1989). Myotonic Dystrophy. Philadelphia, PA: W. B. Saunders. Harper, P. S., & Keith, J. (2001). Myotonic dystrophy. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The Metabolic & Molecular Bases of Inherited Disease (8th ed.). New York: McGraw-Hill. International Myotonic Dystrophy Consortium (IDMC). (2000). New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). Neurology, 54, 1218–1221. Joseph, J. T., Richards, C. S., Anthony, D. C., et al. (1997). Congenital myotonic dystrophy pathology and somatic mosaicism. Neurology, 49, 1457–1460. Kakourou, G., Dhanjal, S., Mamas, T., et al. (2008). Preimplantation genetic diagnosis for myotonic dystrophy type 1 in the UK. Neuromuscular Disorders, 18, 131–136. Koch, M. C., Grimm, T., Harley, H. G., et al. (1991). Genetic risks for children of women with myotonic dystrophy. American Journal of Human Genetics, 48, 1084–1091. Liquori, C. L., Ricker, K., Moseley, M. L., et al. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293, 864–867. Logigian, E. L., Martens, W. B., & Moxley, R. T. (2010). Mexiletine is an effective antimyotonia treatment in myotonia dystrophy type 1. Neurology, 74, 1441–1448. Magee, A. C., Hughes, A. E., Kidd, A., et al. (2002). Reproductive counselling for women with myotonic dystrophy. Journal of Medical Genetics, 39, E15. Mathieu, J., Allard, P., Gobeil, G., et al. (1997). Anesthetic and surgical complications in 219 cases of myotonic dystrophy. Neurology, 49, 1646–1650. Mathieu, J., Allard, P., Potvin, L., et al. (1999). A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology, 52, 1658–1662. Meola, G. (2000). Clinical and genetic heterogeneity in myotonic dystrophies. Muscle & Nerve, 23, 1789–1799. Meola, G., & Sansone, V. (1996). A newly described myotonic disorder (proximal myotonic myopathy-PROMM): Personal experience and review of the literature. Italian Journal of Neurological Sciences, 17, 347–353. Miller, T. M. (2008). Differential diagnosis of myotonic disorders. Muscle & Nerve, 37, 293–299. Nicole, S., Davoine, C. S., Topaloglu, H., et al. (2000). Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nature Genetics, 26, 480–483. Osanai, R., Kinoshita, M., Hirose, K., et al. (2000). CTG triplet repeat expansion in a laryngeal carcinoma from a patient with myotonic dystrophy. Muscle & Nerve, 23, 804–806. Pearse, R. G., & Howeler, C. J. (1979). Neonatal form of dystrophic myotonica: Five cases in preterm babies and a review of earlier reports. Archives of Disease in Childhood, 54, 331–338. Renner, D. R., & Ptacek, L. J. (2002). Periodic paralyses and nondystrophic myotonias. Advances in Neurology, 88, 235–252. Rudnik-Scho¨neborn, S., & Zerres, K. (2004). Outcome in pregnancies complicated by myotonic dystrophy: a study of 31 patients and review of the literature. Reproductive Biology, 114, 44–53.

1494 Simmons, Z., Thornton, C. A., Seltzer, W. K., et al. (1998). Relative stability of a minimal CTG repeat expansion in a large kindred with myotonic dystrophy. Neurology, 50, 1501–1504. Thornton, C. (1999). The myotonic dystrophies. Seminars in Neurology, 19, 25–32. Timchenko, L. T., Tapscott, S. J., Cooper, T. A., et al. (2002). Myotonic dystrophy: Discussion of molecular basis.

Myotonic Dystrophy Type I Advances in Experimental Medicine and Biology, 516, 27–45. Udd, B., Krahe, R., Wallgren-Pettersson, C., et al. (1997). Proximal myotonic dystrophy–a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Neuromuscular Disorders, 7, 217–228.

Myotonic Dystrophy Type I Fig. 1 An adult (a) with myotonic dystrophy showing hard to release after shaking hand (b) and thenar myotonia after tapping (c)

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1496 Fig. 2 (a, b) An adult with myotonia dystrophy showing long thin face with frontal bossing and thenar myotonia after tapping

Myotonic Dystrophy Type I

a

b

Myotonic Dystrophy Type I Fig. 3 (a–c) A 23-year-old mother and her 21-month-old daughter with myotonia congenita type 1. The mother has myotonia (hard to relax after shaking hand), thenar myotonia after tapping, and absent tendon reflexes. The pregnancy was complicated by polyhydramnios, feeble fetal movement, and breech presentation. After scheduled cesarean section, the baby breathed only once and needed intubation for 5 days. She was very floppy and just started to walk about 2 months prior to the clinic visit. She chokes easily and does not chew and talk. On physical examination, in addition to hypotonia, there is a long and sagging face with marked tented-mouth. Molecular genetic testing of the daughter showed CTG repeats of 1,050

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c

Nail-Patella Syndrome

In 1820, Chatelain first observed the nail-patella syndrome in a patient with a triad of abnormal nails, elbows, and knees. The hereditary nature of the syndrome was first described by Pye-Smith in 1883 in the English literature. The presence of iliac horns was first noted by Kieser in 1939 and later by Fong in 1946. In 1948, Mino et al. described the tetrad of abnormal nails, elbows, knees, and iliac horns for which the name hereditary onycho-osteodysplasia was coined by Duncan and Souter in 1963.

Synonyms and Related Disorders Hereditary onycho-osteodysplasia

Genetics/Basic Defects 1. An autosomal dominant disorder with complete penetrance 2. LMX1B a. The only gene known to be associated with nailpatella syndrome b. A LIM-homeodomain transcription factor involved in normal patterning of the dorsoventral axis of the limb during development and early morphogenesis of the glomerular basement membrane

Clinical Features 1. Classic clinical tetrad a. Onychodysplasia: the most constant feature of the syndrome (approximately 98% of cases) i. Absent, hypoplastic, or dystrophic nails usually noted at birth ii. Bilateral or symmetrically involved iii. Longitudinally or horizontally ridged (grooved) nails iv. Thin or less often thickened nails v. Triangular lunules (lunulae): a characteristic feature of the syndrome vi. Most pronounced involvement in thumbnails, decreases in severity ulnarward vii. Dysplasia of toenails usually less marked, often affecting little toenails, and less frequent than that of the fingernails b. Knee dysplasia (approximately 74% of cases) i. Small, irregularly shaped, or absent patella that is prone to dislocate ii. May be asymmetrically involved iii. Hypoplastic patella often located laterally and superiorly, even though not actually dislocated iv. May be associated with prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities v. Appearance of flattened profile of knee joints

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_172, # Springer Science+Business Media, LLC 2012

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c. Elbow dysplasia (approximately 70% of cases) i. May be asymmetrical ii. The deformity is characterized by hypoplasia of the capitellum, commonly by secondary dysplasia and dislocation, usually posteriorly, of the radial head, associated with limitation of rotation (pronation and supination) of variable degree. iii. Triceps hypoplasia with antecubital pterygia, a frequent accompaniment of the syndrome, further limiting extension resulting in cubitus valgus d. “Iliac horns” i. Clinically palpable ii. Generally symmetrical iii. Known to develop a secondary center of ossification iv. The iliac horns can be present at birth by X-ray examination Other skeletal abnormalities a. Talipes equinovarus, talipes calcaneovalgus deformities, and flat feet b. Mild short stature Associated nephropathy (30–50% of cases) (renal failure in approximately 5% of cases) a. Proteinuria i. Usually the first sign of renal involvement ii. With or without hematuria iii. May present at any age from birth onward iv. May be intermittent v. May remit spontaneously, remain asymmetric, progress to nephritic syndrome, and occasionally to renal failure vi. May be exacerbated during pregnancy b. Progression to chronic glomerulonephritis leading rarely to renal failure i. May occur rapidly ii. May occur after many years of asymptomatic proteinuria Eye involvement a. Primary open-angle glaucoma b. Ocular hypertension c. Iris pigmentary changes: frequent observation of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris (Lester’s sign) Gastrointestinal involvement (about one-third of cases) a. Constipation b. Irritable bowel syndrome

Nail-Patella Syndrome

6. Neurological involvement a. Intermittent numbness, tingling, and burning sensations in the hands and feet in some cases b. Epilepsy (6% of cases) 7. Vasomotor problems in some cases a. Poor peripheral circulation, presenting as very cold hands and feet even in warm weather b. Raynaud’s phenomenon 8. Dental problems a. Weak, crumbling teeth b. Thin dental enamel

Diagnostic Investigations 1. Diagnosis based on clinical and radiographic findings 2. Laboratory studies a. Urinalysis: proteinuria, hematuria b. Plasma urea, BUN, creatinine concentrations 3. Radiologic features a. Elbow involvement i. Dysplasia of the radial head ii. Hypoplasia of the lateral epicondyle and capitellum iii. Prominence of the medial epicondyle iv. Dislocation of the radial head, usually posteriorly b. Iliac horns i. Bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis ii. Present in about 70% of cases iii. Considered pathognomonic of the syndrome iv. Pelvic X-ray a) Usually necessary for detection of iliac horns, but large horns may be palpable clinically b) Iliac horns: may be observed at birth c) An epiphysis at the apex of iliac horns: may be present in children 4. MRI for possible bone/soft tissue abnormalities 5. Ultrastructural (electron microscopic) abnormalities: the most specific histologic changes seen in nail-patella syndrome a. Collagen fibril deposition within the basement membrane and the mesangial matrix

Nail-Patella Syndrome

b. Irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled “moth-eaten” appearance 6. Molecular genetic testing: LMX1B gene mutation analysis available clinically

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. An affected parent: a 50% risk ii. Clinically unaffected parents a) A low risk in a case of de novo mutation in the proband b) An increased risk if germline mosaicism exists in a parent (not been reported) b. Patient’s offspring: a 50% risk 2. Prenatal diagnosis: demonstration of the diseasecausing mutation previously identified in the proband on fetal DNA obtained from amniocentesis or CVS 3. Management a. Patella dysplasia: most patients asymptomatic, rarely require surgical treatment b. Physiotherapy for orthopedic complaints c. Surgical treatment i. Bilateral elbow soft tissue release ii. Bilateral radial head excisions iii. Foot and ankle reconstructive procedures for equinus, pes cavus, calcaneovalgus, congenital vertical talus, and clubfoot deformities iv. Congenital permanent dislocation of the patella d. Screening for proteinuria e. Screening for glaucoma

References Beals, R. K., & Eckhardt, A. L. (1969). Hereditary onychoosteodysplasia (Nail-Patella syndrome). A report of nine kindreds. Journal of Bone and Joint Surgery, American Volume, 51, 505–516. Beguiristain, J. L., de Rada, P. D., & Barriga, A. (2003). Nailpatella syndrome: Long term evolution. Journal of Pediatric Orthopaedics. Part B, 12, 13–16. Bennett, W. M., Musgrave, J. E., Campbell, R. A., et al. (1973). The nephropathy of the nail-patella syndrome. Clinicopathologic analysis of 11 kindred. The American Journal of Medicine, 54, 304–319.

1501 Bongers, E. M., Gubler, M. C., & Knoers, N. V. (2002). Nailpatella syndrome. Overview on clinical and molecular findings. Pediatric Nephrology, 17, 703–712. Bongers, E. M., Huysmans, F. T., Levtchenko, E., et al. (2005). Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. European Journal of Human Genetics, 13, 935–946. Bongers, E. M., van Kampen, A., van Bokhoven, H., et al. (2005). Human syndromes with congenital patellar anomalies and the underlying gene defects. Clinical Genetics, 68, 302–319. Browning, M. C., Weidner, N., & Lorentz, W. B., Jr. (1988). Renal histopathology of the nail-patella syndrome in a twoyear-old boy. Clinical Nephrology, 29, 210–213. Burkhart, C. G., Bhumbra, R., & Iannone, A. M. (1980). Nailpatella syndrome. A distinctive clinical and electron microscopic presentation. Journal of the American Academy of Dermatology, 3, 251–256. Carbonara, P., & Alpert, M. (1964). Hereditary Osteo-OnychoDysplasia (HOOD). The American Journal of the Medical Sciences, 248, 139–151. Chatelain: Quoted by Roeckerath, W. (1951). Heredtaire osteoonycho-dysplasia. Fortschritte auf dem Gebiete der Ro¨ntgenstrahlen, 75, 709. Chen, H., Lun, Y., Ovchinnikov, D., et al. (1998). Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nature Genetics, 19, 51–55. Chua, H. L., Tan, L. K., Tan, H. K., et al. (2002). The course of pregnancy in a patient with nail-patella syndrome. Annals of the Academy of Medicine, Singapore, 31, 349–352. Cormier-Daire, V., Chauvet, M. L., Lyonnet, S., et al. (2000). Genitopatellar syndrome: A new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. Journal of Medical Genetics, 37, 520–524. Cottereill, C. P., & Jacobs, P. (1961). Hereditary Arthro-osteoonchyodysplasia associated with iliac horns. British Journal of Clinical Practice, 15, 933–941. Darlington, D., & Hawkins, C. F. (1967). Nail patella syndrome with iliac horns and hereditary nephropathy: Necropsy report and anatomical dissection. Journal of Bone and Joint Surgery, American Volume, 49B, 164–174. Dreyer, S. D., Zhou, G., Baldini, A., et al. (1998). Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nature Genetics, 19, 47–50. Duncan, J. G., & Souter, W. A. (1963). Hereditary onychoosteodysplasia. The nail-patella syndrome. Journal of Bone and Joint Surgery, 45-B, 242–258. Dunston, J. A., Lin, S., Park, J. W., et al. (2005). Phenotype severity and genetic variation at the disease locus: An investigation of nail dysplasia in the nail patella syndrome. Annals of Human Genetics, 69(Pt 1), 1–8. Dunston, J. A., Reimschisel, T., Ding, Y. Q., et al. (2005). A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression. European Journal of Human Genetics, 13, 330–335. Eisenberg, K. S., Potter, D. E., & Bovill, E. G., Jr. (1972). Osteoonychodystrophy with nephropathy and renal osteodystrophy. A case report. Journal of Bone and Joint Surgery, American Volume, 54, 1301–1305.

1502 Elston, D. M., Peters, J., & Morrison, W. B. (2000). What is your diagnosis? Nail-patella syndrome. Cutis, 66(71), 75–76. Feingold, M., Itzchak, Y., & Goodman, R. M. (1998). Ultrasound prenatal diagnosis of the Nail-Patella syndrome. Prenatal Diagnosis, 18, 854–856. Fong, E. E. (1946). ‘Iliac horns’ (symmetrical bilateral central posterior iliac processes): A case report. Radiology, 47, 517–518. Galloway, G., & Vivian, A. (2003). An ophthalmic screening protocol for nail-patella syndrome. Journal of Pediatric Ophthalmology and Strabismus, 40, 51–53. Goshen, E., Schwartz, A., Zilka, L. R., et al. (2000). Bilateral accessory iliac horns: Pathognomonic findings in Nailpatella syndrome. Scintigraphic evidence on bone scan. Clinical Nuclear Medicine, 25, 476–477. Guidera, K. J., Satterwhite, Y., Ogden, J. A., et al. (1991). Nail patella syndrome: A review of 44 orthopaedic patients. Journal of Pediatric Orthopedics, 11, 737–742. Kieser, W. (1939). Die sog Flughaut beim Menschen. Ihre Beziehung zum Status Dysraphicus und ihre Erblichkeit. Zeitchr f Menschl Vererb u Konstitutionslehre, 23, 594–619. Leahy, M. S. (1966). The hereditary nephropathy of osteoonychodysplasia. Nail-patella syndrome. American Journal of Diseases of Children, 112, 237–241. Looij, B. J., Jr., te Slaa, R. L., Hogewind, B. L., et al. (1988). Genetic counselling in hereditary osteo-onychodysplasia (HOOD, nail- patella syndrome) with nephropathy. Journal of Medical Genetics, 25, 682–686. McIntosh, I., Clough, M. V., & Gak, E. (1999). Prenatal diagnosis of nail-patella syndrome [letter]. Prenatal Diagnosis, 19, 287–288. McIntosh, I., Dreyer, S. D., Clough, M. V., et al. (1998). Mutation analysis of LMX1B gene in nail-patella syndrome patients. American Journal of Human Genetics, 63, 1651–1658. McIntosh, I., Dunston, J. A., Liu, L., et al. (2005). Nail patella syndrome revisited: 50 years after linkage. Annals of Human Genetics, 69(Pt 4), 349–363.

Nail-Patella Syndrome Meyrier, A., Rizzo, R., & Gubler, M. C. (1990). The nail-patella syndrome. A review. Journal of Nephrology, 2, 133–140. Mino, R. A., Mino, V. H., & Livingstone, R. G. (1948). Osseous dysplasia and dystrophy of the nails: Review literature and report of a case. American Journal of Roentgenology, 60, 633–641. Morita, T., Laughlin, L. O., Kawano, K., et al. (1973). NailPatella syndrome. Light and electron microscopic studies of the kidney. Archives of Internal Medicine, 131, 271–277. Nandedkar-Thomas, M. A., & Scher, R. K. (2005). An update on disorders of the nails. Journal of the American Academy of Dermatology, 52, 877–887. Ogden, J. A., Cross, G. L., Guidera, K. J., et al. (2002). Nail patella syndrome. A 55-year follow-up of the original description. Journal of Pediatric Orthopaedics. Part B, 11, 333–338. Sabnis, S. G., Antonovych, T. T., Argy, W. P., et al. (1980). Nail-patella syndrome. Clinical Nephrology, 14, 148–153. Schulz-Butulis, B. A., Welch, M. D., & Norton, S. A. (2003). Nail-patella syndrome. Journal of the American Academy of Dermatology, 49, 1086–1087. Silahtaroglu, A., Hol, F. A., Jensen, P. K., et al. (1999). Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome. European Journal of Human Genetics, 7, 68–76. Sprecher, E. (2005). Genetic hair and nail disorders. Clinics in Dermatology, 23, 47–55. Sweeney, E., Fryer, A., Mountford, R., et al. (2003). Nail patella syndrome: A review of the phenotype aided by developmental biology. Journal of Medical Genetics, 40, 153–162. Sweeney, E., Hoover-Fong, J. E., & McIntosh, I. (2009). Nail-patella syndrome. GeneReviews. Retrieved July 28, 2009. Available at: http://www.ncbi.nlm.nih.gov/books/ NBK1132/ Towers, A. L., Clay, C. A., Sereika, S. M., et al. (2005). Skeletal integrity in patients with nail patella syndrome. Journal of Clinical Endocrinology and Metabolism, 90, 1961–1965.

Nail-Patella Syndrome

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d

g

e

b h

f i

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Fig. 1 (a–i) A 10-year-old boy has classic nail-patellar syndrome. Note webbings of the neck and the elbows causing marked elbow contractures, abnormal muscle distribution of

the upper extremities, nail hypoplasia, and absent patella. The radiographs show “iliac horn” sign of the pelvis and patella agenesis

Neonatal Herpes Simplex Infection

Hass in 1935 described a fatal case of neonatal herpes simplex virus (HSV) infection with hepatoadrenal necrosis and intranuclear inclusion bodies. Neonatal herpes is defined as the diagnosis of HSV infection in an infant within the first 28 days of life.

Synonyms and Related Disorders Fetal/intrauterine herpes simplex infection

Genetics/Basic Defects 1. HSV-1 and HSV-2 a. Belong to Herpesvirus family i. Herpes simplex viruses a) Enveloped, double-stranded DNA viruses b) Exist as two serotypes, 1 and 2 (HSV-1 and HSV-2) ii. Infections with HSV-1 generally involve the face and skin “above the waist” and are associated with orolabial disease. Most infections occur during childhood. HSV-1 also can cause genital infection, resulting more frequently from oral-genital contact. iii. Infections with HSV-2 usually involve the genitalia and skin “below the waist” in sexually active adolescents and adults, usually resulting from sexual intercourse. Most HSV disease in neonates is due to HSV-2. HSV-2 also causes oral lesions in approximately 25% of the infected population. b. Viruses are transmitted from infected to susceptible individuals during close personal contact.

c. Recurrent HSV infections occur in over onethird of the world’s population due to the rare fatal nature of the infection and a latency period. d. Infections in children and nonpregnant adults i. Recurrent herpes labialis: the largest reservoir of HSV infections in the community ii. Genital herpes a) A first-episode primary infection occurs in a person with no prior HSV-1 or HSV-2 antibody. b) A first-episode nonprimary infection occurs in a person with preexisting HSV-1 antibody acquiring HSV-2 genital infection. c) Recurrent infections can result from viral reactivation from latency and subsequent antegrade translocation of virus back to the skin and mucosal surfaces. e. Maternal genital infections i. Twenty-two percent of pregnant women are seropositive for herpes simplex virus (HSV)2, and more than 2% of women acquire genital herpes during pregnancy. ii. Recurrent genital herpes infections: the most common form of genital HSV infections during gestation iii. The most devastating complication of genital HSV is infection of the neonate caused by contact with infected genital secretions at the time of delivery. iv. Woman with primary genital HSV disease: at highest risk of transmitting the virus to her baby v. Neonatal transmission occurs in the peripartum period, provided the gravid woman is shedding

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_173, # Springer Science+Business Media, LLC 2012

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virus, either symptomatically or asymptomatically, at the time of delivery. vi. Factors influencing transmission from mother to neonate a) Type of maternal infection (primary versus recurrent): Mothers with a first episode of genital HSV infection near term are at much greater risk of developing neonatal herpes than those whose mothers have recurrent genital herpes. b) Maternal antibody status c) Duration of rupture of membranes: Cesarean delivery within 4 h of membrane rupture in a woman with active genital lesions can reduce the infant’s risk of acquiring HSV. d) Integrity of mucocutaneous barriers (e.g., use of fetal scalp electrodes) e) Mode of delivery (cesarean section versus vaginal): effective in the prevention of HSV transmission to the neonate from a mother actively shedding virus from the genital tract. Neonatal infection has occurred in spite of cesarean delivery performed prior to the rupture of membranes. f. Incidence of neonatal disease: estimated at approximately 1 in 3,200 deliveries (an estimated 1,500 cases of neonatal HSV infection annually in the United States) g. Transmission of HSV disease to neonates occurs in the following three distinct time intervals: i. Intrauterine (in utero): 5% infected with HSV in utero ii. Peripartum (perinatal): overwhelming majority (85%) of infected neonates iii. Postpartum (postnatal): an additional 10% of infected neonates h. Disease classification of HSV infections acquired either peripartum or postpartum: predictive of both morbidity and mortality i. Disease localized to the skin, eyes, and/or mouth (SEM disease, accounting for 45% of cases of neonatal HSV) ii. Encephalitis, with or without SEM involvement (CNS disease, accounting for 30% of cases of neonatal HSV) iii. Disseminated infection involving multiple organs, including the CNS, lungs, liver,

Neonatal Herpes Simplex Infection

adrenal glands, skin, eyes, and/or mouth (disseminated disease, accounting for 25% of cases of neonatal HSV) 2. Two biologic properties of HSV that directly influence human diseases a. Latency: a period of reactivation of virus multiplication, resulting in clinically apparent disease (lesions) or clinically inapparent (asymptomatic, or subclinical) infection b. Neurovirulence: an affinity with which HSV is drawn to and propagated in neuronal tissue, resulting in profound disease with severe neurologic sequelae: i. Neonatal HSV central nervous system (CNS) disease ii. Herpes simplex encephalitis in older children and adults

Clinical Features 1. Intrauterine infection a. Incidence: approximately 1 in 300,000 deliveries b. In utero disease unlikely to be missed due to the extent of involvement of affected babies c. A triad of clinical findings i. Cutaneous manifestations a) Scarring b) Active lesions c) Hypo-/hyperpigmentation d) Aplasia cutis e) Erythematous macular exanthem ii. Ophthalmologic findings a) Microphthalmia b) Retinal dysplasia c) Optic atrophy d) Chorioretinitis iii. Neurologic involvement a) Microcephaly b) Encephalomalacia c) Hydranencephaly d) Intracranial calcification 2. Disseminated disease involving multiple organs, most prominently the liver and lungs and possibly with a central nervous system (CNS) component a. Incidence: approximately 25% of all children with neonatal HSV disease

Neonatal Herpes Simplex Infection

3.

4.

5.

6.

b. Has the earliest age of onset, often during the first postnatal week c. Encephalitis: about 60–75% of infants with disseminated disease d. Vesicular rash: over 20% of neonates with disseminated HSV disease do not develop cutaneous vesicles during the course of their illness e. Death relates primarily to the severe coagulopathy, liver dysfunction, and pulmonary involvement of the disease. Localized CNS disease with or without SEM involvement: observed in almost one-third of all neonates with HSV infection and has the latest age of onset, usually between the second and third weeks after birth a. Seizures (both focal and generalized) b. Lethargy c. Irritability d. Tremors e. Poor feeding f. Temperature instability g. Bulging fontanelle h. Associated skin vesicles in 60% and 70% of babies classified as having CNS disease i. Death usually caused by devastating brain destruction, with resulting acute neurologic and autonomic dysfunction SEM disease a. Incidence: approximately 45% of all cases of neonatal HSV disease b. Represents a spectrum of disease manifestations having more limited viral dissemination but without visceral involvement (e.g., liver, lung) as detected biochemically (e.g., elevated transaminase levels) or clinically (e.g., pneumonitis) Factors affecting the severity of neonatal disease a. Prompt diagnosis: PCR assay to detect HSV DNA in neonates has improved early diagnosis of disease. b. Initiation of antiviral (intravenous acyclovir) therapy i. Reduces mortality and morbidity among neonates with skin, eye, and mouth disease ii. Unable to reduce morbidity associated with disseminated or CNS disease Despite early intervention with high-dose antiviral therapy, 30% of infants with disseminated

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disease die, and 40% of survivors of CNS disease have severe neurologic damage. Therefore, prevention of neonatal infection is critical.

Diagnostic Investigations 1. Clinical diagnosis based on: a. Typical findings (HSV culture not necessary): i. Herpes labialis ii. Gingivostomatitis iii. Genital herpes b. Atypical HSV infections (culture and antiviral susceptibility testing needed to guide antiviral therapy) i. Immunocompromised patients ii. HSV conjunctivitis and keratitis: need an ophthalmologist consultation 2. Diagnostic evaluations obtained prior to initiation of acyclovir therapy a. HSV cultures: remains the definitive diagnostic method of establishing HSV disease i. Skin vesicles, if present ii. Oropharynx iii. Conjunctivae iv. Urine v. Blood vi. Stool vii. Rectum viii. Cerebrospinal fluid (CSF) b. Liver transaminase: Elevated levels suggest disseminated HSV infection. 3. Serologic testings a. Type-specific antibody assays to distinguish between HSV-1 and HSV-2 antibodies b. Identifies only past infection but cannot identify the site of HSV infection c. Patients with cold sores due to HSV-1 will test HSV-1 seropositive regardless of presence or absence of genital HSV-1 infection. d. Possible to identify serodiscordant couples in which the woman is HSV-2 seronegative and the partner is seropositive. Women in such couples are at risk for acquiring primary genital HSV infection during pregnancy and are thus at higher risk of transmitting the virus to their babies during birth.

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e. Serologic studies, in general, play no role in the diagnosis of neonatal HSV disease. 4. Classification of genital HSV based on serologic and viral detection test results: important in pregnancy because the risk of perinatal HSV transmission varies accordingly a. Primary first episode: characterized by isolation of HSV-1 or HSV-2 from genital secretions in the absence of HSV antibodies in serum b. Nonprimary first episode: characterized by isolation of HSV-2 from genital secretions in the presence of HSV-1 antibodies in serum c. Reactivation disease: characterized by isolation of HSV-1 or HSV-2 from the genital tract in the presence of HSV antibodies of the same serotype as the isolate 5. PCR amplification a. Able to correctly diagnose neonatal HSV disease, especially in patients without overt manifestations such as skin vesicles b. Able to assess the response to therapy i. Having HSV DNA detected in CSF at or after the completion of intravenous therapy is associated with poor outcomes. ii. Repeat lumbar puncture of all patients with CNS HSV involvement is indicated at the end of intravenous acyclovir therapy to determine that the specimen is PCR negative in a reliable laboratory and to document the end-of-therapy CSF indices. Persons who remain PCR positive should continue to receive intravenous antiviral therapy until PCR negativity is achieved.

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Unknown ii. No cases in siblings reported b. Patient’s offspring i. Unknown 2. Prenatal diagnosis a. Genetic counseling complicated due to: i. Fetal infection may follow primary or recurrent disease. ii. Fetal infection can occur at any time in gestation.

Neonatal Herpes Simplex Infection

iii. Only approximately one third of cases have a history suggestive of maternal herpes infection during pregnancy. b. Isolation of the virus from amniotic fluid obtained at amniocentesis does not necessarily imply fetal infection. c. Currently no accurate risk estimate available for congenital malformations following maternal herpes infection during pregnancy i. Appears to be small ii. Highest risk for women with primary infection during the first trimester 3. Management a. Antiviral drugs i. Vidarabine (1-b-D-arabinofuranosyl-adenine): the first systemically administered antiviral medication with activity against HSV for which the therapeutic efficacy outweighed its toxicity a) Administered over prolonged infusion times and in large volumes of fluid b) Management of life-threatening HSV and varicella zoster virus infections, HSV encephalitis, and herpesvirus infections in immunocompromised patients ii. Acyclovir a) Lower dose: lower toxicity and improved ease of administration b) Higher dose: improved outcome in mortality and morbidity achieved with use of higher-dose acyclovir b. Antibody therapy i. Use of passive immunotherapy as an adjuvant to active antiviral interventions. ii. Neonates with higher neutralizing antibody titers: less likely to become infected with HSV following perinatal exposure and being more likely to have localized disease (and less likely to have disseminated disease) once they are infected iii. Intravenous gamma globulin currently not recommended for the management of neonates with HSV disease due to variable amount of anti-HSV antibodies present in conventional intravenous gamma globulin preparations iv. A monoclonal antibody directed against gD may be available for clinical investigation as an adjuvant therapeutic agent by

Neonatal Herpes Simplex Infection

the NIAID Collaborative Antiviral Study Group in the future. c. Prevention of neonatal HSV infections i. Prevention strategies a) Identification of women at risk for HSV acquisition during pregnancy by testing women and possibly their partners for HSV antibodies b) Provide counseling to prevent transmission to women in late pregnancy ii. Cesarean section a) Reduces the infant’s risk of acquiring HSV in women with active genital lesions present at the time of delivery b) Limitations: 60–80% of babies who develop neonatal HSV disease are born to women without a history of genital herpes, and thus, infection in these babies may not be prevented by this approach, and women with recurrent infections who are shedding virus at the time of delivery are at low risk of their babies developing neonatal HSV disease. iii. Antiviral therapy during pregnancy a) Oral acyclovir near the end of pregnancy to suppress genital HSV recurrences becoming increasingly common in clinical practice b) Additional studies are needed to more definitively establish the effectiveness and safety of late-pregnancy maternal HSV suppression. iv. Vaccine development for genital herpes: A candidate HSV-2 gD subunit vaccine adjuvanted with alum combined with 3-deacylated monophosphoryl lipid A has recently demonstrated promising results in preventing HSV-1 or HSV-2 genital herpes

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disease and HSV-2 infection, efficacy limited only to women who were HSV-1 and HSV-2 seronegative prior to vaccination. d. Avoid unnecessary invasive procedures in labor. i. Vaginal delivery in women with genital herpes but without lesions or symptoms at the time of labor ii. Avoid the following procedures to lessen the risk of HSV transmission, except when critical to obstetric care: a) Artificial rupture of membranes b) Fetal scalp electrodes c) Vacuum or forceps delivery

References Baldwin, S., & Whitley, R. J. (1989). Teratogen update: Intrauterine herpes simplex virus infection. Teratology, 39, 1–10. Brown, Z. A., Gardella, C., Wald, A., et al. (2005). Genital herpes complicating pregnancy. Obstetrics and Gynecology, 106, 845–856. Frij, B. J., & Sever, J. L. (1990). Fetal herpes simplex virus infection. In M. L. Buyse (Ed.), Birth defects encyclopedia (pp. 713–714). Dover: Center for Birth Defects Information Services. Hass, M. (1935). Hepatoadrenal necrosis with intranuclear inclusion bodies: Report of a case. American Journal of Pathology, 11, 127. Hutto, C., et al. (1987). Intrauterine herpes simplex virus infections. Journal of Pediatrics, 110, 97–101. Kimberlin, D. W. (2004). Neonatal herpes simplex infection. Clinical Microbiology Reviews, 17, 1–13. Looker, K. J., & Garnett, G. P. (2005). A systematic review of the epidemiology and interaction of herpes simplex virus types 1 and 2. Sexually Transmitted Infections, 81, 103–107. Waggoner-Fountain, L. A., & Grossman, L. B. (2004). Herpes simplex virus. Pediatrics in Review, 25, 86–93. Zervoudakis, I. A., et al. (1980). Herpes simplex in the amniotic fluid of an affected fetus. Obstetrics and Gynecology, 55, 16S–17S.

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Fig. 1 (a, b) A neonate born with congenital herpes simplex infection showing generalized vesicular rash

Neonatal Herpes Simplex Infection

Nephrogenic Diabetes Insipidus

Hereditary nephrogenic diabetes insipidus (NDI) is a rare disorder of defective vasopressin-stimulated water reabsorption via the luminal water channels in the cortical and medullary collecting ducts (Knoers and Deen 2001).

Genetics/Basic Defects 1. Causes of diabetes insipidus (Linshaw 2007) a. Central: hypothalamic/pituitary lesions leading to insufficient production or release of antidiuretic hormone (ADH) i. Postoperative brain surgery ii. Intracranial lesions (cysts, aneurysms, tumors of pituitary, brainstem) iii. Infiltrative malignancies (lymphoma, leukemia) iv. Infections, including encephalitis, meningitis, abscess v. Head trauma vi. Hypoxic injury vii. Congenital, inherited as an autosomal dominant disorder b. Nephrogenic: renal resistance (lack of response of the distal nephron) to ADH from lesions interfering with the renal concentrating mechanism i. Acquired metabolic aberrations a) Hypokalemia (chronic, Bartter syndrome) b) Hypercalcemia c) Hypercalciuria (rare) d) Diabetes mellitus

ii. Medullary damage a) Chronic pyelonephritis b) Infiltrative disease (leukemia, lymphoma, amyloidosis) c) Sickle cell disease d) Cystinosis e) Other forms of chronic renal failure f) Obstructive uropathy iii. Drugs a) Lithium b) Demeclocycline c) Amphotericin B d) Diphenylhydantoin iv. Inherited a) X-linked recessive: approximately 90% of cases of hereditary nephrogenic diabetes insipidus b) Autosomal recessive: approximately about 9% of cases c) Autosomal dominant: about 1% of cases 2. X-linked inheritance a. Caused by mutations in the arginine vasopressin V2 receptor (AVPR2) gene on the X chromosome (mapped on Xq28), encoding the arginine vasopressin receptor type 2 (VR2): molecular basis for lack of concentration of urine b. Males who carry the defective gene i. Do not concentrate urine after administration of arginine vasopressin (AVP): defined as the excretion of increased (>30 ml/kg/day) volumes of diluted urine (143 mEq/L in the presence of a low urine

Nephrogenic Diabetes Insipidus

ii. Autosomal recessive inheritance a) Obligatory carriers for a disease-causing mutation in the AQP2 gene b) A low recurrence risk unless the spouse is affected or a carrier iii. Autosomal dominant inheritance: a 50% risk of offspring affected (inheriting the AQP2 mutation) 2. Prenatal diagnosis a. X-linked recessive: available for pregnancies at increased risk if the AVPR2 mutation has been identified in an affected family member by amniocentesis of CVS if the fetal karyotype is 46,XY b. Autosomal recessive and autosomal dominant: available for pregnancies at increased risk for the AQP2 mutation c. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation(s) has/have been identified. 3. Management (Linshaw 2007) a. Sufficient water to maintain normal electrolytes b. Low renal solute load to minimize water loss c. Adequate calories to support growth d. Pharmacotherapy: usually needed i. Thiazide a) Hydrochlorothiazide: 1–3 mg/kg/day bid b) Hypokalemia c) Hyponatremia d) Alkalosis e) Hypercalcemia f) Hyperglycemia g) Hyperuricemia h) Hepatitis i) Intestinal symptoms j) Bone marrow suppression e. Amiloride i. 20 mg/1.73 m2/day bid–tid ii. Hyperkalemia iii. Headaches iv. Gastrointestinal discomfort f. Indomethacin i. 1.5–2.5 mg/kg/day tid ii. Gastrointestinal discomfort iii. Gastrointestinal bleeding

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iv. Headaches v. Renal toxicity vi. Hematopoietic adverse effects

References Arthus, M.-F., Lonergan, M., Crumley, M. J., et al. (2000). Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. Journal of the American Society of Nephrology, 11, 1044–1054. Bichet, D. G., Oksche, A., & Rosenthal, W. (1997). Congenital nephrogenic diabetes insipidus. Journal of the American Society of Nephrology, 8, 1951–1958. Bircan, Z., Karacayir, N., & Cheong, H. H. (2008). A case of aquaporin 2 R85X mutation in a boy with congenital nephrogenic diabetes insipidus. Pediatric Nephrology, 23, 663–665. Chan, J. C. M., & Roth, K. S. (2009). Diabetes insipidus. Updated Feb 6, 2009. Available at: http://imedicine.com/ DisplayTopic.asp?bookid¼10&topic¼580 Cooperman, M. (2008). Diabetes insipidus. Updated Feb 13, 2008. Available at: http://imedicine.com/DisplayTopic.asp? bookid¼6&topic¼543 Fujiwara, T. M., & Bichet, D. G. (2005). Molecular biology of hereditary diabetes insipidus. Journal of the American Society of Nephrology, 16, 2836–2846. Hochberg, Z., Van Lieburg, A., Even, L., et al. (1997). Autosomal recessive nephrogenic diabetes insipidus caused by an aquaporin-2 mutation. Journal of Clinical Endocrinology and Metabolism, 82, 686–689. Hoekstra, J. A., van Lieburg, A. F., Monnens, L. A. H., et al. (1996). Cognitive and psychosocial functioning of patients with congenital nephrogenic diabetes insipidus. American Journal of Medical Genetics, 61, 81–88. Knoers, N. (2007). Nephrogenic diabetes insipidus. GeneReviews. Updated June 8, 2007. Available at: http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book¼gene&part¼ndi Knoers, N. V., & Deen, P. M. (2001). Molecular and cellular defects in nephrogenic diabetes insipidus. Pediatric Nephrology, 16, 1146–1152. Linshaw, M. A. (2007). Back to basics: Congenital nephrogenic diabetes insipidus [Review]. Pediatrics in Review, 28, 372–380. Sands, J. M., & Bichet, D. G. (2006). Nephrogenic diabetes insipidus. Annals of Internal Medicine, 144, 186–194. Spanakis, E., Milord, E., & Gragnoli, C. (2008). AVPR2 variants and mutations in nephrogenic diabetes insipidus: Review and missense mutation significance. Journal of Cellular Physiology, 217, 605–617. Vargas-Poussou, R., Forestier, L., Dautzenberg, M. D., et al. (1997). Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus. Journal of the American Society of Nephrology, 8, 1855–1862.

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Fig. 1 A 3-year-old girl was evaluated because her father has nephrogenic diabetes insipidus. He has problems with dehydration, polyuria, and polydipsia. His mother is a carrier and his maternal grandfather died of nephrogenic diabetes insipidus. The girl was found to have a mutation in the AVPR2 gene. The mutation detected is g692–693delCT where two bases (CT) in codon 111 are deleted. The deletion causes a frameshift mutation that begins with a change of the amino acid at position 111 and results in a premature termination of protein synthesis at codon 190.This mutation has been reported to cause nephrogenic diabetes insipidus (NDI). The genetic data along with the family history are consistent with this female being a carrier of X-linked NDI

Nephrogenic Diabetes Insipidus

Netherton Syndrome

Netherton syndrome is a rare hereditary disorder of keratinization. It was described by Come`l in 1949 and Netherton in 1958. The syndrome is sometimes called Come`l–Netherton syndrome. The incidence is about 1 in 200,000 (Bitoun et al. 2002b).

Synonyms and Related Disorders Netherton disease

Genetics/Basic Defects 1. Inheritance: autosomal recessive (Bitoun et al. 2002b) 2. Defective gene in Netherton syndrome a. Serine protease inhibitor, Kazal-type 5 (SPINK5) mapped on chromosome 5q31-32 b. The protein encoded by SPINK5 is highly expressed in thymus and mucous epithelia, thereby termed LEKTI for lymphoepithelial Kazal type–related inhibitor. i. LEKTI possibly plays a role in antiinflammatory and/or antimicrobial protection of mucous epithelia. ii. LEKTI possibly have similar function in the epidermis.

Clinical Features 1. Clinical triad a. Congenital ichthyosis i. Extent of involvement: highly variable

ii. Natural course a) At birth: usually normal appearing skin b) Within a few weeks of age: skin becomes erythematous and develops serpiginous double-edged scales typical of ichthyosis linearis circumflexa or ichthyosiform erythroderma. b. Hair abnormality i. Trichorrhexis invaginata/nodosa a) Sparse and brittle scalp hair with a characteristic “bamboo” shape under light microscope due to invagination of the distal part of the hair shaft to its proximal part b) The major diagnostic sign (considered pathognomonic) but may be difficult to detect in infancy and early childhood c) May not affect all hair and can be limited to the lateral part of the eyebrows ii. Pili torti iii. Eyelashes and eyebrows may be affected. c. Atopic manifestations (Bitoun et al. 2002b) i. Eczema-like rashes ii. Atopic dermatitis iii. Pruritus iv. Allergic rhinitis v. Asthma vi. Urticaria/angioedema 2. Prognosis: poor (Bitoun et al. 2002b) a. Frequent life-threatening complications during the neonatal period i. Hypernatremic dehydration ii. Hypothermia iii. Extreme weight loss

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iv. Recurrent infections v. Bronchopneumonia vi. Sepsis b. Failure to thrive common during childhood resulting from i. Malnutrition ii. Metabolic disorders iii. Chronic erythroderma iv. Persistent cutaneous infections v. Severe enteropathy with villous atrophy vi. Growth retardation c. Other abnormalities i. Renal failure ii. Aminoaciduria iii. Congenital heart defects iv. Hydroureter v. Infantile pyloric stenosis vi. Increased susceptibility to skin cancer a) Squamous cell carcinoma b) Vulvar cancer

Diagnostic Investigations 1. Clinical laboratory a. Increased serum immunoglobulin E levels b. Hypereosinophilia c. No consistent or significant abnormalities of immune function d. IgG abnormalities (both hypo- and hyper-IgG) e. T-cell and neutrophil defects may also occur. f. Selective humoral deficiency to bacterial polysaccharide antigens has been described. g. Specific IgE antibodies against airborne and food allergens frequently present 2. Dermatoscopy (trichoscopy) (Sun and Linden 2005; Burk et al. 2008; Rakowska et al. 2009) a. Trichorrhexis invaginata (bamboo hairs) i. A focal defect of the hair shaft that produces development of torsion nodules and invaginated nodules ii. The proximal element of the node overlaps the distal portion, causing an intussusception. b. Golf tee–like endings of hair shafts: If hair is pulled distally from this focal defect, a golf tee–like deformity is left. Hence, any hairs examined should be cut, rather than plucked. c. The hair shaft nodules caused by this defect are sometimes able to be seen by the naked eye.

Netherton Syndrome

These hair defects can be found in scalp, eyebrow, or eyelash hairs. Grossly, scalp hair is described to be sparse and brittle. d. The hair shaft abnormality was reported to be secondary to intermittent incomplete formation of disulfide bonds in the keratogenous zone (Ito et al. 1984). e. Other hair shaft abnormalities i. Pili torti ii. Trichorrhexis nodosa iii. Helical hairs (Lurie and Garty 1995) 3. Immunohistochemistry using anti-LEKTI antibodies: shows a complete absence of LEKTI in the skin samples (Shimomura et al. 2005) 4. Histology and ultrastructural studies of skin sections a. Incomplete keratinization or defective cornification of the epidermis b. Dermal lymphocytic infiltrate c. Ultrastructure of the stratum corneum: characterized by premature degradation of corneodesmosomes with separation of corneocytes (Chao et al. 2005). 5. Molecular genetic testing of SPINK5: clinically available a. Mutation analysis of patients b. Carrier testing

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier of the gene 2. Prenatal diagnosis (Bitoun et al. 2002a) a. Ultrastructural examination of fetal skin biopsies for defective cornification of the epidermis is not reliable, since fetal skin keratinization does not begin until the 24th week of gestation, whereas in utero, fetal skin biopsy is usually performed between 19 and 22 weeks. b. DNA-based prenatal diagnosis on fetal DNA obtained from amniocentesis or CVS. i. SPINK5 mutation detection ii. Indirect genotype analysis at the SPINK5 locus using linkage analysis a) This approach is reliable since there is no evidence of locus heterogeneity.

Netherton Syndrome

b) Presence of a large number of SPINK5 intragenic restriction fragment length polymorphisms (RFLPs) showing a high percentage of heterozygosity 3. Management a. No specific treatment available b. Emollients c. Keratolytics d. Antibiotics for recurrent infections e. Topical corticosteroids f. Topical tacrolimus and pimecrolimus with good control of skin disease without toxic effect (Saif and Al-Khenizan 2007) g. Medium dose of psoralen-UVA1 phototherapy may be effective and tolerated in adult.

References Ansai, S., Itsuhashi, U., & Sasaki, K. (1999). Netherton’s syndrome in siblings. British Journal of Dermatology, 141, 1097–1100. Bitoun, E., Bodemer, C., Amiel, J., et al. (2002a). Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis. Prenatal Diagnosis, 22, 121–126. Bitoun, E., Chavanas, S., Irvine, A. D., et al. (2002b). Netherton syndrome: Disease expression and spectrum of SPINK5 mutations in 21 families. Journal of Investigative Dermatology, 118, 352–361. Bitoun, E., Micheloni, A., Lamant, L., et al. (2003). LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Human Molecular Genetics, 12, 2417–2430. Burk, C., Hu, S., Lee, C., et al. (2008). Netherton syndrome and trichorrhexis invaginata-a novel diagnostic approach. Pediatric Dermatology, 25, 287–288. Capezzera, R., Venturini, M., Bianchi, D., et al. (2004). UVA1 phototherapy of Netherton syndrome. Acta DermatoVenereologica, 84, 69–70. Chao, S. C., Richard, G., & Lee, J. Y. Y. (2005). Netherton syndrome: Report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5. British Journal of Dermatology, 152, 159–165. Chao, S. C., Tsai, Y. M., & Lee, J. Y. (2003). A compound heterozygous mutation of the SPINK5 gene in a Taiwanese boy with Netherton syndrome. Journal of the Formosan Medical Association, 102, 418–423. Chavanas, S., Bodemer, C., Rochat, A., et al. (2000). Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nature Genetics, 25, 141–142. Chavanas, S., Garner, C., Bodemer, C., et al. (2000). Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. American Journal of Human Genetics, 66, 914–921. De Felipe, I., Vazquez-Doval, F. J., & Vicente, J. (1997). Comel–Netherton syndrome: A diagnostic challenge. British Journal of Dermatology, 137, 468–469.

1517 Hausser, I., & Anton-Lamprecht, I. (1996). Severe congenital generalized exfoliative erythroderma in newborns and infants: A possible sign of Netherton syndrome. Pediatric Dermatology, 13, 183–199. Hedberg, C. L., Hogan, D. J., & Bahna, S. L. (2003). An infant with generalized rash and abnormal hair. Annals of Allergy, Asthma & Immunology, 91, 1–6. Ito, M., Ito, K., & Hashimoto, K. (1984). Pathogenesis in trichorrhexis invaginata (bamboo hair). Journal of Investigative Dermatology, 83, 1–6. Jones, S. K., Thomasson, L. M., Surbrugg, S. K., et al. (1986). Neonatal hypernatraemia in two siblings with Netherton’s syndrome. British Journal of Dermatology, 114, 741–743. Judge, M. R., Morgan, G., & Harper, J. I. (1994). A clinical and immunological study of Netherton’s syndrome. British Journal of Dermatology, 131, 615–621. Krasagakis, K., Ioannidou, D. J., Stephanidou, M., et al. (2003). Early development of multiple epithelial neoplasms in Netherton syndrome. Dermatology, 207, 182–184. Lurie, R., & Garty, B. Z. (1995). Helical hairs: A new hair anomaly in a patient with Netherton’s syndrome. Cutis, 55, 349–352. M€ uller, F. B., Hausser, I., Berg, D., et al. (2002). Genetic analysis of a severe case of Netherton syndrome and application for prenatal testing. British Journal of Dermatology, 146, 495–499. Netherton, E. W. (1958). A unique case of trichorrhexis invaginata ‘bamboo hair’. Archives of Dermatology, 78, 483–487. Powell, J. (2000). Increasing the likelihood of early diagnosis of Netherton syndrome by simple examination of eyebrow hairs. Archives of Dermatology, 136, 423–424. Rakowska, A., Kowalska-Oledzka, E., Slowinska, M., et al. (2009). Hair shaft videodermoscopy in Netherton syndrome. Pediatric Dermatology, 26, 320–322. Sahari, S., Wollery-Lloyd, H., & Nouri, K. (2002). Squamous cell carcinoma in a patient with Netherton’s syndrome. British Journal of Dermatology, 144, 415–416. Saif, G. B., & Al-Khenaizan, S. (2007). Netherton syndrome: Successful use of topical tacrolimus and pimecrolimus in four siblings. International Journal of Dermatology, 46, 290–294. Seraly, M. P., Sheehan, M., Collins, M., et al. (1994). Netherton syndrome revisited. Pediatric Dermatology, 11, 61–64. Shimomura, Y., Sata, N., Kariya, N., et al. (2005). Netherton syndrome in two Japanese siblings with a novel mutation in the SPINK5 gene: Immunohistochemical studies of LEKTI and other epidermal molecules. British Journal of Dermatology, 153, 1026–1030. Smith, D. L., Smith, J. G., Womg, S. W., et al. (1995). Netherton’s syndrome: A syndrome of elevated IgE and characteristic skin and hair findings. The Journal of Allergy and Clinical Immunology, 95, 116–123. Sprecher, E., Chavanas, S., DiGiovanna, J. J., et al. (2001). The spectrum of pathogenic mutations in SPINK5 in 19 amilies with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis. Journal of Investigative Dermatology, 117, 179–187.

1518 Stevanovic, D. V. (1969). Multiple defects of the hair shaft in Netherton’s disease. British Journal of Dermatology, 81, 851–857. Stoll, C., Alembik, Y., Tchomakov, D., et al. (2001). Severe hypernatremic dehydration in an infant with Netherton syndrome. Genetic Counseling, 12, 237–243. Stryk, S., Siegfried, E. C., & Knutsen, A. P. (1999). Selective antibody deficiency to bacterial polysaccharide antigens in

Netherton Syndrome patients with Netherton syndrome. Pediatric Dermatology, 16, 19–22. Sun, J. D., Linden, K. G. (2005). Netherton syndrome: A case report and review of the literature. International Journal of Dermatology, 45, 693–697. Van Gysel, D., Koning, H., Baert, M. R., et al. (2001). Clinicoimmunological heterogeneity in Comel–Netherton syndrome. Dermatology, 202, 99–107.

Netherton Syndrome

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a

c

Fig. 1 A neonate (a) with Netherton syndrome showing erythroderma. The patient had markedly elevated serum total IgE levels of 409 IU/mL at age 8 months and 285 IU/mL at 14 months of age. Molecular genetic analysis of SPINK5 showed a compound heterozygote with a mutation 316DelGA in exon 5 inherited from the mother, and a mutation 2441+1delGTGA in exon 25 inherited from the father. The same patient at age 3 years

b

d

(b) showed generalized erythroderma and marked growth retardation (height age of 7 months and weight age of 4 months). Microscopic analysis of the hair (c and d, lower and higher magnification) showed trichorrhexis invaginata/nodosa (bamboo hair) (pink arrows), pili torti (yellow arrow), and fractured hair shaft at the site of invagination (blue arrow)

Neu–Laxova Syndrome

The Neu–Laxova syndrome is a lethal disorder characterized by multiple congenital malformations. Microcephaly, lissencephaly, absence of corpus callosum, facial anomalies (notably absent eyelids), short broad neck, peripheral edema, ichthyosis, limb anomalies, and other malformations are common findings. The syndrome was described first by Neu et al. in 1971 and Laxova et al. in 1972 (Neu et al. 1971; Laxova et al. 1972).

f. Ichthyotic skin changes: the cause of the deformed limbs, reduced movement, massive edema, and IUGR (Karimi-Nejad et al. 1987; Russo et al. 1989) g. Mechanism of ichthyosis proposed as hypoproteinemia caused by protein leakage through skin fissures as the primary pathogenesis of Neu–Laxova syndrome (Karimi-Nejad et al. 1987) h. It is the restrictive dermopathy that leads the various authors to characterize Neu–Laxova syndrome as a malformation sequence

Genetics/Basic Defects 1. Inheritance: autosomal recessive inheritance (King et al. 1995) 2. Pathogenesis (Coto-Puckett et al. 2010): remains unknown and differing etiologies have been postulated: a. A form of neuroectodermal dysplasia given the CNS and skin findings (Lazjuk et al. 1979; Ejeckam et al. 1986; Muller et al. 1987; Naveed and Sreenivas 1990) b. CNS pathology described as a neuronal migration defect with arrest of development early at 12–14 weeks of embryogenesis (Muller et al. 1987; Ostrovskaya and Lazjuk 1988) c. A neurodegenerative disorder with abnormal cell death causing neuronal atrophy and depletion (Allias et al. 2004) d. Limb deformities: caused by failure of muscle, bone, nerve, and arterial development in early embryogenesis (Shved et al. 1985) e. Contractures: secondary to reduced fetal movements or fetal akinesia/hypokinesis (Fitch et al. 1982; Russo et al. 1989)

Clinical Features 1. Considerable intrafamilial and interfamilial variation in clinical features 2. Prenatal history a. Severe intrauterine growth retardation b. Polyhydramnios 3. Spectrum of skin lesions a. Edema over the dorsum of foot and hand, often associated with hypoplastic phalanges b. Thick, waxy, and stretched in appearance c. Peeling of skin, scaling, and extensive plaque formation over scalp, face, neck, back, and arm d. Translucent flexible membrane covering most of the skin e. Varying degrees of lamellar ichthyosis 4. Craniofacial features a. Receding forehead b. Ocular hypertelorism c. Exophthalmos (protruding eyes) d. Absence of the eyelids e. Flat, abnormal nose

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5.

6.

7.

8.

f. Eclabium g. Cataract h. Micrognathia i. Cleft palate/lip j. Hypodontia k. Low-set, malformed ears CNS abnormalities a. Microcephaly b. Lissencephaly c. Hypoplastic or abnormal cerebellum d. Agenesis or dysgenesis of the corpus callosum e. Decreased or absent gyri f. Dilatation or abnormal ventricles g. Dandy–Walker malformation h. Choroid plexus cysts Limb anomalies a. Deformed digits b. Deformed limbs c. Flexion deformity d. Severe edema of the hands and feet e. Syndactyly f. Rocker-bottom feet Other features a. Short broad neck b. Cystic hygroma c. Subcutaneous edema d. Small thorax e. Hypoplastic or atelectatic lungs f. Small abdomen g. Hypoplastic genitalia h. Short umbilical cord i. Absence of hair j. Muscle atrophy Classification proposed by Curry (1982): may represent heterogeneity of the condition or different grades of severity, representing the wide spectrum of varying expressivity of the heterogeneous condition (Coto-Puckett et al. 2010). a. Group I i. Joint contractures ii. Partial syndactyly iii. Thin scaly skin iv. Mild ichthyosis v. Poor mineralization of bones b. Group II i. Massive swelling of hands and feet ii. More severe ichthyosis

Neu–Laxova Syndrome

iii. Undermineralized bones leading to intrauterine fractures c. Group III i. Hypoplastic digits ii. Most severe ichthyosis (harlequin-like fetus) iii. Short limbs iv. Stick-like long bones 9. Prognosis a. Stillborn b. Die shortly after birth 10. Differential diagnosis a. Harlequin ichthyosis: see the chapter b. Restrictive dermatopathy (dermopathy) (Kulkarni et al. 2006; Khanna et al. 2008) i. A rare autosomal recessive disorder characterized by extreme tautness of the skin causing restricted intrauterine movement and a fetal akinesia deformation sequence ii. Uniformly mostly neonatally fatal iii. Diagnostic findings a) Skin tautness with near absence of the dermal elastic fibers, usually with no or only minor anomalies of the internal organs b) Abnormal face c) Absence of skin cracking (tight skin) d) Absence of skin edema e) Arthrogryposis multiplex iv. Secondary skeletal changes with variable radiographic findings which when present is pathognomonic of restrictive dermatopathy a) Poorly mineralized skull with large fontanelle b) Micrognathia c) Thin dysplastic clavicles d) Ribbon-like ribs e) Overtubulated humerus and forearm bones c. Lethal arthrogryposis with ichthyosis (Thakur et al. 2004) i. A lethal condition with joint contractures ii. Subcutaneous edema, ectropion iii. A severely flattened nose iv. “O”-shaped open mouth v. Extensive peeling of the skin (skin changes of ichthyosis)

Neu–Laxova Syndrome

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Diagnostic Investigations

References

1. Radiography a. Multiple contractures b. Hemivertebrae c. Kyphoscoliosis 2. Histopathology of the skin a. Hyperkeratosis i. With or without parakeratosis ii. Associated with abundant subcutaneous tissue and excess of fat b. Myxomatous connective tissue associated with excess subcutaneous adipose tissue c. Epidermal and dermal atrophy 3. Ultrasound of the brain for CNS anomalies 4. Normal chromosomes

Abdel Meguid, N., & Temtamy, S. A. (1991). Neu Laxova syndrome in two Egyptian families. American Journal of Medical Genetics, 41, 30–31. Allias, F., Buenard, A., Bouvier, R., et al. (2004). The spectrum of type III lissencephaly: A clinicopathological update. Fetal and Pediatric Pathology, 23, 305–317. Aslan, H., Gul, A., Polat, I., et al. (2002). Prenatal diagnosis of Neu–Laxova syndrome: A case report. BMC Pregnancy and Childbirth, 2, 1–4. Coto-Puckett, W. L., Gilbert-Barness, E., Steelman, C. K., et al. (2010). A spectrum of phnotypical expression of Neu–Laxova syndrome: Three case reports and a review of the literature. Fetal and Pediatric Pathology, 29, 108–119. Curry, C. J. (1982). Further comments on the Neu–Laxova syndrome. American Journal of Medical Genetics, 13, 441–444. Driggers, R. W., Isbister, S., McShane, C., et al. (2002). Early second trimester prenatal diagnosis of Neu–Laxova syndrome. Prenatal Diagnosis, 22, 118–120. Durr-e-Sabih, Khan, A. N., & Sabih, Z. (2001). Prenatal sonographic diagnosis of Neu–Laxova syndrome. Journal of Clinical Ultrasound, 29, 531–534. Ejeckam, G. G., Wadhwa, J. K., Williams, J. P., et al. (1986). Neu–Laxova syndrome: Report of two cases. Pediatric Pathology, 5, 295–306. Fitch, N. (1983). Comments on Dr. Curry’s classification of the Neu–Laxova syndrome. American Journal of Medical Genetics, 15, 515–517. Fitch, N., Resch, L., & Rochon, L. (1982). The Neu–Laxova syndrome: Comments on syndrome identification. American Journal of Medical Genetics, 13, 445–452. Gulmezoglu, A. M., & Ekici, E. (1994). Sonographic diagnosis of Neu–Laxova syndrome. Journal of Clinical Ultrasound, 22, 48–51. Hickey, P., Piantanida, E., Lentz-Kapua, S., et al. (2003). Neu–Laxova syndrome: A case report. Pediatric Dermatology, 20, 25–27. Hirota, T., Hirota, Y., Asagami, C., et al. (1998). A Japanese case of Neu–Laxova syndrome. Journal of Dermatology, 25, 163–166. Horn, D., Muller, D., Thiele, H., et al. (1997). Extreme microcephaly, severe growth and mental retardation, flexion contractures, and ichthyotic skin in two brothers: A new syndrome or mild form of Neu–Laxova syndrome? Clinical Dysmorphology, 6, 323–328. Kainer, F., Prechtl, H. F., Dudenhausen, J. W., et al. (1996). Qualitative analysis of fetal movement patterns in the Neu–Laxova syndrome. Prenatal Diagnosis, 16, 667–669. Karimi-Nejad, M. H., Khajavi, H., Gharavi, M. J., et al. (1987). Neu–Laxova syndrome: Report of a case and comments. American Journal of Medical Genetics, 28, 17–23. Khanna, P., Opitz, J. M., & Gilbert-Barness, E. (2008). Restrictive dermopathy: Report and review. Fetal and Pediatric Pathology, 27, 105–118. King, J. A. C., Blackburn, W., Chen, H., et al. (1995). Neu–Laxova syndrome: Pathological evaluation of a fetus and review of the literature. Pediatric Pathology & Laboratory Medicine, 15, 57–79.

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: a lethal entity not surviving to reproductive age 2. Prenatal ultrasonography (Durr-e-Sabih et al. 2001; Rode et al. 2001) a. Severe growth retardation: a major feature b. Polyhydramnios c. Microcephaly/deficient calvarial ossification d. CNS abnormalities e. Abnormal facies including receding forehead f. Exophthalmos g. Cataract h. Cystic hygromas i. Pulmonary hypoplasia j. Contractures k. Excessive edema of the hands and feet l. Syndactyly m. Clubbing of the feet n. Absence of breathing movements, sucking, swallowing, or normal isolated arm and leg movements o. Restricted fetal movement 3. Management a. No specific treatment for the uniformly lethal disorder b. Mainly supportive with initial management of ventilatory, thermal, and nutritional support

1524 Kulkarni, M. L., Shetty, K. S., Chandrasekar, V. K., et al. (2006). Restrictive dermatopathy: A lethal congenital dermatosis and review of literature. American Journal of Medical Genetics, 140A, 294–297. Laxova, R., Ohdra, P. T., & Timotthy, J. A. D. (1972). A further example of a lethal autosomal recessive condition in sibs. Journal of Mental Deficiency Research, 16, 139–143. Lazjuk, G. I., Lurie, I. W., Ostrowskaja, T. I., et al. (1979). Brief clinical observations: The Neu–Laxova syndrome–a distinct entity. American Journal of Medical Genetics, 3, 261–267. Manning, M. A., Cunniff, C. M., Colby, C. E., et al. (2004). Neu–Laxova syndrome: Detailed prenatal diagnostic and post-mortem findings and literature review. American Journal of Medical Genetics, 125A, 240–249. Meguid, N. A., & Temtamy, S. A. (1991). Neu–Laxova syndrome in two Egyptian families. American Journal of Medical Genetics, 41, 30–31. Monaco, R., Stabile, M., Guida, F., et al. (1992). Echographic, radiological and anatomo-pathological evaluation of a foetus with Neu–Laxova syndrome. Australasian Radiology, 36, 51–53. Mueller, R. F., Winter, R. M., & Naylor, C. P. (1983). Neu–Laxova syndrome: Two further case reports and comments on proposed subclassification. American Journal of Medical Genetics, 16, 645–649. Muller, L. M., de Jong, G., Mouton, S. C., et al. (1987). A case of the Neu–Laxova syndrome: prenatal ultrasonographic monitoring in the third trimester and the histopathological findings. American Journal of Medical Genetics, 26, 421–429. Naveed, M. C. S., & Sreenivas, V. (1990). New manifestations of Neu–Laxova syndrome. American Journal of Medical Genetics, 35, 55–59.

Neu–Laxova Syndrome Neu, R. L., Kajii, T., Gardner, L. I., et al. (1971). A lethal syndrome of microcephaly with multiple congenital anomalies in three siblings. Pediatrics, 47, 610–612. Ostrovskaya, T. I., & Lazjuk, G. I. (1988). Cerebral abnormalities in the Neu–Laxova syndrome. American Journal of Medical Genetics, 30, 747–756. Rode, M. E., Mennuti, M. T., Giardine, R. M., et al. (2001). Early ultrasound diagnosis of Neu–Laxova syndrome. Prenatal Diagnosis, 21, 575–580. Russo, R., D’Armiento, M., Martinelli, P., et al. (1989). Neu–Laxova syndrome: Pathological, radiological, and prenatal findings in a stillborn female. American Journal of Medical Genetics, 32, 136–139. Scott, C. I., Louro, J. M., Laurence, K. M., et al. (1981). Comments on the Neu–Laxova syndrome and CAD complex. American Journal of Medical Genetics, 9, 165–175. Shapiro, I., Borochowitz, Z., Degani, S., et al. (1992). Neu–Laxova syndrome: Prenatal ultrasonographic diagnosis, clinical and pathological studies, and new manifestations. American Journal of Medical Genetics, 43, 602–605. Shivarajan, M. A., Suresh, S., Jagadeesh, S., et al. (2003). Second trimester diagnosis of Neu–Laxova syndrome. Prenatal Diagnosis, 23, 21–24. Shved, I. A., Lazjuk, G. I., & Cherstvoy, E. D. (1985). Elaboration of the phenotypic changes of the upper limbs in the Neu–Laxova syndrome. American Journal of Medical Genetics, 20, 1–11. Thakur, S., Pai, L., & Phadke, S. R. (2004). Lethal arthrogryposis with ichthyosis: Overlap with Neu–Laxova syndrome, restrictive dermopathy and harlequin fetus. Clinical Dysmorphology, 13, 117–119.

Neu–Laxova Syndrome

Fig. 1 An infant with Neu–Laxova syndrome showing severe ichthyosis (thick, cracked skin lesions forming deep fissures), characteristic facial features (absent eyelids, flattened nose, round gaping mouth, low-set ears with poorly developed pinnae), short broad neck, flexion contractures of the limbs, and short, small-caliber umbilical cord. Photomicrographs of skin (not shown) demonstrated a prominent hyperkeratosis of the epidermis and a thick layer of subcutaneous adipose tissue due to edema

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1526 Fig. 2 (a, b) Radiographs showing hemivertebrae, kyphoscoliosis, and 11 pairs of ribs

Neu–Laxova Syndrome

a

b

Neural Tube Defects

Neural tube defects (NTDs) are among the most common severe congenital malformations of the central nervous system. Approximately 1 in 500 to 1 in 1,000 pregnancies result in NTDs. About 4,000 fetuses are affected each year in the USA. The incidence varies with geographic areas and ethnic groups. The incidence, however, appears to be decreasing recently.

Synonyms and Related Disorders Anencephaly; Cranial meningocele; Cranio/spinal rachischisis; Cranium bifidum occultum; Encephalocele; Iniencephaly; Spina bifida

Genetics/Basic Defects 1. Caused by a defect in closure of the neural tube, which is normally closed by 28 days 2. Etiology: complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. 3. Specific causes are identified in less than 10% of affected infants. a. Chromosomal abnormalities b. Single gene mutations c. Teratogens 4. Defects in the neural tube closure linked to 5,10methylenetetrahydrofolate reductase deficiency and defects in the metabolism of folic acid 5. Low erythrocyte folate in the first trimester of pregnancy: associated with an increased risk of neural tube defects

6. Mildly elevated homocysteine in some pregnant women who subsequently give birth to infants with NTDs (Akar 2000) 7. Genetic factor: MTHFR C677T polymorphism: a specific mutation known as C677T polymorphism a. More common in parents of children affected with NTDs b. This polymorphism affects the enzyme methylenetetrahydrofolate reductase (MTHFR), causing it to require more folic acid to work properly 8. Major epidemiologic finding in NTDs: the protective effect of perinatal folic acid supplementation that reduces risk by 60–70% 9. Genetic studies in NTDs a. Have focused mainly on folate-related genes and identified a few significant associations between variants in these genes and an increased risk for NTDs b. However, we are witnessing a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the development of whole genome innovative technologies and the powerful tool of animal models (Bassuk and Kibar 2009).

Clinical Features There are several morphologic types of NTDs: open NTDs (anencephaly, cranial or spinal rachischisis, iniencephaly, meningomyelocele, cranioectomesodermal hypoplasia), closed NTDs (cranial meningocele, cranial encephalocele, spinal meningocele alone or with spinal cord abnormality), and myelocystocele.

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1. Anencephaly a. Refers to an absence of the brain and the calvarium covering the brain b. The most severe form of NTDs c. Incidence: about 1/1,000 live births d. Responsible for about 50% of all NTDs e. Infants with anencephaly i. Stillborn ii. Die shortly after birth f. Anterior pituitary, eyes, and brainstem usually spared g. Remaining tissue covering the basal cranium: a highly vascular and friable membrane referred to as area cerebrovasculosa h. Striking craniofacial appearance i. Absent cranial vault ii. An angiomatous membranous mass lying on the floor of the cranium iii. An absent or backward sloping of the forehead iv. Frog-like eyes (ocular proptosis) v. Puffy eyelids vi. A flattened nose vii. Large folded-down ears viii. Often an open mouth ix. A short neck i. Syndromes associated with anencephaly i. Chromosomal disorders [e.g., r(13), trisomy 18, del(13q)] ii. Monogenic disorder (e.g., Meckel syndrome) iii. Disruptive sequences (e.g., amniotic bands, maternal hyperthermia) iv. Associations (e.g., spina bifida, holoprosencephalic face syndrome, craniofacial duplication) 2. Craniorachischisis or spinal rachischisis a. Rachischisis: refers to anencephaly with a contiguous spinal defect involving at least the cervical spine region and extending for varying degrees down the spinal column b. The area cerebrovasculosa and the area medullovasculosa fill the skeletal defects of the cranium and of the spinal column. c. Short neck d. Upward-turned face e. Ears touching the shoulders f. Frequent polyhydramnios g. Frequently stillborn

Neural Tube Defects

h. Neurologic involvement i. Primarily limited to brainstem and spinal reflexes ii. Occasional seizures resembling infantile spasms 3. Iniencephaly (Balci et al. 2001) a. The name iniencephaly derived from an abnormality of the neck (inion) and the brain (cephaly) b. Triad i. Deficient cranial bone ii. Cervical dysraphism (rachischisis) iii. Fixed retroflexion of the fetal head and severe lordosis of the cervicothoracic spine c. Closed or open lesions i. A closed lesion when the occipital bone is not malformed ii. An open lesion when the occipital bone is hypoplastic d. Site of the neural tube lesion: at the level of the cervical spine e. Severity of lesion i. Spina bifida with intact skin ii. Meningomyeloencephalocele iii. Open rachischisis f. Associated CNS malformations i. Anencephaly ii. Encephalocele iii. Microcephaly iv. Hydrocephaly v. Holoprosencephaly vi. Posterior fossa defects vii. Spinal defects such as cervical dysraphism viii. Fixed cervical hyperlordosis g. Other associated malformations i. Diaphragmatic hernia ii. Omphalocele iii. Thoracic cage deformities iv. Hypoplastic lungs v. Genitourinary malformations vi. Cyclopia vii. Cleft lip and palate viii. Imperforate anus ix. Clubfoot x. Single umbilical artery h. Die within a few hours in most newborns 4. Cranium bifidum occultum a. The most benign type b. Generally asymptomatic c. Skull defects often close over time

Neural Tube Defects

d. Persistent parietal foramina (sometimes called “Caitlin marks” after the family for which it was described; transmitted as an autosomal dominant trait via a gene located on 11p) e. Persistent wide fontanelle 5. Cranial meningocele a. Associated with a defect in the skull b. Associated with protrusion of the leptomeninges 6. Encephalocele a. A type of cephalocele (a herniation of cranial contents though a skull defect) that contains brain b. Incidence: 1/10,000 live births c. Occurring most frequently in the occipital region (80–90%) and commonly associated with a variety of syndromes, notably Meckel–Gruber syndrome and Walker–Warburg syndrome d. Anterior encephaloceles: found more commonly in Roberts syndrome e. An isolated malformation of frontal encephalocele: more commonly seen in southeast Asia f. Outcome depending on the position of the defect and on the associated anomalies g. Chromosome syndromes associated with encephalocele i. Trisomy 13 ii. Trisomy 18 iii. Del(13q) iv. Del(2)(q21 ! q24) v. Dup(1q) vi. Dup(6) (q21 ! qter) vii. Dup(7)(qter ! p11) viii. Dup(8)(q23 ! qter) ix. Turner syndrome h. Monogenic disorders associated with encephalocele i. Meckel syndrome ii. Cryptophthalmos syndrome iii. Silverman–Handmaker type and Rolland–Desbuquois type of dyssegmental dysplasias iv. Knobloch syndrome v. Chemke syndrome vi. Roberts syndrome vii. Walker–Warburg syndrome viii. van Voss–Cherstovy syndrome i. Disruptive sequences associated with encephalocele i. Maternal hyperthermia ii. Warfarin embryopathy iii. Amniotic bands

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j. “Associations” associated with encephalocele i. Absent corpus callosum ii. Dandy–Walker malformations iii. Arnold–Chiari malformation iv. Holoprosencephaly v. Craniosynostosis vi. Ectrodactyly vii. Frontonasal dysplasia viii. Hypothalamic-pituitary dysfunction ix. Klippel–Feil anomaly x. Iniencephaly xi. Myelomeningocele xii. Oculoauriculovertebral spectrum 7. Spina bifida cystica (the most common lesion) a. Myelomeningoceles (meningomyeloceles) i. A herniation of the spinal cord and/or nerves through a bony defect of the spine ii. Usually open defects in which meninges and/or neural tissue is exposed to the environment associated with leaking CSF iii. The most common type of spina bifida cystica (about 90%) iv. Approximately 20% of affected infants have additional congenital anomalies, such as gastrointestinal, cardiac, and urogenital malformations. v. Surviving infants with spina bifida likely have severe, lifelong disabilities, and psychosocial maladjustment. vi. Medical problems a) Paralysis b) Hydrocephalus c) Arnold–Chiari type II malformation (herniation of the cerebellar vermis and brainstem below the foramen magnum) d) Endocrine abnormalities e) Tethered cord f) Syringomyelia (cavitation of the spinal cord whose walls are composed of glial tissue) g) Syringobulbia h) Deformed limbs and spine i) Bladder/bowel/sexual dysfunction j) Learning disabilities vii. Neonates with Arnold–Chiari malformation presenting with: a) Stridor secondary to vocal cord paralysis b) Central apnea c) Aspiration

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d) Dysphagia e) Hypotonia f) Progressive brainstem dysfunction g) Myelopathy h) Quadriparesis i) Nystagmus j) Strabismus k) Poor sucking l) Swallowing difficulties b. Meningoceles i. A saccular herniation of meninges and CSF through a bony defect of spine and usually covered by normal skin ii. No herniation of the spinal cord or nerve roots into the dorsal dural sac iii. A cystic mass full of cerebrospinal fluid iv. Without associated neurologic problems such as hydrocephalus and Chiari II malformation c. Lipomeningocele or lipomyelomeningocele i. A lipomatous mass herniating through the bony defect and attaching to the spinal cord, tethering the cord and often its nerve roots ii. Presentation with a skin-covered mass above the buttocks and eventual neurologic deficits iii. Absent associated hydrocephalus d. Myelocystocele i. A large terminal cystic dilatation of the spinal cord secondary to hydromyelia giving rise to a large terminal skin-covered sac ii. Constituting 4–6.5% of the skin-covered masses overlying the lower spine iii. The majority of cases are dorsally located; only rarely (about 0.5%) are ventral in location iv. The ventral type is an anterior sacral meningocele, most often presenting as a pelvic mass in females v. Cervical myelocystocele vi. Lumbar myelocystocele vii. Terminal myelocystoceles accompanying midline abdominal and pelvic defects such as part of the OEIS (omphaloceleexstrophy of the bladder-imperforate anusspinal defects) complex viii. Chiari malformation less frequent since the lesion is covered by dura with regular hydrodynamics of the cerebrospinal fluid ix. Other associated malformations a) Genitourinary tract anomalies

Neural Tube Defects

b) Intestinal malrotation c) Club feet x. Differential diagnoses a) Meningomyelocele b) Lumbosacral and sacrococcygeal teratomas c) Lipomas d) Lipomyelomeningoceles e) Hamartomas e. Lifelong disability risks in infants with spina bifida i. At risk for psychosocial maladjustment ii. Medical problems resulting from the neurologic defects or from its repair a) Paralysis b) Hydrocephalus c) Arnold–Chiari malformation d) Endocrine abnormalities e) Tethered cord f) Syringomyelia g) Syringobulbia iii. Medical problems as sequelae of the neurologic deficits a) Deformations of the limbs and spine b) Bowel, bladder, and sexual dysfunction c) Learning disabilities 8. Spina bifida occulta a. A bony defect of the spine occurs most often at S1 and/or S2 and is covered by normal skin (a closed lesion) b. No herniation of the meninges through the bony defect c. Without associated hydrocephalus or Chiari II malformations d. Paraspinal cutaneous lesions with high index of suspicion pointing towards the underlying spina bifida (Drolet 2000) i. Hypertrichosis or hairy patches ii. Lumbosacrococcygeal dimples and sinuses iii. Acrochordons (skin tags): a small, fleshcolored to dark brown, sessile or pedunculated lesion consisting of a hyperplastic epidermis enclosing a dermal stalk of connective tissue iv. True tails: a caudal midline appendage capable of spontaneous or reflex motion consisting of skin covering muscle, adipose, connective tissue, blood vessels, and nerves but lack vertebrae and abnormal tissue

Neural Tube Defects

v. Pseudotails: a caudal protrusion composed of adipose (lipoma), teratomatous elements, or cartilage vi. Lipomas vii. Hemangiomas: indicator for tethered cord syndrome viii. Aplasia cutis congenita (congenital absence of skin) or scar ix. Dermoid cyst or sinus: 12–35% of children with spina bifida occulta have sacrococcygeal dermoid cysts or sinuses, which rarely connect with the intraspinal canal. Lesions above these levels along the spine are more likely to connect with the intraspinal canal and increasingly associated with spina bifida occulta. e. Paraspinal cutaneous lesions with low index of suspicion (Drolet 2000) i. Telangiectasia ii. Capillary malformation (port-wine stain) iii. Hyperpigmentation (lentigines or cafe´-aulait-like lesions) iv. Melanocytic nevi v. Teratomas: most common in the sacrococcygeal region in infancy f. Neurologic deficits (Ellenbogen 2001) i. Weakness of leg or legs ii. Leg atrophy or asymmetry iii. Loss of sensation iv. Painless sores v. Hyperreflexia vi. Unusual back pain vii. Abnormal gait viii. Radiculopathy ix. Neurogenic bladder x. Incontinence 9. Multiple NTDs at different sites (Ahmad et al. 2008): The presence of meningomyelocele and/or encephaloceles at multiple (two or more) sites along the vertebral axis is a very rare event occurring in 1% of cases a. Double NTDs b. Triple NTDs

Diagnostic Investigations 1. Neurological examination of neonates a. Size, site, and level of the lesion b. Motor and sensory level

1531

2. 3.

4.

5.

c. Presence of associated hydrocephalus d. Presence of associated symptomatic hindbrain herniation such as Chiari II malformation e. Presence of associated orthopedic deformity Neonatal cranial ultrasonography to demonstrate hydrocephalus Radiography a. Occult spinal disorders in children (Ellenbogen 2001) i. Lamina defects ii. Hemivertebrae iii. Scoliosis iv. Widening of interpedicular distance v. Butterfly vertebrae b. Generally to detect bony defects CT a. Cranial defects b. Spinal defects MRI: provide exquisite detail of both the cranial defect and the herniated contents a. Cranial defects b. Cerebral defects i. Hydrocephalus ii. Gray matter heterotopia iii. Schizencephaly iv. Gyral abnormalities v. Agenesis and thinning of the corpus callosum vi. Abnormal thalami vii. Abnormal white matter c. Herniated contents in Chiari malformations d. Associated lesions i. Diastematomyelia ii. Syringomyelia iii. Hydromyelia iv. Tethered cord

Genetic Counseling 1. Recurrence risk a. Affected first-degree relatives i. 1 sib affected (5%) ii. 2 sibs affected (10%) iii. 3 sibs affected (21%) iv. 1 parent affected (3–4.5%) v. 1 parent and 1 sib affected (13%)

1532

b. Affected second-degree relative: uncle/aunt, half sib (2%) c. Third-degree relative: first cousin (1% or less) 2. Prenatal diagnosis (Cameron and Moran 2009) a. Risk assessment prior to biochemical and/or ultrasonic screening i. The most significant risk factor: a history of having a previous child affected with neural tube defect ii. Other independent (nongenetic) risk factors (Cameron and Moran 2009; Copp and Greene 2010) a) Valproic acid b) Folic acid antagonists (methotrexate, aminopterin, carbamazepine, fumonisin, trimethoprim) c) Vitamin A d) Maternal diabetes e) Maternal obesity f) Hyperthermia g) Micronutrient deficiencies (folate, inositol, vitamin B12, zinc) b. Two approaches used for NTD screening in lowrisk population i. Biochemical testing of maternal blood for alpha-fetoprotein (AFP) a) Measurement of maternal serum alphafetoprotein (MSAFP): a useful tool for mass screening of pregnant women for NTDs b) All cases of anencephaly and about 65% of cases of spina bifida are identified by measurement of MSAFP and ultrasonography. c) Not effective in closed NTDs (10% of lesions) which do not increase AFP d) AFP needs to be expressed as multiples of the median (MoM), since the maternal serum level of AFP varies with gestation. e) Using 2.5 MoM as screen positive in singleton pregnancies, the detection rate for anencephaly is expected to be >95% and for open NTD between 65% and 80%. f) False-positive rates should lie between 1% and 3% (Bradley et al. 2005). A raised serum AFP is not diagnostic for open NTD as it can be associated with other abnormalities including gastroschisis, omphalocele, congenital nephrosis, and fetal demise.

Neural Tube Defects

ii. Use of 2D/3D ultrasonography a) Used both as a screening test and as a follow-up test after positive results on MSAFP screening b) First trimester detection rates for anencephaly and encephalocele: typically quoted as >90% for anencephaly and encephalocele and lower rates for spina bifida (44%) c) Second trimester scanning improves the detection of spina bifida, typically to 92–95% d) Direct demonstration of the spinal defect e) Indirect signs: lemon sign (referring to a symmetrical bifrontal narrowing of the skull) and banana sign (cerebellar abnormality) f) Carefully evaluate the whole fetus because of associated malformations in around 20% (Stoll et al. 2007) iii. Fetal MRI (Saleem et al. 2009) a) An important adjunct to US in assessing NTD b) Can identify topography and contents of sacs, add CNS and non-CNS findings c) Influence management decision c. Prenatal diagnosis of iniencephaly by careful sonography i. Marked fixed retroflexion of the head and neck ii. Rachischisis iii. Extreme lordosis of the fetus d. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE): confirmatory tests for spina bifida 3. Management: complex and challenging a. Prevention i. Folic acid supplementation of 0.4 mg/day to all women capable of becoming pregnant: decrease the first occurrence of NTDs by at least 40% ii. Folic acid supplementation of 4 mg/day in families with previous children born with NTDs: decrease risk of recurrence by 70% iii. Periconceptional use of folic acid supplementation will prevent 50–70% of NTDs. b. Medical management i. Antibiotic prophylaxis to prevent meningitis and ventriculitis

Neural Tube Defects

ii. Urological management iii. Management of rectal incontinence iv. Preventable conditions a) Urinary tract infections b) Calculi c) Skin ulcerations d) Latex allergy and sensitization c. Surgical treatment i. Closing all but the prognostically worst cases ii. Concurrent shunting of coexisting hydrocephalus often necessary iii. Decompression of the posterior fossa and/or cervical cord in Chiari II malformations iv. Spina bifida occulta: prophylactic surgical repair more effective than waiting for patients to experience a significant neurologic deficit such as a neurogenic bladder or leg weakness from these occult spinal lesions v. Orthopedic management of scoliosis d. Fetal spina bifida repair (Fichter et al. 2008) i. Several reports of intrauterine repair of meningomyelocele with benefits to motor function and a decreased incidence of shunt-dependent hydrocephalus and a reversal of hindbrain herniations ii. Especially fetuses treated before 26 weeks of gestational age, with small ventricles (95% 12. Presymptomatic/preconceptional genetic testing: molecular characterization in familial and in sporadic cases 13. Limitation of genetic testing a. Lack of genotype–phenotype correlations: A positive test will not predict disease severity or outcome b. Two exceptions i. Complete loss of the NF1 gene along with multiple contiguous genes

1554

Neurofibromatosis I

a) Occurs in 4–5% of patients with NF1 (Kluwe et al. 2004) b) Patients with whole gene deletion present with a very large neurofibroma burden, more severe cognitive impairment, large hands and feet, dysmorphic facial features, and have a higher lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST) (Leppig et al. 1997; De Raedt et al. 2003). ii. A 3-base pair in-frame deletion in exon 17 of the NF1 gene: Patients with this genetic mutation have an absence of cutaneous neurofibromas and appear to have a lower incidence of serious complications.

Genetic Counseling 1. Recurrence risk a. Patient’s sibling i. Risk not increased unless a parent is affected or has gonadal mosaicism. ii. If a parent is affected, the risk to the sibs is 50%. iii. Possibility of germ-line mosaicism in a clinically normal parent: recurrence risk based on the percentage of the germ-line mosaicism b. Patient’s offspring i. Risk: 50% of inheriting the disease with extremely variable disease manifestations ii. Risk of having a child with NF1 in a patient affected with segmental NF1 a) A small but greater than the general population risk b) Some cases of segmental NF1 apparently being “transmitted” to offspring; the mechanism (if one exists) behind this is unclear (Boyd et al. 2009). c) Segmental neurofibromatosis is believed to be due to somatic mosaicism for a mutation in the NF gene. The mutation occurred postconceptionally and present in the limited population of cells. Gonadal cells may or may not have a mutation (Dupuis and Nezarati 2001). 2. Prenatal diagnosis a. Influence of knowledge of the disease in the reproductive decisions of affected individuals (Ars et al. 1999)

i. Interest in prenatal test by 41% of the subjects considering becoming pregnant ii. Only 10% considering terminating an affected pregnancy b. Prenatal diagnosis of NF1 difficult to be made in the past due to the following reasons (Vitale et al. 2002): i. Large size of the NF1 gene ii. Lack of any hotspots where the mutations arise iii. Variable expression even within members of a family with NF1 iv. Lack of a tight genotype–phenotype correlation v. High spontaneous mutation rate c. Currently available prenatal diagnosis i. Direct characterization of the mutation from a parent affected by NF1 ii. Analysis of the genomic DNA mutation from the fetus either by amniocentesis or CVS iii. Indirect linkage analysis to familial cases using informative polymorphic markers iv. Protein truncation test v. Fluorescence in situ hybridization d. Molecular diagnosis, unfortunately, cannot predict clinical expression of the disease in the fetus. 3. Management a. Developmental assessment in children b. Medical management for itching, pain, depression, and other psychological and social problems c. Treatment of hypertension depending on the etiology i. Pheochromocytomas ii. Renal artery stenosis d. Laser or electrocautery for small discrete cutaneous or subcutaneous neurofibromas e. Surgical resection of tumors i. Resection of neurofibromas pressing on vital structures, obstructing vision, or rapidly growing lesions causing irritation, discomfort, and pain ii. Plexiform neurofibromas: extremely difficult to approach surgically and often recur after resection because of residual cells resting deeply in the soft tissues iii. Resection of spinal cord tumors: quite difficult but often is necessary to prevent progressive paraplegia or quadriplegia

Neurofibromatosis I

f. Surgical treatment of disfigurement i. Excision of multiple neurofibromas ii. Reconstructive surgery for plexiform neurofibromas g. Orthopedic care indicated for rapidly progressive scoliosis and for some severe bony defects h. Optic pathway gliomas in most children with NF1 (Jett and Friedman 2010) i. Usually do not require treatment ii. Chemotherapy is the treatment of choice for progressive tumors. iii. Surgical treatment: reserved for cosmetic palliation in a blind eye iv. Radiotherapy usually avoided because of the risk of inducing malignancy or moyamoya in the exposed field i. Treatment of congenital pseudarthrosis of the tibia: challenging (Vitale et al. 2002) i. Bracing mainly of early treatment before fracture develops ii. A knee-ankle-foot-orthosis when weight bearing iii. Intramedullary rod fixation, often in combination with autogenous bone grafting of the pseudarthrosis site j. Advise high-risk pregnancy care to pregnant patient with neurofibromatosis i. Maternal hypertension ii. Aggravating features of neurofibromatosis

References American Academy of Pediatrics Committee on Genetics. (1995). Health supervision for children with neurofibromatosis. Pediatrics, 96, 368–372. Ars, E., Kruyer, H., Gaona, A., et al. (1999). Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation. Prenatal Diagnosis, 19, 739–742. Barker, D., Wright, E., Nguyen, K., et al. (1987). Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science, 236, 1100–1102. Benjamin, C. M., Colley, A., Donnai, D., et al. (1993). Neurofibromatosis type 1 (NF1): Knowledge, experience, and reproductive decisions of affected patients and families. Journal of Medical Genetics, 30, 567–574. Blickstein, I., Lancet, M., & Shoham, Z. (1989). The obstetric perspective of neurofibromatosis. American Journal of Obstetrics and Gynecology, 158, 385–388, Comment in 161:501. Boyd, K. P., Korf, B. R., & Theos, A. (2009). Neurofibromatosis type 1. Journal of the American Academy of Dermatology, 61, 1–16.

1555 Brasfield, R. D., & DasGupta, T. K. (1972). Van Recklinghausen’s disease. A clinicopathological study. Annals of Surgery, 175, 86–104. Brems, H., Beert, F., de Ravel, T., et al. (2009). Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. The Lancet Oncology, 10, 508–515. Brems, H., Chmara, M., Sahbatou, M., et al. (2007). Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genetics, 39, 1120–1126. Carey, J. (1992). Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatric Clinics of North America, 39, 25–53. Carey, J. C., Baty, B. J., Johnson, J. P., et al. (1986). The genetic aspects of neurofibromatosis. Annals of the New York Academy of Sciences, 486, 45–56. Carey, J. C., Laub, J. M., & Hall, B. D. (1979). Penetrance and variability in neurofibromatosis: A genetic study of 60 families. Birth Defects, 15(5B), 271. Cnossen, M. H., Moon, K. G. M., Garssen, M. P. J., et al. (1998). Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 children 8 large cafe´-au-lait spots, bilateral axillary freckling, several cutaneous, intradermal, and subcutaneous neurofibromas. A heterozygous missense alteration in exon 13 of the NF1 gene was identified

d

(c.2072 T>C) (p.Leu691Pro). The 2-year and 3-month-old daughter was found to have multiple cafe´-au-lait spots with a single neurofibroma on the right scalp

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Fig. 18 A 14-month-old infant was seen because of multiple cafe´-au-lait spots without neurofibroma. A splice mutation was identified in the NF1 gene, 6641 + 1 G > T, leading to skipping of exon 35. This finding confirms the diagnosis of NF1 in this patient

Neurofibromatosis I

Fig. 19 A 13-year-old boy with multiple cafe´-au-lait spots, axillary freckles, and small neurofibromas throughout the body. The molecular study revealed a recurrent deep intronic splicing mutation in the NF1 gene (c.5749 + 322 A > G). This mutation leads to missplicing of intron 30. This finding confirms the diagnosis of neurofibromatosis I

Neurofibromatosis 2

Historically, neurofibromatosis 2 (NF2) has been previously known as bilateral acoustic neurofibromatosis or central neurofibromatosis. It has frequently been confused with the more common neurofibromatosis 1 (NF1), also known as von Recklinghausen disease or peripheral neurofibromatosis (MacCollin and Mautner 1998). Gardner and Frazier in 1930 were the first to persuasively argue that bilateral vestibular tumors can be clinically and pathologically distinguished from both von Recklinghausen neurofibromatosis and from sporadic tumors from studying a large family with 38 affected members over five generations. The first clear description of NF2 was made by Wishart in 1822 (Wishart 1822). NF2 occurs in about 1 in 25,000 live births.

Synonyms and Related Disorders Bilateral acoustic neurinoma; Bilateral acoustic neurofibromatosis; Bilateral acoustic Schwannomas; Central neurofibromatosis

Genetics/Basic Defects 1. An autosomal dominant disorder: resulting from a mutation in the NF2 tumor suppressor gene on chromosome 22q12 (Asthagiri et al. 2009) a. Truncating mutations (nonsense and frameshifts): most frequent germ line event causing the most severe disease b. Single and multiple exon deletions are also common.

2. NF2 tumor suppressor gene: consists of 17 exons that encode for a 69-kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin (Rouleau et al. 1993; Trofatter et al. 1993) 3. Consistent with Knudson’s two-hit hypothesis for tumorigenesis (tumor formation initiates when both alleles of this gene are inactivated) (Knudson 1971) a. Patients inherit a germ line mutation of one affected allele from a parent or acquire a de novo mutation of an allele at the postzygotic stage of embryogenesis. b. Subsequent development of tumors in susceptible target organs, such as nervous system, eyes, and skin, from cells that lose function of the wild-type (normal) NF2 allele. 4. Abnormal or absent merlin function can disrupt tumor suppression in NF2. 5. High frequency of somatic mosaicism in patients with de novo mutations (Kluwe and Mautner 1998; Moyhuddin et al. 2003; Evans et al. 2007) a. Mutation takes place after conception in patients with mosaicism, resulting in two separate cell lineages. b. Patients with mosaicism tend to have mild generalized or even localized disease (e.g., unilateral vestibular schwannoma with ipsilateral tumors). c. Only a portion of the germ cells in a person with NF2 mosaicism are likely to carry the mutation. i. Risk of transmission to offspring will be less than the expected one in two (50%) for an inherited mutation. ii. Children who inherit the mutation from a mosaic parent will probably have more severe disease than will the parent because the mutation will be present in all their somatic cells.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_179, # Springer Science+Business Media, LLC 2012

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Clinical Features 1. Young adulthood (age 20–30 years) (Asthagiri et al. 2009) a. Hearing loss from a vestibular schwannoma, often unilateral initially b. Accompanied symptoms i. Tinnitus ii. Dizziness iii. Imbalance c. A significant proportion of cases (20–30%) present with i. Headaches and/or seizures from an intracranial meningioma ii. Pain, muscle weakness, and/or paresthesia from spinal tumor iii. Cutaneous tumor induced symptoms 2. Children (up to 30%) a. May present with the same symptoms as adults b. More frequently present with the following: i. Visual disturbance a) Cataract b) Hamartomas c) Intracranial tumors ii. Skin tumors iii. Mononeuropathy a) Facial paresis b) Foot drop iv. Symptomatic spinal cord tumors v. Non-vestibular intracranial tumors 3. Lesions associated with NF2 a. Neurological lesions i. Bilateral vestibular schwannomas (90–95%) ii. Other cranial nerve schwannomas (24–51%) iii. Intracranial meningiomas (45–58%) iv. Spinal tumors (63–90%) a) Extramedullary tumors (55–90%) b) Intramedullary tumors (18–53%) v. Peripheral neuropathy (66%) b. Ophthalmological lesions i. Cataracts (60–81%) ii. Epiretinal membranes (12–40%) iii. Retinal hamartomas (6–22%) c. Cutaneous lesions i. Skin tumors (59–68%) ii. Skin plaques (41–48%)

Neurofibromatosis 2

iii. Subcutaneous tumors (43–48%) iv. Intradermal tumors (rare) 4. Diagnostic criteria for NF2 including the NIH criteria with additional criteria (Manchester criteria which expanded the previous NIH diagnostic criteria and were designed to include patients with neither a family history of NF2 nor bilateral vestibular schwannomas, but who had multiple schwannomas or meningiomas). (Evans et al. 2005; Evans 2009a, b; Asthagiri et al. 2009) a. Major criteria i. Bilateral vestibular schwannomas or ii. First degree family relative with NF2 plus unilateral vestibular schwannoma or two NF2-associated lesions (meningioma, glioma, neurofibroma, schwannoma, or cataract) b. Additional criteria i. Unilateral vestibular schwannoma plus any two NF2-associated lesions (meningioma, glioma, neurofibroma, schwannoma, or cataract), or ii. Multiple meningiomas plus unilateral vestibular schwannoma or two other NF2associated lesions (glioma, neurofibromas, schwannoma, or cataract) 5. Patient populations at risk for NF2 (Evans et al. 2005) a. First-degree relative with NF2 (affected parent, sibling, or children) b. People younger than age 30 years with a unilateral vestibular schwannoma or meningiomas c. People with multiple spinal tumors (schwannomas, meningiomas) 6. Recommended intervals for screening children of an affected parent (Evans et al. 2005) a. Ophthalmological examination yearly from infancy b. Neurological examination yearly from infancy c. Audiology with auditory brain stem evoked potentials yearly from infancy d. Presymptomatic genetic testing: one test from 10 years of age e. Cranial MRI at 10–12 years of age f. Spinal MRI at 10–12 years of age (every 2–3 years) g. For presymptomatic genetic testing, cranial MRI, and spinal MRI, screening may start

Neurofibromatosis 2

7.

8. 9.

10.

earlier than age 10 years in severely affected families and families in which early detection of disease would aid family preparation for future events related to NF2. Variable expressivity of NF2 among individuals a. Varying size, location, and number of tumors. b. Although these tumors are not malignant, their anatomical location and multiplicity lead to great morbidity and early mortality. c. The average age of death is 36 years. d. Actuarial survival from the time of establishing the correct diagnosis is 15 years. e. Survival is improving with earlier diagnosis and better treatment in specialty centers (Baser et al. 2002; Evans et al. 2005). f. Underrecognized in children in whom skin tumors and ocular findings may be the first manifestations (NF2 is usually considered an adult-onset disease). Penetrance: 100% Differential diagnosis a. Main differential diagnosis of NF2: schwannomatosis (multiple schwannomas without the vestibular schwannomas that are diagnostic of NF2) b. Multiple non-cranial schwannomas: Some patients turn out to have mosaic NF2 (Moyhuddin et al. 2003; Evans et al. 2007). c. Neurofibromatosis 1 Prognosis is adversely affected by a. Early age at onset b. A higher number of meningiomas c. Having a truncating mutation

Diagnostic Investigations 1. Clinical and family history (Evans 2009a) 2. Physical examination including cutaneous and ophthalmic (slip lamp) 3. Craniospinal MRI 4. Hearing evaluation, including BAER 5. Chromosome analysis: Gross chromosomal changes are rare but may reveal a variety of chromosome abnormalities. a. Cytogenetically visible deletions encompassing the NF2 gene: may cause mental retardation

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and multiple congenital abnormalities (Barbi et al. 2002) i. Ring chromosome 22 (Tsilchorozidou et al. 2004) ii. Can cause multiple meningiomas and vestibular schwannomas fulfilling NF2 diagnostic criteria, NF2 locus itself is usually present within the ring, but the ring itself is frequently loss as a result of instability. iii. Apparently balanced chromosomal translocations disrupting the NF2 gene causing NF2 iv. Fluorescence in situ hybridization (FISH) to identify smaller deletions that remove multiple exons of the NF2 gene or the whole gene 6. Molecular genetic analysis a. Sequence analysis/mutation scanning of NF2 gene (Evans et al. 2007) i. In 73% of families with NF2, sequence analysis identified a mutation in a member of the second generation. ii. In simplex cases (a single occurrence in a family), the mutation detection rate is approximately 60%. iii. Approximately 25–33% of mutations are not detected as a result of somatic mosaicism. iv. Mutations with mosaicism levels >10% can be detected in lymphocyte DNA. v. Identification of the remainder of mosaic mutations usually requires testing of tumor material. b. Deletion/duplication analysis i. Systematically detects whole exon deletions and duplications ii. Most large deletions and, less commonly, duplications of single exons or multiple exons can be detected by multiple ligationdependent probe amplification (MLPA). c. Linkage analysis i. In families in whom no disease-causing mutation is identified, and at least two family members of different generations are affected. ii. Modified linkage analysis using both constitutional and tumor DNA can exclude NF2 in those children of a simplex case who have not inherited the allele lost in the tumor.

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7. Presymptomatic genetic testing is an integral part of the management of NF2 families. a. At-risk relatives whose genetic status is unknown can be tested for presence of the NF2 mutation (either constitutional or somatic mosaic) identified in an affected relative. b. In the rare instance in which an NF2 mutation cannot be identified, linkage analysis can be used in families with at least two affected family members of different generations, or tumor DNA can be used to clarify the genetic status of children of a simplex case.

Neurofibromatosis 2

b. c.

d.

e.

ii. More difficult to determine the timing of removal of vestibular schwannomas Stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Important to balance the use of microsurgery and radiation treatment, which can have a role in patients who have particularly aggressive tumors, or who are poor surgical risks, or who refuse surgery. Hearing preservation and augmentation with hearing aids or auditory rehabilitation with a cochlear or brain stem implant. Watchful waiting with careful surveillance and occasionally radiation treatment have a role.

Genetic Counseling 1. Recurrence risk: presence of an affected parent in approximately 50% of individuals with NF2 (other 50% have NF2 as the result of a de novo mutation; 20–33% of simplex cases without family history are mosaic for an NF2 mutation) (Evans 2009a) a. Patient’s sib i. Affected parent: a 50% risk ii. Asymptomatic parents: a low risk since the age of onset of symptoms is relatively uniform within families a) A single case of germ line mosaicism in a clinically normal parent has been reported. b) Somatic mosaicism which may include germ line mosaicism is found in 25–33% of individuals with NF2 who are simplex cases. b. Patient’s offspring i. The risk of disease transmission is 50% in the second generation and beyond. ii. The risk of transmission in people with new NF2 mutations is less than 50% due to mosaicism, in which only a proportion of cells have the mutated NF2 gene (Evans et al. 1998; Kluwe and Mautner 1998). 2. Prenatal diagnosis and preimplantation genetic diagnosis: possible for at risk pregnancies, provided prior identification of the disease-causing mutation in the family 3. Management a. Surgery remains the focus of current management. i. Surgical removal of symptomatic cranial and spinal tumors

References Asthagiri, A. R., Parry, D. M., Butman, J. A., et al. (2009). Neurofibromatosis type 2 (Seminar). Lancet, 373, 1974–1986. Barbi, G., Rossier, E., Vossbeck, S., et al. (2002). Constitutional de novo interstitial deletion of 8 Mb on chromosome 22q12.1-12.3 encompassing the neurofibromatosis type 2 (NF2) locus in a dysmorphic girl with severe malformations. Journal of Medical Genetics, 39, E6. Baser, M. E. (2006). The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene. Human Mutation, 27, 297–306. Baser, M. E., Friedman, J. M., Aeschliman, D., et al. (2002). Predictors of the risk of mortality in neurofibomatosis 2. American Journal of Human Genetics, 71, 715–723. Consensus Development Panel. (1994). National Institutes of Health Consensus Development Conference statement on acoustic neuroma, December 11–13, 1991. Archives of Neurology, 51, 201–207. Evans, D. G. (2009a). Neurofibromatosis type 2 (NF2): A clinical and molecular review (Review). Orphanet Journal of Rare Diseases, 4, 16–26. Evans, D. G. (2009b). Neurofibromatosis 2. GeneReviews. Updated August 18, 2011. Available at: http://www.ncbi. nlm.nih.gov/books/NBK1201/ Evans, D. G. R., Baser, M. E., O’Reilly, B., et al. (2005). Management of the patient and family with neurofibromatosis 2: A consensus conference statement. British Journal of Neurosurgery, 19, 5–12. Evans, D. G. R., Ramsden, R. T., Shenton, A., et al. (2007). Mosaicism in neurofibromatosis type 2: An update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. Journal of Medical Genetics, 44, 424–428. Evans, D. G. R., Wallace, A. J., Wu, C. L., et al. (1998). Somatic mosaicism: A common cause of classic disease in tumourprone syndromes? Lessons from type 2 neurofibromatosis. American Journal of Human Genetics, 63, 727–736.

Neurofibromatosis 2 Gardner, W. J., Frazier, C. H. (1930). Bilateral acoustic neurofibromas: a clinical study and field survey of a family of five generations with bilateral deafness in thirty eight members. Archives of Neurology and Psychiatry, 23, 266–302. Kluwe, L., & Mautner, V.-F. (1998). Mosaicism in sporadic neurofibromatosis-2 patients. Human Molecular Genetics, 7, 2051–2055. Knudson, A. G., Jr. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proceedings of the National Academy of Sciences United States of America, 68, 820–823. MacCollin, M., & Mautner, V.-F. (1998). The diagnosis and management of neurofibromatosis 2 in childhood. Seminars in Pediatric Neurology, 5, 243–253. Moyhuddin, A., Baser, M. E., Watson, C., et al. (2003). Somatic mosaicism in neurofibromatosis 2: Prevalence and risk of disease transmission to offspring. Journal of Medical Genetics, 40, 459–463.

1575 National Institutes of Health Consensus Development Conference. (1988). Neurofibromatosis conference statement. Archives of Neurology, 45, 575–578. Rouleau, G. A., Merel, P., Lutchman, M., et al. (1993). Alteration in a new gene encoding a putative membraneorganizing protein causes neurofibromatosis type 2. Nature, 363, 515–521. Trofatter, J. A., MacCollin, M. M., Rutter, J. L., et al. (1993). A novel moesin, ezrin-radixin-like gene is a candidate for the neurofibromatosis suppressor. Cell, 75, 826. Tsilchorozidou, T., Menko, F. H., Lalloo, F., et al. (2004). Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2. Journal of Medical Genetics, 41, 529–534. Wishart, J. H. (1822). Case of tumours in the skull, dura mater, and brain. Edinburgh Medical and Surgical Journal, 18, 393–397.

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a

b

Fig. 1 (a, b) A 23-year-old female had resection of anterior fossa meningioma 2 years previously. She complained worsening headaches with intermittent vomiting and blurry vision recently. She underwent a posterior fossa craniectomy and resection of a large cervical medullary tumor, consistent with a spindle cell tumor (schwannoma). She also has history of bilateral hearing loss and balance dysfunction. Molecular genetic testing revealed a truncating mutation in the NF2 gene (c.553delG) confirming the diagnosis of NF2 in this patient

Neurofibromatosis 2

Noonan Syndrome

Noonan syndrome (NS) is a relatively common but genetically heterogeneous autosomal dominant malformation syndrome. The incidence of Noonan syndrome is estimated to be 1 in 1,000–1 in 2,500 live births.

Synonyms and Related Disorders Female pseudo-Turner syndrome; Male Turner syndrome; Turner phenotype with normal karyotype

Genetics/Basic Defects 1. Inheritance (Allanson 1987; Tartaglia et al. 2010) a. Autosomal dominant inheritance b. Many affected individuals with de novo mutations c. Affected parent recognized in 30–70% of families 2. Caused by mutations in the PTPN11, SOSI, KRAS, RAF1, BRAF, and MEK1 (MAP2K1) genes: accounting for approximately 70% of affected individuals a. The gene PTPN11 (protein tyrosine phosphatase, nonreceptor type 11), mapped on 12q24.1, encoding the protein tyrosine phosphatase SHP-2. i. Heterozygous point mutations in the gene PTPN11 identified in the following: a) Families showing linkage to the NS1 locus in 12q24 b) Some sporadic cases with NS ii. All mutations detected to date: missense mutations iii. The majority of mutations found in exons 3 and 8, which correspond to the interacting

regions of the N-SH2 and protein tyrosine phosphatase domains of the gene iv. Genotype-phenotype correlation of PTPN11 mutations a) Increased frequency of PTPN11 mutations observed in individuals with Noonan syndrome with pulmonary stenosis (70%) b) Infrequent frequency of PTPN11 mutations observed in individuals with hypertrophic cardiomyopathy (6%) b. SHP-2 (encoded by PTPN11), SOS1, BRAF, RAF1, and MEK1 positively contribute to RAS-MAPK signaling and possess complex autoinhibitory mechanisms that are impaired by mutations. c. Similarly, reduced GTPase activity or increased guanine nucleotide release underlies the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. 3. Mutation in SHOC2 a. Encodes a cytoplasmic scaffold positively controlling RAF1 activation. b. Has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. c. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. 4. PTPN11, BRAF, and RAF1 mutations a. Also account for approximately 95% of LEOPARD syndrome. i. A condition which resembles NS phenotypically

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ii. Characterized by multiple lentigines dispersed throughout the body, cafe´-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy, and sensorineural hearing deficits b. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

Clinical Features 1. Clinical features (Allanson 1987) a. Growth i. Average length at birth: 47 cm ii. Generally normal birth weight but can be high due to subcutaneous edema iii. Prepubertal growth parallel to the third centile (40%) with a relatively normal growth velocity iv. Pubertal growth spurt often reduced or absent b. Craniofacial features: change with age (see below) c. Ocular abnormalities (observed up to 95% of cases) i. Strabismus ii. Refractive errors iii. Amblyopia iv. Nystagmus v. Anterior segment and fundal changes d. Congenital heart defects (two thirds of cases) i. Pulmonary valvular stenosis (50%) ii. Hypertrophic cardiomyopathy (20–30%): may be present at birth or appears in infancy or childhood iii. Atrial septal defect (10%) iv. Asymmetrical septal hypertrophy (10%) v. Ventricular septal defect (5%) vi. Persistent ductus arteriosus (3%) vii. Other cardiac defects a) Pulmonary artery branch stenosis b) Mitral valve prolapse c) Ebstein anomaly d) Single ventricles e. Genitourinary abnormalities i. Males: ranging from normal prepubertal virilization to delayed fertility and

Noonan Syndrome

inadequate secondary sexual development associated with deficient spermatogenesis secondary to earlier cryptorchidism (60%) ii. Females: normal or delayed puberty but fertile in majority of cases f. Skeletal abnormalities i. Characteristic pectus deformity (see detail description below) ii. Common features a) Cubitus valgus (50%) b) Hand anomalies including clinobrachydactyly and blunt fingertips (30%) c) Vertebral and sternal anomalies (25%) d) Dental malocclusion (35%) g. Ectodermal abnormalities i. Various skin manifestations a) Cafe´-au-lait patches (10%) b) Pigmented nevi (25%) c) Lentigines (2%) d) Keratosis pilaris atrophicans faciei ii. Several instances of neurofibromatosis and the Noonan phenotype documented h. Bleeding diathesis (about one third of cases with a coagulation defect) i. Factor XI deficiency ii. Von Willebrand disease iii. Platelet dysfunction which may be associated with trimethylaminuria i. Lymphatic abnormalities i. Congenital dysplasia, hypoplasia, or aplasia of lymphatic channels (20%) ii. General lymphedema iii. Peripheral lymphedema iv. Pulmonary lymphangiectasia v. Intestinal lymphangiectasia vi. Hydrops fetalis vii. Cystic hygroma j. Rare associated features i. Autoimmune thyroiditis ii. Pheochromocytoma iii. Ganglioneuroma iv. Malignant schwannomas v. Congenital contractures vi. Chiari malformation with syringomyelia vii. Skin and oral xanthomas viii. Odontogenic keratosis k. Behavioral and developmental abnormalities i. Failure to thrive in infancy (40%) ii. Motor developmental delay (26%)

Noonan Syndrome

iii. Learning disability with specific visualconstructional problems and verbalperformance discrepancy (15%) iv. Language delay (20%) secondary to perceptual motor disabilities, mild hearing loss (12%), or articulation abnormalities (72%) v. Intelligence a) IQ: 64–127 with a median of 102 b) IQ: ten points below that of unaffected family members c) Mild mental retardation reported in up to 35% of cases 2. Changing phenotype with age (Allanson 1987) a. Newborn period i. Marked edema a) Contributing to a normal-to-high birth weight b) Rapid reduction after birth simulating failure to thrive ii. Excess nuchal skin iii. Sloping and broad forehead iv. Apparent ocular hypertelorism v. Downslanting palpebral fissures vi. A deep philtrum vii. Mild retrognathia viii. Posteriorly angulated ears with a thick helix b. Neonatal period to 2 years i. Head a) Relatively large appearance b) Flat malar eminence c) Bitemporal narrowing accentuated by lateral supraorbital fullness d) “Coarse” and occasional asymmetric facial appearance ii. Eyes a) Prominent and round b) Ocular hypertelorism c) Telecanthus d) Lessening downslanting of the palpebral fissures e) Occasional strabismus f) Thick eyelid hooding the upper iris g) Sharp arched eyebrows iii. Nose a) Depressed nasal root b) Low nasal bridge c) Wide nasal base

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d) Bulbous nasal tip e) Anteverted nares f) Short columella iv. Deep philtrum v. Arched upper lip with high and wide peaks of the vermilion border vi. Ears a) Posteriorly rotated b) Occasionally small or square vii. Neck a) Short b) Less excess skin than in the newborn period c) A low posterior hairline viii. Often failure to thrive and hypotonia ix. Occasional hepatosplenomegaly, swarthy skin, and wispy hair x. 12–18 months of age a) Changing body shape with stocky and square upper body b) Occasional presence of an umbilical hernia or diastasis recti c) The limbs becoming relatively longer and thinner secondary to resolving edema d) Blunt finger tips c. Childhood i. Face a) Appearance remaining coarse b) Becoming more triangular as the chin lengthens c) Forehead becoming lower and may be bossed d) Flatter malar eminence ii. Eyes a) Less prominent eyes with reduced epicanthus b) Increasing ptosis c) Increasing lateral supraorbital fullness d) Higher nasal root and bridge iii. Full lips with sublabial protrusion iv. Neck a) Appearing longer b) Accentuating webbing c) Prominent trapezius v. Thorax a) Broad b) An inverted pyramid shape c) Increasing pectus

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d) Upper chest length increases with relatively low-set nipples and axillary webbing which persist to adulthood. vi. Scapula a) Round shape b) Winged scapulae vii. Limbs a) Thin b) Marked cubitus valgus c) Flat feet viii. Skin a) Lentigines b) Nevi c) Cafe´-au-lait spots ix. Often markedly curly or woolly hair d. Teenage and young adulthood i. Facial shape becoming increasingly triangular ii. Facial features becoming sharper iii. Less prominent eyes with occasional ptosis iv. Nose a) Thinner b) A pinched root c) Higher bridge d) Wide base e) Pointed tip f) A longer columella v. Eyebrows becoming sparse e. Older adulthood i. Prominent nasolabial folds ii. Higher anterior hairline iii. Occasional sloping forehead iv. Transparent wrinkled skin f. Prominent abnormalities at all ages i. Striking blue or blue-green irides ii. Increased number of fingertip whorls iii. Posteriorly angulated ears with a thick helix iv. Characteristic pectus deformity a) Pectus carinatum superiorly b) Pectus excavatum inferiorly 3. Disorders clinically related to Noonan syndrome (Tartaglia et al. 2010) a. LEOPARD syndrome b. Cardiofaciocutaneous syndrome i. A rare sporadic multiple congenital anomalies/mental retardation syndrome characterized by: a) Failure to thrive b) Severe feeding problems c) Developmental delay

Noonan Syndrome

d) Short stature e) Distinguished face f) Abnormalities of the skin gastrointestinal tract and CNS g) Cardiac defects (pulmonary stenosis, hypertrophic cardiomyopathy) ii. Genetically heterogeneous, with mutations in the KRAS, BRAF, MEK1, and MEK2 genes occurring in approximately 60–90% of affected individuals c. Costello syndrome i. Clinical features a) Prenatal overgrowth b) Followed by postnatal feeding difficulties and severe failure to thrive c) Distinctive “coarse” facial features d) Mental retardation e) Short stature f) Cardiac defects (pulmonary stenosis, hypertrophic cardiomyopathy) g) Musculoskeletal ( joint laxity) and skin abnormalities ii. Caused by germline missense mutations in the HRAS proto-oncogene iii. Other causative genes: KRAS, BRAF, and MEK1 d. Neurofibromatosis-Noonan syndrome (NFNS) i. Most individuals with NFNS harbor an NF1 mutation and that a single mutation can be sufficient to engender the trait. ii. Double heterozygosity for NF1 and PTPN11 mutations rarely causes NFNS, and it is not yet clear how frequently mutations in other NS disease genes co-occur with NF1 defects in the disorder. iii. These findings support the view that NFNS is genetically distinct from NS and emphasize the extreme phenotypic variability associated with lesions in the NF1 gene. iv. The identification of specific NF1 alleles recurring in NFNS, the evidence that these alleles cosegregate with the condition in families, and the observation of a peculiar mutational spectrum strongly suggest that the term “NFNS” does characterize a phenotypic variant of NF1, which manifests with a lower incidence of plexiform neurofibromas, skeletal anomalies, and internal tumors, in association with

Noonan Syndrome

hypertelorism, ptosis, low-set ears, and congenital heart defects. v. Some of the mutations identified in patients with NFNS have also been reported in NF1 without any feature suggestive of NS. e. Legius syndrome i. Previously known as neurofibromatosis type 1–like syndrome. ii. An autosomal dominant disorder. iii. Clinical features. a) Multiple axillary freckling b) Cafe´-au-lait spots c) Macrocephaly d) NS–like facial dysmorphism in some individuals iv. Caused by loss-of-function mutations of the SPRED1 gene, which encodes a negative modulator of RAS-MAPK signaling (Brems et al. 2007). v. SPRED1 mutational analysis of sporadic or familial cases with a diagnosis of NF1 or with a phenotype suggestive of the disorder indicates that mutations account for approximately 0.5–1% of NF1 mutation-negative cases.

Diagnostic Investigations 1. Growth curves for males and females with Noonan syndrome now available 2. Echocardiography for previously described congenital heart defects 3. Electrocardiography a. A wide QRS complex b. Left axis deviation c. Giant Q wave d. A negative pattern in the left precordial leads 4. Radiography: pectus deformity 5. Renal ultrasound for renal anomalies 6. Coagulation studies when needed 7. Chromosome analysis: normal karyotype 8. Molecular genetic testing available clinically a. Mutations in the gene PTPN11 identified in 50% of patients (familial and sporadic cases) b. Germline mutations i. Detected in 59% of patients with familial Noonan syndrome ii. Detected in 37% of individuals with sporadic Noonan syndrome

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Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Fifty percentage if a parent is affected ii. Low risk (A nucleotide substitution in exon 3, resulting in the replacement of a glycine codon (GGT) with a Serine codon (AGT) at amino acid position 60 of the tyrosine phosphatase SHP-2 protein (p.Gly60Ser or G60S) (c.178G>A)

Oblique Facial Cleft Syndrome

Oblique facial clefts are extremely rare congenital anomalies occurring in about 1/100 to 12/1,000 of facial clefts (Rintala et al. 1980).

Synonyms and Related Disorders Mandibular process clefts; Naso-ocular clefts; Oculomaxillofacial dysplasia with oblique facial cleft; Oro-aural clefts; Oro-ocular clefts; Tessier clefts

Genetics/Basic Defects 1. Genetic heterogeneity (Richieri-Costa and Gorlin 1994). a. Sporadic in most cases b. A disruptive event resulting from amniotic band rupture sequence considered as a main etiological agent (Coady et al. 1998) i. Twenty six percentage of nonsyndromal craniofacial cleft displays congenital limb anomalies. ii. Thirteen percentage of nonsyndromal craniofacial cleft shows evidence of limb ring constrictions. c. Occasional association with malformation syndrome (e.g., Fryns anophthalmia-microphthalmiaoblique clefting syndrome) d. Rare autosomal recessive inheritance 2. Classification of facial clefts: A universally accepted classification scheme that fully encompasses, accurately describes, and integrates all the various types of orofacial and craniofacial clefts does not exist (Stellzig et al. 1997: Eppley et al. 2005).

a. The American Association for Cleft Palate Rehabilitation (1962) divided facial clefts into four major groups according to the anatomic location. i. Mandibular process clefts ii. Naso-ocular clefts iii. Oro-ocular clefts iv. Oro-aural clefts b. Boo-Chai (1990) proposed a subdivision of the oro-ocular group into: i. Medial (Type I) ii. Lateral (Type II) c. Tessier (1976) presented an anatomic classification of the facial clefts by using numbers 0–14 anticlockwise to point the location of the cleft when the orbit is used as the central point. i. Commonly used by surgeons because it is purely descriptive and makes no pretense at causation and developmental relationships. ii. Proven validity in analyzing complex facial deformities. iii. Careful examination in confirming the diagnosis and in managing the patients. iv. The Tessier classification includes numbered clefts from 0 (midline cleft of the lip and nose) to 30 (clefting of lower face or a mandibular cleft). v. Tessier cleft numbers 4, 5, and 6 are oroocular clefts. vi. Tessier cleft numbers 7, 8, and 9 are lateral facial or commissural clefts. vii. The oblique clefts: indicated by Tessier cleft numbers 3 through 5 (Eppley et al. 2005).

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3. Classification of orofacial clefts (Tolarova´ and Cervenka 1998). a. Isolated anomaly (61.63%) i. Cleft lip ii. Cleft lip and palate iii. Cleft palate iv. Atypical facial cleft b. Sequence (3.9%) i. Robin sequence ii. Holoprosencephaly sequence iii. Frontonasal dysplasia sequence iv. Amyoplasia congenital disruption sequence c. Chromosome aberrations (8.79%) i. Trisomy 21 syndrome ii. Trisomy 13 syndrome iii. Trisomy 18 syndrome iv. Other trisomies v. Other chromosomal aberrations d. Monogenic syndromes (6.02%) i. Autosomal dominant a) Stickler syndrome b) Craniosynostosis syndromes c) Van der Woude syndrome d) Others ii. Autosomal recessive a) Smith-Lemli-Opitz syndrome b) Meckel syndrome c) Others iii. X-linked dominant e. Known environmental cause (0.2%) i. Fetal alcohol syndrome ii. Dilantin embryopathy iii. Congenital syphilis f. Associations (0.79%) i. CHARGE association ii. VATER association g. Multiple congenital anomalies (MCA) (18.5%) i. MCA of malformation origin ii. MCA of deformation origin iii. MCA of malformation and malformation origin iv. MCA of other combinations h. Conjoined twins 4. Oblique clefts a. Considered as late or secondary defects resulting from outgrowth of one or more bone centers in membranous bones b. Including certain types of Tessier classification (1976): oblique clefts corresponding to

Oblique Facial Cleft Syndrome

the numbers 3–6 distally or “southward” and 8–11 proximally or “northward” from the orbit in the extreme forms (Rintala et al. 1980) c. Arbitrary classification in some instances d. Presence of intermediate forms of facial clefts

Clinical Features 1. Clinical variability 2. Oblique facial clefts a. Naso-ocular clefts i. Whole stretch from the lip through the nose to the eyelid and orbit ii. Nasolacrimal duct always involved iii. Defective and upwardly dislocated ala nasi b. Oro-ocular clefts i. Type I (medial): cleft medial to infraorbital region of the nasolabial groove to end in the inner canthus or the lower eyelid ii. Type II (lateral): cleft extending from the angle of the mouth upward to the orbit ending in the lateral canthus or in a coloboma in the midportion of the lower eyelid iii. Twice as frequent as the naso-ocular types c. Bilateral clefts in 20–35% of cases d. Presence of complete or incomplete forms e. Possible involvement of palate and extending into the temporal region 3. Concordant clinical signs a. Short stature b. Sparse eyebrows c. Sparse eyelashes d. Lower lid coloboma e. Abnormal nose f. Involvement of the nasolacrimal duct g. Malar hypoplasia 4. Other variable clinical signs a. Mental retardation b. Anophthalmia/microphthalmia c. Hemimelia (possibly resulting from in utero vascular accident in some cases) 5. Associated anomalies a. Amniotic bands i. Amniotic band affecting premaxillary-nasalocular areas of the midface producing oblique tissue disruptions ii. Intrauterine amputation

Oblique Facial Cleft Syndrome

iii. iv. v. vi.

Constriction rings Distal lymphedema Distal pseudosyndactyly Remnant of amniotic band still attached to the lesion b. CNS abnormalities i. Encephalocele ii. Hydrocephaly c. Aplasia cutis congenita d. Talipes equinovarus

Diagnostic Investigations 1. Radiography for craniofacial anomalies 2. Three-dimensional CT scan for visualization of the extent and location of the cleft 3. MRI of the brain for CNS anomalies 4. Blood for chromosome analysis to rule out chromosome etiology

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b. Surgical repair of facial cleft (Chiong et al. 1981) i. General principle a) Accurate approximation of each tissue layer b) Meticulous layered closure to prevent loss of anatomical continuity and a depressed scar along the site of the operative procedure c) Multiple Z-plasty when the repair crosses lines of minimal skin tension or when there is loss of length ii. Closure of the cleft and reconstruction of the underlying bony deficiencies at a very early age iii. Followed by subsequent correction of orbital hypertelorism between the ages of 2–5 years iv. Followed by orthognathic correction of maxillary and mandibular deformities in the teens c. Multidisciplinary approach to early intervention

References Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Recurrence risk not increased since most cases are sporadic, especially in a case where amniotic band rupture sequence is considered to be the etiologic factor ii. Recurrence risk possibly increased in occasional cases of autosomal recessive inheritance b. Patient’s offspring: not increased 2. Prenatal diagnosis: possible by ultrasonographic documenting oblique facial cleft associated with other commonly associated anomalies (CNS anomaly, anophthalmia, and findings of amniotic band disruption sequence) 3. Management a. Early orthopedic treatment i. To achieve both the proper alignment of the maxillary segments and a reduction of cleft width in cases of unilateral cleft lip, alveolus, and palate ii. Presurgical orthopedic devices to approximate the distorted segments and to facilitate lip closure in the treatment of maxillary clefts

Boo-Chai, K. (1970). The oblique facial cleft. A report of 2 cases and a review of 41 cases. British Journal of Plastic Surgery, 23, 352–359. Boo-Chai, K. (1990). The oblique facial cleft: A 20-year followup. British Journal of Plastic Surgery, 43, 355–358. Butow, K. W., & de Witt, T. W. (1990). Bilateral oblique facial cleft–tissue expansion with primary reconstruction. The Journal of the Dental Association of South Africa, 45, 507–511. Chiong, A. T., Guevarra, E. S., Jr., & Zantua, R. V. (1981). Oblique facial cleft. Archives of Otolaryngology, 107, 59–62. Coady, M. S. E., Moore, M. H., & Wallis, K. (1998). Amniotic band syndrome: The association between rare facial clefts and limb ring constrictions. Plastic and Reconstructive Surgery, 101, 640–648. Darzi, M. A., & Chowdri, N. A. (1993). Oblique facial clefts: A report of Tessier numbers 3, 4, 5, and 9 clefts. The Cleft Palate-Craniofacial Journal, 30, 414–415. Dasouki, M., Barr, M., Jr., Erickson, R. P., et al. (1988). Translocation (1;22) in a child with bilateral oblique facial clefts. Journal of Medical Genetics, 25, 427–431. David, D. J., Moore, M. H., & Cooter, R. D. (1989). Tessier clefts revisited with a third dimension. The Cleft Palate Journal, 26, 163–184. Dey, D. L. (1973). Oblique facial clefts. Plastic and Reconstructive Surgery, 52, 258–263. Ecker, H. A. (1970). An unusual bilateral oblique facial cleft: Report of case. Journal of Oral Surgery, 28, 619–620. Eppley, B. L., David, L., Li, M., et al. (1998). Amniotic band facies. The Journal of Craniofacial Surgery, 9, 360–365. Eppley, B. L., van Aalst, J. A., Robey, A., et al. (2005). The spectrum of orofacial clefting. Plastic and Reconstructive Surgery, 115, 101e–114e.

1590 Kara, I. G., & Ocsel, H. (2001). The Tessier number 5 cleft with associated extremity anomalies. The Cleft PalateCraniofacial Journal, 38, 529–532. Kawamoto, H. K. (1976). The kaleidoscopic world of rare craniofacial clefts: Order out of chaos (Tessier classification). Clinics in Plastic Surgery, 5, 529–572. Kubacˇek, V., & Pe˘nkava, J. (1974). Oblique clefts of the face. Acta Chirurgiae Plastic (Praha), 16, 152–163. MacKinnon, C. A., & David, D. J. (2001). Oblique facial clefting associated with unicoronal synostosis. The Journal of Craniofacial Surgery, 12, 227–231. Mavili, E., Gursu, G., Ercal, M. D., et al. (1992). Three cases of oblique facial cleft: Etiology, tomographic evaluation and reconstruction. Clinical Dysmorphology, 1, 229–234. Mayou, B. J., & Fenton, O. M. (1981). Oblique facial clefts caused by amniotic bands. Plastic and Reconstructive Surgery, 68, 675–681. Mishima, K., Sugahara, T., Mori, Y., et al. (1996). Three cases of oblique facial cleft. Journal of Cranio-Maxillo-Facial Surgery, 24, 372–377. Miyajima, K., Natsume, N., Kawai, T., et al. (1994). Oblique facial cleft, cleft palate, and supernumerary teeth secondary to amniotic bands. The Cleft Palate-Craniofacial Journal, 31, 483–486. Ranta, R., & Rintala, A. (1988). Oblique lateral oro-ocular facial cleft. Case report. International Journal of Oral and Maxillofacial Surgery, 17, 186–189. Richieri-Costa, A., & Gorlin, R. J. (1994). Oblique facial clefts: Report on 4 Brazilian patients. Evidence for clinical variability and genetic heterogeneity. American Journal of Medical Genetics, 53, 222–226. Rintala, A., Leisti, J., Liesmaa, M., et al. (1980). Oblique facial clefts. Scandinavian Journal of Plastic and Reconstructive Surgery, 14, 291–297. Rowsell, A. R. (1989). The amniotic band disruption complex. The pathogenesis of oblique facial clefts; an experimental study in the foetal rat. British Journal of Plastic Surgery, 42, 291–295.

Oblique Facial Cleft Syndrome Sakurai, E. H., Mitchell, D. F., & Holmes, L. A. (1966). Bilateral oblique facial clefts and amniotic bands: A report of two cases. The Cleft Palate Journal, 3, 181–185. Sano, S., Tani, T., & Nishimura, Y. (1983). Bilateral oblique facial cleft. Annals of Plastic Surgery, 11, 434–437. Schlenker, J. D., Ricketson, G., & Lynch, J. B. (1979). Classification of oblique facial clefts with microphthalmia. Plastic and Reconstructive Surgery, 63, 680–688. Schweckendiek, W. (1974). Nasal abnormalities in facial clefts. Journal of Maxillofacial Surgery, 4, 141–149. Stellzig, A., Basdra, E. K., Muhling, J., et al. (1997). Early maxillary orthopedics in a child with an oblique facial cleft. The Cleft Palate-Craniofacial Journal, 34, 147–150. Tessier, P. (1976). Anatomical classification of facial, craniofacial and latero-facial clefts. Journal of Maxillofacial Surgery, 4, 69–92. Tolarova´, M. M., & Cervenka, J. (1998). Classification and birth prevalence of Orofacial clefts. American Journal of Medical Genetics, 75, 126–137. Tsur, H., Winkler, E., & Kessler, A. (1991). Oblique facial cleft with anophthalmia in a mentally normal child. Annals of Plastic Surgery, 26, 449–455. Van der Meulen, J. C. (1985). Oblique facial clefts: Pathology, etiology, and reconstruction. Plastic and Reconstructive Surgery, 76, 212–224. Warburg, M., Jensen, H., Prause, J. U., et al. (1997). Anophthalmia-microphthalmia-oblique clefting syndrome: Confirmation of the Fryns anophthalmia syndrome. American Journal of Medical Genetics, 73, 36–40. Wilson, L. F., Musgrave, R. H., Garrett, W., et al. (1972). Reconstruction of oblique facial clefts. The Cleft Palate Journal, 9, 109–114. Yang, S. S. (1990). ADAM sequence and innocent amniotic band: Manifestations of early amnion rupture. American Journal of Medical Genetics, 37, 562–568. Zimmer, E. T., Taub, E., Sova, Y., et al. (1985). Tetra-amelia with multiple malformations in six male fetuses in one kindred. European Journal of Pediatrics, 144, 412–414.

Oblique Facial Cleft Syndrome

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Fig. 1 (a, b) An infant with oblique facial cleft syndrome (at birth and postoperative) showing unilateral oro-ocular cleft with cleft beginning at the angle of the mouth and ending in a coloboma of the lower eyelid and corneal opacity

Fig. 2 (a, b) An infant with oblique facial cleft syndrome showing extensive unilateral oro-naso-ocular cleft and encephalocele

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Oblique Facial Cleft Syndrome

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Fig. 3 (a–c) A newborn with oblique facial cleft syndrome associated with amniotic band syndrome and cutis aplasia congenita of the scalp showing bilateral frontonasal clefts, scalp defect, pseudotail, hypertelorism, anophthalmia,

clubhands, digital amputation, constriction bands, and an amniotic band still attached to the left finger. The infant also had hydrocephalus, atrial septal defect, and clubfoot

Oblique Facial Cleft Syndrome

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Fig. 4 (a–d) A 4-year- and 11-month-old boy was seen for Tessier complex orofacial cleft. He was born without right eyeball, absent right nostril, and large oblique orofacial cleft. The photographs show before and after operations

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Fig. 5 (a–d) An infant with Tessier number 7 cleft with a 3D reconstruction CT

Oligohydramnios Sequence

Oligohydramnios is defined as deficiency of amniotic fluid, i.e., decrease in the volume of amniotic fluid. It may result from decreased urinary production or excretion, or fluid loss from rupture of membranes. The incidence is estimated to be 0.5–8% of all pregnancies.

Genetics/Basic Defects 1. Associated maternal conditions (Peipert and Donnenfeld 1991) a. Ureteroplacental insufficiency i. Antiphospholipid antibodies ii. Chronic hypertension iii. Collagen vascular diseases iv. Diabetic vasculopathy v. Maternal hypovolemia vi. Preeclampsia/pregnancy-induced hypertension b. Drugs i. Prostaglandin synthetase inhibitors ii. Angiotensin converting enzyme inhibitors c. Placental i. Abruption ii. Twin-to-twin transfusion d. Maternal hydration status 2. Associated fetal conditions a. Renal malformations i. Bilateral agenesis ii. Bilateral cystic dysplasia iii. Unilateral cystic dysplasia/agenesis iv. Meckel syndrome v. Infantile polycystic kidneys

vi. Renal tubular dysgenesis (Lacoste et al. 2006) a) Probably an underrecognized disorder b) An autosomal recessive disorder c) Should be considered for fetuses who present early oligohydramnios, normal or nearly normal kidneys on ultrasound examination, and skull ossification defects vii. Posterior urethral valves viii. Renal hypoplasia ix. Horseshoe kidney b. Other congenital anomalies i. Amniotic band syndrome ii. Branchio-oto-renal syndrome iii. Cystic hygroma iv. Encephalocele v. Endocardial fibroelastosis vi. Holoprosencephaly vii. Hypophosphatasia (homozygous dominant form) viii. MURCS association ix. Sacral agenesis (caudal regression) x. Sirenomelia xi. VATER association xii. Others c. Chromosome abnormalities i. Trisomy 13 ii. Trisomy 18 d. Twin-to-twin transfusion syndrome (“stuck twin syndrome”) i. A complication of monochorionic diamniotic twinning

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ii. One twin stucked because of severe oligohydramnios and compressed by the significant polyhydramnios associated with its co-twin iii. Perinatal mortality associated with severe oligohydramnios/polyhydramnios sequence in a monochorionic twin pregnancy before 28 weeks: 70–100% e. Intrauterine growth retardation f. Intrauterine fetal demise g. Postmaturity possibly caused by a decline in placental function h. Rupture of membranes: the most common cause of oligohydramnios i. Preterm ii. Prolonged i. Idiopathic 3. Dynamic of amniotic fluid a. Presence of amniotic fluid throughout gestation i. Enables normal development of the fetal respiratory, gastrointestinal, and urinary tracts and musculoskeletal system ii. Continued fetal growth in a nonrestricted, sterile, and thermally controlled environment iii. Amniotic fluid volume is gestational-age dependent. b. Factors contributing to the formation and removal of amniotic fluid i. Formation a) Fetal urination b) Tracheal secretions c) Intramembranous pathway including transfers between amniotic fluid and fetal blood perfusing the fetal surface of the placenta, fetal skin, and umbilical cord d) Transmembranous pathway involving direct exchange across the fetal membranes between amniotic fluid and maternal blood within the uterus ii. Removal: fetal swallowing c. Significance of oligohydramnios i. A sign of potential fetal compromise ii. Associated with an increased incidence of adverse perinatal morbidity and mortality, especially in conjunction with the following: a) Structural fetal anomalies b) Fetal growth restriction c) Post dates pregnancies d) Maternal disease

Oligohydramnios Sequence

Clinical Features 1. Consequences of severe fetal constraints secondary to early and prolonged oligohydramnios a. Potter facies: associated with renal agenesis and any other cause of severe oligohydramnios i. Hypertelorism ii. Deep crease under the eyes iii. Epicanthal folds iv. Flat nose v. Receding chin vi. Low-set, aberrantly folded ears b. Lung hypoplasia i. Respiratory insufficiency ii. Death c. Limb positional anomalies i. Arthrogryposis ii. Spade-like hands iii. Talipes equinovarus d. Intrauterine growth retardation: one of the most common complications associated with sever oligohydramnios 2. Presence of fetal abnormalities in cases associated with severe oligohydramnios (Shipp et al. 1996) a. 50.7% in the second trimester b. 22.1% in the third trimester c. Rate of aneuploidy: at least 4.4% 3. Correlation of the rate of survivors and the gestation when the severe oligohydramnios is diagnosed a. 10.2% survivors in the second trimester b. 85.6% survivors in the third trimester

Diagnostic Investigations 1. Ultrasonography a. Ultrasonographic modalities to assess oligohydramnios i. Single deepest vertical pocket (range: A (p.Ala-1764-Thr) in the FLNA gene. The first sequence variation is previously reported to be associated with periventricular heterotropia. The significance of the second sequence variant is unknown. FLNA mutations with presumed gain of function are previously reported in association with four other disorders: otopalatodigital syndrome type I and II, frontometaphyseal dysplasia, and Melnick-Needles syndrome

Otopalatodigital Spectrum Disorders

a

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f j b

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Fig. 2 (a–l) Radiographs show hypoplastic scapulae, curved humeri, radii, and ulnae, duplicated fourth fingers with four unusually shaped metacarpals and phalanges, markedly bent

femora, bent tibiae, unossified fibulae, and four toes in each foot with unusually shaped metatarsals and phalanges

Pachyonychia Congenita

Pachyonychia congenita is a group of rare genetically inherited diseases characterized by nail dystrophy and by varying features of ectodermal dysplasias. There are two major clinical subtypes recognized: type I with oral leukokeratosis and type II with multiple pilosebaceous cysts (C¸elebi et al. 1999).

Synonyms and Related Disorders Jadassohn-Lewandowsky syndrome; Pachyonychia congenita, Jadassohn-Lewandowsky type; Pachyonychia congenita, Jackson-Lawler type

Genetics/Birth Defects 1. Inheritance (C¸elebi et al. 1999; Conners et al. 2001) a. Type I pachyonychia congenita (Jadassohn–Lewandowsky type) i. Autosomal dominant inheritance ii. Possible autosomal recessive inheritance b. Type II pachyonychia congenita (Jackson–Lawler type): autosomal dominant 2. Etiology a. Type I: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, KRT6a or KRT16, resulting in i. Fragility of specific epithelia ii. Phenotypes of pachyonychia congenita I or focal nonepidermolytic palmoplantar keratoderma with insignificant nail changes

b. Type II: caused by mutations in genes encoding one of the paired keratins of specialized epidermis, KRT6b or KRT17 i. Linkage analysis mapped pachyonychia congenita type II phenotype within the type I keratin gene cluster on chromosome 17q12-21 ii. A germline mutation has been identified in keratin 17 gene (K17). iii. Colocalization of K17 with keratin 6b 3. Genotype-phenotype correlation a. Differences in type I and type II phenotypes: largely explainable by the difference in expression patterns between the K6a/K16 and K6b/K17 expression pairs b. K6b/K17 expresses at higher levels in the pilosebaceous unit than K6a/K16: responsible for the pilosebaceous cysts in type II c. Conversely, K6a/K16 more widely expressed in oral epithelia: responsible for the greater predominance of oral leukokeratosis in type I

Clinical Features 1. Presence of intra- and interfamilial phenotypic variation (Feinstein et al. 1988) 2. Pachyonychia congenita type I (56.2% of cases) a. The most common subtype b. Onset in infancy c. Severe nail dystrophy affecting all the nails symmetrically (Dogra et al. 2002) i. The best hallmark of the disease

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ii. Thickened wedge-shaped nails iii. Proximal portions of the nails: smooth and normally attached to the lateral nail folds iv. Distal portions of the nails: may increase to many times the normal thickness, producing a subungual keratinous mass that pushes the nail plate upward, arching it transversally, folding it longitudinally, and elevating it distally v. Nails commonly shed and regrow with similar but more severe changes. vi. Projections from the nail beds make the nails susceptible to trauma with consequent chronic paronychial infections. d. With or without following associated anomalies i. Focal nonepidermolytic palmoplantar keratoderma (predominantly a feature of type I) ii. Follicular keratoses observed on a) Temple b) Eyebrows c) Extensor aspect of the proximal parts of the extremities iii. Hyperkeratosis of palms, soles, knees, and elbows iv. Localized foot blistering v. Oral leukokeratosis: a prominent sign vi. Neonatal teeth vii. Blister formation on palms and soles viii. Hoarse voice due to laryngeal involvement (leukokeratosis) ix. Palmar and plantar hyperhidrosis 3. Pachyonychia congenita type II (24.9% of cases) a. Nail dystrophy b. Less pronounced or absent palmoplantar keratoderma and oral changes c. Follicular keratoses d. Oral leukokeratosis e. Multiple pilosebaceous cysts (most useful distinguishing feature for type II but usually occurring at puberty) i. Epidermoid or infundibular cysts (arising from the hair follicle infundibulum) ii. Eruptive vellus hair cysts and multiple steatocystomas (characteristic of type II) (arising from the sebaceous duct epithelium) f. Bullae of palms and soles g. Palmar and plantar hyperhidrosis h. Natal or neonatal teeth

Pachyonychia Congenita

i. Pili torti in children j. Bushy eyebrows k. Hidradenitis suppurativa 4. Pachyonychia congenita type III (Schafer– Brunauer type) (11.7%) a. Features of type I and type II b. Angular cheilosis c. Leukokeratosis of the cornea d. Cataracts 5. Pachyonychia congenita tarda (type IV) (7.2%) a. A rare form of pachyonychia congenita b. Features of type I, type II, and type III c. Laryngeal lesions d. Hoarseness e. Mental retardation f. Hair anomalies g. Alopecia h. Nail changes occurring in the second or third decade i. Abnormal painful nails j. Palmoplantar keratoderma 6. Pachyonychia congenita with early onset nail changes in the absence of other associated features

Diagnostic Investigations 1. Histology and ultrastructure of cutaneous and oral lesions: suggest a keratin disorder (Munro 2001) 2. Molecular analyses of mutations in genes encoding one of the paired keratins of specialized epidermis, K6a/K16 and K6b/K17

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier 2. Prenatal diagnosis: genomic mutation detection possible in prenatal diagnosis of pachyonychia congenita type I (KRT6a/KRT16) or type II (KRT6b/KRT17) by CVS or amniocentesis

Pachyonychia Congenita

3. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation) has been identified. 4. Management (Dahl et al. 1995) a. No ideal treatment for the thickened nail plate available b. Vigorous use of topical lubricants and keratolytics c. Antiseptic wet dressings for secondarily infected areas d. Systemic treatment with acitretin producing variable and inconsistent results with caution of side effects (teratogenicity and hyperostosis) e. Custom-fitted footwear for protective support of painful fissures and blisters on the soles f. Simple avulsion of the distorted nails is inadequate because the dystrophic nail regrows. g. Curettage and electrofulguration or surgical excision of the nail matrix and bed can improve function and appearance. h. Surgical excision of focal, hyperplastic epithelial mass results in improvement of hoarseness due to laryngeal obstruction by laryngeal lesions. Additional microsurgery may be necessary for the recurrence of the laryngeal lesions. i. Therapeutic small interfering RNAs (siRNAs) for pachyonychia congenita (Leachman et al. 2008) i. A new siRNA entering clinical trials in PC patients with the KRT6A N171K mutation, with a gene-specific KRT6A siRNA study possibly to follow ii. This is the first-in-man siRNA therapeutic trial for a skin indication and the first siRNA to target a gene mutation.

References C¸elebi, J. T., Tanzi, E. L., Yao, Y. J., et al. (1999). Mutat report: Identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. Journal of Investigation Dermatology, 113, 848–850. Conners, J. B., Rahil, A. K., Smith, A. F. D., et al. (2001). Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. British Journal of Dermatology, 144, 1058–1062. Dahl, P. R., Daoud, M. S., & Su, W. P. (1995). Jadassohn– Lewandowski syndrome (pachyonychia congenita). Seminars in Dermatology, 14, 129–134.

1673 Dogra, S., Handa, S., & Jain, R. (2002). Pachyonychia congenita affecting only the nails. Pediatric Dermatology, 19, 91–92. Feinstein, A., Friedman, J., & Schewach, M. (1988). Pachyonychia congenita. Journal of the American Academy of Dermatology, 19, 705–711. Feng, Y.-G., Xiao, S.-X., Ren, X.-R., et al. (2003). Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts. British Journal of Dermatology, 148, 452–455. Haber, R. M., & Rose, T. H. (1986). Autosomal recessive pachyonychia congenita. Archives of Dermatology, 122, 919–923. Hannaford, R. S., & Stapleton, K. (2000). Pachyonychia congenita tarda. Australasian Journal of Dermatology, 41, 175–177. Irvine, A. D., & McLean, W. H. I. (1999). Human keratin diseases: Increasing spectrum of disease and subtlety of phenotype-genotype correlation. British Journal of Dermatology, 140, 815–828. Leachman, S. A., Hickerson, R. P., Hull, P. R., et al. (2008). Therapeutic siRNAs for dominant genetic skin diseases including pachyonychia congenita. Journal of Dermatological Science, 51, 151–157. Lucker, G., & Steijlen, P. (1995). Pachyonychia congenita tarda. Clinical and Experimental Dermatology, 20, 226–229. McLean, W. H. I., Rugg, E. L., Lunny, D. P., et al. (1995). Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nature Genetics, 9, 273–278. Moon, S. E., Lee, Y. S., & Youn, J. I. (1994). Eruptive vellus hair cyst and steatocystoma multiplex in a patient with pachyonychia congenita. Journal of the American Academy of Dermatology, 30, 275–276. Mouaci-Midoun, N., Cambiaghi, S., & Abimelec, P. (1996). Pachyonychia congenita tarda. Journal of the American Academy of Dermatology, 35, 334–335. Munro, C. S. (2001). Pachyonychia congenita: mutations and clinical presentations. British Journal of Dermatology, 144, 929–930. Munro, C. S., Carter, S., Bryce, S., et al. (1994). A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21. Journal of Medical Genetics, 31, 675–678. Smith, F. J. D., Corden, L. D., Rugg, E. L., et al. (1997). Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. Journal of Investigative Dermatology, 108, 220–223. Smith, F. J. D., Jonkman, M. F., van Goor, H., et al. (1998). A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Human Molecular Genetics, 7, 1143–1148. Smith, F. J. D., Kaspar, R. L., Schwartz, M. E., et al (2009) Pachyonychia congenita. Updated June 25, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br. fcgi?book¼gene&part¼pc Smith, F. J. D., McKenna, K. E., Irvine, A. D., et al. (1999). A mutation detection strategy for the human K6A gene and novel mutations in two cases of pachyonychia congenita type 1. Experimental Dermatology, 8, 109–114.

1674 Smith, F. J. D., McKusick, V. A., Nielsen, K., et al. (1999). Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1. Prenatal Diagnosis, 19, 941–946. Su, W. P. D., Chun, S., Hammond, D. E., et al. (1990). Pachyonychia congenita: A clinical study of 12 cases and review of the literature. Pediatric Dermatology, 7, 33–38.

Pachyonychia Congenita Terrinoni, A., Smith, F. J. D., Didona, B., et al. (2001). Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. Journal of Investigative Dermatology, 117, 1391–1396.

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Fig. 1 (a–d) Characteristic nail changes in an 8-month-old girl with pachyonychia congenita type I showing smooth proximal ends and thick distal ends of the nails, producing a subungual

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keratinous mass that pushes the nail bed upward, arching it transversally, folding it longitudinally, and elevating it distally. The patient also has oral leukokeratosis

Pallister–Killian Syndrome

Pallister–Killian syndrome is a rare sporadic cytogenetic abnormality, caused by a tissue-specific mosaic distribution of an additional isochromosome 12p, first described in three adults by Pallister et al. in 1977 and followed by report of a child by Teschler-Nicola and Killian in 1981 (Pallister et al. 1977; Teschler-Nicola and Killian 1981). The syndrome is also known as Teschler-Nicola/Killian syndrome, Pallister mosaic aneuploidy syndrome, or isochromosome 12p mosaicism. It is the most frequent autosomal tetrasomy in humans (Bresson et al. 1991).

Synonyms and Related Disorders Isochromosome 12p syndrome; Mosaic tetrasomy 12p syndrome

Genetics/Basic Defects 1. Genetics a. Always reported as sporadic b. Appears to be associated with increased maternal age 2. Basic cytogenetic defect (Bresson et al. 1991; Yeung et al. 2009). a. Caused by tetrasomy 12p b. Generally a mosaic c. Frequently undetectable by standard cytogenetic analysis of peripheral blood d. In the great majority of patients, the i(12p) is maternal in origin, with the underlying mechanism thought to involve a combination of centromere misdivision and nondisjunction at meiosis.

e. As a result, the i(12p) is present at conception, and mosaicism results from postzygotic mitotic loss (Peltomaki et al. 1987). f. There is no apparent correlation between the proportion of tetrasomic cells and the severity of clinical presentation (Schinzel 1991).

Clinical Features 1. Normal or large birth weight (Mathieu et al. 1997) 2. Craniofacial dysmorphism a. Brachycephaly b. High and broad forehead with frontal bossing c. Temporal alopecia d. Sparse eyebrows and eyelashes e. Hypertelorism f. Short nose with anteverted nares g. A thick philtrum h. A large mouth with down-slanting corners i. Full cheeks j. Cleft lip/palate k. High-arched palate l. Micrognathia m. Macroglossia n. Oral frenula o. Delayed dental eruption p. Dental anomalies q. Low-set and posteriorly rotated ears r. Hypertrophy of anthelix crux s. Thick earlobes 3. Short neck 4. Diaphragmatic hernia with or without lung hypoplasia

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5. Imperforate anus 6. CNS/neurologic abnormalities a. Severe hypotonia b. Mental retardation c. Dilated ventricles d. Bifrontal cortical atrophy e. Absent speech f. Poor vision g. Epilepsy 7. Congenital heart defects a. Ventricular septal defect: the most frequent single malformation b. Coarctation of the aorta c. Patent ductus arteriosus d. Atrial septal defect e. Aortic stenosis 8. Limb defects a. Talipes b. Broad and short hands and fingers c. Hypoplastic nails d. Abnormal palmar creases e. Lymphedema 9. Skin anomalies a. Loose/excess skin b. Pigmentary dysplasia c. Mild hyperkeratosis d. Dry skin e. Sweating abnormalities 10. Occasional internal organ malformations a. Umbilical hernia b. Malrotation of the gut c. Omphalocele d. Abnormalities of urogenital tract including cystic or dysplastic kidneys e. Genital anomalies in males i. Cryptorchidism ii. Small scrotum f. Occasional genital anomalies in females i. Ambiguous external genitalia ii. Hypoplasia of the labia majora iii. Absence of the upper vagina and uterus 11. Majority of patients die prenatally, perinatally, or early postnatally, and may die even after 10 or 15 years. 12. Phenotype in older children and young adults: marked phenotypic changes occurring during childhood and adolescence (Horneff et al. 1993) a. Coarse and flat facies b. Macroglossia

Pallister–Killian Syndrome

c. d. e. f. g.

Prognathia Everted lower lip Muscular hypertonia Contractures Severe psychomotor retardation

Diagnostic Investigations 1. Cytogenetic studies a. Demonstration of a supernumerary isochromosome of 12p b. Confirmation of 12p tetrasomy by FISH techniques i. Using centromere probe on chromosome 12 ii. Using whole chromosome 12 painting probe c. Cytogenetic studies of several tissues because of mosaicism (Mathieu et al. 1997): the mosaicism is usually detected in cultured skin fibroblasts or amniotic cells and rarely in phytohemagglutininstimulated lymphocytes, which suggests stimulation of T lymphocytes may distort the percentage of abnormal cells. i. Circulating lymphocytes: mosaicism as low as 1–3% ii. Amniocytes, chorionic cells and skin fibroblasts: mosaicism ranging from 6% to 100% 2. aCGH (comparative genomic hybridization) can detect partial tetrasomy of 12p in blood without invasive skin biopsy (Theisen et al. 2009). 3. Radiography a. Asymmetry of diaphyseal length b. Short humerus or femur c. Radial notch d. Diaphyseal irregularities e. Costovertebral defect 4. Echocardiography for congenital heart defect 5. EEG for seizure activities 6. MRI of the brain (Saito et al. 2006) a. Normal MRI findings b. Abnormal MRI findings i. Cortical atrophy with frontal predominance ii. Ventricular dilatation iii. Hydrocephalus iv. Reduced white matter v. Thickened cortex vi. Micropolygyria

Pallister–Killian Syndrome

vii. Heterotopic neurons viii. Agenesis of corpus callosum ix. Pineal gland tumor x. Multiple T2-high lesions xi. T2-elongation in the white matter 7. Postmortem pathologic examinations (Mathieu et al. 1997). a. Malpositioned feet b. Diaphragmatic defect c. Hypoplastic nails d. Genital malformation e. Imperforate or anteriorly placed anus f. Supernumerary spleen g. Heart valvular dysplasia h. Hypoplasia of the fibula

Genetic Counseling 1. Recurrence risk a. Patient’s sib: low recurrence risk (All cases are sporadic with only one preliminary case report of recurrence.) (Mathieu et al. 1997) b. Patient’s offspring: not surviving to reproductive age or severely handicapped by profound mental retardation 2. Prenatal diagnosis (Doray et al. 2002) a. Ultrasound anomalies i. Hydramnios (84%) ii. Diaphragmatic hernia (16%) iii. Short limbs, predominantly rhizomelic type of micromelia (10%) iv. Hydrops fetalis (6%) v. Cystic hygroma (3%) vi. Increased nuchal translucency (3%) vii. Fetal overgrowth (3%) viii. Flat fetal facial profile with a small nose and protruding lips (Liberati et al. 2008) ix. Ventriculomegaly (3%) x. Dilatation of cavum pellucidum (3%) xi. Absence of visualization of the stomach (3%) xii. Presence of a sacral appendix (3%) xiii. Cardiac malformation xiv. Hypertelorism xv. Short neck xvi. Other congenital anomalies b. Cytogenetic studies on amniocytes, cells from CVS, or fetal blood cells from cordocentesis i. Conventional karyotyping

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ii. FISH using chromosome 12 centromeric and whole chromosome painting probes a) Interphase cells b) Metaphase cells 3. Management a. Supportive treatment b. Surgical repair of diaphragmatic hernia or other congenital anomalies in nonlethal cases

References Bernert, J., Bartels, I., Gatz, G., et al. (1992). Prenatal diagnosis of the Pallister–Killian mosaic aneuploidy syndrome by CVS. American Journal of Medical Genetics, 42, 747–750. Bresson, J. L., Arbez-Gindre, F., Peltie, J., et al. (1991). Pallister Killian-mosaic tetrasomy 12 p syndrome. Another prenatally diagnosed case. Prenatal Diagnosis, 11, 271–275. Bulter, M. G., & Dev, V. G. (1995). Pallister–Killian syndrome detected by fluorescence in situ hybridization. American Journal of Medical Genetics, 57, 498–500. Buyse, M. L., & Korf, B. R. (1983). “Killian syndrome”, Pallister mosaic syndrome, or mosaic tetrasomy 12P? - An analysis. The Journal of Clinical Dysmorphology, 1, 2–5. Chiesa, J., Hoffet, M., Rousseau, O., et al. (1998). Pallister–Killian syndrome [i(12p)]: First pre-natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybridization. Clinical Genetics, 54, 294–302. Doray, B., Girard-Lemaire, F., Gasser, B., et al. (2002). Pallister–Killian syndrome: Difficulties of prenatal diagnosis. Prenatal Diagnosis, 22, 470–477. Genevieve, D., Cormier-Daire, V., Sanlaville, D., et al. (2003). Mild phenotype in a 15-year-old boy with Pallister–Killian syndrome. American Journal of Medical Genetics, 116A, 90–93. Hall, B. D. (1985). Mosaic tetrasomy 21 is mosaic tetrasomy 12p some of the time. Clinical Genetics, 27, 284–286. Horneff, G., Majewski, F., Hildebrand, B., et al. (1993). Pallister–Killian syndrome in older children and adolescents. Pediatric Neurology, 9, 312–315. Hunter, A. G., Clifford, B., & Cox, D. M. (1985). The characteristic physiognomy and tissue specific karyotype distribution in the Pallister–Killian syndrome. Clinical Genetics, 28, 47–53. Liberati, M., Melchiorre, K., D’Emilio, I., et al. (2008). Fetal facial profile in Pallister–Killian syndrome. Fetal Diagnosis and Therapy, 23, 15–17. Mathieu, M., Piussan, C., Thepot, F., et al. (1997). Collaborative study of mosaic tetrasomy 12p or Pallister–Killian syndrome (nineteen fetuses or children). Annales de Genetique, 40, 45–54. Pallister, P. D., Meisner, L. F., Elejalde, B. R., et al. (1977). The Pallister mosaic syndrome. Birth Defects Original Article Series, XIII(3B), 103–110. Peltomaki, P., Knuutila, S., Ritvanen, A., et al. (1987). Pallister–Killian syndrome: Cytogenetic and molecular studies. Clinical Genetics, 31, 399–405.

1680 Quarrell, O. W., Hamill, M. A., & Hughes, H. E. (1988). Pallister–Killian mosaic syndrome with emphasis on the adult phenotype. American Journal of Medical Genetics, 31, 841–844. Reynolds, J. F., Daniel, A., Kelly, T. E., et al. (1987). Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister–Killian syndrome): Report of 11 cases. American Journal of Medical Genetics, 27, 257–274. Saito, Y., Masuko, K., Kaneko, K., et al. (2006). Brain MRI findings of older patients with Pallister–Killian syndrome. Brain & Development, 28, 34–38. Schinzel, A. (1991). Tetrasomy 12p (Pallister–Killian syndrome). Journal of Medical Genetics, 28, 122–125. Shivashankar, L., Whitney, E., Colmorgen, C., et al. (1988). Prenatal diagnosis of tetrasomy 47, XY,+i(12p) confirmed by in situ hybridization. Prenatal Diagnosis, 8, 85–91. Soukup, S., & Neidich, K. (1990). Prenatal diagnosis of Pallister–Killian syndrome. American Journal of Medical Genetics, 35, 526–528. Speleman, F., Leroy, J. G., Van Roy, N., et al. (1991). Pallister–Killian syndrome: Characterization of the isochromosome 12p by fluorescent in situ hybridization. American Journal of Medical Genetics, 41, 381–387.

Pallister–Killian Syndrome Teschler-Nicola, M., & Killian, W. (1981). Case report 72: Mental retardation, unusual facial appearance, abnormal hair. Syndrome Identification, 7, 6–7. Theisen, A., Rosenfeld, J. A., Farrell, S. A., et al. (2009). aCGH detects partial tetrasomy of 12p in blood from Pallister–Killian syndrome cases without invasive skin biopsy. American Journal of Medical Genetics. Part A, 149A, 914–918. Warburton, D., Anyana-Yeboa, K., & Francke, U. (1988). Mosaic tetrasomy 12p: Four new cases, and confirmation of the chromosomal origin of supernumerary chromosome in one of the original Pallister-mosaic syndrome cases. American Journal of Medical Genetics, 27, 275–283. Wenger, S. L., Steele, M. W., & Yu, W.-D. (1988). Risk effect of maternal age in Pallister i(12p) syndrome. Clinical Genetics, 34, 181–184. Yeung, A., Francis, D., Giouzeppos, D., et al. (2009). Pallister–Killian syndrome caused by mosaicism for a supernumerary ring chromosome 12p. American Journal of Medical Genetics. Part A, 149A, 505–509. Young, I. D., Duckett, D. P., & O’Reilly, K. M. (1989). Lethal presentation of mosaic tetrasomy 12p (Pallister–Killian) syndrome. Annales de Genetique, 32, 62–64.

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Fig. 2 A G-banded karyotype showing a supernumerary i(12p) (arrow)

Fig. 1 Postmortem picture of a neonate with prenatally diagnosed mosaic i(12p). Amniocentesis was performed because of ultrasonographic finding of diaphragmatic hernia

Fig. 3 FISH of an interphase cell with centromere specific probe for chromosome 12 showing three signals

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Pallister–Killian Syndrome

Fig. 4 FISH of a metaphase chromosome spread with a whole chromosome probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow)

a

Fig. 5 FISH of a metaphase chromosome spread with a centromere probe specific for chromosome 12 showing two chromosome 12s and the i(12p) (arrow)

b

Fig. 6 (a, b) Another child with Pallister–Killian syndrome confirmed by cytogenetic studies showing prominent forehead, flat nasal bridge, sparse eyebrows, bitemporal alopecia, and everted lower lip

Phenylketonuria

Classical phenylketonuria (PKU) is a rare metabolic disorder, resulting from a deficiency of a liver enzyme, phenylalanine hydroxylase. The deficiency of the enzyme leads to elevated phenylalanine (Phe) levels in the blood and various tissues including the brain. The incidence in Caucasians is approximately one in 10,000, giving a heterozygote frequency of one in 50 to one in 70. About one in 15,000 infants is born with PKU in the United States.

Synonyms and Related Disorders Hyperphenylalaninemia; Phenylalanine hydroxylase deficiency; PKU

Genetics/Basic Defects 1. Inheritance a. Autosomal recessive b. Parents: obligatory carriers 2. Basic defect a. Deficient activity of the enzyme phenylalanine hydroxylase (PAH), resulting in hyperphenylalaninemia. PAH, a liver-specific enzyme, catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin as a cofactor. Chromosomal locus of the PAH gene is on 12q24.1. b. Identification of more than 400 different mutations in the PAH gene (National Institutes of Health Consensus Development Conference Statement 2001) i. Deletions ii. Insertions

iii. Missense mutations iv. Splicing defects v. Nonsense mutations c. Compound heterozygotes in most PKU patients, contributing to the clinical heterogeneity and biochemical heterogeneity d. Consequences of accumulation of phenylalanine (Phe) and other amino acids in the CNS i. Irreversible brain damage from the first few weeks of life ii. Severe learning disabilities and associated behavioral and psychological problems

Clinical Features 1. Treated patients a. Symptom-free on strict metabolic control using a low-phenylalanine diet for the infants detected by newborn screenings b. Normal development with a normal life span when diagnosed early in the newborn period and treated effectively with lifelong dietary control 2. Untreated patients a. Profound mental retardation b. Psychomotor handicaps c. Microcephaly d. Delayed speech e. Seizures f. Light hair and eyes and fair skin secondary to decreased formation of melanin pigment because of compromised tyrosine formation g. Musty body or urine odor secondary to excretion of phenylacetic acid into the sweat and the urine

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_191, # Springer Science+Business Media, LLC 2012

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Phenylketonuria

h. i. j. k.

d. Women with mild forms of PKU having relatively mild elevations of the phenylalanine are at risk of adversely affecting the fetuses if the mothers are unmonitored and untreated during pregnancies. Because placental gradient favors the fetus, the levels of Phe are higher in the fetus than in the mother. e. Effects of uncontrolled maternal PKU occur regardless of the genetic PKU status of the fetus.

Vomiting Irritability Eczema Subtle neurologic findings, sometimes noted even in treated individuals i. Hypertonic reflexes ii. Intention tremor l. Behavior problems i. Autistic-like behaviors ii. Hyperactivity iii. Agitation iv. Aggression 3. Maternal PKU a. Background information i. Loss of dietary compliance frequently starting during midchildhood ii. Noncompliance on special diet by many affected adolescent females, capable of reproduction, with blood phenylalanine levels above the current recommended therapeutic range iii. Loss of follow-up of such females despite effort to identify them iv. Teratogenic effect of elevated phenylalanine levels during pregnancy v. Fetal anomalies preventable by dietary therapy starting before conception and throughout pregnancy on women with PKU b. Abnormalities in the children of women with uncontrolled PKU during pregnancy i. Psychomotor retardation (92%) ii. Intrauterine growth retardation (40%) iii. Microcephaly iv. Congenital heart defects (10%) v. Postnatal growth retardation vi. Neurologic deficits vii. Mild craniofacial dysmorphic features viii. The frequency of abnormalities directly related to the degree of elevation of maternal phenylalanine levels during pregnancy ix. Abnormalities more likely to occur if maternal phenylalanine levels are not controlled during critical periods of embryogenesis and organogenesis early in pregnancy c. Currently, the control of phenylalanine levels during pregnancy is recommended at 2–6 mg/ dL or 1–4 mg/dL: at least as strict, if not more strict, as that currently recommended for PKU treatment during early childhood.

Diagnostic Investigations 1. Universal newborn screening from a heel stick bloodspot for PKU (since the 1960s) for early detection and treatment of the disorder (National Institutes of Health Consensus Development Conference Statement 2001) a. Guthrie bacterial inhibition assay i. Inexpensive ii. Simple iii. Reliable b. Fluorometric analysis i. Quantitative and automated test ii. Fewer false positive c. Tandem mass spectrometry i. Quantitative and automated test ii. Fewer false positive iii. Measurements of tyrosine iv. Identification of other metabolic disorders on a single sample 2. Plasma quantitative amino acid analysis especially phenylalanine and tyrosine levels (National Institutes of Health Consensus Development Conference Statement 2001) a. Phe concentrations persistently >2 mg/dL in the untreated state b. Recommended blood Phe levels in US clinics i. 2–6 mg/dL for age 12 years c. Frequent monitoring of blood Phe levels i. During first year: once a week to once a month ii. After first year: once a month to once every 3 months d. Recommended blood Phe levels in pregnant maternal PKU i. 50% of patients by age 60 c. Systemic involvement i. Arterial hypertension developing early and observed in >50% of patients ii. Vascular aneurysms iii. Cardiac valve defects iv. Colonic diverticula

Clinical Features 1. Intrafamilial and interfamilial variability in the onset, phenotype, and progression of the disease a. Due to genetic heterogeneity i. More common PKD1 (accounting for approximately 85% of cases associated with more severe disease) ii. Evidence of significant intrafamilial phenotypic variation suggesting modifying factors (such as the angiotensin-converting enzyme insertion/deletion polymorphism) as well as environmental factors that influence the clinical course iii. Association of the position of the PKD1 mutation with earlier end-stage renal disease b. Age of onset i. Presenting at any age ii. Generally presenting in the fourth and fifth decades of life iii. Occasionally presenting in the fetal or neonatal period

Polycystic Kidney Disease, Autosomal Dominant Type

2. Onset of disease in the childhood in children who carry PKD1 gene a. Frequency of children with renal cysts detectable by ultrasound i. Sixty percent by 5 years of age ii. Seventy-five to Eighty percent among children aged 5–18 years b. Number of renal cysts at 11 years i. One to ten in 60% of children ii. More than ten cysts in 40% of children 3. Age at the time of diagnosis and progression of the disease a. Diagnosis in utero or in the first year of life (intrauterine or infantile onset) i. Manifesting unusually severe disease ii. End-stage renal disease during childhood in 18% of cases b. Diagnosis after the first year of life i. Increase in the number of cysts over a mean interval of 3.7 years ii. Systolic hypertension in 9% of cases iii. None with decreased renal function 4. Renal manifestations (Fick et al. 1994) a. Development of bilateral renal cysts i. Primary renal manifestation ii. Leading to functional changes (impaired renal concentrating capacity, hypertension) iii. Leading to various clinical manifestations b. Flank or back pain (about 60%) c. Acute pain i. Infected cyst ii. Ruptured cyst (associated with gross hematuria) iii. Nephrolithiasis (20–36%) d. Urinary tract infection (40–68%) e. Hematuria f. Mild proteinuria g. End-stage renal disease 5. Extrarenal manifestations a. Liver involvement i. Most common extrarenal manifestation ii. Liver cysts uncommon before 16 years of age iii. Liver cysts observed in about 75% of patients older than 60 years iv. No liver symptoms in most patients with ADPKD v. Occasionally encountered liver changes a) Congenital hepatic fibrosis b) Segmental dilation of the biliary tract

Polycystic Kidney Disease, Autosomal Dominant Type

vi. Liver cysts responsible for most of the hepatic complications vii. Acute complications (Chauvear et al. 2000) a) Cyst infection b) Cyst hemorrhage c) Cyst rupture d) Cyst torsion viii. Chronic complications related to progressive increase of the polycystic liver (Chauvear et al. 2000) a) Abdominal mass b) Ascites c) Hepatic venous outflow obstruction (Budd-Chiari syndrome) d) Portal hypertension with variceal bleeding e) Inferior vena cava compression f) Bile duct compression g) Jaundice ix. Intrahepatic biliary cysts a) More common in women b) Exacerbated by pregnancy b. Other rare cystic involvement (Fick et al. 1994) i. Pancreatic cysts (10%) ii. Arachnoid cysts (5%) iii. Ovarian cysts c. Cardiovascular manifestations not uncommon i. Intracranial berry aneurysms (5–10%) ii. Dolichoectatic arteries iii. Aortic root dilatation iv. Dissections of intracerebral, coronary, thoracic, iliac, aortic, and splenic arteries reported v. Cardiac valve defects d. Other noncystic involvement i. Colonic diverticula (80% of patients with end-stage renal disease) ii. Hernias (25%) 6. Clinical course in children a. Clinical spectrum ranging from severe neonatal manifestations mimicking autosomal recessive polycystic kidney disease to renal cysts noted on ultrasound in asymptomatic children b. Diagnosis made in utero by ultrasound: massively enlarged cystic kidneys c. Newborn presenting with Potter phenotype and death from pulmonary hypoplasia d. Newborn with large abdominal masses

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e. After neonatal period i. Hypertension ii. Abdominal pain iii. Palpable abdominal mass iv. Hematuria v. Renal insufficiency, only rarely vi. Renal infections f. Rare extrarenal manifestations i. Liver cysts ii. Cerebral vessel aneurysms g. Prognosis i. Severe symptoms in neonatal or infantile cases ii. Milder symptoms in late childhood cases 7. Reproductive issues for adults with ADPKD (Vora et al. 2008) a. Men with ADPKD i. Necrospermia ii. Immotile sperm iii. Seminal vesicle cysts iv. Ejaculatory duct cysts b. Female fertility is not affected i. Affected women with ADPKD and normal renal function have a high rate of successful uncomplicated pregnancies. ii. Pregnant women with ADPKD with compromised kidney function should be monitored carefully for the development of hypertension and preeclampsia. 8. Risk factors precipitating faster progression of the disease a. The PKD-1 gene b. Male gender c. Earlier onset of symptoms i. Renal enlargement ii. Hematuria iii. Proteinuria iv. Incipient renal failure v. Hypertension d. Having >10 renal cysts before age 12 years e. Having blood pressures above the 75th percentile for age, height, and gender f. Polycystic liver disease i. Frequently associated with autosomal dominant polycystic kidney disease ii. Develops later than renal cysts iii. Develops earlier and more severe in women than in men

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9. End-stage renal disease a. The most feared renal complication of ADPKD b. Occurs in more than half of patients by the seventh decade of life 10. Differential diagnosis (Wolyniec et al. 2008) a. Autosomal recessive polycystic kidney disease: manifests advanced renal insufficiency present already in childhood or early youth (see the chapter on Autosomal Recessive Polycystic Kidney Disease) b. Tuberous sclerosis complex (see the chapter) i. Cysts in the kidneys observed in 20% of patients with tuberous sclerosis complex ii. Associated with characteristic skin and neurological symptoms c. Von Hippel-Lindau disease (see the chapter) d. Medullary cystic kidney disease i. Most commonly occurs as juvenile nephronophtisis ii. Associated with chronic renal failure in childhood e. Oral-facial-digital syndrome (see the chapter) f. Multicystic renal dysplasia in adults i. Usually a unilateral disorder ii. Frequent presence of calcification in the cyst walls and abnormal structure of parenchyma between the cysts visible on ultrasound g. Medullary sponge kidney: lithiasis and nephrocalcinosis commonly observed in the course of the disease h. Acquired cystic kidney disease

Diagnostic Investigations 1. Urinalysis a. Hematuria b. Mild proteinuria c. Evidence of infection 2. Sonography a. Prenatal presentation i. Large hyperechogenic kidneys ii. Variable size iii. Mixtures of small and large cysts iv. Exceptionally uncommon oligohydramnios b. Postnatal presentation: invariably large cysts 3. Renal ultrasound and IVP a. Enlarged kidneys b. Macrocysts and distortion of the collecting system

Polycystic Kidney Disease, Autosomal Dominant Type

4. CT scan and/or MRI for renal, hepatic, pancreatic, and ovarian cysts 5. CT scan and/or MRI angiography for intracranial aneurysm 6. Renal function tests 7. Renal ultrasound to assess carrier status a. A painless and relatively noninvasive procedure b. Detection rate in asymptomatic subjects from families with known ADPKD i. Twenty-two percent of cases in the first decade ii. Sixty-six percent of cases by the second decade iii. Eighty-six percent by age 25 8. Molecular diagnosis (Harris and Rossetti 2010) a. Diagnosis of ADPKD before the onset of symptoms is usually performed using renal imaging by either ultrasonography, CT, or MRI. In general, these modalities are reliable for the diagnosis of ADPKD in older individuals. b. However, molecular testing can be valuable when a definite diagnosis is required in young individuals, in individuals with a negative family history of ADPKD, and to facilitate preimplantation genetic diagnosis. c. Although linkage-based diagnostic approaches are feasible in large families, direct mutation screening is generally more applicable. d. Identification and characterization of PKD1 and PKD2 provided an opportunity for mutationbased molecular diagnostics to be used for ADPKD. Mutations in PKD1 account for 85% of cases and cause more severe disease than mutations in PKD2. e. As ADPKD displays a high level of allelic heterogeneity, complete screening of both genes is required. f. Consequently, such screening approaches are expensive. Screening of individuals with ADPKD detects mutations in up to 91% of cases. g. However, only 65% of patients have definite mutations, with 26% having nondefinite changes that require further evaluation. h. Collation of known variants in the ADPKD mutation database and systematic scoring of nondefinite variants is increasing the diagnostic value of molecular screening.

Polycystic Kidney Disease, Autosomal Dominant Type

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Not increased in de novo case ii. Fifty percent if one of the parent is affected b. Patient’s offspring i. Fifty percent risk of acquiring the disease ii. Both sexes of offspring affected equally 2. Carrier testing for family members at risk a. Ultrasound and radiography b. Molecular mutation analysis of PKD1 and PKD2 genes 3. Prenatal diagnosis a. Prenatal ultrasonography i. Enlarged kidneys (hyperechogenic) with or without cysts: the most common fetal findings ii. Absence of urine in the bladder iii. May not be evident until the third trimester iv. Evidence of uteroplacental insufficiency (Vora et al. 2008) a) Intrauterine growth restriction b) Oligohydramnios b. Molecular mutation analysis of PKD1 and PKD2 genes on fetal DNA obtained from amniocentesis or CVS, provided the mutation has been identified in the affected family members or linkage has been established in the family c. Preimplantation genetic diagnosis possible, provided the mutation has been identified previously 4. Management (Harris 2002) a. No treatment currently directed at the disease process b. Monitoring of presymptomatic patients with ADPKD i. Monitor blood pressure ii. Test renal function iii. Advantages a) Prevent or control hypertension b) Prevent or control infection c) Identify potential kidney donors from among the family d) Offer advice on reproduction e) Provide prenatal diagnosis c. Treatment of polycystic kidney disease i. Narcotic analgesics for pain ii. Antibiotics for infection iii. Treatment of nephrolithiasis

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a) Potassium citrate for uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects b) Extracorporeal shock wave lithotripsy c) Percutaneous nephrostolithotomy iv. Needle aspiration of dominant cysts v. Laparoscopic cyst decortication vi. Open renal cyst decortication vii. Therapeutic intervention aimed at slowing the progression of renal failure a) Control of hypertension b) Control of hyperlipidemia c) Dietary protein restriction d) Control of acidosis e) Prevention of hyperphosphatemia viii. Renal dialysis ix. Renal transplantation for end-stage renal disease i. Treatment of massive polycystic liver disease i. Aspiration of cyst fluid ii. Stenting iii. Cyst fenestration iv. Liver resection v. Liver transplantation j. Treatment of intracranial aneurysms i. Asymptomatic aneurysm a) Observation and yearly follow-up b) Surgery for enlarging aneurysm ii. Ruptured or symptomatic aneurysm: surgical clipping at its neck k. Management of aortic dissection i. Aortic root dilatation a) Yearly follow-up b) Strict blood pressure control with b-blockade ii. Surgery (replacement of the aorta) for aortic root greater than 55–60 mm

References Ariza, M., Alvarez, V., Marin, R., et al. (1997). A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. Journal of Medical Genetics, 34, 587–589. Arnaout, M. A. (2001). Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease. Annual Review of Medicine, 52, 93–123. Bear, J. C., McManamon, P., Morgan, J., et al. (1984). Age at clinical onset and at ultrasonographic diction of adult

1704 polycystic kidney disease: Data for genetic counselling. American Journal of Medical Genetics, 18, 45–53. Chauvear, D., Fakhouri, F., & Gr€ unfeld, J.-P. (2000). Liver involvement in autosomal-dominant polycystic kidney disease: Therapeutic dilemma. Journal of the American Society of Nephrology, 11, 1767–1775. Chen, M.-F. (2000). Surgery for adult polycystic liver disease. Journal of Gastroenterology and Hepatology, 15, 1239–1242. Daoust, M. C., Reynolds, D. M., Biche, T. D. G., et al. (1995). Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics, 25, 733–736. Edwards, O. P., & Baldinger, S. (1989). Prenatal onset of autosomal dominant polycystic kidney disease. Urology, 34, 265–270. Fick, G. M., Duley, I. T., Johnson, A. M., et al. (1994). The spectrum of autosomal dominant polycystic kidney disease in children. Journal of the American Society of Nephrology, 4, 1654–1660. Fick, G. M., & Gabow, P. A. (1994). Natural history of autosomal dominant polycystic kidney disease. Annual Review of Medicine, 45, 23–29. Fick, G. M., Johnson, A. M., Strain, J. D., et al. (1993). Characteristics of very early onset autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, 3, 1863–1870. Fick-Brosnahan, G. M., Tran, Z. V., Johnson, A. M., et al. (2001). Progression of autosomal-dominant polycystic kidney disease in children. Kidney International, 59, 1654–1662. Gabow, P. A., Johnson, A. M., Kaehny, W. D., et al. (1992). Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney International, 41, 1311–1319. Grantham, J. J. (1996). The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances. American Journal of Kidney Diseases, 28, 788–803. Gupta, S., Seith, A., Dhiman, R. K., et al. (1999). CT of liver cysts in patients with autosomal dominant polycystic kidney disease. Acta Radiologica, 40, 444–448. Harris, P. C., & Rossetti, S. (2010). Molecular diagnostics for autosomal dominant polycystic kidney disease. Nature Reviews Nephrology, 6, 197–206. Harris, P. C., Torres, V. E. (2009). Autosomal dominant polycystic kidney disease. Gene Reviews. Retrieved June 2, 2009. Available at: http://www.ncbi.nlm.nih.gov/books/ NBK1246/

Polycystic Kidney Disease, Autosomal Dominant Type Hateboer, N., Lazarou, L. P., Williams, A. J., et al. (1999). Familial phenotype differences in PKD1. Kidney International, 56, 34–40. Hateboer, N., van Dijk, M. A., Bogdanova, N., et al. (1999). Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet, 353, 103–107. Hemal, A. K. (2001). Laparoscopic management of renal cystic disease. Urologic Clinics of North America, 28, 115–126. Kimberling, W. J., Kumar, S., Gabow, P. A., et al. (1993). Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13–q23. Genomics, 18, 467–472. McDonald, R. A., & Avner, E. D. (1991). Inherited polycystic kidney disease in children. Seminars in Nephrology, 11, 632–642. Pei, Y., Paterson, A. D., Wang, K. R., et al. (2001). Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. American Journal of Human Genetics, 68, 355–363. Perrone, R. D. (1997). Extrarenal manifestations of ADPKD. Kidney International, 51, 2022–2036. Pirson, Y., Chauveau, D., & Torres, V. (2002). Management of cerebral aneurysms in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology, 13, 269–276. Rossetti, S., Burton, S., Strmecki, L., et al. (2002a). The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with severity of renal disease. Journal of the American Society of Nephrology, 13, 1230–1237. Rossetti, S., Chauveau, D., Walker, D., et al. (2002b). A complete mutation screen of the ADPKD genes by DHPLC. Kidney International, 61, 1588–1599. Rossetti, S., Strmecki, L., Gamble, V., et al. (2001). Mutation analysis of the entire PKD1 gene: Genetic and diagnostic implications. American Journal of Human Genetics, 68, 46–63. Torres, V. E., Wilson, D. M., Hattery, R. R., et al. (1993). Renal stone disease in autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases, 22, 513–519. Vora, N., Perrone, R., & Bianchi, D. W. (2008). Reproductive issues for adults with autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases, 51, 307–318. Wilson, P. D. (2004). Polycystic kidney disease. The New England Journal of Medicine, 350, 151–164. Wolyniec, W., Jankowska, M. M., Kro´l, E., et al. (2008). Current diagnostic evaluation of autosomal dominant polycystic kidney disease. Polskie Archiwum Medycyny Wewne˛trznej, 118, 767–772.

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Fig. 1 A lady (a) with autosomal dominant polycystic kidney disease and with family history of multiple affected family members. Her liver was markedly enlarged as shown by a pencil mark on the patient’s photo. The ultrasonography of the kidneys showed numerous cysts with minimal residual normal appearing cortex. The right kidney (b) measured 11 cm, with the largest cyst measuring 2.9 cm. The left kidney measured

d

13.3 cm in length, with the largest cyst measuring 3.8 cm (image not shown). The abdominal CT scan (c) showed marked hepatomegaly which occupies the entire abdomen. Numerous hepatic cysts and renal cysts were evident. Numerous cysts of different sizes were also detected in her brother’s enlarged kidneys by ultrasonography (the left kidney is shown here on image d)

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Polycystic Kidney Disease, Autosomal Dominant Type

a

b

c

Fig. 2 (a–c) Three CT scans of an adult patient with polycystic kidney disease with and without contrast showing multiple cysts in the kidneys and liver

Polycystic Kidney Disease, Autosomal Dominant Type

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Fig. 3 (a, b) Appearance of the gross and cut section of a kidney (745 g) surgically removed from a 43-year-old female with autosomal dominant polycystic kidney disease

Fig. 4 Multiple hepatic cysts of a patient with autosomal dominant polycystic kidney disease

Polycystic Kidney Disease: Autosomal Recessive Type

Autosomal recessive polycystic kidney disease (ARPKD) or polycystic kidney and hepatic disease 1 (PKHD1) is an often devastating form of polycystic kidney disease. It is also known as infantile polycystic kidney disease. The incidence of ARPKD is estimated to be 1 in 20,000 live births, and the frequency of the heterozygous carrier state is 1 in 70 (Lonergan et al. 2000).

Synonyms and Related Disorders Infantile polycystic kidney disease; Polycystic kidney and hepatic disease

e. The majority of patients are compound heterozygotes, and preliminary genotype/phenotype studies associate two truncating mutations with severe disease. f. The complexities of PKHD1, marked allelic heterogeneity, and high level of missense changes complicate gene-based diagnostics. 4. Genotype-phenotype correlations (Denamur et al. 2010) a. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise (Dell and Avner 2011). b. Patients who survive have at least one missense mutation.

Genetics/Basic Defects Clinical Features 1. Inheritance: autosomal recessive 2. No clear evidence of genetic heterogeneity 3. Molecular cause (Harris and Rossetti 2004) a. Mutations in the PKHD1 gene on chromosome 6p21.1-p12, encoding a putative receptor protein, fibrocystin (or polyductin) b. The ARPKD protein, fibrocystin, is predicted to be an integral membrane, receptor-like protein containing multiple copies of an Ig-like domain (TIG). c. Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue. d. In common with other PKD-related proteins, fibrocystin is localized to the primary cilia of renal epithelial cells, reinforcing the link between ciliary dysfunction and cyst development.

1. The most common heritable cystic renal disease manifesting in infancy and childhood (Lonergan et al. 2000) 2. A wide variable clinical spectrum, ranging from severe renal impairment, and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis, cholangitis, and portal hypertension 3. Principal manifestations a. Fusiform dilatation of renal collecting ducts and distal tubuli b. Dysgenesis of the hepatic portal triad 4. Clinical characteristics at presentation a. Zero to 1 month i. Prenatal diagnosis made ii. Positive family history

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iii. Pneumothorax iv. Flank mass v. Hypertension vi. Renal insufficiency b. >1 month–1 year i. Frank mass ii. Hepatomegaly iii. Hypertension iv. Urinary tract infection c. >1–5 years i. Hepatomegaly ii. Portal hypertension d. >5 years i. Hepatomegaly ii. Hypertension iii. Renal insufficiency iv. Portal hypertension e. Predominance of renal abnormalities in younger children f. Predominance of hepatic disease in older children and adolescents g. Tendency of inverse relative degrees of kidney and liver involvement i. Children with severe renal disease usually with milder hepatic disease ii. Children with severe hepatic disease with milder renal impairment 5. “Potter” phenotype developed in affected fetuses a. Pulmonary hypoplasia, often incompatible with life b. Characteristic face i. Short and snubbed nose ii. Deep eye creases iii. Micrognathia iv. Low-set flattened ears c. Deformities of the spine and limbs (clubfoot) 6. Renal manifestations a. Frequent loss of concentrating ability of the kidney b. Common recurrent urinary tract infections c. Proteinuria d. Hematuria e. Creatinine clearance improving early but declining progressively during adolescence f. Hypertension early in life but usually regresses g. Enlarged kidneys h. End-stage renal disease 7. Hepatic manifestations a. Congenital hepatic fibrosis i. Invariably present but only occasionally do hepatic symptoms predominate

Polycystic Kidney Disease: Autosomal Recessive Type

b.

c. d.

e.

ii. Two predominant features characterizing the liver in ARPKD a) Bile ducts: abnormally/irregularly formed, often increased in number, and dilated intrahepatic bile ducts b) Portal tracts: enlarged and fibrotic iii. Normal hepatic parenchyma iv. Hepatocellular function almost always normal in affected patients, even when they have relatively severe portal tract disease. v. Not by itself a diagnostic (not pathognomonic) sign. Congenital hepatic fibrosis has been observed in the following situations (Lonergan et al. 2000): a) Meckel-Gruber syndrome b) Vaginal atresia c) Tuberous sclerosis d) Juvenile nephronophthisis e) Rarely autosomal dominant polycystic kidney disease Caroli disease i. Congenital hepatic fibrosis accompanied by a nonobstructive dilation of the intrahepatic bile ducts ii. Clinical risk of secondary complications a) Stone formation b) Recurrent cholangitis: may result from ectatic bile ducts c) Hepatic abscesses d) Rare cholangiocarcinoma Hepatomegaly Portal hypertension (Lonergan et al. 2000) i. The most common sequelae of congenital hepatic fibrosis ii. Splenomegaly iii. Variceal bleeding iv. Hypersplenism a) Leukopenia b) Thrombocytopenia c) Anemia d) Increased susceptibility to infections resulting from leukopenia associated with splenic sequestration Ascending cholangitis (Lonergan et al. 2000) i. Presumably caused by entry of nonsterile gastrointestinal contents into the dilated intrahepatic bile ducts ii. Common in patients with macroscopically dilated bile ducts

Polycystic Kidney Disease: Autosomal Recessive Type

iii. Clinical features a) Abdominal pain b) Fever c) Elevation in levels of hepatic enzymes iv. Tends to recur v. May lead to hepatic abscess formation, sepsis, and death 8. Cerebral aneurysm, a common feature of ADPKD, reported in an adult with ARPKD 9. Prognosis a. Thirty to fifty percent of affected neonates die shortly after birth in respiratory insufficiency due to pulmonary hypoplasia. b. Recent trend with improved prognosis c. Sixty-seven percent of children who survive the newborn period with life-sustaining renal function at 15 years of age

Diagnostic Investigations 1. Radiography in neonates and infants with moderate to severe renal disease a. Smoothly enlarged kidneys because of the numerous dilated collecting ducts b. Abdominal distension c. Gas-filled bowel loops often deviated centrally d. Pulmonary hypoplasia and small thorax in the baby with severe kidney disease e. Pneumothorax common at birth following assisted ventilation 2. Ultrasonography a. Absence of renal cysts in both parents as demonstrated by ultrasound examination b. Neonatal ultrasonography with more marked renal cystic disease i. Massive enlarged kidneys ii. Increased echogenicity of entire parenchyma iii. Loss of corticomedullary differentiation iv. Loss of central echo complex v. Small macrocysts vi. Usually small bladder vii. Increased hepatic echogenicity, mainly in medulla c. Ultrasonography in children with more prominent hepatic fibrosis i. Massive kidney enlargement ii. Increased hepatic echogenicity, mainly in medulla

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iii. Macrocysts a) Less than 2 cm in diameter b) Tend to become larger and more numerous over time iv. Enlarged echogenic liver v. Hepatic cysts vi. Pancreatic cysts vii. Splenomegaly secondary to portal hypertension viii. Hepatofugal-flow duplex and color-flow Doppler 3. CT scan a. Nonenhanced CT: smooth, enlarged, and low-attenuating kidneys, likely the reflection of the large fluid volume in the dilated ducts b. CT with contrast i. Kidneys with a striated pattern representing accumulation of contrast material in the dilated tubules ii. Linear opacifications representing retention of contrast medium in dilated medullary collecting ducts iii. Macrocysts appearing as well-circumscribed rounded lucent defects iv. Time of delay in visualizing the contrast medium in the kidneys, proportionate to the severity of renal impairment 4. Ultrasonography and magnetic resonance cholangiography to investigate the presence of an extent of Caroli disease in children with autosomal recessive polycystic kidney disease 5. MRI of affected children (perinatal, neonatal, and infantile course) (Kern et al. 1999) a. Kidney appearance i. Enlarged, humpy but still reniform in shape ii. Homogeneously grainy parenchyma b. Signal intensity i. Hypointense on T1-W spin-echo sequences ii. Hyperintense on T2-W turbo spin-echo sequences c. RARE (rapid acquisition with relaxation enhancement)-MR-urography i. Hyperintense, linear radial pattern seen in the cortex and medulla representing the characteristic microcystic dilatation of collecting ducts ii. Possible few circumscribed small subcapsular cysts

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6. Histopathology of the kidney a. Radially arranged cylindrical and fusiform ducts are present throughout renal medulla and cortex, due to a generalized dilatation of collecting ducts. b. The portal tracts of the liver are enlarged and contain abundant fibrous tissue and many cistern-like dilated bile ducts. The abnormal changes are the result of ductal plate malformation. 7. Molecular diagnosis a. Linkage analysis of the affected family using 6p21 markers demonstrating linkage to the ARPKD1 gene with the affected proband b. 33 different mutations detected on 57 alleles (Rossetti et al. 2003) i. 51.1% in ARPKD ii. 32.1% in congenital hepatic fibrosis/(Caroli disease) iii. Two frequent truncating mutations a) 9689delA (9 alleles) b) 589insA (8 alleles) iv. Mutation detection rate a) High in severely affected patients (85%) b) Lower in moderate severe ARPKD (41.9%) c) Low, but significant, in adults with congenital hepatic fibrosis/Caroli disease (323.1%) v. Complications for the prospects for genebased diagnostics a) Large gene size b) Marked allelic heterogeneity c) Clinical diversity of the ARPKD phenotype c. Direct DNA analysis: available clinically i. Mutation scanning ii. Sequence analysis iii. Targeted mutation analysis iv. Deletion/duplication analysis v. Linkage analysis

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (theoretical risk 0.7%)

Polycystic Kidney Disease: Autosomal Recessive Type

2. Prenatal diagnosis a. Ultrasonography in most severely affected fetuses i. Enlarged, echogenic kidneys ii. Dilated collecting ducts iii. Characteristic hepatic ductal plate malformation iv. A small or nonvisualized bladder v. Oligohydramnios attributable to poor fetal renal output vi. Unreliable especially in early pregnancy b. Molecular genetic testing by mutation scanning of PKHD1 is available clinically by analysis of fetal DNA obtained by amniocentesis or CVS. Both disease-causing alleles of an affected family member must be identified or linkage has been established in the family before prenatal testing can be performed. The ARPKD locus mapped to proximal chromosome 6p allowing haplotypebased prenatal diagnosis in “at-risk” family with a previously affected child in whom prior family studies have identified informative linked markers. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in the previously affected sib (Zerres et al. 1998b; Dell 2011). c. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. 3. Management (Dell 2011) a. Initial management of affected infants to focus on stabilization of respiratory function. Mechanical ventilation may be necessary to treat both pulmonary hypoplasia and respiratory compromise from massively enlarged kidneys. b. Water and electrolyte balance c. Peritoneal dialysis may be required for neonates with oliguria or anuria within the first days of life. d. Vigorous treatment of systemic hypertension with antihypertensive agents i. ACE inhibitors ii. Calcium channel blockers iii. Beta blockers iv. Judicious use of diuretics (e.g., thiazides, loop diuretics) e. Antibiotics for treatment of urinary tract infections

Polycystic Kidney Disease: Autosomal Recessive Type

f. Management of renal osteodystrophy in children with ARPKD and chronic renal insufficiency i. Calcium supplements ii. Phosphate binders iii. 1,25-dihydroxyvitamin D3 to suppress parathyroid hormone (PTH) iv. Erythropoietin (EPO) a) Increases hemoglobin levels b) Improves the overall well-being of the child g. Potential use of recombinant human growth hormone therapy to improve the growth of children with uremia h. Therapeutic options available for the treatment of portal hypertension in children (Lonergan et al. 2000) i. Conservative management ii. Control of variceal bleeding a) Sclerotherapy effective in controlling bleeding b) Banding of varices c) Placement of portosystemic shunts occasionally necessary to reduce bleeding and the formation of additional varices iii. Prompt management with antibiotics and, when indicated, surgical drainage to help reduce morbidity and mortality associated with ascending cholangitis iv. Splenectomy for hypersplenism v. Liver transplantation in patients with severe hepatic dysfunction or chronic cholangitis i. Replacement therapy for renal failure i. Renal dialysis ii. Renal transplant j. Combined liver/kidney transplantation

References Bergmann, C., Senderek, J., Sedlacek, B., et al. (2003). Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). Journal of the American Society of Nephrology, 14, 76–89. Dell, K. M., Avner, E. D. (2011). Polycystic kidney disease, autosomal recessive. GeneReviews. http://www.ncbi.nlm. nih.gov/books/NBK1326/ Denamur, E., Delezoide, A.-L., Alberti, C., et al. (2010). Genotype-phenotype correlations in fetuses and neonates

1713 with autosomal recessive polycystic kidney disease. Kidney International, 77, 350–358. Guay-Woodford, L. M., & Desmond, R. A. (2003). Autosomal recessive polycystic kidney disease: The clinical experience in North America. Pediatrics, 111, 1072–1080. Harris, P. C., & Rossetti, S. (2004). Molecular genetics of autosomal recessive polycystic kidney disease. Molecular Genetics and Metabolism, 81, 75–85. Herrin, J. T. (1989). Phenotypic correlates of autosomal recessive (infantile) polycystic disease of kidney and liver: Criteria for classification and genetic counseling. Progress in Clinical and Biological Research, 305, 45–54. Jamil, B., McMahon, L. P., Savige, J. A., et al. (1999). A study of long-term morbidity associated with autosomal recessive polycystic kidney disease. Nephrology, Dialysis, Transplantation, 14, 205–209. Jung, G., Benz-Bohm, G., Kugel, H., et al. (1999). MR cholangiography in children with autosomal recessive polycystic kidney disease. Pediatric Radiology, 29, 463–466. Kern, S., Zimmerhackl, L. B., Hildebrandt, F., et al. (1999). Rare-MR-urography–a new diagnostic method in autosomal recessive polycystic kidney disease. Acta Radiologica, 40, 543–544. Lieberman, E., Salinas-Madrigal, L., Gwinn, J. L., et al. (1971). Infantile polycystic disease of the kidneys and liver: Clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine, 50, 277–318. Lilova, M., Kaplan, B. S., & Meyers, K. E. (2003). Recombinant human growth hormone therapy in autosomal recessive polycystic kidney disease. Pediatric Nephrology, 18, 57–61. Lonergan, G. J., Rice, R. R., & Suarez, E. S. (2000). Autosomal recessive polycystic kidney disease: Radiologic-pathologic correlation. Radiographics, 20, 837–855. MacRae, K., & Avner, E. D. (2009). Polycystic kidney disease, autosomal recessive. GeneReviews. Updated July 14, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/ br.fcgi?book¼gene&part¼pkd-ar Pe´rez, L., Torra, R., Badenas, C., et al. (1998). Autosomal recessive polycystic kidney disease presenting in adulthood. Molecular diagnosis of the family. Nephrology Dialysis Transplantation, 13, 1273–1276. Rossetti, S., Torra, R., Coto, E., et al. (2003). A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees. Kidney International, 64, 391–403. Roy, S., Dillon, M. J., Trompeter, R. S., et al. (1997). Autosomal recessive polycystic kidney disease: Long-term outcome of neonatal survivors. Pediatric Nephrology, 11, 302–306. Stein-Wexler, R., & Jain, K. (2003). Sonography of macrocysts in infantile polycystic kidney disease. Journal of Ultrasound in Medicine, 22, 105–107. Sumfest, J. M., Burns, M. W., & Mitchell, M. E. (1993). Aggressive surgical and medical management of autosomal recessive polycystic kidney disease. Urology, 42, 309–312. Zerres, K., Becker, J., Mucher, G., et al. (1997). Autosomal recessive polycystic kidney disease. Contributions to Nephrology, 122, 10–16.

1714 Zerres, K., Hansmann, M., Mallmann, R., et al. (1988). Autosomal recessive polycystic kidney disease. Problems of prenatal diagnosis. Prenatal Diagnosis, 8, 215–229. Zerres, K., Mucher, G., Bachner, L., et al. (1994). Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nature Genetics, 7, 429–432. Zerres, K., Mucher, G., Becker, J., et al. (1998a). Prenatal diagnosis of autosomal recessive polycystic kidney disease

Polycystic Kidney Disease: Autosomal Recessive Type (ARPKD): Molecular genetics, clinical experience, and fetal morphology. American Journal of Medical Genetics, 76, 137–144. Zerres, K., Rudnik-Schoneborn, S., Steinkamm, C., et al. (1998b). Autosomal recessive polycystic kidney disease. Journal of Molecular Medicine, 76, 303–309. Zerres, K., Rudnik-Schoneborn, S., Senderek, J., et al. (2003). Autosomal recessive polycystic kidney disease (ARPKD). Journal of Nephrology, 16, 453–458.

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Fig. 1 (a, b) A newborn with ARPKD showing Potter facies. The spongy appearing cut surface of a kidney from the same patient is due to generalized dilatation of the collecting ducts in both cortex and medulla

Fig. 2 Photomicrograph of a kidney of a neonate (37 weeks gestation) with ARPKD showing markedly dilated collecting ducts in the medulla (top) and the cortex (bottom). The infant also had intrahepatic bile duct proliferation and mild cystic changes, and pulmonary hypoplasia

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Polycystic Kidney Disease: Autosomal Recessive Type

Fig. 3 Photomicrograph of the liver of a 2-year-old girl with congenital hepatic fibrosis, consistent with ARPKD. Note the irregularly dilated branching bile ducts. There is abundant fibrous connective tissue in this enlarged portal tract

a

b

Fig. 4 (a, b) Two neonates with ARPKD showing markedly distended abdomen

a

Fig. 5 (a, b) Kidneys in another neonate with ARPKD

b

Popliteal Pterygium Syndrome

In 1968, Gorlin et al. described an autosomal dominant form of popliteal pterygium syndrome (PPS), a syndrome comprising cleft lip and palate, popliteal and intercrural pterygia, and digital and genital anomalies. Van der Woude syndrome (VWS) is one of the most common oral cleft syndromes. It accounts for about 2% of all cleft lip and palate cases. Both syndromes are caused by IRF6 mutations. In 1972, Bartsocas and Papas reported on four sibs of third-cousin parents with a severe, presumably autosomal recessive form of popliteal pterygium syndrome.

Synonyms and Related Disorders Bartsocas-Papas syndrome; IRF6-Related Disorders including Van der Woude syndrome

Genetics/Basic Defects 1. Interferon regulatory factor 6 (IRF6) encodes a member of the IRF family of transcription factors (de Lima et al. 2009) 2. Mutations in IRF6 cause popliteal pterygium syndrome and Van der Woude syndrome. 3. Popliteal pterygium syndrome a. Inherited as an autosomal dominant trait b. Exonic mutations in IRF6 are found in nearly all families with PPS (De Lima et al. 2009). 4. Van der Woude syndrome a. Inherited as an autosomal dominant trait with high penetrance (96.7%) but with variable expression

b. A nonsense mutation in the interferon regulatory factor 6 (IRF6) gene in the affected sib of two monozygotic twins discordant for VWS, suggesting IRF6 as a candidate for VWS (Kondo et al. 2002) c. This hypothesis was confirmed in the same study by the detection of IRF6 mutations in 45 additional unrelated families with VWS. In addition, a unique set of mutations in IRF6 was discovered in 13 families with PPS, demonstrating that VWS and PPS as allelic, as previously suggested (Lees et al. 1999). d. Subsequently, mutations in IRF6 were identified in 56 additional families with VWS and three with PPS (de Lima et al. 2009). e. Exonic mutations in IRF6 are found in 68% of families with VWS. 5. Bartsocas-Papas syndrome (BPS) a. Inherited as an autosomal recessive trait b. Early lethality c. IRF6 mutation has not been studied in BPS.

Clinical Features 1. Autosomal dominant popliteal pterygium syndrome a. Cleft lip with or without cleft palate b. Fistula of the lower lip c. Filiform synechiae may connect the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). d. Webbing of the skin extending from the ischial tuberosities to the heels e. Bifid scrotum and cryptorchidism in males f. Hypoplasia of the labia majora in females

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g. Syndactyly of fingers and/or toes h. Anomalies of the skin around the nails: A characteristic pyramidal fold of skin overlying the nail of the hallux is almost pathognomonic. i. Normal growth and intelligence 2. Van der Woude syndrome (Gorlin et al. 2001) a. Congenital lower-lip fistulae (pits) i. Usually bilateral and paramedian ii. The phenotype of the lower lip varies from a single barely evident depression to bilateral fistulae of the lower lip. iii. Phenotypes of the orofacial cleft vary from a bifid uvula to a complete cleft lip and palate. b. Cleft lip with or without cleft palate and cleft palate only c. Hypodontia d. Less common features i. Syndactyly of the fingers ii. Syngnathia iii. Ankyloblepharon e. Normal growth and intelligence 3. Autosomal recessive Bartsocas-Papas syndrome a. Oral clefts b. Filiform bands between jaws c. Ankyloblepharon d. Popliteal pterygium e. Syndactyly of fingers and toes f. Phalangeal anomalies such as hypoplasia and/or synostosis g. Nail hypoplasia h. Genital anomalies in both sexes i. Early lethality is common j. Causes of death i. Bronchopneumonia ii. Respiratory distress iii. Sepsis

Diagnostic Investigations 1. Histology of popliteal pterygium (Gorlin et al. 1968) a. Bilateral pterygium extending from the heel to the ischial tuberosity b. Limiting extension and abduction as well as rotation of the leg c. A hard, inelastic subcutaneous cord or fibrous band runs along the free edge of the pterygium

Popliteal Pterygium Syndrome

d. The sciatic nerve lies free within the pterygium deep to the fibrous band about halfway between the free edge and the apex being covered by fibromuscular septa. e. The popliteal vessels are normally situated deep in the popliteal space. f. Absence of muscle groups or abnormal muscle insertions in many cases 2. Molecular genetic testing by sequence analysis of the IRF6 coding region (exons 1–9) (Durda et al. 2011) a. Detects mutations in approximately 70% of individuals with the Van der Woude syndrome phenotype b. Detects mutations in approximately 97% of individuals with the popliteal pterygium syndrome phenotype

Genetic Counseling 1. Recurrence risk for autosomal dominant IRF6related disorders a. Patient’s sib i. Appears to be low when parents are clinically unaffected, but the possibility of incomplete penetrance in a parent or of germline mosaicism need to be considered ii. Fifty percent if a parent of the proband is affected or has an IRF6 mutations b. Patient’s offspring i. Each child of an individual with an IRF6 mutation has a 50% chance of inheriting the mutation. ii. The clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the offspring. 2. Prenatal diagnosis a. Ultrasonography i. Oral cleft ii. Popliteal pterygium b. Molecular genetic testing i. Prenatal diagnosis for pregnancies at increased risk is possible if the diseasecausing allele of an affected family member is previously identified. ii. Preimplantation genetic diagnosis: may be available for families in which the diseasecausing mutation has been identified in an affected family member

Popliteal Pterygium Syndrome

3. Management (Gahm et al. 2007) a. Early surgical treatment is of importance to enable and preserve oral feeding. b. Intranasal flexible fiber intubation with the patient awake is a possible anesthetic strategy to secure the airway prior to surgery in patients with multiple or extensive interalveolar syngnathia. c. Surgical removal for synechiae d. Cleft lip/cleft palate: surgical and orthodontic management e. Speech therapy and audiologic evaluation for cleft palate f. Surgery for lip pits for cosmetic purpose g. Syndactyly may require surgery. h. To accomplish knee extension (Gardetto and Piza-Katzer 2003) i. Resect fibrous bands ii. Free the sciatic nerve iii. Z-lengthening of the Achilles tendon and multiple Z-plasties iv. Surgery result: 1 year after surgery, the patient can put his heel on the ground and has almost complete range of motion in the knee and ankle joints. i. Orthopedic care and physical therapy may be needed.

References Bartsocas, C. S., & Papas, C. V. (1972). Popliteal pterygium syndrome: Evidence for a severe autosomal recessive form. Journal of Medical Genetics, 9, 222–226. De Lima, R. L. L. F., Hoper, S. A., Ghassibe, M., et al. (2009). Prevalence and non-random distribution of exonic mutations in Interferon Regulatory Factor 6 (IRF6) in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. Genetics in Medicine, 11, 241–247. Durda, K. M., Schutte, B. C. (2011). IRF6-related disorders. GeneReviews. Retrieved March 1, 2011. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1407/ Gahm, C., Kuylenstierna, R., & Papatziamos, G. (2007). Popliteal pterygium syndrome (PPS) with intra-alveolar syngnathia: A discussion of anesthetic and surgical considerations. International Journal of Pediatric Otorhinolaryngology, 71, 1613–1616.

1719 Gardetto, A., & Piza-Katzer, H. (2003). A case of familial popliteal pterygium syndrome: Early surgical intervention for successful treatment. Pediatric Surgery International, 19, 612–614. Giannotti, A., DiGilio, M. C., Standoli, L., et al. (1992). New case of Bartsocas-Papas syndrome surviving at 20 months. American Journal of Medical Genetics, 42, 733–735. Gorlin, R. J., Cohen, A. A., & Hennekam, R. C. M. (2001). Syndromes of the head and neck (Vol. 4). Oxford: Oxford University Press. Gorlin, R. J., Sedano, H. O., & Cervenka, J. (1968). Popliteal pterygium syndrome. A syndrome comprising cleft lip-palate, popliteal and intercrural pterygia, digital and genital anomalies. Pediatrics, 41, 503–509. Hall, J. G., Reed, S. D., Rosenbaum, K. N., et al. (1982). Limb pterygium syndromes: A review and report of eleven patients. American Journal of Medical Genetics, 12, 377–409. Hennekam, R. C. M., Huber, J., & Vriend, D. (1994). BartsocasPapas syndrome with internal anomalies: Evidence for a more generalized epithelial defect or new syndrome? American Journal of Medical Genetics, 53, 102–107. Houweling, A. C., Gille, J. J. P., Baart, J. A., et al. (2009). Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling. Clinical Dysmorphology, 18, 225–227. Kondo, S., Schutte, B. C., Richardson, R. J., et al. (2002). Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics, 32, 285–289. Lees, M. M., Winter, R. M., Malcolm, S., et al. (1999). Popliteal pterygium syndrome: A clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32. Journal of Medical Genetics, 36, 888–892. Martinez-Frias, M. L., Frias, J. L., Vazquez, I., et al. (1991). Bartsocas-Papas syndrome: Three familial cases from Spain. American Journal of Medical Genetics, 39, 34–37. Massoud, A. A., AAmmaari, A. N., Khan, A. S. S., et al. (1998). Bartsocas-Papas syndrome in an Arab family with four affected sibs: further characterization. American Journal of Medical Genetics, 79, 16–21. Papadia, F., & Longo, N. (1988). Nosological differences between the Bartsocas-Papas syndrome and lethal multiple pterygium syndrome. American Journal of Medical Genetics, 29, 699–700. Papadia, F., & Zimbalatti, F. (1984). Gentile la Rosa C: The Bartsocas-Papas syndrome: Autosomal recessive form of popliteal pterygium syndrome in a male infant. American Journal of Medical Genetics, 17, 841–847. Reich, E., Wishnick, M., McCarthy, J., et al. (1984). Long term follow-up in an 8-year old with the “lethal” popliteal pterygium syndrome (Bartsocas-Papas syndrome). American Journal of Human Genetics, 36(Suppl.), 70s.

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a

Popliteal Pterygium Syndrome

b

c

Fig. 1 (a–c) The newborn was evaluated for multiple congenital anomalies, consisting of ankyloblepharon connecting upper and lower eyelids by fimbria (thin thread-like connective tissue), unilateral cleft lip and palate, thin strings of connective tissue connecting the upper and lower alveolar ridge on both sides, absence of labia majora, hypoplastic labia minor, a clitoral hood, a sacral dimple, popliteal pterygium (webbing of the skin

extending from the ischial tuberosities to the heels), skin over the nails of her great toes giving the nail a somewhat triangular shape with a flat base, and syndactyly over second to fifth toes bilaterally. The clinical diagnosis of popliteal pterygium syndrome was confirmed by molecular genetic analysis of IRF6 gene which showed a missense mutation of exon 4 [c252G > A or p.Arg841His (R84H)]

Popliteal Pterygium Syndrome

a

b

Fig. 2 (a, b) Another baby with popliteal pterygium syndrome

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Prader–Willi Syndrome

Prader–Willi syndrome is a neurogenetic disorder characterized by hypotonia and feeding difficulties in infancy, followed by hyperphagia, hypogonadism, mental retardation, and short stature. It was the first recognized microdeletion syndrome identified with high-resolution chromosome analysis, the first recognized human genomic imprinting disorder, and the first recognized disorder resulting from uniparental disomy. The incidence of Prader–Willi syndrome is approximately 1/10,000–1/15,000 individuals.

Genetics/Basic Defects 1. Inheritance a. Usually sporadic events (de novo deletions of 15q11–q13) b. Rare familial transmission (balanced translocations involving 15q11–q13) ( A) which are both known to be pathogenic. The results are consistent with a diagnosis of SEPN1-related myopathy, an autosomal recessive myopathy. Note the myopathic face

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Fig. 3 Note his rigid neck that cannot bend

Fig. 4 Note difficulty in bending his neck and spine

Rigid Spine Syndrome

Rigid Spine Syndrome Fig. 5 (a–c) Radiographs of the spine showed stiff spinal column (lateral views) and mild scoliosis (AP view)

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c

Roberts Syndrome

Roberts syndrome is a rare hereditary disorder characterized by symmetrical reduction of all limbs and a unique cytogenetic abnormality of premature centromere separation, which disrupts the process of chromatid pairing.

Synonyms and Related Disorders Roberts-SC Phocomelia syndrome

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. Associated with unique cytogenetic abnormality: premature centromere separation a. Disrupts the process of chromatid pairing b. Responsible for the development of multiple structural anomalies observed in Roberts syndrome 3. Caused by mutations in establishment of cohesion 1 homologue 2 (ESCO2) on 8p21.1, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion (Vega et al. 2005) 4. Loss of ESCO2 acetyltransferase activity was recently implicated in the molecular mechanism of Roberts syndrome (Gordillo et al. 2008).

Clinical Features 1. Craniofacial malformations: marked variability a. Bilateral cleft lip and cleft palate in severe cases b. No clefting of the lip or palate in some cases

c. Hypertelorism secondary to widely spaced orbits d. Ophthalmic manifestations i. Exophthalmos due to shallow orbits ii. Microphthalmia iii. Peter anomaly iv. Cloudy cornea v. Cataracts e. Wide nasal bridge f. Hypoplastic nasal alae g. Hemangiomata of the lip, nose, face, or forehead h. Micrognathia i. Dark scalp hair becomes thin and silvery blond. 2. Limb defects a. Phenotype varies from a complete absence of arms and legs with rudimentary digits to mild growth reduction in the limbs. b. Limb reduction defects tend to be symmetric and more severely involved in the upper extremities than the lower extremities. c. Presence of phocomelia i. Tetraphocomelia: a prominent characteristic of the syndrome ii. Two deficient limbs in 11% of cases iii. No phocomelia in 2% of cases d. Often reduced number of fingers (oligodactyly) e. Radial aplasia or dysplasia common f. Lack of 1st metacarpal, thumb, or first phalanx 3. Other associated anomalies a. CNS anomalies i. Mental retardation ii. Microcephaly iii. Hydrocephalus iv. Absent olfactory lobes v. Calcification of the basal ganglia vi. Encephalocele

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vii. Cranial nerve paralysis viii. Seizures b. Congenital heart defects i. Atrial septal defect ii. Patent ductus arteriosus iii. Pulmonic stenosis iv. Aortic stenosis v. AV canal defect c. Renal anomalies i. Polycystic kidneys ii. Dysplastic kidneys iii. Horseshoe kidney iv. Hydronephrosis v. Renal agenesis d. Gastrointestinal obstruction e. Splenogonadal fusion f. Cryptorchidism g. Enlarged phallus h. Failure to thrive i. Neoplasms i. Sarcoma botryoides ii. Malignant melanoma 4. Prognosis a. Severe cases i. Often resulting in spontaneous abortions or stillbirths ii. Few cases survive past one month of life. b. Phenotypically milder cases i. Requiring minimal to full time care depending on the degree of mental retardation ii. May require surgical interventions to correct craniofacial and limb anomalies 5. Differential diagnosis (Gordillo et al. 2009) a. SC phocomelia (Herrmann et al. 1969) i. Clinical characteristics a) Tetraphocomelia b) Scanty silvery blond hair c) Microcephaly d) Mild mental retardation e) Facial hemangioma f) Cloudy cornea g) Hypoplastic nasal alae and ears ii. Originally thought to differ from Roberts syndrome by a) Usual absence of midfacial clefting b) Prolonged survival c) Lesser degree of mental and physical retardation d) Relatively milder degree of phocomelia

Roberts Syndrome

b.

c.

d. e.

iii. Now considered to be the same entity as Roberts syndrome (Roberts-SC phocomelia syndrome) based on the following observations (Sch€ule et al. 2005): a) The presence of severely and mildly affected individuals in the same sibship raised the suspicion that the two disorders are allelic, representing spectrum of severity. b) Furthermore, both are characterized by heterochromatin repulsion (HR) or premature centromere separation in mitotic cells (Judge 1973; Freeman et al. 1974a, 1974b; Tomkins et al. 1979). c) Somatic-cell complementation studies revealed that cells positive for HR (HR+) from individuals with Roberts syndrome and from those with SC do not complement each other, further supporting the notion that the same gene is affected in the two disorders (McDaniel et al. 2000). Thrombocytopenia-absent radius (TAR) syndrome (see the chapter on ThrombocytopeniaAbsent Radius (TAR) Syndrome). i. Absent radii with thumbs present ii. Hypomegakaryocytic thrombocytopenia iii. Absent cleft palate Baller-Gerold syndrome i. Autosomal recessive disorder ii. Craniosynostosis (brachycephaly) iii. Ocular proptosis iv. Bulging forehead v. Radial ray defect (oligodactyly) vi. Aplasia or hypoplasia of the thumb and/or aplasia or hypoplasia of the radius vii. Growth retardation viii. Poikiloderma ix. Caused by mutations in RECQL4 Fanconi anemia (see the chapter on Thrombocytopenia-Absent Radius (TAR) Syndrome). Tetra-amelia, X-linked (Zimmer tetraphocomelia) i. Tetra-amelia ii. Facial clefts iii. Absence of ears and nose iv. Anal atresia v. Absence of frontal bones vi. Pulmonary hypoplasia with adenomatoid malformation vii. Absence of thyroid

Roberts Syndrome

f.

g.

h.

i. j.

viii. Dysplastic kidneys, gallbladder, spleen, uterus, and ovaries ix. Imperforate vagina Tetra-amelia, autosomal recessive i. Caused by mutations in the WNT3 ii. Amelia iii. Severe lung hypoplasia and aplasia of the peripheral pulmonary vessels iv. Cleft lip/palate v. Hypoplasia of the pelvis vi. Malformed uterus vii. Atresia of the urethra, vagina, and anus viii. Diaphragmatic defect ix. Agenesis of the kidney, spleen, and adrenal glands Splenogonadal fusion with limb defects and micrognathia i. Autosomal recessive inheritance ii. Abnormal fusion between the spleen and the gonad or the remnants of the mesonephros iii. Tetramelia iv. Mild mandibular and oral abnormalities (micrognathia, multiple unerupted teeth, crowding of the upper incisors, and deep, narrow, V-shaped palate without cleft) DK phocomelia syndrome i. Autosomal recessive inheritance ii. Phocomelia iii. Absence of radius and digits iv. Thrombocytopenia v. Encephalocele vi. Cleft palate and absence of radius and digits vii. Anal atresia viii. Abnormal lobation of the lungs ix. Diaphragmatic agenesis Holt-Oram syndrome (see the chapter) Thalidomide embryopathy (see the chapter on dysmelia) i. Abnormalities of the long bones of the extremities a) Upper limb bones are affected in an order of frequency starting with the thumb, followed by the radius, the humerus, the ulna, and finally the fingers on the ulnar side of the hand. b) In extreme cases, the radius, ulna, and humerus are lacking; the hand bud arises from the shoulders. c) Legs may be affected but less severely.

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ii. The second major group of defects involves the ears (anotia, microtia, accessory auricles) and the eyes (coloboma of the iris, anophthalmia, microphthalmia). iii. Internal defects commonly involve the heart, kidneys, and urinary, alimentary, and genital tracts. k. Cornelia de Lange syndrome (see the chapter) l. Mosaic variegated aneuploidy syndrome i. Autosomal recessive inheritance ii. Caused by mutations in BUB1B which encodes BUBR1, a key protein in the mitotic spindle checkpoint, which have been found in individuals with this disease iii. Severe microcephaly iv. Growth deficiency v. Mental retardation vi. Childhood cancer predisposition vii. Associated with constitutional mosaicism for chromosomal gains and losses viii. Cytogenetic findings include premature centromere division, in which mitotic cells show split centromeres and splayed chromatids in all or most chromosomes (Plaja et al. 2001).

Diagnostic Investigations 1. Cytogenetics a. Distinctive abnormality of the constitutive heterochromatin (the RS effect): premature centromere separation (PCS) i. Detected in a) Fibroblasts and lymphocytes in neonates b) Chorionic villi and amniocytes in the fetus ii. Consists of “puffing” or “repulsion” of the constitutive heterochromatin a) Chromosome puffing most obvious at the large heterochromatic regions of chromosomes 1, 9, and 16 b) Chromosome repulsion most evident at the short arms of the acrocentrics and the distal long arm of the Y chromosome iii. A “railroad-track” or “tram-track” appearance of the sister chromatids due to the

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3. 4. 5. 6.

absence of a constriction at the centromere in several other chromosomes a) This phenomenon, called heterochromatin repulsion, is observed in cells of different tissue origin with several chromosomes in each metaphase showing a visible abnormality. b) Most evident in chromosomes containing the largest amount of heterochromatin b. Sporadic aneuploidy was noted with the pattern of aneuploidy different in each patient. The possible relationship between centromere “splaying” and aneuploidy is yet to be determined. c. Normal karyotypes lacking any microdeletion or chromosomal rearrangement from either leukocytes or fibroblasts in about a fifth of all cases Radiography for phocomelia evaluation a. Absence of the radius and fibula: the most common skeletal abnormalities in the upper and lower limbs b. Absent, short, deformed, and/or hypoplastic ulna and tibia: the second most common bone defects c. Absent, short, deformed, or hypoplastic humerus and femur: the third and least common abnormalities Echocardiography for congenital heart defect Renal ultrasound for renal anomalies MRI of the brain for CNS anomalies Molecular genetic testing: sequence analysis of the ESCO2 gene available clinically

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased (not surviving to reproduction in severe cases) 2. Prenatal diagnosis for pregnancies at risk (Schulz et al. 2008) a. Ultrasonography i. Intrauterine growth retardation ii. Bilateral phocomelia (tetraphocomelia in majority of cases) of varying degree iii. Cleft lip and palate iv. Associate anomalies a) Hydrocephalus b) Congenital heart defects c) Renal anomalies

Roberts Syndrome

b. DNA from fetal cells obtained from amniocentesis or CVS i. Confirmed by characteristic disjunction of centromeres (premature centromere separation in metaphases) ii. Molecular diagnosis of ESCO2 gene mutations 3. Management a. Special education b. Cornea grafting c. Corrective surgery i. Cleft lip/palate ii. Limb defects d. Prosthetic devices i. For underdeveloped or missing limbs ii. Used to increase independence

References Benzacken, B., Savary, J. B., Manouvrier, S., et al. (1996). Prenatal diagnosis of Roberts syndrome: Two new cases. Prenatal Diagnosis, 16, 125–130. Concolino, D., Sperli, D., Cinti, R., et al. (1996). A mild form of Roberts/SC phocomelia syndrome with asymmetrical reduction of the upper limbs. Clinical Genetics, 49, 274–276. de Ravel, T. J., Seftel, M. D., & Wright, C. A. (1997). Tetraamelia and splenogonadal fusion in Roberts syndrome. American Journal of Medical Genetics, 68, 185–189. Freeman, M. V., Williams, D. W., Schimke, R. N., et al. (1974a). The Roberts syndrome. Birth Defects Original Article Series, 10, 87–95. Freeman, M. V., Williams, D. W., Schimke, R. N., et al. (1974b). The Roberts syndrome. Clinical Genetics, 5, 1–16. Fryns, J. P., Kleczkowska, A., Moerman, P., et al. (1987). The Roberts tetraphocomelia syndrome: Identical limb defects in two siblings. Annales de Genetique, 30, 243–245. German, J. (1979). Roberts’ syndrome. I. Cytological evidence for a disturbance in chromatid pairing. Clinical Genetics, 16, 441–447. Gordillo, M., Vega, H., Jabs, E. W. (2009). Roberts syndrome. GeneReviews. Updated April 14, 2009. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼gene &part¼rbs Gordillo, M., Vega, H., Trainer, A. H., et al. (2008). The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. Human Molecular Genetics, 17, 2172–2180. Herrmann, J., Feingold, M., Tuffli, G., et al. (1969). A familial dysmorphogenetic syndrome of limb deformities, characteristic facial appearance and associated anomalies: the “pseudothalidomide” or “SC-syndrome. Birth Defects Original Article Series, 5, 81–89. Herrmann, J., & Opitz, J. M. (1977). The SC phocomelia and the Roberts syndrome: Nosologic aspects. European Journal of Pediatrics, 125, 117–134.

Roberts Syndrome Holden, K. R., Jabs, E. W., & Sponseller, P. D. (1992). Roberts/ pseudothalidomide syndrome and normal intelligence: Approaches to diagnosis and management. Developmental Medicine and Child Neurology, 34, 534–539. Holmes-Siedle, M., Seres-Santamaria, A., Crocker, M., et al. (1990). A sibship with Roberts/SC phocomelia syndrome. American Journal of Medical Genetics, 37, 18–22. Hwang, K., Lee, D. K., Lee, S. I., et al. (2002). Roberts syndrome, normal cell division, and normal intelligence. The Journal of Craniofacial Surgery, 13, 390–394. Jabs, E. W., Tuck-Muller, C. M., Cusano, R., et al. (1989). Centromere separation and aneuploidy in human mitotic mutants: Roberts syndrome. Progress in Clinical and Biological Research, 318, 111–118. Jabs, E. W., Tuck-Muller, C. M., Cusano, R., et al. (1991). Studies of mitotic and centromeric abnormalities in Roberts syndrome: Implications for a defect in the mitotic mechanism. Chromosoma, 100, 251–261. Judge, C. (1973). A sibship with the pseudothalidomide syndrome and an association with Rh incompatibility. Medical Journal of Australia, 2, 280–281. Karabulut, A. B., Aydin, H., Erer, M., et al. (2001). Roberts syndrome from the plastic surgeon’s viewpoint. Plastic and Reconstructive Surgery, 108, 1443–1445. Keppen, L. D., Gollin, S. M., Seibert, J. J., et al. (1991). Roberts syndrome with normal cell division. American Journal of Medical Genetics, 38, 21–24. Lenz, W. D., Marquardt, E., & Weicker, H. (1974). Pseudothalidomide syndrome. Birth Defects, 10, 97–107. Lopez-Allen, G., Hutcheon, R. G., Shaham, M., et al. (1996). Picture of the month. Roberts-SC phocomelia syndrome. Archives of Pediatrics and Adolescent Medicine, 150, 645–646. Louie, E., & German, J. (1981). Roberts’s syndrome. II. Aberrant Y-chromosome behavior. Clinical Genetics, 19, 71–74. Mann, N. P., Fitzsimmons, J., Fitzsimmons, E., et al. (1982). Roberts syndrome: Clinical and cytogenetic aspects. Journal of Medical Genetics, 19, 116–119. Maserati, E., Pasquali, F., Zuffardi, O., et al. (1991). Roberts syndrome: Phenotypic variation, cytogenetic definition and heterozygote detection. Annales de Genetique, 34, 239–246. McDaniel, L. D., Prueitt, R., Probst, L. C., et al. (2000). Novel assay for Roberts syndrome assigns variable phenotypes to one complementation group. American Journal of Medical Genetics, 93, 223–229. Otan˜o, L., Matayoshi, T., & Gadow, E. C. (1996). Roberts syndrome: First-trimester prenatal diagnosis. Prenatal Diagnosis, 16, 770–771. Paladini, D., Palmieri, S., Lecora, M., et al. (1996). Prenatal ultrasound diagnosis of Roberts syndrome in a family with negative history. Ultrasound in Obstetrics & Gynecology, 7, 208–210. Parry, D. M., Mulvihill, J. J., Tsai, S., et al. (1986). SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma. American Journal of Medical Genetics, 24, 6530672. Plaja, A., Vendrell, T., Smeets, D., et al. (2001). Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease. American Journal of Medical Genetics, 98, 216–223.

1809 Qazi, O. H., Kassner, E. G., Masakawa, A., et al. (1979). The SC phocomelia syndrome: Report of two cases with cytogenetic abnormality. American Journal of Medical Genetics, 4, 231–238. Roberts, J. B. (1919). A child with double cleft of lip and palate, protrusion of the intermaxillary portion of the upper jaw and imperfect development of the bones of the four extremities. Annals of Surgery, 70, 252–253. Robins, D. B., Ladda, R. L., Thieme, G. A., et al. (1989). Prenatal detection of Roberts-SC phocomelia syndrome: Report of 2 sibs with characteristic manifestations. American Journal of Medical Genetics, 32, 390–394. Ro¨mke, C., Froster-Iskenius, U., Heyne, K., et al. (1987). Roberts syndrome and SC phocomelia. A single genetic entity. Clinical Genetics, 31, 170–177. Sch€ ule, B., Oviedo, A., Johnston, K., et al. (2005). Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: No phenotype-genotype correlation. American Journal of Human Genetics, 77, 1117–1128. Schulz, S., Gerloff, C., Ledig, S., et al. (2008). Prenatal diagnosis of Roberts syndrome and detection of an ESCO2 frameshift mutation in a Pakistani family. Prenatal Diagnosis, 28, 42–45. Sherer, D. M., Shah, Y. G., Klionsky, N., et al. (1991). Prenatal sonographic features and management of a fetus with Roberts-SC phocomelia syndrome (pseudothalidomide syndrome) and pulmonary hypoplasia. American Journal of Perinatology, 8, 259–262. Sinha, A. K., Verma, R. S., & Mani, V. J. (1994). Clinical heterogeneity of skeletal dysplasia in Roberts syndrome: A review. Human Heredity, 44, 121–126. Stioui, S., Privitera, O., Brambati, B., et al. (1992). Firsttrimester prenatal diagnosis of Roberts syndrome. Prenatal Diagnosis, 12, 145–149. Stoll, C., Levy, J. M., & Beshara, D. (1979). Roberts’s syndrome and clonidine. Journal of Medical Genetics, 16, 486–487. Tomkins, D. J. (1989). Premature centromere separation and the prenatal diagnosis of Roberts syndrome. Prenatal Diagnosis, 9, 450–452. Tomkins, D., Hunter, A., & Roberts, M. (1979). Cytogenetic findings in Roberts-SC phocomelia syndrome(s). American Journal of Medical Genetics, 4, 17–26. Urban, M., Opitz, C., Bommer, C., et al. (1998). Bilaterally cleft lip, limb defects, and haematological manifestations: Roberts syndrome versus TAR syndrome. American Journal of Medical Genetics, 79, 155–160. Van Den Berg, D. J., & Francke, U. (1993). Roberts syndrome: A review of 100 cases and a new rating system for severity. American Journal of Medical Genetics, 47, 1104–1123. Vega, H., Trainer, A. H., Gordilo, M., et al. (2010). Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. Journal of Medical Genetics, 47, 30–37. Vega, H., Waisfisz, Q., Gordillo, M., et al. (2005). Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nature Genetics, 37, 468470.

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Roberts Syndrome

Fig. 1 The G-banded metaphase spread from fibroblast culture of a male infant with Roberts syndrome showing characteristic heterochromatin separation: puffing of the centromeric heterochromatin of some chromosomes and splaying of the Yqh region (arrows). The patient had profound psychomotor retardation, corneal clouding, and tetraphocomelia

Fig. 2 A newborn with Roberts syndrome variant showing bilateral cleft lip and cleft palate, phocomelia, club hands with an appendage-like thumb on the right, and a missing thumb on the left. The infant also had intrauterine growth retardation, hydrocephalus, cloudy cornea, AV canal heart defect, and normal lower extremities. Cytogenetic studies revealed no premature centromere separation. The mother took Diflucan during pregnancy and the teratogenic etiology was a possibility

Robinow Syndrome

In 1969, Robinow et al. described a new dwarfing syndrome characterized by mesomelic shortening of extremities, hemivertebrae, genital hypoplasia, and “fetal facies.” The incidence is estimated to be approximately 1 in 500,000.

conserved cysteines, are associated with autosomal dominant Robinow syndrome b. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient.

Synonyms and Related Disorders Clinical Features Acral dysostosis with facial and genital abnormalities; Costovertebral segmentation defect with mesomelia; Fetal face syndrome; Robinow dwarfism

Genetics/Basic Defects 1. Autosomal recessive form a. Phenotype tends to be more severe than the autosomal dominant form. b. Caused by different homozygous (and compound heterozygous) missense, nonsense, and frameshift mutations of the ROR2 gene (Tufan et al. 2005) c. ROR2 gene i. Mapped to chromosome 9q22 ii. Encoding an orphan receptor tyrosine kinase 2 with orthologues in mouse and other species iii. Allelic to dominant brachydactyly type B (characterized by terminal deficiency of fingers and toes) 2. Autosomal dominant form (Person et al. 2010) a. Caused by missense mutations in WNT5A, which result in amino acid substitutions of highly

1. Characteristic craniofacial appearance a. Early childhood i. Midfacial hypoplasia ii. Occasional midline capillary hemangioma iii. Eyes a) Marked hypertelorism b) Prominent eyes giving the appearance of exophthalmos (pseudoexophthalmos) iv. A short upturned nose v. Mouth a) “Tented” upper lip having an inverted-V appearance with tethering in the center b) Midline clefting of the lower lip c) Gum hypertrophy at birth d) Dental crowding/irregular teeth e) “Tongue tie” (ankyloglossia) resembling a bifid tongue when the tongue tie is marked vi. Ears a) Low-set b) Simple c) Deformed pinna

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vii. Resemblance to a fetal face a) Relatively small face b) Laterally displaced eyes c) Forward-pointing alae nasi d) “Fetal facies” becomes less prominent over time b. Adulthood i. Loss of fetal facial proportions ii. Absent midfacial hypoplasia iii. Persistent hypertelorism with a broad nasal root and broad forehead Short stature a. Reduced birth length b. Not a universal finding with some reports of normal growth Limb abnormalities a. Mesomelic or acromesomelic limb shortening b. Shortening of the forearms more striking than the shortening of the legs c. Occasional Madelung deformity d. Hands/feet i. Brachydactyly with shortening of the distal phalanx and nail hypoplasia or dystrophy ii. Thumbs a) Displaced b) Occasionally bifid c) Partial cutaneous syndactyly d) Ectrodactyly (especially patients reported from Turkey) Other skeletal abnormalities a. Chest deformities b. Kyphoscoliosis c. Vertebral anomalies d. Rib defects e. Pectus excavatum f. Acrodysostosis g. Delayed bone age Genital hypoplasia a. Genital abnormalities: may be present at birth causing concern regarding gender assignment i. Males a) Micropenis b) Normal scrotum and testes ii. Females a) Reduced clitoral size b) Hypoplasia of the labia minor c) Associated vaginal atresia and hematocolpos

Robinow Syndrome

6.

7.

8. 9.

10.

11.

iii. Onset of puberty normal in both sexes iv. Several reports of both male and female patients having normal children Congenital heart defects (15%) a. Severe pulmonary stenosis or atresia (the most common cardiac abnormalities) b. Atrial septal defect c. Ventricular septal defect d. Coarctation of the aorta e. Bicuspid aortic valve f. Tetralogy of Fallot g. Tricuspid atresia h. Double-outlet right ventricle i. Patent ductus arteriosus Renal abnormalities a. Hydronephrosis (relatively common) b. Cystic dysplasia of the kidney Developmental delay but intelligence is usually normal Dermatoglyphics a. Absent interphalangeal creases b. Bilateral transverse creases c. Hypothenar whorl pattern Clinical characteristics of recessive Robinow syndrome: more frequently manifests orthopedic involvement (vertebral/rib anomalies and more severe mesomelic brachymelia) than the dominant form a. Short stature b. Mesomelic and acromelic brachymelia c. Thick abnormally modeled radius and ulna d. Characteristic face i. Hypertelorism ii. Wide palpebral fissures iii. Broad-based nose with everted nares iv. Large mouth v. Gum hypertrophy vi. Irregular and crowded teeth e. Costovertebral anomalies f. Endocrine dysfunction i. Empty sella ii. Partial insensitivity of Leydig cells to HCG iii. Low basal testosterone in prepubertal boys iv. Defective sex-steroid feedback mechanism g. Micropenis in males Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome,

Robinow Syndrome

based on inheritance pattern in familial cases and presence of rib fusions as diagnostic of the recessive variant (Mazzeu et al. 2007): a. Clinical signs present in more than 75% of patients with either form, and therefore the most important for the characterization of this syndrome i. Hypertelorism ii. Nasal features (large nasal bridge, short upturned nose, and anteverted nares) iii. Midfacial hypoplasia iv. Mesomelic limb shortening v. Brachydactyly vi. Clinodactyly vii. Micropenis viii. Short stature b. Hemivertebrae and scoliosis were present in more than 75% of patients with the recessive form but in less than 25% of patients with the dominant form c. Umbilical hernia (32.3%) and supernumerary teeth (10.3%) were found exclusively in patients with the dominant form 12. Differential diagnosis of mesomelic dwarfism (Giedion et al. 1975) a. With Madelung deformity: dyschondrosteosis b. With malformations of long bones depending on various distribution/severity patterns and types of transmission i. Ulnofibular a) With mild triangular deformity b) With extreme variety: boomerang bone disease ii. Radio-tibial with “normal” fibula iii. Ulno-fibular-mandibular (Langer type, homozygous dyschondrosteosis) iv. Ulno-radio-fibular-tarsal with square, triangular, or rhomboid tibia v. Ulno-radio-tibial with absent fibula c. With associated malformations of spine i. Robinow syndrome ii. Wegmann syndrome iii. Campallia and Martinelli syndrome iv. “Spondylo-epiphyso-metaphyseal” dysplasia d. With acrodysplasia i. Acromesomelic dwarfism

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ii. Ellis-van Creveld syndrome iii. Grebe achondrogenesis

Diagnostic Investigations 1. Radiography a. Skull i. Macrocephaly ii. Prominent forehead iii. Hypertelorism iv. Hypoplastic mandible v. Dental anomalies b. Spine/ribs: widespread fusion of thoracic vertebrae with frequent hemivertebrae and fusion of the ribs, resembling Jarcho-Levin syndrome (spondylocostal dysostosis) in severe cases (autosomal recessive form) i. Hemivertebrae and vertebral fusions ii. Fusion of ribs iii. Shortened interpeduncular distance c. Extremities (long bones): mesomelic shortening i. Upper extremities ii. Lower extremities iii. Ulna shorter than radius iv. Luxation of the radius d. Hands and feet i. Brachymesophalangism of fifth digits ii. Clinodactyly of the fifth digits iii. Shortening of other phalanges iv. Brachymetacarpism v. Fusion of carpal bones vi. Bifid terminal phalanges (splitting of one or more distal phalanges) vii. Fusion of phalanges viii. Retarded bone age 2. Renal ultrasound for renal anomalies 3. Echocardiography for congenital heart disease 4. Growth hormone assay for possible growth hormone deficiency 5. DNA mutation analysis: available on clinical basis (Afzal and Taylor 2005) a. ROR2 gene is the gene responsible for autosomal recessive ROR2-related Robinow syndrome b. Sequence analysis of ROR2 gene detects 65–100% of affected individuals

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Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance: not increased unless a parent is affected ii. Autosomal recessive inheritance: 25% b. Patient’s offspring i. Autosomal dominant inheritance: 50% ii. Autosomal recessive inheritance: not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Ultrasonography: possible by measuring the length of the long bones and the ulna/humerus ratio for the fetus at risk b. Prenatal diagnosis: also possible for pregnancies at increased risk for ROR2-related Robinow syndrome by sequencing of entire coding region of ROR2 gene on fetal DNA obtained by amniocentesis or CVS, provided the disease-causing alleles have been previously identified in the proband (Afzal and Taylor 2005) 3. Management a. Anticipate difficult intubation because of midfacial hypoplasia b. Orthopedic care for vertebral anomalies and hip dislocation c. Orthodontics for dental malalignment d. Surgery for cleft lip and palate, inguinal hernia, and undescended testes e. Growth hormone therapy if associated with growth hormone deficiency f. Testosterone therapy for micropenis not proven useful g. Psychologic support

References Afzal, A. R., & Jeffery, S. (2003). One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B. Human Mutation, 22, 1–11. Afzal, A. R., Rajab, A., Fenske, C., et al. (2000a). Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Human Genetics, 106, 351–354. Afzal, A. R., Rajab, A., Fenske, C., et al. (2000b). Autosomal recessive Robinow syndrome is allelic to dominant brachydactyly type B and caused by loss of function mutations in ROR2. Nature Genetics, 25, 419–422.

Robinow Syndrome Afzal, A. R., & Taylor, R. (2005). ROR2-related Robinow syndrome. GeneReviews. Initial posting July 28, 2005. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br. fcgi?book¼gene&part¼rob Al-Ata, J., Paquet, M., & Teebi, A. S. (1998). Congenital heart disease in Robinow syndrome. American Journal of Medical Genetics, 77, 332–333. Atalay, S., Ege, B., Imamoglu, A., et al. (1993). Congenital heart disease and Robinow syndrome. Clinical Dysmorphology, 2, 208–210. Butler, M. G., & Wadlington, W. B. (1987). Robinow syndrome: Report of two patients and review of literature. Clinical Genetics, 31, 77–85. Castells, S., Chakurkar, A., Qazi, Q., et al. (1999). Robinow syndrome with growth hormone deficiency: Treatment with growth hormone. Journal of Pediatric Endocrinology & Metabolism, 12, 565–571. Giedion, A., Battaglia, G. F., Bellini, F., et al. (1976). The radiological diagnosis of the fetal-face (¼ Robinow) syndrome (mesomelic dwarfism and small genitalia). Report of 3 cases. Helvetica Paediatric Acta, 30, 409–423. Kantaputra, P. N., Gorlin, R. J., Ukarapol, N., et al. (1999). Robinow (fetal face) syndrome: report of a boy with dominant type and an infant with recessive type. American Journal of Medical Genetics, 84, 1–7. Kawai, M., Yorifuji, T., Yamanaka, C., et al. (1997). A case of Robinow syndrome accompanied by partial growth hormone insufficiency treated with growth hormone. Hormone Research, 48, 41–43. Lee, P. A., Migeon, C. J., Brown, T. R., et al. (1982). Robinow’s syndrome. Partial primary hypogonadism in pubertal boys, with persistence of micropenis. American Journal of Disease Children, 136, 327–330. Lovero, G., Guanti, G., Caruso, G., et al. (1990). Robinow’s syndrome: Prenatal diagnosis. Prenatal Diagnosis, 10, 121–126. Mazzeu, J. F., Pardono, E., Vianna-Morgante, A. M., et al. (2007). Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome. American Journal of Medical Genetics. Part A, 143A, 320–325. Patton, M. A., & Afzal, A. R. (2002). Robinow syndrome. Journal of Medical Genetics, 39, 305–310. Percin, E. F., Guvenal, T., Cetin, A., et al. (2001). First-trimester diagnosis of Robinow syndrome. Fetal Diagnosis and Therapy, 16, 308–311. Person, A. D., Beiraghi, S., Sieben, C. M., et al. (2010). WNT5A mutations in patients with autosomal dominant Robinow syndrome. Developmental Dynamics, 239, 327–337. Robinow, M. (1993). The Robinow (fetal face) syndrome: a continuing puzzle. Clinical Dysmorphology, 2, 189–198. Robinow, M., Silverman, F. N., & Smith, H. D. (1969). A newly recognized dwarfing syndrome. American Journal of Diseases of Children, 117, 645–651. Schorderet, D. F., Dahoun, S., Defrance, I., et al. (1992). Robinow syndrome in two siblings from consanguineous parents. European Journal of Pediatrics, 151, 586–589. Soliman, A. T., Rajab, A., Alsalmi, I., et al. (1998). Recessive Robinow syndrome: With emphasis on endocrine functions. Metabolism, 47, 1337–1343. Teebi, A. S. (1990). Autosomal recessive Robinow syndrome. American Journal of Medical Genetics, 35, 64–68.

Robinow Syndrome Tufan, F., Cefle, K., Tu¯rkmen, S., et al. (2005). Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome. American Journal of Medical Genetics, 136A, 185–189. van Bokhoven, H., Celli, J., Kayserili, H., et al. (2000). Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nature Genetics, 25, 423–426. Erratum in Nat Genet 26:383, 2000. Wadlington, W. B., Tucker, V. L., & Schimke, R. N. (1973). Mesomelic dwarfism with hemivertebrae and small genitalia (the Robinow syndrome). American Journal of Diseases of Children, 126, 202–205.

1815 Webber, S. A., Wargowski, D. S., Chitayat, D., et al. (1990). Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome? American Journal of Medical Genetics, 37, 519–521. Wiens, L., Strickland, D. K., Sniffen, B., et al. (1990). Robinow syndrome: Report of two patients with cystic kidney disease. Clinical Genetics, 37, 481–484. Wilcox, D. T., Quinn, F. M., Ng, C. S., et al. (1997). Redefining the genital abnormality in the Robinow syndrome. Journal of Urology, 157, 2312–2314.

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Robinow Syndrome

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Fig. 1 (a–e) A child with Robinow syndrome showing prominent forehead, ocular hypertelorism, short upturned nose, pectus excavatum, penile hypoplasia, and acromesomelic shortening of the limbs

Rubinstein-Taybi Syndrome

In 1963, Rubinstein and Taybi described a new syndrome characterized by broad thumbs and toes, facial abnormalities, and mental retardation. The prevalence of Rubinstein-Taybi syndrome (RTS) is estimated to be 1 in 100,000–1 in 125,000 live births in the Netherlands.

Synonyms and Related Disorders Broad thumb-hallux syndrome; Broad thumbs and great toes, characteristic facies, and mental retardation; Rubinstein syndrome

5. Also rarely caused by mutations in EP300 gene (located on 22q13.2): individuals reported with mutations in EP300 have a milder skeletal phenotype, lacking typical broadening and angulation of the thumb and hallux (Bartholdi et al. 2007). 6. No clear phenotypic differences are observed between patients in whom microdeletions or truncating mutations were found. 7. Variable expression and somatic mosaicism contribute to the phenotypic variability of RTS. Somatic mosaicism may be more frequent in RTS than previously assumed (Bartsch et al. 2010).

Genetics/Basic Defects Clinical Features 1. Inheritance: autosomal dominant 2. Most cases are sporadic (
99%); familial cases are extremely rare (Bartsch et al. 2010). 3. Caused by deletions or heteroallelic mutations of CREBBP, the gene for cAMP-responsive elementbinding (CREB) protein, which resides on chromosome 16p13.3. CREBBP is a large nuclear protein involved in transcription regulation, chromatin remodeling, and the integration of several different signal transduction pathways. The following mutations of CREBBP were reported in patients with Rubinstein-Taybi syndrome: a. Chromosomal translocations/inversions b. Deletions at the microscopic and submicroscopic levels c. Molecular mutations 4. Mutations in the CREBBP gene are responsible for: a. Rubinstein-Taybi syndrome b. t(8;16)-associated acute myeloid leukemia

1. Characteristic craniofacial features a. Microcephaly (35–94%) b. Prominent forehead c. Down-slanting palpebral fissures d. Apparent ocular hypertelorism e. High-arched or heavy eyebrows f. Long eyelashes g. Epicanthal folds h. Prominent nose with columella (lower margin of the nasal septum) below the alae nasi i. Malpositioned ears with dysplastic helices j. Grimacing smile k. Hypoplastic maxilla l. Mild retrognathia m. High-arched palate 2. Skeletal abnormalities a. Thumbs i. Broad terminal phalanges

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_207, # Springer Science+Business Media, LLC 2012

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3. 4. 5. 6.

7.

ii. Severe radial angulation deformity (“hitchhiker thumbs”) with abnormal shape of proximal phalanx, which prevents opposition and functional gripping strength b. Great toes i. Broad terminal phalanges ii. Angulation deformity with abnormal shape of proximal phalanx or first metatarsal iii. Duplicated proximal phalanx iv. Duplicated distal phalanx c. Short stature (78%) d. Fifth finger clinodactyly e. Overlapping toes f. Broad terminal phalanges of other fingers g. Pelvic anomalies i. Flat acetabular angles ii. Flaring of the ilia iii. Notch in the ischia h. Stiff gait i. Lax ligaments j. Hyperextensible joints k. Vertebral anomalies i. Spina bifida ii. Kyphosis iii. Lordosis iv. Scoliosis l. Sternal or rib anomalies i. Premature fusion ii. Simian sternum iii. Pectus excavatum or carinatum iv. Forked ribs v. Cervical ribs vi. Fusion of the first and second ribs History of maternal polyhydramnios (39%) Hypotonia Developmental delay Variable mental retardation a. Severe in some patients b. Moderate degree in many patients c. Mild in some patients Behavioral/psychiatric disorders a. Childhood i. Short attention span ii. Impulsiveness iii. Clinically nonsignificant stereotype iv. Withdrawal v. Nonspecific “maladaptive behavior” vi. Repetitive motions

Rubinstein-Taybi Syndrome

8. 9.

10.

11.

vii. Resistance to change viii. Distractibility ix. Aggressive outbursts x. Difficulty in sleeping b. Adulthood i. Mood disorders ii. Chronic motor tic disorder iii. Obsessive compulsive disorder iv. Depressive disorder v. Bipolar disorder vi. Tourette disorder vii. Trichotillomania viii. Pervasive developmental disorder ix. Self-injurious behaviors x. Autistic features Seizures (27–28%) Ophthalmologic problems a. Strabismus (60–71%) with subsequent risk of amblyopia b. Refractive errors (41–56%) c. Lacrimal duct obstructions (38–47%) d. Ptosis (29–32%) e. Coloboma (9–11%) f. Duane retraction syndrome (8%) g. Ghost vessels h. Peters anomaly i. Optic nerve hypoplasia j. Cataracts k. Corneal opacities l. Congenital glaucoma m. Retinal abnormalities Dental manifestations (67%) a. Talon cusps of secondary dentition b. Crowding and malpositioned teeth c. Anterior and posterior crossbites secondary to a narrow palate or jaw size discrepancy d. Natal teeth e. Gingivitis f. Hypodontia/hyperdontia g. Increased rate of carries Upper airway obstruction during sleep due to: a. Hypotonia b. Anatomy of the oropharynx and airway i. Small nasal passages ii. Retrognathia iii. Micrognathia iv. Hypertrophy of the tonsils and adenoids v. Obesity

Rubinstein-Taybi Syndrome

12. Gastrointestinal problems a. Significant gastroesophageal reflux b. Feeding difficulties c. Constipation 13. Congenital heart disease (24–38%) a. ASD b. VSD c. PDA d. Coarctation of the aorta e. Pulmonary stenosis f. Bicuspid aortic valve g. Pseudotruncus h. Aortic stenosis i. Hypoplastic left heart syndrome j. Complex congenital heart defects k. Dextrocardia l. Vascular rings m. Conduction problems 14. Renal anomalies (52%) a. Hydronephrosis b. Duplications c. Vesicoureteral reflux d. Urinary tract infections e. Renal stones f. Nephrotic syndrome g. Neurogenic bladder 15. Cutaneous manifestations a. Tendency of keloid and hypertrophic scar formation b. Ingrown toenails c. Toenail paronychia (44%) d. Fingernail paronychia (9%) e. Pilomatrixomas f. Capillary hemangioma i. Forehead ii. Nape of the neck iii. Back g. Supernumerary nipples h. Hirsutism i. Transverse palmar creases j. Deep plantar crease between the first and second toes 16. Orthopedic problems a. Hypotonia b. Lax ligaments c. Tight heel cords d. Elbow abnormalities e. Legg-Perthes disease (3%)

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f. g. h. i.

Dislocated patella (2.5%) Congenital hip dislocation (1.4%) Slipped capital femoral epiphysis (0.6%) Congenital or acquired scoliosis, kyphosis, and lordosis j. An increased risk of associated thickened filum terminale, tethering of the cord, and lipoma k. An increased risk of fractures 17. An increased risk of having benign and malignant tumors as well as leukemia and lymphoma a. Oligodendroglioma b. Medulloblastoma c. Neuroblastoma d. Meningioma e. Pheochromocytoma f. Nasopharyngeal rhabdomyosarcoma g. Leiomyosarcoma h. Seminoma i. Embryonal carcinoma j. Odontoma k. Choristoma l. Dermoid cyst m. Pilomatrixomas

Diagnostic Investigations 1. 2. 3. 4. 5. 6. 7. 8.

Developmental evaluation Echocardiography for cardiac defects Ophthalmologic examination Renal ultrasound Voiding cystourethrogram Hearing evaluation EEG abnormalities Radiography a. Hands i. Broad first distal phalanx ii. Broad first ray iii. Duplicated first distal phalanx iv. Delta-shaped proximal phalanges of the thumbs v. Mushroom-shaped distal phalanges vi. Angulation of the distal phalanges vii. Thin tubular bones viii. Delayed bone age (74%) b. Feet i. Broad first distal phalanx ii. Broad first ray

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iii. Duplicated first distal phalanx iv. Duplicated first proximal and distal phalanges v. Delta-shaped first proximal phalanx. A duplicated longitudinal bracketed epiphysis (“kissing delta” phalanx) always involves the proximal phalanx of the great toe. vi. Angulation deformity of the hallux vii. Mushroom-shaped distal phalanges viii. Very small distal phalanges ix. Thin tubular bones x. Protruding calcaneus xi. Synostosis of cuneiform ossicles xii. Proximally split fifth metatarsal bone c. Limbs i. Thin tubular bones ii. Fractures iii. Patella luxations d. Spine i. Cervical hyperkyphosis ii. Lumbar hyperlordosis iii. Scoliosis iv. Spina bifida occulta: cervical or lumbosacral v. Spondylolisthesis vi. Irregular thoracic endplates e. Skull i. Microcephaly ii. Absent sinus frontalis iii. Deviated nasal septum iv. Steep skull base v. Abnormally shaped sella turcica vi. Foramina parietal permagna vii. Prominent digital marking f. Thorax i. Narrow thoracic aperture ii. 11 ribs iii. Fusion of ribs iv. High diaphragm g. Pelvis i. Small iliac wings ii. Flaring iliac wings iii. Irregularly formed acetabulum iv. Symphysiolysis 9. Diagnosis of Rubinstein-Taybi syndrome a. Made primarily by clinical examination b. Confirmed by the presence of microdeletion 10. Cytogenetic analysis: chromosome abnormalities observed in about 10% of patients (Breuning et al. 1993; Blough et al. 2000; Petrij et al. 2000b)

Rubinstein-Taybi Syndrome

a. FISH analysis with cosmids from the CBP region to detect chromosome 16p13.3 b. Chromosome abnormalities i. t(2;16)(p13.3;p13.3) ii. t(7;16)(q34;p13.3) iii. Inv(16)(p13.3q13) 11. Clinical testing of CREBBP gene: available clinically a. Fluorescent in situ hybridization (FISH) probes i. Specific for chromosome region 16p13.3 ii. Containing regions of the cyclic AMPresponsive element-binding protein gene (CBP gene) iii. Microdeletions identified in approximately 10% of patients by five cosmid probes containing almost the entire gene b. Sequence analysis/mutation scanning available clinically: detects CREBBP mutation in another 30–50% of affected individuals c. Deletion/duplication analysis using array CGH or quantitative multiplex fluorescent-PVR 12. Clinical testing of EP300 gene: available clinically a. EP300 mutations available clinically can identify approximately 3% of affected individuals. b. Deletion/duplication analysis.

Genetic Counseling 1. Recurrence risk a. Patient’s sib: Accumulating data suggest a recurrence risk of approximately 0.5–1.0% for parents of a child with RTS due to gonadal mosaicism, exceeding the so far empiric estimated risk of 0.1% for siblings (Chiang et al. 2009; Bartsch et al. 2010) b. Patient’s offspring: as high as 50%, particularly in individuals with deletions 2. Prenatal diagnosis: possible for fetuses at risk on fetal cells obtained by amniocentesis or chorionic villus sampling, provided the diseasecausing CREBBP or EP300 mutation or deletion in an affected family member is known (Stevens 2009) 3. Preimplantation genetic diagnosis for at-risk pregnancies requires prior identification of the diseasecausing mutation in the family (Stevens 2009)

Rubinstein-Taybi Syndrome

4. Management a. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy b. Management of gastroesophageal reflux c. Prophylaxis for subacute bacterial endocarditis for patients at risk d. Requires assistance and training in self-help skills but can become self-sufficient in most self-help areas such as feeding, dressing, and toileting e. Special education f. Behavioral modification g. Surgery to correct a delta phalanx deformity h. Caution with general anesthesia in children i. Challenging to intubate due to airway anomalies a) Relatively anterior position of the larynx b) Easily collapsible laryngeal wall ii. Important to intubate due to the high risk of aspiration during induction and emergence iii. Presence of skeletal anomalies iv. Cardiac arrhythmia may result from use of cardioactive drugs. a) Atropine b) Neostigmine c) Succinylcholine d) Suxamethonium

References Allanson, J. E. (1990). Rubinstein-Taybi syndrome: The changing face. American Journal of Medical Genetics. Supplement, 6, 38–41. Bartholdi, D., Roelfsema, J. H., Papadia, F., et al. (2007). Genetic heterogeneity in Rubinstein-Taybi syndrome: Delineation of the phenotype of the first patients carrying mutations in EP300. Journal of Medical Genetics, 44, 327–333. Bartsch, O., Kress, W., Kempf, O., et al. (2010). Inheritance and variable expression in Rubinstein-Taybi syndrome. American Journal of Medical Genetics. Part A, 152A, 2254–2261. Bartsch, O., Locher, K., Meinecke, P., et al. (2002). Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP. Journal of Medical Genetics, 39, 496–501. Bartsch, O., Wagner, A., Hinkel, G. K., et al. (1999). FISH studies in 45 patients with Rubinstein-Taybi syndrome: Deletions associated with polysplenia, hypoplastic left heart and death in infancy. European Journal of Human Genetics, 7, 748–756.

1821 Baxter, G., & Beer, J. (1992). Rubinstein-Taybi syndrome. Psychological Reports, 70, 451–456. Berry, A. C. (1987). Rubinstein-Taybi syndrome. Journal of Medical Genetics, 24, 562–566. Blough, R. I., Petrij, F., Dauwerse, J. G., et al. (2000). Variation in microdeletions of the cyclic AMP-responsive elementbinding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome. American Journal of Medical Genetics, 90, 29–34. Breuning, M. H., Dauwerse, H. G., Fugazza, G., et al. (1993). Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3. American Journal of Human Genetics, 52, 249–254. Cantani, A., & Gagliesi, D. (1998). Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. European Review for Medical and Pharmacological Sciences, 2, 81–87. Carey, J. C., & Curry, C. J. R. (1990). Rubinstein-Taybi syndrome: New look at an “old” syndrome. American Journal of Medical Genetics. Supplement, 6, 2. Chiang, P.-W., Lee, N.-C., Chien, N., et al. (2009). Somatic and germ-line mosaicism in Rubinstein-Taybi syndrome. American Journal of Medical Genetics. Part A, 149A, 1463–1467. Coupry, I., Roudaut, C., Stef, M., et al. (2002). Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome. Journal of Medical Genetics, 39, 415–421. Filippi, G. (1972). The Rubinstein-Taybi syndrome. Report of 7 cases. Clinical Genetics, 3, 303–318. Giles, R. H., Petru, F., Dauwerse, H. G., et al. (1997). Constructions of a 1.2-Mb contig surrounding, and molecular analysis of the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3. Genomics, 42, 96–114. Gotts, E. E., & Liemohn, W. P. (1977). Behavioral characteristics of three children with the broad thumb-hallux (RubinsteinTaybi) syndrome. Biological Psychiatry, 12, 413–423. Hellings, J. A., Hossain, S., Martin, J. K., et al. (2002). Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. American Journal of Medical Genetics, 114, 190–195. Hennekam, R. C. (1990). Bibliography on Rubinstein-Taybi syndrome. American Journal of Medical Genetics. Supplement, 6, 77–83. Hennekam, R. C. (1993). Rubinstein-Taybi syndrome: A history in pictures. Clinical Dysmorphology, 2, 87–92. Hennekam, R. C. (2006). Rubinstein-Taybi syndrome. European Journal of Human Genetics, 14, 981–985. Hennekam, R. C., Baselier, A. C., Beyaert, E., et al. (1992). Psychological and speech studies in Rubinstein-Taybi syndrome. American Journal of Mental Retardation, 96, 645–660. Hennekam, R. C., Lommen, E. J., Strengers, J. L., et al. (1989). Rubinstein-Taybi syndrome in a mother and son. European Journal of Pediatrics, 148, 439–441. Hennekam, R. C., Stevens, C. A., & Van de Kamp, J. J. (1990). Etiology and recurrence risk in Rubinstein-Taybi syndrome. American Journal of Medical Genetics. Supplement, 6, 56–64. Hennekam, R. C., Tilanus, M., Hamel, B. C., et al. (1993). Deletion at chromosome 16p13.3 as a cause of RubinsteinTaybi syndrome: Clinical aspects. American Journal of Human Genetics, 52, 255–262.

1822 Hennekam, R. C., Van Den Boogaard, M. J., Sibbles, B. J., et al. (1990). Rubinstein-Taybi syndrome in The Netherlands. American Journal of Medical Genetics. Supplement, 6, 17–29. Hennekam, R. C., & Van Doorne, J. M. (1990). Oral aspects of Rubinstein-Taybi syndrome. American Journal of Medical Genetics. Supplement, 6, 42–47. Imaizumi, K., & Kuroki, Y. (1991). Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3). American Journal of Medical Genetics, 38, 636–639. Imaizumi, K., Kurosawa, K., Masuno, M., et al. (1993). Chromosome aberrations in Rubinstein-Taybi syndrome. Clinical Genetics, 43, 215–216. Lacombe, D., Saura, R., Taine, L., et al. (1992). Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3. American Journal of Medical Genetics, 44, 126–128. Levitas, A. S., & Reid, C. S. (1998). Rubinstein-Taybi syndrome and psychiatric disorders. Journal of Intellectual Disability Research, 42(Pt 4), 284–292. Masuno, M., Imaizumi, K., Kurosawa, K., et al. (1994). Submicroscopic deletion of chromosome region 16p13.3 in a Japanese patient with Rubinstein-Taybi syndrome. American Journal of Medical Genetics, 53, 352–354. McGaughran, J. M., Gaunt, L., Dore, J., et al. (1996). RubinsteinTaybi syndrome with deletions of FISH probe RT1 at 16p13.3: Two UK patients. Journal of Mediacl Genetics, 33, 82–83. Miller, R. W., & Rubinstein, J. H. (1995). Tumors in RubinsteinTaybi syndrome. American Journal of Medical Genetics, 56, 112–115. Partington, M. W. (1990). Rubinstein-Taybi syndrome: A follow-up study. American Journal of Medical Genetics. Supplement, 6, 65–68. Petrij, F., Dauwerse, H. G., Blough, R. I., et al. (2000a). Diagnostic analysis of the Rubinstein-Taybi syndrome: Five cosmids should be used for microdeletion detection and low number of protein truncating mutations. Journal of Medical Genetics, 37, 168–176. Petrij, F., Dorsman, J. C., Dauwerse, H. G., et al. (2000b). Rubinstein-Taybi syndrome caused by a De Novo reciprocal translocation t(2;16)(q36.3;p13.3). American Journal of Medical Genetics, 92, 47–52. Petrij, F., Giles, R. H., Breuning, M. H., et al. (2001). RubinsteinTaybi syndrome. In C. R. Scriver, A. L. Beaudet, D. Valle, & W. S. Sly (Eds.), The metabolic and molecular bases of inherited disease (8th ed., pp. 6167–6182). New York: McGraw-Hill. Chapter 248. Petrij, F., Giles, R. H., Dauwerse, H. G., et al. (1995). Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature, 376, 348–351. Rubenstein, J. H., & Taybi, H. (1963). Broad thumbs and facial abnormalities. American Journal of Diseases of Children, 105, 588–608.

Rubinstein-Taybi Syndrome Rubinstein, J. H. (1969). The broad thumbs syndrome-Progress report 1968. Birth Defects Original Article Series, 5(2), 25–41. Rubinstein, J. H. (1990). Broad thumb-hallux (RubinsteinTaybi) syndrome 1957–1988. American Journal of Medical Genetics. Supplement, 6, 3–16. Smith, D. W. (1990) Rubinstein-Taybi syndrome. Papers presented at the 9th annual Workshop on Malformations and Morphogenesis. Oakland, 1988. Proceedings. American Journal of Medical Genetics Suppl. 6:1–131 Selmanowitz, V. J., & Stiller, M. J. (1981). Rubinstein-Taybi syndrome. Cutaneous manifestations and colossal keloids. Archives of Dermatology, 117, 504–506. Stevens, C. A. (2009) Rubinstein-Taybi syndrome. GeneReviews. Updated August 20, 2009. Available at: http://www.ncbi.nlm. nih.gov/bookshelf/br.fcgi?book¼gene&part¼rsts Stevens, C. A., & Bhakta, M. G. (1995). Cardiac abnormalities in the Rubinstein-Taybi syndrome. American Journal of Medical Genetics, 59, 346–348. Stevens, C. A., Carey, J. C., & Blackburn, B. L. (1990). Rubinstein-Taybi syndrome: A natural history study. American Journal of Medical Genetics. Supplement, 6, 30–37. Stirt, J. A. (1981). Anesthetic problems in Rubinstein-Taybi syndrome. Anesthesia and Analgesia, 60, 534–536. Taine, L., Goizet, C., Wen, Z. Q., et al. (1998). Submicroscopic deletion of chromosome 16p13.3 in patients with RubinsteinTaybi syndrome. American Journal of Medical Genetics, 78, 267–270. Tommerup, N., van der Hagen, C. B., & Heiberg, A. (1992). Tentative assignment of a locus for Rubinstein-Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3). American Journal of Medical Genetics, 44, 237–241. van Genderen, M. M., Kinds, G. F., Riemslag, F. C., et al. (2000). Ocular features in Rubinstein-Taybi syndrome: Investigation of 24 patients and review of the literature. British Journal of Ophthalmology, 84, 1177–1184. Wallerstein, R., Anderson, C. E., Hay, B., et al. (1997). Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: Frequency and clinical manifestations in a North American population. Journal of Medical Genetics, 34, 203–206. Wiley, S., Swayne, S., Rubinstein, J. H., et al. (2003). Rubinstein-Taybi syndrome medical guidelines. American Journal of Medical Genetics, 119A, 101–110. Wood, V. E., & Rubinstein, J. (1999). Duplicated longitudinal bracketed epiphysis “kissing delta phalanx” in RubinsteinTaybi syndrome. Journal of Pediatric Orthopaedics, 19, 603–606. Wood, V. E., & Rubinstein, J. H. (1987). Surgical treatment of the thumb in the Rubinstein-Taybi syndrome. Journal of Handle Surgery (British), 12, 166–172.

Rubinstein-Taybi Syndrome

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Fig. 1 (a–l) A patient with Rubinstein-Taybi syndrome at different ages (childhood and adulthood) showing typical facial appearance (prominent beaked nose with the columella below

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the alae nasi), broad thumbs, and broad/bifid great toes, which are illustrated by radiographs

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Rubinstein-Taybi Syndrome

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Fig. 2 (a, b) An adult with Rubinstein-Taybi syndrome showing the characteristic facies and broad thumbs

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Fig. 3 (a, b) A young patient with Rubinstein-Taybi syndrome showing characteristic facies, broad thumbs, and great toes

Saethre-Chotzen Syndrome

Saethre in 1931 and Chotzen in 1932 separately described a group of patients with cranial vault dysmorphology (“acrocephaly”), skull asymmetry, and incomplete simple syndactyly of the index and middle fingers and the third and fourth toes. Saethre-Chotzen syndrome (SCS) is one of the more common forms of syndromic craniosynostosis. Its prevalence was estimated to range from 1:25,000 to 1:50,000, approximately the same prevalence as Crouzon syndrome.

Synonyms and Related Disorders Acrocephalosyndactyly, Type III; Acrocephaly, skull asymmetry, and mild syndactyly; Chotzen syndrome

Genetics/Basic Defects 1. An autosomal dominant disorder with high penetrance and wide variable expressivity 2. A variety of mutations, including missense and nonsense mutations, small insertions, duplications, and deletions (Gripp et al. 2000; Chun et al. 2002) on the TWIST gene, which was mapped at 7p21, lead to heterogeneous symptoms of the syndrome. 3. Also, patients with characteristics of SaethreChotzen syndrome but without TWIST mutations have been described (de Heer et al. 2005). a. Some of these patients harbored the FGFR3 P250R mutation, nowadays considered to cause a distinct and unique craniosynostosis syndrome, Muenke syndrome (Muenke et al. 1997; Graham et al. 1998).

b. Strikingly, it was found that all Saethre-Chotzen syndrome patients with large genetic deletions, encompassing the TWIST gene and extending onto chromosome 7p, had mental retardation, a rare feature in the syndrome (Johnson et al. 1998; Zackai and Stolle 1998; Chun et al. 2002).

Clinical Features 1. Widely variable phenotype 2. Craniosynostosis (premature fusion of one or more sutures of calvarium) (Paznekas et al. 1998) a. Coronal suture (unilateral or bilateral): most commonly affected i. Bilateral (59% of cases) ii. Unilateral (23% of cases) b. Other cranial sutures (21% of cases), such as sagittal, lambdoid, and metopic, and even pansynostosis, may be involved. i. Can undergo premature fusion ii. Reports of affected individuals with no evidence of pathologic suture c. Often presents with an abnormal skull shape i. Brachycephaly (short, broad skull) ii. Acrocephaly (tall skull) 3. Other craniofacial features a. Facial asymmetry (the most conspicuous facial feature), particularly in individuals with unicoronal synostosis b. Low frontal hairline c. Ptosis of the eyelids: often results from a defective functioning or agenesis of the levator palpebrae muscle d. Downslanting of the palpebral fissures

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e. f. g. h. i. j.

present in SCS, however, craniosynostosis is not an obligatory finding (some affected relatives may not have been diagnosed with a craniosynostosis syndrome) 8. Differential diagnosis a. Muenke syndrome i. Characterized by “nonsyndromic” coronal craniosynostosis caused by the specific point mutation p.Pro250Arg in FGFR3 (encoding fibroblast growth factor receptor-3) ii. Shares features with Saethre-Chotzen syndrome (SCS) iii. Individuals with TWIST1 mutations distinguished from those with the FGFR3 p.Pro250Arg mutations from a recent study of 39 pedigrees (71 affected individuals) ascertained on the basis of coronal synostosis with the following clinical features: a) A low frontal hairline b) Ptosis c) Small ears d) Parietal foramina e) Interdigital webbing f) Hallux valgus or broad great toe with bifid distal phalanx b. Isolated unilateral coronal synostosis i. Represents coronal suture fusion with no evidence of other malformations ii. Approximately ten times more common than SCS. Coronal synostosis is the second most common form of single-suture fusion after sagittal synostosis. iii. Facial asymmetry resembling SCS can result from untreated or incompletely treated isolated unilateral coronal synostosis. c. Baller-Gerold syndrome (BGS) i. Characteristic clinical features a) Coronal craniosynostosis manifesting as abnormal shape of the skull (brachycephaly) with ocular proptosis and bulging forehead b) Radial ray defect manifesting as oligodactyly (reduction in number of digits), aplasia or hypoplasia of the thumb, and/or aplasia or hypoplasia of the radius

4.

5.

6.

7.

Epicanthal folds Strabismus Amblyopia Midface hypoplasia A broad nose with depressed nasal bridge Characteristic appearance of the ears: low-set and rotated ears with small pinna with a prominent superior and/or inferior crus Limb anomalies a. Brachydactyly: most frequent finding b. Cutaneous syndactyly of the second and third digits of the hands and feet: highly variable degree but nearly diagnostic in the presence of limb anomalies c. Clinodactyly of the fifth fingers d. Transverse palmar creases often present e. Broad digit I of the feet f. Hallux valgus g. Duplicated distal phalanx of the hallux h. Triangular epiphyses of the hallux Other variable clinical features a. Short stature b. Presence of foramina parietalia permagna (bony defects on both sides of the parietal suture exceeding 1 cm in diameter) c. Impressiones digitatae, considered to be an indicator of raised intracranial pressure, often recorded without the presence of increased intracranial pressure d. Conductive, mixed, and profound sensorineural hearing loss e. Ocular hypertelorism f. Occasional blepharophimosis g. Lacrimal duct stenosis h. Maxillary hypoplasia i. High-arched and/or cleft palate j. Congenital heart defects k. Vertebral fusion l. Radioulnar synostosis m. Increased risk of cancers (breast, kidney) Intelligence a. More commonly normal intelligence b. Significant learning disability usually noted in affected individuals with microdeletion in 7p21 but severe delay or mental retardation is not typical Family history of abnormal skull shape and/or a combination of other physical findings: usually

Saethre-Chotzen Syndrome

c) Growth retardation d) Poikiloderma ii. RECQL4: the only gene currently known to be associated with BGS iii. Clinical findings overlap with those of Rothmund-Thomson syndrome and Rapadilino syndrome, also caused by mutations in RECQL4.

Diagnostic Investigations 1. Diagnosis primarily based on clinical findings 2. Molecular genetic testing a. TWIST1 mutations: identified in 46–80% of affected individuals using a combination of deletion/duplication analysis and sequence analysis (positive in 46–80% of cases) b. Consider testing for FGFR3 (p.Pro250Arg) mutation if no TWIST1 mutation is identified in an individual with a presumed diagnosis of Saethre-Chotzen syndrome since clinical findings of Muenke syndrome overlap with Saethre-Chotzen syndrome. 3. Cytogenetic analysis: a chromosome translocation or inversion involving 7p21 or ring chromosome 7 reported in occasional patients with atypical findings, including developmental delay

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3. Management a. Cranioplasty in the first year of life i. To prevent progressive facial asymmetry in those with asymmetric coronal fusion ii. To prevent increased intracranial pressure (ICP) in those with multiple sutural synostosis iii. To prevent developmental delay and impaired vision secondary to increased intracranial pressure b. Midfacial surgery needed for dental malocclusion, swallowing difficulties, and respiratory problems c. Cleft palate surgery usually follows cranioplasty. d. Orthodontic treatment and/or orthognathic surgery as needed near the completion of facial growth; developmental intervention e. Routine treatment of hearing loss f. Prevention of secondary complications i. Attention to possible cervical vertebral instability secondary to vertebral anomalies ii. Periodic ophthalmologic evaluation for chronic papilledema iii. Brain imaging in later life for evidence of increased intracranial pressure iv. Routine evaluation for facial asymmetry, psychomotor development, and hearing loss

References Genetic Counseling 1. Recurrence risk a. Patient’s sib i. A 50% risk if a parent is also affected ii. An apparently low risk if the parents are clinically unaffected and do not have a TWIST1 mutation a) Spontaneous mutation rate if the proband represents de novo mutation b) Possible parental germ line mosaicism exists although no instances of germ line mosaicism have been reported. b. Patient’s offspring: a 50% recurrence risk for an affected individual to have an affected offspring 2. Prenatal diagnosis: possible for pregnancies at increased risk if the disease-causing mutation has been identified in the family

Anderson, P. J., Hall, C. M., Evans, R. D., et al. (1997). The cervical spine in Saethre-Chotzen syndrome. The Cleft Palate-Craniofacial Journal, 34, 79–82. Bartlett, S. P., & Foo, R. (2009). Reoperation for intracranial hypertension in TWIST1-confirmed Saethre-Chotzen syndrome: A 15-year review. Plastic and Reconstructive Surgery, 123, 1811–1812. Cai, J., Goodman, B. K., Patel, A. S., et al. (2003). Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: An improved strategy for TWIST mutation screening. Human Genetics, 114, 68–76. Chotzen, F. (1932). Eine eigenartige familiaere Entwicklungsstoerung (Akrocephalosyndaktylie, Dysostosis craniofacialis und Hypertelorismus). Monatsschrift Kinderheilkunde, 55, 97–122. Chun, K., Teebi, A. S., Jung, J. H., et al. (2002). Genetic analysis of patients with the Saethre-Chotzen phenotype. American Journal of Medical Genetics, 110, 136–143. de Heer, I. M., de Klein, A., van den Ouweland, A. M., et al. (2005). Clinical and genetic analysis of patients with Saethre-Chotzen syndrome. Plastic and Reconstructive Surgery, 115, 1894–1902.

1828 de Heer, I. M., Hoogeboom, J., Vermeij-Keers, C., et al. (2004). Postnatal onset of craniosynostosis in a case of SaethreChotzen syndrome. The Journal of Craniofacial Surgery, 15, 1048–1052. Dollfus, H., Biswas, P., Kumaramanickavel, G., et al. (2002). Saethre-Chotzen syndrome: Notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation. American Journal of Medical Genetics, 109, 218–225. El Ghouzzi, V., Le Merrer, M., Perrin-Schmitt, F., et al. (1997). Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nature Genetics, 15, 42–46. Gallagher, E. R., Ratisoontorn, C., & Cunningham, M. L. (2011). Saethre-Chotzen syndrome. GeneReviews. Retrieved June 21, 2011. Available at: http://www.ncbi.nlm.nih.gov/ books/NBK1189/. Graham, J. M. J., Braddock, S. R., Mortier, G. R., et al. (1998). Syndrome of coronal craniosynostosis with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene. American Journal of Medical Genetics, 77, 322. Gripp, K. W., Kasparcova, V., McDonald-McGinn, D. M., et al. (2001). A diagnostic approach to identifying submicroscopic 7p21 deletions in Saethre-Chotzen syndrome: Fluorescence in situ hybridization and dosage-sensitive Southern blot analysis. Genetics in Medicine, 3, 102–108. Gripp, K. W., Zackai, E. H., & Stolle, C. A. (2000). Mutations in the human TWIST gene. Human Mutation, 15, 479. Johnson, D., Horsley, S. W., Moloney, D. M., et al. (1998). A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1. American Journal of Human Genetics, 63, 1282–1293. Kasparcova, V., Stolle, C. A., Gripp, K. W., et al. (1998). Molecular analysis of patients with Saethre-Chotzen syndrome: Novel mutations and polymorphisms in the TWIST gene. American Journal of Medical Genetics, 63, A367. Kress, W., Schropp, C., Lieb, G., et al. (2006). Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: Functional

Saethre-Chotzen Syndrome differentiation from Muenke coronal synostosis syndrome. European Journal of Human Genetics, 14, 39–48. Lee, S., Seto, M., Sie, K., et al. (2002). A child with SaethreChotzen syndrome, sensorineural hearing loss, and a TWIST mutation. The Cleft Palate-Craniofacial Journal, 39, 110–114. Muenke, M., Gripp, K. W., McDonald-McGinn, D. M., et al. (1997). A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. American Journal of Human Genetics, 60, 555–564. Paznekas, W. A., Cunningham, M. L., Howard, T. D., et al. (1998). Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. American Journal of Human Genetics, 62, 1370–1380. Saethre, M. (1931). Ein Beitrag zum Turmschaedelproblem (Pathogenese, Erblichkeit und Symptomatologie). Deutsche Zeitschrift f€ ur Nervenheilkunde, 119, 533–555. Sahlin, P., Tarmow, P., Martinsson, T., et al. (2009). Germline mutation in the FGFR3 gene in a TWIST1-negative family with Saethre-Chotzen syndrome and breast cancer (Letter). Genes Chromosomes Cancer, 48, 285–288. Sahlin, P., Windh, P., Lauritzen, C., et al. (2007). Women with Saethre-Chotzen syndrome are at increased risk of breast cancer. Genes, Chromosomes & Cancer, 46, 656–660. Sayer, K. E. (1989). Techniques in aesthetic craniofacial surgery. Philadelphia, PA: JB Lippincott. Seifert, G., Kress, W., Meisel, C., et al. (2006). Genetic investigations of Saethre-Chotzen syndrome presenting with renal cell carcinoma. Cancer Genetics and Cytogenetics, 171, 76–78. Trusen, A., Beissert, M., Collmann, H., et al. (2003). The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation. Pediatric Radiology, 33, 168–172. Zackai, E. H., & Stolle, C. A. (1998). A new twist: Some patients with Saethre-Chotzen syndrome have a microdeletion syndrome. American Journal of Human Genetics, 63, 1277–1281.

Saethre-Chotzen Syndrome Fig. 1 (a, b) A 2-month-old boy was evaluated for trigonocephaly (metopic suture premature synostosis)

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a

Fig. 2 His mother was diagnosed to have Saethre-Chotzen syndrome clinically. Preoperatively, she was noted to have marked forehead asymmetry, retrusion of the right side of the supraorbital region, disproportion of the orbits with the right orbit higher, and temporal fossa hollowness. The diagnosis was confirmed molecularly by detection of a TWIST gene mutation (c.396–416 dup mutation, i.e., c.417ins21) which has been previously detected in other Saethre-Chotzen syndrome patients

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Fig. 3 (a–c) Follow-up visit of the child and the mother

Saethre-Chotzen Syndrome

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d

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Fig. 4 (a–f) A 42-year-old man was diagnosed to have SaethreChotzen since childhood. He was noted to have a brachycephalic skull with midfacial hypoplasia, a high forehead with a low hairline, a small cranial vault, asymmetric face with a curved nose, marked ptosis, down turned upper lip, underbite, repaired cleft palate, an underbite, low-set ears with prominent crus, cutaneous syndactyly and contractures at the proximal interphalangeal joints in the second and fifth digits bilaterally, a single flexion crease in the fifth digit of both hands with

f

unusual palmar creases, short toes with broad great toes bilaterally, minimal cutaneous syndactyly of toes 2–3 bilaterally, and bilateral hearing aids in place. In addition, he had developmental delay, seizures, heart murmur, and toeing-in requiring braces in childhood, keratoconus requiring corneal transplants, hypertension, and colon polyps and spastic colon. Southern blot analysis of genomic DNA showed complete deletion of one allele of the TWIST gene. Such mutations are diagnostic for Saethre-Chotzen syndrome

Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

Craniosynostosis, defined as the premature closure of >1 cranial suture with an estimated prevalence of 1 in 2,000–3,000 births (Cohen 2000), comprises a heterogeneous group of birth defects, including isolated forms and syndromic cases. Sagittal craniosynostosis (or synostosis), usually an isolated congenital abnormality in otherwise normal infants, is characterized by scaphocephaly. It is the most common form of craniosynostosis with prevalence of 1 in 5,000 children, comprising approximately 50% of all craniosynostosis cases (Lajeunie et al. 1996, 2005). Rarely, when sagittal synostosis is a part of a syndrome, it can be due to a chromosome abnormality associated with multiple congenital abnormalities or due to a single gene abnormality such as Crouzon or Carpenter syndrome, invariably associated with obvious facial or digital anomalies, with clinically evident closure of multiple sutures.

Genetics/Basic Defects 1. Classification of craniosynostosis based on suture involvement (Kimonis et al. 2007) a. Simple (involving one suture) or complex (involving two or more sutures) b. Primary (caused by an intrinsic defect in the suture) or secondary (premature closure of normal sutures because of another medical condition such as deficient brain growth) c. Isolated (occurring without other anomalies) or syndromic (accompanied by other dysmorphic features or developmental defects)

d. Frequencies of the various sutures involved i. Sagittal: 40–58%, etiology unknown ii. Coronal: 20–29%, estimated one-third caused by single-gene mutations iii. Metopic: 4–10%, etiology unknown iv. Lambdoidal: 2–4%, etiology unknown 2. Etiologies of nonsyndromic craniosynostosis (Passos-Bueno et al. 2008) a. Familial recurrence (Hennekam and Van den Boogaard 1990; Lajeunie et al. 1996, 1998, 2005; Cohen and McLean 2000) i. Nonsyndromic coronal synostosis (14%) ii. Nonsyndromic sagittal synostosis (6%) iii. Nonsyndromic metopic synostosis (3–9%) versus 22% in syndromic metopic synostosis iv. Pedigrees from familial recurrence: compatible with: a) Autosomal dominant inheritance b) Autosomal recessive inheritance c) X-linked inheritance b. Genetic etiology i. Poorly understood ii. EFNA4: The only gene that when mutated causes only nonsyndromic craniosynostosis (Merrill et al. 2006). 3. Etiologies of isolated (nonsyndromic) sagittal synostosis a. Suggestions of possible genetic and environmental factors (Johnson et al. 2000; Zeiger et al. 2002; Lajeunie et al. 2005) b. Possible intrauterine pressure on the neurocranium on the etiology of craniosynostosis (Johnson et al. 2000; Kirschner et al. 2002)

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c. Preference for (Butzelaar et al. 2009) i. Male sex ii. Twinning iii. Prematurity 4. Etiologies of syndromic craniosynostosis (PassosBueno et al. 2008; Jehee et al. 2008) a. To date, well over 180 syndromes are associated with craniosynostosis as a major clinical feature. Mendelian and chromosomal alterations are important causative mechanisms. b. Mutations associated with syndromic craniosynostosis i. Mutations in seven genes (FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, and RAB23): unequivocally associated with mendelian forms of syndromic craniosynostosis and explain the etiology of about 30% of syndromic cases (Wilkie et al. 2007) ii. Mutations in four other genes, FBN1, POR, TGFBR1, and TGFBR2: also associated with craniosynostosis, but not causing the major clinical feature of the phenotype and/or with an apparently low penetrance (Sood et al. 1996; Fl€ uck et al. 2004; Loeys et al. 2005) 5. Chromosome alterations in the etiology of craniosynostosis (Passos-Bueno et al. 2008) a. All types of chromosomal abnormalities have already been described in patients with craniosynostosis, including deletions and duplications in almost all human chromosomes. b. Approximately 16% of syndromic cases have been associated with chromosomal abnormalities in conventional cytogenetics studies (Cohen 2000). i. A high association of craniosynostosis with duplication 13q21–q34 ii. A high association of craniosynostosis with deletion 7p15–p21, 9p21–p24, and 11q23–q25 (Brewer et al. 1998, 1999) iii. Deletion and/or duplication 1p36 (Gajecka et al. 2005; McDonald-McGinn et al. 2005) c. Jehee et al. (2008) screened 45 patients with craniosynostotic disorders with a variety of methods including conventional karyotype, microsatellite segregation analysis, subtelomeric multiplex ligation-dependent probe amplification, and array-based comparative genome hybridization with the following results: i. Causative abnormalities were present in 42.2% (19/45) of the samples.

ii. 27.8% (10/36) of the patients with normal conventional karyotype carried submicroscopic imbalances. iii. Sagittal synostosis a) Del(1p) b) Dup(5)(p15.1–p14.1) c) Dup17q d) Dup(X)(p11.23) iv. Metopic synostosis a) Del(1q) b) Del(1q)/dup(15q) c) Del(9)(p22.3p24.2) d) Del(9q)/dup(17q) e) Del(11)(q23.3) f) Del(X)(p11.3) g) Del(Y)(q11) h) Der(9)t(9;4)(p22.3;q34) i) Der(9)t(9;?)(p21.3;?) j) Dup(3)(p25.2) k) Dup(6)(q27) l) Dup(15)(q13.2) m) Dup(22)(q11.23) n) Dup(X)(p22.3) v. Bilateral coronal synostosis: Dup(3)(q26.33) vi. Bilateral coronal and metopic synostosis: Dup(X)(q22.2) 6. Sagittal synostosis associated with chromosome abnormalities a. Our patient 1: del(4)(q26 ! q28.3ter) and del (13)(q21.2 ! q21.31) b. Our patient 2: del(13)(q33.1 ! qter) and dup(17) (q25.3 ! qter) [der(13)(13)(t13;17)(q33.1;q25.3)] c. Our patient 3: t(4;18)(p12p11.2) 7. Multiple craniosynostosis involving sagittal and other sutures associated with chromosome abnormalities a. Sagittal and metopic synostosis (Hiraki et al. 2006): 46,X,der(Y)(t(Y;1)(q12;p36.3) inherited from father [46,X,t(Y;1)(q12;p36.3)] b. Sagittal and bilateral lambdoid synostosis (called craniofacial dyssynostosis, “Mercedes Benz” syndrome, or nonsyndromic multisutural synostosis) (Hing et al. 2009) i. Case reported by Shiihara et al. (2004): sagittal and metopic suture synostosis a) An unbalanced translocation, 46,XX,der (13)t(5;13)(q33.3;q34)mat resulting in monosomy 13 q34–qter and trisomy 5q33.3–qter

Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

b) FISH analysis showed three MSX2 signals indicating the presence of three copies of the MSX2 gene. ii. Case reported by Cohen (2000): complex rearrangement of chromosome 5, resulting in three paracentric inversions/two insertions and a duplication of 5q35 inclusive of the MSX2 gene region iii. Case reported by Tagariello et al. (2006) a) A de novo–balanced translocation, t(9;11)(q33;p15) b) Both breakpoint regions were cloned, and the chromosome 11p15 breakpoint was noted to disrupt the SOX6 gene between exons 6 and 7. However, the potential role of the SOX6 gene disruption in BLSS remains undetermined. iv. Case reported by Hing et al. (2009): an Xp11.2 deletion c. Sagittal, metopic, and coronary synostosis (Hiraki et al. 2008): 46,XX,der(15)(q15.2q22.1) d. Sagittal, metopic, lambdoid, temporal, and squamosal synostosis (Jehee et al. 2007): De novo interstitial 11q duplication [46,XY,dup(11) (q11–q13.3)(/46,XY] included the duplication of genes FGF3 and FGF4.

Clinical Features 1. Natural history of sagittal synostosis (Chatterjee et al. 2007) a. As the condition occurs in utero, diagnosis should be possible at birth with careful attention to the sagittal suture and the deformity that is created. b. If uncorrected, sagittal synostosis leads to progression of the scaphocephalic deformity which can be an esthetic problem as well as raised intracranial pressure and speech and language impairment in almost 40% of patients. 2. Clinical features of sagittal synostosis a. Scaphocephaly or dolichocephaly due to growth restriction transverse to the sagittal suture resulting in a biparietally narrowed skull and continuing growth of the calvaria in the ventraldorsal direction resulting in the elongation of the skull

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b. Variable appearance of the elongation of the skull depending on which portion of the sagittal suture is fused c. Ridging of the sagittal suture d. Frontal bossing: resulting from premature closure of the anterior portion of the sagittal suture (Jane et al. 2000) e. Variants of posterior sagittal synostosis (Jane et al. 2000): Closure of the posterior portion of the sagittal sutures occurs less commonly than anterior closure. i. Occipital knob: The occipital bone becomes the site of compensatory overgrowth because it is located distal and perpendicular to the fused suture. ii. “Golf tee” deformity a) An exaggerated form of the occipital knob, simulating a golf tee b) The skull is narrower posteriorly and protrudes more prominently. In addition, the unfused anterior portion of the sagittal suture may widen the parietal bone anteriorly, accentuating the occipital narrowing. iii. Bathrocephalic deformities: an extreme consequence of premature posterior closure of the sagittal suture a) Characterized by the appearance of a podium in the occipital region b) The posterior portion of the parietal bone slants inferiorly while the occipital bone juts superiorly. f. Complete sagittal synostosis: the most extreme form of the sagittal synostosis, resulting in both anterior and posterior deformity 3. Sagittal synostosis associated with chromosome abnormalities (our cases) a. Patient 1 (monosomies 4q and 13q) i. Sagittal suture synostosis (palpable bonny ridge along the sagittal suture) ii. Ocular hypertelorism iii. Proptotic eyes iv. Micrognathia b. Patient 2 (translocation 4p and 18p) i. Sagittal synostosis (scaphocephaly) ii. Tetralogy of Fallot 4. Multiple suture synostoses (including sagittal synostosis) associated with chromosome abnormalities: wide variation of clinical features depending on the gain or loss of the chromosome(s) and

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Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

chromosome segments involved. Following are some of the examples: a. Multiple craniosynostoses involving the sagittal and metopic sutures with 1p36.3–pter trisomy (Hiraki et al. 2006) i. Borderline mental retardation ii. Bitemporal narrowing iii. Sloping forehead iv. Blepharophimosis v. Blepharoptosis b. Multiple craniosynostoses involving sagittal and bilateral lambdoid sutures: Premature fusion of the sagittal and both lambdoid sutures results in a characteristic head shape with frontal bossing, turribrachycephaly, biparietal narrowing, occipital concavity, inferior displacement of the ears, and ridging of the sagittal and lambdoid sutures (Hing et al. 2009). i. Case reported by Shiihara et al. (2004) a) Sagittal and bilateral lambdoid sutures b) Developmental delay c) Atrial septal defect d) Patent ductus arteriosus e) Unbalanced translocation, 46,XX,der (13)t(5;13)(q33.3;q34)mat resulting in monosomy 13 q34–qter and trisomy 5q33.3–qter f) FISH analysis demonstrated three copies of the MSX2 gene. ii. Case reported by Cohen (2000) a) Sagittal and bilateral lambdoid sutures b) Hypotonia c) Ventricular septal defect d) Coarctation of the aorta e) A complex rearrangement of chromosome 5 resulting in three paracentric inversions/two insertions and a duplication of 5q35 inclusive of the MSX2 gene region f) MSX2 is known to play an important role in cranial bone formation as haploinsufficiency of MSX2 results in parietal skull defects and overexpression causes craniosynostosis. iii. Case reported by Tagariello et al. (2006) a) Sagittal and bilateral lambdoid sutures b) Mild speech delay c) A de novo balanced translocation, t(9;11) (q33;p15)

d) Both breakpoint regions were cloned, and the chromosome 11p15 breakpoint was noted to disrupt the SOX6 gene between exons 6 and 7. iv. Case reported by Hing et al. (2009) a) Sagittal and bilateral lambdoid sutures: frontal bossing, brachycephaly, narrow occiput b) Hypotonia at birth c) Progressive apnea d) Seizures e) Expired at 4 months of age f) Xp11.22 deletion: clinical significance unknown c. Multiple craniosynostoses involving the sagittal, metopic, and coronary sutures i. Cases reported by Hiraki et al. (2008) with a de novo 15q15q22 deletion a) Hypotonia b) Profound growth and psychomotor retardation c) Craniofacial dysmorphic features (bowshaped eyebrows, downslanting palpebral fissures, mild blepharophimosis, strabismus, nystagmus, optic nerve atrophy, lowset ears with stenotic bilateral ear canals, bulbous nasal tip, hypoplastic alae nasi, upturned nostrils, high-arched palate, bifid uvula, epiglottic hypoplasia, a thin upper lip, and tucked-in lower lip) d) Other anomalies (pectus excavatum, accessory nipples, small hands and feet, long fingers, abducted and proximally placed thumbs, clinodactyly of the fifth fingers, four finger creases, overlapping third and fifth over fourth toes, metatarsus adductus) d. Sagittal, metopic, lambdoid, temporal, and squamosal synostosis (Jehee et al. 2007): de novo interstitial 11q duplication i. Developmental delay ii. Marked trigonocephalic, turricephalic, and scaphocephalic-shaped skull iii. Blue sclerae iv. Nystagmus v. Strabismus vi. Short neck vii. Short philtrum viii. Supernumerary maxillary lateral incisor ix. PDA

Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

x. xi. xii. xiii. xiv. xv. xvi. xvii.

Patent foramen ovale Seizures Recurrent infections Mild brachydactyly of the finger Clinodactyly of the fifth fingers Slightly broad thumbs Shortened distal phalanges Hypoplastic nails

Diagnostic Investigations 1. Radiographic study to demonstrate sagittal synostosis 2. Three-dimensional computed tomographies to discern the characteristics of sagittal synostosis (David et al. 2009) a. Anterior type: characterized by a transverse retrocoronal band b. Central type: Prematurely fused sagittal suture is marked by a prominent heaped-up appearance. c. Posterior type: a significantly elongated occiput as the most striking radiographic feature d. Complex type: combined characteristics of anterior, central, and posterior types 3. Conventional karyotype 4. Microsatellite segregation analysis 5. Subtelomeric multiplex ligation-dependent probe amplification 6. Array-based comparative genome hybridization

Genetic Counseling 1. Recurrence risk (Kimonis et al. 2007; Wilkie et al. 2007) a. Patient’s sib i. “Truly nonsyndromic craniosynostosis”: thought to be a multifactorial trait with recurrent risk around 5% for coronal and around 1% for sagittal suture fusion ii. Autosomal dominant craniosynostosis a) Common in craniosynostosis syndromes with a relatively high proportion of new mutations b) Genetic counseling for the parents of a child with an apparently new mutation: difficult by uncertainties over the

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recurrence risk attributable to occult germ line mosaicism in a parent c) Negative parental mutation testing: still leaves a small ( expression induced by intrauterine constraint. Plastic and Reconstructive Surgery, 109, 2338–2346. Lajeunie, E., Crimmins, D. W., Arnaud, E., et al. (2005). Genetic considerations in nonsyndromic midline craniosynostosis: A study of twins and their families. Journal of Neurosurgery, 103(4 Suppl), 353–356. Lajeunie, E., Le Merrer, M., Bonaiti-Pellie, C., et al. (1996). Genetic study of scaphocephaly. American Journal of Medical Genetics, 62, 282–285. Lajeunie, E., Le Merrer, M., Marchac, D., et al. (1998). Syndromal and nonsyndromal primary trigonocephaly: Analysis of a series of 237 patients. American Journal of Medical Genetics, 2, 211–215. Loeys, B. L., Chen, J., Neptune, E. R., et al. (2005). A syndrome of altered cardiovascular, craniofacial, neurocongnitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics, 37, 275–281. McDonald-McGinn, D. M., Gripp, K. W., Kirschner, R. E., et al. (2005). Craniosynostosis: Another feature of the 22q11.2 deletion syndrome. American Journal of Medical Genetics Part A, 136A, 358–362. Merrill, A. E., Bochukova, E. G., Bruggar, S. M., et al. (2006). Cell mixing at a neural crest-mesoderm boundary and deficient Ephrin-Eph signaling in the pathogenesis of craniosynostosis. Human Molecular Genetics, 15, 1319–1328. Passos-Bueno, M. R., Sertie, A. L., Jehee, F. S., et al. (2008). Genetics of craniosynostosis: Genes, syndromes, mutations and genotype-phenotype correlations. Frontiers of Oral Biology, 12, 107–143. Shiihara, T., Kato, M., Kimura, T., et al. (2004). Craniosynostosis with extra copy of MSX2 in a patient with partial 5qtrisomy. American Journal of Medical Genetics. Part A, 128A, 214–216. Sood, S., Eldahdah, Z. A., Krause, W. L., et al. (1996). Mutations in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nature Genetics, 12, 209–211. Tagariello, A., Heller, R., Greven, A., et al. (2006). Balanced translocation in a patient with craniosynostosis disrupts theSOX6gene and an evolutionarily conserved nontranscribed region. Journal of Medical Genetics, 43, 534–540. Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., et al. (2007). Clinical dividends from the molecular genetic diagnosis of craniosynostosis. American Journal of Medical Genetics. Part A, 143A, 1941–1949. Zeiger, J. S., Beaty, T. H., Hetmanski, J. B., et al. (2002). Genetic and environmental risk factors for sagittal craniosynostosis. The Journal of Craniofacial Surgery, 13, 602–606.

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Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

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Fig. 1 (a, b) An 8-month-old infant was evaluated for sagittal suture synostosis. Her craniofacial features were characterized by palpable bonny ridge along the sagittal suture, ocular hypertelorism with proptotic eyes, and mild retrognathia. Conventional cytogenetics showed a complex chromosomal rearrangement involving chromosomes 2, 4, and 13, and deletions

a

in chromosomes 4 and 13 [46,XX,ins(2;4)(p21;q31.2q33),del(4) (q26q28.3),t(4;13)(q31.3;q21.32),del(13)(q21.2q21.31)]. Oligonucleotide array CGH analysis showed a 22-Mb deletion in bands 4q26 to 4q28.3 and a 3.5-Mb deletion in 13q21.2 to13q21.31. The karyotype is therefore monosomic for genes in these regions

b

Fig. 2 (a, b) Three-dimensional CT reconstructions from the same patient shows dolichocephalic skull resulting from premature fusion of the sagittal suture and sagittal ridge

Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis Fig. 3 (a, b) Her karyotype showed del(4)(q26 ! q28.3ter) and del(13) (13q21.2 ! q21.31) (Pencil marks are intentionally left here to show the complex chromosome rearrangements)

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Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

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Fig. 4 (a–c) FISH with wcp2 and wcp4 confirmed an insertion of chromosome 4 material (4q31.2–33) into the short arm of 4q31.1 to 4qter. This translocation was confirmed with FISH

subtelomeric probes, showing the qter of the translocation positive for the 13q subtelomere sequences, and the qter of the translocation 13 positive for 4q subtelomere

Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

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Fig. 5 (a, b) A 2-month-old infant was evaluated for scaphocephaly (sagittal suture ridge palpable) with Tetralogy of Fallot

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Sagittal Craniosynostosis Associated with Chromosome Abnormalities with a Brief Review on Craniosynostosis

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Fig. 6 (a–c) Her karyotype and ideogram with partial karyotypes showed a balanced translocation t(4;18)(p12;p11.2)

Schizencephaly

Schizencephaly is a rare congenital brain malformation characterized by deep clefts of the cerebral mantle that extend from the cortical surface to the lateral ventricles. The conditions are often associated with convolutional anomalies such as polymicrogyria or nodular subependymal heterotopias.

Genetics/Birth Defects 1. Inheritance a. Isolated schizencephaly: mainly sporadic b. Rare reports of familial cases 2. Etiology a. A developmental defect in the blood vessels supplying the cerebral cortex i. Resulting in tissue death and cleft formation due to lack of oxygen (in utero vascular insufficiency) ii. With preferential location in the parasylvian regions following the frontoparietal distribution of the middle cerebral artery b. Mutations in the homeodomain gene EMX2 as a possible cause of some cases of schizencephaly i. At least some schizencephaly cases result from germline mutations. ii. EMX2: expressed in restricted areas of the developing mammalian forebrain, including areas that develop into the cerebral cortex iii. Discovery of EMX2 mutations in both sporadic and familial cases of schizencephaly marking an important advance in establishing genetic causes for brain malformations

iv. Lack of EMX2 mutations in most schizencephaly patients has increased the likelihood of other genes being involved. v. EMX2 mutations were not confirmed from recent studies on large schizencephaly case series (Tietjen et al. 2007; Merello et al. 2008; Hehr et al. 2010). c. Heterozygous mutations in SIX3 and SHH are associated with schizencephaly: a subset of patients with schizencephaly may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway, and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly (Hehr et al. 2010) 3. Schizencephaly a. Refers to gray matter–lined clefts that extend through the entire hemisphere from the ependymal lining of the lateral ventricles to the pial covering of the cortex b. Cleft i. A cleft in the cerebral mantle which communicates between the subarachnoid space laterally and ventricular system medially a) Unilateral or bilateral cleft b) Symmetric or asymmetric cleft ii. The sides of clefts generally lined with heterotopic gray matter (an abnormal accumulation of neurons) c. Two types of schizencephaly depending on the size of the area involved and the separation of the cleft lips i. Type I (closed-lip schizencephaly) a) Consisting of a fused cleft

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b) This fused pial-ependymal seam forms a furrow in the developing brain and is lined by polymicrogyric gray matter. ii. Type II (open-lip schizencephaly): presence of a large defect, a holohemispheric cleft in the cerebral cortex filled with cerebral spinal fluid and lined by polymicrogyric gray matter d. Associated malformations commonly accompanying schizencephaly i. Mild hypoplasia of the corpus callosum ii. Total or nearly total absence of cavum septum pellucidum in 70–90% of patients with schizencephaly. 30–50% of patients show associated optic nerve hypoplasia on clinical examination (septo-optic dysplasia with schizencephaly). iii. Focal cortical dysplasia iv. Coloboma of the retina v. Hydrocephalus 4. Syndromes associated with schizencephaly a. Septo-optic dysplasia-schizencephaly syndrome i. Clinical features distinct from isolated septooptic dysplasia ii. Significant global developmental delay and spastic motor deficits iii. Seizures and visual symptoms rather than with endocrine abnormalities b. Other rare schizencephaly syndromes i. Prenatal cytomegalovirus infection ii. Vascular disruption related to twinning c. Schizencephaly (plus polymicrogyria) as part of multiple congenital anomaly/mental retardation syndromes i. Adam-Oliver syndrome ii. Aicardi syndrome iii. Arima syndrome iv. Delleman (oculocerebrocutaneous) syndrome v. Galloway-Mowat syndrome vi. Micro syndrome

Clinical Features 1. Clinical manifestations depend on the size and location of involved brain. a. A narrow, unilateral cleft i. Usually present with seizures and mild focal neurological deficits ii. Otherwise developmentally normal

Schizencephaly

b. Bilateral clefts i. Severe developmental delay ii. Early intractable epilepsy iii. Severe motor dysfunction 2. Clinical features a. Mental retardation (varying degree) b. Developmental delay: moderate to severe if the defects are large c. Microcephaly (varying degree) d. Hydrocephalus in some patients e. Hypotonia in the postnatal period f. Motor difficulties g. Seizures in most patients h. Generalized spasticity i. Hemiparesis or quadriparesis j. Blindness secondary to optic nerve hypoplasia k. Prognosis depending on the size of the clefts and the degree of neurological deficits i. Patients with type I abnormalities a) Almost normal b) May have seizures and spasticity ii. Patients with smaller, unilateral clefts (clefts in only one hemisphere) a) Often paralyzed on one side of the body b) May have normal intelligence iii. Patients with type II abnormalities a) Mental retardation b) Seizures c) Hypotonia d) Spasticity e) Inability to walk or speak f) Blindness iv. Patients with bilateral open-lip schizencephaly generally with the worst clinical symptoms

Diagnostic Investigations 1. Ultrasonography of the brain to demonstrate closedlip or open-lip brain cleft communicating with lateral ventricle(s) 2. Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain a. Open-lip or closed-lip schizencephaly b. Associated absence of the septum pellucidum and hypoplasia of the optic chiasm 3. Potential role of diffusion tensor imaging with tractography in providing insights into the

Schizencephaly

evaluation of white matter tracts in patients with schizencephaly (Sarikaya 2009) 4. Pathology a. Clefts most commonly in the Rolandic fissures b. Frequently associated with pachygyria, polymicrogyria, or lissencephaly 5. Molecular genetic testing of EMX2 mutation for familial schizencephaly: not considered to be appropriate and not available clinically

Genetic Counseling 1. Recurrence risk: low unless germline mutation is present in one of the parent 2. Prenatal diagnosis a. Ultrasonography and/or fetal MRI of the brain to demonstrate brain clefts connecting to the lateral ventricles b. Differential diagnosis of CSF-containing abnormalities in the fetal brain (Oh et al. 2005) i. Developmental lesions a) Arachnoid cyst b) Ventriculomegaly c) Monoventricle in holoprosencephaly d) Agenesis of the corpus callosum with an interhemispheric cyst e) Schizencephaly ii. Destructive lesions a) Porencephalic cyst b) Ventriculomegaly (infection or bleeding) c) Hydranencephaly c. EMX2 mutation analysis on amniocytes or CVS: not considered to be appropriate and not available clinically 3. Management a. Physical therapy b. Seizure control c. VP shunt for hydrocephalus

References Aniskiewicz, A. S., Frumkin, N. L., Brady, D. E., et al. (1990). Magnetic resonance imaging and neurobehavioral correlates in schinzencephaly. Archives of Neurology, 47, 911–916. Barkovich, A. J., Fram, E. K., & Norman, D. (1989). Septo-optic dysplasia: MR imaging. Radiology, 171, 189–192. Barkovich, A. J., & Kjos, B. O. (1992). Schizencephaly: correlation of clinical findings with MR characteristics. American Journal of Neuroradiology, 13, 85–94.

1847 Barkovich, A. J., Kuzniecky, R. I., Jackson, G. D., et al. (2001). Classification system for malformations of cortical development. Neurology, 57, 2168. Brunelli, S., Faiella, A., Capra, V., et al. (1996). Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nature Genetics, 12, 94–96. Byrd, S. E., Osborn, R. E., Bohan, T. P., et al. (1989). The CT and MR evaluation of migrational disorders of the brain. Part I. Lissencephaly and pachygyria. Pediatric Radiology, 19, 151–156. Capra, V., De Marco, P., Moroni, A., et al. (1996). Schizencephaly: Surgical features and new molecular genetic results. European Journal of Pediatric Surgery, 6 (Suppl 1), 27–29. Ceccherini, A. F., Twining, P., & Variend, S. (1999). Schizencephaly: Antenatal detection using ultrasound. Clinical Radiology, 54, 620–622. Chamberlain, M. C., Press, G. A., & Bejar, R. F. (1990). Neonatal schizencephaly: Comparison of brain imaging. Pediatric Neurology, 6, 382–387. Denis, D., Chateil, J. F., Brun, M., et al. (2000). Schizencephaly: Clinical and imaging features in 30 infantile cases. Brain & Development, 22, 475–483. Denis, D., Maugey-Laulom, B., Carles, D., et al. (2001). Prenatal diagnosis of schizencephaly by fetal magnetic resonance imaging. Fetal Diagnosis and Therapy, 16, 354–359. Faiella, A., Brunelli, S., Granata, T., et al. (1997). A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. European Journal of Human Genetics, 5, 186–190. Granata, T., Battaglia, G., D’Incerti, L., et al. (1996). Schizencephaly: Neuroradiologic and epileptologic findings. Epilepsia, 37, 1185–1193. Granata, T., Farina, L., Faiella, A., et al. (1997). Familial schizencephaly associated with EMX2 mutation. Neurology, 48, 1404–1406. Haverkamp, F., Zerres, K., Ostertun, B., et al. (1995). Familial schizencephaly: Further delineation of a rare disorder. Journal of Medical Genetics, 32, 242–244. Hayashi, N., Tsutsumi, Y., & Barkovich, A. J. (2002). Morphological features and associated anomalies of schizencephaly in the clinical population: detailed analysis of MR images. Neuroradiology, 44, 418–427. Hehr, U., Pineda-Alvarez, D. E., Uyanik, G., et al. (2010). Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. Human Genetics, 127, 555–561. Herman, M., & Rico, S. (1999). Schizencephaly: Presentation in a 6-week-old boy with fetal death of co-twin. International Pediatrics, 14, 32–34. Hilburger, A. C., Willis, J. K., Bouldin, F., et al. (1993). Familial schizencephaly. Brain & Development, 15, 234–236. Hosley, M. A., Abroms, I. F., & Ragland, R. L. (1991). Schizencephaly: Case report of familial incidence. Pediatric Neurology, 8, 148–150. Klingensmith, W. C., III, & Cioffi-Ragan, D. T. (1986). Schizencephaly: Diagnosis and progression in utero. Radiology, 159, 617–618. Komarniski, C. A., Cyr, D. R., Mack, L. A., et al. (1990). Prenatal diagnosis of schizencephaly. Journal of Ultrasound in Medicine, 9, 305–307.

1848 Kuban, K. C., Teele, R. L., & Wallman, J. (1989a). Septo-opticdysplasia-schizencephaly. Radiographic and clinical features. Pediatric Radiology, 19, 145–150. Kuban, K. C., Teele, R. L., & Wallman, J. (1989b). Septo-optic dysplasia-schizencephaly: Radiographic and clinical features. Pediatric Radiology, 19, 145–150. Landrieu, P., & Lacroix, C. (1994). Schizencephaly, consequence of a developmental vasculopathy? A clinicopathological report. Clinical Neuropathology, 13, 192–196. Lituania, M., Passamonti, U., Cordono, M. S., et al. (1989). Schizencephaly: Prenatal diagnosis by computed sonography and magnetic resonance imaging. Prenatal Diagnosis, 9, 649–655. Lubinsky, M. S. (1997). Hypothesis: Septo-optic dysplasia is a vascular disruption sequence. American Journal of Medical Genetics, 69, 235–236. Merello, E., Swanson, E., de Marco, P., et al. (2008). No major role for the EMX2 gene in Schizencephaly. American Journal of Medical Genetics. Part A, 146A, 1142–1150. Miller, S. P., Shevell, M. I., Patenaude, Y., et al. (2000). Septo-optic plus: A spectrum of malformations of cortical development. Neurology, 54, 1701–1703. Miller, G. M., Stears, I. C., Cuggenheim, M. A., et al. (1982). The clinical and computerized tomographic spectrum of schinzencephaly in six patients. Neurology, 32, A218–A219. Miller, G. M., Stears, I. C., Cuggenheim, M. A., et al. (1984). Schizencephaly: A clinical and CT study. Neurology, 34, 997–1001. Oh, K. Y., Kennedy, A. M., Frias, A. E., et al. (2005). Fetal schizencephaly: Pre- and postnatal imaging with a review of the clinical manifestations. Radiographics, 25, 647–657.

Schizencephaly Packard, A. M., Miller, V. S., & Delgado, M. R. (1997). Schizencephaly: Correlations of clinical and radiologic features. Neurology, 48, 1427–1434. Page, L. K., Brown, S. B., Gargano, F. P., et al. (1975). Schizencephaly: A clinical study and review. Child’s Brain, 1, 348–358. Pilu, G. L., Falco, P., Perolo, A., et al. (1997). Differential diagnosis and outcome of fetal intracranial hypoechoic lesions: report of 21 cases. Ultrasound in Obstetrics & Gynecology, 9, 229–236. Robinson, R. O. (1991). Familial schizencephaly. Developmental Medicine and Child Neurology, 33, 1010–1012. Sarikaya, B. (2009). MR tractography of schizencephaly. Diagnostic and Interventional Radiology, 16(4), 270–275. Tietjen, I., Bodell, A., Apse, K., et al. (2007). Comprehensive EMX2 genotyping of a large Schizencephaly case series. American Journal of Medical Genetics Part A, 143A, 1313–1316. Yakovlev, P. I., & Wadsworth, R. C. (1946a). Schizencephalies. A study of the congenital clefts in the cerebral mantle. I. Clefts with fused lips. Journal of Neuropathology and Experimental Neurology, 5, 116–130. Yakovlev, P. I., & Wadsworth, R. C. (1946b). Schizencephalies. A study of the congenital clefts in the cerebral mantle. II. Clefts with hydrocephalus and lips separated. Journal of Neuropathology and Experimental Neurology, 5, 169–206. Yoshida, M., Suda, Y., Matsuo, I., et al. (1997). Emx1 and Emx2 functions in development of dorsal telencephalon. Development, 124, 101–110.

Schizencephaly

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Fig. 1 (a–d) An infant with asymmetric open-lip parietal schizencephaly, illustrated by MRI

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Schizencephaly

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Fig. 2 (a, b) An infant with schizencephaly with global delay and spastic quadriplegia. His MRI of the brain showed bilateral large open-lip schizencephaly in frontotemporal regions

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Fig. 3 (a, b) MRI of the brain of another patient showing bilateral open-lip schizencephaly in the parietal regions in communication with a large cavity filled by cerebrospinal fluid

Schizencephaly

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Fig. 4 (a–c) MRI of the brain of a neonate showed a large open-lip schizencephaly extending to the right convexity causing a large gap in the right cerebellar hemisphere. There is also absence of the corpus callosum

Schmid Metaphyseal Chondrodysplasia

Schmid metaphyseal chondrodysplasia (SMCD) is a mild hereditary chondrodysplasia resulting from growth plate cartilage abnormalities (Chan et al. 1998).

Genetics/Basic Defects 1. Inheritance a. Autosomal dominant b. Variable expression 2. Molecular pathogenesis a. SMCD: caused by heterozygous mutations in the gene COL10A1 (mapped to chromosome 6q21-q22), the gene which encodes a1(X) chains of type X collagen, a short-chain collagen whose expression is largely restricted to the hypertrophic chondrocytes of growth plate cartilage (Bateman et al. 2003) i. Most mutations reside in the carboxylterminal globular domain (CN1) (Ridanp€a€a et al. 2003) ii. Two mutations observed In a putative signal peptide cleavage site b. Growth plate abnormalities of SMCD: resulting from collagen X haploinsufficiency, a reduction by 50% in collagen X (Bateman et al. 2003)

Clinical Features 1. Mild to moderate short-limbed dwarfism (Beluffi et al. 1982) 2. Bowed legs

3. Waddling gait, often a presenting sign at second year 4. Coxa vara 5. Genu varum 6. Exaggerated lumbar lordosis 7. Flared anterior rib cage 8. Leg pain during childhood 9. Prognosis a. Radiological changes appearing early with a tendency to heal and change slowly with time, giving rise to mildly dwarfed patients b. Normal intelligence

Diagnostic Investigations 1. Radiography (Lachman et al. 1988) a. Hip i. Abnormal acetabular roofs ii. Enlarged capital femoral epiphyses iii. Coxa vara iv. Femoral bowing v. Abnormal proximal femoral metaphyses b. Knee i. Abnormal distal femoral metaphyses ii. Abnormal proximal tibial metaphyses iii. Abnormal proximal fibular metaphyses c. Ankle i. Abnormal distal tibial metaphyses ii. Abnormal distal fibular metaphyses d. Wrist i. Abnormal distal radial metaphyses ii. Abnormal distal ulnar metaphyses e. Ribs: anterior cupping, splaying and sclerosis

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f. Wide metaphyses with cupping and fraying g. Short and stubby long bones h. Mild hand involvement: a common feature (Elliott et al. 2005) i. Shortening of the tubular bones ii. Metaphyseal cupping of the proximal phalanges and metacarpals i. Normal spine 2. Histology: variable bone changes (Dimson 1968) a. Mild sharp serrations of the metaphyses with increased density of the provisional zone of calcification b. Irregularity with flaring and fragmentation and widening of the growth plate 3. Molecular genetic analysis of COL10A1 mutation (Milunsky et al. 1998) a. Mutation analysis b. Mutation scanning

Genetic Counseling 1. Recurrence risk a. Patient’s sib: low recurrence risk unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis by amniocentesis or CVS: can be offered to families at-risk for DMCD with a previously characterized disease-causing COL10A1 mutation 3. Management a. Supportive b. Orthopedic management of bowed legs: generally does not require orthopedic surgery

References Bateman, J. F., Freddi, S., Nattrass, G., et al. (2003). Tissuespecific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Human Molecular Genetics, 12, 217–225. Beluffi, G., Fiori, P., Notarangelo, C. D., et al. (1983). Metaphyseal dysplasia type Schmid. Early X-ray detection and evolution with time. Annual Radiology (Paris), 26, 237–243. Beluffi, G., Fiori, P., Schifino, A., et al. (1982). Metaphyseal dysplasia, type Schmid. Progress in Clinical and Biological Research, 104, 103–110.

Schmid Metaphyseal Chondrodysplasia Bonaventure, J., Chaminade, F., & Maroteaux, P. (1995). Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias. Human Genetics, 96, 58–64. Chan, D., Ho, M. S., & Cheah, K. S. (2001). Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia. Implications for the molecular basis of the disease. Journal of Biological Chemistry, 276, 7992–7997. Chan, D., & Jacenko, O. (1998). Phenotypic and biochemical consequences of collagen X mutations in mice and humans. Matrix Biology, 17, 169–184. Chan, D., Weng, Y. M., Graham, H. K., et al. (1998). A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in Schmid metaphyseal chondrodysplasia. The Journal of Clinical Investigation, 101, 1490–1499. Dharmavaram, R. M., Elberson, M. A., Peng, M., et al. (1994). Identification of a mutation in type X collagen in a family with Schmid metaphyseal chondrodysplasia. Human Molecular Genetics, 3, 507–509. Dimson, S. B. (1968). Metaphyseal dysostosis type Schmid. Proceedings of the Royal Society of Medicine, 61, 1260–1261. Elliott, A. M., Field, F. M., Rimoin, D. L., et al. (2005). Hand involvement in Schmid metaphyseal chondrodysplasia. American Journal of Medical Genetics, 132A, 191–193. Lachman, R. S., Rimoin, D. L., & Spranger, J. (1988). Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatric Radiology, 18, 93–102. Matsui, Y., Yasui, N., Kawabata, H., et al. (2000). A novel type X collagen gene mutation (G595R) associated with Schmidtype metaphyseal chondrodysplasia. Journal of Human Genetics, 45, 105–108. Miller, S. M., & Paul, L. W. (1964). Roentgen observations in familial metaphyseal dysostosis. Radiology, 83, 665–673. Milunsky, J., Maher, T., Lebo, R., et al. (1998). Prenatal diagnosis for Schmid metaphyseal chondrodysplasia in twins. Fetal Diagnosis and Therapy, 13, 167–168. M€akitie, O., Susie, M., Ward, L., et al. (2005). Schmid type of metaphyseal chondrodysplasia and COL10A1 mutationsfindings in 10 patients. American Journal of Medical Genetics, 137A, 241–248. Ridanp€a€a, M., Ward, L. M., Rockas, S., et al. (2003). Genetic changes in the RNA components of RNase MRP and RNase P in Schmid metaphyseal chondrodysplasia. Journal of Medical Genetics, 40, 741–746. Sawai, H., Ida, A., Nakata, Y., et al. (1998). Novel missense mutation resulting in the substitution of tyrosine by cysteine at codon 597 of the type X collagen gene associated with Schmid metaphyseal chondrodysplasia. Journal of Human Genetics, 43, 259–261. Schmid, F. (1949). Beitrag zur dysostosis enchondralis metaphysaria. Monatsschr Kinderheilk, 97, 393–397. Schmid, T. M., & Linsenmayer, T. F. (1985). Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. The Journal of Cell Biology, 100, 598–605.

Schmid Metaphyseal Chondrodysplasia Wallis, G. A., Rash, B., Sweetman, W. A., et al. (1994). Amino acid substitutions of conserved residues in the carboxylterminal domain of the alpha 1(X) chain of type X collagen occur in two unrelated families with metaphyseal chondrodysplasia type Schmid. American Journal of Human Genetics, 54, 169–178. Wallis, G. A., Rash, B., Sykes, B., et al. (1996). Mutations within the gene encoding the alpha 1 (X) chain of type X collagen

1855 (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. Journal of Medical Genetics, 33, 450–457. Warman, M. L., Abbott, M., Apte, S. S., et al. (1993). A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nature Genetics, 5, 79–82.

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Schmid Metaphyseal Chondrodysplasia

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Fig. 1 (a–i) Three young children with Schmid metaphyseal chondrodysplasia showing short stature, lumbar lordosis, and bowing of the legs. Radiographs showed genu varum and metaphyseal widening with fraying and cupping. Epiphyses are normal

Seckel Syndrome

In 1960, Seckel reported 2 personal cases and 13 cases from the literature of a clinical condition characterized by severe intrauterine and postnatal proportionate dwarfism, severe microcephaly, “bird-headed” profile with receding forehead and chin, large and beaked nose, severe mental retardation, and other anomalies (Majewski and Goecke 1982). Seckel syndrome (SCKL) is a rare heterogeneous type of primordial dwarfism with frequency of less than 1 in 10,000 live births.

b.

c.

d.

Synonyms and Related Disorders Bird-headed dwarfism; Microcephalic primordial dwarfism; Nanocephalic dwarfism; Seckel-type dwarfism

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. Genetic heterogeneity a. SCKL1: A gene for Seckel syndrome was mapped to human chromosome 3q22.1–q24 in two inbred Pakistani families originating from the same village (Driscoll 2003). i. The gene encoding ataxia-telangiectasia and Rad3-related protein (ATR) maps to the critical region to an interval of 5Mbp between markers D3S1316 and D3S1557. ii. A synonymous mutation in affected individuals was identified that alters ATR splicing.

e.

iii. The mutation confers a phenotype including marked microcephaly and dwarfism. SCKL2: Another gene locus was mapped to chromosome 18p11.31–q11.2 in one inbred Iraqi family (Børglum et al. 2001). SCKL3: A novel locus at 14q23 by linkage analysis in 13 Turkish families. The novel gene locus SCKL3 is 1.18 cM and harbors me´nage a trios 1, a gene with a role in DNA repair (Kilinc¸ et al. 2003). Caused by mutations of the pericentrin gene (PCNT) (mapped to 21q22.3) (Griffith et al. 2008; Rauch et al. 2008; Willems et al. 2009) i. The gene encodes cetrosomal protein which plays a key role in the organization of mitotic spindles. ii. The mutations also can cause microcephalic osteodysplastic primordial dwarfism type II. Mutations in CENPJ, a gene that has hitherto been linked to primary microcephaly only (Bond et al. 2005; Gul et al. 2006), also can cause Seckel syndrome (Al-Dosari et al. 2009).

Clinical Features 1. Broad interfamilial clinical heterogeneity (Arnold et al. 1999) 2. Growth a. Severe proportionate short stature of prenatal onset

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b. Severe postnatal growth deficiency c. Intrauterine growth retardation d. Low-birth-weight dwarfism 3. Mental retardation 4. Characteristic craniofacial features a. Cranial manifestations i. Severe microcephaly ii. Premature closure of cranial sutures b. Receding forehead c. “Birdlike” face d. Antimongoloid slant of palpebral fissures e. Large eyes f. Beak-like protrusion of the nose g. Narrow face h. Receding lower jaw (retrognathia) i. Micrognathia j. High-arched or cleft palate k. Ears i. Low set ii. Hypoplastic lobules l. Dental abnormalities i. Enamel hypoplasia ii. Missing permanent teeth iii. Precocious eruption of teeth iv. Microdontia v. Malocclusion vi. Taurodontism m. “Dysplastic” ears 5. Associated anomalies a. Ocular manifestations (Guirgis et al. 2001) i. Severe myopia and astigmatism ii. Severe, early onset, bilateral retinal degeneration iii. Hypotelorism iv. Bilateral ptosis v. Microphthalmos vi. Megacornea vii. Glaucoma viii. Retrolental membrane ix. Macular coloboma x. Optic hypoplasia xi. Strabismus xii. Lens dislocation b. Skeletal defects i. Premature closure of cranial sutures ii. Dislocation of the radial head iii. Clinodactyly of the 5th fingers iv. Hip “dysplasia”/dislocation v. Retardation of ossification

Seckel Syndrome

vi. Clubfoot vii. Hypoplastic patella viii. Scoliosis c. CNS anomalies (Shanske et al. 1997) i. Small cerebrum with simplified, apelike convolutional pattern (pongidoid micrencephaly) ii. Dysgenesis of cerebral cortex iii. Agenesis of corpus callosum iv. Cerebellar vermis hypoplasia v. Dorsal cerebral cyst vi. Arachnoid cyst vii. Dilated ventricles viii. Pachygyria ix. Agyria x. Intracranial aneurysms d. Endocrine abnormalities i. Pituitary gland abnormalities a) Delayed development b) Decreased adrenocorticotropic hormone production c) Decreased growth hormone production d) Absence of adenohypophysis e) Hypophyseal hypoplasia f) Precocious puberty ii. Adrenal hypoplasia iii. Hirsutism e. Hematopoietic abnormalities i. Acute myelogenous leukemia ii. Refractory anemia with excess blasts iii. Pancytopenia iv. Fanconi anemia f. Urogenital abnormalities i. Males a) Cryptorchidism b) Hypoplasia of testis ii. Females a) Clitoromegaly b) Hypoplasia of labia majora g. Features of premature senility i. Receding hair ii. Redundant wrinkled skin on the palms h. Miscellaneous findings i. Congenital heart defects a) Patent ductus arteriosus b) Atrial septal defect c) Ventricular septal defects d) Atrioventricular canal defect ii. Multiple intestinal atresia

Seckel Syndrome

6. Seckel-like syndromes (Majewski and Goecke 1982; Arnold et al. 1999) a. Microcephalic osteodysplastic primordial dwarfism type I i. Distinguished from Seckel syndrome by: a) Broad, low “dysplastic” pelvis with poor development of the acetabula b) Disproportionately short, broad bowing of humeri and femora with rather unremarkable metaphysis c) Agenesis of the corpus callosum and lissencephaly have also been noted. ii. Classified as Seckel syndrome by Majewski and Goecke (1982) b. Microcephalic osteodysplastic primordial dwarfism type II: differences from the Seckel syndrome include the following (mainly based on X-ray features): i. Short limbs with preferential distal involvement (disproportionate shortness of forearms and legs) in the first years of life ii. Brachymesophalangy iii. Brachymetacarpy I iv. Coxa vara v. Epiphysiolysis vi. Metaphyseal flaring with V-shaped distal femoral metaphyses c. Microcephalic osteodysplastic primordial dwarfism type III i. Alopecia ii. Seckel-like features a) Intrauterine growth retardation b) Microcephaly c) Receding forehead and chin d) Large ears e) Large prominent nose f) Platyspondyly g) Long dysplastic clavicles h) Hypoplasia of iliac wing and acetabula i) Broad femora iii. Currently considered to be the same entity as type I (Meinecke et al. 1991) d. A variant of osteodysplastic bird-headed dwarfism described by Bangstad et al. (1989) i. Progressive ataxia ii. Primary gonadal insufficiency iii. Endocrine abnormalities a) Insulin-resistant diabetes mellitus b) Goiter

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e. Chromosome abnormalities i. Chromosome instability/breakage (BobabillaMorales et al. 2003) ii. Deletion 1q22–q24.3 iii. Interstitial deletion 2q33.3–q34 (Courtens et al. 1997) iv. Ring chromosome 4 mosaicism (Anderson et al. 1997)

Diagnostic Investigations 1. Hematological workup indicated in selected patients a. Anemia b. Pancytopenia c. Acute myeloid leukemia 2. Endocrine workup for pituitary and adrenal dysfunction 3. Radiography a. Microcephaly with a rather steeply sloping base of the skull b. Premature closure of the cranial sutures c. Delayed bone age d. Hip dysplasia e. Elbow dislocation f. Dislocation of the radial head g. Ivory epiphyses (dense sclerotic areas in the phalanges) h. Cone-shaped epiphyses i. Disharmonic bone development i. Hypoplasia of proximal radii and fibulae ii. Absence of epiphyseal ossification centers in fingers and toes 4. Neuropathology and CT/MRI of the brain a. Microcephaly b. Neuroglial ectopia c. Agenesis of the corpus callosum d. Micropolygyria e. Disproportion of the cerebrum and cerebellum f. Dysgenetic cerebral cortex g. Hypoplasia of the cerebellar vermis h. Dorsal cerebral cyst 5. Growth plate histology a. Normal column formation b. No structural abnormality of chondrocytes c. Decrease in cellularity of chondrocytes

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Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not likely to have offspring due to severe mental retardation 2. Prenatal diagnosis possible by serial ultrasonography for families at risk for Seckel syndrome a. Severe intrauterine growth retardation b. Craniofacial abnormalities i. Microcephaly ii. Receding forehead iii. A prominent nose iv. Severe micrognathia c. Short limbs 3. Management a. Symptomatic b. Psychosocial support for mental retardation c. Dental cares d. Orthopedic cares e. Treatments for hematological abnormalities

References Abou-zahr, F., Bejjani, B., Kruyt, F. A. E., et al. (1999). Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome. American Journal of Medical Genetics, 83, 388–391. Al-Dosari, M. S., Shaheen, R., Colak, D., et al. (2009). Novel CENPJ mutation causes Seckel syndrome. Journal of Medical Genetics, 47, 411–414. Anderson, C. E., Wallerstein, R., Zamerowski, S. T., et al. (1997). Ring chromosome 4 mosaicism coincidence of oligomeganephronia and signs of Seckel syndrome. American Journal of Medical Genetics, 72, 281–285. Arnold, S. R., Spicer, D., Kouseff, B., et al. (1999). Seckel-like syndrome in three siblings. Pediatric and Developmental Pathology, 2, 180–187. Bangstad, H. J., Beck-Nielsen, H., Hother-Neilsen, O., et al. (1989). Primordial bird-headed nanism associated with progressive ataxia, early onset insulin resistant diabetes, goiter, and primary gonadal insufficiency. A new syndrome. Acta Paediatrica Scandinavica, 78, 488–493. Bobabilla-Morales, L., Corona-Rivera, A., Corona-Rivera, J. R., et al. (2003). Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients. American Journal of Medical Genetics, 123A, 148–152. Bond, J., Roberts, E., Springell, K., et al. (2005). A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nature Genetics, 37, 353–355. Børglum, A. D., Balslev, T., Haagerup, A., et al. (2001). A new locus for Seckel syndrome on chromosome 18p11.31-q11.2. European Journal of Human Genetics, 9, 753–757.

Seckel Syndrome Butler, M. G., Hall, B. D., Maclean, R. N., et al. (1987). Do some patients with Seckel syndrome have hematological problems and/or chromosome breakage? American Journal of Medical Genetics, 27, 645–649. Courtens, W., Speleman, F., Messiaen, L., et al. (1997). Interstitial deletion 2q33.3-q34 in a boy with a phenotype resembling the Seckel syndrome. American Journal of Medical Genetics, 71, 479–485. D’Angelo, V. A., Ceddia, A. M., Zelante, L., et al. (1998). Multiple intracranial aneurysms in a patient with Seckel syndrome. Child’s Nervous System, 14, 82–84. De Elejalde, M. M., & Elejalde, B. R. (1984). Visualization of the fetal face by ultrasound. Journal of Craniofacial Genetics and Developmental Biology, 4, 251–257. Faivre, L., Le Merrer, M., Lyonnet, S., et al. (2002). Clinical and genetic heterogeneity of Seckel syndrome. American Journal of Medical Genetics, 112, 379–383. Featherstone, L. S., Sherman, S. J., & Quigg, M. H. (1996). Prenatal diagnosis of Seckel syndrome. Journal of Ultrasound in Medicine, 15, 85–88. Goodship, J., Gill, H., Carter, J., et al. (2000). Autozygosity mapping of a Seckel syndrome locus to chromosome 3q22. 1-q24. American Journal of Human Genetics, 67, 498–503. Griffith, E., Walker, S., Martin, C. A., et al. (2008). Mutations in pericentrin cause Seckel syndrome with defective ATRdependent DNA damage signaling. Nature Genetics, 40, 232–236. Guirgis, M. F., Lam, B. L., & Howard, C. W. (2001). Ocular manifestations of Seckel syndrome. American Journal of Ophthalmology, 132, 596–597. Gul, A., Hassan, M. J., Hussain, S., et al. (2006). A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. Journal of Human Genetics, 51, 760–764. Harper, R. G., Orti, E., & Baker, R. K. (1967). Bird-headed dwarfs (Seckel’s syndrome). A familial pattern of developmental, dental, skeletal, genital, and central nervous system anomalies. Journal of Pediatrics, 70, 799–804. Kilinc¸, M. O., Ninis, V. N., Ug˘ur, S. A., et al. (2003). Is the novel SCKL3 at 14q23 the predominant Seckel locus? European Journal of Human Genetics, 11, 851–857. Majewski, F. (1992). Caroline Crachami and the delineation of osteodysplastic primordial dwarfism type III, and autosomal recessive syndrome. American Journal of Medical Genetics, 44, 203–209. Majewski, F., & Goecke, T. (1982). Studies of microcephalic primordial dwarfism I: Approach to a delineation of the Seckel syndrome. American Journal of Medical Genetics, 12, 7–21. Majewski, F., & Goecke, T. O. (1998). Microcephalic osteodysplastic primordial dwarfism type II: Report of three cases and review. American Journal of Medical Genetics, 80, 25–31. Majewski, F., Ranke, M., & Schinzel, A. (1982a). Studies of microcephalic primordial dwarfism II: The osteodysplastic type II of primordial dwarfism. American Journal of Medical Genetics, 12, 23–35. Majewski, F., Stoeckenius, M., & Kemperdick, H. (1982b). Studies of microcephalic primordial dwarfism III: An intrauterine dwarf with platyspondyly and anomalies

Seckel Syndrome of pelvis and clavicles–osteodysplastic primordial dwarfism type III. American Journal of Medical Genetics, 12, 37–42. Majoor-Krakauer, D. F., Wladimiroff, J. W., et al. (1987). Microcephaly, micrognathia, and bird-headed dwarfism: Prenatal diagnosis of a Seckel-like syndrome. American Journal of Medical Genetics, 27, 183–188. McKusick, V. A., Mahloudji, M., Abbott, M. H., et al. (1967). Seckel’s bird-headed dwarfism. The New England Journal of Medicine, 277, 279–286. Meinecke, P., & Passarge, E. (1991). Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. Journal of Medical Genetics, 28, 795–800. Meinecke, P., Schaefer, E., Wiedemann, H. R., et al. (1991). Microcephalic osteodysplastic primordial dwarfism: Further evidence for identity of the so-called types I and III. American Journal of Medical Genetics, 39, 232–236. Nadjari, M., Fasouliotis, S. J., Ariel, I., et al. (2000). Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III. Prenatal Diagnosis, 20, 666–669. O’Driscoll, M., Ruiz-Perez, V. L., Woods, C. G., et al. (2003). A splicing mutation affecting expression of ataxiatelangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nature Genetics, 33, 497–501.

1861 Rauch, A., Thiel, C. T., Schindler, D., et al. (2008). Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science, 319, 816–819. Sauk, J. J., Litt, R., Espiritu, C. E., et al. (1973). Familial birdheaded dwarfism (Seckel’s syndrome). Journal of Medical Genetics, 10, 196–198. Seckel, H. P. G. (1960). Bird headed dwarfs: Studies in developmental anthropology including human proportions. Springfield, IL: CC Thomas. Shanske, A., Caride, D. G., Menasse-Palmer, L., et al. (1997). Central nervous system anomalies in Seckel syndrome: Report of a new family and review of the literature. American Journal of Medical Genetics, 70, 155–158. Syrrou, M., Georgiou, I., Paschopoulos, M., et al. (1995). Seckel syndrome in a family with three affected children and hematological manifestations associated with chromosome instability. Genetic Counseling, 6, 37–41. Thompson, E., & Pembrey, M. (1985). Seckel syndrome: An overdiagnosed syndrome. Journal of Medical Genetics, 22, 192–201. Willems, M., Genevie`ve, D., Borck, G., et al. (2009). Molecular analysis of pericentrin gene (PCNT) series of 24 Seckel/MOPD II families. Journal of Medical Genetics, 47, 797–802.

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Seckel Syndrome

Fig. 1 (a–c) A girl with Seckel syndrome showing marked short stature, severe microcephaly, sloping forehead, “bird-headed” face, large eyes, beaked nose, and severe retro/micrognathia

a

b

Fig. 2 (a–b) Two adults with Seckel syndrome showing severe short stature, mental retardation, extreme microcephaly, sloping forehead, a beaked nose, and retro/micrognathia

a

c

b

Severe Combined Immune Deficiency

Severe combined immune deficiency (SCID) is a fatal, heterogeneous group of immune disorder, characterized by T-cell lymphopenia, a profound lack of cellular (T-cell) and humoral (B-cell) immunity, and, in some cases, decreased NK-cell number and function. All infants with SCID develop infections from both common and opportunistic pathogens because protection from maternal antibodies wanes early in life (Buckley et al. 1997; Friedrich et al. 2007). The incidence of SCID is estimated to be 1/100,000 live births, but this may be an underestimate due to some children dying before diagnosis or having unrecognized less severe disease (Stephan et al. 1993; Chan and Puck 2005; McGhee et al. 2005).

Synonyms and Related Disorders Autosomal recessive SCID (Swiss-type agammaglobulinemia); Bare lymphocyte syndrome; Interleukin (IL)-2 deficient SCID; Janus-associated kinase 3 (JAK3) deficient SCID; Omenn syndrome; Purine nucleoside phosphorylase (PNP) deficient SCID; Reticular dysgenesis; SCID; X-linked SCID; ZAP-70 protein tyrosine kinase (PTK) deficient SCID

Genetics/Basic Defects 1. A heterogeneous syndrome of varied genetic origins (Secord 2009) a. X-linked type SCID (X-SCID) i. The most common type (50% of all patients with SCIDs), characterized by the absence of the cytokine receptor common g chain

ii. A combined cellular and humoral immunodeficiency resulting from lack of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes iii. Caused by a mutation in the X-linked gene IL2RG, which encodes the common g chain, gc (mapped on Xq13), of the leukocyte receptors for interleukin-2 and multiple other cytokines (Fanos et al. 2001) a) Significant frequency of de novo mutations accounting for one third of the cases b) Occurrence of maternal germ line mosaicism iv. Atypical X-SCID: less frequently seen in patients with mutations that result in production of a small amount of gene product or a protein with residual activity b. Autosomal recessive type SCID i. Formerly known as Swiss-type agammaglobulinemia ii. Causes a) Adenosine deaminase deficiency (10–20% of all cases of SCID): the ADA gene mapped on chromosome 20q13.11 (Arredondo-Vega et al. 1998) b) Purine nucleoside phosphorylase (PNP) deficiency: the PNP gene mapped on 14q13 c) Janus-associated kinase 3 (JAK3) deficiency causing autosomal recessive T-B + SCID: the JAK3 gene mapped on 19p13 d) Interleukin (IL)-2 deficiency e) ZAP-70 protein tyrosine kinase (PTK) deficiency: ZAP-70 mapped on 2q12

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f) Bare lymphocyte syndrome g) Reticular dysgenesis h) Omenn syndrome 2. Pathophysiology a. Varies among various forms of SCID b. Common end point in all forms of SCID i. Lack of T-cell function ii. Lack of B-cell function c. Cellular hallmarks differentiating various forms of SCID i. X-linked SCID a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Variable levels of B cells that produce no functional antibodies ii. JAK3 deficiency a) Absence or near absence of T cells (CD3+) and natural killer (NK) cells leading to lymphopenia b) Normal or high levels of B cells that produce no functional antibodies iii. ADA deficiency a) Death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Decreased or absence of functional antibodies iv. PNP deficiency a) Death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway leading to lymphopenia b) Normal number of circulating B cells with poor B-cell function, evidenced by the lack of antibody formation v. IL-2 deficiency a) Normal or near normal numbers of T cells (both CD4+ and CD8+) b) Decreased production of functional antibody vi. ZAP-70 PTK deficiency a) Absence of CD8+ T cells leading to lymphopenia b) No antibody formation vii. Bare lymphocyte syndrome a) Normal or mildly reduced lymphocyte count

Severe Combined Immune Deficiency

b) Decreased CD4+ T cells c) Normal or mildly increased CD8+ T-cell numbers d) Normal or mildly decreased B-cell numbers with decreased antibody production viii. Reticular dysgenesis a) Absence of myeloid cells in the bone marrow leading to lymphopenia b) Presence of functioning red blood cells and platelets ix. Omenn syndrome a) Presence of normal or elevated T-cell numbers of maternal origin b) Usually undetectable B cells c) Presence of NK cells d) Markedly low total immunoglobulin level with poor antibody production e) Elevated eosinophils and total serum immunoglobulin E (IgE) level 3. Molecular defects a. X-linked SCID i. Mutation of the common gamma chain of the IL receptors (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) resulting in loss of cytokine function (Cavazzana-Calvo et al. 2000) ii. Loss of IL-2R function leading to the loss of a lymphocyte proliferation signal iii. Loss of IL-4R function leading to the inability of B cells to class switch iv. Loss of IL-7R function leading to the loss of an antiapoptotic signal resulting in a loss of T-cell selection in the thymus and also associated with the loss of a T-cell receptor v. Loss of IL-15R function leading to the ablation of NK cell development b. JAK3 deficiency i. JAK, a protein tyrosine kinase that associates with the common gamma chain of the IL receptors ii. Deficiency of JAK3 resulting in the same clinical manifestations as those of X-linked SCID c. ADA and PNP deficiencies i. Associated with enzyme deficiencies in the purine salvage pathway ii. Toxic metabolites responsible for the destruction of lymphocytes that cause the immune deficiency

Severe Combined Immune Deficiency

d. IL-2 deficiency i. Molecular defect unknown ii. Often associated with other cytokine production defects e. ZAP-70 PTK deficiency: caused by a mutation in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus f. Bare lymphocyte syndrome i. Deficiency of major histocompatibility complex (MHC) ii. Absent or decreased MHC type I levels iii. Decreased MHC type II levels on mononuclear cells g. Omenn syndrome: believed to be caused by a mutation impairing the function of immunoglobulin and TCR recombinase genes, such as RAG1 and RAG2 genes

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15. 16. 17. 18. 19.

20.

Clinical Features 1. Age of onset: 3–6 months of life 2. Usual presentation with infections due to lack of T-cell function a. Opportunistic organisms i. Pneumocystis carinii pneumonia ii. Systemic candidiasis iii. Atypical mycobacterium iv. Cryptosporidium v. Pneumococcus b. Recurrent infections c. Persistence of infections despite conventional treatment 3. Failure to thrive 4. Oral or diaper candidiasis 5. Dehydration from chronic diarrhea 6. Fevers 7. Rashes 8. Cough and congestion 9. Increased respiratory rate and effort 10. Absence of tonsils and lymph nodes 11. Absence of lymphadenopathy or increased tonsillar tissue despite serious infections 12. Pneumonias 13. Sepsis 14. Disseminated infections a. Salmonella b. Varicella

21. 22.

c. Cytomegalovirus d. Epstein-Barr virus e. Herpes simplex virus f. BCG g. Vaccine strain (live) polio virus Recurrent sinopulmonary infections Recurrent skin infections Abscesses Poor wound healing Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition causing graft-vs-host disease (GVHD), characterized by a. Erythematous skin rashes b. Hepatomegaly c. Lymphadenopathy ADA deficiency and PNP deficiency with later onset and milder or atypical clinical presentation a. Diagnosis suspected in patients with i. Unexplained T-cell lymphopenia ii. Late manifestations of immunodeficiency a) Chronic pulmonary insufficiency b) History of autoimmunity and neurologic abnormalities c) Onset during the first two decades of life and even later b. Diagnosis confirmed by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells Lymphadenopathy or hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome Prognosis a. Fatal if untreated b. Bone marrow transplantation or enzyme replacement to reconstitute the immune system compatible with long survival

Diagnostic Investigations 1. Newborn screening (Adeli and Buckley 2010; Lipstein et al. 2010; Secord 2009) a. Newborn screening would not only make the diagnosis at birth but would lead to measures to protect infants from becoming infected before they could receive a transplant. b. Newborn screening would also reveal the true incidence of SCID and define the range of conditions characterized by severely impaired T-cell development.

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c. Evidence indicates the benefits of early treatment of SCID and the possibility of populationbased newborn screening. d. Better information on optimal treatment and the costs of treatment and screening would benefit policy makers deciding among competing health care priorities. 2. Laboratory workup a. X-SCID (Davis and Puck 2005) i. Lymphocyte count a) Usually very low number of T cells b) B cells generally present, but nonfunctional c) Low or absent number of NK cells d) Typical X-SCID designated as T–B+NK– ii. Lymphocyte functional tests a) Absent antibody responses to vaccines and infections agents b) Lacking T-cell responses to mitogens iii. Immunoglobulin concentrations a) Low serum concentrations of IgA and IgM b) IgG generally normal at birth but declines as maternally transferred IgG disappears by 3 months of age iv. Thymus: absent thymic shadow on chest radiogram v. Molecular genetic testing clinically available: IL2RF is the only gene known to be associated with X-SCID. a) Sequence analysis b) Targeted mutation analysis b. Adenosine deaminase deficiency (Hershfield 2009) i. Immune function a) Lymphopenia, the laboratory hallmark of ADA-deficient SCID, is present at birth. The total blood lymphocyte count is usually lower than 500/mL (normal for neonates: 2,000 to >5,000). b) All lymphoid lineages (T-, B-, and NK-cells) are depleted as demonstrated by flow cytometry. c) Lower or absent in vitro lymphocyte function, as measured by proliferative response to mitogens and antigens d) Low serum immunoglobulins and absence of specific antibody response to infections and immunizations ii. Adenosine deaminase (ADA) catalytic activity

Severe Combined Immune Deficiency

a) Affected individuals who have not been transfused have less than 1% of normal ADA catalytic activity in erythrocyte hemolysates. b) Affected individuals who have been recently transfused may require testing of another cell type, such as fibroblasts or leukocytes. iii. Biochemical markers of ADA deficiency a) Elevated erythrocyte deaminate 20 deoxyadenosine (dAdo) nucleotides (dAXP): pathognomonic b) Reduced erythrocyte Sadenosylhomocysteine hydrolase (AdoHcyase, SAHase) activity ( C) (p.L1956P). There were no apparent deletions or duplications within the coding region of NSD1

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. It is a clinically and genetically heterogeneous group of neuromuscular diseases. It is the second most common lethal autosomal recessive disorder after cystic fibrosis in Caucasian populations with an overall incidence of 1 in 10,000 live births and a carrier frequency of approximately 1 in 50 (Biros and Forrest 1999).

Synonyms and Related Disorders Adult SMA; Arthrogryposis multiplex congenitaSMA; Congenital axonal neuropathy; Dubowitz disease; Kugelberg-Welander disease; WerdnigHoffman disease

Genetics/Basic Defects 1. Inheritance a. Autosomal recessive in most cases (SMA1, SMA2, SMA3) b. Autosomal dominant in both juvenile and adult form, representing 2% of infantile and about 30% of adult SMA 2. Caused by mutation or deletion of Survival Motor Neuron-1 (SMN1) 3. Mutation in all three forms (SMA1, SMA2, and SMA3) mapped to chromosome 5q13 (SMA critical region)

4. SMN deletions a. High frequency of SMN deletions in SMA patients (92.8%) provides a direct and accurate genetic test for: i. Diagnostic confirmation of SMA ii. Prenatal prediction of SMA b. Homozygous deletion of SMN observed in: i. Atypical forms of SMA associated with congenital heart defects ii. Arthrogryposis iii. Some cases of congenital axonal neuropathy iv. Some patients affected with adult form of SMA c. Rare cases of homozygous SMN exon 7 deletion or conversion reported in asymptomatic relatives of haploidentical type II or III SMA patients d. Absence of deletion of the SMN gene or linkage to chromosome 5q in: i. SMA associated with diaphragmatic involvement ii. SMA with olivopontocerebellar atrophy iii. Autosomal dominant form of SMA iv. Amyotrophic lateral sclerosis v. Post-polio syndrome 5. Molecular-phenotype correlation (Lorson et al. 2010; MacKenzie 2010) a. Phenotype of SMA associated with diseasecausing mutations of the SMN gene spans a continuum without a clear delineation of subtypes. b. The severity of the SMA phenotype inversely correlated with: i. SMN2 copy number: The greater the SMN2 copy number (both in infants and children

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Spinal Muscular Atrophy

with spinal muscular atrophy and in mouse models), the milder the disease. ii. The level of full-length SMN protein produced by SMN2 (10–15% compared with SMN1)

Clinical Features 1. Existing classification system based on age of onset of symptoms: useful for prognosis and management a. Congenital axonal neuropathy i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios iv. Severe muscle weakness (hypotonia) v. Absence of movement vi. Joint contractures vii. Facial diplegia viii. Ophthalmoplegia ix. Respiratory failure requiring immediate endotracheal intubation and ventilation x. Death from respiratory failure within days b. Arthrogryposis multiplex congenita-SMA i. Prenatal onset of SMA ii. Decreased fetal movement iii. Maternal polyhydramnios iv. Breech presentation v. Severe muscular weakness (hypotonia) vi. Arthrogryposis multiplex congenita vii. Absence of movement except for extraocular and facial movement viii. Death from respiratory failure before 1 month of age c. SMA1 (acute spinal muscular atrophy, WerdnigHoffman disease) i. Represents about 30% of all SMA cases ii. Onset before 6 months of age iii. The most severe form with fatal outcome iv. Severe generalized muscular weakness (hypotonia) v. Lack of motor development vi. Mild joint contractures at the knees and rarely at the elbows vii. Most severely affected neonates a) Difficulty in sucking and swallowing b) Abdominal breathing

viii. Facial muscles spared completely with a bright, normal expression ix. Ocular muscles and the diaphragm not involved until late in the course of the disease x. Fasciculation of the tongue seen in most but not all cases xi. Intercostal paralysis with severe collapse of the chest: the rule xii. Affected children unable to sit without support xiii. Absence of tendon reflexes (areflexia) xiv. Normal intelligence xv. Usually die within 2 years due to the following: a) Feeding difficulty b) Breathing difficulty d. SMA2 (chronic infantile spinal muscular atrophy, Dubowitz disease) i. Represent about 45% of SMA cases ii. Onset between 6 and 12 months iii. The intermediate form (a more slowly progressive generalized disease with a variable prognosis) iv. Poor muscle tone at birth or within first 2 months of life v. Slow attainment of motor milestones a) Not sitting independently by age 9–12 months b) Not standing by 1 year of age vi. Frequent tongue fasciculations and atrophy vii. Common finger trembling and general flaccidity viii. Diminished or absent deep tendon reflexes ix. Intact sensation x. Loss of the ability to sit independently by the mid-teens xi. Slow or arrest of clinical progression xii. Severe scoliosis if untreated xiii. Defect in respiratory ventilation xiv. Highly variable life expectancy, ranging up to adult life in some cases e. SMA3 (juvenile spinal muscular atrophy, Kugelberg-Welander disease) i. Represents abut 8% of all SMA cases ii. Childhood onset after 12 months (usually after 18 months to 30 years of life) iii. The mild chronic form

Spinal Muscular Atrophy

iv. Motor milestones a) Ability to walk but frequent fall on walking b) Trouble walking upstairs and downstairs at age 2–3 years v. Muscle weakness a) Proximal muscle weakness associated with muscle atrophy b) Legs more severely affected than the arms vi. Normal sensation vii. No evidence of upper motor neuron involvement viii. Hypertrophy of the calves in about 25% of cases ix. Prognosis generally correlates with the maximum motor function attained. f. SMA4 (adult SMA) i. Adult onset (after 20 or 30 years of age) ii. Muscle weakness (after 30 years of age) iii. Clinical features similar to those described for SMA3 with evidence of lower motor neuron involvement a) Tongue fasciculations b) Muscle atrophy c) Depressed deep tendon reflexes d) Normal sensation 2. Consider diagnosis of SMA in infants presenting with the following clinical features: a. During neonatal period i. Severe hypotonia ii. Absent movement iii. Contractures, usually of a mild degree iv. Evidence of anterior horn cell (i.e., lower motor neuron) involvement a) Tongue fasciculations b) Absence of deep tendon reflexes v. Respiratory failure vi. Variable cranial nerve involvement usually apparent late in the course a) Ophthalmoplegia b) Facial diplegia b. After neonatal period i. Poor muscle tone ii. Symmetric muscle weakness a) Sparing the ocular muscles b) Involving the facial muscles and diaphragm late in the course of the disease iii. Delayed acquisition of motor skills

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iv. Evidence of anterior horn (i.e., lower motor neuron) involvement a) Tongue fasciculations (seen in only 65% of patients) b) Absence of deep tendon reflexes v. Normal reaction to sensory stimuli vi. Normal intelligence 3. Natural history (Lorson et al. 2010; MacKenzie 2010) a. Clinical features of the disease are caused by specific degeneration of a-motor neurons in the spinal cord, leading to muscle weakness, atrophy, and, in the majority of cases, premature death. b. Most afflicted infants and children, while largely neurologically and completely cognitively intact, grow progressively weaker over time, with many ultimately succumbing to respiratory failure at a young age. c. The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. 4. Other forms of severe spinal muscular atrophy not linked to SMN gene (Wang et al. 2007) a. Scapuloperoneal spinal muscular atrophy i. Autosomal dominant (gene mapped on 12q24.1-q24.31) ii. Clinical presentations a) Congenital absence of muscles b) Progressive weakness of scapuloperoneal and laryngeal muscles b. Pontocerebellar hypoplasia with spinal muscular atrophy i. Autosomal recessive ii. Clinical presentations a) Onset at 0–6 months b) Cerebellar and brainstem hypoplasia c) Absent dentate nucleus d) Neuronal loss in basal ganglia e) Cortical atrophy c. X-linked infantile spinal muscular atrophy with arthrogryposis i. X-linked (gene mapped on Xp11.3-q11.2) ii. Clinical presentations a) Onset at birth or infancy b) Contractures c) Death before 2 years of age

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d. Spinal muscular atrophy with respiratory distress type 1 i. Autosomal recessive (gene mapped on 11q13.2-q13.4) ii. Clinical presentations a) Onset within the first 3 months of age b) Eventuation of the right or both hemidiaphragms c) Finger contractures d) Pes equines foot deformities

Diagnostic Investigations 1. Increased serum creatine phosphokinase (CK) activity in about half of the patients with type III SMA 2. Electromyography (EMG) a. During voluntary effort i. Spontaneous discharge activity in resting muscle ii. Increased amplitude iii. Prolonged duration of motor unit potentials b. Severe denervation commonly found in older patients c. Nerve conduction velocity i. Generally considered normal ii. Some decrease in velocity in severe case 3. Muscle histology a. Denervation changes with small groups of atrophic muscle fibers associated with markedly hypertrophied fibers. b. Small angular fibers randomly intermixed with normal-sized fibers c. Atrophic fibers arranged in groups i. Usually of uniform fiber type based on the myosin ATPase reaction ii. Considered as an extensive collateral reinnervation of previously denervated muscle fibers by sprouts from surviving motor neurons d. In SMA type III, but not in infantile SMA (type I or II) i. Markedly hypertrophic fibers ii. Excessive variation in fiber size iii. Internal nuclei iv. Observation of degenerative changes with necrosis and regenerative fibers associated with proliferative interstitial connective tissue a) Interpreted as “pseudomyopathic” changes

Spinal Muscular Atrophy

b) Usually found in patients with high serum levels of CK activity suggesting the presence of a myopathic process secondary to neurogenic process c) These pseudomyopathic changes not observed in other human neurogenic diseases, suggesting that they can be specific to the molecular mechanism resulting in or associated with juvenile SMA 4. Neuropathologic features found at autopsy of SMA patients a. Loss of the large anterior horn cells of the spinal cord (most striking feature) b. Severe degree of central chromatolysis in the remaining surviving motor neurons, appearing as large ballooned cells without stored substances c. Other anterior horn cells i. Pyknotic ii. Presence of occasional figures of neuronophagia associated with astrogliosis iii. Small anterior roots 5. Molecular diagnosis of SMA (Prior and Russman 2011) a. The following relatively simple DNA tests enable confirmation of a suspected clinical diagnosis of SMA or prediction of the outcome of a pregnancy in families with a history of SMA (Biros and Forrest 1999). i. SSCP analysis ii. PCR followed by restriction enzyme digestion b. Mutation analysis of SMN1 available on clinical basis i. Used to detect deletion of exons 7 and 8 of SMN1 ii. Homologous deletions of exon 7 of SMN1 in 95% of cases with clinical diagnosis of SMA iii. Compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1 in 2–5% of patients with a clinical diagnosis of SMA c. Sequence analysis of all SMN1 exons and intron/ exon borders available on clinical basis i. Used to identify the intragenic SMN1 mutations present in the 2–5% of patients who are compound heterozygotes ii. Limitations a) Cannot determine whether the point mutation is in the SMN1 gene or the SMN2 gene, unless one of these genes is absent

Spinal Muscular Atrophy

b) Does not detect exonic duplications c) Cannot detect deletions of whole exons if more than one SMN gene copy is present d. Duplication analysis to determine SMN2 copy number i. SMN2 copy number ranges from 0 to 5 ii. Quantitative PCR: currently used for accurate determination of SMN2 copy number e. SMA carrier testing (gene dosage analysis) available clinically i. Mutation analysis not reliable for carrier detection since it does not quantitate the number of SMN1 gene copies ii. A PCR-based dosage assay (called SMA carrier testing or SMN gene dosage analysis) allows for the determination of the number of SMN1 gene copies, thus permitting highly accurate carrier detection. iii. Dosage analysis to differentiate carriers from non-carriers f. Linkage analysis available on clinical basis i. Available to families in which direct DNA testing is not informative ii. May be used for confirmation of carrier testing results and prenatal testing results 6. Newborn screening: An effective technology exists for newborn screening of SMA (Prior et al. 2010).

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal recessive inheritance: 25% ii. Autosomal dominant inheritance: not increased unless a parent is affected b. Patient’s offspring: only milder forms of SMA likely to reproduce i. Autosomal recessive inheritance a) All offspring: carriers b) Recurrence risk not increased unless the spouse is affected or a carrier ii. Autosomal dominant inheritance: 50% 2. Prenatal diagnosis a. Possible to detect fetuses at 25% risk when the disease-causing SMN mutations in both parents are known b. Mutation analysis on fetal DNA obtained from CVS or amniocentesis

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c. Linkage analysis i. Many diagnostic laboratories still perform linkage analysis in addition to direct SMNT mutation analysis in families where the previously affected child lacks both copies of SMNT, since there are people in the normal population who lack both copies of SMNT but not clinically affected. ii. The only option available to the families where no deletion has been observed but the clinical findings are consistent with 5q SMA d. Preimplantation genetic diagnosis: available clinically for families in which the diseasecausing mutations have been identified in an affected family member 3. Management (Iannaccone 2007; Sendtner 2010) a. Treat and prevent complications of weakness and maintain quality of life. b. Several organ systems affected by weakness i. Respiratory (restrictive lung disease) a) Noninvasive ventilation support using new technology for patients with sufficient orofacial muscle strength. Long-term ventilatory support is not usually considered. b) A new awareness of the importance of identifying sleep-disordered breathing c) A new multidisciplinary approach to standard of care ii. Gastrointestinal (dysphagia): feeding gastrostomy for children with difficult in sucking and swallowing iii. Orthopedic (progressive deformities) a) Orthosis to allow to sit upright rather than bedridden b) Option of surgical repair for the severe scoliosis c. Therapy development i. Previous therapy approaches have focused on upregulation of SMN expression from a second SMN (SMN2) gene that gives rise to low amounts of functional SMN protein. ii. Drug development to target disease-specific mechanisms at cellular and physiological levels is in its early stages, as the pathophysiological processes that underlie the main disease symptoms are still not fully understood. iii. Human induced pluripotent stem cell technology for generation of large numbers of

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Spinal Muscular Atrophy

human motor neurons could help to fill this gap and advance the power of drug screening. iv. In parallel, advances in oligonucleotide technologies for engineering SMN2 pre-mRNA splicing are approaching their first clinical trials, whose success depends on improved technologies for drug delivery to motor neurons. v. If this obstacle can be overcome, this could boost therapy development, not only for SMA but also for other neurodegenerative disorders.

References Benady, S. G. (1978). Spinal muscular atrophy in childhood. Review of 50 cases. Developmental Medicine and Child Neurology, 20, 746–757. Bingham, P. M., Shen, N., Rennert, H., et al. (1997). Arthrogryposis due to infantile neuronal degeneration associated with deletion of the SMNT gene. Neurology, 49, 848–851. Biros, I., & Forrest, S. (1999). Spinal muscular atrophy: Untangling the knot? Journal of Medical Genetics, 36, 1–8. Brahe, C., & Bertini, E. (1996). Spinal muscular atrophies: Recent insights and impact on molecular diagnosis. Journal of Molecular Medicine, 74, 555–562. Burglen, L., Amiel, J., Viollet, L., et al. (1996). Survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association. The Journal of Clinical Investigation, 98, 1130–1132. Burglen, L., Seroz, T., Miniou, P., et al. (1997). The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with WerdnigHoffmann disease. American Journal of Human Genetics, 60, 72–77. Byers, R. K., & Banker, B. Q. (1961). Infantile muscular atrophy. Archives of Neurology, 5, 140–164. Carter, T. A., Bonnemann, C. G., Wang, C. H., et al. (1997). A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. Human Molecular Genetics, 6, 229–236. Crawford, T. O., & Pardo, C. A. (1996). The neurobiology of childhood spinal muscular atrophy. Neurobiology of Disease, 3, 97–110. Dubowitz, V. (1995). Chaos in the classification of SMA: A possible resolution. Neuromuscular Disorders, 5, 3–5. Emery, A. E. H. (1971). The nosology of the spinal muscular atrophies. Journal of Medical Genetics, 8, 481–495. Herrera, J. A., Crawford, A. H., & Mehlman, C. T. (2010). Spinal muscle atrophy. eMedicien from WebMd. Retrieved September 16, 2010. Available at: http://emedicine. medscape.com/article/1264401-overview Iannaccone, S. T. (2007). Modern management of spinal muscular atrophy. Journal of Child Neurology, 22, 974–978.

Iannaccone, S. T., Browne, R. H., Samaha, F. J., et al. (1993). Prospective study of spinal muscular atrophy before age 6 years. DCN/SMA Group. Pediatric Neurology, 9, 187–193. Ignatius, J. (1994). The natural history of severe spinal muscular atrophy–further evidence for clinical subtypes (letter). Neuromuscular Disorders, 4, 527–528. Korinthenberg, R., Sauer, M., Ketelsen, U. P., et al. (1997). Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region. Annals of Neurology, 42, 364–368. Kugelberg, E., & Welander, L. (1956). Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. Acta Neurologica et Psychiatrica, 75, 500. Lefebvre, S., Burglen, L., Reboullet, S., et al. (1995). Identification and characterization of a spinal muscular atrophydetermining gene. Cell, 80, 155–165. Lorson, C. L., Rindt, H., & Shababi, M. (2010). Spinal muscular atrophy: Mechanisms and therapeutic strategies. Human Molecular Genetics, 19, R111–R118. MacKenzie, A. (2010). Genetic therapy for spinal muscular atrophy. Nature Biotechnology, 28, 235–237. Matthijs, G., Devriendt, K., & Fryns, J.-P. (1998). The prenatal diagnosis of spinal muscular atrophy. Prenatal Diagnosis, 18, 607–610. Melki, J. (1997). Spinal muscular atrophy. Current Opinion in Neurology, 10, 381–385. Munsat, T. L., & Davies, K. E. (1992). Meeting report: International SMA consortium meeting. Neuromuscular Disorders, 2, 423428. Nicole, S., Diaz, C. C., Frugier, T., et al. (2002). Spinal muscular atrophy: Recent advances and future prospects. Muscle & Nerve, 26, 4–13. Ogino, S., Leonard, D. G., Rennert, H., et al. (2002). Genetic risk assessment in carrier testing for spinal muscular atrophy. American Journal of Medical Genetics, 110, 301–307. Panozzo, C., Frugier, T., Cifuentes-Diaz, C., et al. (2001). Spinal muscular atrophy. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic and molecular bases of inherited disease (8th ed.). New York: McGraw-Hill. Pearn, J. (1978). Autosomal dominant spinal muscular atrophy. A clinical and genetic study. Journal of the Neurological Sciences, 38, 263–275. Pearn, J. (1980). Classification of spinal muscular atrophies. Lancet, 1, 919–922. Pearn, J. H., Gardner-Medwin, D., & Wilson, J. (1978). A clinical study of chronic childhood spinal muscular atrophy. A review of 141 cases. Journal of the Neurological Sciences, 38, 23–37. Prior, T. W., & Russman, B. (2011). Spinal muscular atrophy. GeneReviews. Retrieved January 27, 2011. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1352/ Prior, T. W., Snyder, P. J., Rink, B. D., et al. (2010). Newborn and carrier screening for spinal muscular atrophy. American Journal of Medical Genetics. Part A, 152A, 1608–1616. Roy, N., McLean, M. D., Besner-Johnston, A., et al. (1995). Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays. Genomics, 26, 451–460. Rudnik-Schoneborn, S., Forkert, R., Hahnen, E., et al. (1996). Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: Further delineation on the basis of SMN gene deletion findings. Neuropediatrics, 27, 8–15.

Spinal Muscular Atrophy Russman, B. S., Buncher, C. R., White, M., et al. (1996). Function changes in spinal muscular atrophy II and III. The DCN/ SMA Group. Neurology, 47, 973–976. Sendtner, M. (2010). Therapy development in spinal muscular atrophy. Nature Neuroscience, 13, 795–799. Stewart, H., Wallace, A., McGaughran, J., et al. (1998). Molecular diagnosis of spinal muscular atrophy. Archives of Disease in Childhood, 78, 531–535. Thomas, N. H., & Dubowitz, V. (1994). The natural history of type I (severe) spinal muscular atrophy. Neuromuscular Disorders, 4, 497–502. Tsao, B., & Armon, C. (2011). Spinal muscular atrophy. eMedicien from WebMD. Retrieved March 8, 2011.

1943 Available at: http://emedicine.medscape.com/article/ 1181436-overview Wang, C. H., Finkel, R. S., Bertini, E. S., et al. (2007). Consensus statement for standard of care in spinal muscular atrophy. Journal of Child Neurology, 22, 1027–1049. Zeesman, S., Whelan, D. T., Carson, N., et al. (2002). Parents of children with spinal muscular atrophy are not obligate carriers: Carrier testing is important for reproductive decisionmaking. American Journal of Medical Genetics, 107, 247–249. Zerres, K., Wirth, B., & Rudnik-Schoneborn, S. (1997). Spinal muscular atrophy-clinical and genetic correlations. Neuromuscular Disorders, 7, 202–207.

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Fig. 3 Residual muscle seen in a 14-year-old female showed chronic denervative change with presence of scattered target fibers (arrows) (H & E 400)

Fig. 1 A 2 1/2-week-old white male died of respiratory failure associated with congenital spinal muscular atrophy (Werdnig–Hoffman disease). There was generalized muscle atrophy including respiratory muscle

Fig. 2 Quadriceps muscle shows many exceedingly atrophic muscle fibers which tend to be in groups (arrow). No degenerative muscle fibers are present (H & E, 100)

Fig. 4 Biopsy of quadriceps muscle from a 10-month-old girl shows a group atrophy involving several entire fascicles (arrow). Both type I (light-stained) and type II (dark-stained) fibers are affected. This is accompanied by an enervative phenomenon (the large muscle fibers all stain pale) (Myosin ATPase, at 9.4, 50)

Spinal Muscular Atrophy

a

Fig. 5 (a, b) A 3-month-old infant boy with Werdnig-Hoffman disease showing generalized hypotonia. He had a small chest with diaphragmatic breathing, fasciculation of the tongue, and

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b

absence of deep tendon reflexes. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the survival motor neuron genes (SMN)

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Fig. 6 A 27-month-old girl with SMA1. She could not stand holding or independently and had foot drops, absence of deep tendon reflexes, and muscle weakness. She was confined to a wheelchair. Molecular genetic analysis revealed homozygous exon 7 deletion and homozygous exon 8 deletion for the SMN gene

Fig. 7 A 5-year-old girl with SMA showing tongue fasciculation

Spinal Muscular Atrophy

Fig. 8 A 30-year-old man with Kugelberg-Welander disease showing muscle weakness and had been confined to a wheelchair for some time. He had trouble standing and began to walk at 6 years of age. Molecular genetic diagnosis revealed homozygous exon 7 deletion and homozygous exon 8 deletion

Spondyloepiphyseal Dysplasia

Spondyloepiphyseal dysplasia (SED) refers to a group of disorders with primary involvement of the vertebrae and epiphyseal centers resulting in a short-trunk disproportionate dwarfism. Two major types (congenita and tarda) will be discussed here.

Synonyms and Related Disorders SED congenita; SED tarda

Genetics/Basic Defects 1. Genetic basis of SED a. SED congenita i. Autosomal dominant inheritance ii. Spondyloepiphyseal dysplasia congenita gene mapped to chromosome 12q13 iii. Gonadal mosaicism reported iv. Advanced paternal age recognized as a risk factor b. SED tarda i. X-linked recessive inheritance a) Most common b) The gene mapped to Xp22.12-p22.31 ii. Autosomal recessive inheritance iii. Autosomal dominant inheritance 2. Molecular basis of SED (Cole et al. 1993) a. SED congenita i. Caused by mutations in COL2A1 gene, which encodes the a1(II) chain of type II collagen. The gene was mapped on chromosome 12.

ii. The mutations result in abnormal type II collagen, which is the major collagen of nucleus pulposus of the spine, hyaline cartilages, fibrocartilages, and vitreous humor of the eyes. iii. Other skeletal dysplasias affected by collagen II abnormalities a) Autosomal forms of SED tarda b) Achondrogenesis type II c) Hypochondrogenesis d) Kniest dysplasia e) Stickler dysplasia f) Spondylometaepiphyseal (Strudwick) dysplasia b. SED tarda, X-linked form (Christie et al. 2001; Savarirayan et al. 2003) i. Caused by mutations in SEDL (SED late) gene (designated “sedlin”), mapped on Xp22.12-p22.31 ii. SEDL gene encodes a protein of 140 amino acids with a role in vesicular transport. iii. Over 30 novel mutations affecting the SEDL gene recognized: the most common type of SEDL-gene disruption being deletion, representing 50% of identified mutations

Clinical Features 1. SED congenita a. Clinical features present at birth b. Short newborn with disproportionately shortened trunk c. Delayed motor development d. Short neck

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_222, # Springer Science+Business Media, LLC 2012

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e. Cervical myelopathy resulting from atlantoaxial instability, odontoid hypoplasia, and spinal cord compression, often presenting at age 5–10 years i. Delayed motor development ii. Decreased endurance iii. Progressive motor weakness iv. Hypotonia v. Sleep apnea vi. Alterations in respiration vii. Pyramidal tract signs (spasticity, hyperreflexia, Babinski sign, and clonus) f. Respiratory insufficiency may develop secondary to thoracic dysplasia. g. Barrel-shaped chest with pectus carinatum deformity h. Protuberant abdomen i. Spine abnormalities i. Lumbar lordosis ii. Thoracic kyphoscoliosis evident in adolescence j. Hip abnormalities i. Hip flexion contractures ii. Coxa vara a) An almost universal finding b) Varying severity c) Progressive d) Associated progressive hip dislocation if ligamentous laxity present iii. The delayed ossification of the capital femoral epiphysis predisposing the hip to deformation with flattening, lateral extrusion, hinge abduction, and premature osteoarthritis k. Knee abnormalities i. Valgus alignment of the knees often associated with overgrowth of the medial femoral condyle ii. Rare genu varum l. Other clinical features i. Gait problems often attributed to hip and knee deformities ii. Clubfeet (talipes equinovarus) present in some patients iii. Ocular anomalies a) Myopia and retinal detachment (>50%): important clinical findings in many patients b) Cataracts c) Buphthalmos secondary glaucoma and strabismus d) Clear corneas

Spondyloepiphyseal Dysplasia

iv. Deafness v. Cleft palate vi. Abdominal or inguinal hernias 2. SED tarda a. X-linked recessive form i. Normal appearance at birth ii. Variable age of onset a) Hip and trunk features appearing around 4 years of age b) Diagnosis not recognized until the adolescent years in some patients iii. Only males are affected. iv. Mild disproportionate trunk shortening v. Barrel-shaped chest vi. Atlantoaxial instability secondary to odontoid hypoplasia vii. Progressive joint and back pain with osteoarthritis commonly involving hip, knee, elbows, and shoulder joints viii. Hip involvement a) Hip pain or stiffness presenting around the first or second decade of life b) Changes mimic bilateral Legg-CalvePerthes disease c) Varying degrees of coxa magna, flattening, extrusion, and subluxation d) Osteoarthritis of the hip, a common sequelae ix. Kyphoscoliosis x. Lumbar lordosis xi. Epiphyseal involvement a) Primarily in the shoulders, hips, and knees b) Symmetrical and bilateral xii. Rare association with nephrotic syndrome xiii. Craniofacial appearance, vision, and hearing not affected in X-linked SED tarda xiv. Normal intelligence xv. Normal life span b. Autosomal recessive form i. Onset between the age of 4 and 10 years ii. Short stature iii. Waddling gait iv. Disproportionately short trunk v. Accentuated spinal curvatures vi. Restricted mobility of the hip joints vii. Hip pain becomes worse with increasing age.

Spondyloepiphyseal Dysplasia

c. Autosomal dominant form i. Clinical features identical to those in the recessive form of SED tarda ii. Hip pain and waddling gait noted after the fourth year of life iii. Mild shortness of the trunk iv. Progressive hip changes causing considerable discomfort

Diagnostic Investigations 1. Radiography a. SED congenita i. A generalized delay in the development of ossification centers a) Absent epiphyseal centers of the distal femur and proximal tibia, os pubis, calcaneus, and talus, which are usually present at birth b) Femoral heads usually not visible on radiographs until patients are aged 5 years c) Femoral capital epiphyses: flattened and irregular in shape when they appear on radiographs ii. Vertebral abnormalities a) Varying degrees of platyspondyly b) Oval, trapezoid, or pear-shaped vertebrae resulting from posterior wedging of vertebral bodies c) Incompletely fused ossification centers of the vertebral bodies d) End plate irregularities and intervertebral disk spaces narrowing become obvious with an increased anteroposterior diameter of the vertebral bodies in adolescents and young adults. e) Exaggerated lumbar lordosis f) Progressive kyphoscoliosis developing in late childhood g) Odontoid hypoplasia or os odontoideum leading to atlantoaxial instability: common iii. Pelvic abnormalities a) Short and small iliac crests with horizontal acetabular roofs and delayed ossification of the pubis b) Small iliac bones with lack of normal flaring of the iliac wings

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c) Deep acetabular fossae appearing empty due to the severely retarded ossification of femoral heads d) Varying severity of coxa vara e) Delayed ossification of the femoral head predisposing hip to deformation with flattening, lateral extrusion, hinge abduction, and premature osteoarthritis iv. Tubular bone abnormalities a) Delayed ossification centers of the distal femur and proximal tibia leading to flattening and irregularity b) Genu valgum usually present with overgrowth of the medial femoral condyle c) Relatively short and broad long tubular bones d) Presence of some metaphyseal flaring especially in the region of the distal femur and proximal and distal humerus e) Delayed or disorganized ossification of carpal and tarsal centers with occasional extra epiphyses b. SED tarda, X-linked recessive form i. Radiographic changes usually apparent in children older than 4–6 years (not evident at birth) ii. Changes suggestive of atlantoaxial instability, platyspondyly, kyphoscoliosis, and epiphyseal involvement similar to those seen in patients with SED congenita iii. Predominantly affecting the spinal vertebral bodies and epiphyses during skeletal growth iv. A mound of bone (“donkey hump”) typically present in the central and posterior portions of the superior and inferior end plates on lateral radiographs in patients with X-linked recessive type of SED tarda (not features of the autosomal dominant or recessive types of SED tarda). However, absence of ossification at the upper and lower anterior margins of the vertebral bodies is considered to be the distinctive radiographic feature. v. Symmetric epiphyseal involvement primarily in the shoulders, hips, and knees vi. Delayed ossification predisposing the weight bearing joints of the lower extremities to deformation and premature osteoarthritis

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vii. Changes in the hip (dysplastic changes of femoral heads and neck), mimic bilateral Legg-Calve-Perthes disease viii. Presence of varying degrees of coxa magna, flattening, extrusion, and subluxation ix. Minor skeletal changes in carrier women with X-linked recessive SED tarda in a 6-generation kindred from Arkansas a) Subtle abnormal shape of the pelvis and knees b) Premature occurrence of degenerative changes in the spine leading to frequent complaint of arthralgia in the middle age c. SED tarda, autosomal recessive form i. Irregular upper and lower plates of the vertebral bodies ii. Anteriosuperior ossification defects of some vertebras iii. Less frequent findings a) Additional ossification defects of the anterioinferior edges of the vertebral bodies b) Anterior protrusion f central portions of the vertebral bodies iv. Femoral heads a) Well-developed capital femoral epiphyses in the younger child b) Progressive flattening and destruction of the femoral heads with advancing age c) Milder abnormalities in the knee joints d) Small and irregular carpal bones e) Slightly short and irregular metacarpals and phalanges in some patients d. SED tarda, autosomal dominant form i. Accentuated dorsal flattening of the vertebral bodies in the younger patient ii. Platyspondyly with a rectangular shape of the vertebral bodies in the older patient iii. Mild and slowly progressive deformities of capital femoral epiphyses and knee epiphyses iv. Slightly short phalanges and metacarpals with narrowing of the joint spaces 2. MRI a. To delineate cord compression due to C1–C2 instability

Spondyloepiphyseal Dysplasia

3.

4.

5.

6.

b. To evaluate severe spinal deformities prior to surgical intervention c. To evaluate the condition of the epiphyseal centers prior to reconstructive procedures CT scan a. To assess the configuration of bones and joints prior to surgical intervention b. To reconstruct three-dimensional images for help in surgical planning of severe cases Hip arthrography a. To document congruity of the femoral head or hinged abduction b. To evaluate severe varus deformity of the femoral neck Laboratory features of SED congenita a. Fine metachromatic inclusions in the peripheral lymphocytes b. Normal urinary excretion of acid mucopolysaccharides including keratosulfate c. Histopathology i. Mildly disorganized physis (epiphyseal growth plate) ii. Chondrocytes containing PAS-positive cytoplasmic inclusions iii. Ultrastructurally, the inclusions correspond to the accumulations of finely granular material in dilated cisterns of rough endoplasmic reticulum. Molecular genetic analysis a. Mutations in COL2A1 gene in SED congenita b. Mutation in SEDL gene in X-linked recessive SED tarda (Tiller and Hannig 2011) i. Sequence analysis clinically available ii. Mutation types a) Deletions b) Splice mutations c) Missense mutations d) Nonsense mutations iii. Detected in >80% of affected males with X-linked spondyloepiphyseal dysplasia tarda iv. Molecular genetic testing in new patients relied largely on mutation screening by sequencing the entire coding region. v. Carrier testing of at risk female relatives available once the mutation has been identified in the proband

Spondyloepiphyseal Dysplasia

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Spondyloepiphyseal dysplasia congenita (autosomal dominant): recurrence risk low unless presence of parental gonadal mosaicism ii. Spondyloepiphyseal dysplasia tarda, X-linked a) The risk to sibs depends on the carrier status of the mother. b) When the mother is a carrier: a 25% risk of having an affected brother; a 25% risk of having an unaffected brother; a 25% risk of having a carrier sister; a 25% risk of having a noncarrier sister c) When the mother is not a carrier: The risk to sibs is low (the risk of gonadal mosaicism in mothers not yet known). iii. Spondyloepiphyseal dysplasia tarda, autosomal recessive: 25% iv. Spondyloepiphyseal dysplasia tarda, autosomal dominant: low unless a parent is affected b. Patient’s offspring i. Spondyloepiphyseal dysplasia congenita, autosomal dominant a) When the spouse is not affected: 50% of offspring will be affected. b) When the spouse is also affected with spondyloepiphyseal dysplasia congenita: 50% of offspring are heterozygous and affected; 25% are homozygous, which is ordinarily fatal in the first few months of life and 25% are unaffected. ii. Spondyloepiphyseal dysplasia tarda a) Autosomal recessive form: recurrence risk to offspring low unless the spouse is a carrier b) Autosomal dominant form: 50% iii. Spondyloepiphyseal dysplasia tarda, X-linked recessive a) None of the sons of an affected male will be affected. b) All daughters of an affected male are carriers.

1951

2. Prenatal diagnosis a. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS available in families at risk for SED congenita, provided the disease-causing mutation (COL2A1) is identified in the proband b. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS possible in families at risk for X-linked SED tarda, provided the disease-causing mutation (SEDL) is identified in the proband c. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified in an affected family member. 3. Management a. SED congenita i. Supportive care including psychosocial support ii. Tracheostomy for severe respiratory difficulties to maintain adequate ventilation iii. Posterior atlantoaxial fusion for patients with signs and symptoms of atlantoaxial instability measuring 8 mm or more or myelopathy iv. Brace for scoliosis initially v. Posterior spinal fusion for severe scoliosis or for patients resistant to bracing vi. Surgical correction for hip and knee abnormalities vii. Surgical correction of equinovarus deformities unmanageable by physical therapy or serial casting b. SED tarda, X-linked type i. Supportive care a) Avoid activities and occupations that place undue stress on the spine and weight bearing joints to prevent premature arthritis. b) Chronic pain management c) Psychosocial support for the patient and family ii. Bracing for scoliosis iii. Posterior spinal fusion for severe scoliosis iv. Posterior stabilization for atlantoaxial instability v. Valgus or valgus-extension intertrochanteric osteotomy to improve hip congruity vi. Total joint arthroplasty for osteoarthritis in adulthood

1952

Spondyloepiphyseal Dysplasia

vii. Management of hip dysplasia a) Acetabular augmentation if the acetabulum is insufficient to contain the enlarged femoral head (coxa magna) b) May require hip replacement

References Augenstein, K. B., Ward, M. J., & Nelson, V. S. (1996). Spondyloepiphyseal dysplasia congenita with ventilator dependence: Two case reports. Archives of Physical Medicine and Rehabilitation, 77, 1201–1204. Bannerman, R. M., Ingall, G. B., & Mohn, J. F. (1971). X-linked spondyloepiphyseal dysplasia tarda: Clinical and linkage data. Journal of Medical Genetics, 8, 291–301. Chan, D., Rogers, J. F., Bateman, J. F., et al. (1995). Recurrent substitutions of arginine 789 by cysteine in pro-alpha 1 (II) collagen chains produce spondyloepiphyseal dysplasia congenita. The Journal of Rheumatology. Supplement, 43, 37–38. Choi, M. Y., Chan, C. C. Y., Chan, D., et al. (2009). Biochemical consequences of sedlin mutations that cause spondyloepiphyseal dysplasia tarda. Biochemical Journal, 423, 323–342. Christie, P. T., Curley, A., Nesbit, M. A., et al. (2001). Mutational analysis in X-linked spondyloepiphyseal dysplasia tarda. Journal of Clinical Endocrinology and Metabolism, 86, 3233–3236. Cole, W. G., Hall, R. K., & Rogers, J. G. (1993). The clinical features of spondyloepiphyseal dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1(II) chain of type II collagen. Journal of Medical Genetics, 30, 27–35. Dahiya, R., Cleveland, S., & Megerian, C. A. (2000). Spondyloepiphyseal dysplasia congenita associated with conductive hearing loss. Ear, Nose, & Throat Journal, 79, 178–182. Diamond, L. S. (1970). A family study of spondyloepiphyseal dysplasia. Journal of Bone Joint and Surgery (America), 52, 1587–1594. Elizondo, L. I., Luecke, T., Boerkoel, C. F. (2006). Schimke immunoosseous dysplasia (spondyloepiphyseal dysplasia, autosomal recessive). Updated December 7, 2006. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼ gene&part¼siod Gedeon, A. K., Colley, A., Jamieson, R., et al. (1999). Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nature Genetics, 22, 400–404. Gedeon, A. K., Tiller, G. E., Le Merrer, M., et al. (2001). The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. American Journal of Human Genetics, 68, 1386–1397. Grunebaum, E., Arpaia, E., MacKenzie, J. J., et al. (2001). A missense mutation in the SEDL gene results in delayed onset of X linked spondyloepiphyseal dysplasia in a large pedigree. Journal of Medical Genetics, 38, 409–411. Harding, C. O., Green, C. G., Perloff, W. H., et al. (1990). Respiratory complications in children with spondyloepiphyseal dysplasia congenita. Pediatric Pulmonology, 9, 49–54.

Harrod, M. J., Friedman, J. M., Currarino, G., et al. (1984). Genetic heterogeneity in spondyloepiphyseal dysplasia congenita. American Journal of Medical Genetics, 18, 311–320. Heuertz, S., Smahi, A., Wilkie, A. O., et al. (1995). Genetic mapping of Xp22.12-p22.31, with a refined localization for spondyloepiphyseal dysplasia (SEDL). Human Genetics, 96, 407–410. James, P. A., Shaw, J., du Sart, D., et al. (2003). Molecular diagnosis in a pregnancy at risk for both spondyloepiphyseal dysplasia congenita and achondroplasia. Prenatal Diagnosis, 23, 861–863. Kozlowski, K., Masel, J., & Nolte, K. (1977). Dysplasia spondylo-epiphysealis congenita Springer-Wiedemann. A critical analysis. Australasian Radiology, 2, 260–280. Langer, L. O., Jr. (1964). Spondyloepiphyseal dysplasia tarda: Hereditary chondrodysplasia with characteristic vertebral configuration in the adult. Radiology, 82, 833–839. Lee, B., Vissing, H., Ramirez, F., et al. (1989). Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science, 244, 978–980. MacKenzie, J. J., Fitzpatrick, J., Babyn, P., et al. (1996). X linked spondyloepiphyseal dysplasia: a clinical, radiological, and molecular study of a large kindred. Journal of Medical Genetics, 33, 823–828. Macpherson, R. I., & Wood, B. P. (1980). Spondyloepiphyseal dysplasia congenita. A cause of lethal neonatal dwarfism. Pediatric Radiology, 9, 217–224. Massa, G., & Vanderschueren-Lodeweyckx, M. (1989). Spondyloepiphyseal dysplasia tarda in Turner syndrome. Acta Paediatrica Scandinavica, 78, 971–974. Naumoff, P. (1977). Thoracic dysplasia in spondyloepiphyseal dysplasia congenita. American Journal of Diseases of Children, 131, 653–654. Parikh, S. N., Crawford, A. H. (2008). Spondyloepiphyseal dysplasia. eMedicine from WebMD. Updated march 4, 2008. Available at: http://emedicine.medscape.com/article/ 1260836-overview Reardon, W., Hall, C. M., Shaw, D. G., et al. (1994). New autosomal dominant form of spondyloepiphyseal dysplasia presenting with atlanto-axial instability. American Journal of Medical Genetics, 52, 432–437. Savarirayan, R., Thompson, E., & Gecz, J. (2003). Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). European Journal of Human Genetics, 11, 639–642. Spranger, J. W., & Langer, L. O., Jr. (1970). Spondyloepiphyseal dysplasia congenita. Radiology, 94, 313–322. Spranger, J. W., & Langer, L. O., Jr. (1974). Spondyloepiphyseal dysplasias. Birth Defects Original Article Series, X(9), 19–61. Spranger, J. W., & Maroteaux, P. (1982). Genetic heterogeneity of spondyloepiphyseal dysplasia congenita? American Journal of Medical Genetics, 13, 241–242. Spranger, J. W., & Wiedemann, H. R. (1966). Dysplasia spondyloepiphysaria congenita. Helvetica Paediatrica Acta, 21, 598–611. Tiller, G. E., Hannig, V. L. (2011) X-linked Spondyloepiphyseal dysplasia tarda. GeneReviews. Retrieved February 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/books/ NBK1145/ Tiller, G. E., Weis, M. A., Polumbo, P. A., et al. (1995). An RNAsplicing mutation (G + 5IVS20) in the type II collagen gene

Spondyloepiphyseal Dysplasia (COL2A1) in a family with spondyloepiphyseal dysplasia congenita. American Journal of Human Genetics, 56, 388–395. Turner, L. M., & Steffensen, T. S. (2010). Spondyloepiphyseal dysplasia congenita. Fetal and Pediatric Pathology, 29, 57–62. Unger, S., Korkko, J., Krakow, D., et al. (2001). Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. American Journal of Medical Genetics, 104, 140–146. Whyte, M. P., Gottesman, G. S., Eddy, M. C., et al. (1999). X-linked recessive spondyloepiphyseal dysplasia tarda.

1953 Clinical and radiographic evolution in a 6-generation kindred and review of the literature. Medicine (Baltimore), 78, 9–25. Williams, B. R., & Cranley, R. E. (1974). Morphologic observations on four cases of SED congenita. Birth Defects Original Article Series, 10(9), 75–87. Yang, S. S., Chen, H., Williams, P., et al. (1980). Spondyloepiphyseal dysplasia congenita. A comparative study of chondrocytic inclusions. Archives of Pathology and Laboratory Medicine, 104, 208–211.

1954

Spondyloepiphyseal Dysplasia

a

b

Fig. 1 (a, b) A neonate with SED congenita showing moderately shortened limbs, short trunk, and large head. Radiograph shows small oval vertebral bodies, reniform ilia, and moderately shortened limb bones

a

Fig. 2 (a, b) Photomicrograph of a neonate with SED congenita shows frequent presence of cytoplasmic inclusions in the chondrocytes of resting cartilage and the zone of proliferation.

b

The cytoplasmic inclusion is a dilated rough endoplasmic reticulum containing finely granular material

Spondyloepiphyseal Dysplasia

1955

a

c

b

d

Fig. 3 (a–d) A boy with SED congenita showing short trunk, short, broad chest with pectus excavatum, globoid abdomen, and hyperlordosis. Radiographs showed lack of ossification of the

femoral epiphysis, short femoral neck, platyspondyly, and thoracolumbar scoliosis

generalized

1956

a

Spondyloepiphyseal Dysplasia

b

c

d

Fig. 4 (a–d) An adult with SED showing short-trunk dwarfism. Radiographs showed flat vertebral bodies, severe scoliosis, and retarded ossification of femoral head and neck

Spondyloepiphyseal Dysplasia

a

1957

b

c

Fig. 5 (a–d) A 9-year-old boy with spondyloepiphyseal dysplasia tarda showing kyphosis. The spinal radiographs showed anterior body projection, widening of vertebral body spaces, and

d

lumbar kyphosis. Femoral epiphysis was poorly developed (flat epiphyses) and acetabular sockets were not well formed

Stickler Syndrome

In 1965, Stickler et al. described a family with progressive myopia, retinal detachment and blindness, and premature degenerative changes in various joints. The disorder was subsequently termed “hereditary progressive arthroophthalmopathy.” The incidence is estimated to be about 1 in 10,000 (Admiraal et al. 2002).

Synonyms and Related Disorders Hereditary progressive arhroophthalmopathy

Genetics/Basic Defects 1. Inheritance: autosomal dominant with wide variation in expression 2. Association of the Stickler syndrome with following collagen gene mutations: a. COL2A1 gene mutations (Hoornaert et al. 2010) i. Observed in membranous or type I vitreous phenotype (afibrillar phenotype) ii. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history was shown to be good indicator for a COL2A1 defect. iii. Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsensemediated decay. b. COL11A1 gene mutations (Richards et al. 2010) i. Observed in beaded or type II vitreous phenotype

ii. Stickler syndrome type II (Marshall syndrome) a) More severe facial features (short nose, midfacial flattening) b) High myopia c) Less risk of retinal detachment d) Moderate hearing impairment iii. Some mutations in COL11A1 have been classified as Marshall syndrome, but as demonstrated by Annunen et al. (1999), the short nose, anteverted nares, midfacial hypoplasia, and flat nasal bridge that are common in cases of Marshall syndrome with COL11A1 mutations, are also often present in young individuals with mutations in COL2A1, making differential diagnosis based on facial phenotypes difficult (Marjava et al. 2007). c. COL11A2 gene mutations i. Cause nonocular Stickler syndrome type III a) Stickler-like facial features b) Mild to moderate deafness c) Normal eyes ii. Also found in patients with a recessively inherited variant denoted as otospondylomegaepiphyseal dysplasia (OSMED) iii. Also cause autosomal dominant nonsyndromic deafness (DFNA13) d. COL9A1 mutations (autosomal recessive Stickler syndrome): vitreous syneresis with an optically empty vitreous due to progressive gel liquefaction (Van Camp et al. 2006)

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_223, # Springer Science+Business Media, LLC 2012

1959

1960

3. Genotype-phenotype correlations a. Type I Stickler syndrome: ocular Stickler syndrome with mutations in COL2A1 (chromosome locus: 12q13.11-q13.2) b. Type II Stickler syndrome: ocular Stickler syndrome with mutations in COL11A1 (chromosome locus: 1p21) c. Type III Stickler syndrome: nonocular Stickler syndrome with mutations in COL11A2 (chromosome locus: 6p21.3)

Clinical Features 1. Considerable clinical variability within families and between families, explainable in part by locus and allelic heterogeneity 2. Ocular features a. Myopia i. Congenital ii. Nonprogressive iii. Of high degree b. Abnormalities of vitreous formation and gel architecture i. Pathognomonic of Stickler syndrome ii. A prerequisite for diagnosis iii. Vitreous anomalies a) Characteristic congenital “membranous” vitreous anomaly (type I phenotype) in type I Stickler syndromes b) Sparse and irregularly thickened bundles of fibers throughout the vitreous cavity (type II phenotype) in type II Stickler syndrome c. Retinal detachment: the most serious ophthalmologic complication d. Cataracts e. Strabismus f. Open-angle glaucoma g. No ocular abnormalities in Stickler syndrome type III 3. Hearing impairment (Admiraal et al. 2002) a. Considerable variability b. Conductive hearing impairment i. Resulting from recurrent otitis media ii. Secondary to cleft palate

Stickler Syndrome

c. Sensorineural hearing impairment i. Type I Stickler syndrome with mutations in the COL2A1 gene a) Occurring in 50–60% b) Typically mild to moderate degrees c) Predominantly affecting higher frequencies d) No tangible progression beyond presbycusis ii. Type II Stickler syndrome (Marshall syndrome) with the mutations in the COL11A1 gene a) Occurring in 80–100% b) More severely affected c) Starting at a younger age or congenital in origin d) Showing progression iii. Type III Stickler syndrome with mutations in the COL11A2 gene a) A typical feature b) Hundred percent penetrance c) Mild to moderate impairment d) Nonprogressive when accounted for presbycusis e) Showing different audiometric configurations 4. Associated anomalies a. Orofacial anomalies i. Facial bone hypoplasia a) Flat midface b) Depressed nasal bridge c) Maxillary hypoplasia d) Mandibular hypoplasia (Pierre-Robin anomaly) ii. High arched/cleft palate iii. Bifid uvula iv. Abnormal teeth v. Malocclusion b. Generalized musculoskeletal abnormalities i. Joint hyperextensibility ii. Enlarged joints iii. Premature osteoarthritis iv. Slender extremities v. Long fingers vi. Hypotonia vii. Relative muscle hypoplasia viii. Kyphosis

Stickler Syndrome

ix. Scoliosis x. Pectus carinatum xi. Accessory carpal ossicles xii. Hip dislocation xiii. Coxa valga xiv. Genu valga xv. Talipes equinovarus c. Mitral valve prolapse i. Fifty percent of patients in one series ii. 0% in another series 5. Intelligence: normal 6. Clinical features seen in different types of Stickler syndrome (Li and Thorne 2010) a. Type I i. Ocular a) Myopia b) Vitreoretinal degeneration c) Cataracts d) Retinal detachment ii. Musculoskeletal a) Mild degenerative changes b) Hypermobility iii. Auditory: Normal to slight hearing impairment iv. Craniofacial: cleft palate b. Type II i. Ocular a) Congenital nonprogressive myopia b) Cataracts ii. Musculoskeletal a) Mild degenerative changes b) Hypermobility iii. Auditory: early-onset sensorineural hearing loss iv. Craniofacial: cleft palate c. Type III i. Ocular: none ii. Musculoskeletal: early-onset osteoarthritis iii. Auditory: high-tone sensorineural hearing loss iv. Craniofacial: Pierre-Robin sequence 7. Differential diagnosis (Snead and Yates 1999; Bowling et al. 2000) a. Wagner hereditary vitreoretinal degeneration i. Consisting solely of ocular abnormalities a) Myopia b) Vitreous degeneration c) Preretinal avascular membranes d) Retinal degeneration and thinning

1961

b.

c.

d.

e.

f. g.

ii. No increased risk of retinal detachment or systemic abnormalities Weissenbacher-Zweym€uller syndrome and otospondylomegaepiphyseal dysplasia (OSMED) i. Pierre-Robin sequence ii. Snub nose iii. Proximal limb shortening resolved by adulthood iv. Dumbbell-shaped femora and humeri v. Coronal vertebral clefts vi. Sensorineural hearing loss vii. No eye abnormalities viii. COL11A2 mutations ix. Appears to represent the same entity as nonocular Stickler syndrome Erosive vitreoretinopathy i. Autosomal dominant eye disorder ii. Phenotype resembling Wagner syndrome but lacking any systemic abnormalities iii. Condition mapped to 5q13-q14 suggesting it may be an allelic variant of Wagner syndrome Marshall syndrome i. Autosomal dominant disorder ii. Clinical phenotype a) Cataracts b) Myopia c) Abnormal vitreous d) Midfacial hypoplasia e) Congenital deafness iii. Associated with COL11A1 mutation in a family affected with Marshall syndrome Kniest dysplasia i. Ocular abnormalities a) Severe myopia b) Vitreous veils c) Perivascular lattice d) Retinal detachment e) Cataracts ii. Systemic findings a) Short trunk dwarfism b) Kyphoscoliosis c) Deafness d) Depressed nasal bridge e) Cleft palate Spondyloepiphyseal dysplasia Marfan syndrome

1962

h. Goldmann-Farve syndrome i. A rare recessively inherited condition ii. Ocular abnormalities a) Night blindness b) Retinal detachment c) Pigmentary choroidoretinal degeneration d) Vascular sheathing in the fundus i. Jansen syndrome i. Ocular abnormalities similar to Wagner syndrome ii. Absent systemic abnormalities j. Congenital retinoschisis i. A sex-linked recessive trait ii. Usually occurring in emmetropic or hyperopic patients iii. Membrane-like structures in midvitreous

Diagnostic Investigations 1. Audiological testing for hearing loss 2. Radiographic features a. Generalized spondyloepiphyseal dysplasia b. Flattening of the epiphyses c. Narrowing of the diaphyses d. Flaring or widening of the metaphyses e. Wedging of the tubular bones f. Coxa valga g. Widening of femoral neck h. Acetabular protrusio i. Chondrolysis j. Avascular necrosis k. Premature arthritic changes l. Anterior maxillary and mandibular underdevelopment 3. Clinically available molecular genetic testing for mutations affecting four different genes (COL2A1, COL11A1, COL11A2, and COL9A1) a. Sequence analysis b. Deletion/duplication analysis

Genetic Counseling 1. Recurrence risk (Robin et al. 2010) a. Variable clinical expression of Stickler syndrome may complicate the genetic counseling (Faber et al. 2000).

Stickler Syndrome

i. Exercise caution on assuming a de novo mutation: radiographic studies and clinical examination of the parents including formal testing of hearing and vision ii. Mutation search whenever possible iii. Uncertainty in predicting clinical consequences of inheriting a mutation b. Patient’s sib i. Autosomal dominant inheritance (COL2A1, COL11A1, COL11A2-related Stickler syndrome) a) A 50% risk if a parent has Stickler syndrome b) A low recurrence risk if the parents are clinically affected and the diseasecausing mutation not identified ii. Autosomal recessive inheritance (COL9A1): a 25% risk c. Patient’s offspring i. Autosomal dominant: a 50% risk ii. Autosomal recessive: risk not increased unless the spouse is a carrier 2. Prenatal diagnosis a. Ultrasonographic demonstration of Pierre-Robin sequence as a part of Stickler syndrome b. Mutation analysis on amniocytes or CVS cells in at-risk families with known mutations c. Linkage analysis of the 3’VNTR polymorphism on the involved gene (COL2A1) using amniocytic DNA d. Preimplantation genetic diagnosis for atrisk pregnancies require prior identification of the disease-causing mutations in the family 3. Management (Bowling et al. 2000) a. Early evaluation of at-risk patients for the development of the following complications i. Retinal tears ii. Retinal detachment iii. Cataracts iv. Glaucoma b. Long-term monitoring c. Cleft palate repair with appropriate feeding techniques d. Corrective lenses for myopia e. Avoid contact sports which may lead to retinal detachment f. Laser photocoagulation of vitreoretinopathy as preventive treatment for retinal detachment

Stickler Syndrome

g. Surgical repair of retinal detachments and remove cataracts with possible lens implantation h. Glaucoma management i. Corrective treatment for strabismus j. Hearing aids for hearing loss k. Speech therapy l. Symptomatic treatment for arthropathy i. Joint pain management ii. Appropriate splints for strengthening and stabilizing lax joints iii. Braces or aids to assist daily activities iv. Hydrotherapy or other physical therapy modalities to increase range of motion, endurance, and strength m. Management for mitral valve prolapse i. Antibiotics prophylaxis ii. Beta-blocker for symptomatic patients

References Admiraal, R. J., Szymko, Y. M., Griffith, A. J., et al. (2002). Hearing impairment in Stickler syndrome. Advances in Oto-Rhino-Laryngology, 61, 216–223. Annunen, S., Korkko, J., Czarny, M., et al. (1999). Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall / Stickler phenotypes. American Journal of Human Genetics, 65, 974–983. Bennett, J. T., & McMurray, S. W. (1990). Stickler syndrome. Journal of Pediatric Orthopaedics, 10, 760–763. Blair, N. P., Albert, D. M., Liberfarb, R. M., et al. (1979). Hereditary progressive arthro-ophthalmopathy of Stickler. American Journal of Ophthalmology, 88, 876–888. Bowling, E. L., Brown, M. D., & Trundle, T. V. (2000). The Stickler syndrome: Case reports and literature review. Optometry, 71, 177–182. Brown, D. M., Graemiger, R. A., Hergersberg, M., et al. (1995). Genetic linkage of Wagner disease and erosive vitreoretinopathy to chromosome 5q113-14. Archives of Ophthalmology, 113, 671–675. Brown, D. M., Kimura, A. E., Weingeist, T. A., et al. (1994). Erosive vitreoretinopathy. A new clinical entity. Ophthalmology, 101, 694–704. Brunner, H. G., van Beersum, S. E., Warman, M. L., et al. (1994). A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Human Molecular Genetics, 3, 1561–1564. Faber, J., Winterpacht, A., Zabel, B., et al. (2000). Clinical variability of Stickler syndrome with a COL2A1 haploinsufficiency mutation: Implications for genetic counselling. Journal of Medical Genetics, 37, 318–320. Freddi, S., Savarirayan, R., & Bateman, J. F. (2000). Molecular diagnosis of Stickler syndrome: A COL2A1 stop codon mutation screening strategy that is not compromised by mutant mRNA instability. American Journal of Medical Genetics, 90, 398–406.

1963 Griffith, A. J., Sprunger, K. L., Siko-Osadsa, D. A., et al. (1998). Marshall syndrome associated with a splicing defect at the COL11A1 locus. American Journal of Human Genetics, 62, 816–823. Hall, J. (1974). Stickler syndrome. Presenting as a syndrome of cleft palate, myopia and blindness inherited as a dominant trait. Birth Defects Original Article Series, 10, 157–171. Herrmann, J., France, T. D., & Opitz, J. M. (1975). The Stickler syndrome. Birth Defects Original Article Series, 11, 203–204. Herrmann, J., France, T. D., Spranger, J. W., et al. (1975). The Stickler syndrome (hereditary arthroophthalmopathy). Birth Defects Original Article Series, 11(2), 76–103. Hoornaert, K. P., Vereecke, I., Dewinter, C., et al. (2010). Stickler syndrome caused by COL2A1 mutations: Genotype–phenotype correlation in a series of 100 patients. European Journal of Human Genetics, 18, 872–881. Jacobson, J., Jacobson, C., & Gibson, W. (1990). Hearing loss in Stickler’s syndrome: A family case study. Journal of the American Academy of Audiology, 1, 37–40. Leiba, H., Oliver, M., & Pollack, A. (1996). Prophylactic laser photocoagulation in Stickler syndrome. Eye, 10(Pt 6), 701–708. Lewkonia, R. M. (1992). The arthropathy of hereditary arthroophthalmopathy (Stickler syndrome). Journal of Rheumatology, 19, 1271–1275. Li, K., & Thorne, C. (2010). Adult presentation of Stickler syndrome type III. Clinical Rheumatology, 29, 795–797. Liberfarb, R. M., & Goldblatt, A. (1986). Prevalence of mitralvalve prolapse in the Stickler syndrome. American Journal of Medical Genetics, 24, 387–392. Liberfarb, R. M., Hirose, T., & Holmes, L. B. (1981). The Wagner-Stickler syndrome: A study of 22 families. Journal of Pediatrics, 99, 394–399. Liberfarb, R. M., Levy, H. P., Rose, P. S., et al. (2003). The Stickler syndrome: Genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genetics in Medicine, 5, 21–27. Lisi, V., Guala, A., Lopez, A., et al. (2002). Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome. Genetic Counseling, 13, 163–170. Marjava, M., Hoornaert, K. P., Bartholdi, D., et al. (2007). A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies. American Journal of Medical Genetics, 143A, 258–264. Marshall, D. (1958). Ectodermal dysplasia. Report of a kindred with ocular deformities and hearing defect. American Journal of Ophthalmology, 45, 143–156. McGuirt, W. T., Prasad, S. D., Griffith, A. J., et al. (1999). Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nature Genetics, 23, 413–419. Nowak, C. B. (1998). Genetics and hearing loss: A review of Stickler syndrome. Journal of Communication Disorders, 31, 437–453; 453–454. Popkin, J. S., & Polomeno, R. C. (1974). Stickler’s syndrome (hereditary progressive arthro-ophthalmopathy). Canadian Medical Association Journal, 111, 1071–1076. Richards, A. J., Baguley, D. M., Yates, J. R., et al. (2000). Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the

1964 X position of the type II collagen Gly-X-Y triple helix. American Journal of Human Genetics, 67, 1083–1094. Richards, A. J., McNinch, A., Martin, H., et al. (2010). Stickler syndrome and the vitreous phenotype: Mutations in COL2A1 and COL11A1. Human Mutation, 31, E1461–E1471. Richards, A. J., Yates, J. R., Williams, R., et al. (1996). A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. Human Molecular Genetics, 5, 1339–1343. Robin, N. H., Moran, R. T., Warman, M., et al. (2010). Stickler syndrome. GeneReviews. Updated October 21, 2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? book¼gene&part¼stickler Sirko-Osadsa, D. A., Murray, M. A., Scott, J. A., et al. (1998). Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen. Journal of Pediatrics, 132, 368–371. Snead, M. P. (1996). Hereditary vitreopathy. Eye, 10, 653–663. Snead, M. P., & Yates, J. R. (1999). Clinical and molecular genetics of Stickler syndrome. Journal of Medical Genetics, 36, 353–359. Soulier, M., Sigaudy, S., Chau, C., et al. (2002). Prenatal diagnosis of Pierre-Robin sequence as part of Stickler syndrome. Prenatal Diagnosis, 22, 567–568. Spallone, A. (1987). Stickler’s syndrome: A study of 12 families. British Journal of Ophthalmology, 71, 504–509. Spranger, J. (1998). The type XI collagenopathies. Pediatric Radiology, 28, 745–750. Stickler, G. B., Belau, P. G., Farrell, F. J., et al. (1965). Hereditary progressive arthro-ophthalmopathy. Mayo Clinic Proceedings, 40, 433–455. Stickler, G. B., Hughes, W., & Houchin, P. (2001). Clinical features of hereditary progressive arthro-ophthalmopathy

Stickler Syndrome (Stickler syndrome): A survey. Genetics in Medicine, 3, 192–196. Stickler, G. B., & Pugh, D. G. (1967). Hereditary progressive arthro-ophthalmopathy. II. Additional observations on vertebral abnormalities, a hearing defect, and a report of a similar case. Mayo Clinic Proceedings, 42, 495–500. Van Camp, G., Snoeckx, R. L., Hilgert, N., et al. (2006). A New Autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. American Journal of Human Genetics, 79, 449–457. Van Steensel, M. A. M., Buma, P., de Waal Malefijt, M. C., et al. (1997). Oto-spondylo-megaepiphyseal dysplasia (OSMED): Clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. American Journal of Medical Genetics, 70, 315–323. Vikkula, M., Mariman, E. C. M., Lui, V. C. H., et al. (1995). Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell, 80, 431–437. Wilkin, D. J., Liberfarb, R., Davis, J., et al. (2000). Rapid determination of COL2A1 mutations in individuals with Stickler syndrome: Analysis of potential premature termination codons. American Journal of Medical Genetics, 94, 141–148. Wilkin, D. J., Liberfarb, R. M., & Francomano, C. A. (2001). Stickler syndrome. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes (pp. 405–416). New York: Wiley-Blackwell. Wilkin, D. J., Mortier, G. R., Johnson, C. L., et al. (1998). Correlation of linkage data with phenotype in eight families with Stickler syndrome. American Journal of Medical Genetics, 80, 121–127. Zlotogora, J., Sagi, M., Schuper, A., et al. (1992). Variability of Stickler syndrome. American Journal of Medical Genetics, 42, 337–339.

Stickler Syndrome Fig. 1 A 32-year-old female with Stickler syndrome having severe myopia, retinal detachment, cleft palate, sensorineural hearing loss, mitral valve prolapse, hyperextensible joints, and severe degenerative joint disease

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Sturge-Webber Syndrome

Sturge-Weber syndrome comprises of vascular malformations of the central nervous system and the port-wine stain or nevus flammeus of the face in a trigeminal nerve distribution. The syndrome is also known as encephalotrigeminal angiomatosis. The incidence is estimated to be approximately 1 in 50,000 (Sturge 1879; Parkes Weber 1922; Thomas-Sohl et al. 2004).

Synonyms and Related Disorders Encephalofacial or Encephalotrigeminal angiomatosis

Genetics/Basic Defects 1. Genetics a. A sporadic, nonfamilial disease b. Uncertain inheritance: only a few familial clusters of the syndrome reported; most of these have not exhibited the clear-cut autosomal dominant inheritance pattern c. Proposed to represent a genetically mosaic condition. Lesions in the Sturge-Weber syndrome result from somatic mutations in affected areas, such as the port-wine stain or leptomeningeal angioma, but not in blood or normal skin (Huq et al. 2002). d. A potential role of fibronectin in the pathogenesis of Sturge-Weber syndrome. The gene expression findings in fibroblast supported the hypothesis of a somatic mutation underlying the disorder.

e. A novel synonymous mutation (c.1229G > A) (p.K420K) of RASA1 was identified in a Chinese patient with sporadic Sturge-Weber syndrome (Zhou et al. 2011): Further study is needed. 2. Basic defect: caused by residual embryonal blood vessels and their secondary effects on surrounding brain tissue 3. Pathophysiology: Neurologic dysfunction of the syndrome results from secondary effects of residual embryonal blood vessels on surrounding brain tissue. a. Hypoxia b. Ischemia c. Venous occlusion d. Thrombosis e. Infarction f. Vasomotor phenomenon g. Seizures

Clinical Features 1. Variable natural history of the disease (Mirowski et al. 1999) 2. Three cardinal features (Comi 2003) a. Capillary malformation (port-wine stain, cutaneous angioma) in the upper trigeminal neural distribution i. Involves the ophthalmic branch of the trigeminal nerve, in particular, the upper eyelid and supraorbital region ii. May extend into the maxillary and mandibular regions

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iii. May be associated with soft tissue and bony overgrowth iv. May be hidden in scalp or mouth v. May be absent in the forme fruste of SturgeWeber syndrome b. Ocular abnormalities i. Ipsilateral to the port-wine stain ii. Can be seen with V1 or V2 involvement iii. Glaucoma (60%) iv. Buphthalmos v. Vascular malformations of the conjunctiva, episclera, choroids, and retina c. Leptomeningeal vascular malformation (angioma) i. May be unilateral (more common) or bilateral ii. Usually ipsilateral to port-wine stain iii. Capillary and venous anomalies of leptomeninges iv. No correlation between the size of facial and CNS malformations 3. CNS manifestations a. Seizures (75–90% of cases) b. Mental retardation present in approximately 50% of cases c. Contralateral hemiplegia or hemisensory deficits d. Contralateral homonymous hemianopsia (impaired vision in half of the visual field) e. Headaches f. Developmental delay g. Learning disorders h. Attention deficit hyperactivity disorder 4. Soft tissue and skeletal overgrowth (60–83%) (Greene et al. 2009) a. Often exhibit localized cutaneous growths, either pyogenic granuloma or fibrovascular nodules b. Do not combine venous, lymphatic, or arterial anomalies in an extremity, although simple diffuse venous varicosities have been seen c. Often erroneously diagnosed as having either Klippel-Trenaunay syndrome (extremity capillary-lymphatico- venous malformation with overgrowth) or Parkes Weber syndrome (extremity capillary-arteriovenous malformation with overgrowth) 5. Long-term outcome (Arzimanoglou et al. 2000) a. Distribution of port-wine stain i. Cranial: 98% ii. Extracranial: 52%

Sturge-Webber Syndrome

b. Glaucoma (60%) c. Seizures (83%) d. Developmental delay usually associated with seizures i. With seizures: 43% ii. Without seizures: 0% e. Presence of behavior and emotional problems i. With seizures: 85% ii. Without seizures: 58% f. Require special education i. With seizures: 71% ii. Without seizures: 0% g. Employability i. With seizures: 46% ii. Without seizures: 78% h. Normal fertility i. Indications of progressive nature i. Increasing duration of seizures and postictal deficits ii. Increase in atrophy or of calcified lesions or both

Diagnostic Investigations 1. Radiography a. Asymmetric skull b. Double contour “gyriform” patterns of intracranial calcifications i. Classic “tram-line,” “tram-track”, or “trolleytrack” intracranial calcifications a) Considered pathognomonic prior to modern neuroimaging b) Often a late finding c) May not be present initially ii. Distribution a) In the subcortical region, primarily in the parietal and occipital regions b) Unilateral (80%) or bilateral (20%) 2. EEG to evaluate seizure activities 3. Angiographic findings a. Lack of superficial cortical veins b. Nonfilling dural sinuses c. Abnormal, tortuous vessels 4. CT scan findings (Di Rocco and Tamburrini 2006) a. Intracranial dense gyriform or “tram-truck” calcifications which more commonly affect the parieto-occipital cortical area and/or the choroid plexus and are usually absent in early infancy

Sturge-Webber Syndrome

5.

6.

7. 8.

b. Diffuse high attenuation of the superficial and deep white matter, presumably due to microcalcifications c. Gyriform enhancement after iodinated contrast enhancement, expression of the pial angiomatosis d. Brain atrophy, consequence of vascular steal phenomena of the pial angioma on the surrounding cortical structures e. Thickening of the calvarium, more frequently observed in patients with early onset symptoms as an indirect feature of loss of the brain substance f. Abnormal draining veins g. Enlarged ipsilateral choroid plexus h. Blood-brain barrier breakdown during seizures MRI findings: the gold standard imaging modality for the identification of structural brain abnormalities (Di Rocco and Tamburrini 2006) a. Leptomeningeal enhancement with Gddiethyltriaminepentaacetic acid on T1-weighted images is considered one of the most important signs that help define the extent of the vascular malformation; however, its absence does not exclude the diagnosis (Elster and Chen 1990). b. Enlarged choroid plexus c. Sinovenous occlusion d. Cortical atrophy e. Accelerated myelination Single-photon emission computed tomography to measure cerebral blood flow (Pinton 1997) a. Hyperperfusion early (before 1 year) b. Hypoperfusion late (after 1 year) Positron emission tomography (PET) for hypometabolism Histology a. Thickened and discolored leptomeninges b. Abnormal venous structures c. Calcifications i. Cerebral vessel walls ii. Perivascular tissue iii. Rarely within neurons

Genetic Counseling 1. Recurrence risk a. Patient’s sib: low b. Patient’s offspring: low

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2. Prenatal diagnosis: not been reported 3. Management (Thomas-Sohl 2004) a. Medical care i. Medications for recurrent headaches/ migraine a) Ibuprofen: first choice b) Abortive therapy with sumatriptan c) Preventive therapy with propranolol or nortriptyline ii. Management of glaucoma to control the intraocular pressure and prevent progressive visual loss and blindness a) Beta blocker drops: first choice b) Adrenergic drops or carbonic anhydrase inhibitor drops: second choice iii. Anticonvulsants for seizure (partial epilepsy most prevalent in children) control a) Carbamazepine: first choice b) Valproate, topiramate, phenobarbital, phenytoin iv. Strokelike episodes: aspirin v. Neurobehavioral problems a) Methylphenidate: first choice b) Clonidine: second choice c) Dextroamphetamine or risperidone vi. Dermatologic laser therapy for port-wine stain b. Surgical care i. Surgery (trabeculectomy) for glaucoma if medications fail to lower intraocular pressure ii. Option of early surgery for patients with Sturge-Weber syndrome with drug-resistant epilepsy a) Focal cortical resection b) Hemispherectomy c) Corpus callosotomy d) Vagal nerve stimulation iii. Lesionectomy provided that the pial angioma is unilateral and the resection can be complete

References Alonso, A., Taboada, D., Ceres, L., et al. (1979). Intracranial calcification in a neonate with the Sturge Weber syndrome and additional problems. Pediatric Radiology, 8, 39–41. Arzimanoglou, A., & Aicardi, J. (1992). The epilepsy of SturgeWeber syndrome: Clinical features and treatment in 23 patients. Acta Neurologica Scandinavica. Supplementum, 140, 18–22.

1970 Arzimanoglou, A. A., Andermann, F., Aicardi, J., et al. (2000). Sturge-Weber syndrome: Indications and results of surgery in 20 patients. Neurology, 55, 1472–1479. Boltshauser, E., Wilson, J., & Hoare, R. D. (1976). SturgeWeber syndrome with bilateral intracranial calcification. Journal of Neurology, Neurosurgery, and Psychiatry, 39, 429–435. Brenner, R. P., & Sharbrough, F. W. (1976). Electroencephalographic evaluation in Sturge-Weber syndrome. Neurology, 26, 629–632. Celebi, S., Alagoz, G., & Aykan, U. (2000). Ocular findings in Sturge-Weber syndrome. European Journal of Ophthalmology, 10, 239–243. Chamberlain, M. C., Press, G. A., & Hesselink, J. R. (1989). MR imaging and CT in three cases of Sturge-Weber syndrome: Prospective comparison. AJNR. American Journal of Neuroradiology, 10, 491–496. Chao, D. H. (1959). Congenital neurocutaneous syndromes of childhood. III. Sturge-Weber disease. Journal of Pediatrics, 55, 635–649. Chapieski, L., Friedman, A., & Lachar, D. (2000). Psychological functioning in children and adolescents with Sturge-Weber syndrome. Journal of Child Neurology, 15, 660–665. Cibis, G. W., Tripathi, R. C., & Tripathi, B. J. (1984). Glaucoma in Sturge-Weber syndrome. Ophthalmology, 91, 1061–1071. Comi, A. M. (2003). Pathophysiology of Sturge-Weber syndrome. Journal of Child Neurology, 18, 509–516. Comi, A. M., Hunt, P., Vawter, M. P., et al. (2003). Increased fibronectin expression in Sturge-Weber syndrome fibroblasts and brain tissue. Pediatric Research, 53, 762–769. Del Monte, M. A. (2011). eMedicine from WebMD. Retrieved July 29, 2011. Available at: http://emedicine.medscape.com/ article/1219317-overview Di Rocco, C., & Tamburrini, G. (2006). Sturge-Weber syndrome. Child’s Nervous System, 22, 909–921. Di Trapani, G., Di Rocco, C., Abbamondi, A. L., et al. (1982). Light microscopy and ultrastructural studies of SturgeWeber disease. Child’s Brain, 9, 23–36. Dolkart, L. A., & Bhat, M. (1995). Sturge-Weber syndrome in pregnancy. American Journal of Obstetrics and Gynecology, 173, 969–971. Elster, A. D., Chen, M. Y. (1990). MR imaging of Sturge-Weber syndrome: role of gadopentetate dimeglumine and gradientecho techniques. AJNR. American Journal of Neuroradiology, 11(4), 685–689. Falconer, M. A., & Rushworth, R. G. (1960). Treatment of encephalotrigeminal angiomatosis (Sturge-Weber disease) by hemispherectomy. Archives of Disease in Childhood, 35, 433–447. Greene, A. K., Taber, S. F., Ball, K. L., et al. (2009). SturgeWeber syndrome: Soft-tissue and skeletal overgrowth. The Journal of Craniofacial Surgery, 20, 617–621. Griffiths, P. D. (1996). Sturge-Weber syndrome revisited: The role of neuroradiology. Neuropediatrics, 27, 284–294.

Sturge-Webber Syndrome Happle, R. (1987). Lethal genes surviving by mosaicism: A possible explanation for sporadic birth defects involving the skin. Journal of the American Academy of Dermatology, 16, 899–906. Huq, A. H., Chugani, D. C., Hukku, B., et al. (2002). Evidence of somatic mosaicism in Sturge-Weber syndrome. Neurology, 59(5), 780–782. Ito, M., Sato, K., Ohnuki, A., et al. (1990). Sturge-Weber disease: Operative indications and surgical results. Brain & Development, 12, 473–477. Jay, V. (2000). Sturge-Weber syndrome. Pediatric and Developmental Pathology, 3, 301–305. King, G., & Schwarz, G. A. (1954). Sturge-Weber syndrome (encephalotrigeminal angiomatosis). AMA Archives of Internal Medicine, 94, 743–758. Kossoff, E. H., Buck, C., & Freeman, J. M. (2002). Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Neurology, 59, 1735–1738. Mirowski, G. W., Liu, A. A.-T., Stone, M. L., et al. (1999). Sturge-Weber syndrome. Journal of the American Academy of Dermatology, 41, 772–773. Oakes, W. J. (1992). The natural history of patients with the SturgeWeber syndrome. Pediatric Neurosurgery, 18, 287–290. Parkes Weber, F. (1922). Right-sided hemihypertrophy resulting from right-sided congenital spastic hemiplegia with a morbid condition of the left side of the brain revealed by radiogram. Journal of Neurology, Neurosurg Psychiatry, 37, 301–311. Pascual-Castroviejo, I., Diaz-Gonzalez, C., Garcia-Mclian, R. M., et al. (1993). Sturge-Weber syndrome: Study of 40 patients. Pediatric Neurology, 9, 283–288. Pinton, F., Chiron, C., Enjolras, O., et al. (1997). Early single photon emission computed tomography in Sturge-Weber syndrome. Journal of Neurology and Neurosurgery Psychiatry 63(5), 616–621. Sturge, W. A. (1879). A case of partial epilepsy apparently due to a lesion of one of the motor centers of the brain. Transactions of Clinical Society of London, 12, 112. Sujansky, E., & Conradi, S. (1995a). Outcome of Sturge-Weber syndrome in 52 adults. American Journal of Medical Genetics, 57, 35–45. Sujansky, E., & Conradi, S. (1995b). Sturge-Weber syndrome: Age of onset of seizures and glaucoma and the prognosis for affected children. Journal of Child Neurology, 10, 49–58. Takeoka, M., & Riviello, J. J. Jr. (2010). Peditric Sturge-Weber syndrome. eMedicine from WebMD. Updated January 5, 2010. Available at: http://emedicine.medscape.com/article/ 1177523-overview Thomas-Sohl, K. A., Vaslow, D. F., & Maria, B. L. (2004). Sturge-Weber syndrome: A review. Pediatric Neurology, 30, 303–310. Zhou, Q., Zheng, J.- W., Yang, X.- J., et al. (2011). Detection of RASA1 mutations in patients with sporadic Sturge-Weber syndrome. Childs Nervous System, 27(4), 603–607.

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a

Fig. 1 An infant with Sturge-Weber syndrome showing portwine stain primarily affecting right side of the face

b

Fig. 3 (a, b) Radiographs of the skull in another patient demonstrate the typical gyriform pattern of cortical calcification

Fig. 2 A girl with typical Sturge-Weber syndrome showing port-wine stain affecting left side of the face

Tay-Sachs Disease

Tay-Sachs disease is a hereditary neurodegenerative disorder resulting from excess storage of GM2 ganglioside within the lysosomes of cells, caused by deficiency of hexosaminidase A. The incidence of the disease is estimated to be 1 in 3,600 in Ashkenazi Jews with carrier frequency of 1 in 30 and 1 in 360,000 in other population with carrier frequency of 1 in 300. Tay-Sachs disease is the most frequently occurring sphingolipidoses.

Synonyms and Related Disorders GM2-gangliosidosis type 1; Hexosaminidase A deficiency

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. Biochemical defect: deficiency of the isoenzyme b-hexosaminidase A (Hex A) 3. Genetic basis a. Mutations in the HEXA gene (on chromosome 15q23-q24) that codes for the subunit of the b-hexosaminidases result in the deficiency of Hex A (ab) that results in Tay-Sachs disease. b. Over 100 different mutations have been identified in the HEXA gene to date. c. Presence of a small number of common mutations in populations where the carrier frequency is high (Sutton 2002) i. Ashkenazi Jews (Bach 2001) a) Two common mutations associated with Tay-Sachs disease [a four base-pair

insertion into exon 11 of the HEXA gene (1278insTATC) accounting for 75–80% of all mutations in this population; a splice site mutation in intron 12 (1421+1G ! C) accounting for 15% of mutations] b) One mutation associated with a late-onset form of the disease (G269S in 3% of carriers) c) Pseudodeficiency polymorphism (R247W in 2% of carriers) ii. Pennsylvania Dutch a) An intron 9 splice site mutation (1,073 +1G ! A) b) Pseudodeficiency allele (R247W) iii. Cajuns in Southern Louisiana a) An intron 9 splice site mutations (1,073 +1G ! A) b) Four base-pair insertion in exon 11 (1278insTATC) iv. French Canadians in Eastern Quebec a) A large (7.6 kb) deletion at the 50 end of the gene b) A splice site mutation in intron 7 (805 +1G ! A) c) Common 4 base-pair insertion in exon 11 seen in Ashkenazi Jews (1278insTATC)

Clinical Features 1. Classic infantile acute-onset Tay-Sachs disease a. Natural history (Sutton 2002) i. Appears normal at birth ii. Normal motor development in the first few months of life

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iii. Progressive weakness and loss of motor skills beginning around 2–6 months of life iv. Followed by decreased social interaction, increased sensitivity to noise (hyperacusis), and an increased startle response to noise v. Progressive neurodegeneration vi. Uniformly fatal: death from pneumonia usually occurring between 2 and 5 years of age b. Clinical features i. Delayed development ii. Poor feeding iii. Lethargy iv. Hypotonia v. Hyperreflexia vi. Opisthotonos vii. Hyperacusis viii. A cherry red spot on the fovea centralis of the macula, representing loss of ganglion cells in the foveal area with the remaining ones filled with the ganglioside ix. Progressive neurodegeneration a) Developmental regression b) Macrocephaly secondary to accumulation of storage material within the brain after about 15 months of age. There is no evidence of hepatosplenomegaly or other peripheral evidence of storage disease. c) Myoclonic seizures, most during the first year of life d) Progressive macular degeneration leading to blindness, usually by 1 year of age e) Deafness f) Spasticity g) Complete disability 2. Subacute (juvenile) Tay-Sachs disease (2–18 years of age) (Maegawa et al. 2006): characterized by progressive neurologic deterioration that mainly affects motor and spinocerebellar function leading to: a. Progressive spasticity with seizures and dementia b. A vegetative state by late childhood or mid-teens 3. Late-onset (adult) Tay-Sachs disease (Shapiro et al. 2008) a. A chronic, progressive, lysosomal storage disorder caused by a partial deficiency of beta hexosaminidase A (HEXA) activity

Tay-Sachs Disease

b. Deficient levels of HEXA result in the intracellular accumulation of GM2-ganglioside, resulting in toxicity to nerve cells c. Clinical manifestations primarily involve the central nervous system (CNS) and lower motor neurons, including: i. Ataxia ii. Weakness iii. Spasticity iv. Dysarthria v. Dysphagia vi. Dystonia vii. Seizures viii. Psychosis ix. Mania x. Depression xi. Cognitive decline d. The prevalence of peripheral nervous system: a predominantly axon loss polyneuropathy affecting distal nerve segments in the lower and upper extremities (27% of cases)

Diagnostic Investigations 1. Diagnosis and carrier testing a. Indications for carrier testing i. Fully or partially Jewish ii. Pennsylvania Dutch iii. Cajuns of Southern Louisiana iv. French Canadians of Eastern Quebec b. Preconceptional counseling for at-risk couples c. Enzyme assay i. Using fluorimetric study measuring activity of both Hex A and Hex B in either serum or leukocytes ii. Decreased activity of Hex A with normal or increased activity of Hex B in carriers iii. Limitations of serum assay a) Overlapping of the values between carriers and noncarriers b) Unreliable in pregnant women and in women taking oral contraceptives c) Inability to distinguish carriers of pseudodeficiency alleles from carriers of disease-causing mutations iv. Clarification of abnormal or inconclusive results of enzyme assay by: a) Enzyme assay on leukocytes

Tay-Sachs Disease

2. 3.

4.

5.

b) DNA mutation analysis for common mutations and pseudodeficiency alleles d. Molecular genetic testing (Kaback and Desnick 2011) i. Targeted mutation analysis: using a panel of common HEXA mutations when assay of HEX A enzymatic activity is abnormal: a) In a symptomatic individual in order to identify the disease-causing mutations b) In an asymptomatic individual to evaluate for the presence of a pseudodeficiency allele ii. Sequence analysis/mutation scanning: to identify HEXA mutations in an individual who: a) Is affected but had only one or neither mutation identified using a panel of standard mutations, or b) Has carrier-level enzymatic results but did not have a mutation identified using a panel of standard mutations CT scan of the brain: areas of low density in the basal ganglia and cerebral white matter MRI of the brain: an increased signal in the basal ganglia and cerebral white matter on T2-weighted images MR spectroscopy (Aydin et al. 2005) a. Demonstrates an increase in myoinositol/creatine and choline/creatine ratios with a decrease in the N-acetyl aspartate/creatine ratio b. The spectroscopy findings support demyelination, gliosis, and neuronal loss in the neuropathological process of Tay-Sachs disease. Characteristic neuropathological findings (Kaback et al. 1993) a. Pathologic changes are restricted to the nervous system. b. Ballooning of neurons with massive intralysosomal accumulation of lipophilic membranous bodies c. Nature and structure of the stored intraneuronal material : GM2 ganglioside d. Abnormal cytoplasmic inclusion bodies identified in fetal spinal cord at 12 weeks and retina and spinal ganglia during 19th–22nd week of gestation (Adachi et al. 1974) e. Cisternae of the endoplasmic reticulum: the primary site of lipid accumulation in neurons during the fetal stage of Tay-Sachs disease (Adachi et al. 1974)

1975

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring i. Acute infantile form: not surviving to reproductive age ii. Late-onset form may reproduce: risk not increased unless the spouse is a carrier 2. Prenatal diagnosis (Kaback and Desnick 2011) is available when HEX A enzyme assay has shown both parents to be heterozygous, and molecular genetic testing has ruled out the presence of a pseudodeficiency allele in either parent: a. Enzyme analysis (absence of hexosaminidase A) on cultured amniocytes or chorionic villus cells b. DNA analysis when one of the common mutations had been identified in the family i. Preferred method of prenatal diagnosis ii. Less prone to error c. Preimplantation genetic diagnosis may be available for families in which the diseasecausing mutations have been identified in an affected family member. 3. Management a. No effective treatment to alter the natural history b. Primarily supportive i. Provide adequate nutrition and hydration ii. Manage infections iii. Protect airway iv. Control seizures v. Bowel management c. Enzyme replacement therapy and bone marrow transplantation: not yet successful d. Options to modify 25% risk of having an affected child with each pregnancy if both partners are found to be carriers (Sutton 2002) i. Prenatal diagnosis by amniocentesis or chorionic villus sampling ii. Egg or sperm donation iii. Preimplantation genetic diagnosis iv. Adoption

References Adachi, M., Schneck, L., & Volk, B. W. (1974). Ultrastructural studies of eight cases of fetal Tay-Sachs disease. Laboratory Investigation, 30, 102–112.

1976 Adachi, M., Torii, J., Schneck, L., et al. (1971). The fine structure of fetal Tay-Sachs disease. Archives of Pathology, 91, 48–54. Akerman, B. R., Natowicz, M. R., Kaback, M. M., et al. (1997). Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease. American Journal of Human Genetics, 60, 1099–1106. Akli, S., Boue, J., Sandhoff, K., et al. (1993). Collaborative study of the molecular epidemiology of Tay-Sachs disease in Europe. European Journal of Human Genetics, 1, 229–238. Ambani, L. M., Bhatia, R. S., Shah, S. B., et al. (1989). Prenatal diagnosis of Tay-Sachs disease. Indian Pediatrics, 26, 1052–1053. Argov, Z., & Navon, R. (1984). Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase A deficiency. Annals of Neurology, 16, 14–20. Aydin, K., Bakir, B., Tatli, B., et al. (2005). Proton MR spectroscopy in three children with Tay-Sachs disease. Pediatric Radiology, 35, 1081–1085. Bach, G., Tomczak, J., Risch, N., et al. (2001). Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure. American Journal of Medical Genetics, 99(1), 70–75. Brady, R. O. (2001). Tay-Sachs disease: The search for the enzymatic defect. Advances in Genetics, 44, 51–60. Brett, E. M., Ellis, R. B., Haas, L., et al. (1973). Late onset GM2gangliosidosis. Clinical, pathological, and biochemical studies on 8 patients. Archieves of Disease in Children, 48, 775–785. Callahan, J. W., Archibald, A., Skomorowski, M. A., et al. (1990). First trimester prenatal diagnosis of Tay-Sachs disease using the sulfated synthetic substrate for hexosaminidase A. Clinical Biochemistry, 23, 533–536. Chamoles, N. A., Blanco, M., Gaggioli, D., et al. (2002). TaySachs and Sandhoff diseases: Enzymatic diagnosis in dried blood spots on filter paper: Retrospective diagnoses in newborn-screening cards. Clinica Chimica Acta, 318, 133–137. Childs, B., Gordis, L., Kaback, M. M., et al. (1976). Tay-Sachs screening: Social and psychological impact. American Journal of Human Genetics, 28, 550–558. Cotlier, E. (1974). Tay-Sachs’ disease and Fabry’s disease: Clinical and chemical diagnosis of two metabolic eye diseases. Bulletin of the New York Academy of Medicine, 50, 777–787. Cutz, E., Lowden, J. A., & Conen, P. E. (1974). Ultrastructural demonstration of neuronal storage in fetal Tay-Sachs disease. Journal of Neurological Sciences, 21, 197–202. Desnick, R. J., & Goldberg, J. D. (1977). Tay-Sachs disease: Prospects for therapeutic intervention. Progress in Clinical and Biological Research, 18, 129–141. Desnick, R. J., & Kaback, M. M. (2001). Future perspectives for Tay-Sachs disease. Advances in Genetics, 44, 349–356. Eeg-Olofsson, L., Kristensson, K., Sourander, P., et al. (1966). Tay-Sachs disease. A generalized metabolic disorder. Acta Paediatrica Scandinavica, 55, 546–562. Grabowski, G. A., Kruse, J. R., Goldberg, J. D., et al. (1984). First-trimester prenatal diagnosis of Tay-Sachs disease. American Journal of Human Genetics, 36, 1369–1378.

Tay-Sachs Disease Gravel, R. A., Triggs-Raine, B. L., & Mahuran, D. J. (1991). Biochemistry and genetics of Tay-Sachs disease. Canadian Journal of Neurological Sciences, 18, 419–423. Grebner, E. E., & Jackson, L. G. (1985). Prenatal diagnosis for Tay-Sachs disease using chorionic villus sampling. Prenatal Diagnosis, 5, 313–320. Hansis, C., & Grifo, J. (2001). Tay-Sachs disease and preimplantation genetic diagnosis. Advances in Genetics, 44, 311–315. Kaback, M. M. (1977). Tay-Sachs disease: From clinical description to prospective control. Progress in Clinical and Biological Research, 18, 1–7. Kaback, M. M. (1982). Screening for reproductive counseling: Social, ethical, and medicolegal issues in the Tay-Sachs disease experience. Progress in Clinical Biological Research, 103, 447–459. Kaback, M. M. (2000). Population-based genetic screening for reproductive counseling: The Tay-Sachs disease model. European Journal of Pediatrics, 159(Suppl. 3), S192–S195. Kaback, M. M. (2001). Screening and prevention in Tay-Sachs disease: Origins, update, and impact. Advances in Genetics, 44, 253–265. Kaback, M. M., & Desnick, R. J. (2011). Hexosaminidase a deficiency. GeneReviews. Retrieved August 11, 2011. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1218/ Kaback, M. M., & Desnick, R. J. (2001). Tay-Sachs disease: From clinical description to molecular defect. Advances in Genetics, 44, 1–9. Kaback, M., Lim-Steele, J., Dabholkar, D., et al. (1993). TaySachs disease–carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. Journal of American Medical Association, 270, 2307–2315. Kaback, M. M., Nathan, T. J., & Greenwald, S. (1977). TaySachs disease: Heterozygote screening and prenatal diagnosis–US experience and world perspective. Progess in Clinical Biological Research, 18, 13–36. Kaback, M. M., Zeiger, R. S., Reynolds, L. W., et al. (1974). Approaches to the control and prevention of Tay-Sachs disease. Progress in Medical Genetics, 10, 103–134. Kivlin, J. D., Sanborn, G. E., & Myers, G. G. (1985). The cherryred spot in Tay-Sachs and other storage diseases. Annals of Neurology, 17, 356–360. MacQueen, G. M., Rosebush, P. I., & Mazurek, M. F. (1998). Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 10, 10–19. Maegawa, G. H. B., Stockley, T., Tropak, M., et al. (2006). History of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics, 118, e1550–e1562. Mahuran, D. J., Triggs-Raine, B. L., Feigenbaum, A. J., et al. (1990). The molecular basis of Tay-Sachs disease: Mutation identification and diagnosis. Clinical Biochemistry, 23, 409–415. O’Brien, J. S., Okada, S., Fillerup, D. L., et al. (1971). Tay-Sachs disease: Prenatal diagnosis. Science, 172, 61–64. Rattazzi, M. C., & Dobrenis, K. (2001). Treatment of GM2 gangliosidosis: Past experiences, implications, and future prospects. Advances in Genetics, 44, 317–339.

Tay-Sachs Disease Risch, N. (2001). Molecular epidemiology of Tay-Sachs disease. Advances in Genetics, 44, 233–252. Rodriguez-Torres, R., Schneck, L., & Kleinberg, W. (1971). Electrocardiographic and biochemical abnormalities in Tay-Sachs disease. Bulletin of the New York Academy of Medicine, 47, 717–730. Schneck, L., Adachi, M., & Volk, B. W. (1972). The fetal aspects of Tay-Sachs disease. Pediatrics, 49, 342–351. Schweitzer-Miller, L. (2001). Tay-Sachs disease: Psychologic care of carriers and affected families. Advances in Genetics, 44, 341–347. Shapiro, B. E., Logigian, E. L., Kolodny, E. H., et al. (2008). Lateonset Tay-Sachs disease: The spectrum of peripheral neuropathy in 30 affected patients. Muscle & Nerve, 38, 1012–1015. Streifler, J., Golomb, M., & Gadoth, N. (1989). Psychiatric features of adult GM2 gangliosidosis. The British Journal of Psychiatry, 155, 410–413.

1977 Streifler, J. Y., Gornish, M., Hadar, H., et al. (1993). Brain imaging in late-onset GM2 gangliosidosis. Neurology, 43, 2055–2058. Sutton, V. R. (2002). Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstetrics and Gynecology Clinics of North America, 29, 287–296. Suzuki, K., & Saul, R. (1994). Korey Lecture. Molecular genetics of Tay-Sachs and related disorders: A personal account. Journal of Neuropathology and Experimental Neurology, 53, 344–350. Thurmon, T. F. (1993). Tay-Sachs genes in Acadians. American Journal of Human Genetics, 53, 781–783. Volk, B. W. (1966). Understanding Tay-Sachs disease. Recent advances. Clinical Pediatrics (Philadelphia), 5, 653–654. Wilkins, R. H., & Brody, I. A. (1969). Tay-Sachs’ disease. Archives of Neurology, 20, 103–111.

1978

Fig. 1 A cherry red spot on the fovea centralis of the macula from the fundus of an infant with Tay-Sachs disease

Fig. 2 Myenteric plexus of the rectum (H & E, 400) showing many enlarged ganglion cells with abundant foamy cytoplasm due to ganglioside storage. Rectal biopsy can be a good source of neurons in confirming neuronal storage disease. In this patient, Tay-Sachs disease was confirmed by electron microscopic examination of ganglion cells

Tay-Sachs Disease

Tay-Sachs Disease Fig. 3 A section of medulla showing a group of neurons with markedly distended foamy cytoplasm (arrows) due to accumulation of GM2 ganglioside (H & E, 1,000)

1979

Tetrasomy 9p Syndrome

Tetrasomy 9p syndrome, a clinically diagnosable condition, is a rare cytogenetic disorder characterized by tetrasomy 9p associated with a distinctive patterns of multiple congenital anomalies. In 1973, Ghymers et al. first described the syndrome.

Synonyms and Related Disorders Supernumerary isochromosome 9p syndrome

with duplication of the short arm and loss of the acentric long arm at the subsequent mitosis c. Dicentric vs monocentric (de Azevedo Moreira et al. 2003) i. Using conventional cytogenetics and banding techniques revealed an additional dicentric 9p chromosome in most cases. ii. Using molecular studies using a chromosome 9 classic satellite probe shows an error in the division of centromere 9 by a double-break event, resulting in the formation of a monocentric isochromosome 9p.

Genetics/Basic Defects 1. Caused by de novo supernumerary isochromosome 9p (presence of four copies of the short arm of the chromosome 9) a. Pure tetrasomy 9p b. Tetrasomy involving the varying segment of the short arm of chromosome 9 2. Cytogenetic types of tetrasomy 9p a. Presence of an extra dicentric chromosome 9 consisting entirely of 9p b. Presence of an extra dicentric chromosome 9 consisting of 9p and the proximal part of 9q c. Mosaicism involving tetrasomy 9p: mosaic of i(9p) cells 3. Hypotheses proposed to explain tetrasomy 9p a. A meiosis I disturbance with nondisjunction and rearrangement in two of the four chromatids of a bivalent 9, resulting in the formation of an isochromosome 9p b. Meiosis II nondisjunction followed by rearrangements (isochromosome formation)

Clinical Features 1. Craniofacial abnormalities a. Delayed closure of the anterior fontanel b. Ocular hypertelorism c. Telecanthus d. Strabismus e. Enophthalmos/microphthalmia f. Epicanthal folds g. Prominent beaked or bulbous nose h. Down-turned corners of the mouth i. Microretrognathia j. Low-set, malformed ears k. Cleft lip/palate l. High-arched palate 2. Cardiac anomalies a. Ventricular septal defect b. Atrial septal defect c. Patent ductus arteriosus d. Persistent left superior vena cava

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3.

4.

5.

6.

7.

8.

9.

e. Double outlet of the right ventricle f. Hypoplastic right ventricle g. Hypoplastic left heart ventricle Lung anomalies a. Lung hypoplasia b. Abnormal lobulation of the lung Renal anomalies a. Renal hypoplasia b. Multicystic dysplasia c. Hydroureter d. Hydronephrosis Genital anomalies a. Cryptorchidism b. Genital hypoplasia c. Micropenis d. Hypoplastic shawl-like scrotum e. Ambiguous genitalia Gastrointestinal anomalies a. Intestinal malrotation b. Hirschsprung disease CNS anomalies a. Psychomotor retardation b. Hypotonia c. Microcephaly d. Brachycephaly e. Hydrocephalus f. Cerebral hypoplasia g. Dandy-Walker cyst h. Absence of olfactory bulbs i. Hypoplastic cerebellum Skeletal anomalies a. Growth retardation b. Short stature c. Short neck d. Dysplastic fingernails e. Limb anomalies f. Clinodactyly of the fifth fingers g. Club feet h. Articular dislocations i. Shortened hands and feet Other features a. Single umbilical artery b. Failure to thrive c. Redundant skin d. Widely spaced nipples e. Single palmar crease f. Sacral dimple

Tetrasomy 9p Syndrome

10. The severity of the phenotype correlates with size of the tetrasomic region and the degree of tissue mosaicism for the tetrasomy 9p.

Diagnostic Investigations 1. Cytogenetic studies to identify supernumerary marker chromosomes (Tan et al. 2007) a. Conventional and high-resolution analyses b. A whole-chromosome paint probe for chromosome 9 to identify the supernumerary chromosome, using the fluorescence in situ hybridization (FISH) technique (Callen et al. 1992; Crolla et al. 1998) c. Microdissection and reverse FISH (microFISH) (Mahjoubi et al. 2005; de Pater et al. 2006) d. Multiplex-FISH (M-FISH) technique (Uhrig et al. 1999) e. Centromere-specific multicolor-FISH assays (Nietzel et al. 2001) f. AcroM-FISH technique (Langer et al. 2001) 2. Echocardiography for cardiovascular malformations 3. Radiography a. Microcephaly b. Hypertelorism c. Hypoplastic first and 12th ribs d. Kyphoscoliosis e. Clinodactyly and brachymesophalangy of the fifth fingers f. Delayed ossification of pubic bones and ischiopubic synchondrosis g. Delayed ossification of femoral heads h. Spina bifida occulta i. Generalized osteoporosis 4. Ultrasonography of renal abnormalities

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased b. Patient’s offspring: patient not surviving to reproductive age

Tetrasomy 9p Syndrome

2. Prenatal diagnosis a. Ultrasonography (Tan et al. 2007) i. Intrauterine growth retardation ii. Genitourinary/renal anomalies iii. Cleft lip/palate iv. CNS anomalies a) Dandy-Walker malformation b) Ventriculomegaly c) Hypoplastic/absent vermis d) Agenesis of corpus callosum v. Limb malformations vi. Vertebral anomalies vii. Cardiac anomalies viii. Genitourinary anomalies ix. Polyhydramnios/oligohydramnios b. Chromosome analysis of amniocytes, CVS, or fetal blood: Microdissection and pre-G-banded FISH is important in determining the origin of supernumerary marker chromosome in prenatal diagnosis. 3. Management a. Early intervention programs for mild developmental delay with minor anomalies b. Supporting care for severe cases with early death

References Abe, T., Morita, M., Kawai, K., et al. (1977). partial tetrasomy 9 (9qter 9q2101) due to extra iso-dicentric chromosome. Annales de Genetique, 20, 111–114. Callen, D. F., Eyre, H. J., Yip, M. Y., et al. (1992). Molecular cytogenetic and clinical studies of 42 patients with marker chromosomes. American Journal of Medical Genetics, 43, 709–715. Crolla, J. A., Long, F. L., Rivera, H., et al. (1998). FISH and molecular study of autosomal supernumerary marker chromosomes excluding those derived from chromosomes 15 and 22. American Journal of Medical Genetics, 75, 355–366. Cuoco, C., Gimelli, G., Pasquali, F., et al. (1982). Duplication of the short arm of chromosome 9. Analysis of five cases. Human Genetics, 61, 3–7. de Azevedo Moreira, L. M., Freitas, L. M., Gusmao, F. A., et al. (2003). New case of non-mosaic tetrasomy 9p in a severely polymalformed newborn girl. Birth Defects Research. Part A, Clinical and Molecular Teratology, 67, 985–988. de Pater, J., Van der Sijs-Bos, C., Prins, M., et al. (2006). Prenatal identification of a marker chromosome 16 by chromosome microdissection and reverse FISH. European Journal of Medical Genetics, 49, 306–312.

1983 Dhandha, S., Hogge, W. A., Surti, U., et al. (2002). Three cases of tetrasomy 9p. American Journal of Medical Genetics, 113, 375–380. Dutly, F., Balmer, D., Baumer, A., et al. (1998). Isochromosomes 12p and 9p: Parental origin and possible mechanisms of formation. European Journal of Human Genetics, 6, 140–144. Eggermann, T., Rossier, E., Theurer-Mainka, U., et al. (1998). New case of mosaic tetrasomy 9p with additional neurometabolic findings. American Journal of Medical Genetics, 75, 530–533. Fryns, J. P. (1998). Trisomy 9p and tetrasomy 9p: A unique, clinically recognisable syndrome. Genetic Counseling, 9, 229–230. Ghymers, D., Hermann, B., Disteche, C., et al. (1973). [Partial tetrasomy of number 9 chromosome, and mosaicism in a child with multiple malformations (author’s translation)]. Humangenetik, 20(3), 273–282. Jalad, S. M., Kukolich, M. K., Garcia, M., et al. (1991). Tetrasomy 9p: An emerging syndrome. Clinical Genetics, 39, 60–64. Kukolich, M., Jalal, S., Garcia, M., et al. (1990). Occurrence of 9p tetrasomy. American Journal of Human Genetics, Suppl. 47, 360. Langer, S., Fauth, C., Murken, M. R. J., et al. (2001). AcroM fluorescent in situ hybridization analyses of marker chromosomes. Human Genetics, 109, 152–158. Lloveras, E., Perez, C., Sole, F., et al. (2004). Two cases of tetrasomy 9p syndrome with tissue limited mosaicism.American Journal of Medical Genetics, 124A, 402–406. Mahjoubi, F., Peters, G. B., Malafiej, P., et al. (2005). An analphoid marker chromosome inv dup(15)(q26.1qter), detected during prenatal diagnosis and characterized via chromosome microdissection. Cytogenet Genome Research, 109, 485–490. McDowall, A. A., Blunt, S., Berry, A. C., et al. (1989). Prenatal diagnosis of a case of tetrasomy 9p. Prenatal Diagnosis, 9, 809–811. Melaragno, M. I., Brunoni, D., da Silva Patricio, F. R., et al. (1992). A patient with tetrasomy 9p, Dandy-Walker cyst and Hirschsprung disease. Annales de Genetique, 35, 79–84. Nietzel, A., Rocchi, M., Starke, H., et al. (2001). A new multicolor-FISH approach for the characterization of marker chromosomes: Centromere-specific multicolor-FISH (cenM-FISH). Human Genetics, 108, 199–204. Orye, E., Verhaaren, H., Van Egmond, E., et al. (1975). A new case of trisomy 9p syndrome. Clinical Genetics, 7, 134–143. Park, J. P., Rawnsley, B. E., & Marin-Padilla, M. (1995). Tetrasomy 9p syndrome. Annales de Genetique, 38, 54–56. Penhausen, P., Riscile, G., Miller, K., et al. (1990). Tissue limited mosaicism in a patient with tetrasomy 9p. American Journal of Medical Genetics, 37, 388–391. Peters, J., Pehl, C., Miller, K., et al. (1982). Case report of mosaic partial tetrasomy 9p mimicking Klinefelter syndrome. Birth Defects, 18, 287–293. Petit, P., Devriendt, K., Vermeesch, J. R., et al. (1998). Localization by FISH of centric fission breakpoints in de novo trisomy 9p patient with i(9p) and t(9p;11p). Genetic Counseling, 9, 215–221. Rutten, F. J., Scheres, J. M. C., Hustinx, T. W. J., et al. (1974). A presumptive tetrasomy of the short arm of chromosome 9. Humangenetik, 25, 163–170.

1984 Schaefer, G. B., Domek, D. B., Morgan, M. A., et al. (1991). Tetrasomy of the short arm of chromosome 9: Prenatal diagnosis and further delineation of the phenotype. American Journal of Medical Genetics, 38, 612–615. Shapiro, S., Hansen, K., & Littlefield, C. (1985). Non-mosaic partial tetrasomy and partial trisomy 9. American Journal of Medical Genetics, 20, 271–276. Steril, G. F., Parke, J. C., Kirkman, H. N., et al. (1993). Tetrasomy 9p: Tissue-limited idic(9p) in a child with mild manifestations and a normal CVS result. Report and review. American Journal of Medical Genetics, 47, 812–816. Tan, W., Wenger, S. L., Boyd, B. K., et al. (2004). Prenatal diagnosis of tetrasomy 9p. American Journal of Medical Genetics, 126A, 328.

Tetrasomy 9p Syndrome Tan, Y.-Q., Chen, X. M., Hu, L., et al. (2007). Prenatal diagnosis of nonmosaic tetrasomy 9p by Microdissection and FISH: Case report. Chinese Medical Journal, 120, 1281–1283. Tonk, V. S. (1997). Moving towards a syndrome: A review of 20 cases and a new case of non-mosaic tetrasomy 9p with long-term survival. Clinical Genetics, 52, 23–29. Uhrig, S., Schuffenhauer, S., Fauth, C., et al. (1999). MultiplexFISH (M-FISH) for pre- and postnatal diagnostic applications. American Journal of Human Genetics, 65, 448–462. Wilson, G. N., Faj, A., & Baker, D. (1985). The phenotypic and cytogenetic spectrum of partial trisomy 9. American Journal of Medical Genetics, 20, 277–282. Wisniewski, L., Politis, G., & Higgins, J. (1978). Partial tetrasomy 9 in a liveborn infant. Clinical Genetics, 14, 141–153.

Tetrasomy 9p Syndrome Fig. 1 (a–c) An infant with tetrasomy 9p syndrome presenting with widened anterior fontanel, microbrachycephaly, a broad nasal root, telecanthus, bilateral cleft lip and palate, retromicrognathia, small eyes, low-set lop ears, and a skin tag on the antihelix of the right ears. In addition, the infant had short neck with excess nuchal fold, bilateral webbing of the anterior axillary folds, pectus excavatum, congenital heart defects, right hydronephrosis, diastasis recti with an umbilical hernia, a right inguinal hernia, sacral dimple with a tag, micropenis, bilateral metatarsus adductus, bilateral transverse palmar creases, clinodactyly of the fifth fingers, short thumbs, and hypoplastic nails. Chest X-ray showed hemivertebrae in the thoracic spine and fractured right clavicle with callus formation. A rectal biopsy confirmed the diagnosis of Hirschsprung disease

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b

Thalassemia

The term thalassemia was first applied to the anemias encountered frequently in people of the Italian and Greek coasts and nearby islands. The term now refers to a group of inherited disorders of globin chain synthesis. Thalassemia comprises of a group of hemoglobinopathies, which are classified according to the specific globin chain (a or b) whose synthesis is impaired. Thus, a- and b-thalassemia are depression of synthesis of the respective chain.

Synonyms and Related Disorders Alpha-thalassemia (Hb H disease or alpha-thalassemia intermedia, Hb Bart’s hydrops fetalis or alpha thalassemia major); Beta-thalassemia (beta-thalassemia major or Cooley anemia or homozygous beta-thalassemia, beta-thalassemia intermedia or compound heterozygote, beta-thalassemia minor or beta-thalassemia trait)

Genetics/Basic Defects 1. Inheritance: autosomal recessive 2. a-thalassemia (Vichinsky 2010) a. Normal fetal hemoglobin synthesis i. Early in gestation, embryonic hemoglobins (Gower1, Gower2, and Portland), which do not contain a-globin chains, are the predominant hemoglobins. ii. They are rapidly replaced by fetal and then adult hemoglobin, which contain a-globin chains.

iii. Therefore, a-thalassemia mutations become phenotypically evident by 12 weeks of gestation. b. Synthesis of a-chains is directed by four a-genes, two on each chromosome 16. c. a-thalassemia represents a group of conditions with reduced or absent synthesis of one to all four of a-globin genes. i. a-thalassemia-2 (a-/aa): resulting from deletion of one of the two a-globin genes ii. a-thalassemia-1 (

/aa): resulting from deletion of both a-globin genes iii. Hb H disease (

/
a): resulting from deletion of three a-globin genes iv. Hb Bart’s hydrops fetalis (

/

): resulting from deletion of all four a-globin genes: Physiologically nonfunctional homotetramers g4 and b4 make up most of the hemoglobin in the erythrocytes in infants with the Bart’s hydrops fetalis syndrome. d. When both a-genes on a single chromosome are inactive, the designation ao-thalassemia is used. When there is some production of a-globin chains, a+-thalassemia is designated. 3. b-thalassemia a. Synthesis of b-chains: directed by a single b-gene on each chromosome 11 b. Caused by the reduced (b+) or absent (bo) synthesis of the b-globin chains of the hemoglobin tetramer which is made up of two a-globin and two b-globin chains (a2b2). c. Mutations in b-thalassemia

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i. In contrast to the a-thalassemias, most of the common b-thalassemia mutants are caused by point mutations rather than by gene deletion. ii. Single base–pair mutations in the DNA alter processing of messenger RNA: most common iii. Chain terminator defects iv. Frameshift mutations v. Polyadenylation mutations vi. Promoter mutations d. bo-thalassemia i. The mutations prevent b-globin chain synthesis entirely. ii. Absent b-globin synthesis in bo-thalassemia homozygotes iii. Accounts for about one-third of thalassemia patients e. b+-thalassemia i. The mutations prevent b-chain synthesis partially. ii. b-globin synthesis reduces to 5–30% of normal levels in b+-thalassemia homozygotes. + o f. b /b -thalassemia compound heterozygotes 4. Pathogenesis (Yaish 2010) a. Basic defect in all types of thalassemia: imbalanced globin chain synthesis b. A decrease in the rate of production of a certain globin chain (a, b, g, d) impedes hemoglobin (Hb) synthesis and creates an imbalance with the other globin chain that normally produce globin chains. c. Consequences of impaired production of globin chains i. Result in less Hb deposit in each RBC, leading to hypochromasia ii. Deficiency in Hb causes RBCs to be smaller, leading to the classic hypochromic microcytic features of thalassemia. 5. Phenotype-genotype correlation (Cao and Galanello 2010) a. Homozygosity or compound heterozygosity for b-thalassemia most commonly results in the clinical phenotype of transfusion-dependent thalassemia major. b. However, a consistent proportion of homozygotes develop milder forms, called thalassemia intermedia, which range in severity from thalassemia major to the b-thalassemia carrier state.

Thalassemia

c. Ascertained molecular mechanisms leading to thalassemia intermedia i. b-thalassemia mutations a) Mild mutation b) Silent mutation c) Mild/silent mutation ii. Coinherited a-thalassemia a) Single a-globin gene deletion (
a/aa) b) Deletion of two a-globin gene (
a/
a or – /aa) c) Point mutations of the major a-2-globin gene iii. Genetic determinant of high Hb F production a) Due to the b-thalassemia mutation per se (db-thalassemia, b-promoter deletion) b) Coinherited Agamma or Ggamma promoter mutation (
158 Ggamma (A ! T);
196 Agamma (C ! T)) c) Heterocellular HPFH, BCL11A on chromosome 2, and HBS1L-MYB region on chromosome 6

Clinical Features 1. a-thalassemia (Harteveld and Higgs 2010) a. The most common genetic disorder of hemoglobin synthesis, affects up to 5% of the world’s population (Vichinsky 2010) b. Found in people of African descent, Indochina, Malaysia, and China c. Severity of resulting anemia quite variable ranging from asymptomatic carriers to a fatal in utero disease: depends on the number of functioning a-genes i. a-thalassemia-2 or silent carrier a-thalassemia (a-/aa) (deficiency of only one globin gene) a) Twenty-five percent of African Americans b) 3.4% of Greek Americans c) Slight microcytic red blood cells d) Borderline or minimal anemia ii. a-thalassemia-1 or a-thalassemia trait ( – /aa) (deficiency of two globin genes) a) Fifteen to twenty percent of Thai b) Mildly anemic

Thalassemia

c) d) e) f) g)

Microcytic red blood cells Slight variation in red blood cell size Mild splenomegaly Work capacity not impaired Same phenotypic effect in the individual homozygous for a-thalassemia-2 (a
/ a
): This form is much more common in black populations. iii. Hb H disease or a-thalassemia intermedia (–/
a) (deficiency of three globin genes) a) One percent of Thai b) Significant hypochromic anemia in the neonatal period c) Microcytic anemia d) Reticulocytosis e) Jaundice f) Splenomegaly (may be severe and occasionally complicated by hypersplenism) g) Growth retardation may be seen in children. h) Hemolysis precipitated by infections or oxidant drugs (e.g., iron, sulfonamides) i) Leg ulcers j) Gallstones k) Folic acid deficiency l) Needs occasional transfusions, splenectomy, or avoidance of precipitating drugs m) Severity of clinical features: related to the molecular basis of the disease: Patients with nondeletional types of Hb H disease are more severely affected than those with the common deletional types of Hb H disease iv. Hb Bart’s hydrops fetalis or a-thalassemia major (–/–) (deficiency of all four globin genes) a) Most severe form of a-thalassemia b) Incompatible with life unless intrauterine blood transfusion is given because not enough functional hemoglobin is produced to sustain tissue oxygenation c) Profound oxygen deprivation in utero with resulting heart failure (hydrops fetalis) d) Stillborn or die soon after birth e) Pale edematous infant with signs of cardiac failure (edema and ascites) and prolonged intrauterine anemia

1989

f) Massive hepatosplenomegaly g) Severe erythroblastic anemia h) Retardation in brain growth i) Skeletal and cardiovascular anomalies j) Enlargement of the placenta 2. b-thalassemia (Cao and Galanello 2010) a. Found largely in people of African and Mediterranean descent, Far East, Middle East, and the Asian subcontinent i. Highest incidence a) Cyprus (14%) b) Sardinia (12%) c) Southeast Asia ii. The high gene frequency of beta-thalassemia in these regions a) Most likely related to the selective pressure from Plasmodium falciparum malaria, as it is indicated by its distribution quite similar to that of present or past malaria endemics. Carriers of betathalassemia are indeed relatively protected against the invasion of Plasmodium falciparum. b) However, because of population migration and, to a limited extent, slave trade, beta-thalassemia is, at present, also common in Northern Europe, North and South America, Caribbean, and Australia. b. Clinical features dependent on reduced (b+) or absent (bo) synthesis of b-globin i. b-thalassemia major (also known as Cooley’s anemia or homozygous b-thalassemia) a) Due to inheritance of two b-thalassemia alleles, one on each copy of chromosome 11 b) Generally recognized to be a homozygous state for whichever thalassemia gene is involved c) Clinically a severe disorder d) Infants born free of significant anemia, protected by prenatal Hb F production e) Onset: 6–12 months f) Diagnosis: evident by 2 years of age g) Manifestations in early childhood: anemia, pallor, growth retardation, tiredness, abdominal swelling due to hepatosplenomegaly, infection, and jaundice

1990

Thalassemia

h) Manifestations in childhood and adult: severe anemia, infection, tiredness, growth retardation, distinctive facies, hepatosplenomegaly, cardiomegaly, abdominal pain, leg ulcers, osteoporosis, and iron overload i) At significant risk for developing overwhelming, often fatal infection after splenectomy (postsplenectomy syndrome) j) Severe anemia usually necessitating chronic blood transfusions k) Prognosis: average survival of children with untreated thalassemia major (20 ng/mL: suggest possible a-thalassemia syndrome b. Normal MCV, normal electrophoresis: thalassemia syndrome unlikely 2. a-thalassemia: More difficult to diagnose because characteristic elevations in Hb A2 (a2d2) or Hb F (a2g2), seen in b-thalassemia, do not occur. a. a-thalassemia-2 i. Laboratory notation: FA + Bart’s ii. Small amount of Hb Bart’s (1–2%) in affected infants at birth iii. Remainder of the hemoglobin: Hb F and Hb A (a2b2) iv. Hb F and Hb Bart’s: disappear after a few months of age v. Minimal microcytosis: remains b. a-thalassemia-1 i. Laboratory notation: FA + Bart’s (impossible to differentiate the two forms of a-thalassemia from the electrophoretic pattern) ii. Slightly larger amount of Hb Bart’s in cord blood (3–5%) iii. Hb F and Hb Bart’s: disappear after birth iv. Unequivocal microcytosis: Mean red cell volume of 65–70 fl/cell remains. v. Abnormally low Hb A2 proportion c. Hb H disease i. Reduction in a-chain does not affect the production of b-chain which is produced in excess and tends to form tetramers (b4 or Hb H). ii. Hb A + Hb H (b4) + Hb Bart’s (g4) iii. Presence of Heinz bodies: inclusions representing b-chain tetramers (Hb H), which are unstable and precipitate in the RBC, giving the appearance of a golf ball d. Hb Bart’s hydrops fetalis i. Hypochromic macrocytes with nucleated red blood cells

Thalassemia

ii. g4 (Bart’s hemoglobin): nonfunctional as an oxygen transporter 3. b-thalassemia a. b-thalassemia major i. Small, thin, and distorted red blood cells containing markedly reduced amounts of hemoglobin ii. Peripheral blood smear a) Severe microcytic hypochromic anemia (no anemia at birth) b) Anisocytosis c) Poikilocytosis (speculated teardrop and elongated cells) d) Abundant nucleated red cells (i.e., erythroblasts) e) Occasional immature leukocytes iii. Hemolytic anemia iv. Hemoglobin profile: predominant Hb F v. In patient with homozygous bo-thalassemia: absent Hb A with normal amounts of Hb A2 vi. In newborn with b+-thalassemia: Hb F (about 90%) decreases with advancing age but always considerably higher than normal (10–90%). b. b-thalassemia intermedia i. Intermediate Hb concentration (8–10 gm/dL) ii. Microcytic hypochromic anemia iii. Hb F (5–99%) c. b-thalassemia minor i. Mild hypochromic microcytosis ii. Target cells iii. Mild to minimal anemia (hemoglobin concentration average 1–2 gm/dL below normal) iv. Elevation of Hb A2 and Hb F (70–99%) during early years of life v. Anemia worsen during pregnancy 4. Imaging studies a. Chest X-ray to evaluate cardiac size and shape b. Skeletal survey i. Skeletal response to marrow proliferation a) Expanding marrow space b) Thinning of cortical bone c) Resorption of cancellous bone d) Resulting in generalized loss of bone density e) Frequent small lucencies resulting from focal proliferation of marrow

1991

f) “Periosteal response” caused by perforation of the cortex by hypertrophic and hyperplastic marrow subperiosteally ii. Classic facies observed in thalassemia major a) Classic “hair-on-end” appearance of the skull b) Maxilla overgrowth resulting in maxillary overbite c) Prominent upper incisors d) Separation of the orbits iii. Various bone deformities seen in ribs, long bones, and flat bones iv. Premature fusion of the epiphyses c. MRI/CT scans to evaluate the amount of iron in the liver in patients on chelation therapy 5. Carrier screening a. a-thalassemia (Vichinsky 2010) i. Commonly, microcytosis using an MCV 90%) c) Edematous placenta (>90%) d) Ascites (>90%) e) Oligohydramnios (82%) f) Subcutaneous edema (75%) g) Decreased fetal movement (74%) h) Cord edema (63%) i) Enlarged umbilical vessel (62%) j) Pericardial or pleural effusion (15%) ii. Molecular hybridization technique to detect complete absence of a-genes in fetal amniocytes in a pregnancy at risk for homozygous a-thalassemia-1 and the hydrops fetalis syndrome iii. Quantitative polymerase chain reaction for the rapid prenatal diagnosis of homozygous athalassemia (Hb Bart’s hydrops fetalis) b. b-thalassemia i. Available to couples who are carriers of b-thalassemia and their hemoglobin gene mutations have been identified by DNA analysis ii. Direct DNA analysis by molecular hybridization methods for the presence of the thalassemia mutation from fetal cells obtained by amniocentesis and chorionic villus biopsy iii. DNA analysis of fetal nucleated RBCs from maternal peripheral blood iv. Approach to prenatal diagnosis complicated by presence of the heterogeneity of thalassemia mutations v. Preimplantation genetic diagnosis available for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. 3. Management a. a-thalassemia (Segel et al. 2002) i. No therapy necessary for patients with a-thalassemia trait ii. Avoid exposure to oxidant medications (e.g., iron, sulfonamides) which accelerate precipitation of Hb H and exacerbate hemolysis

Thalassemia

iii. Prompt treatment of infection especially in postsplenectomy iv. Hb H disease a) Folate supplementation b) Chronic transfusion therapy (consider iron chelation therapy to avoid iron overloading) c) Splenectomy in rare instances of hypersplenism d) Allogeneic bone marrow transplantation limited to the most severely affected patients v. Bart’s hemoglobinopathy a) Usually results in neonatal death b) Patients rarely salvaged by intrauterine transfusions and subsequent stem cell transplantation c) The diagnosis, management, and prognosis of homozygous a-thalassemia/ hydrops fetalis is changing; advances in antenatal diagnosis, intrauterine intervention, and postnatal therapy have resulted in long-term survival of children previously felt to have an invariably fatal disease(Singer et al. 2000; Weisz et al. 2009; Vichinsky 2010). b. b-thalassemia i. No specific therapy required for bthalassemia trait ii. Regular blood transfusions in thalassemia major a) Correct the anemia b) Suppress erythropoiesis c) Inhibit increased gastrointestinal absorption of iron iii. Treatment of individuals with thalassemia intermedia a) Symptomatic treatment b) Splenectomy c) Folic acid supplementation d) Treatment of extramedullary erythropoietic masses (radiotherapy, transfusions, or hydroxyurea in selected cases) iv. Iron chelation with desferrioxamine to eliminate the iron overload secondary to multiple blood cell transfusions and to increase iron absorption

1993

v. Bone marrow transplantation a) From an HLA-identical sib b) Outcome dependent on pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, and magnitude of iron accumulation c) Risk of chronic graft-versus-host disease of variable severity: 5–8% vi. Cord blood transplantation (Kelly et al. 1997) a) Human umbilical cord blood contains hematopoietic stem cells capable of reconstituting bone marrow. b) Possibility of using cord blood obtained from unrelated donors with a decrease in the incidence of graft-versus-host disease vii. Attempts to increase Hb F production by following agents: variable without substantial effects a) 5-azacytidine b) Erythropoietin c) Butyrate compounds d) Hydroxyurea viii. Hematopoietic stem cells to correct the molecular defect by transfer of a normal gene via a suitable vector or by homologous recombination: currently under investigation

References Abramson, S. D. (1999). “Common” uncommon anemias. American Family Physician, 59, 851–858. Cao, A., & Galanello, R. (2010). Beta-thalassemia. GeneReviews. Updated June 17, 2010. Available at: http://www.ncbi.nlm. nih.gov/bookshelf/br.fcgi?book¼gene&part¼b-thal Cao, A., & Galantello, R. (2010). Beta-thalassemia. Genetics in Medicine, 12, 61–76. Cao, A., Rosatelli, M. C., Monni, G., et al. (2002). Screening for thalassemia: A model of success. Obstetrics and Gynecology Clinics of North America, 29, 305–328. Cao, A., Rosatelli, M. C., Monni, G., et al. (2003). Screening for thalassemia: A model of success. Obstetrics and Gynecology Clinics, 29, 305–328. Carr, S., Rubin, L., et al. (1995). Intrauterine therapy for homozygous alpha-thalassemia. Obstetrics and Gynecology, 85, 876. Chen, H. (1992). Genetic testing & counseling for hemoglobinopathies. In H. Chen (Ed.), Ohio Department of Health the Resource Manual for hemoglobinopathies. An essential guide for health professionals (pp. 97–107). Columbus, OH: Advisory Council on Newborn Screening for Hemoglobinopathies.

1994 Cheung, M.-C., Goldberg, J., & Kan, Y. (1996). Prenatal diagnosis of sickle cell anaemia and thalassemia by analysis of fetal cells in maternal blood. Nature Genetics, 14, 264. Dozy, A. M., Kan, Y. W., Forman, E. N., et al. (1979). Antenatal diagnosis of homozygous & alpha thalassemia. Journal of the American Medical Association, 241, 1610. Dumars, K. W., Boehm, G., Eckman, J. R., et al. (1996). Practical guide to the diagnosis of thalassemia. American Journal of Medical Genetics, 62, 29–37. Galanello, R., & Cao, A. (2008). Alpha-thalassemia. GeneReviews. Updated July 15, 2008. Available at: http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book¼gene&part¼a-thal Galanello, R., & Origa, R. (2010). Beta-thalassemia. Orphanet Journal of Rare Diseases, 6, 11–40. Giardini, C., & Lucarelli, G. (1999). Bone marrow transplantation for beta-thalassemia. Hematology/Oncology Clinics of North America, 13, 1059–1064. Harteveld, C. L., & Higgs, D. R. (2010). Alpha-thalassaemia. Orphanet Journal of Rare Diseases, 5, 13–65. Irwin, J. J. (2001). Anemia in children. American Family Physician, 64, 1379–1386. Kan, Y. W., Golbus, M. S., Klein, P., et al. (1975). Successful application of prenatal diagnosis in a pregnancy at risk for homozygous b-thalassemia. The New England Journal of Medicine, 292, 1096–1099. Kan, Y. W., Lee, K. Y., Furbetta, M., et al. (1980). Polymorphism of DNA sequence in the b-globin gene region: Application to prenatal diagnosis of b-thalassemia in Sardinia. The New England Journal of Medicine, 302, 185–188. Kan, Y. W., Schwartz, E., & Nathan, D. G. (1968). Globin chain synthesis in the alpha thalassemia syndrome. The Journal of Clinical Investigation, 45, 2515. Kelly, P., Kurtzberg, J., Vichinsky, E., et al. (1997). Umbilical cord blood stem cells: Application for the treatment of patients with hemoglobinopathies. Journal of Pediatrics, 130, 695–703. Locatelli, F., Rocha, V., Reed, W., et al. (2003). Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood, 101, 2137–2143.

Thalassemia Lucarelli, G., Giardini, C., & Baronciani, D. (1995). Bone marrow transplantation in thalassemia. Seminars in Hematology, 32, 297–303. Rucknagel, D. L. (1992). Microcytosis and the thalassemias. In H. Chen (Ed.), Ohio Department of Health the Resource Manual for hemoglobinopathies. An essential guide for health professionals (pp. 15–18). Columbus, OH: Advisory Council on Newborn Screening for Hemoglobinopathies. Sackey, K. (1999). Hemolytic anemia: Part 2. Pediatrics in Review, 20, 204–208. Schwartz, E., & Benz, E. J., Jr. (1991). The thalassemia syndromes. In R. Hoffman, E. J. Benz Jr., & S. J. Shattil (Eds.), Hematology. Basic principles and practice (pp. 368–392). New York: Churchill Livingstone. Segel, G. B., Hirsh, M. G., & Feig, S. A. (2002). Managing anemia in pediatric office practice: Part 1. Pediatrics in Review, 23, 75–84. Singer, S. T., Styles, L., Bojanowski, J., et al. (2000). Changing outcome of homozygous alpha-thalassemia: Cautious optimism. Journal of Pediatric Hematology/Oncology, 22, 539–542. Tongson, T., Wanapirak, C., Srisomboon, J., et al. (1998). Antenatal sonographic features of 100 alpha-thalassemia hydrops fetalis fetuses. Journal of Clinical Ultrasound, 24, 73–77. Vichinsky, E. (2010). Complexity of alpha thalassemia: Growing health problem with new approaches to screening, diagnosis, and therapy. Annals of the New York Academy of Sciences, 1202, 180–187. Vichinsky, E. P. (2009). Alpha thalassemia major-new mutations, intrauterine management, and outcomes. American Society of Hematology Education Program, 1, 35–41. Weisz, B., Rosenbaum, O., Chayen, B., et al. (2009). Outcome of severely anaemic fetuses treated by intrauterine transfusions. Archives of Disease in Childhood. Fetal and Neonatal Edition, 94, F201–F204. Yaish, H. M. (2010). Medscape reference. Updated April 30, 2010. Available at: http://emedicine.medscape.com/article/958850overview

Thalassemia

Fig. 1 Peripheral blood smear from a 58-year-old woman with microcytic anemia and frequent target cells (codocytes). Hemoglobin electrophoresis showed an AA pattern with an increased hemoglobin A2 (5.8% by HPLC) consistent with beta+- thalassemia trait

Fig. 2 Peripheral blood smear from a patient with alphathalassemia minor shows hypochromia, target cells (arrows), and anisopoikilocytosis (Wright-Giemsa stain, 1,000)

1995

Thanatophoric Dysplasia

Thanatophoric dysplasia was originally described by Maroteaux et al. in 1967. The term “thanatophoric” was coined to mean “death bearing” in Greek. Thanatophoric dysplasia is probably the most common lethal neonatal dwarfism with an estimated incidence of 0.2–0.5 per 10,000 births.

Synonyms and Related Disorders Thanatophoric dysplasia type I (thanatophoric dwarfism, lethal short-limbed platyspondylic dwarfism, San diego type, platyspondylic lethal skeletal dysplasia, San Diego type); Thanatophoric dysplasia type II (cloverleaf skull with thanatophoric dwarfism, thanatophoric dysplasia with kleeblattschaedel, thanatophoric dysplasia with straight femur and cloverleaf skull)

Genetics/Basic Defects 1. Genetic heterogeneity a. Sporadic in most cases b. A new autosomal dominant mutation c. Caused by mutations in the transmembrane domains of the fibroblast growth factor receptor 3 (FGFR3) 2. Having the most extreme micromelia and the most extensive craniofacial involvement compared to two other short limb skeletal dysplasias (achondroplasia and hypochondroplasia) which are also caused by mutations of FGFR3 3. Pathogenesis for the phenotypic features of thanatophoric dysplasia

a. Normal function of FGFR3: to regulate endochondral ossification by “putting the brakes on growth” b. “Gain-of-function” type of known mutations on FGFR3 i. Primarily affects the cranial base and nasal capsule (endochondral bones) ii. With secondary effect on membrane bones which articulates with endochondral bones 4. Two major forms (TD1, TD2) of thanatophoric dysplasia, postulated based on subtle differences in skeletal radiographs and the underlying genetic mutation a. TD1 i. Curved femora ii. Very flat vertebral bodies iii. Very few TD1 patients with cloverleaf skull iv. Molecular defect consisting of a stop codon mutation or missense mutation in the extracellular domain of the FGFR3 protein, resulting in a newly created cysteine residue (Arg248Cys, most common) b. TD2 i. Straight femora ii. Taller vertebral bodies iii. Most TD2 patients with cloverleaf skull (severe craniosynostosis) iv. Molecular defect consisting of a single nucleotide substitution resulting in replacement of lysine with glutamine at position 650 (Lys650Glu) in the tyrosine kinase 2 domain of the receptor 5. Activating mutations in the FGFR3 gene can cause following conditions: a. Achondroplasia

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_228, # Springer Science+Business Media, LLC 2012

1997

1998

b. Thanatophoric dysplasia type I and type II c. Hypochondroplasia d. Severe achondroplasia with developmental delay and acanthosis nigricans

Clinical Features 1. Unique and homogeneous clinical features observed in patients with TD1 2. General features a. Virtually lethal neonatally b. A few reports with survival up to 4–5 years of age with aggressive neonatal intervention i. Markedly limited growth potential ii. Markedly delayed cognitive development iii. Respiratory insufficiency iv. Neurologic abnormalities v. Long-term medical care and chronic ventilator dependence 3. Craniofacial features a. Head i. Disproportionally large (macrocephaly) ii. Frontal bossing iii. With or without cloverleaf (Kleeblattschdel) anomaly of the skull resulting from premature closure of cranial sutures b. Facial features i. Bulging eyes ii. Hypertelorism iii. Severely depressed or indented nasal bridge 4. Short neck 5. Chest a. Extremely narrow b. Constricted thoracic cage c. Reduced size of the thoracic cavity d. Short ribs e. Hypoplastic lungs 6. Protuberant abdomen 7. Limbs a. Extremely short b. Thickened skin c. Excessive skin folds d. Usually outstretched arms e. Externally rotated legs with abducted thighs f. Syndactyly 8. Early death in most children secondary to: a. Chest constriction and consequent respiratory insufficiency

Thanatophoric Dysplasia

b. Foramen magnum stenosis resulting in failure of respiratory control 9. A few children with longer survival (up to 9–10 years) a. Respiratory insufficiency i. Reduced chest circumference ii. Upper cervical cord compression resulting from a diminutive foramen magnum b. Markedly limited growth potential c. Markedly delayed cognitive development d. Seizures e. Hearing loss f. Additional CNS anomalies (Baker et al. 1997) i. Hydrocephalus ii. Polymicrogyria iii. Neuronal heterotopia iv. Megalencephaly v. Cerebral gyral disorganization vi. Hippocampal malformation vii. Temporal lobe malformations viii. Nuclear dysplasia ix. Abnormal axonal bundles x. Cerebellar hypoplasia in the small posterior fossa xi. Partial agenesis of the corpus callosum xii. Spinal stenosis xiii. Hyperreflexia xiv. Clonus g. Acanthosis nigricans, an associated rare skin disorder 10. Differential diagnosis (Schild et al. 1996) a. Achondroplasia i. Autosomal dominant disorder ii. Rhizomelic shortening of the bones, less prominent than thanatophoric dysplasia iii. Macrocrania iv. Heterozygous achondroplasia a) Compatible with normal life span b) Normal intelligence v. Homozygous achondroplasia with two affected parents b. Campomelic dysplasia i. Autosomal recessive disorder ii. Typical anterior bowing of the lower limbs iii. Hypoplastic fibula iv. Hypoplastic scapulae v. A sex reversal phenomenon (phenotypical female with male karyotype) c. Osteogenesis imperfecta type II and type III

Thanatophoric Dysplasia

i. ii. iii. iv.

Varying degree of bone demineralization Shortened long bones with multiple fractures Blue sclerae Polyhydramnios frequently associated with type II d. Hypophosphatasia i. Demineralization of bone tissue ii. Lack of calcification of the fetal skull iii. Mild to moderate shortening of limb bones iv. Difficult to differentiate from osteogenesis imperfecta if fractures are present e. Achondrogenesis i. Severe micromelia ii. Poor ossification of the vertebral bodies, cranium, pelvis, and sacrum iii. Narrow and shortened thorax iv. Frequent complications with fetal hydrops and hydramnios f. Short rib-polydactyly and other rare skeletal dysplasia syndromes

Diagnostic Investigations 1. Radiographic features a. Skull i. Relatively large calvarium ii. A small foramen magnum iii. Trilobed skull with a towering calvarium and bitemporal bulging in the cloverleaf skull type (type II) b. Ribs i. Very short ribs with cupped anterior ends ii. Short ribs (type II) c. Vertebrae i. Flat vertebral bodies (platyspondyly) ii. Increasing intervertebral disc space iii. “Inverted U–shaped or H-shaped” vertebral bodies iv. Narrow interpedunculate distance at the lumbar level v. Taller vertebral bodies (type II) d. Pelvis i. Short ii. Small sacrosciatic notches e. Tubular bones i. Extremely shortened long bones of the limbs ii. Rhizomelic shortening of the limbs

1999

iii. Flared metaphyses iv. “Telephone receiver”–like curved femora in the noncloverleaf type v. Relatively straight femora (type II) 2. Histologic features a. Generalized disruption of endochondral ossification i. Hallmark of the histologic findings ii. Physeal growth zone shows minimal proliferation and hypertrophy of chondrocytes with absence of column formation. iii. Lateral overgrowth of metaphyseal bone around the physis iv. Mesenchymal cells extending inward from the perichondrium as a narrow band at the periphery of the physeal zone (the so-called fibrous band) v. Increased vascularity of the resting cartilage b. Brain i. Neuronal migration abnormalities of the temporal lobe ii. Hydrocephalus iii. Partial agenesis of the corpus callosum iv. Upper cord compression v. Spinal stenosis 3. DNA mutation analysis of FGFR3 a. TD1 i. 742C ! T (Arg248Cys): most common ii. Tyr373Cys iii. Ser249Cys iv. Other missense mutations v. Stop codon mutations b. TD2: missense mutation of 1948A ! G (Lys650Glu) in TD2 c. Clinical testing i. Targeted mutation analysis ii. Sequence analysis of select regions of FGFR3 or of the entire FGFR3 coding region

Genetic Counseling 1. Recurrence risk a. Patient’s sib: about 2% b. Patient’s offspring: not surviving to reproduction age 2. Prenatal diagnosis a. Ultrasonography i. Hydramnios in most cases

2000

ii. Megacephaly with or without cloverleafshaped skull iii. Progressive hydrocephaly iv. Hypoplastic thorax disproportionately small in relation to the abdomen v. Small chest and lung measurement to predict severe pulmonary hypoplasia vi. Short ribs vii. Short limbs with curved “telephone handle–shaped” or straight femurs viii. Excessive skin giving fetus a “boxer’s face” appearance ix. Flattened vertebrae with increased intervertebral spaces, giving the vertebral bodies the form of an “H” b. Prenatal radiography for documenting characteristic skeletal anomalies c. DNA mutation analysis of FGFR3 in fetal cells from amniocentesis or CVS d. Prenatal and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified 3. Management a. Limited intervention i. Appropriate because of the inevitable lethal outcome ii. Aggressive neonatal management, at times, not even resulting in short-term survival b. Debatable issues about the level of intensity of medical care for unanticipated long-term survival i. Long-term medical care ii. Chronic ventilator support iii. Requiring extensive health maintenance measures iv. Anticipate frequent medical exacerbations requiring recurrent hospitalizations v. Possibility of lethal complication, an ever present concern vi. Special education programs for the longer survivals

References Baker, K. M., Olson, D. S., Harding, C. O., et al. (1997). Longterm survival in typical thanatophoric dysplasia type 1. American Journal of Medical Genetics, 70, 427–436. Bonaventure, J., Rousseau, F., Legeai-Mallet, L., et al. (1996a). Common mutations in the gene encoding fibroblast growth

Thanatophoric Dysplasia factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia. Acta Paediatrica. Supplement, 417, 33–38. Bonaventure, J., Rousseau, F., Legeai-Mallet, L., et al. (1996b). Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. American Journal of Medical Genetics, 63, 148–154. Chen, C. P., Chern, S. R., Chang, T. Y., et al. (2002). Second trimester molecular diagnosis of a stop codon FGFR3 mutation in a type I thanatophoric dysplasia fetus following abnormal ultrasound findings. Prenatal Diagnosis, 22, 736–737. Chen, C. P., Chern, S. R., Shih, J. C., et al. (2001). Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenatal Diagnosis, 21, 89–95. Cohen, M. M., Jr. (1998). Achondroplasia, hypochondroplasia and thanatophoric dysplasia: Clinically related skeletal dysplasias that are also related at the molecular level. International Journal of Oral and Maxillofacial Surgery, 27, 451–455. Coulter, C. L., Leech, R. W., Brumback, R. A., et al. (1991). Cerebral abnormalities in thanatophoric dysplasia. Child’s Nervous System, 7, 21–26. De Biasio, P., Prefumo, F., Baffico, M., et al. (2000). Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenatal Diagnosis, 20, 835–837. Defendi, G. L. (2009). Thanatophoric dysplasia. eMedicine from WebMD. Updated November 6, 2009. Available at: http://emedicine.medscape.com/article/949591-overview Horton, W. A., Hood, O. J., Machado, M. A., et al. (1988). Abnormal ossification in thanatophoric dysplasia. Bone, 9, 53–61. International Working Group on Constitutional Diseases of Bone. (1998). International nomenclature and classification of the osteochondrodysplasias (1997). American Journal of Medical Genetics, 79, 376–382. Isaacson, G., Blakemore, K. J., & Chervenak, F. A. (1983). Thanatophoric dysplasia with cloverleaf skull. American Journal of Diseases of Children, 137, 896–898. Karezeski, B., & Cutting, G. R. (2008). Thanatophoric dysplasia. GeneReviews. Updated September 30, 2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book¼ gene&part¼td Langer, L. O., Jr., Yang, S. S., Hall, J. G., et al. (1987). Thanatophoric dysplasia and cloverleaf skull. American Journal of Medical Genetics. Supplement, 3, 167–179. Lemyre, E., Azouz, E. M., Teebi, A. S., et al. (1999). Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: Review and update. Canadian Association of Radiologists Journal, 50, 185–197. MacDonald, I. M., Hunter, A. G., MacLeod, P. M., et al. (1989). Growth and development in thanatophoric dysplasia. American Journal of Medical Genetics, 33, 508–512. Machado, L. E., & Bonilla-Musoles, F. (2001). Osborne Nat Genet: Thanatophoric dysplasia. Ultrasound in Obstetrics & Gynecology, 18, 85–86. Maroteaux, P., Lamy, M., & Robert, J.-M. (1967). Le nanisme thanatophore. Presse Me´dicale, 49, 2519–2524. Martinez-Frias, M. L., Ramos-Arroyo, M. A., & Salvador, J. (1988). Thanatophoric dysplasia: An autosomal dominant condition? American Journal of Medical Genetics, 31, 815–820.

Thanatophoric Dysplasia Nerlich, A. G., Freisinger, P., & Bonaventure, J. (1996). Radiological and histological variants of thanatophoric dysplasia are associated with common mutations in FGFR-3. American Journal of Medical Genetics, 63, 155–160. Norman, A. M., Rimmer, S., Landy, S., et al. (1992). Thanatophoric dysplasia of the straight-bone type (type 2). Clinical Dysmorphology, 1, 115–120. Orioli, I. M., Castilla, E. E., & Barbosa Neto, J. G. (1986). The birth prevalence rates for the skeletal dysplasias. Journal of Medical Genetics, 23, 328–332. Partington, M. W., Gonzales-Crussi, F., Khakee, S. G., et al. (1971). Cloverleaf skull and thanatophoric dwarfism. Report of four cases, two in the same sibship. Archives of Disease in Childhood, 46, 656–664. Passos-Bueno, M. R., Wilcox, W. R., Jabs, E. W., et al. (1999). Clinical spectrum of fibroblast growth factor receptor mutations. Human Mutation, 14, 115–125. Rousseau, F., el Ghouzzi, V., Delezoide, A. L., et al. (1996). Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type 1 (TD1). Human Molecular Genetics, 5, 59–512. Rousseau, F., Saugier, P., Le Merrer, M., et al. (1995). Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nature Genetics, 10, 11–12. Schild, R. L., Hunt, G. H., Moore, J., et al. (1996). Antenatal sonographic diagnosis of thanatophoric dysplasia: A report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound in Obstetrics & Gynecology, 8, 62–67. Spranger, J., & Maroteaux, P. (1990). The lethal osteochondrodysplasias. Advances in Human Genetics, 19, 1–103.

2001 Stensvold, K., Ek, J., & Hovland, A. R. (1986). An infant with thanatophoric dysplasia surviving 169 days. Clinical Genetics, 29, 157–159. Tavormina, P. L., Shiang, R., Thompson, L. M., et al. (1995). Thanatophoric dysplasia (types 1 and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genetics, 9, 321–328. Tonoki, H. (1987). A boy with thanatophoric dysplasia surviving 212 days. Clinical Genetics, 32, 415–416. Vajo, Z., Francomano, C. A., & Wilkin, D. J. (2000). The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocrine Reviews, 21, 23–29. Weber, M., Johannisson, T., Thomsen, M., et al. (1998). Thanatophoric dysplasia type I: New radiologic, morphologic, and histologic aspects toward the exact definition of the disorder. Journal of Pediatric Orthopaedics. Part B, 7, 1–9. Wilcox, W. R., Tavormina, P. L., Krakow, D., et al. (1998). Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. American Journal of Medical Genetics, 78, 274–281. Wongmongkolrit, T., Bush, M., & Roessmann, U. (1983). Neuropathological findings in thanatophoric dysplasia. Archives of Pathology & Laboratory Medicine, 107, 132–135. Yang, S. S., Heidelberger, K. P., Brough, A. J., et al. (1976). Lethal short-limbed chondrodysplasia in early infancy. Perspectives in Pediatric Pathology, 3, 1–40.

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Fig. 1 (a–c) Front views of three infants showing frontal bossing, flat facies, short neck, micromelia, and small chest

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Fig. 2 (a–c) AP radiographic views of three infants with typical findings of TD1 showing profound platyspondyly, decreased thoracic volume, characteristic pelvic configuration, micromelia, and so-called “telephone receiver” femoral bowing

Thanatophoric Dysplasia Fig. 3 (a, b) Lateral radiographic views of the spines of two infants with typical TD1 showing extreme platyspondyly and short ribs

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Fig. 4 Gross appearance of a femur resembling a “telephone receiver”

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Thanatophoric Dysplasia

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Fig. 6 Thanatophoric dysplasia in identical twin fetuses. The pregnancy was terminated following ultrasonographic diagnosis at 22 weeks’ gestation. The placenta was diamniotic monochorionic, consistent with monozygotic pregnancy

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Fig. 7 Thanatophoric dysplasia with cloverleaf skull in a neonate. The head is large and trilobed. The narrow chest and rhizomelic shortening of limbs are similar to those of classic thanatophoric dysplasia. Radiograph revealed platyspondyly and small ilium that are similar to those of classic thanatophoric dysplasia (not shown). However, the femur is straight and not as curved as seen in the classic type

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Fig. 8 Photomicrograph of the cartilage-bone junction, cloverleaf skull type of thanatophoric dysplasia. The physeal growth zone is markedly retarded and disorganized. Similar changes are seen in the classic type thanatophoric dysplasia. A partially ossified cartilage canal is present at the center of physis. It is more prominent in size and number in cloverleaf type than in classic type

Thanatophoric Dysplasia

Fig. 9 A neonate with short limb dwarfism, characterized by flat face, short neck, short chest, and micromelia. A single sequence mutation (Nt742C > T) was identified in the FGFR3 gene. This causes the substitution of arginine for cysteine at codon 248 (C248R). This mutation has been previously reported in thanatophoric dysplasia type I

Thrombocytopenia-Absent Radius Syndrome

Thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii and congenital thrombocytopenia.

Synonyms and Related Disorders TAR syndrome

Genetics/Basic Defects 1. Genetic inheritance: unknown but autosomal recessive inheritance was suspected based on the following observations a. Families with at least two affected children born to unaffected parents b. Rare instances of association with consanguinity 2. Associated with an interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization (Klopocki et al. 2007) a. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. b. The phenotype develops only in the presence of an additional as-yet-unknown modifier. 3. Etiology of thrombocytopenia: unknown but is considered to be the result of a decreased production of platelets from the bone marrow

Clinical Features 1. Thrombocytopenia (100%) a. May be transient b. Symptomatic in over 90% of cases within the first 4 months of life i. Purpura ii. Petechiae iii. Epistaxis iv. Gastrointestinal bleeding a) Hematemesis b) Melena v. Hemoptysis vi. Hematuria vii. Intracerebral bleeding c. More severe thrombocytopenia can be precipitated by stress, infection, gastrointestinal disturbances, or surgery (Fayen and Harris 1980). d. Platelet count tends to rise as the child gets older and may approach normal levels in adulthood (spontaneous improvement of platelet counts after 1 year). 2. Upper extremity anomalies (100%) (Hall 1987) a. Bilateral absence of the radius (100%): the most striking skeletal manifestation b. Hand anomalies i. Presence of the thumbs (100%) a) An important clinical feature distinguishing TAR syndrome from other disorders featuring radial aplasia, which are usually associated with absent thumbs b) Relatively functional thumbs

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c) Thumbs often adducted d) Thumbs often hypoplastic ii. Radially deviated iii. Limited extension of the fingers iv. Hypoplasia of the carpal and phalangeal bones c. Associated ulnar anomalies i. Usually short ii. Usually malformed iii. Absent ulna a) Absent bilaterally in about 20% of cases b) Absent unilaterally in about 10% of cases d. Associated humeral anomalies i. Often abnormal in about 50% of cases ii. Absent humeri in about 5–10% of cases (rare phocomelia) e. Associated shoulder and arm anomalies i. One arm shorter than the other in about 15% of cases ii. Hypoplasia of muscles and soft tissue in the arm and shoulder iii. Abnormal shoulder joint secondary to abnormal humeral head 3. Lower limb anomalies (47%) a. Correlation exists between the severity of skeletal changes in the lower limbs and the severity of abnormalities of the upper limbs. b. Variable involvement but usually milder than the upper limbs i. Dislocation of the patella and/or of the hips ii. Knee involvement a) Dysplasia: rare severe knee dysplasia due to agenesis of cruciate ligaments and menisci b) Ankylosis c) Subluxation iii. Hip dislocation iv. Coxa valga v. Absent tibiofibular joint vi. Femoral or tibial torsion vii. Lower limb phocomelia viii. Valgus and varus foot deformities ix. Abnormal toe placement x. Severe cases with lower limb phocomelia 4. Cow’s milk intolerance (62%) a. Presentation symptoms i. Persistent diarrhea ii. Failure to thrive

Thrombocytopenia-Absent Radius Syndrome

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b. Thrombocytopenia episodes i. Precipitated by introduction of cow’s milk ii. Relieved by its exclusion from the diet Urogenital anomalies (23%) a. Horseshoe kidney b. Absent uterus Cardiac anomalies (22–33%) a. Tetralogy of Fallot b. Atrial septal defect c. Ventricular septal defect Other associated congenital anomalies a. Facial capillary hemangiomata in the glabella region b. Micrognathia c. Cleft palate d. Intracranial vascular malformation e. Sensorineural hearing loss f. Epilepsy g. Other skeletal anomalies i. Scoliosis ii. Cervical rib iii. Fused cervical spine iv. Short stature h. Neural tube defect Prognosis a. Variable clinical course among patients b. Survival related to the severity and duration of thrombocytopenia c. Good prognosis after surviving the first year of life d. Early diagnosis and treatment with platelet therapy minimize mortality risks. e. Mental retardation secondary to intracranial bleed (7%) f. Good hand and upper extremity functions, especially if bilateral radial aplasia is the only skeletal abnormality Differential diagnosis (Hedburg and Lipton 1988 Greenhalgh et al. 2002) a. Holt-Oram syndrome i. An autosomal dominant condition caused by mutations in the TBX5 gene ii. Often with a family history of heart and limb defects iii. Absence of the thumb associated with radial aplasia iv. Absence of thrombocytopenia b. Roberts syndrome i. An autosomal recessive trait ii. Pre- and postnatal growth retardation

Thrombocytopenia-Absent Radius Syndrome

iii. Facial clefting iv. Genitourinary abnormalities v. Limb defects involving upper or lower limbs or both vi. Characteristic chromosome abnormality in the majority (79%) of cases a) Premature centromeric separation (PCS) b) “Puffing” of the chromosomes caused by repulsion of the heterochromatic regions near the centromeres of chromosomes 1, 9, and 16 with splaying of the short arms of the acrocentric chromosomes and of distal Yp.33 c) Evidence of abnormal mitosis vii. Postulated that TAR syndrome and Roberts syndrome might be part of the same condition, with TAR syndrome being the milder and Roberts the severer variant c. Fanconi anemia i. An autosomal recessive disorder ii. Bone marrow failure iii. Skeletal defects iv. Cutaneous pigmentation v. Microcephaly vi. Short stature vii. May present with thrombocytopenia viii. Upper limb abnormalities also involve the radial ray. ix. Hypoplastic thumbs may be accompanied by radial hypoplasia but absence of the radius is associated with absence of the thumbs. x. Spontaneous chromosome breakage, a consistent feature of Fanconi anemia and is a reliable diagnostic test d. Aase syndrome i. Radial hypoplasia ii. Triphalangeal thumbs iii. Hypoplastic anemia, similar to BlackfanDiamond syndrome iv. Thrombocytopenia not a feature e. Thalidomide embryopathy i. May present with radial anomalies of the upper limb ii. Malformations of the lower limbs showing a less consistent pattern iii. Diagnosed based on: a) Phenotype b) History of exposure to thalidomide during pregnancy

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c) Increasing use of thalidomide as a therapeutic agent for the treatment of conditions such as Bec¸het disease, graft versus host disease, multiple myeloma, and Kaposi sarcoma f. Rapadilino syndrome i. Absent thumbs and radial aplasia/hypoplasia ii. Patellar aplasia/hypoplasia iii. Cleft palate g. Other syndromes with limb reduction abnormalities predominantly involving the upper extremities (Donnenfeld et al. 1990) i. Adams-Oliver syndrome a) Transverse limb defects b) Aplasia cutis congenita c) Growth deficiency ii. Aglossia-adactylia a) Absence/hypoplasia of digits b) Absence/hypoplasia of the tongue iii. Amniotic band sequence a) Limb constriction or amputation b) Asymmetric facial clefts c) Cranial defects d) Compression deformities iv. CHILD syndrome a) Unilateral hypomelia b) Ichthyosiform erythroderma c) Cardiac septal defect v. Cornelia de Lange syndrome a) Micromelia b) Growth deficiency c) Facial dysmorphism vi. Femur-fibula-ulnar syndrome a) Femoral/fibular defects associated with malformations of the arms b) Amelia c) Peromelia at the lower end of the humerus d) Humeroradial synostosis e) Defects of the ulna and ulnar rays vii. Poland anomaly a) Unilateral defect of pectoralis major muscle b) Ipsilateral limb abnormalities viii. VATER association (vertebral, anal, tracheoesophageal, renal, and radial anomalies) ix. Weyers ulnar ray/oligodactyly syndrome a) Deficient ulnar and fibular rays b) Oligodactyly c) Hydronephrosis

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h. Megakaryocytic aplasia i. Amegakaryocytic thrombocytopenia ii. Congenital hypoplastic thrombocytopenia with microcephaly iii. Thrombocytopenia associated with trisomy 13 and trisomy 18

Diagnostic Investigations 1. Hematological studies a. Blood platelet counts: thrombocytopenia b. Anemia secondary to bleeding c. Eosinophilia d. Leukemoid reaction (Hall 1987) i. Reported in about 60–70% of patients during the first year of life ii. White blood counts >35,000 per mm3 with a shift to the left, particularly with the stress and infections iii. Usually associated with worse thrombocytopenia and often with hepatosplenomegaly e. Bone marrow aspirates i. Normal or hypercellular bone marrow ii. Hypomegakaryocytic thrombocytopenia (99%): clinically available 5. Combination of the proton nuclear magnetic resonance (NMR) spectroscopy to assess activity of the mutant enzyme with gene sequence and expression technology provides a powerful means of determining genotype-phenotype relationships in trimethylaminuria (Murphy 2000).

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Genetic Counseling e. 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier 2. Prenatal diagnosis: possible by demonstrating the previously characterized mutation in the fetal DNA obtained by amniocentesis or CVS 3. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified 4. Management (Rehman 1999; Mitchell 2001; Chalmers et al. 2006) a. Restriction of dietary sources of trimethylamine: the main therapeutic approach (Chen and Aiello 1993; Phillips and Shephard 2008) i. Restriction of trimethylamine (milk obtained from wheat-fed cows)

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ii. Restriction of its precursors including choline-rich food a) Egg yolk b) Liver c) Kidney d) Peas e) Beans f) Peanuts g) Soya products h) Brassicas (include cabbage, broccoli, and turnip) i) Legumes j) Fish iii. Trimethylamine N-oxide source a) Some saltwater fish (cod, skate) b) Cephalopods (include cuttlefish, squid, and octopus) c) Crustaceans (include crabs, lobsters, and shrimp) iv. Dietary restriction appears to be successful in the management of the majority of patients. v. Appears to be most effective in mild to moderate forms of fish odor syndrome arising from particular mutations or haplotypes Suitable diet include: i. Dark green leafy vegetables ii. Fortified bread and cereals iii. Orange juice Freshwater fish may be eaten freely. Avoid exacerbation factors such as pyrexia and stress. Vitamin supplementation with riboflavin, a precursor of the FAD cofactor for flavin monooxygenase function, in an attempt to maximize any residual activity Drug treatment: Occasionally a short course of metronidazole, neomycin, and lactulose may suppress production of TMA by reducing the activity of gut microflora in some patients (Fraser-Andrews 2003). Copper-chlorophyllin tablets to moderate gut flora activity and complex TMA Use of “malodor suppressants” in hygiene products and soaps and body lotions with a low pH (3.5–6.5) to disguise the offensive smell of trimethylamine Counseling of the social/behavioral problems Gene therapy and enzyme induction with drugs provide hope for the future.

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References Akerman, B. R. (1999a). Two novel mutations of the FMO3 gene in a proband with Trimethylaminuria. Human Mutation, 13, 376–379. Akerman, B. R. (1999b). Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort. Molecular Genetics and Metabolism, 68, 24–31. Al-Waiz, M., Ayesh, R., Mitchell, S. C., et al. (1987a). Trimethylaminuria (fish-odour syndrome): An inborn error of oxidative metabolism. Lancet, 1, 634–635. Al-Waiz, M., Ayesh, R., Mitchell, S. C., et al. (1987b). A genetic polymorphism of the N-oxidation of trimethylamine in humans. Clinical Pharmacology and Therapeutics, 42, 588–594. Al-Waiz, M., Ayesh, R., Mitchell, S. C., et al. (1988). Trimethylaminuria (“fish-odour syndrome”): A study of an affected family. Clinical Science, 74, 231–236. Al-Waiz, M., Ayesh, R., Mitchell, S. C., et al. (1989). Trimethylaminuria: The detection of carriers using a trimethylamine load test. Journal of Inherited Metabolic Disease, 12, 80–85. Ayesh, R., Mitchell, S. C., Zhang, A., et al. (1993). The fish odour syndrome: Biochemical, familial, and clinical aspects. British Medical Journal, 307, 655–657. Basarab, T. (1999). Sequence variations in the flavin-containing mono-oxygenase 3 gene (FMO3) in fish odour syndrome. British Journal of Dermatology, 140, 164–167. Blumenthal, I., Lealman, G. T., & Franklyn, P. P. (1980). Fracture of the femur, fish odour, and copper deficiency in a preterm infant. Archives of Disease in Childhood, 55, 229–231. Cashman, J. R. (2000). Population-specific polymorphisms of the human FMO3 gene: Significance for detoxication. Drug Metabolism and Disposition, 28, 169–173. Cashman, J. R., Camp, K., Fakharzadeh, S. S., et al. (2003). Biochemical and clinical aspects of the human flavincontaining monooxygenase form 3 (FMO3) related to trimethylaminuria. Current Drug Metabolism, 4, 151–170. Chalmers, R. A., Bain, M. D., Michelakakis, H., et al. (2006). Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. Journal of Inherited Metabolic Disease, 29, 162–172. Chen, H., & Aiello, F. (1993). Trimethylaminuria in a girl with Prader-Willi syndrome and del(15)(q11q13). American Journal of Medical Genetics, 45, 335–339. Dolphin, C. T., Janmohamed, A., Smith, R. L., et al. (1997). Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nature Genetics, 17, 491–494. Forrest, S. M. (2001). A novel deletion in the flavin-containing monooxygenase gene (FMO3) in a Greek patient with trimethylaminuria. Pharmacogenetics, 11, 169–174. Fraser-Andrews, E. A., Manning, N. J., Ashton, G. H., et al. (2003). Fish odour syndrome with features of both primary and secondary trimethylaminuria. Clinical Experimental Dermatology, 28(2), 203–205.

Trimethylaminuria Hollinger, M. A., & Sheikholislam, B. (1991). Effects of dietary alteration on Trimethylaminuria as measured by mass spectrometry. The Journal of International Medical Research, 19, 63–66. Kashyap, A. S., & Kashyap, S. (2000). Fish odour syndrome. Postgraduate Medical Journal, 76, 318–319. Lambert, D. M. (2001). In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Molecular Genetics and Metabolism, 73, 224–229. Lunden, A., Gustafsson, V., Imhof, M., et al. (2002). High trimethylamine concentration in milk from cows on standard diets is expressed as fish off-flavour. Journal of Dairy Research, 69(3), 383–390. Marks, R., Greaves, M. W., Danks, D., et al. (1976). Trimethylaminuria or fish odour syndrome in a child. British Journal of Dermatology, 95, 11–12. Marks, R., Greaves, M. W., Prottey, C., et al. (1977). Trimethylaminuria: The use of choline as an aid to diagnosis. British Journal of Dermatology, 96, 399–402. Mayatepek, E., & Kohlmuller, D. (1998). Transient trimethylaminuria in childhood. Acta Paediatrica, 87, 1205–1207. Mills, G. A. (1999). Quantitative determination of trimethylamine in urine by solid-phase microextraction and gas chromatography-mass spectrometry. Journal of Chromatography. B, Biomedical Sciences and Applications, 723, 281–285. Mitchell, S. C. (1996). The fish-odor syndrome. Perspectives in Biology and Medicine, 39, 514–526. Mitchell, S. C. (1999). Trimethylaminuria: Susceptibility of heterozygotes. Lancet, 354, 2164–2165. Mitchell, S. C. (2001). Trimethylaminuria: The fish malodor syndrome. Drug Metabolism and Disposition, 29, 517–521. Mitchell, S. C., & Smith, R. L. (2001). Trimethylaminuria: The fish malodor syndrome. Drug Metabolism and Disposition, 29, 517–521. Murphy, H. C. (2000). A novel mutation in the flavin-containing monooxygenase 3 gene, FMO3, that causes fish-odour syndrome: Activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetics, 10, 439–451. Pellicciari, A., Posaar, A., Cremonini, M. A., et al. (2010). Epilepsy and trimethylaminuria: A new case report and literature review. Brain & Development, 33(7), 593–596. Phillips, I. R., & Shephard, E. A. (2008). Trimethylaminuria. Updated March 18, 2008. Available at: http://www.ncbi.nlm. nih.gov/bookshelf/br.fcgi?book¼gene&part¼trimethylaminuria Rehman, H. U. (1999). Fish odor syndrome. Postgraduate Medical Journal, 75, 451–452. Ruocco, V., Florio, M., Filioli, F. G., et al. (1989). An unusual case of Trimethylaminuria. British Journal of Dermatology, 120, 459–461. Shelley, E. D., & Shelley, W. B. (1984). The fish odor syndrome. Trimethylaminuria. Journal of the American Medical Association, 251, 253–255. Tjoa, S., & Fennessey, P. (1991). The identification of trimethylamine excess in man: Quantitative analysis and biochemical origins. Analytical Biochemistry, 197, 77–82. Zschocke, J. (1999). Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet, 354, 834–835.

Trimethylaminuria

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Fig. 1 (a–d) A 12-year-old girl with trimethylaminuria showing multiple sores on the hands and legs. At age 4, she developed unpleasant fish odor and constant scratching of her skin. Trimethylaminuria was diagnosed based on markedly increased urinary TMA by gas chromatography after loading with choline. The patient started with a baseline level of 0.28 mg TMA mg/mg creatine that is 4 times of control. After 8, 16, and 24 h of loading

with choline, the values went up to 2.8 mg (41), 3.99 mg (57), and 9.93 mg (95), respectively. In addition, the diagnosis of Prader–Willi syndrome was made at age 9 because of relative obesity, hypotonia, delayed psychomotor development, almond-shaped eyes, small hands and feet, and presence of chromosome abnormality of del(15)(q11q13)

Triploidy

Triploidy is defined as the presence of three sets of haploid (69) chromosomes. Triploid fetuses occur in about 1% of recognized pregnancies, 1 in 100,000 live borns, and constitute about 15% of all fetuses with chromosome abnormalities. There is a slight excess of males (M1.5:F1). Most triploid fetuses often result in spontaneous abortions between 7 and 17 weeks of gestation. However, rare instances of a live triploid infant have been reported (Allen and Pritchard 2000).

Synonyms and Related Disorders Partial hydatidiform mole of the placenta; Triploid fetus (69,XXY, 69,XXX, diploid/triploid mosaicism)

Genetics/Basic Defects 1. Origin of triploidy (Allen and Pritchard 2000; Benn et al. 2001) a. Diandric origin of the triploid fetuses (type I) i. Mechanisms of paternal origin of the supernummary haploid set a) Dispermy: fertilization of a haploid egg by two haploid sperms (dispermy) accounting for 66% (most common mechanism leading to triploidy) b) Faulty meiotic division in the male: fertilization of a normal ovum by a diploid sperm (diandry) (about 24%) ii. Characteristics of diandric fetuses a) Relatively normal fetal growth b) Slight macrocephaly c) Marked syncytiotrophoblastic hyperplasia

d) Hydatidiform changes of the placental villi (partial mole) (large cystic placenta) b. Digynic origin of triploid fetuses (type II) i. Mechanisms of maternal origin of the supernummary haploid set a) Mitotic errors in female germ cell precursors: fertilization of a diploid ovum by a normal sperm (digyny) (about 10%) b) Errors in maternal meiosis: an error at meiosis I or II or incorporation of the second polar body postulated ii. Characteristics of digynic fetuses a) Generally marked fetal (asymmetric) growth retardation b) Relative macrocephaly c) Small, non-cystic placenta d) Maternally derived triploidy was often found in those fetuses that survived until late pregnancy. 2. Diploidy/triploidy mosaicism a. Mechanisms (Phelan et al. 2001) i. Postzygotic maldivision of a triploid or diploid zygote ii. Incorporation of the second polar body into a daughter nucleus of the developing embryo iii. Fertilization of a diploid ovum with incorporation of the second diploid polar body iv. Fertilization of the first polar body and ovum by individual spermatozoa with suppression of one second polar body v. Dispermy or diploid sperm fertilization with incorporation of an independently fertilized second polar body

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vi. Chimera formation by union of diploid and triploid embryos vii. Vanishing twin and chimerism b. Characteristics of diploid/triploid fetuses: rarer and less severe phenotype than true triploidy 3. Triploidy and in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) (Dayal et al. 2009) a. Diandric triploidy is observed with spontaneous as well as conventional IVF and is assumed to be the most common form of triploidy (Jun et al. 2006). b. Intracytoplasmic sperm injection, by its virtue of injecting a single sperm into a single oocyte, negates the potential for dispermic triploidy. c. Digynic triploidy occurs secondary to failed meiosis II expulsion of the second polar body and subsequent fertilization of a diploid oocyte. Cytogenetic evidence of three pronuclei post-ICSI zygotes that result from failed extrusion of the second polar body (Tsuchiya et al. 2002). d. Mechanistically, this may occur with a damaged metaphase plate or oocyte cytoskeleton (Kimura and Yanagimachi 1995), after abnormal spindle formation or increased female age (Spandorfer et al. 1998; Tsuchiya et al. 2002). The latter etiologies may represent an occult oocyte factor.

Triploidy

3.

4.

Clinical Features 1. Prenatal history a. IUGR i. Asymmetrical (digynic) ii. Symmetrical (diandric) b. Prematurity c. Hydrops d. Polyhydramnios e. Oligohydramnios f. Partial hydatidiform mole (placenta) 2. Craniofacial features a. Dysplastic calvarium b. Microcephaly c. Large posterior fontanelle d. Ocular hypertelorism or hypotelorism e. Epicanthal folds f. Exomphalos

5.

6.

g. Microphthalmia h. Iris and choroid colobomas i. Midfacial hypoplasia j. Arhinia k. Small upturned nose l. Choanal atresia m. Single nostril (in holoprosencephaly) n. Micrognathia o. Cleft lip/palate p. Low-set ears q. Short neck r. Thick nuchal fold s. Cystic hygroma CNS a. Hypotonia b. Arnold-Chiari malformation c. Posterior fossa cyst (Dandy-Walker malformation) d. Holoprosencephaly e. Hydranencephaly f. Hydrocephalus (20%) g. Absent corpus callosum (15%) h. Absent gyri of the brain i. Hypoplastic cerebellum j. Absent first cranial nerve k. Encephalocele l. Lumbosacral meningomyelocele (20%) Gastrointestinal malformations a. Omphalocele b. Ventral wall defects c. Incomplete rotation of colon d. Agenesis of gallbladder e. Meckel diverticulum f. Duodenal atresia g. Malfixation of cecum h. Inguinal hernia Endocrine abnormalities a. Adrenal hypoplasia b. Thyroid hypoplasia c. Lingual thyroid d. Thymic hypoplasia e. Leydig cell hyperplasia f. Gonadal dysgenesis Genitourinary abnormalities a. 69,XXY triploid fetus i. Varying degree of ambiguous genitalia (40%) ii. Hypospadias (40%) iii. Cryptorchidism (85%) iv. Micropenis (75%)

Triploidy

7.

8.

9.

10.

11.

v. Scrotal abnormalities (60%) including bifidity, scrotal hypoplasia, or agenesis vi. Leydig cell hyperplasia (20%) b. 69,XXX triploid fetus i. Gonadal dysgenesis ii. Renal abnormalities a) Multicystic kidneys b) Hydronephrosis c) Glomerulosclerosis Gastrointestinal abnormalities a. Omphalocele b. Diaphragmatic hernia c. Gastroschisis d. Malrotation e. Gallbladder hypoplasia f. Pancreas hypoplasia Cardiovascular anomalies a. VSD b. ASD c. PDA d. PA e. Tetralogy of Fallot f. Truncus arteriosus g. Aberrant right subclavian artery h. Cardiomegaly Respiratory tract abnormalities a. Small chest b. Pulmonary hypoplasia c. Absent lung lobation d. Congenital cystic adenomatoid malformation of the lung Prognosis a. Majority die early in gestation. b. Very few surviving into the third trimester c. The fetuses rarely survive to delivery. i. Profoundly malformed ii. Growth-restricted iii. Survival measured in hours to days d. Fetuses with extra maternal haploid set of chromosomes appear to survive longer in utero than those with extra paternal haploid set of chromosomes (Allen and Pritchard 2000). e. Some cases of diploid/triploid mixoploidy survive after the neonatal period, which is exceptional. Diploid/triploid mosaicism (Van De Laar et al. 2002) a. A well-known malformation syndrome b. Common features i. Mental retardation ii. Growth retardation

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iii. Body and/or facial asymmetry iv. Hypotonia v. Truncal obesity vi. Prominent forehead vii. Depressed nasal bridge viii. Micrognathia ix. Malformed low-set ears x. Syndactyly xi. Clinodactyly xii. Transverse palmar creases xiii. A small phallus xiv. Cryptorchidism xv. Precocious puberty c. Additional features i. Sandal gap ii. Short halluces iii. Seizures iv. Respiratory distress v. Microstomia vi. Irregular skin vii. Feeding difficulties viii. Muscular atrophy of the limbs d. Rarer and less severe than true triploidy in which infants can survive beyond neonatal period till over 20 years e. Presence of a normal diploid cell line and a second triploid cell line in varying degrees and with varying tissue distribution

Diagnostic Investigations 1. Karyotype of fetus and newborn a. 69,XXX (one third of cases) b. 69,XXY (Two thirds of cases) c. Diploid/triploid mosaicism i. Less severe phenotype ii. More compatible with life iii. Harder to diagnose clinically iv. Peripheral lymphocyte cultures showing a normal karyotype only v. Need fibroblast culture to show the cell line with triploid complement d. Molecular determination of the origin of the extra haploid set of chromosomes i. Fluorescent polymerase chain reaction (F-PCR) analysis of short tandem repeats (STRs) located on chromosomes such as 21, 18, and 13 (Ba´n et al. 2002)

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ii. Assessment of numerous polymorphic DNA markers 2. Radiography a. Poor ossification of calvarium b. Craniolacunae c. Chondrodysplasia punctata-like calcification d. Vertebral fusions e. Harlequin orbits f. Gracile ribs g. Upswept clavicles h. Diaphyseal overtubulation of long bones i. Vertical ilia j. Proximal radioulnar synostosis k. Asymmetry of occipitoparietal calvaria (50%) 3. CT and MRI of the brain a. Cortical hypoplasia b. Agenesis of corpus callosum (15%) c. Hypoplasia of basal ganglia/occipital lobe d. Dandy-Walker anomaly e. Arnold-Chiari malformation 4. Histopathology of the placenta a. Partial hydatidiform mole change of villi on gross and microscopic examination b. The partial mole is caused by a triploidy (Devriendt 2005). c. The villi with molar change show hydropic swelling of the stroma, and trophoblastic proliferation (hyperplasia) is also present in scattered areas. d. Irregular cystic cavitation may be seen in larger hydropic villi.

Genetic Counseling 1. Recurrence risk a. Patient’s sib: The true recurrence risk for cytogenetic abnormalities in subsequent offspring is uncertain but may be slightly increased and higher than expected (Graham et al. 1989). b. Patient’s offspring: a lethal condition not surviving to reproduce 2. Prenatal diagnosis a. First-trimester markers screening (De Graaf et al. 1999) i. Low serum marker pregnancy-associated plasma protein A (PAPP-A) ii. Low serum marker free b-chain of chorionic gonadotrophin (free b-hCG)

Triploidy

b. Second trimester maternal serum screening (Benn et al. 2001) i. High maternal serum hCG associated with triploidy a) Nearly always indicating placenta with partial mole (93%) b) A high frequency of open neural tube defects or ventral wall defects (29%) c) With either XXX or XXY karyotype ii. Low hCG associated with triploidy a) Infrequently associated with a molar placenta (9%) b) Not appear to be associated with open neural tube defects or ventral wall defects c) An excess of XXX over XXY karyotypes iii. Large placentas with molar changes (diandry) generally associated with increased maternal serum AFP (MSAFP) and high hCG levels iv. Those with digyny and small monocystic placentas generally associated with normal MSAFP and low hCG c. Isolation of nucleated red blood cells from the maternal peripheral circulation at the first trimester (12 weeks gestation): FISH analysis using X and Y and other chromosome-specific probes (De Graaf et al. 1999) d. Amniocentesis/CVS i. Triploidy ii. Diploidy/triploidy mosaicism e. Ultrasonography of structural anomalies compatible with triploidy i. Severe, early-onset asymmetrical growth restriction in the late first and early second trimester (the head size remains almost normal whereas the remainder of the fetal body and skeleton is severely growthrestricted) ii. Oligohydramnios, asymmetric growth restriction, and a small placenta when the third set of chromosomes is maternal iii. Large, hydropic-appearing placenta consistent with partial moles (60–80%) when the third set of chromosomes is paternal iv. Most common sonographic abnormalities a) Large thickened placenta containing multiple sonolucent areas b) Characteristic sharply defined, large and small cystic spaces within the placenta

Triploidy

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c) d) e) f) g) h) i) j) k) l) m) n) o)

Hydrops Ventriculomegaly Dandy-Walker malformation Holoprosencephaly Agenesis of the corpus callosum Micrognathia Echogenic bowel Omphalocele Renal malformations Thickened nuchal folds Neural tube defects Club feet Syndactyly of the third and fourth fingers f. Preimplantation genetic diagnosis in conjunction with in vitro fertilization by a single sperm injection: a viable approach when there are clinical or genetic indications of repeated dispermy, unreduced (diploid) spermatozoa, or unreduced (diploid) oocytes (Pergament et al. 2000) 3. Management a. No treatment available for true triploidy, a lethal condition. b. Supportive therapy for diploid/triploid mosaicism who may survive beyond neonatal period.

References Al Saadi, A., Juliar, J. F., Harm, J., et al. (1976). Triploidy syndrome: A report of two live–born (69, XXY) and one still–born (69, XXX) infant. Clinical Genetics, 9, 43–50. Allen, R. W., & Pritchard, J. K. (2000). DNA analysis in a paternity case involving a triploid fetus. Transfusion, 40, 240–244. Ba´n, Z., Nagy, B., Papp, C., et al. (2002). Rapid diagnosis of triploidy of maternal origin using fluorescent PCR and DNA fragment analysis in the third trimester of pregnancy. Prenatal Diagnosis, 22, 984–987. Baumer, A., Balmer, D., Binkert, F., et al. (2000). Parental origin and mechanisms of formation of triploidy: A study of 25 cases. European Journal of Human Genetics, 8, 911–917. Bendon, R. W., Siddiqi, T., Soukup, S., et al. (1988). Prenatal detection of triploidy. Journal of Pediatrics, 112, 149–153. Benn, P. A., Gainey, A., Ingardia, C. J., et al. (2001). Second trimester maternal serum analytes in triploid pregnancies: Correlation with phenotype and sex chromosome complement. Prenatal Diagnosis, 21, 680–686. Blackburn, W. R., Miller, W. P., Superneau, D. W., et al. (1982). Comparative studies of infants with mosaic and complete triploidy: An analysis of 55 cases. Birth Defects Original Article Series, 18(3B), 251–274. Book, J. A., & Santession, B. (1960). Malformation syndrome in man associated with triploid (69) chromosomes. Lancet, 1, 858–859.

Carakushansky, G., Teich, E., Ribeiro, M. G., et al. (1994). Diploid/triploid mosaicism: Further delineation of the phenotype. American Journal of Medical Genetics, 52, 399–401. Craig, K., Pinette, M., Blackstone, J., et al. (2000). Highly abnormal maternal serum inhibin and (beta)-human chorionic gonadotropin levels along with severe HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome at 17 weeks’ gestation with triploidy. American Journal of Obstetrics and Gynecology, 182, 737–739. Daniel, A., Wu, Z., Bennetts, B., et al. (2001). Karyotype, phenotype and parental origin in 19 cases of triploidy. Prenatal Diagnosis, 21, 1034–1048. Dayal, M. B., Gindoff, P. R., Sarhan, A., et al. (2009). Effects of triploidy after intracytoplasmic sperm injection on in vitro fertilization cycle outcome. Fertility and Sterility, 91, 101–105. De Graaf, I. M., van Bezouw, S. M. C. A., Jakobs, M. E., et al. (1999). First-trimester non-invasive prenatal diagnosis of triploidy. Prenatal Diagnosis, 19, 175–177. Dean, J., Cohen, G., Kemp, J., et al. (1997). Karyotype 69, XXX/ 47, XX,+15 in a 1½-year-old child. Journal of Medical Genetics, 34, 246–249. Delatycki, M. B., Pertile, M. D., & Garner, R. J. M. (1998). Trisomy 13 mosaicism at prenatal diagnosis: Dilemmas in interpretation. Prenatal Diagnosis, 18, 45–49. Deshi, N., Surti, U., & Szulman, N. E. (1983). Morphologic anomalies in triploid liveborn fetuses. Human Pathology, 14, 716. Devriendt, K. (2005). Hydatidiform mole and triploidy: The role of genetic imprinting in placental development. Human Reproduction Update, 11, 137–142. Dewald, G., Alvarez, M. N., Clouthier, M. D., et al. (1975). A diploid-triploid human mosaic with cytogenetic evidence of double fertilization. Clinical Genetics, 8, 149–160. Dietzsch, E., Ramsay, M., Christianson, A. L., et al. (1995). Maternal origin of extra haploid set of chromosomes in third trimester triploid fetuses. American Journal of Medical Genetics, 58, 360–364. Egozcue, S., Blanco, J., Vidal, E., et al. (2002). Diploid sperm and the origin of triploidy. Human Reproduction, 17, 5–7. Fejgin, M., Amiel, A., Goldberger, S., et al. (1992). Placental insufficiency as a possible cause of low maternal serum human chorionic gonadotropin and low maternal serum unconjugated estriol levels in triploidy. American Journal of Obstetrics and Gynecology, 167, 766–767. Ferna´ndez-Moya, J. M., Sanz, R., Rodrı´guez de Alba, M., et al. (2000). Sonographic, cytogenetic and DNA analysis in four 69. XXX fetuses diagnosed in the second trimester. Fetal Diagnosis and Therapy, 15, 97–101. Fryns, J. P., van de Kerckhove, A., Goddeeris, P., et al. (1977). Unusually long survival in a case of full triploidy of maternal origin. Human Genetics, 38, 147–155. Fryns, J. P., Vinken, L., Geutjens, J., et al. (1980). Triploiddiploid mosaicism in a deeply mentally retarded adult. Annales de Genetique, 23, 232–234. Graham, J. M., Rawnsley, E., Simmons, G. M., et al. (1989). Triploidy: Pregnancy complications and clinical findings in seven cases. Prenatal Diagnosis, 9, 409–419. Harris, M. J., Poland, B. J., & Dill, F. J. (1981). Triploidy in 40 human spontaneous abortuses. Assessment of phenotype in embryos. Obstetrics and Gynecology, 151, 600–606.

2036 Hasegawa, T., Harada, N., Ikeda, K., et al. (1999). Digynic triploid infant surviving for 46 days. American Journal of Medical Genetics, 87, 306–310. Hsu, L. Y. F., Kaffe, S., Jenkins, E. C., et al. (1992). Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenatal Diagnosis, 12, 555–573. Jacobs, P. A., Szulman, A. E., Funkhouser, J., et al. (1982). Human triploidy: Relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Annals of Human Genetics, 46, 223–231. Jauniaux, E. (1999). Partial moles: From postnatal to prenatal diagnosis. Placenta, 20, 379–388. Jauniaux, E., Brown, R., Rodeck, C., et al. (1996). Prenatal diagnosis of triploidy during the second trimester of pregnancy. Obstetrics and Gynecology, 88, 983–989. Jauniaux, E., Brown, R., Snijders, R. J. M., et al. (1997). Early prenatal diagnosis of triploidy. American Journal of Obstetrics and Gynecology, 176, 550–554. Jauniaux, E., & Campbell, S. (1990). Ultrasound assessment of placental abnormalities. American Journal of Obstetrics and Gynecology, 163, 1650–1658. Jauniaux, E., & Hustin, J. (1998). Chromosomally abnormal early ongoing pregnancies: Correlation of ultrasound and placental histological findings. Human Pathology, 29, 1195–1199. Jonasson, J., Therkelsen, A. J., Lauritsen, J. G., & Linsten, J. (1972). Origin of triploidy in human abortuses. Hereditas, 71, 168–171. Jun, S. H., O’Leary, T., Jackson, K. V., & Racowsky, C. (2006). Benefit of intracytoplasmic injection in patients with a high incidence of triploidy in a prior in vitro fertilization cycle. Fertility and Sterility, 86, 825–829. Kalousek, D. K. (1984). Adrenal hypoplasia in triploidy. Pediatric Pathology, 2, 359. Kennerknecht, I., Just, W., & Vogel, W. (1993). A triploid fetus with a diploid placenta: Proposal of a mechanism. Prenatal Diagnosis, 13, 885–886. Kimura, Y., & Yanagimachi, R. (1995). Intracytoplasmic sperm injection in the mouse. Biology of Reproduction, 52, 709–720. Kjaer, I., et al. (1999). Pattern of malformations in the axial. skeleton in human triploid fetuses. American Journal of Medical Genetics, 72, 216–221. Lawler, S. D., Fisher, R. A., Pickthall, V. J., et al. (1982). Genetic studies on hydatidiform moles. I. The origin of partial moles. Cancer Genetics and Cytogenetics, 5, 309–320. Lockwood, C., Scioscia, A., Stiller, R., et al. (1987). Sonographic features of the triploid fetus. American Journal of Obstetrics and Gynecology, 157, 285–287. MacFadden, D. E., & Pantzar, J. T. (1996). Placental pathology of triploidy. Journal of Pediatrics, 27, 1018–1020. McFadden, D. E., & Kalousek, D. K. (1991). Two different phenotypes of fetuses with chromosomal triploidy: Correlation with parental origin of the extra haploid set. American Journal of Medical Genetics, 38, 535–538. McFadden, D. E., & Langlois, S. (2000). Parental and meiotic origin of triploidy in the embryonic and fetal periods. Clinical Genetics, 58, 192–200.

Triploidy Merlob, P., et al. (1991). Phenotypic expression of the first liveborn 68, XX triploid newborn. Journal of Medical Genetics, 28, 886–887. Miny, P., et al. (1995). Parental origin of the extra haploid chromosome set in triploidies diagnosed prenatally. American Journal of Medical Genetics, 57(1), 102–106. Mittal, T. K., Vujanic, G. M., Morrissey, B. M., et al. (1998). Triploidy: Antenatal sonographic features with post-mortem correlation. Prenatal Diagnosis, 18, 153–162. Muller, U., Weber, J. L., Berry, P., et al. (1993). Second polar body incorporation into a blastomere results in 46, XX/69, XXX mixoploidy. Journal of Medical Genetics, 30, 597–600. Niebuhr, E. (1974). Triploidy in man. Cytogenetical and clinical aspects. Humangenetik, 21, 103–125. Nolting, D., Hansen, B. F., Keeling, J. W., et al. (2002). Histological examinations of bone and cartilage in the axial skeleton of human triploidy fetuses. APMIS, 110, 186–192. Pergament, E., Confino, E., Zhang, J. X., et al. (2000). Recurrent triploidy of maternal origin. Prenatal Diagnosis, 20, 561–563. Petit, P., et al. (1992). Full 69, XXY triploidy and sex-reversal: A further example of true hermaphroditism associated with multiple malformations. Clinical Genetics, 41, 175–177. Phelan, M. C., Rogers, R. C., Michaelis, R. C., et al. (2001). Prenatal diagnosis of mosaicism for triploidy and trisomy 13. Prenatal Diagnosis, 21, 457–460. Pircon, R. A., Towers, C. V., Porto, M., et al. (1989). Maternal serum alpha-fetoprotein and fetal triploidy. Prenatal Diagnosis, 9, 701–707. Priest, J. H., Adams, W. R., Sanford-Hanna, J., et al. (1995). The nature of recurrent triploidy in humans. American Journal of Human Genetics, 57(Suppl), A123. Redline, R. W., Hassold, T., & Zaragoza, M. V. (1998). Prevalence of the partial molar phenotype in triploidy of maternal and paternal origin. Human Pathology, 28, 505–511. Rijhsinghani, A., Yankowitz, J., Strauss, R. A., et al. (1997). Risk of preeclampsia in second-trimester triploid pregnancies. Obstetrics and Gynecology, 90, 884–888. Silverthorn, K. G., et al. (1989). Radiographic findings in liveborn triploidy. Pediatric Radiology, 19, 237–241. Spandorfer, S. D., Avrech, O. M., Colombero, L. T., et al. (1998). Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection. Human Reproduction, 13, 334–338. Spencer, K., Liao, A. W. J., Skentou, H., et al. (2000). Screening for triploidy by fetal nuchal translucency and maternal serum free b-hCG and PAPP-A at 10–14 weeks of gestation. Prenatal Diagnosis, 20, 495–499. Szulman, A. E., Philippe, E., Boue, J. G., et al. (1981). Human triploidy: Association with partial hydatidiform moles and nonmolar conceptuses. Human Pathology, 12, 1016–1021. Szulman, A. E., & Surti, U. (1978). The syndromes of hydatidiform mole II: Morphologic evolution of the complete and partial mole. American Journal of Obstetrics and Gynecology, 132, 20–27. Tharapel, A. T., Wilroy, R. S., Martens, P. R., et al. (1983). Diploid/triploid mosaicism: Delineation of the syndrome. Annales de Genetique, 26, 229–233. Tsuchiya, K., Kamiguchi, Y., Sengoku, K., et al. (2002). A cytogenetic study of in-vitro matured murine oocytes

Triploidy after ICSI by human sperm. Human Reproduction, 17, 420–425. Tuerlings, J. H. A. M., Breed, A. S. P. M., Vosters, R., et al. (1993). Evidence of a second gamete fusion after the first cleavage of the zygote in a 47, XX,+18/70, XXX,+18 mosaic. A remarkable diploid-triploid discrepancy after CVS. Prenatal Diagnosis, 13, 301–306. Van De Laar, I., Rabelink, G., Hochstenbach, R., et al. (2002). Diploid/triploid mosaicism in dysmorphic patients. Clinical Genetics, 62, 376–382. Wertelecki, V., Graham, J. M., & Sergovich, F. R. (1976). The clinical syndrome of triploidy. Obstetrics and Gynecology, 47, 69–76.

2037 Wulfsberg, E. A., Wassel, W. C., & Polo, C. A. (1991). Monozygotic twin girls with diploid/triploid chromosome mosaicism and cutaneous pigmentary dysplasia. Clinical Genetics, 39, 370–375. Yu, C. W., Chen, H., & Fowler, M. (1983). Specific terminal DNA replication sequence of X chromosomes in different tissues of a live-born triploid infant. American Journal of Medical Genetics, 14, 501–511. Zaragoza, M. V., Surti, U., Redline, R. W., et al. (2000). Parental origin and phenotype of triploidy in spontaneous abortions: Predominance of diandry and association with the partial hydatidiform mole. American Journal of Human Genetics, 66, 1807–1820.

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Triploidy

a

c

d

b

e

Fig. 1 (a–e) A newborn with triploidy (69,XXY) showing woolly hair, distinctive facial appearance (epicanthal folds, microphthalmia, beaked nose, small mouth, receding jaw, lowset and malformed ears), partial syndactyly between third-fourth

fingers and toes, and ambiguous genitalia. The infant also had bilateral coloboma and cataracts, short neck, loud continuous heart murmur along the left sternal border, and bilateral transverse palmar creases. The infant died at 25 h

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Fig. 2 (a, b) An infant with triploidy showing abnormal craniofacial features, omphalocele, thick nuchal fold, and lumbosacral meningomyelocele

a

a

b

b

c

Fig. 3 (a–c) An infant with triploidy (69,XXX) showing low-set/malformed ears, syndactyly of two-three-four fingers, spina bifida, and pulmonary hypoplasia at autopsy. The infant also had a large ventricular septal defect

2040 Fig. 4 Partial mole of triploidy placenta. Many villi are enlarged, hydropic, and hypovascular. Prominent infolding and nests of trophoblastic cells in the villous stroma are seen in other areas

Fig. 5 A G-banded karyotype showing 69,XXX

Triploidy

Triploidy Fig. 6 Triploidy for all chromosomes shown by multicolor FISH on interphase cells. Three copies of chromosome 13 (green) and chromosome 21 (orange) are shown here

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Trismus-Pseudocamptodactyly Syndrome

The trismus-pseudocamptodactyly syndrome, a relatively rare hereditary disorder, is characterized by inability to open the mouth fully, pseudocamptodactyly, mild foot deformities, and mild short stature. This malformation syndrome was first reported by Hecht and Beals and Wilson et al. in 1969 (Hecht and Beals 1969; Wilson et al. 1969). The term Dutch–Kentucky syndrome was coined for trismus pseudocamptodactyly by Mabry et al. because the earliest affected member was a young Dutch girl who emigrated to the southern United States soon after the American Revolution.

Syonyms and Related Disorders Dutch–Kentucky syndrome; Hecht–Beals syndrome

Genetics/Basic Defects 1. Inheritance a. Autosomal dominant b. High penetrance c. Variable expression 2. Caused by a single mutation, p.R674Q, in MYH8 (myosin heavy chain 8) gene (Toydemir et al. 2006a) 3. Pathogenesis a. Possible mechanisms of trismus i. The shortened lengths of certain mastication muscles presumed to be responsible for the clinical manifestations. a) Temporalis muscle b) Internal pterygoid muscle c) Masseter muscle

ii. Enlarged coronoid processes a) Resulted from tension exerted by short temporal muscle tendon units b) Impinging on the body of the zygomatic bone and inner margin of the arch, thereby limiting mandibular excursion iii. Secondary to an abnormal ligament between the maxilla and that of the mandible anterior to the masseter muscles iv. Fibrotic abnormality of the masseter muscle mass in the vicinity of the ascending ramus b. Pseudocamptodactyly of fingers i. More appropriate term than camptodactyly because of a) Not associated with progressive deformities b) Not associated with fixed joint contractures ii. Caused by a shortening of the flexor digitorum profundus muscle tendon units, involving all fingers c. Foot deformities explainable by a shortening of the various muscle tendon groups in the leg and foot d. Several individuals with this mutation also had a so-called variant of Carney complex (a high incidence of myxomas, skin pigmentation disorders, endocrine tumors, or overactivity in schwannomas that manifest with cardiac myxomas and spotty skin pigmentation) (Veugelers et al. 2004), suggesting that the pathogenesis of trismus-pseudocamptodactyly syndrome and Carney complex might be shared. However, none of the individuals with

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_233, # Springer Science+Business Media, LLC 2012

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trismus-pseudocamptodactyly syndrome studied had features of Carney complex, and p.R674Q was not found in 49 independent cases of Carney complex that were screened. The findings show that distal arthrogryposis syndromes share a similar pathogenesis and are, in general, caused by disruption of the contractile complex of muscle (Toydemir et al. 2006a). e. The trismus found in trismuspseudocamptodactyly syndrome can also be present in Freeman–Sheldon syndrome (also known as distal arthrogryposis type 2A) and Sheldon–Hall syndrome (also known as distal arthrogryposis type 2B). Both of these conditions are caused by mutations in the MYH3 gene (Toydemir et al. 2006b), confirming the hypothesis that the distal arthrogryposis syndromes are caused by aberrant function of the contractile complex of fast-twitch myofibers.

Clinical Features 1. Highly variable expression 2. Two main clinical features a. Limited excursion of the mandible i. Trismus (restricted opening of the mouth) a) Present at birth and persisting throughout life b) Greatly variable degree of restricted opening of the mouth c) The mouth opening is measured between the incisal edges of the central upper and lower incisors (in millimeter). d) Children: less than the value for normal children (36.6  5.7 for age 7 years to 47.2  6.4 for age 18 years) e) Adults: less than the value for normal adults (53.8  6.5 for males, 50.4  5.9 for females) ii. Mastication problems iii. Feeding problems with inadequate caloric intake iv. Swallowing difficulty (dysphagia) v. Difficulty with dental care vi. Delayed in speech development vii. Difficulty in endotracheal intubation for general anesthesia

Trismus-Pseudocamptodactyly Syndrome

b. A flexion deformity of the fingers i. Clenched fists may be present at birth. ii. Typically crawling on the knuckles later in infancy iii. Occurring with wrist extension (pseudocamptodactyly) which is reversed by wrist flexion iv. Flexion of the fingers when the hand is dorsiflexed in minimally affected patients v. Pronounced flexion with ulnar deviation of the fingers in severely affected patients 3. Other clinical features a. Lower extremity and foot deformities (5% of cases) i. Mild calcaneovalgus ii. Equinovarus iii. Metatarsus varus iv. Camptodactyly v. Vertical talus vi. Hammertoe deformities vii. Shortening of both the gastrocnemiae and hamstring muscles b. Soft-tissue syndactyly occasionally present c. Mild short stature 4. Differential diagnosis of restricted mouth opening and/or (pseudo)camptodactyly a. Restricted mandibular opening caused by i. Intra-articular processes a) Trauma b) Infection c) Ankylosis ii. Extra-articular processes a) Soft tissue and bony obstructions b) Neurologic disorders such as tetanus b. Trismus in temporomandibular joint dysfunction c. Trismus caused by hypoplasia and fibrosis of the muscles around the mouth in Freeman–Sheldon syndrome d. Trismus and camptodactyly in patients with distal arthrogryposis who may have hyperextension of the metacarpophalangeal joints but also have contractures of the hips and feet, and short stature e. Trismus with a fixed facies secondary to hypoplasia or atrophy of small muscle fibers in Schwartz–Jampel syndrome f. A new arthrogryposis syndrome with facial and limb anomalies i. An autosomal dominant disorder

Trismus-Pseudocamptodactyly Syndrome

ii. Small mouth and jaw with limited jaw movement in infancy iii. Associated with short stature and severe flexion contractures of the hands and feet g. Digitotalar syndrome i. An autosomal dominant disorder ii. Flexion deformities iii. Ulnar deviation and narrowing of the fingers iv. Soft-tissue webbing causing abnormal positions of the thumbs v. A vertical talus

Diagnostic Investigations 1. Radiography a. Enlargement of the coronoid processes b. Normal hands and forearms 2. Manometry for demonstrating abnormal swallowing 3. Histology of the affected muscles showing presence of fibrous tissue along with some muscle atrophy 4. Molecular genetic testing of MYH8 mutations

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected (A mildly affected parent may be missed) or has germinal mosaicism (Bonapace et al. 2010) b. Patient’s offspring: 50% 2. Prenatal diagnosis: not been reported but possible in family at risk by MYH8 mutation analysis of fetal DNA obtained from amniocentesis of CVS, provided the mutation has been previously identified in the affected family member 3. Management a. Use a flattened nipple to assist feeding in infancy. b. Anesthetic implications i. Limited excursion of the mandible ii. Potentially difficult or impossible to apply artificial ventilation and endotracheal intubation iii. Inhalational anesthesia with spontaneous breathing recommended for minor surgery

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iv. Bullard laryngoscope, an excellent device for intubating patients with limited mouth opening v. Fiber-optic nasotracheal intubation vi. Needs for emergency tracheostomy and cricothyrotomy c. Surgical release in the severe cases of trismus i. Bilateral coronoidotomies with excision of accessory fibrous tissue ii. Bilateral excision of hypertrophic coronoid processes iii. Surgical release of the shortened muscle–tendon units iv. Ongoing physical therapy with postsurgical stretching of the jaw opening on a daily basis to avoid relapse d. Surgical flexor slide-through procedure on the flexion tendons of the forearms

References Bonapace, G., Ceravolo, F., Piccirillo, A., et al. (2010). Germline mosaicism for the c.2021G > A (p.Arg674Gln) mutation in siblings with trismus pseudocamptodactyly. American Journal of Medical Genetics. Part A, 152A, 2898–2900. Browder, F. H., Lew, D., & Shahbazian, T. S. (1986). Anesthetic management of a patient with Dutch-Kentucky syndrome. Anesthesiology, 65, 218–219. Chen, H., Fowler, M., Hogan, G. R., et al. (1992). Trismuspseudocamptodactyly syndrome: Report of a family and review of literature with special consideration of morphologic features of the muscles. Dysmorphology of Clinical Genetics, 6, 165–174. Chen, H., Hogan, G. R., Fowler, M., et al. (1986). Trismuspseudocamptodactyly syndrome: Morphologic studies of muscle. American Journal of Medical Genetics, 25, 736–737. DeJong, J. G. Y. (1971). A family showing strongly reduced ability to open the mouth and limitation of some movements of the extremities. Humangenetik, 13, 210–217. Gasparini, G., Boniello, R., Moro, A., et al. (2008). Trismuspseudocamptodactyly syndrome. Case report ten years after. European Journal of Paediatric Dentistry, 9, 199–203. Hall, J. G., Reed, S. D., & Green, A. (1982). The distal arthrogryposis: Delineation of new entities. Review and nosologic discussion. American Journal of Medical Genetics, 11, 185–239. Hecht, F., & Beals, R. K. (1969). Inability to open the mouth fully: An autosomal dominant phenotype with facultative camptodactyly and short stature. Preliminary note. Birth Defects Original Article Series, 5(3), 96–98. Hertrich, K., & Schuch, H. (1991). Restricted mouth opening as a leading symptom of trismus-pseudocamptodactyly syndrome. Deutsche zahn€ arztliche Zeitschrift, 46, 416–419.

2046 Horowitz, S. L., McNutty, E. C., & Chabora, A. J. (1973). Limited intermaxillary opening, an inherited trait. Oral Surgery, 36, 490–492. Lano, C. F., & Werkhaven, J. (1997). Airway management in a patient with Hecht’s syndrome. Southern Medical Journal, 90, 1241–1243. Lefaivre, J.-F., & Aitchison, M. J. (2003). Surgical correction of trismus in a child with Hecht syndrome. Annals of Plastic Surgery, 50, 310–314. Mabry, C. C., Barnett, I. S., Hutcheson, M. W., et al. (1974). Trismus pseudocamptodactyly syndrome. Dutch-Kentucky syndrome. Journal of Pediatrics, 85, 503–508. Markus, A. F. (1986). Limited mouth opening and shortened flexor muscle-tendon units: Trismus-pseudocamptodactyly syndrome. The British Journal of Oral & Maxillofacial Surgery, 24, 137–142. Mercuri, L. G. (1981). The Hecht, Beals and Wilson syndrome. Journal of Oral and Maxillofacial Surgery, 39, 53–56. Minzer-Conzetti, K., Wu, E., Vargervik, K., et al. (2008). Phenotypic variation in of trismus-pseudocamptodactyly syndrome caused by a recurrent MYH8 mutation. Clinical Dysmorphology, 17, 1–4. O’Brien, P. J., Gropper, P. T., Tredwell, S. J., et al. (1984). Orthopaedic aspects of the trismus pseudocamptodactyly syndrome. Journal of Pediatric Orthopaedics, 4, 469–471. Robertson, R. D., Spence, M. A., Sparkes, R. S., et al. (1982). Linkage analysis with the trismus-pseudocamptodactyly syndrome. American Journal of Medical Genetics, 12, 115–120. Seavello, J., & Hammer, G. B. (1999). Tracheal intubation in a child with trismus pseudocamptodactyly (Hecht) syndrome. Journal of Clinical Anesthesia, 11, 254–256.

Trismus-Pseudocamptodactyly Syndrome Ter Haar, B. G. A., & Van Hoof, R. F. (1974). The trismuspseudocamptodactyly syndrome. Journal of Medical Genetics, 11, 41–49. Toydemir, R. M., Chen, H., Proud, V. K., et al. (2006a). Trismuspseudocamptodactyly syndrome is caused by recurrent mutation of MYH8. American Journal of Medical Genetics. Part A, 140A, 2387–2393. Toydemir, R. M., Rutherford, A., Whitby, F. G., et al. (2006b). Mutations in embryonic myosin heavy chain (MYH8) cause Freeman–Sheldon syndrome and Sheldon–Hall syndrome. Nature Genetics, 38, 561–565. Tsukahara, M., Shinozaki, F., & Kajii, T. (1985). Trismuspseudocamptodactyly syndrome in a Japanese family. Clinical Genetics, 28, 247–250. Vaghadia, H., & Blackstock, D. (1988). Anaesthetic implications of the trismus pseudocamptodactyly syndrome (DutchKentucky or Hecht-Beals) syndrome. Canadian Journal of Anaesthesia, 35, 80–85. Veugelers, M., Bressan, M., McDermott, D. A., et al. (2004). Mutation of perinatal myosin heavy chain associated with a Carney complex variant. The New England Journal of Medicine, 351, 460469. Wilson, R. V., Gaines, D. L., Brooks, A., et al. (1969). Autosomal dominant inheritance of shortening of the flexor profundus muscle-tendon unit with limitation of jaw excursion. Birth Defects Original Article Series, 5(3), 99–102. Yamashita, D.-D. R., & Amet, G. F. (1980). Trismuspseudocamptodactyly syndrome. Journal of Oral Surgery, 38, 625–630.

Trismus-Pseudocamptodactyly Syndrome

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Fig. 1 Facial appearance of a child and his mother with trismus pseudocamptodactyly

Fig. 2 (a, b) Front and lateral views of the child and his mother illustrating maximal abilities to open their mouth. The mother and the child both had MYH8 mutations (p. R674Q)

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b

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Trismus-Pseudocamptodactyly Syndrome

a

b

Fig. 3 (a, b) Hands of the child and his mother demonstrating no contractures of fingers on neutral positions but flexion contractures of fingers on dorsiflexion. Interphalangeal webbings are also seen

Fig. 4 (a, b) Marked flexion contractures of fingers on dorsiflexion in the mother and her brother

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Trismus-Pseudocamptodactyly Syndrome

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Fig. 5 Affected father and son in different family showing trismus and flexion contractures of fingers on dorsiflexion

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Fig. 6 (a–c) Affected three individuals in two generations in different family showing trismus and flexion contractures of fingers on dorsiflexion

Trisomy 8 Mosaicism Syndrome

In 1971, de Grouchy et al. first described trisomy 8 mosaicism which was further delineated by Fryns et al., Sanchez and Yunis, Schinzel, and Riccardi in 1977. This syndrome, also known as Warkany syndrome, is a well-recognized syndrome despite its phenotypic variability.

again low levels of trisomic cells in AF cells and/or fetal blood lymphocytes. f. LTC villi are more likely to reflect the true fetal chromosomal constitution than STC villi.

Clinical Features Synonyms and Related Disorders Warkany syndrome

Genetics/Basic Defects 1. Trisomy 8 mosaicism: chromosome complement mosaic for chromosome 8 (presence of a chromosomally normal cell line in addition to the trisomic 8 cell line) 2. Origin of trisomy 8 mosaicism a. Different from the common autosomal trisomies that usually result from maternal meiotic errors b. Trisomy 8 in spontaneous abortions: meiotic origin in the majority of cases c. Postzygotic (mitotic) nondisjunction error in a diploid conceptus: the most likely origin of trisomy 8 in the live-born population d. Postzygotic (mitotic) nondisjunction error in a diploid conceptus, followed by nonrandom distribution of aneuploid cells between the different compartments e. Affected fetuses usually show a pattern of absence, or low levels of trisomy in cytotrophoblast cells (STC villi), high levels in extraembryonic mesoderm (LTC villi), and

1. Wide range of phenotypic variation 2. Central nervous system a. Intelligence: range from normal to mental retardation b. Agenesis of the corpus callosum c. Arrhinencephaly 3. Craniofacial features a. Skull i. Asymmetrical skull ii. Microcephaly iii. Hydrocephaly iv. Prominent forehead v. Flattened occiput vi. Low posterior hairline b. Eyes i. Ocular hypertelorism ii. Deep-set eyes iii. Strabismus iv. Corneal clouding v. Cataracts vi. Amblyopia c. Nose i. Plump nose with broad base ii. Prominent nares d. Mouth i. Micrognathia ii. Everted lower lip

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iii. High palate iv. Cleft soft palate Chest a. Pectus excavatum b. Widely spaced nipples Heart: congenital heart disease Gastrointestinal tract a. Meckel diverticulum b. Hirschsprung disease c. Anal anomalies Genitourinary tract a. Cryptorchidism b. Unilateral renal agenesis c. Wilms tumor d. Ureteral anomalies e. Perineal anomalies f. Inguinal hernia g. Genital hypoplasia in males Skeletal system a. Short stature b. Abnormal clavicle c. Absent or dysplastic patellae d. Joint contracture or limitation e. Vertebral anomalies f. Narrow pelvis g. Rib anomalies h. Scoliosis i. Camptodactyly of second through fifth fingers and toes Skin a. Deep palmar skin furrows b. Deep plantar skin furrows: a hallmark of the syndrome Fertility: an increased risk of infertility for males and females with trisomy 8 Life expectancy: usually normal

Diagnostic Investigations 1. Traditional cytogenetic diagnosis a. Detection of mosaic trisomy 8 from various tissue b. Abnormal cell line tends to disappear from lymphocytes with age. c. In older patients, aneuploidy can sometimes be demonstrated in fibroblast cultures only.

Trisomy 8 Mosaicism Syndrome

2. Interphase fluorescent in situ hybridization (FISH) using a chromosome 8 centromere-specific probe 3. Array comparative genomic hybridization (arrayCGH)

Genetic Counseling 1. Recurrence risk a. Patient’s sib: recurrence risk not increased b. Patient’s offspring i. An increased risk of spontaneous abortion for trisomic conceptuses ii. Fetuses with complete trisomy 8: nonviable iii. Chromosomally normal pregnancies possible 2. Prenatal diagnosis a. Prenatal cytogenetic diagnosis of mosaicism i. Metaphase analysis of cultured cells from either amniotic fluid or chorionic villi: currently the standard technique (analysis of 30 colonies needed to exclude 10% mosaicism with a 95% confidence level) ii. Interphase fluorescent in situ hybridization (FISH) with a centromere-specific probe: to further define the level of mosaicism iii. Array comparative genomic hybridization (array-CGH): enables faster results than standard cell culture and metaphase analysis (capable of detecting mosaicism at levels as low as 7%) b. Problems in genetic counseling i. Prediction of phenotype difficult since clinical severity is not related to the level of mosaicism ii. Problems in detecting trisomy 8 mosaicism in chorionic villi a) Do not necessarily reflect a constitutional mosaicism of the fetus b) Most likely represent confined placental mosaicism (a chromosomally abnormal cell line limited to the trophoblast tissue and/or extraembryonic mesoderm, with a normal karyotype in the fetus proper) c) Possible false-negative cases of trisomy 8 mosaicism in short-term culture villi, as well as cultured amniotic fluid cells

Trisomy 8 Mosaicism Syndrome

d) Follow-up investigations in fetal blood cells recommended when trisomy 8 mosaicism is encountered in chorionic villi iii. Problems in detecting trisomy 8 mosaicism in amniotic fluid a) Amniocentesis: not the best way to reveal trisomy 8 mosaicism b) Cases of missed trisomy 8 mosaicism reported 3. Management a. Mostly supportive b. Surgical management may be needed for those individuals with major malformations

References Aksit, S., Turker, M., & Yaprak, I. (1998). A case of trisomy 8 mosaicism. Turkish Journal of Medical Sciences, 28, 107–109. Camurri, L., & Chiesi, A. (1992). A three-year follow-up on a child with low level trisomy 8 mosaicism which was diagnosed prenatally. Prenatal Diagnosis, 11, 59–62. De Grouchy, J. C., Turleau, C., & Leonard, C. (1971). Etude en fluorescence d’une trisomie C mosaique probablement 8: 46, XY/47, XY,?8+. Annales de Genitique, 14, 69–72. Featherstone, T., Cheung, S. W., Spitznagel, E., et al. (1994). Exclusion of chromosomal mosaicism in amniotic fluid cultures: Determination of number of colonies needed for accurate analysis. Prenatal Diagnosis, 14, 1009–1017. Fineman, R. M., Ablow, R. C., Howard, R. O., et al. (1975). Trisomy 8 mosaicism syndrome. Pediatrics, 56, 762–767. Guichet, A., Briault, S., Toutain, A., et al. (1995). Prenatal diagnosis of trisomy 8 mosaicism in CVS after abnormal ultrasound findings at 12 weeks. Prenatal Diagnosis, 15, 769–772. Habecker-Green, J., Naeem, R., Goh, W., et al. (1998). Reproduction in a patient with trisomy 8 mosaicism: Case report and literature review. American Journal of Medical Genetics, 75, 382–385. Hanna, J. S., Neu, R. L., & Barton, J. R. (1995). Difficulties in prenatal detection of mosaic trisomy 8. Prenatal Diagnosis, 15, 1196–1197. Hsu, L. Y. F., Kaffe, S., Jenkins, E. C., et al. (1992). Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenatal Diagnosis, 12, 555–573.

2053 James, R. S., & Jacobs, P. A. (1996). Molecular studies of the aetiology of trisomy 8 in spontaneous abortions and the liveborn population. Human Genetics, 97, 283–286. Jordan, M., Marques, I., Rosendorff, J., et al. (1998). Trisomy 8 mosaicism: A further five cases illustrating marked clinical and cytogenetic variability. Genetic Counseling, 9, 139–146. Karadima, G., Bugge, M., Nicolaidis, P., et al. (1998). Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism. European Journal of Human Genetics, 6, 432–438. Klein, J., Graham, J. M., Jr., & Platt, L. D. (1994). Trisomy 8 mosaicism in chorionic villus sampling: Case report and counselling issues. Prenatal Diagnosis, 14, 451–454. Kurtyka, Z. E., Krzykwa, B., Piatkowska, E., et al. (1988). Trisomy 8 mosaicism syndrome: Two cases demonstrating variability in phenotypes. Clinical Pediatrics, 27, 557–564. Ledbetter, D. H., Zachary, J. M., Simpson, J. L., et al. (1992). Cytogenetic results from the U.S. Collaborative Study on CVS. Prenatal Diagnosis, 12, 317–345. Menten, B., Maas, N., Thienpont, B., et al. (2006). Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: A new series of 140 patients and review of published reports. Journal of Medical Genetics, 43, 625–633. Riccardi, V. M. (1977). Trisomy 8: An international study of 70 patients. Birth Defects Original Article Series, 13, 171–184. Rosengren, S. S., & Cassidy, S. B. (1990). Chromosome 8, trisomy 8. In: Buyse, M. L. (Ed.), Birth defects encyclopedia. Sahoo, T., Cheung, S. W., Ward, P., et al. (2006). Prenatal diagnosis of chromosomal abnormalities using array-based comparative genomic hybridization. Genetics in Medicine, 8, 719–727. Schneider, M., Klein-Vogler, U., Tomiuk, J., et al. (1994). Pitfall: Amniocentesis fails to detect mosaic trisomy 8 in a male newborn. Prenatal Diagnosis, 14, 651–652. Van Haelst, M. M., Van Opstal, D., Lindhout, D., et al. (2001). Management of prenatally detected trisomy 8 mosaicism. Prenatal Diagnosis, 21, 1075–1078. Webb, A. L., Wolstenholme, J., Evans, J., et al. (1998). Prenatal diagnosis of mosaic trisomy 8 with investigations of the extent and origin of trisomic cells. Prenatal Diagnosis, 18, 737–741. Wisniewska, M., & Mazurek, M. (2002). Trisomy 8 mosaicism syndrome. Journal of Applied Genetics, 43, 115–118. Wolstenholme, J. (1996). Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16 and 22: Their incidence, likely origins, and mechanisms for cell lineage compartmentalization. Prenatal Diagnosis, 16, 511–524. Wood, E., Dowey, S., Saul, D., et al. (2008). Prenatal diagnosis of mosaic trisomy 8q studied by ultrasound, cytogenetics, and array-CGH. American Journal of Medical Genetics, 146A, 764–769.

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Trisomy 8 Mosaicism Syndrome

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Fig. 1 (a–d) An infant boy with trisomy 8 mosaicism showing typical craniofacies (prominent forehead, ocular hypertelorism, plump nose with broad base, micrognathia) and characteristic Fig. 2 (a, b) A 2-year-and6-month-old boy with trisomy 8 mosaicism showing typical craniofacial features (prominent forehead, ocular hypertelorism, plump nose with broad base, micrognathia) and characteristic deep plantar furrows in both feet

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deep plantar skin furrows. Chromosome analysis showed trisomy 8 mosaicism (only trisomy 8 karyotype is shown here)

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Trisomy 8 Mosaicism Syndrome Fig. 3 Another child with trisomy 8 mosaicism with typical phenotype

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Trisomy 8 Mosaicism Syndrome

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Fig. 4 (a–c) Two infants with trisomy 8 mosaicism showing characteristic deep plantar furrows in both feet

Trisomy 13 Syndrome

In 1960, Patau et al. first recognized the relation of trisomy 13 to a clinical syndrome. Incidence is estimated to be 1/4,000–1/10,000 live births.

Synonyms and Related Disorders Patau syndrome

d. Variable mental retardation with longer survival e. Trisomy 13/triploidy mosaicism: a rare event 4. Partial trisomy 13 a. Partial trisomy of proximal segment with nonspecific clinical features and little similarity to full trisomy 13 b. Partial trisomy of distal segment with specific clinical features

Genetics/Basic Defects Clinical Features 1. Trisomy 13 a. Mechanism: due to meiotic nondisjunction i. Maternal origin of the extra chromosome (90%) ii. Stage of nondisjunction: mostly maternal meiosis I (vs. meiosis II in trisomy 18) iii. Paternal origin of the extra chromosome (10%): The majority is primarily postzygotic mitotic errors. b. Frequency: 75% of cases 2. Translocation trisomy 13 a. Mechanism: de novo (75%) or familial transmission (25%) b. Frequency: 20% of cases c. Trisomy 13 due to t(13;13): The structural abnormalities are usually isochromosomes originating in mitosis. 3. Mosaic trisomy 13 a. Mechanism: due to postzygotic (postfertilization) mitotic nondisjunction b. Frequency: 5% of cases c. Variable phenotype from full trisomy to near normal

1. General a. Low birth weight b. Thrombocytopenia 2. CNS a. Severe mental retardation b. Holoprosencephaly c. Seizures d. Central apnea 3. Craniofacial abnormalities a. Microcephaly b. Wide sagittal sutures c. Wide fontanels d. Scalp defect (aplasia cutis congenita, 50%) e. Capillary hemangioma of the forehead f. Ocular abnormalities i. Microphthalmia/anophthalmia ii. Colobomas iii. Retinal dysplasia g. Cleft lip/palate h. Abnormal auricles i. Low-set ears j. Sensorineural and conductive deafness

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k. Recurrent otitis media l. Abundant nuchal skin folds Cardiovascular abnormalities a. Ventricular septal defect b. Atrial septal defect c. Patent ductus d. Coarctation of the aorta e. Dextrocardia Gastrointestinal abnormalities a. Omphalocele b. Malrotation c. Umbilical hernia d. Inguinal hernia e. Accessory spleen f. Heterotopic pancreatic tissue g. Meckel’s diverticulum h. Diaphragmatic defects i. Large gallbladder Genitourinary abnormalities a. Polycystic kidneys b. Cryptorchidism c. Hypospadias d. Bicornuate uteri e. Abnormal fallopian tubes f. Hypoplastic ovaries Skeletal abnormalities a. Polydactyly b. Posterior prominence of heel c. Flexed fingers d. Hypoplasia of pelvis e. Shallow acetabulum f. Thin posterior ribs g. Flexion deformity of large joints h. Limb deficiency (5.3%) i. Radial aplasia j. Hyperconvex narrow fingernails Dermatoglyphics a. Transverse palmar crease b. t0 c. Hallucal arch fibular or loop tibial Others a. Thymic cyst b. Persistence of fetal hemoglobin Prognosis a. Majority of trisomy 13 conceptuses i. Abort during pregnancy ii. Stillborn b. Twenty-five percent die by 24 h of life c. Forty-five percent die by 1 month of life

Trisomy 13 Syndrome

d. Sixty percent die by 6 months of life e. Seventy-two die by 1 year of age f. Usual mode of death: primary apnea g. Survivals up to 11 and 19 years old reported 11. Mosaic trisomy 13 a. The phenotype ranges i. Typical features of trisomy 13 ii. More mild mental retardation or even normal intellectual function (rare), milder physical features, and longer survival b. The range in clinical severity is likely due to the varying proportion of trisomy 13 cells and their distribution within the body. 12. Partial trisomy 13 of the proximal segment a. Severe mental retardation b. Large nose c. Short upper lip d. Receding mandible e. Clinodactyly of the fifth fingers 13. Partial trisomy 13 of the distal segment a. Severe mental retardation b. Bushy eyebrows (synophrys) with long incurved lashes c. Frontal capillary hemangioma d. Long philtrum e. Prominent antihelix

Diagnostic Investigations 1. Cytogenetic studies a. Conventional technique b. FISH of interphase cells for rapid diagnosis c. Parental karyotyping in case of translocation trisomy 13 d. Trisomy 13 mosaicism 2. Echocardiography for cardiovascular anomalies 3. EEG: hypsarrhythmia 4. CT/MRI for central nervous system anomalies 5. Radiography a. Wide anterior fontanel b. Presence of a cervical rib c. Absence of the 12th rib d. Anomalies of rib morphology e. Low acetabular angle f. Long distal phalanges g. Cranial bone abnormalities in case of holoprosencephaly h. Clefting of the vertebral bodies

Trisomy 13 Syndrome

i. Abnormal postsphenoid component of the sphenoid bone j. Agenesis of the nasal bones 6. Placenta: Partial molar change of the placenta may rarely occur in trisomy 13 (Has et al. 2002).

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Trisomy 13: about 1 in 4,000 ii. De novo translocation: about 1 in 4,000 iii. Familial translocation: 5–15% iv. Mosaicism: 1 in 4,000 b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis a. Prenatal ultrasonography: prevalence of ultrasound abnormalities (91%) i. General a) IUGR (48%) b) Single umbilical artery c) Polyhydramnios (15%) d) Oligohydramnios (12%) ii. Cranium and CNS abnormalities (58%) a) Holoprosencephaly (39%) b) Neural tube defects c) Lateral ventricular dilatation without holoprosencephaly (9%) d) Enlarged cisterna magna or DandyWalker variant (15%) e) Microcephaly (12%) f) Linear branching echogenicity of the thalamus or basal ganglia (representing vasculopathy) g) Choroid plexus cyst iii. Facial anomalies a) Cyclopia b) Proboscis c) Hypotelorism d) Hypoplastic midface e) Cleft lip/palate (36%) f) Micrognathia iv. Neck anomalies a) Nuchal thickening b) Cystic hygroma c) Hydrops d) Lymphangiectasia

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v. Chest/cardiac abnormalities a) Diaphragmatic hernia b) Ventricular septal defect c) Hypoplastic left heart d) Echogenic chorda tendineae (30%) vi. Renal abnormalities (33%) a) Echogenic kidneys b) Pyelectasis c) Enlarged kidneys d) Hydronephrosis vii. Abdominal abnormalities a) Omphalocele b) Echogenic bowel (6%) c) Bladder exstrophy viii. Limb abnormalities (33%) a) Clenched and overlapping digits b) Polydactyly c) Radial aplasia d) Short femur length e) Talipes equinovarus f) Rocker bottom feet b. Chromosome analyses i. Amniocentesis ii. CVS, followed by amniocentesis iii. Fetal cells isolated from maternal blood using either flow sorting or magnetic sorting c. Dilemma for genetic counseling with trisomy 13 mosaicism i. Infrequent occurrence ii. Single-cell pseudomosaicism (3.3%) iii. Multiple-cell pseudomosaicism (4%) iv. Often represents pseudomosaicism or confined placental mosaicism v. True fetal mosaicism (in the context of lowlevel single-digit percentage mosaicism): not necessarily associated with congenital defects and/or mental abnormalities vi. An optimistic approach in case of normal ultrasonography and absence of trisomy 13 cells in the fetal blood vii. Possibility of adverse phenotype and intellectual function in case of true low-level fetal mosaicism 3. Management a. Feedings i. Nasal tube feeding ii. Oral gastric tube feeding iii. Gastrostomy feeding

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b. Nissan fundoplication for gastroesophageal reflux c. Risk for anesthesia d. Early intervention programs e. Seizure control f. Monitor apneic spells g. Treat infections h. Symptomatic treatment for heart failure i. Cardiac operation rarely performed

References Alizad, A., & Seward, J. B. (2000). Echocardiographic features of genetic diseases: Part 7. Complex genetic disorders. Journal of the American Society of Echocardiography, 13, 707–714. Baty, B. J., Blackburn, B. L., & Carey, J. C. (1994). Natural history of trisomy 18 and trisomy 13: I. Growth physical assessment, medical histories, survival, and recurrence risk. American Journal of Medical Genetics, 49, 175–188. Baty, B. J., Jorde, L. B., & Blackburn, B. L. (1994). Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. American Journal of Medical Genetics, 49, 189–194. Benacerraf, B. R., Miller, W. A., & Frigoletto, F. D., Jr. (1988). Sonographic detection of fetuses with trisomies 13 and 18: Accuracy and limitations. American Journal of Obstetrics and Gynecology, 158, 404–409. Brewer, C. M., Holloway, S. H., Stone, D. H., et al. (2002). Survival in trisomy 13 and trisomy 18 cases ascertained from population based registers. Journal of Medical Genetics, 39, e54. Chabra, S., Kriss, V. M., Pauly, T. H., et al. (1997). Neurosonographic diagnosis of thalamic/basal ganglia vasculopathy in trisomy 13-An important diagnostic aid. American Journal of Medical Genetics, 72, 291–293. Colacino, S. C., & Pettersen, J. C. (1978). Analysis of the gross anatomical variations found in four cases of trisomy 13. American Journal of Medical Genetics, 2, 31–50. Curtin, W. M., Marcotte, M. P., Myers, L. L., et al. (2001). Trisomy 13 appearing as a mimic of a triploid partial mole. Journal of Ultrasound in Medicine, 20, 1137–1139. Delatycki, M., & Gardner, R. J. (1997). Three cases of trisomy 13 mosaicism and a review of the literature. Clinical Genetics, 51, 403–407. Delatycki, M. B., Pertile, M. D., & Gardner, R. J. (1998). Trisomy 13 mosaicism at prenatal diagnosis: Dilemmas in interpretation. Prenatal Diagnosis, 18, 45–50. Eubanks, S. R., Kuller, J. A., Amjadi, D., et al. (1998). Prenatal diagnosis of mosaic trisomy 13: A case report. Prenatal Diagnosis, 18, 971–974. Goldstein, H., & Nielsen, K. G. (1988). Rates and survival of individuals with trisomy 13 and 18. Data from a 10-year period in Denmark. Clinical Genetics, 34, 366–372. Hahnemann, J. M., & Vejerslev, L. O. (1997). European collaborative research on mosaicism in CVS (EUCROMIC)–fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. American Journal of Medical Genetics, 70, 179–187.

Trisomy 13 Syndrome Hansen, C. B., Fergestad, J. M., Barnes, A., et al. (2000). An analysis of heart surgery in children with trisomy 18, 13. The Journal of Medical Investigation, 48, 47A. Has, R., Ibrahimog˘lu, L., Ergene, H., et al. (2002). Partial molar appearance of the placenta in trisomy 13. Fetal Diagnosis and Therapy, 17, 205–208. Hodes, M. E., et al. (1978). Clinical experience with trisomies 18 and 13. Journal of Medical Genetics, 15, 48–60. Janiaux, E., Halder, A., & Partington, C. (1998). A case of partial mole associated with trisomy 13. Ultrasound in Obstetrics & Gynecology, 11, 62–64. Kjaer, I., Keeling, J. W., & Hansen, B. F. (1997). Pattern of malformations in the axial skeleton in human trisomy 13 fetuses. American Journal of Medical Genetics, 70, 421–426. Lehman, C. D., Nyberg, D. A., Winter, T. C., III, et al. (1995). Trisomy 13 syndrome: Prenatal US findings in a review of 33 cases. Radiology, 194, 217–222. Martı´nez-Frı´as, M. L., Villa, A., de Pablo, R. A., et al. (2000). Limb deficiencies in infants with trisomy 13. American Journal of Medical Genetics, 93, 339–341. Moerman, P., Fryns, J. P., van der Steen, K., et al. (1988). The pathology of trisomy 13 syndrome: A study of 12 cases. Human Genetics, 80, 349–356. Nyberg, D. A., & Souter, V. L. (2001). Sonographic markers of fetal trisomies. Journal of Ultrasound in Medicine, 20, 655–674. Oosterwijk, J. C., Mesker, W. E., Ouwerkerk-van Velzen, M. C. M., et al. (1998). Prenatal diagnosis of trisomy 13 on fetal cells obtained from maternal blood after minor enrichment. Prenatal Diagnosis, 18, 1082–1085. Patau, K., Therman, D. G., Cameron, A. H., et al. (1960). A new trisomic syndrome. Lancet, 1, 787–789. Pettersen, J. C., et al. (1979). An examination of the spectrum of anatomic defects and variations found in eight cases of trisomy 13. American Journal of Medical Genetics, 3, 183–210. Phelan, M. C., Rogers, R. C., Michaelis, R. C., et al. (2001). Prenatal diagnosis of mosaicism for triploidy and trisomy 13. Prenatal Diagnosis, 21, 457–460. Redheendran, R., Neu, R. L., & Bannerman, R. M. (1981). Long survival in trisomy 13 syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old. American Journal of Medical Genetics, 8, 167–172. Robinson, W. P., Bernasconi, F., Dutly, F., et al. (1996). Molecular studies of translocations and trisomy involving chromosome 13. American Journal of Medical Genetics, 61, 158–163. Rogers, J. F. (1984). Clinical delineation of proximal and distal partial 13q trisomy. Clinical Genetics, 25, 221–229. Schinzel, A., et al. (1976). Further delineation of the clinical picture of trisomy for the distal segment of chromosome 13. Human Genetics, 32, 1–12. Smith, K., Lowther, G., Maher, E., et al. (1999). The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS: Experience from the ACC U.K. Collaborative Study. Association of Clinical Cytogeneticists Prenatal Diagnosis Working Party. Prenatal Diagnosis, 19, 817–826. Snijders, R. J., Sebire, N. J., Nayar, R., et al. (1999). Increased nuchal translucency in trisomy 13 fetuses at 10–14 weeks of gestation. American Journal of Medical Genetics, 86, 205–207.

Trisomy 13 Syndrome Taylor, A. I. (1968). Autosomal trisomy syndromes: A detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. Journal of Medical Genetics, 5, 227–241. Tharapel, S. A., Lewadowski, R. C., Tharapel, A. T., et al. (1986). Phenotype-karyotype correlation in patients trisomic for various segments of chromosome 13. Journal of Medical Genetics, 23, 310–315. Tongson, T., Sirichotiyakul, S., Wanapirak, C., et al. (2002). Sonographic features of trisomy 13 at midpregnancy. International Journal of Gynecology and Obstetrics, 76, 143–148. Tuohy, J. F., & James, D. K. (1994). Pre-eclampsia and trisomy 13. British Journal of Obstetrics and Gynaecology, 99, 891–894.

2061 Wallerstein, R., Yu, M.-T., Neu, R. L., et al. (2000). Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: Karyotype-phenotype correlations. Prenatal Diagnosis, 20, 103–122. Warkany, J., et al. (1966). Congenital malformations in autosomal trisomy syndromes. American Journal of Diseases of Children, 112, 502–517. Wyllie, J. P., Wright, M. J., Burn, J., et al. (1994). Natural history of trisomy 13. Archives of Disease in Childhood, 71, 343–345. Zoll, B., Wolf, J., Lensing-Hebben, D., et al. (1993). Trisomy 13 (Patau syndrome) with an 11-year survival. Clinical Genetics, 43, 46–50.

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Trisomy 13 Syndrome

Fig. 1 (a, b) An infant with trisomy 13 showing microcephaly, microphthalmia, forehead hemangioma, cleft lip/palate, and postaxial polydactyly

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Fig. 2 (a, b) An infant with trisomy 13 showing microcephaly, microphthalmia, cleft lip/ palate, and omphalocele

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Trisomy 13 Syndrome

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Fig. 3 (a, b) Postaxial polydactyly of the hand and the feet in an infant with trisomy 13

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Fig. 4 (a, b) An infant with trisomy 13 showing microcephaly, forehead hemangioma, upslanted palpebral fissures, cleft lip/ palate, and short neck

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Fig. 5 (a, b) An infant with trisomy 13 showing scalp defect on the vertex

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Fig. 6 Another infant with trisomy 13 showing microphthalmia and cleft lip/palate

Trisomy 13 Syndrome

Trisomy 13 Syndrome Fig. 7 (a–c) A neonate with trisomy 13 showing ethmocephaly, transverse reduction of the left forearm, and polydactyly of the right hand and both feet

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Trisomy 13 Syndrome

Fig. 8 A child with trisomy 13 associated with premaxillary dysgenesis, hypotelorism, cleft nose, and smooth philtrum

Fig. 10 (a–e) A neonate with trisomy 13 showing similar facial features. In addition, the infant has polydactyly. Prenatal ultrasound examination showed microcephaly, scalp edema, and holoprosencephaly (a normal ultrasound at the same gestation is given here)

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Fig. 9 An infant with trisomy 13-Klinefelter syndrome showing hypotelorism and a single nostril (holoprosencephaly)

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Trisomy 13 Syndrome

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Fig. 11 Trisomy 13 karyotype (G-banded)

Fig. 13 Trisomy 13 shown by FISH analysis of interphase cells with three copies of the green signal (LSI 13/SpectrumGreen) representing three chromosome 13s and two copies of the red signal representing two chromosome 21s (LSI 21/ SpectrumOrange)

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Fig. 12 Translocation of trisomy 13 karyotype [t(13q;14q)]

Trisomy 18 Syndrome

Edwards et al. and Smith et al. independently described trisomy 18 syndrome in 1960 (Edwards et al. 1960; Smith et al. 1960). It is the second most common autosomal trisomy after trisomy 21. Prevalence is approximately 1 in 6,000–8,000 live births.

Synonyms and Related Disorders

indicating a prenatal selection against trisomy 18 males after the time of amniocentesis (Nicolaidis and Petersen 1998) 4. The smallest extra region necessary for expression of serious anomalies of trisomy 18: Two critical regions, one proximal (18q12-q21.2) and one distal (18q22.3-qter), which work jointly to produce the typical trisomy 18 phenotype.

Edwards syndrome

Clinical Features Genetics/Basic Defects 1. Caused by an extra chromosome 18 resulting from nondisjunction in meiosis a. Maternal origin of an extra chromosome 18 in 90% of cases b. An error in maternal meiosis II is the most frequent cause of nondisjunction for chromosome 18, unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I. c. Increased incidence with advanced maternal age 2. Types of trisomy 18 a. Full trisomy 18 in 95% of cases b. Rare mosaicism and translocation cases: translocation trisomy giving rise to partial trisomy 18 syndrome 3. Preponderance of females with trisomy 18 in liveborns (sex ratio 0.63) (sex ratio defined as the number of males divided by the number of females) compared to fetuses diagnosed prenatally (sex ratio 0.90)

1. Prenatal history (Chen 2011) a. Maternal polyhydramnios possibly related to defective fetal sucking and swallowing reflexes in utero b. Oligohydramnios secondary to renal defects c. Disproportionately small placenta d. Single umbilical artery e. Intrauterine growth retardation f. Weak fetal activity g. Fetal distress 2. Clinical history a. Apneic episodes b. Poor feeding c. Marked failure to thrive 3. Physical growth: profound growth retardation 4. Central nervous system (CNS) a. Inevitable profound delay in psychomotor development and mental retardation (100%) b. Neonatal hypotonia followed by hypertonia c. Jitteriness d. Apnea

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_236, # Springer Science+Business Media, LLC 2012

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e. Seizures f. Malformations i. Microcephaly ii. Cerebellar hypoplasia iii. Meningoencephalocele iv. Meningomyelocele v. Anencephaly vi. Hydrocephaly vii. Holoprosencephaly viii. Arnold-Chiari malformation ix. Hypoplasia or aplasia of the corpus callosum x. Defective falx cerebri xi. Frontal lobe defect xii. Abnormal gyri xiii. Migration defect xiv. Arachnoid cyst 5. Cranial a. Microcephaly b. Elongated skull c. Narrow bifrontal diameter d. Wide fontanels and cranial sutures e. Prominent occiput 6. Facial a. Microphthalmia b. Ocular hypertelorism c. Epicanthal folds d. Short palpebral fissures e. Iris coloboma f. Cataracts g. Corneal clouding h. Abnormal retinal pigmentation i. Short nose with upturned nares j. Choanal atresia k. Micrognathia/retrognathia l. Microstomia m. Narrow palatal arch n. Infrequent cleft lip and cleft palate o. Preauricular tags p. Low-set, malformed ears (faun-like with flat pinnae and a pointed upper helix) 7. Skeletal a. Severe growth retardation b. Characteristic hand posture, with clenched hands with the index finger overriding the middle finger, and the fifth finger overriding the fourth finger c. Camptodactyly d. Radial hypoplasia or aplasia

Trisomy 18 Syndrome

e. f. g. h. i. j. k. l. m. n. o. p.

Thumb aplasia Syndactyly of the second and third digits Arthrogryposis Rocker-bottom feet with prominent calcanei Talipes equinovarus Hypoplastic nails Dorsiflexed great toes Short neck with excessive skin folds Short sternum Narrow pelvis Limited hip abduction Severe kyphoscoliosis and tendency to spontaneous fracture of long bones emerging later 8. Cardiac malformations in more than 90% of infants with trisomy 18 a. Ventricular septal defects i. Present in about two-thirds of cases ii. Large defect unlikely to undergo spontaneous closure b. Polyvalvular heart disease pulmonary and aortic valve defects) c. Double outlet right ventricle d. Atrial septal defects e. Patent ductus arteriosus f. Overriding aorta g. Coarctation of aorta h. Hypoplastic left heart syndrome i. Tetralogy of Fallot j. Transposition of great arteries k. Endocardial fibroelastosis l. Persistent left superior vena cava m. Absent right superior vena cava n. Dextrocardia 9. Pulmonary a. Pulmonary hypoplasia b. Abnormal lobation of the lung 10. Gastrointestinal a. Omphalocele b. Malrotation of the intestine c. Ileal atresia d. Common mesentery e. Meckel diverticulum f. Esophageal atresia with or without tracheoesophageal fistula g. Diaphragmatic eventration h. Prune belly anomaly i. Diastasis recti j. Abnormal lobulation of the liver

Trisomy 18 Syndrome

11.

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k. Absent or hypoplasia of gallbladder l. Absent appendix m. Accessory spleens n. Exstrophy of cloaca o. Pyloric stenosis p. Common mesentery q. Megacolon r. Imperforate or malpositioned anus s. Pilonidal sinus t. Umbilical, inguinal, or diaphragmatic hernias Genitourinary a. Micromulticystic kidneys b. Double ureters c. megaloureters d. Hydroureters e. Hydronephrosis f. Horseshoe kidneys g. Ectopic kidney h. Unilateral renal agenesis i. Cryptorchidism, hypospadias, and micropenis in males j. Hypoplasia of labia and ovaries, bifid uterus, hypoplastic ovaries, and clitoral hypertrophy in females Endocrine a. Thymic hypoplasia b. Thyroid hypoplasia c. Adrenal hypoplasia Dermatoglyphics a. Increased number of simple arches (6 or more) on the finger tips b. Transverse palmar crease c. Increased atd angle d. Clinodactyly of the fifth fingers with a single flexion crease Prognosis a. Approximately 95–97.5% of conceptuses with trisomy 18 die in embryonic or fetal life. b. Only 30% of live fetuses at midtrimester amniocentesis surviving to term c. Five to ten percent of affected children survive beyond the first year. d. Rare reports of long survival into 20s e. High mortality rate secondary to cardiac and renal malformations, feeding difficulties, sepsis, and central apnea caused by CNS defects f. Severe psychomotor and growth retardation invariably present for those who survive beyond infancy.

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g. Milder nonspecific phenotype in mosaic trisomy 18 correlates with the proportion of normal cells in the body

Diagnostic Investigations 1. Conventional cytogenetic study to detect full trisomy, mosaic trisomy, or rare translocation type trisomy 18 2. Echocardiography for cardiac anomalies 3. Barium swallow for gastrointestinal anomalies 4. Ultrasound for genitourinary anomalies 5. Skeletal radiography a. Phocomelia b. Absent radius c. Tight flexion of the fingers with second over the third and the fifth over the fourth d. Talipes equinovarus e. Short sternum f. Hemivertebrae g. Fused vertebrae h. Short neck i. Scoliosis j. Rib anomaly k. Dislocated hips 6. Histopathological study of temporal bone (auditory organ) (Tadaki et al. 2003) a. External ear: arctation or atresia of external acoustic meatus (38%) b. Middle ear i. Anomalies of auditory ossicles (61%) a) Incus or malleus b) Stapes ii. Absence or aberration of tensor tympani muscle or its tendon (31%) iii. Complete absence or hypoplasia of stapedial muscle or its tendon (28%) c. Inner ear i. Hypoplasia of the ductus semicirculares (37%) ii. Shortened cochlea (22%) iii. Anomalies of stria vascularis (22%) iv. Absence or hypoplasia of lymphatic valve in utricle (21%) v. Enlargement of canaliculus cochleae (11%) d. Facial nerve: geniculate ganglion cells displaced into the internal auditory meatus (53%)

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Genetic Counseling 1. Recurrence risk a. Patient’s sib i. De novo full trisomy 18: 1% or less ii. Low-grade parental mosaicism has been reported in two occasions in sporadic cases of trisomy 18. iii. A parent being a balanced carrier of a structural rearrangement: increased recurrence risk pending on the type of structural rearrangement and the pattern of segregation b. Patient’s offspring: unlikely to survive to reproduction 2. Prenatal diagnosis a. Prenatal screening in families without history of trisomy 18 using maternal serum markers i. Low human chorionic gonadotropin hCG) and low unconjugated estriol (uE3) in maternal serum during midtrimester: useful predictors for an increased risk for trisomy 18 ii. Possible future first-trimester biochemical screening for trisomy 18: reduced levels of pregnancy-associated plasma protein A (PAPP-A) and free beta–human chorionic gonadotropin (beta-hCG) at 8–13 weeks gestation. The mean MOM in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG. iii. Screening for trisomy 18 using a combination of maternal age, PAPP-A, and beta-hCG: reported to achieve a detection rate of 76.6% with a false-positive rate of 0.5% (Biagiotti et al. 1998) b. Prenatal ultrasonography: The majority of fetuses with trisomy 18 have detectable structural abnormalities. i. First-trimester sonographic findings (Sepulveda et al. 2010) a) Nuchal translucency (77–91%) b) Absent/hypoplastic nasal bone (53%) c) Generalized subcutaneous edema (49%) d) Omphalocele (21%) e) Abnormal posturing of hands (6%) f) Megacystis (4%) g) Cardiac defect (4%) h) Pleural effusions (4%) i) Echogenic yolk sac (4%)

Trisomy 18 Syndrome

ii. iii. iv. v.

Oligohydramnios/polyhydramnios (12%) Intrauterine growth retardation (29%) Two-vessel umbilical cord (40%) CNS a) Abnormally shaped fetal head (strawberry or lemon) (43%) b) Microcephaly c) Dandy-Walker malformation (posterior fossa enlargement associated with cerebellar hypoplasia) d) Enlarged cisterna magna e) Choroid plexus cysts (43%) f) Neural tube defects (9%) vi. Micrognathia vii. Thickened nuchal skin fold viii. Cystic hygroma or lymphangiectasia (14%) ix. Omphalocele (20%) x. Esophageal atresia xi. Cardiac defects (37%): septal defects with polyvalvular disease xii. Renal anomalies (9%) a) Polycystic kidneys b) Horseshoe and ectopic kidneys xiii. Limb abnormalities a) Clenched hands with overlapping index finger (89%) b) Forehand and hand abnormalities such as a short radial ray c) Rocker-bottom feet d) Club feet c. 3D/4DUS offers diagnostic advantages for most anomalies associated with trisomy 18, especially anomalies of the extremities and face (Zheng et al. 2008). d. Amniocentesis or CVS by conventional cytogenetic or FISH techniques i. Straight trisomy 18 ii. Trisomy 18 mosaicism: 54% risk for an abnormal outcome, including phenotypically abnormal offspring, IUGR, or fetal demise. The risk is increased with increasing percentage of amniotic fluid trisomic cell line. e. Culturing fetal hematopoietic stem-progenitor cells from maternal blood during pregnancy: a new strategy holding great promise for noninvasive prenatal genetic diagnosis 3. Management a. Genetic counseling in prenatally diagnosed trisomy 18

Trisomy 18 Syndrome

i. Traumatic experience in the lives of all couples having a fetus with trisomy 18 ii. Emotional upheaval persisting for variable time periods after the diagnoses and the decisions concerning the pregnancy outcomes b. Medical care of trisomy 18 infants i. Supportive ii. Treat infections a) Otitis media b) Upper respiratory infections (bronchitis, pneumonia) c) Urinary tract infections iii. Nasogastric and gastrostomy supplementation for feeding problems iv. Orthopedic management of scoliosis secondary to hemivertebrae v. Primarily medical management of congenital heart disease vi. Diuretic and digoxin for congestive heart failure vii. Referral for early intervention including physical and occupational therapy viii. Psychosocial management: Discuss implications, possible outcomes, and available supportive services in the community. ix. Severe developmental delay exhibited by long-term survivors presenting the greatest challenge to parental coping during the childhood years x. Informed and empathetic care to families undergoing a complex grieving process that combines both the reactive grief predominant in chronic illness and the preparatory grief associated with impending death (Van Dyke and Allen 1990) c. Surgical care of trisomy 18 infants: Because of the extremely poor prognosis, surgical repair of severe congenital anomalies such as esophageal atresia or congenital heart defects is not likely to improve the survival rate of infants and should be discussed with families.

References Adler, B., & Kushnick, T. (1982). Genetic counseling in prenatally diagnosed trisomy 18 and 21: Psychosocial aspects. Pediatrics, 69, 94–99.

2073 Alizad, A., & Seward, J. B. (2000). Echocardiographic features of genetic diseases: part 7. Complex genetic disorders. Journal of the American Society of Echocardiography, 13, 707–714. Bass, H. N., Fox, M., Wulfsberg, E., et al. (1982). Trisomy 18 mosaicism: Clues to the diagnosis. Clinical Genetics, 22, 327–330. Baty, B. J., Blackburn, B. L., & Carey, J. C. (1994). Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. American Journal of Medical Genetics, 49, 175–188. Baty, B. J., Jorde, L. B., & Blackburn, B. L. (1994). Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. American Journal of Medical Genetics, 49, 189–194. Benacerraf, B. R., Miller, W. A., & Frigoletto, F. D., Jr. (1988). Sonographic detection of fetuses with trisomies 13 and 18: Accuracy and limitations. American Journal of Obstetrics and Gynecology, 158, 404–409. Bersu, E. T., & Ramirez-Castro, J. L. (1977). Anatomical analysis of the developmental effects of aneuploidy in man – the 18-trisomy syndrome: I. Anomalies of the head and neck. American Journal of Medical Genetics, 1, 173–193. Biagiotti, R., Cariati, E., & Brizzi, L. (1998). Maternal serum screening for trisomy 18 in the first trimester of pregnancy. Prenatal Diagnosis, 18, 907–913. Bugge, M., Collins, A., Petersen, M. B., et al. (1998). Nondisjunction of chromosome 18. Human Molecular Genetics, 7, 661–669. Carey, J. (1992). Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I). Pediatric Clinics of North America, 39, 25–53. Carey, J. C. (2000). The trisomy 18 and 13 syndromes. In S. Cassidy & J. Allanson (Eds.), Management of genetic syndromes. New York: Wiley. Chen, H. (2011). Trisomy 18. eMedicine from WebMD. Retrieved August 11, 2011. Available at: http://emedicine. medscape.com/article/943463-overview Collins, A. L., Fisher, J., & Crolla, J. A. (1995). Further case of trisomy 18 mosaicism with a mild phenotype (letter). American Journal of Medical Genetics, 56, 121–122. Edwards, J. H., Harnden, D. G., & Cameron, A. H. (1960). A new trisomic syndrome. Lancet, 1, 787–789. Embleton, N. D., Wyllie, J. P., & Wright, M. J. (1996). Natural history of trisomy 18. Archives of Disease in Childhood. Fetal and Neonatal Edition, 75, F38–F41. Findlay, I., Toth, T., & Matthews, P. (1998). Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: Applications for prenatal diagnosis and preimplantation genetic diagnosis. Journal of Assisted Reproduction and Genetics, 15, 266–275. Gardner, R. J. M., & Sutherland, G. R. (1996). Chromosome abnormalities and genetic counselling (2nd ed.). Oxford: Oxford University Press. Gilbert-Barnes, E. (1997). Chromosome abnormalities. In E. Gilbert-Barnes (Ed.), Potter’s pathology of the fetus and infant (Vol. I, pp. 402–404). St. Louis, MO: Mosby. Gross, S. J., & Bombard, A. T. (1998). Screening for the aneuploid fetus. Obstetrics and Gynecology Clinics of North America, 25, 573–595.

2074 Hansen, C. B., Fergestad, J. M., Barnes, A., et al. (2000). An analysis of heart surgery in children with trisomy 18, 13. The Journal of Medical Investigation, 48, 47A. Hecht, F., Bryant, J. S., & Motulusky, A. G. (1963). The No. 17–18 (E) trisomy syndrome. Journal of Pediatrics, 63, 605–621. Hook, E. B., Lehrke, R., Roesner, A., et al. (1965). Trisomy-18 in a 15-year-old female. Lancet, 2, 910–911. Huether, C. A., Martin, R. L., & Stoppelman, S. M. (1996). Sex ratios in fetuses and liveborn infants with autosomal aneuploidy. American Journal of Medical Genetics, 63, 492–500. Kinoshita, M., Nakamura, Y., & Nakano, R. (1989). Thirty-one autopsy cases of trisomy 18: Clinical features and pathological findings. Pediatric Pathology, 9, 445–457. Kjaer, I., Keeling, J. W., & Hansen, B. F. (1996). Pattern of malformations in the axial skeleton in human trisomy 18 fetuses. American Journal of Medical Genetics, 65, 332–336. Lam, Y. H., & Tang, M. H. (1999). Sonographic features of fetal trisomy 18 at 13 and 14 weeks: four case reports. Ultrasound in Obstetrics & Gynecology, 13, 366–369. Leporrier, N., Herrou, M., & Herlicoviez, M. (1996). The usefulness of hCG and unconjugated oestriol in prenatal diagnosis of trisomy 18. British Journal of Obstetrics and Gynaecology, 103, 335–338. Mehta, L., Shannon, R. S., Duckett, D. P., et al. (1986). Trisomy 18 in a 13-year-old girl. Journal of Medical Genetics, 23, 256–278. Nicolaides, K. H., Azar, G., & Byrne, D. (1992). Fetal nuchal translucency: Ultrasound screening for chromosome defects in the first trimester of pregnancy. British Medical Journal, 304, 704–707. Nicolaidis, P., & Petersen, M. B. (1998). Origin and mechanisms of non-disjunction in human autosomal trisomies. Human Reproduction, 13, 313–319. Nyberg, D. A., Kramer, D., & Resta, R. G. (1993). Prenatal sonographic findings of trisomy 18: Review of 47 cases. Journal of Ultrasound in Medicine, 2, 103–113. Nyberg, D. A., & Souter, V. L. (2001). Sonographic markers of fetal trisomies. Journal of Ultrasound in Medicine, 20, 655–674. Ramirez-Castro, J. L., & Bersu, E. T. (1978). Anatomical analysis of the developmental effects of aneuploidy in man – the 18-trisomy syndrome: II. Anomalies of the upper and lower limbs. American Journal of Medical Genetics, 2, 285–306. Ries, M. D., Ray, S., Winter, R. B., et al. (1990). Scoliosis in trisomy 18. Spine, 15, 1281–1284.

Trisomy 18 Syndrome Root, S., & Carey, J. C. (1994). Survival in trisomy 18. American Journal of Medical Genetics, 49, 170–174. Sepulveda, W., Wong, A. E., & Dezerega, V. (2010). First-trimester sonographic findings in trisomy 18: A review of 53 cases. Prenatal Diagnosis, 30, 256–259. Shields, L. E., Carpenter, L. A., & Smith, K. M. (1998). Ultrasonographic diagnosis of trisomy 18: Is it practical in the early second trimester? Journal of Ultrasound in Medicine, 17, 327–331. Smith, A., Field, B., & Learoyd, B. M. (1989). Trisomy 18 at 21 years. American Journal of Medical Genetics, 34, 338–339. Smith, D. W., Patau, K., & Therman, E. (1960). A new autosomal trisomy syndrome: Multiple congenital anomalies caused by an extra chromosome. Journal of Pediatrics, 57, 338–345. Smith, A., Silink, M., Ruxton, T., et al. (1978). Trisomy 18 in an 11-year-old child. Journal of Mental Deficiency Research, 22, 277–286. Sumi, S. M. (1970). Brain malformations in the trisomy 18 syndrome. Brain, 93, 821–830. Surana, R. B., Bain, H. W., & Conen, P. E. (1972). 18 trisomy in a 15-year-old girl. American Journal of Diseases of Children, 123, 75–77. Tadaki, T., Kamiyama, R., Okamura, H. O., et al. (2003). Anomalies of the auditory organ in trisomy 18 syndrome: Human temporal bone histopathological study. Journal of Laryngology and Otology, 117, 580583. Taylor, A. I. (1968). Autosomal trisomy syndromes: a detailed study of 27 cases of Edwards’ syndrome and 27 cases of Patau’s syndrome. Journal of Medical Genetics, 5, 227–252. Van Dyke, D. C., & Allen, M. (1990). Clinical management considerations in long-term survivors with trisomy 18. Pediatrics, 85, 753–759. Wallerstein, R., Yu, M.-T., Neu, R. L., et al. (2000). Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations. Prenatal Diagnosis, 20, 103–122. Weber, W. W., Mamues, P., Day, R., et al. (1964). Trisomy 17–18(E): Studies in long-term survival with reports of two autopsied cases. Pediatrics, 34, 533–541. Zheng, Y., Tzhou, X.-D., Zhu, Y.-L., et al. (2008). Three- and 4-dimensional ultrasonography in the prenatal evaluation of fetal anomalies associated with trisomy 18. Journal of Ultrasound in Medicine, 27, 1041–1051.

Trisomy 18 Syndrome Fig. 1 (a–c) A fetus with trisomy 18 showing malformed and low-set ears, characteristic finger clenching pattern, spina bifida, hyperextended knee, and talipes equinovarus

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Trisomy 18 Syndrome

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Fig. 2 (a, b) An infant with trisomy 18 showing small eyes, microstomia, low-set/malformed ears, and short neck

Fig. 3 An infant with trisomy 18 showing micro/ retrognathia, short neck, and characteristic finger grasping pattern

Trisomy 18 Syndrome

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Fig. 4 (a–c) Three infants with trisomy 18 showing reduction malformations of the upper extremities

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Trisomy 18 Syndrome

c

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d b

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Fig. 6 (a, b) Typical hand grasping pattern (left) and rocker-bottom feet with prominent calcaneus (right) observed in trisomy 18

Trisomy 18 Syndrome Fig. 7 Trisomy 18 karyotype (47,XY,+18)

Fig. 8 Translocation trisomy 18 karyotype [46,XX,+18,der (13)t(13;18)(q10;q10)]

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Fig. 9 Trisomy 18 shown by FISH (CEP X/SpectrumGreen, CEP 18/SpectrumAqua, Vysis/Abbott) on an uncultured amniocyte. Three copies of the aqua signal are present in the cells (CEP 18). Two copies of the green signal (CEP X) confirm a female fetus

Trisomy 18 Syndrome

Tuberous Sclerosis

Tuberous sclerosis is the second most common neurocutaneous syndrome after neurofibromatosis. The term “tuberous sclerosis” derived from the “tubers” (swellings or protuberances) and areas of “sclerosis” (hardening) of the cerebral gyri that calcifies with age. The classic description of the syndrome includes Bogt’s triad: mental retardation, seizures, and adenoma sebaceum (a misnomer) or facial angiofibromas. Tuberous sclerosis affects about 1 in 6,000 newborns (Osborne et al. 1991).

Synonyms and Related Disorders Tuberous sclerosis complex

Genetics/Basic Defects 1. Inheritance a. Autosomal dominant i. Almost complete penetrance ii. Extremely variable in its manifestations and severity b. Sporadic (new mutations) in two thirds of cases 2. Caused by mutations in either of the following two tuberous sclerosis complex (TSC) genes (Curatolo et al. 2008) a. TSC1 i. Located on chromosome 9q34 ii. Encodes protein, hamartin (TSC1), a protein implicated in regulating cell adhesion via

interactions with cortical actin filaments and a plasma membrane binding protein ezrin-radixin-moesin, part of a Rhomediated signaling pathway iii. Approximately 50% of tuberous sclerosis families show linkage to TSC1. iv. Mutations occurrence: 10–15% of sporadic cases v. Most described mutations in the TSC1 gene result in a truncated protein. vi. Phenotype: less severe b. TSC2 i. Located on chromosome 16p13.3 ii. Encodes protein, tuberin (TSC2), a protein implicated in regulating cytoplasmic vesicle transport to the cell membrane iii. Approximately 50% of families show linkage to TSC2. iv. Mutation occurrence: 75–80% of sporadic cases v. Many mutations in the TSC2 gene are large (contiguous) deletions, which may involve the PKD1 gene, resulting in a severe phenotype called very early onset polycystic kidney disease. vi. Phenotype: more severe 3. Both TSC1 and TSC2 a. Have properties consistent with tumor suppressor genes functioning according to Knudson’s “two-hit” hypothesis (Yeung 2003) b. The clinical variability occurs secondary to the random nature of the second “hit” in individuals carrying a germ line mutation.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_237, # Springer Science+Business Media, LLC 2012

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c. Loss of heterozygosity for TSC1 or TSC2 gene i. Suggests that 1 mutation is acquired embryonically and another is acquired later on somatically (two-hit hypothesis) ii. Observed in 41% of all hamartomas including renal angiomyolipomas, cardiac rhabdomyomas, and subependymal giant cell astrocytomas 4. Hamartin and tuberin a. Widely expressed in the brain b. May interact as part of a cascade pathway that modulates cellular differentiation, tumor suppression, and intracellular signaling 5. Mosaicism in tuberous sclerosis reported a. Somatic mosaicism: The mutation is not found in all cell lines. b. Gonadal mosaicism: The mutation found only in gonadal cells and is therefore transmitted to offspring while parents are spared from any disease manifestation. 6. Genotype-phenotype correlations (Dabora et al. 2001) a. Overlap of many clinical features exists among the patients with TSC1 and TSC2 mutations. b. Sporadic patients with TSC1 mutations i. On average, milder phenotypic manifestations compared with patients with TSC2 mutations ii. Lower frequencies of seizures iii. Lower frequencies of moderate to severe mental retardation iv. Fewer subependymal nodules and cortical tubers v. Less severe kidney involvement vi. No retinal hamartomas vii. Less severe facial angiofibroma c. Some features are rare or not seen at all in TSC1 patients. i. Grade 2–4 kidney cysts or angiomyolipomas ii. Forehead plaques iii. Retinal hamartomas iv. Liver angiomyolipomas d. Both germ line and somatic mutations are less common in TSC1 than TSC2. e. Patients without mutation i. Milder than patients with TSC2 mutations ii. Somewhat distinct from patients with TSC1 mutations

Tuberous Sclerosis

Clinical Features 1. Characteristic cutaneous features (virtually 100% of cases) (Schwartz et al. 2007) a. Hypomelanotic macules (“ash-leaf spots”) (87–100% of cases) i. One of the earliest skin lesions (often present at birth) ii. Commonly on trunk and buttocks, rarely on the face, and best appreciated by the Wood’s fluorescence lamp iii. Not specific to tuberous sclerosis because they are seen in unaffected children iv. Smaller depigmented spots over the anterior shins: characteristically distributed in a “confetti” fashion (clustered skin lesions with a reticulated appearance) b. Shagreen patches (a form of collagenomas) (20–80%) i. Elevated discolored skin lesions commonly over lumbosacral region, observed in about 21% of patients ii. Age at presentation: birth to adulthood c. Facial angiofibromas (47–90%) i. One of the most common and specific cutaneous manifestations ii. Causing the most disfigurement among the skin lesions iii. Red to brown nodules, observed over the nose and cheeks in bilaterally symmetrical butterfly distribution. Rarely segmental tuberous sclerosis may present as unilateral facial angiofibromas. iv. Age of presentation a) Usually appear after 2 years of age b) Increase in size and number of facial angiofibromas with time c) Observed in about 80% of adults with tuberous sclerosis v. Chance of small and discrete papules of facial angiofibromas to become confluent and fungating lesions d. Forehead fibrous plaque (15%) i. Large fibromas without angiomatous appearance on the scalp or the forehead areas

Tuberous Sclerosis

ii. Yellowish-brown or skin-colored plaques of variable size and shape usually located on the forehead or scalp iii. Present at any age and can be seen at birth or early infancy e. Periungual fibromas (17–87%) i. Skin-colored or reddish nodules seen on the lateral nail groove, nail plate, or along the proximal mail folds ii. More commonly found on the toes than on the fingers iii. Characteristically appear during puberty and persist through life f. Cafe´ au lait spots: seen in 15–30% of patients with tuberous sclerosis g. “Confetti-like” macules (2.8%) i. Multiple, 1–2 mm white spots symmetrically distributed over extremities ii. Present at the second decade or adulthood h. Molluscum fibrosum pendulum (skin tags) (23%) i. Multiple soft pedunculated skin growths on neck, rarely in axilla or groin ii. More common during first decade of life, rarely during infancy 2. CNS abnormalities (the most common manifestations of the disorder) a. Epilepsy i. The major neurologic manifestation, affecting 85% of patients ii. Onset usually at few months of age iii. Typically with initial classic hypsarrhythmia and infantile spasms, which transform into adult-type partial complex or tonic-clonic seizures iv. Carries a poor prognosis with cognitive impairment v. Intractable seizures b. Presence of cortical “tubers” (O’Callaghan 2008) i. A pathognomonic sign ii. Tubers are developmental abnormalities of the cerebral cortex. iii. The lesions have lost the normal sixlayered laminar architecture of the cerebral cortex and contain dysplastic neurones, astrocytes, and characteristic giant cells.

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iv. Tubers can be identified in fetal life and persist throughout life. v. Tubers do not increase in number after birth, although they may become more visible on magnetic resonance imaging as the brain myelinates in the first 2–3 years of life. c. Subependymal nodules (abnormal neuronal and glial elements): the most common cerebral lesion d. Cortical or subcortical white matter tubers (70% of cases) i. Composed of abnormal giant astrocytes ii. Found in 90% of patients with tuberous sclerosis iii. Large cortical tubers may occasionally block the foramen of Monro resulting in hydrocephalus. e. Subependymal giant cell astrocytomas i. The most common CNS tumors (6–14%) ii. Subependymal nodules, small hamartoma lining the ventricles, may calcify. iii. A radiologically confirmed cortical tuber or calcified subependymal nodule are highly suggestive of tuberous sclerosis. iv. Rare malignant transformation of these astrocytomas, accounting for 25% of deaths in tuberous sclerosis f. Other abnormalities i. Cerebral atrophy ii. Cerebral infarct iii. Cerebral aneurysm iv. Arachnoid cyst v. Chorea (rare manifestation) (Sha et al. 2009) 3. Developmental disorders (>50%) a. Childhood i. Learning disabilities ii. Behavioral problems iii. Pervasive developmental disorder iv. Autism more common in childhood v. Hyperactivity or attention deficit hyperactivity disorder (ADHD) vi. Aggression b. Adulthood: mental retardation present in less than 50% of the affected individuals 4. Ocular involvement (at least 50% of the patients) a. Retinal and optic nerve astrocytic hamartomas (the most frequent manifestations) b. Retinal phakoma

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i. Astrocytomas of the retina ii. Often called “mulberry lesions” iii. Absence of the normal “red reflex” in the newborn suggests the presence of retinal phakoma. c. Visual loss resulting from i. Macular hamartoma ii. Vitreous hemorrhage iii. Papilledema or optic atrophy secondary to intracranial tumors d. Rare sector hypopigmentation of the iris, vitiligo, or poliosis of the eyelid and eyelashes 5. Dental involvement: important findings a. Pitting of the dental enamel i. Invariably present in the permanent teeth ii. Seen in the primary (deciduous) teeth (30%) iii. Rarely produce symptoms b. Gingival angiofibromas (50% of children; 70% of adults) 6. Neoplasms affecting heart, kidneys, lungs, and other organ systems a. Cardiac rhabdomyomas (Caldemeyer and Mirowsk 2001) i. The commonest cardiac tumors of childhood and are often associated with TSC ii. The earliest diagnostic finding in some patients detected on prenatal sonography iii. Detected by echocardiography, rarely causing problems iv. Observed in two thirds of affected children. However, more than 80% of children with cardiac rhabdomyomas have tuberous sclerosis. v. Usually resolve spontaneously or regress with age vi. A rare cause of prenatal and neonatal cardiac failure, mostly from dysrhythmias vii. Rare tumor obstruction to cardiac valves or chambers b. Renal cysts or angiomyolipomas (70–80% of patients) i. Bilateral multiple renal angiomyolipomas (70%) a) Diagnostic of tuberous sclerosis b) Renal angiomyolipomas are benign tumors but contain vascular tissue,

Tuberous Sclerosis

which may cause bleeding, hypovolemic shock, and renal failure. ii. Epithelial cysts (20%) iii. Polycystic kidney disease (2–3%) iv. Rare occurrence of renal cell carcinoma (8 cm) in one sac (the recipient twin persistently has a distended bladder and produces a large amount of urine) b) Presence of oligohydramnios (largest pocket 0.4 predicting growth discordancy of at least 350 g iv. Ultrasound-guided fetal blood sampling a) Establishing the diagnosis of monozygosity when blood group studies are performed on both twins b) Allowing an accurate antenatal assessment of the inter-twin hemoglobin difference and consequently establishing the diagnosis of twin–twin transfusion c) Revealing the degree of fetal anemia in the donor twin c. Fetoscopy i. Plethora donor twin ii. Pale recipient twin 3. Management a. General approach i. Monochorionic twining at high risk for twin–twin transfusion syndrome ii. Requiring close obstetrical monitoring iii. Requiring specialized care in neonatal intensive care unit b. Postpartum therapies i. Directed towards the problems of each twin, such as prematurity, anemia, polycythemia, and hydrops fetalis ii. Severely anemic donor twin: requires packed red blood cell transfusions or partial exchange transfusions iii. Polycythemic recipient twin: requires partial exchange transfusion to lower serum hematocrit c. Prenatal therapies (van Gemert et al. 2001; Ropacka et al. 2002; Gardiner et al. 2003; Walker et al. 2007)

Twin–Twin Transfusion Syndrome

i. Treating the mother with digoxin with favorable results when the recipient twin is showing signs of cardiac failure ii. Treatment options a) Prevent preterm labor and preterm premature rupture of the membranes from polyhydramnios (amniodrainage and septostomy) b) Isolate the twin circulations (cord ligation and selective laser photocoagulation) iii. Serial amniodrainage (amnioreduction): currently the most widely used therapy because it is simple and requires commonly available skills and equipment a) Removing large volumes of amniotic fluid from the recipient twin’s sac b) Reducing the amniotic fluid volume, thereby reducing the risk of preterm labor or ruptured membranes c) Overall perinatal survival with serial aggressive amnioreduction: about 60% in uncontrolled published series d) Double survival rate (50%) and single survival rate (20%) in severe twin–twin transfusion syndrome presenting before 28 weeks of gestation e) Fail to address the underlying cause of twin–twin transfusion syndrome f) Complications: uterine contractions, premature rupture of membranes, chorioamnionitis, abruptio placenta, and inadvertent septostomy resulting in iatrogenic monoamniotic twins iv. Amniotic septostomy: intentionally puncturing the intertwine septum a) To create a hole in the intertwine membrane between the anhydramniotic donor’s sac and the hydramniotic recipient’s sac b) Restoring normal amniotic fluid pressure gradient, allowing fluid to move along a hydrostatic gradient from the hydramnios sac into the oligohydramnios sac c) Also an inadvertent occurrence during amnioreduction procedure d) Limited experience

Twin–Twin Transfusion Syndrome

v. Endoscopic laser coagulation of all placental vascular anastomosis (Wee and Fisk 2002) a) Reduces and abolishes intertwine transfusion by ablating chorionic plate anastomoses, producing functionally dichorionic pregnancies b) Proponents arguing that the procedure reduces the risk of neurological injury in survivors c) Overall survival rate (58%) with single survival of 32% and double survival of 42% for cases presenting prior to 18 weeks d) Rare fetal complications (relationship to the procedure not established): aplasia cutis, limb necrosis, amniotic bands, and microphthalmia/anophthalmia vi. Selective feticide by cord occlusion (umbilical cord ligation): used as a last resort in cases in which both twins are at risk because of the serious condition of one twin a) Considered in case of monochorionic twin pregnancy in which one twin is a nonviable fetus, especially the condition is compromising the nonaffected fetus b) A typical example in twin reversed arterial perfusion sequence. The relatively normal twin risks high-output cardiac failure, complications of polyhydramnios, and death in utero. c) Another example of twin–twin transfusion syndrome, in which one fetus has major congenital anomalies or in utero–acquired abnormality, such as demonstrable cerebral lesions, terminal cardiac failure, or other conditions with a poor prognosis d) Benefits of selective termination of the affected twin: arrest the fetofetal transfusion process and protect the survivor vii. In general, twin–twin transfusion syndrome diagnosed before 26 weeks of gestation has significantly better survival rates and fewer neurological sequelae after laser ablation therapy than amnioreduction. Twin–twin transfusion syndrome diagnosed after 26 weeks can best be treated by amnioreduction or delivery.

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References Banek, C. S., Hecher, K., Hackeloer, B. J., et al. (2003). Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome. American Journal of Obstetrics and Gynecology, 188, 876–880. Barss, V. A., Benacerraf, B. R., & Frigoletto, F. D. (1985). Ultrasonographic determination of chorion type in twin gestation. Obstetrics and Gynecology, 66, 779–783. Bebbington, M. (2010). Twin-to-twin transfusion syndrome: Current understanding of in-utero therapy and impact for future development. Seminars in Fetal & Neonatal Medicine, 15, 15–20. Berghella, V., & Kaufmann, M. (2001). Natural history of twintwin transfusion syndrome. The Journal of Reproductive Medicine, 46, 480–484. Bermu´dez, C., Becerra, C. H., Bornick, P. W., et al. (2002). Placental types and twin-twin transfusion syndrome. American Journal of Obstetrics and Gynecology, 187, 489–494. Blickstein, I. (1990). The twin-twin transfusion syndrome. Obstetrics and Gynecology, 76, 714–722. Chiang, M. C., Lien, R., Chao, A. S., et al. (2003). Clinical consequences of twin-to-twin transfusion. European Journal of Pediatrics, 162, 68–71. Cincotta, R. B., & Fisk, N. M. (1997). Current thoughts on Twintwin transfusion syndrome. Clinical Obstetrics and Gynecology, 40, 290–302. Crombleholme, T. M. (2003). The treatment of twin-twin transfusion syndrome. Seminars in Pediatric Surgery, 12, 175–181. de Laat, M. W. M., Manten, G. T. R., Nikkels, P. G. J., et al. (2009). Hydropic placenta as a first manifestation of twin-twin transfusion in a monochorionic diamniotic twin pregnancy. Journal of Ultrasound in Medicine, 28, 375–378. De Lia, J., Emery, M. G., Sheafor, S. A., et al. (1985). Twin transfusion syndrome: Successful in utero treatment with digoxin. International Journal of Gynaecology and Obstetrics, 23, 197–201. De Lia, J., Fisk, N., Hecher, K., et al. (2000). Twin-to-twin transfusion syndrome–debates on the etiology, natural history and management. Ultrasound in Obstetrics & Gynecology, 16, 210–213. Deprest, J. A., Audibert, F., van Schoubroeck, D., et al. (2000). Bipolar coagulation of the umbilical cord in complicated monochorionic twin pregnancy. American Journal of Obstetrics and Gynecology, 182, 340–345. Duncombe, G. J., Dickinson, J. E., & Evans, S. F. (2003). Perinatal characteristics and outcomes of pregnancies complicated by twin-twin transfusion syndrome. Obstetrics and Gynecology, 101, 1190–1196. Gardiner, H. M., Taylor, M. J., Karatza, A., et al. (2003). Twintwin transfusion syndrome: The influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation, 107, 1906–1911. Jauniaux, E., Holmes, A., Hyett, J., et al. (2001). Rapid and radical amniodrainage in the treatment of severe twintwin transfusion syndrome. Prenatal Diagnosis, 21, 471–476.

2120 Johnson, J. R., Rossi, K. Q., & O’Shaughnessy, R. W. (2001). Amnioreduction versus septostomy in twin-twin transfusion syndrome. American Journal of Obstetrics and Gynecology, 185, 1044–1047. Mari, G., Detti, L., Oz, U., et al. (2000). Long-term outcome in twin-twin transfusion syndrome treated with serial aggressive amnioreduction. American Journal of Obstetrics and Gynecology, 183, 211–217. Quintero, R. A. (2003). Twin-twin transfusion syndrome. Clinics in Perinatology, 30, 591–600. Quintero, R. A., Dickinson, J. E., Morales, W. J., et al. (2003). Stage-based treatment of twin-twin transfusion syndrome. American Journal of Obstetrics and Gynecology, 188, 1333–1340. Quintero, R. A., Martinez, J. M., Bermudez, C., et al. (2002). Fetoscopic demonstration of perimortem feto-fetal hemorrhage in twin-twin transfusion syndrome. Ultrasound in Obstetrics & Gynecology, 20, 638–639. Quintero, R. A., Morales, W. J., Allen, M. H., et al. (1999). Staging of twin-twin transfusion syndrome. Journal of Perinatology, 19, 550–555. Ropacka, M., Markwitz, W., & Blickstein, I. (2002). Treatment options for the twin-twin transfusion syndrome: A review. Twin Research, 5, 507–514. Senat, M. V., Bernard, J. P., Loizeau, S., et al. (2002). Management of single fetal death in twin-to-twin transfusion syndrome: A role for fetal blood sampling. Ultrasound in Obstetrics & Gynecology, 20, 360–363.

Twin–Twin Transfusion Syndrome Seng, Y. C., & Rajadurai, V. S. (2000). Twin-twin transfusion syndrome: A five year review. Archives of Disease in Childhood. Fetal and Neonatal Edition, 83, F168–F170. Taylor, M. J., Govender, L., Jolly, M., et al. (2002). Validation of the Quintero staging system for twin-twin transfusion syndrome. Obstetrics and Gynecology, 100, 1257–1265. Taylor, M. J., Wee, L., & Fisk, N. M. (2003). Placental types and twin-twin transfusion syndrome. American Journal of Obstetrics Gynecology, 188, 1119; author reply 1119–1120. van Gemert, M. J., Umur, A., Tijssen, J. G., et al. (2001). Twintwin transfusion syndrome: Etiology, severity and rational management. Current Opinion in Obstetrics & Gynecology, 13, 193–206. Walker, S. P., Cole, S. A., & Edwards, A. G. (2007). Twin-totwin transfusion syndrome: Is the future getting brighter? The Australian and New Zealand Journal of Obstetrics and Gynaecology, 47, 158–168. Weber, M. A., & Sebire, N. J. (2010). Genetics and developmental pathology of twinning. Seminars in Fetal & Neonatal Medicine, 15, 313–318. Wee, L. Y., & Fisk, N. M. (2002). The twin-twin transfusion syndrome. Seminars in Neonatology, 7, 187–202. Weiner, C. P., & Ludomirski, A. (1994). Diagnosis, pathophysiology, and treatment of chronic twin-to-twin transfusion syndrome. Fetal Diagnosis and Therapy, 9, 283–290.

Twin–Twin Transfusion Syndrome

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a

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Fig. 1 (a, b) Diamniotic monochorionic twin placenta with features of twin–twin transfusion (the placental discs are not fused in this case): The placenta corresponding to the recipient twin (right) is small but plethoric and dark in color. The placenta of the donor twin (left) is large but anemic, pale, and edematous.

The amniotic sacs were removed at the margins of the placental discs. The root of the thin monochorionic septum between the two sacs is shown on the fetal surface (first picture). The color difference between the two placentas is better shown on the maternal surface (second picture)

Fig. 2 The donor twin (right) showing smaller and pallor and the recipient twin (left) showing larger and plethoric at birth

Ulnar-Mammary Syndrome

Ulnar-mammary syndrome was originally described by Gilly in 1882 in a woman with mammary hypoplasia, inability to lactate, and absence of the third to fifth digits and ulna. Later in 1978, Pallister et al. reported a complex malformation syndrome in a young woman with abnormal development of ulnar rays, forearms, mammary gland tissue, axillary apocrine glands, teeth, palate, vertebral column, and urogenital system. Ulnar-mammary syndrome is a pleiotropic disorder affecting limb, apocrine gland, teeth, hair, and genital development.

Synonyms and Related Disorders Pallister ulnar-mammary syndrome

syndrome;

Schinzel

Genetics/Basic Defects 1. Inheritance: autosomal dominant with variable expression 2. A gene for ulnar-mammary syndrome mapped to chromosome 12q23-q24.1 3. Caused by mutations that disrupt the DNA-binding domain of the T-box gene, TBX3 4. Mutations in human TBX3 alter limb, apocrine, and genital development in ulnar-mammary syndrome (Bamshad et al. 1997). 5. No obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts

Clinical Features 1. Posterior limb defects a. Widely variable b. Ulnar ray defects in most patients i. Hypoplasia of the terminal phalanx of the fifth digit ii. Hypoplasia or complete absence of the ulna and third, fourth, and fifth digits c. Postaxial digital duplications d. Camptodactyly e. Digital fusion 2. Apocrine gland abnormalities a. Mammary gland abnormalities: variable i. Hypoplasia to aplasia of the mammary glands and hypoplasia of the nipples ii. Accessory nipples iii. Inability to nipple feed iv. Normal breast development and lactation b. Decreased ability to sweat c. Reduced body odor d. Absent axillary perspiration e. Sparse axillary hair 3. Genital abnormalities: hypogenitalism a. Affected males i. Delayed puberty ii. Diminished to absent axillary hair iii. Micropenis iv. Cryptorchidism v. Small testes vi. Shawl scrotum vii. Reduced fertility b. Affected females i. Diminished to absent axillary hair ii. Imperforate hymen in some affected females

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4. Dental abnormalities a. Misplaced teeth b. Absent teeth c. Hypodontia 5. Other abnormalities a. Delay puberty b. Short stature c. Obesity d. Scanty lateral eyebrows e. Subglottic stenosis f. Pyloric stenosis g. Renal agenesis/malformation h. Pulmonary hypoplasia i. Inguinal hernia j. Anal atresia/stenosis k. Musculoskeletal abnormalities i. Short forearms ii. Hypoplastic humeri, scapulae, and clavicles iii. Hypoplastic pectoralis major muscles iv. Short, stiff, and crooked terminal phalanges of fourth to fifth toes 6. Differential diagnosis a. Hand-foot-uterus syndrome i. Autosomal dominant disorder ii. Allelic to ulnar-mammary syndrome speculated iii. Manifestations similar to ulnar-mammary syndrome include the following: a) Digital hypoplasia b) Carpal fusion c) Supernumerary nipples d) Genital anomalies b. Split hand/split foot syndrome: a causal relationship to ulnar-mammary syndrome suggested c. Scalp-ear-nipple syndrome: overlapping manifestations with ulnar-mammary syndrome i. Mammary hypoplasia ii. Diminished axillary perspiration iii. Dental abnormalities iv. Digital syndactyly: characteristic limb anomaly found in this syndrome (vs limb deficiency or duplications in ulnarmammary syndrome)

Diagnostic Investigations 1. Radiography a. Short and stiff fifth finger b. Absent fifth finger ray

Ulnar-Mammary Syndrome

c. d. e. f. g. h. i.

Absent fourth finger ray Absent fourth to fifth finger rays Absent third to fifth finger rays Camptodactyly Hypoplastic/absent/deformed ulna Hypoplastic/absent/deformed radius Hypoplastic humerus, scapula, clavicle, and pectoralis major muscle j. Absent xiphisternum k. Postaxial polydactyly l. Short, stiff fourth and fifth toes 2. Endocrine investigations for hypogenitalism 3. Mutation analysis a. Missense mutations (L143P and Y149S) b. Nonsense mutation (Q360TER, S343TER) c. Splice-site mutations (IVS2 + 1G ! C, IVS6 + 2T ! A) producing a truncated protein product d. Frameshift mutations of small duplications

Genetic Counseling 1. Recurrence risk a. Patient’s sib: not increased unless a parent is affected b. Patient’s offspring: 50% 2. Prenatal diagnosis a. Ultrasonography and fetoscopy: possible to pregnancy at risk with presence of obvious fetal skeletal anomalies b. Mutation analysis of amniocytes and CVS: possible to families with identified mutation causing ulnar-mammary syndrome 3. Management a. Orthopedic management of limb defects b. Orchiopexy for cryptorchidism c. Testosterone management for hyogonadism in male patients d. Bottle feeding of infants born to mothers who has hypoplastic or absent nipples

References Bamshad, M., Krakowiak, P. A., Watkins, W. S., et al. (1995). A gene for ulnar-mammary syndrome maps to 12q23-q24.1. Human Molecular Genetics, 4, 1973–1977.

Ulnar-Mammary Syndrome Bamshad, M., Le, T., Watkins, W. S., et al. (1999). The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnarmammary syndrome. American Journal of Human Genetics, 64, 1550–1562. Bamshad, M., Lin, R. C., Law, D. J., et al. (1997). Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nature Genetics, 16, 311–315. Bamshad, M., Root, S., & Carey, J. C. (1996). Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome. American Journal of Medical Genetics, 65, 325–331. Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., et al. (2002). TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. Journal of Biological Chemistry, 277, 6567–6572. Carlson, H., Ota, S., Campbell, C. E., et al. (2001). A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: Relevance to mutations in Tbx3 that cause ulnar-mammary syndrome. Human Molecular Genetics, 10, 2403–2413. Coll, M., Seidman, J. G., & Muller, C. W. (2002). Structure of the DNA-bound T-box domain of human TBX3, a transcription factor responsible for ulnar-mammary syndrome. Structure (Cambridge), 10, 343–356. Davenport, T. G., Jerome-Majewska, L. A., & Papaioannou, V. E. (2003). Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development, 130, 2263–2273. Edwards, M. J., McDonald, D., Moore, P., et al. (1994). Scalpear-nipple syndrome: Additional manifestations. American Journal of Medical Genetics, 50, 247–250. Franceschini, P., Vardeu, M. P., Dalforno, L., et al. (1992). Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. American Journal of Medical Genetics, 44, 807–812. Froster, G. U., & Baird, P. A. (1992). Upper limb deficiencies and associated malformations: A population-based study. American Journal of Medical Genetics, 44, 767–781. Gilly, E. (1882). Absence comple`te des mamelles chez une femme me`re: Atrophie du member superieur droit. Courrier Medicine, 32, 27–28.

2125 Gonzalez, C. H., Herrmann, J., & Opitz, J. M. (1976). Studies of malformation syndromes of man XXXXIIB: Mother and son affected with the ulnar-mammary syndrome type Pallister. European Journal of Pediatrics, 123, 225–235. He, M., Wen, L., Campbell, C. E., et al. (1999). Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome. Proceedings of the National Academy of Sciences of the United States of America, 96, 10212–10217. Hecht, J. T., & Scott, C. I. (1984). The Schinzel syndrome in a mother and daughter. Clinical Genetics, 25, 63–67. Pallister, P. D., Hermann, J., & Opitz, J. M. (1976). Studies of Malformation Syndromes in Man XXXXII: A pleiotropic dominant mutation affecting skeletal, sexual and apocrinemammary development. Birth Defects Original Article Series, XII(5), 247–254. Rogers, C., & Anderson, G. (1995). Hand-foot-uterus syndrome vs. ulnar-mammary syndrome in a patient with overlapping phenotypic features. Proceedings of the Greenwood Genetic Center, 14, 17–20. Sasaki, G., Ogata, T., Ishii, T., et al. (2002). Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: Implication for impaired sex development. American Journal of Medical Genetics, 110, 365–369. Schinzel, A. (1987). Ulnar-mammary syndrome. Journal of Medical Genetics, 24, 778–781. Schinzel, A., Illig, R., & Prader, A. (1987). The ulnar-mammary syndrome: An autosomal dominant pleiotropic gene. Clinical Genetics, 32, 160–168. Sherman, J., Angulo, M. A., & Sharp, A. (1986). Mother and infant son with ulnar-mammary syndrome of Pallister plus additional findings. American Journal of Human Genetics, 39, A82. van Bokhoven, H., Jung, M., Smits, A. P., et al. (1999). Limb mammary syndrome: A new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. American Journal of Human Genetics, 64, 538–546. Wollnik, B., Kayserili, H., Uyguner, O., et al. (2002). Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Annales de Genetique, 45, 213–217.

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a

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c

d

Fig. 1 A newborn (a, b) with ulnar mammary syndrome showing ulnar hypoplasia (missing fourth and fifth fingers) (c), ectrodactyly, syndactyly, and hypoplasia of the breast and

nipples (d). The infant also had cryptorchidism, anal atresia, pulmonary hypoplasia, pyloric stenosis, and bilateral renal hypoplasia

Urofacial Syndrome

Urofacial syndrome, also known as Ochoa syndrome is characterized by severe voiding dysfunction and peculiar facies, i.e., inversion of facial expression with grimacing while smiling (Ochoa and Gorlin 1987; Ochoa 1992, 2004).

Synonyms and Related Disorders Ochoa syndrome

Genetics/Basic Defects 1. Autosomal recessive inheritance based on: a. Affected siblings b. Normal parents c. Presence of consanguinity 2. Mutations with a loss of function in the Heparanase 2 (HPSE2) gene were identified in all urofacial syndrome patients originating from Colombia, the United States, and France (Pang et al. 2010) a. HPSE2 encodes a 592 aa protein that contains a domain showing sequence homology to the glycosyl hydrolase motif in the heparanase (HPSE) gene, but its exact biological function has not yet been characterized. b. Complete loss of HPSE2 function in urofacial syndrome patients suggests that HPSE2 may be important for the synergic action of muscles implicated in facial expression and urine voiding. 3. Biallelic mutations in HPSE2 gene on chromosome 10q23-q24, predicted to abolish activity of heparanase 2, cause urofacial syndrome in families from different ethnic groups (Daly et al. 2010).

Clinical Features 1. Characteristic facial expression a. Inversion of the facial expression when attempting to smile or laugh b. Facial grimace while smiling c. Smile looking like weeping d. Peculiar facial expression on smiling 2. Urinary manifestations a. Bladder dysfunction i. Intermittent urinary flow ii. Residual urine after voiding iii. Enuresis iv. Polyuria b. Urinary tract infection c. Hydronephrosis 3. Constipation 4. The urinary abnormalities may lead to renal deterioration and ultimate failure if untreated.

Diagnostic Investigations 1. 2. 3. 4.

Renal ultrasonography Renal scan Voiding cystourethrogram (VCUG) Urodynamic studies

Genetic Counseling 1. Recurrence risk a. Patient’s sib: 25% b. Patient’s offspring: not increased unless the spouse is a carrier or affected

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2. Prenatal diagnosis: not yet reported 3. Management (Aydogdu et al. 2010) a. Intermittent urinary catheterization b. Appendicovesicostomy may be required for continent urinary diversion. c. Nocturnal bladder emptying with an indwelling nighttime catheter for polyuria d. Antibiotic prophylaxis e. Anticholinergic therapy f. Intravesical botulinium toxin injection g. Bowel management h. Augumentation cystoplasty

References Al-Qahtani Fakherah, N. (2003). Ochoa syndrome: New features. Saudi Journal of Kidney Diseases and Transplantation, 14, 61–64. As, T., Farag, T. I., el-Khalifa, M. Y., et al. (1989). Urofacial syndrome. American Journal of Medical Genetics, 34, 608. Aydogdu, O., Burgu, B., & Demirel, F. (2010). Ochoa syndrome: a spectrum of urofacial syndrome. European Journal of Pediatrics, 169, 431–435. Bertolotti, A. F., Gonzalez, S. G., & Etheveny, R. M. (2007). Ochoa’s syndrome in Argentine. Cirugı´a Pedia´trica, 20, 54–56. Chauve, X., Missirian, C., Malzac, P., et al. (2000). Genetic homogeneity of the urofacial (Ochoa) syndrome confirmed in a new French family. American Journal of Medical Genetics, 95, 10–12. Dalibor, K., Phillip, M., Chaitanya, P., et al. (2008). Urofacial (Ochoa) syndrome – A case report and review of literature. Personal communication. Daly, S. B., Urquhart, J. E., Hilton, E., et al. (2010). Mutations in HPSE2 cause urofacial syndrome. American Journal of Human Genetics, 86, 963–969. Elejalde, B. R. (1979). Genetic and diagnostic considerations in three families with abnormalities of facial expression and congenital urinary obstruction: ‘The Ochoa syndrome’. American Journal of Medical Genetics, 3, 97–108.

Urofacial Syndrome Feng, W. C., & Churchill, B. M. (2001). Dysfunctional elimination syndrome in children without obvious spinal cord diseases. Pediatric Clinics of North America, 48, 1489–1504. Garcia-Minaur, S., Oliver, F., Yanez, J. M., et al. (2001). Three new European cases of urofacial (Ochoa) syndrome. Clinical Dysmorphology, 10, 165–170. Madonia, P., Kurepa, D., Pant, C., et al. (2010). Urofacial (Ochoa) syndrome – A case report and review of literature. Personal communication. Munoz Fernandez, M. E., Rodo Salos, J., Groinde Moreillo, C., et al. (2001). [Urofacial Ochoa’s syndrome: A clinical case]. Actas Urologicas Espan˜olas, 25, 578–581. Nicanor, F. A., Cook, A., & Pippi-Salle, J. L. (2005). Early diagnosis of the urofacial syndrome is essential to prevent irreversible renal failure. International Brazilian Journal of Urology, 31, 477–481. Ochoa, B. (1992). The urofacial (Ochoa) syndrome revisited. Journal of Urology, 148, 580–583. Ochoa, B. (2004). Can a congenital dysfunctional bladder be diagnosed from a smile? The Ochoa syndrome updated. Pediatric Nephrology, 19, 6–12. Ochoa, B., & Gorlin, R. J. (1987). Urofacial (Ochoa) syndrome. American Journal of Medical Genetics, 27, 661–667. Pang, J., Zhang, S., Yang, P., et al. (2010). Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. American Journal of Human Genetics, 86, 957–962. Skalova, S., Rejtar, I., Novak, I., et al. (2006). The urofacial (Ochoa) syndrome-first case in the central European population. Prague Medical Report, 107, 125–129. Teebi, A. S., & Hassoon, M. M. (1991). Urofacial syndrome associated with hydrocephalus due to aqueductal stenosis. American Journal of Medical Genetics, 40, 199–200. Wang, C.-Y., Hawkints-Lee, B., Ochoa, B., et al. (1997). Homozygosity and linkage-disequilibrium mapping of the urofacial (Ochoa) syndrome gene to a 1-cM interval on the chromosome 10q23-q24. American Journal of Human Genetics, 60, 1461–1467. Wang, C. Y., Huang, J. Q., She, J. D., et al. (1999). Genetic homogeneity, high-resolution mapping, and mutation analysis of the urofacial (Ochoa) syndrome and exclusion of the glutamate oxaloacetate transaminase gene (GOT1) in the critical region as the disease gene. American Journal of Medical Genetics, 84, 454–459.

Urofacial Syndrome

Fig. 1 This 7-year-old girl presented with vague abdominal discomfort associated with nausea, nonbilious vomiting, and weight loss for past 8–10 weeks duration. Abdominal CT revealed bilateral hydronephrosis. Note the “grimace” facial appearance after smiling

Fig. 2 Patient’s CT scan of the abdomen showed bilateral hydronephrosis

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Fig. 3 Patient’s VCUG showed smooth bladder wall

VATER (VACTERL) Association

VATER association is an acronym for the following nonrandom association of defects: Vertebral defects, Anal atresia, Tracheoesophageal fistula with Esophageal atresia, and Renal or Radial defects. VACTERL association is an expanded acronym to include Cardiac defects and Limb defects. Diagnosis of VACTERL association is made if three out of the seven above defects are present in an infant. The incidence is estimated to be 1.6 cases in 10,000 live births.

Genetics/Basic Defects 1. Etiologic heterogeneity a. Isolated cases in most cases b. Reports of rare familial cases (single gene disorders) c. Reports of chromosome abnormality cases d. Recognized syndromes or phenotypes e. Observed more frequently in infants of diabetic mothers 2. Pathogenesis: suggestion of a defective mesodermal development during embryogenesis due to a variety of causes, leading to overlapping manifestations (Khoury et al. 1983) 3. Molecular basis of VACTERL association a. Report of a family in which a female infant was born and died at age 1 month due to renal failure. The mother and sister later developed classic mitochondrial cytopathy, associated with the A-to-G point mutation at nucleotide position 3,243 of mitochondrial DNA (Damian et al. 1996).

b. Mitochondrial NP 3243 point mutation considered not a common cause of VACTERL association (Damian et al. 1996) c. Sonic hedgehog in the human: a possible explanation for the VATER association (Arsic et al. 2002) d. Recently, microdeletions of the FOX gene cluster at 16q24.1, comprising four genes, FOXF1, MTHFSD, FOXC2, and FOXL1, were reported to cause a phenotype resembling VACTERL association, with vertebral anomalies, gastrointestinal atresias (esophageal, duodenal, and anal), congenital heart malformations, and urinary tract malformations, as well as a rare lethal developmental anomaly of the lung, alveolar capillary dysplasia (ShawSmith, 2010)

Clinical Features 1. Vertebral anomalies a. Hemivertebrae b. Fused vertebrae c. Hypersegmentation of the vertebrae d. Hypersegmentation of the ribs e. Scoliosis f. Sacral anomalies g. Incomplete pedicle h. Sternal anomalies 2. Anal and urachal anomalies a. Anal atresia with or without fistula b. Persistent urachus

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3. Cardiac anomalies a. Ventricular septal defects b. Patent ductus arteriosus c. Tetralogy of Fallot d. Transposition of the great arteries e. Other cardiovascular anomalies i. Right aortic arch ii. Double aortic arch iii. Coarctation of the aorta iv. Dextrocardia v. Total anomalous pulmonary venous drainage vi. Left superior vena cava vii. Congenital mitral stenosis viii. Right anomalous coronary artery ix. Single umbilical artery 4. Tracheoesophageal fistula 5. Esophageal atresia 6. Renal anomalies a. Renal agenesis/dysgenesis b. Ectopic kidney c. Horseshoe kidney d. Ureteral/urethral anomalies e. Hydronephrosis f. Renal ectopia g. Vesicoureteral reflux h. Posterior urethral valves i. Ureteropelvic junction obstruction 7. Limb defects a. Radial aplasia/dysplasia b. Hypoplastic thumbs c. Triphalangeal thumb d. Preaxial polydactyly e. Syndactyly f. Radioulnar synostosis 8. Other associated abnormalities a. Failure to thrive b. Short stature c. Wide cranial suture d. Large fontanel e. Potter facies f. Ear anomalies g. Cleft palate h. Gastrointestinal anomalies i. Malrotation ii. Meckel diverticulum iii. Duodenal atresia iv. Pyloric atresia v. Ileal atresia vi. Pancreatic heterotopia

VATER (VACTERL) Association

vii. Vermiform appendix agenesis viii. Omphalocele ix. Inguinal hernia i. Genital anomalies i. Hypospadias ii. Cryptorchidism iii. Bifid scrotum iv. Micropenis j. Neurological anomalies i. Tethered cord ii. Spinal dysraphia iii. Occipital encephalocele k. Anomalies more commonly associated with CHARGE association

Diagnostic Investigations 1. 2. 3. 4. 5. 6.

Radiography for vertebral and limb defects Echocardiography for congenital heart defects GI investigation for TE fistula or esophageal atresia Renal ultrasonography for renal dysplasia Urological evaluation of urogenital defects Chromosome analysis

Genetic Counseling 1. Recurrence risk a. Patient’s sib: low recurrence risk unless in a single gene disorder b. Patient’s offspring: low recurrence risk unless in a single gene disorder 2. Prenatal diagnosis by ultrasonography revealing multiple congenital anomalies compatible to VACTERL association a. Vertebral anomalies b. Anorectal anomalies c. Congenital heart defects d. TE fistula or esophageal atresia e. Renal anomalies f. Limb defects 3. Management a. Medical care b. Surgical care i. TE fistula and/or esophageal atresia ii. Major cardiac defects iii. Urogenital anomalies iv. Skeletal and limb defects

VATER (VACTERL) Association

References Arsic, D., Qi, B. Q., & Beasley, S. W. (2002). Hedgehog in the human: A possible explanation for the VATER association. Journal of Paediatrics and Child Health, 38, 117–121. Auchterlonie, I. A., & White, M. P. (1982). Recurrence of the VATER association within a sibship. Clinical Genetics, 21, 122–124. Barnes, J. C., & Smith, W. L. (1978). The VATER Association. Radiology, 126, 445–449. Botto, L. D., Khoury, M. J., Mastroiacovo, P., et al. (1997). The spectrum of congenital anomalies of the VATER association: An international study. American Journal of Medical Genetics, 71, 8–15. Corsello, G., Maresi, E., Corrao, A. M., et al. (1992). VATER/ VACTERL association: Clinical variability and expanding phenotype including laryngeal stenosis. American Journal of Medical Genetics, 44, 813–815. Czeizel, A., & Ludanyi, I. (1985). An aetiological study of the VACTERL-association. European Journal of Pediatrics, 144, 331–337. Damian, M. S., Seibel, P., Schachenmayr, W., Reichmann, H., et al. (1996). VACTERL with the mitochondrial 3243 point mutation. American Journal of Medical Genetics, 62, 398–403. Fernbach, S. K., & Glass, R. B. (1988). The expanded spectrum of limb anomalies in the VATER association. Pediatric Radiology, 18, 215–220. Heifetz, S. A. (1986). Requirements for the VATER association. American Journal of Diseases of Children, 140, 1098–1099. Iuchtman, M., Brereton, R., Spitz, L., et al. (1992). Morbidity and mortality in 46 patients with the VACTERL association. Israel Journal of Medical Sciences, 28, 281–284. Khoury, M. J., Cordero, J. F., Greenberg, F., et al. (1983). A population study of the VACTERL association: Evidence for its etiologic heterogeneity. Pediatrics, 71, 815–820. Lubinsky, M. S. (1986). Current concepts: VATER and other associations: Historical perspectives and modern interpretations. American Journal of Medical Genetics. Supplement, 2, 6–16.

2133 Martinez-Frias, M. L., Bermejo, E., & Frias, J. L. (2001). The VACTERL association: Lessons from the sonic hedgehog pathway. Clinical Genetics, 60, 397–398. Martinez-Frı´as, M. L., & Frı´as, J. L. (1999). VACTERL as primary polytopic developmental field defects. American Journal of Medical Genetics, 83, 13–16. McGahan, J. P., Leeba, J. M., & Lindfors, K. K. (1988). Prenatal sonographic diagnosis of VATER association. Journal of Clinical Ultrasound, 16, 588–591. Miller, O. F., & Kolon, T. F. (2001). Prenatal diagnosis of VACTERL association. Journal of Urology, 166, 2389–2391. Quan, L., & Smith, D. W. (1973). The VATER association. Vertebral defects, anal atresia, T-E fistula with esophageal atresia, radial and renal dysplasia: A spectrum of associated defects. Journal of Pediatrics, 82, 104–107. Say, B., Greenberg, D., Harris, R., et al. (1977). The radial dysplasia/imperforate anus/vertebral anomalies syndrome (the VATER association): Developmental aspects and eye findings. Acta Paediatrica Scandinavica, 66, 233–235. Shaw-Smith, C. (2010). Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature. European Journal of Medical Genetics, 53, 6–13. Smith, D. W. (1974). The VATER association. American Journal of Diseases of Children, 128, 767. Stone, D. L., & Biesecker, L. G. (1997). Mitochondrial NP 3243 point mutation is not a common cause of VACTERL association. American Journal of Medical Genetics, 72, 237–238. Temtamy, S. A., & Miller, J. D. (1974). Extending the scope of the VATER association: Definition of the VATER syndrome. Journal of Pediatrics, 85, 345–349. Tongsong, T., Wanapirak, C., Piyamongkol, W., et al. (1999). Prenatal sonographic diagnosis of VATER association. Journal of Clinical Ultrasound, 27, 378–384. Weaver, D. D., Mapstone, C. L., & Yu, P. L. (1986). The VATER association. Analysis of 46 patients. American Journal of Diseases of Children, 140, 225–229. Weber, T. R., Smith, W., & Grosfeld, J. L. (1980). Surgical experience in infants with the VATER association. Journal of Pediatric Surgery, 15, 849–854.

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VATER (VACTERL) Association

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b

c

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Fig. 1 (a–d) An infant with VATER association showing club hands, abnormally rotated left lower limb, fused/split ribs, hemivertebrae, radial aplasia on the right, and radioulnar fusion on the left elbow

VATER (VACTERL) Association

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b

b

Fig. 2 (a, b) A child with VATER association showing club hands and missing thumbs. Radiograph showed absence of the first phalanges and metacarpals and radial aplasia

Fig. 3 (a, b) A male neonate with VATER association showing phocomelia, rudimentary external genitalia, and anal atresia, congenital heart anomalies (type 2 truncus arteriosus, tricuspid valve atresia, ventricular septal defect, large atrial septal defect), type 1 tracheoesophageal fistula, nonlobated lungs, agenesis of kidneys and ureters, malrotation of bowel, and vesicocolonic fistula were demonstrated in the necropsy

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VATER (VACTERL) Association

a

b

Fig. 4 (a, b) An infant with club hands and radial aplasia, illustrated by a radiograph

b

a

c

Fig. 5 (a–c) A girl with VATER association showing a remnant left thumb, anal atresia, and colostomy

Von Hippel–Lindau Disease

Von Hippel-Lindau disease (VHL) is a rare hereditary cancer syndrome. The prevalence is estimated at 1 in 85,000 with an incidence of 1 in 45,500 live births (Friedrich 2001).

Synonyms and Related Disorders Angiomatosis retinae; Von Hippel-Lindau syndrome

Genetics/Basic Defects 1. Inheritance (Schimke et al. 2009) a. Autosomal dominant b. Reduced penetrance (95% penetrance at age 60) c. Positive family history in up to 80% of cases d. Sporadic new mutation in about 20% of cases e. Parental mosaicism described 2. Molecular pathogenesis of VHL disease a. VHL disease i. Caused by deletions or mutations in a tumor suppressor gene, the VHL gene, located on chromosome 3p25-26, which encodes an ubiquitin ligase that is involved in the cellular response to hypoxia ii. Two-hit theory of Knudson in a familial cancer syndrome such as VHL disease (Lubensky et al. 1998) a) Prediction of the genotype of each neoplasm which consists of an allele with an inherited germ line mutation

and loss of the second wild-type allele through allelic deletion b) Loss of heterozygosity at chromosome 3p at the VHL gene region has been demonstrated in different VHL diseaseassociated tumors iii. A germ line mutation in the VHL gene (Hes et al. 2003) a) Predisposes carriers to tumors in multiple organs b) Consistently detected in 100% of classic families with more than one affected family member or classic sporadic patients with multiple VHL-related tumors c) Missense mutations leading to an amino acid substitution in VHL gene product pVHL, observed in 40% of the families with an identified VHL gene germ line mutation d) Microdeletions, insertions, splice site, and nonsense mutations, all predicted to lead to a truncated protein: observed in 30% of the families e) Large deletions including deletions encompassing the entire gene: account for the remaining 30% of the VHL gene germ line mutations iv. Somatic mutations (Hes et al. 2003) a) Independent somatic alteration of both alleles of the VHL tumor suppressor gene leading to tumorigenesis in nonfamilial (VHL-related) tumors

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b.

c.

d.

e.

Von Hippel–Lindau Disease

b) Somatic VHL gene mutations and allele loss: frequent events in sporadic clear cell renal cell carcinomas and sporadic central nervous system hemangioblastoma, uncommon in sporadic (i.e., nontumor syndrome associated) pheochromocytoma VHL gene i. Mapped on chromosome 3p25 ii. Involved in blood vessel formation by regulation of the activity of hypoxia-inducible factor (HIF)-1a Patients with VHL disease i. With a positive family history: have inherited an inactive VHL allele from an affected parent ii. Without a positive family history: have a parent who is mosaic for a VHL mutation, presumably as the result of a de novo mutation during early development Angiogenesis of VHL tumors: critical role of inactivation of VHL gene i. Overexpression of vascular endothelial growth factor (VEGF) resulting in hypervascularization ii. Negative regulation of hypoxia-inducible mRNAs including VEGF mRNA by VHL protein Tumor development in VHL disease i. Linked to inactivation or loss of the remaining wild-type VHL allele in a susceptible cell, leading to loss of the VHL gene product pVHL ii. Inactivation of VHL gene contributing to tumorigenesis of the VHL tumor since VHL protein is required for the downregulation of transcription activity of certain genes

Clinical Features 1. Great variation in the clinical presentation with variable age of onset (Schimke et al. 2009) 2. Classification of VHL disease (Schimke et al. 2009; Sano and Horiguchi 2003) a. VHL type 1 i. Typical VHL manifestations such as hemangioblastomas of the CNS and/or retina and clear cell renal cell carcinomas ii. Without pheochromocytoma iii. Truncating or null mutations in the VHL gene (deletions or frameshift,

nonsense, or splice site mutations) observed in approximately 96–97% of patients with type 1 VHL b. VHL type 2 i. With pheochromocytomas ii. Missense mutations observed in 92–98% of patients with type 2 VHL c. Subtypes of type 2 VHL i. VHL type 2A a) VHL without predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (Y98H, Y112H, V116F, L188V) in the VHL gene conferring an increased risk for VHL disease ii. VHL type 2B a) VHL with predisposition to renal cell carcinoma and pancreatic neuroendocrine tumor b) Specific mutations (R167Q, R167W) in the VHL gene conferring an increased risk for VHL disease iii. VHL type 2C a) VHL with only pheochromocytoma manifestation b) Specific mutations (V155L, R238W) in the VHL gene conferring an increased risk for VHL disease 3. Tumors/cysts linked to VHL disease, typically develop in the second, third, and fourth decades of life a. Retinal angioma/hemangioblastoma i. Responsible for the first manifestation of VHL in 50% of the patients ii. Retinal lesions a) Formerly called retinal angiomas b) Histologically identical to hemangioblastomas c) Identified in about 70% of the patients d) Bilateral in about 50% of the patients e) Multiple in about 66% of the patients iii. Complications when the condition is unrecognized and untreated at early stage a) Majority of retinal angiomas eventually hemorrhage b) Resulting in massive exudation and retinal detachment c) Ultimate development of neovascular glaucoma and blindness

Von Hippel–Lindau Disease

b. Cerebellar hemangioblastomas (80% of CNS hemangioblastoma) (Friedrich 2001) i. The most common initial manifestation (34.9%) ii. Cumulative occurrence: 60.2% iii. The most common cause of death (47.7%) iv. Symptoms and signs a) Headache b) Slurred speech c) Nystagmus d) Positional vertigo e) Labile hypertension (without pheochromocytoma) f) Vomiting g) Wide-based gait h) Dysmetria c. Spinal hemangioblastoma (20% of CNS hemangioblastoma) (Friedrich 2001) i. More specific for VHL disease ii. About 80% of cases are caused by VHL. iii. Cumulative occurrence (14.5%) iv. Symptoms and signs a) Pain b) Sensory and motor loss secondary to cord compression d. Renal lesions i. Renal cysts: precursor lesions to clear cell renal cell carcinomas (75% of patients with VHL) which is a frequent cause of death ii. Hemangioblastoma iii. Renal cell adenoma iv. Renal cell carcinoma (20–40%) e. Pheochromocytomas (tumor of adrenal medulla) i. Type 1 families a) Absence of pheochromocytomas b) Most type 1 families are affected by deletions or premature termination mutations ii. Type 2 families (7–20% of families) a) Presence of pheochromocytomas b) Most type 2 families are affected by missense mutations. iii. Arg238trp and arg238gln mutations: associated with a 62% risk for pheochromocytoma iv. Location of tumors a) Usually located in one or both adrenal glands b) May present anywhere along the sympathetic axis in the abdomen or thorax

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(paragangliomas) or head and neck (chemodectomas) v. Symptoms and signs a) Sustained or episodic hypertension b) Asymptomatic f. Pancreatic lesions i. Type of lesions a) Simple pancreatic cysts b) Serous cystadenomas c) Pancreatic neuroendocrine tumors ii. Rarely causing endocrine or exocrine insufficiency unless the lesion is extensive iii. Occasionally causing biliary obstruction secondary to cysts in the head of the pancreas g. Liver lesions i. Hemangiomas ii. Cyst iii. Adenoma iv. Carcinoid of the common bile duct h. Splenic lesions i. Hemangiomas ii. Cyst i. Pulmonary lesions i. Hemangiomas ii. Cyst j. Bladder hemangioblastoma k. Endolymphatic sac tumors of the inner ears (labyrinth) i. Tinnitus or vertigo ii. Deafness l. Papillary cystadenomas of the epididymis in males i. Relatively common in males ii. Unilateral: rarely causing problem iii. Bilateral: infertility m. Papillary cystadenomas of the broad ligament in females: much less common n. Skin lesions i. Nevus ii. Cafe´ au lait spot o. Bone lesions i. Hemangioma ii. Cyst 4. Diagnosis of VHL disease usually made on clinical grounds (Sanfilippo et al. 2003) a. A positive family history of VHL disease plus one of the following lesions (hemangioblastoma or visceral lesion): i. Retinal hemangioblastoma ii. Cerebellar hemangioblastoma

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iii. Pheochromocytoma iv. Renal cell carcinoma v. Multiple pancreatic cysts b. A negative family history of VHL disease needs one of the following (Friedrich 2001): i. Two or more retinal or cerebellar hemangioblastomas, or ii. One hemangioblastoma plus one visceral tumor 5. Prognosis a. Life expectancy: A; p.Ala25Thr) was

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d. Pectus excavatum e. Scoliosis 6. Occasional cardiac features a. Mitral valve prolapse b. Mitral valve insufficiency c. Mitral valve stenosis d. Pulmonary hypertension e. Subvalvular fibromuscular aortic stenosis f. Congenital pulmonic valve stenosis g. Patent ductus arteriosus h. Ventricular septal defect i. Prolonged QT interval 7. Normal intelligence

Diagnostic Investigations 1. Confirmation by molecular genetic testing in addition to clinical features a. ADAMTS10 sequence analysis available clinically to identified homozygous mutations in autosomal recessive WMS b. Significance of mutations in FBN1 in autosomal dominant WMS is unclear. 2. Carrier testing for relatives at risk requires prior identification of the disease-causing mutations in the family. 3. ECG to detect prolonged QT interval 4. Electron microscopy and immunological studies of skin fibroblasts from WMS patients suggest that the syndrome is associated with impairment of the extracellular matrix.

Genetic Counseling 1. Recurrence risk a. Patient’s sib i. Autosomal dominant inheritance a) Fifty percent risk if one parent is affected b) Recurrence risk: small if neither parent is affected ii. Autosomal recessive inheritance: 25% affected; 50% carriers b. Patient’s offspring i. Autosomal dominant inheritance: 50% risk ii. Autosomal recessive inheritance: 100% obligatory carriers for a disease-causing mutation in the ADAMTS10 gene

Weill–Marchesani Syndrome

2. Prenatal diagnosis: available for pregnancies at risk for autosomal recessive WMS provided prior identification of the disease-causing mutations in the family is known 3. Management a. Early detection and removal of an ectopic lens to decrease the possibility of pupillary block and glaucoma b. Medical treatment of glaucoma: difficult because of paradoxical response to miotics and mydriatics c. Surgical management of glaucoma i. Peripheral iridectomy to prevent or relieve pupillary block ii. Trabeculectomy in advanced chronic angle closure glaucoma d. Airway management: difficult during anesthesia because of stiff joints, poorly aligned teeth, and maxillary hypoplasia e. Periodic ophthalmic examinations for early detection and removal of an ectopic lens f. Avoid ophthalmic miotics and mydriatics to prevent inducing pupillary block.

References Chu, B. S. (2006). Weill–Marchesani syndrome and secondary glaucoma associated with ectopia lentis. Clinical and Experimental Optometry, 89, 95–99. Chung, J. L., Kim, S. W., Kim, J. H., et al. (2007). A case of Weill–Marchesani syndrome with inversion of chromosome 15. Korean Journal of Ophthalmology, 21, 255–260. Dagoneau, N., Benoist-Lasselin, C., Huber, C., et al. (2004). ADAMTS10 mutations in autosomal recessive Weill–Marchesani syndrome. American Journal of Human Genetics, 75, 801–806. Dal, D., Sahin, A., & Aypar, U. (2003). Anesthetic management of a patient with Weill–Marchesani syndrome. Acta Anaesthesiologica Scandinavica, 47, 369–370. Evereklioglu, C., Hepsen, I. F., & Er, H. (1999). Weill–Marchesani syndrome in three generations. Eye, 13, 773–777. Faivre, L., Dollfus, H., Lyonnet, S., et al. (2003). Clinical homogeneity and genetic heterogeneity in Weill–Marchesani syndrome. American Journal of Medical Genetics. Part A, 123, 204–207. Faivre, L., Gorlin, R. J., Wirtz, M. K., et al. (2003). In frame fibrillin-1 gene deletion in autosomal dominant Weill–Marchesani syndrome. Journal of Medical Genetics, 40, 34–36. Faivre, L., Me´garbane´, A., Alswaid, A., et al. (2002). Homozygosity mapping of a Weill–Marchesani syndrome locus to

Weill–Marchesani Syndrome chromosome 19p13.3-p13.2. Human Genetics, 110, 366–370. Fujiwara, H., Takigawa, Y., Ueno, S., et al. (1990). Histology of the lens in the Weill–Marchesani syndrome. British Journal of Ophthalmology, 74, 631–634. Harasymowycz, P., & Wilson, R. (2004). Surgical treatment of advanced chronic angle closure glaucoma in Weill–Marchesani syndrome. Journal of Pediatric Ophthalmology and Strabismus, 41, 295–299. Hayward, C., & Brock, D. J. (1997). Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Human Mutation, 10, 415–423. Karabiyik, L. (2003). Airway management of a patient with Weill–Marchesani syndrome. Journal of Clinical Anesthesia, 15, 214–216. Kloepfer, H. W., & Rosenthal, J. W. (1955). Possible genetic carriers in the spherophakia-brachymorphia syndrome. American Journal of Human Genetics, 7, 398–425. Kojuri, J., Razeghinejad, M. R., & Aslanil, A. (2007). Cardiac findings in Weill–Marchesani syndrome. American Journal of Medical Genetics, 143A, 2062–2064. Kutz, W. E., Wang, L. W., Dagoneau, N., et al. (2008). Functional analysis of an ADAMTS10 signal peptide mutation in Weill–Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme. Human Mutation, 29, 1425–1434. Macken, P. L., Pavlin, C. J., Tuli, R., et al. (1995). Ultrasound biomicroscopic features of spherophakia. Australian and New Zealand Journal of Ophthalmology, 23, 217–220. Marchesani, O. (1939). Brachydaktylie und angeborene kugellines als systemerkrankung. Klinische Monatsbl€ atter f€ ur Augenheilkunde, 103, 392–406.

2153 Razeghinejad, M. R., & Safavian, H. (2006). Central corneal thickness in patients with Weill–Marchesani syndrome. American Journal of Ophthalmology, 142, 507–508. Riad, W., Abouammoh, M., & Fathy, M. (2006). Anesthetic characteristics and airway evaluation of patients with Weill–Marchesani syndrome. Middle East Journal of Anesthesiology, 18, 725–731. Ritch, R., Chang, B. M., & Liebmann, J. M. (2003). Angle closure in younger patients. Ophthalmology, 110, 1880–1889. Ritch, R., & Wand, M. (1981). Treatment of the Weill–Marchesani syndrome. Annals of Ophthalmology, 13, 665–667. Tsilou, E., MacDonald, I. M. (2007). Weill–Marchesani syndrome. GeneReviews. Updated November 1, 2007, Available at: http://www.ncbi.nlm.nih.gov/books/NBK1114/. Van de Woestijne, P. C., Harkel, A. D.-J. T., & Bogers, A. J. J. C. (2004). Two patients with Weill–Marchesani syndrome and mitral stenosis. Interactive Cardiovascular and Thoracic Surgery, 3, 484–485. Verloes, A., Hermia, J. P., Galand, A., et al. (1992). Glaucoma–lens ectopiamicrospherophakia–stiffness–shortness (GEMSS) syndrome: A dominant disease with manifestations of Weill–Marchesani syndromes. American Journal of Medical Genetics, 44, 48–51. Weill, G. (1932). Ectopie du cristallin et malformations ge´ne´rales. Annales d’Oculistique, 169, 21–44. Willi, M., Kut, L., & Cotlier, E. (1973). Pupillary-block glaucoma in the Marchesani syndrome. Archives of Ophthalmology, 90, 504–708. Wirtz, M. K., Samples, J. R., Kramer, P. L., et al. (1996). Weill–Marchesani syndrome–possible linkage of the autosomal dominant form to 15q21.1. American Journal of Medical Genetics, 65, 68–75.

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a

Weill–Marchesani Syndrome

b

c

Fig. 1 (a–c) A 14-year-old female with Weill–Marchesani syndrome. She had short stature, spherophakia, and brachydactyly. She was again followed at 30 years of age with findings of short

stature, shallow orbits, small eyes, myopia, brachydactyly, and enlarged and stiff interphalangeal joints. Her daughter has small lens/cornea, short stature, and brachydactyly

Williams Syndrome

In 1961, Williams et al. described children with a constellation of abnormalities including “unusual” facial features, growth retardation, supravalvular aortic stenosis, and cognitive impairment. In 1962, Beuren described a series of children with similar features, dental anomalies, peripheral pulmonary artery stenosis, and friendly personalities. Consequently, Williams syndrome is also known as Williams-Beuren syndrome. These characteristics are observed in virtually every patient with Williams syndrome, now known to be caused by a microdeletion of chromosome 7q11.23. The incidence of the syndrome is estimated to be between 1 in 20,000 and 1 in 50,000 live births.

Synonyms and Related Disorders Chromosome 7q11.23 Williams–Beuren syndrome

deletion

syndrome;

Genetics/Basic Defects 1. Inheritance a. Sporadic new deletion in most cases b. Rare autosomal dominant transmission of microdeletion involving the Williams syndrome critical region in a few cases 2. Association of the elastin (ELN) gene disruption by chromosome translocation or partial deletion involving chromosome 7q11.23 and the supravalvular aortic stenosis: the first clue to the location of the Williams syndrome microdeletion

3. Caused by the haploinsufficiency of genes within a microdeletion of the long arm of chromosome 7 (7q11.23) 4. Deletions in the ELN gene (Osborne 1999; Donnai and Karmiloff-Smith 2000) a. Mechanism: deletions typically caused by unequal recombination during meiosis b. Deletion with equal frequency on the maternally or paternally inherited chromosome 7 c. A total of at least 16 genes mapped within the commonly deleted interval d. ELN gene mapped approximately at the center of the deletion e. Responsible for supravalvular aortic stenosis and other vascular stenoses f. Possibly responsible for some of the connective tissue problems i. Lax joints ii. Premature aging of the skin iii. Joint contractures iv. A hoarse voice v. Bladder and bowel diverticula vi. Hernias g. Majority of patients with Williams syndrome with large deletion spans (approximately 1.5 Mb of DNA), which contain many genes that contribute to the additional clinical symptoms not seen in patients with isolated supravalvular aortic stenosis h. Genetic studies demonstrate that isolated nonsyndromic supravalvular aortic stenosis is associated with intragenic deletions within the ELN gene, while Williams syndrome involves deletions spanning the entire ELN gene (Lashkari et al. 1999).

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i. Other genes identified in the commonly deleted region: e.g., LIMK1, CYLN2, GTF21RD1, and STX1A (Jurado 2003)

Clinical Features 1. Characteristic dysmorphic facies, frequently referred to as elfin facies (100%). Effort must be made to curtail the use of “elfin facies” to denote a resemblance to a mythological creature since the term is not well received by family members (Lashkari et al. 1999; AAP 2001). a. Periorbital fullness b. Stellate lacy iris pattern c. Short nose with bulbous nasal tip d. Flat nasal bridge e. Prominent full cheeks f. Long philtrum g. Wide mouth h. Full lips i. Mild micrognathia j. Long narrow face and long neck in older children and adults 2. Cardiovascular diseases a. Supravalvular aortic stenosis (80%), often a progressive condition that may require surgical repair b. Generalized arteriopathy (narrowing of arteries secondary to abnormal elastin protein, an important component of elastic fibers in the arterial wall) i. Peripheral pulmonary artery stenosis often present in infancy and usually improves over time ii. Possible worsening over time of the coarctation of the aorta, renal artery stenosis, and systemic hypertension iii. Possible narrowing of any arterial wall since elastin protein is an important component of elastic fibers in the arterial wall c. Other congenital cardiac defects i. Mitral valve prolapse (11.6%) ii. Bicuspid aortic valve (15%) iii. Aortic hypoplasia iv. Septal defects v. Left ventricular hypertrophy 3. Variable mental retardation (75%)

Williams Syndrome

4. Characteristic cognitive/behavioral profile (90%) a. Characteristic behavioral pattern i. Relative preservation of linguistic abilities ii. Gross deficiencies in visual-spatial processing and motor skills b. Motor disabilities affecting balance, strength, coordination, and motor planning c. Delayed speech acquisition, followed by excessive talking (“cocktail party” verbal abilities) d. Overfriendliness and an empathetic nature e. Uncontrollable loquacity f. Behavioral problems i. Hypersensitivity to sound (hyperacusis) ii. Sleep problems iii. Attention deficit/hyperactivity disorder (ADHD) iv. Anxiety v. Distractability vi. Inflexibility vii. Rituralism 5. Idiopathic infantile hypercalcemia (15%) a. Symptoms and signs of hypercalcemia (usually resolves during childhood) i. Extreme irritability ii. Vomiting iii. Constipation iv. Muscle cramps b. Possible lifelong persistence of abnormal calcium and vitamin D metabolism c. Hypercalcinuria predisposing to nephrocalcinosis 6. Other features a. Growth i. Postterm birth (>41 weeks) ii. Failure to thrive iii. Short stature (50%) iv. Hypothyroidism v. A premature and abbreviated pubertal growth spurt b. CNS i. Muscle hypotonia early ii. Muscle tone increases with age; hypertonia in some cases iii. Poor coordination iv. Awkward gait v. Chiari I malformation vi. Hyperreflexia of the lower extremities c. EENT i. Ocular findings a) Strabismus

Williams Syndrome

b) Hyperopia c) Stellate iris d) Retinal vessel tortuosity ii. Chronic otitis media iii. Dental abnormalities a) Hypodontia/Microdontia b) Malocclusion c) Overbite d) Excessive interdental spacing e) Small roots f) High incidence of caries iv. A hoarse or brassy voice d. GI i. Difficulty feeding ii. Gastroesophageal reflux/vomiting iii. Prolong colic iv. Bowel diverticula v. Hernias vi. Rectal prolapse vii. Constipation viii. Peptic ulcers e. Genitourinary (18%) i. Bladder diverticula: the most common defects ii. Renal artery stenosis iii. Renal agenesis iv. Duplicated kidneys v. Horseshoe kidney vi. Renal cysts vii. Nephrocalcinosis viii. Vesicouriteral reflux f. Orthopedic problems i. Low/hoarse voice ii. Hernias iii. Joint laxity mostly during infancy iv. Joint contractures may develop by childhood and adolescence (50%). v. Radioulnar synostosis vi. Kyphosis vii. Lordosis viii. Scoliosis ix. Hallux valgus x. Hypoplastic nails xi. Clinodactyly of fifth fingers

Diagnostic Investigations 1. Echocardiography for cardiac lesions

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2. Ultrasonography a. Bladder and kidneys b. Intravascular ultrasound imaging: to detect vascular wall thickening with secondary lumen narrowing 3. Serum creatinine level 4. Blood calcium levels to detect hypercalcemia during early infancy 5. Thyroid function test 6. Ophthalmologic evaluation for strabismus and retinal vessel tortuosity 7. Urinalysis to detect hypercalcinuria 8. Renal ultrasound for possible nephrocalcinosis if hypercalcinuria is noted 9. Radiography: osteosclerosis of the metaphyses of long bones, the skull vault, or lamina dura of the alveolar bone in adolescence and adulthood, if overt hypercalcemia is present 10. Full cytogenetic studies a. Larger deletions detectable by standard cytogenetic techniques, especially by high-resolution chromosome analysis b. To rule out possible chromosomal rearrangements involving the 7q11.23 locus as well as any other cytogenetic abnormalities 11. Fluorescence in situ hybridization (FISH) with a cosmid probe corresponding to ELN for diagnostic testing: remains the most widely used laboratory test a. Ninety-nine percent of the patients with a hemizygous submicroscopic deletion of 7q11.23 detectable by FISH b. Cases undetectable by FISH i. Rare cases with a smaller deletion which does not fully encompass the FISH probe ii. Cases with phenocopies of Williams syndrome with same clinical phenotype produced by mutation or deletion of other gene(s) iii. Cases with a Williams syndrome–like phenotype associated with various cytogenetic rearrangements 12. Other diagnostic laboratory tests (Pober 2010) a. Microsatellite marker analysis b. Multiplex ligation-dependent probe amplification c. Quantitative polymerase-chain-reaction assay d. Array comparative genomic hybridization

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Genetic Counseling 1. Recurrence risk a. Patient’s sib (Lashkari et al. 1999) i. Recurrence risk low (95% of deletions. Molecular cytogenetic studies using FISH allow the diagnosis to be made in patients with very small deletions or cryptic translocations. FISH uses genetic markers that have been precisely localized to the area of interest. The absence of signal from either the maternal or the paternal allele for the marker is indicative of monosomy for that chromosomal region. 4. Array comparative genomic hybridization (aCGH) a. A new technology that can analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize unbalanced rearrangements b. 33 patients with WHS were analyzed using aCGH (South et al. 2008). i. Observation of a much higher than expected frequency of unbalanced translocations (15/ 33, 45%) ii. 7 of these 15 cases were cryptic translocations not detected by a previous karyotype combined with WHS-specific FISH 5. Immune workup a. Common variable immunodeficiency b. Immunoglobulin A (IgA) and immunoglobulin G2 (IgG2) subclass deficiency c. IgA deficiency d. Impaired polysaccharide responsiveness e. Normal T cell immunity 6. Radiography a. Delayed bone maturation b. Microcephaly c. Hypertelorism d. Micrognathia e. Anterior fusion of vertebrae f. Fused ribs g. Dislocated hips h. Proximal radioulnar synostosis i. Clubfeet 7. Echocardiography to detect heart defects 8. Renal ultrasound to detect renal anomalies 9. MRI and CT scans to demonstrate underlying brain pathology including agenesis of corpus callosum and ventriculomegaly 10. EEG for seizure monitoring 11. Swallowing study for feeding difficulty

Wolf-Hirschhorn Syndrome

12. Comprehensive audiologic and otologic evaluation to rule out possible hearing impairment 13. Ophthalmologic examination 14. Developmental testing a. Speech and motor evaluation b. Appropriate psychometric evaluation 15. Growth charts are available from 0 to 4 years of age, based on the study of 101 individuals (Anntonius et al. 2008). Use of these specific growth charts is recommended because standard growth charts are inapplicable for patients with WHS.

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b. Manage feeding difficulties and failure to thrive i. Gavage feeding ii. Gastrostomy iii. Occasional gastroesophageal fundoplication c. Anticonvulsants for seizure control d. Orthopedic care for skeletal abnormalities i. Clubfoot ii. Scoliosis iii. Kyphosis e. Care for possible immunodeficiency

References Genetic Counseling 1. Recurrence risk a. Patient’s sib i. De novo deletion cases: no significant increased risk ii. Deletion resulting from a parental chromosomal rearrangement: increased risk for unbalanced product in offspring b. Patient’s offspring: reproduction unlikely due to mental retardation 2. Prenatal diagnosis available to families in which one parent is known to be a carrier of a chromosome rearrangement by amniocentesis, CVS, or PUBS a. Ultrasonography to detect in utero manifestation of distinct phenotype i. Severe intrauterine growth retardation ii. Microcephaly iii. Hypertelorism, usually with prominent glabella iv. Micrognathia v. Cleft lip and palate vi. Diaphragmatic hernia b. Chromosome analysis i. Conventional karyotyping ii. FISH iii. Whole chromosome painting 3. Management a. Multidisciplinary team approach i. Early intervention program to improve motor development, cognition, communication, and social skills ii. Speech, physical, and occupational therapies iii. Appropriate school placement

Altherr, M. R., Wright, T. J., Denison, K., et al. (1997). Delimiting the Wolf–Hirschhorn syndrome critical region to 750 kilobase pairs. American Journal of Medical Genetics, 71, 47–53. Anntonius, T., Draaisma, J., Levtchenko, E., et al. (2008). Growth charts for Wolf–Hirschhorn syndrome (0–4 years of age). European Journal of Pediatrics, 167, 807–810. Battaglia, A., & Carey, J. C. (1998). Wolf–Hirschhorn syndrome and Pitt–Rogers–Danks syndrome. American Journal of Medical Genetics, 75, 541. Battaglia, A., & Carey, J. C. (1999). Health supervision and anticipatory guidance of individuals with Wolf–Hirschhorn syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 89, 111–115. Battaglia, A., & Carey, J. C. (2000). Update on the clinical features and natural history of Wolf–Hirschhorn syndrome (WHS): Experience with 48 cases. American Journal of Human Genetics, 67(Suppl 2), 127. Battaglia, A., Carey, J. C., Cederholm, P., et al. (1999). Natural history of Wolf–Hirschhorn syndrome: Experience with 15 cases. Pediatrics, 103, 830–836. Battaglia, A., Carey, J. C., & Wright, T. J. (2001). Wolf–Hirschhorn (4p-) syndrome. Advances in Pediatrics, 48, 75–113. Battaglia, A., Filippi, T., & Carey, J. C. (2008). Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 148C, 246–251. Chen, H. (2011). Wolf–Hirschhorn syndrome. eMedicine from WebMD. Retrieved August 10, 2011. Available at: http:// emedicine.medscape.com/article/950480-overview Clemens, M., Martsolf, J. T., Rogers, J. G., et al. (1996). Pitt–Rogers–Danks syndrome: The result of a 4p microdeletion. American Journal of Medical Genetics, 66, 95–100. Dallapiccola, B., Mandich, P., Bellone, E., et al. (1993). Parental origin of chromosome 4p deletion in Wolf–Hirschhorn syndrome. American Journal of Medical Genetics, 47, 921–924.

2170 Dietze, I., Fritz, B., Huhle, D., et al. (2004). Clinical, cytogenetic and molecular investigation in a fetus with Wolf–Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature. Fetal Diagnosis and Therapy, 19, 251–260. Dufke, A., Seidel, J., Schoning, M., et al. (2000). Microdeletion 4p16.3 in three unrelated patients with Wolf–Hirschhorn syndrome. Cytogenetics and Cell Genetics, 91, 81–84. Estabrooks, L. L., Breg, W. R., Hayden, M. R., et al. (1995). Summary of the 1993 ASHG ancillary meeting “recent research on chromosome 4p syndromes and genes”. American Journal of Medical Genetics, 55, 453–458. Fang, Y. Y., Bain, S., Haan, E. A., et al. (1997). High resolution characterization of an interstitial deletion of less than 1.9 Mb at 4p16.3 associated with Wolf–Hirschhorn syndrome. American Journal of Medical Genetics, 71, 453–457. Fryns, J., Pediatr, S. E., Devriendt, K., et al. (1998). WolfHirschhorn syndrome with cryptic 4p16.3 deletion and balanced/unbalanced mosaicism in the mother. Annales de Ge´ne´tique´, 41, 73–76. Hanley-Lopez, J., Estabrooks, L. L., & Stiehm, R. (1998). Antibody deficiency in Wolf–Hirschhorn syndrome. Journal of Pediatrics, 133, 141–143. Hirschhorn, K., Cooper, H. L., & Firschein, I. L. (1965). Deletion of short arms of chromosome 4–5 in a child with defects of midline fusion. Humangenetik, 1, 479–482. Johnson, V. P., Mulder, R. D., & Hosen, R. (1976). The Wolf–Hirschhorn (4p-) syndrome. Clinical Genetics, 10, 104–112. Lazjuk, G. I., Lurie, I. W., Ostrowskaja, T. I., et al. (1980). The Wolf–Hirschhorn syndrome II. Pathologic anatomy. Clinical Genetics, 18, 6–12. Lesperance, M. M., Grundfast, K. M., & Rosenbaum, K. N. (1998). Otologic manifestations of Wolf–Hirschhorn syndrome. Archives of Otolaryngology – Head & Neck Surgery, 124, 193–196. Lurie, I. W., Lazjuk, G. I., Ussova, Y. I., et al. (1980). The Wolf–Hirschhorn syndrome. I. Genetics. Clinical Genetics, 17, 375–384. Ogle, R., Sillence, D. O., Merrick, A., et al. (1996). The Wolf–Hirschhorn syndrome in adulthood: Evaluation of a 24-year-old man with a rec(4) chromosome. American Journal of Medical Genetics, 65, 124–127. Opitz, J. M. (1995). Twenty-seven-year follow-up in the Wolf–Hirschhorn syndrome [editorial]. American Journal of Medical Genetics, 55, 459–461. Pitt, D. B., Rogers, J. G., & Danks, D. M. (1984). Mental retardation, unusual face, and intrauterine growth retardation: A new recessive syndrome? American Journal of Medical Genetics, 19, 307–313. Rauch, A., Schellmoser, S., Kraus, C., et al. (2001). First known microdeletion within the Wolf–Hirschhorn syndrome critical region refines genotype-phenotype correlation. American Journal of Medical Genetics, 99, 338–342. Roulston, D., Altherr, M., Wasmuth, J. J., et al. (1991). Confirmation of a suspected deletion 4p16 by fluorescent in situ hybridization (FISH) with a cosmid probe. American Journal of Human Genetics, 49, 274.

Wolf-Hirschhorn Syndrome Schlickum, S., Moghekar, A., Simpson, J. C., et al. (2004). LETM1, a gene deleted in Wolf–Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics, 83, 254–261. Shannon, N. L., Maltby, F. L., Rigby, A. S., et al. (2001). An epidemiological study of Wolf–Hirschhorn syndrome: Life expectancy and cause of mortality. Journal of Medical Genetics, 38, 674–679. Sharathkumar, A., Kirby, M., Freedman, M., et al. (2003). Malignant hematological disorders in children with Wolf–Hirschhorn syndrome. American Journal of Medical Genetics, 119A, 194–199. South, S. T., Whitby, H., Battaglia, A., et al. (2008). Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations. European Journal of Human Genetics, 16, 45–52. Tachdjian, G., Fondacci, C., Tapia, S., et al. (1992). The Wolf–Hirschhorn syndrome in fetuses. Clinical Genetics, 42, 281–287. Thomson, P. (1998). Wolf–Hirschhorn syndrome. Review of the literature and three case studies. Journal of the American Podiatric Medical Association, 88, 192–197. Wieczorek, D., Krause, M., Majewski, F., et al. (2000). Effect of the size of the deletion and clinical manifestation in Wolf–Hirschhorn syndrome analysis of 13 patients with a de novo deletion. European Journal of Human Genetics, 8, 519–526. Wilson, M. G., Towner, J. W., Coffin, G. S., et al. (1981). Genetic and clinical studies in 13 patients with the Wolf–Hirschhorn syndrome [del(4p)]. Human Genetics, 59, 297–307. Wolf, U., Reinwein, H., Porsch, R., et al. (1965). Deficiency on the short arms of a chromosome No. 4. Humangenetik, 1, 397–413. Wright, T. J., Clemens, M., Quarrell, O., et al. (1998). Wolf–Hirschhorn and Pitt–Rogers–Danks syndromes caused by overlapping 4p deletions. American Journal of Medical Genetics, 75, 345–350. Wright, T. J., Ricke, D. O., Denison, K., et al. (1997). A transcript map of the newly defined 165 kb Wolf–Hirschhorn syndrome critical region. Human Molecular Genetics, 6, 317–324. Zollino, M., Di Stefano, C., Zampino, G., et al. (2000). Genotypephenotype correlations and clinical diagnostic criteria in Wolf–Hirschhorn syndrome. American Journal of Medical Genetics, 94, 254–261. Zollino, M., Lecce, R., Fischetto, R., et al. (2003). Mapping the Wolf–Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. American Journal of Human Genetics, 72, 590–597. Zollino, M., Murdolo, M., Marangi, G., et al. (2008). On the nosology and pathogenesis of Wolf–Hirschhorn syndrome: Genotype–phenotype correlation analysis of 80 patients and literature review. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 148C, 257–269.

Wolf-Hirschhorn Syndrome Fig. 1 (a–e) A patient with Wolf–Hirschhorn syndrome at different ages showing characteristic facial features consisting of prominent glabella, hypertelorism, beaked nose, and frontal bossing, collectively described as “Greek warrior helmet” facies

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Wolf-Hirschhorn Syndrome Fig. 3 (a–f) Four children with WHS showing characteristic facial features of the syndrome

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chromosome 8 (wcp8/SpectrumOrange) demonstrated a t(4;8) in all metaphases analyzed. These results confirmed a reciprocal translocation between chromosome 4 and chromosome 8 in the mother

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Fig. 6 (a, b) Karyotype and FISH of another patient with Wolf–Hirschhorn syndrome (4p-)

Wolf-Hirschhorn Syndrome Fig. 7 (a–c) A fetus with WHS showing broad triangular-shaped nasal root, and the flat facial profile resembling “Greek warrior helmet.” The radiographs show hypoplasia of the cervical vertebral bodies

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X-Linked Agammaglobulinemia

X-linked agammaglobulinemia (XLA) was first described by Bruton in 1952 (Bruton 1952). It is a prototypical humoral immunodeficiency characterized by early onset of bacterial infections, profound hypogammaglobulinemia, and marked decrease of the peripheral B-lymphocyte population. Associated infections, particularly bacterial meningitis and pneumonia, are often life threatening.

Synonyms and Related Disorders Agammaglobulinemia tyrosine kinase; B-cell progenitor kinase; Bruton-type agammaglobulinemia; Immunodeficiency 1

Genetics/Basic Defects 1. An X-linked recessive disorder 2. The responsible gene for XLA (named as Bruton’s tyrosine kinase, BTK), mapped on Xq21.3-Xq22, is mainly involved in early B-cell maturation through its function in pre-B-cell receptor signaling pathway, and its absence causes an arrest in B-cell development. 3. Mutations in the BTK gene cause XLA. 4. No clear genotype phenotype correlation exists 5. Female XLA can result from heterozygous BTK gene abnormality and extreme nonrandom inactivation of X chromosome on which normal BTK gene is located.

Clinical Features 1. Presenting manifestations a. Infections in affected boys after the decline of passively transferred maternal antibodies: the major presenting feature i. Most frequently respiratory tract and gastrointestinal tract infections (91%), often protracted and recurrent, presenting as otitis media, pneumonitis, and diarrhea ii. Other common infections a) Conjunctivitis b) Sinusitis c) Skin infection iii. S. pneumoniae and H. influenzae: the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gamma globulin therapy iv. Monoarticular or oligoarticular arthritis (20%) affecting large joints: the most common being knees, shoulders, ankles, wrists, and elbows v. Central nervous system infections (16%): meningitis/encephalitis vi. Septicemia (10%) excluding bacterial meningitis and associated bacteremia vii. Virtually, all patients had infections at more than one anatomic site and on more than one occasion. b. Neutropenia (10%): always occur in association with infection, and in all cases resolved after treatment with antibiotics and g-globulin

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c. Failure to thrive: a relatively infrequent occurrence d. Fever of unknown origin e. Complications of immunizations such as paralytic poliomyelitis following live virus vaccine and vaccinia gangrenosum following smallpox vaccination Age at onset of symptoms a. By age 4 months (25%) b. By age 8 months (50%) c. By age 12 months (75%) d. By age 18 months (90%) Chronic complications a. Chronic pulmonary disease (46%): the most frequent long-term complication of XLA i. Obstructive pulmonary disease (half of cases) ii. Combined obstructive and restrictive disease (half of cases) b. Sensory neurologic disorders i. Hearing loss (32%) as a consequence of chronic otitis media and meningoencephalitis ii. Delayed acquisition of speech (14%) iii. Learning disorders (15%) iv. Significant motor dysfunction as a consequence of encephalitis a) Hemiparesis b) Ataxia c) Diplegia d) Quadriplegia Miscellaneous illnesses a. Dermatomyositis-like syndrome occurred in association with arthritis and with meningitis/ encephalitis. b. Viral infections i. Disseminated enterovirus infection ii. Disseminated adenovirus infection c. Hematologic abnormalities: uncommon in treated patients i. Chronic Coombs’ positive hemolytic anemia ii. Transient neutropenia and transient thrombocytopenia in conjunction with infection: resolved when the infection resolved iii. Insulin-dependent diabetes mellitus Complications of g-globulin therapy a. Rash b. Fever c. Apparent anaphylactic-like symptoms d. Acrodynia secondary to g-globulin preparations containing mercury as a preservative

X-Linked Agammaglobulinemia

6. Causes of death a. Cardiorespiratory failure (38%): consequence of chronic pulmonary disease and cor pulmonale b. Severe viral infections (50%) c. Fulminant necrotizing hepatitis d. Aspiration as a consequence of poliomyelitisrelated neurologic impairment e. Systemic staphylococcal infections

Diagnostic Investigations 1. Clinical clues to the diagnosis of XLA a. Chronic or recurrent nature of infections b. Infections at more than one anatomic location c. Family history of immunodeficiency d. An important clinical clue: absent or barely detectable tonsils and cervical lymph nodes e. About 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis 2. Clinical laboratory findings in affected individuals a. Concentration of serum immunoglobulins i. The serum IgG concentration: typically less than 200 mg/dL ii. The serum concentrations of IgM and IgA: typically less than 20 mg/dL (Although decreased serum concentration of IgG and IgA can be seen in children with a constitutional delay in immunoglobulin production, low serum IgM concentration is almost always associated with immunodeficiency.) b. Antibody titers to vaccine antigens: Affected individuals fail to make antibodies to vaccine antigens like tetanus, H. influenzae, or S. pneumoniae. c. Lymphocyte cell surface markers: markedly reduced numbers of B lymphocytes (CD 19+ cells) in the peripheral circulation ( A. The patient currently receives intravenous immunoglobulin (610 mg/kg) and is responding well

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Fig. 2 A 3-year-old male, a brother of the above patient, was also evaluated for immune deficiency because of recurrent upper respiratory infections in the first 2–3 months of life, three pneumonias in later infancy, and a pneumococcus meningitis recently. Recent immunoglobulin levels were IGA of