Human Malformations and Related Anomalies

Human Malformations and Related Anomalies

OXFORD MONOGRAPHS ON MEDICAL GENETICS GENERAL EDITORS

Arno G. Motulsky Martin Bobrow Peter S. Harper Charles Scriver Charles J. Epstein Judith G. Hall 16. C. R. Scriver and B. Child: Garrod’s inborn factors in disease 18. M. Baraitser: The genetics of neurological disorders 21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal development: an atlas 22. J. J. Nora, K. Berg, and A. H. Nora: Cardiovascullar disease: gentics, epidemiology, and prevention 24. A. E. H. Emery: Duchenne muscular dystrophy, second edition 25. E. G. D. Tuddenham and D. N. Cooper: The molecular genetics of haemostasis and its inherited disorders 26. A. Boue´: Foetalmedicine 30. A. S. Teebi and T. I. Farag: Genetic disorders among Arab populations 31. M. M. Cohen, Jr.: The child with multiple birth defects 32. W. W. Weber: Pharmacogenetics 33. V. P. Sybert: Genetic skin disorders 34. M. Baraitser: Genetics of neurological disorders, third edition 35. H. Ostrer: Non-mendelian genetics in humans 36. E. Traboulsi: Genetic diseases of the eye 37. G. L. Semenza: Transcription factors and human disease 38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic disorders of human sexual development 39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X-linked mental retardation 40. M. J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the 21st century 41. J. Weil: Psychosocial genetic counseling 42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam: Syndromes of the head and neck, fourth edition 43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes 44. R. A. King, J. I. Rotter, and A. G. Motulsky: The genetic basis of common diseases, second edition 45. G. P. Bates, P. S. Harper, and L. Jones: Huntington’s disease, third edition 46. R. J. M. Gardner and G. R. Sutherland: Chromosome abnormalities and genetic counselling, third edition 47. I. J. Holt: Genetics of mitochondrial disease 48. F. Flinter, E. Maher, and A. Saggar-Malik: The genetics of renal disease 49. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn errors of development: the molecular basis of clinical disorders of morphogenesis 50. H. V. Toriello, W. Reardon, and R. J. Gorlin: Hereditary hearing loss and its syndromes, second edition 51. P. S. Harper: Landmarks in medical genetics 52. R. E. Stevenson and J. G. Hall: Human malformations and related anomalies, second edition

Human Malformations and Related Anomalies EDITED BY

Roger E. Stevenson

Judith G. Hall

Greenwood Genetic Center

University of British Columbia

Greenwood, South Carolina

Vancouver, British Columbia

ASSOCIATE EDITORS:

Kathleen K. Sulik

Edith Gilbert-Barness

University of North Carolina

Tampa General Hospital

School of Medicine

Tampa, Florida

Chapel Hill, North Carolina

ASSISTANT EDITOR:

Karen Kiernan Buchanan Greenwood Genetic Center Greenwood, South Carolina

1 2006

Second Edition

1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright # 2006 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Human malformations and related anomalies / editors, Roger E. Stevenson . . . [et al.].—2nd ed. p. ; cm.—(Oxford monographs on medical genetics ; no. 52) Includes bibliographical references and index. ISBN-13: 978-0-19-516568-5 ISBN-10: 0-19-516568-3 1. Abnormalities, Human. I. Stevenson, Roger E., 1940–. II. Series. [DNLM: 1. Abnormalities. 2. Genetics, Medical. QS 675 H918 2005] QM691.H88 2005 616'.043—dc22 2004061661

The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy do occur. The authors and publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is accurate and complete, and in accordance with the standards accepted at the time of publication. However, in light of the possibility of human error or changes in the practice of medicine, neither the authors, nor the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete. Readers are encouraged to confirm the information contained herein with other reliable sources, and are strongly advised to check the product information sheet provided by the pharmaceutical company for each drug they plan to administer.

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Preface

O

ver a decade has separated the first and second editions of Human Malformations and Related Anomalies. This interval has been eventful from many standpoints. A major birth defects prevention strategy—periconceptional folic acid utilization—has proved effective in large-scale studies in several countries. New understandings of the genetic basis for malformations and malformation syndromes have emerged and made possible prenatal and postnatal laboratory diagnostic technologies. While molecular advances may be considered the most spectacular, significant advances in the biochemical and cytogenetic bases for malformations have also been impressive. The interval has brought us to the threshold of recognition of potential roles that epigenetic mechanisms, genomic changes, and disruption of molecular pathways exert on human development. During this interval, birth defects have maintained their position as the leading cause of infant mortality and a major contributor to childhood morbidity. The number and scope of birth defects surveillance programs have expanded, and collaboration among the programs is providing a picture of the epidemiology of birth defects worldwide. Increased understanding of the developmental biology of malformations and related anomalies has come primarily from the various branches of genetics. Recognition that inborn errors of cholesterol synthesis are associated with embryodysgenesis is but one of a number of contributions from biochemical genetics. The long biochemical pathway from mevalonic acid to cholesterol can be interrupted at virtually every step by enzyme errors, which leads to an astonishing array of birth defects. Smith-Lemli-Opitz syndrome (caused by a deficiency of 7-dehydrocholesterol reductase), congenital hemidysplasia and ichthyosiform erythroderma and limb defects (deficiency of sterol D8 D7 isomerase), and the Conradi-Hunermann type of chondrodysplasia punctata (deficiency of sterol D8 D7 isomerase) are the most common of the inborn errors of cholesterol metabolism. These biochemical deficiencies and others in the cholesterol pathway were all delineated during the past decade. Application of emerging laboratory technologies has permitted many malformations and malformation syndromes to be explained at the molecular level. Recognition that mutations in the sonic hedgehog gene (SHH) cause holoprosencephaly is typical. The discovery process involved a series of accomplishments.

First came putative localization of a holoprosencephaly gene on 7q36 based on chromosomal rearrangements found in some patients with holoprosencephaly. This localization permitted construction of a yeast artificial chromosome (YAC) contig across the 7q36 locus and definition of a critical region containing the holoprosencephaly gene. Testing of genes within and adjacent to the critical region identified SHH to be the causative gene. Less common, but of equal importance, has been the subsequent identification of other genes on other chromosomes that can also cause holoprosencephaly. This approach to positional cloning of genes that are associated with malformations has been repeatedly successful. Witness the identification of the mutations in several FGF receptors in association with craniosynostosis, mutations in FGFR3 in achondroplasia and related chondrodysplasias, mutations in the NIPBL gene in Cornelia de Lange syndrome, and mutations in the FGD1 gene in Aarskog syndrome, among others. The assignment of genes or gene loci has been most successful perhaps in relation to malformations and malformation syndromes involving the brain and skeleton. Mutations in five genes are associated with the craniosynostoses, mutations in 47 genes are associated with skeletal dysplasias, and mutations in 14 genes are associated with various malformations of the brain. Mutational analysis of many of these genes is currently available in clinical laboratories. Identification of the genes associated with cardiac, respiratory, gastrointestinal, and renal malformations has been less successful. Knowledge that microdeletion syndromes occur throughout the genome, and technologies to detect these microdeletions, have been major contributions from cytogenetics. These advances have permitted better delineation of the structural and neurobehavioral manifestations of many common syndromes such as velocardiofacial/DiGeorge, Williams, Smith-Magenis, Miller-Dieker, and other syndromes. Deletions and duplications in the chromosomal subtelomeric regions have become recognized as important causes of severe mental retardation. These subtelomeric alterations are in some cases accompanied by malformations. In 1993, the only laboratory diagnostic technology relevant to malformations was cytogenetics. And, while cytogenetics has maintained an important and expanding role in the study of malformations, biochemical genetics and molecular genetics have

vi

Preface

become more equal contributors. Numerous are the malformations caused by perturbations of well known (e.g., disorders of cholesterol synthesis) and newly delineated (e.g., congenital disorders of glycosylation) metabolic pathways. In similar fashion, molecular studies are now essential components of the armamentarium of diagnostic and management teams. As the second edition of Human Malformations and Related Anomalies goes to press, the influences of epigenetic phenomena on human development are just being explored. The apparent increased risk for Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Russell-Silver syndrome, and bladder/cloacal exstrophy in infants conceived by assisted reproductive technologies (ARTs) raises suspicion that adverse epigenetic influences may be responsible. To be sure, imprinting defects may underlie alterations in growth and childhood development, but the role as a cause of specific malformations is not clear. Fortunately, no new environmental disasters of the magnitude of prenatal rubella infection or thalidomide exposure have occurred in recent years. Initial concern that transplacental HIV infection might produce maldevelopment has not been realized. Still, on a lesser scale, the recognition of teratogenicity of misoprostol (a prostaglandin inhibitor), fluconazole (an antifungal agent), parvovirus (B19), and early chorionic villus sampling reminds us that hazards to the unborn infant lurk in the environment. Clearly, the most effective birth defects prevention strategy of the past decade has been the use of folic acid during the periconceptional period to prevent neural tube defects. Although the protective effect of folic acid against NTDs was reported by Richard Smithells as early as 1981, it took randomized case-control studies by Great Britain’s Medical Research Council and by Andrew Czeizel in Hungary to convince medical and scientific communities of its efficacy. Increased folic acid concentration in the periconceptional period is now widely advocated for prevention of neural tube defects, and the recommendation has been advanced by decisions in several countries to fortify cereal grain flours. Evidence that folic acid also has a protective effect against other birth defects has been reported, although the magnitude of the protective effect appears to be less than for NTDs. To date, no compelling explanation for the mechanism by which folic acid conveys its protective effect against birth defects has been found. Equally obvious are the disappointments of the past decade. Additional prevention partners to take their places with folic acid have not been identified. Nor has an educational or other strategy been implemented to make significant progress in preventing pervasive teratogen exposures such as alcohol and other drug use during pregnancy. A litany of genes associated with malformations in lower animals has not been relevant to the same malformations in humans. For example, over 60 gene mutations that led to neural tube defects in mice have been identified, and in not a single instance has the homologous gene in humans been found to harbor mutations that cause human neural tube defects. Neither have examples of the much touted concept of gene—environment interactions as the basis for birth defects been found. And most disappointing, as mentioned before, has been the persistence of malformations as the leading cause of infant mortality. As we anticipated during the writing of Edition 1, the application of emerging technologies of molecular biology and developmental genetics would significantly advance the understanding

of normal and abnormal embryonic and fetal development during the ensuing decade. These research advances, continuing observations by clinicians, more comprehensive and accurate epidemiology, and new diagnostic and prevention capabilities related to birth defects called for a substantially revised edition. Human Malformations and Related Anomalies is intended to provide a body of information on individual anomalies and to connect the anomalies to malformation syndromes, primarily through the use of differential diagnostic tables. A central goal is to consider each significant human anomaly from the perspective of the clinician and in the context of the current understanding of embryonic and fetal development. What is the nature of the anatomical defect? What related anomalies and syndromes must be considered? What are the appropriate treatment and prevention strategies? Edition 2 of Human Malformations and Related Anomalies is presented in a single volume. A portion of the information in Volume 1 of Edition 1 has been condensed into an introductory chapter. Thereafter follow 34 chapters that provide detailed accounts of anomalies arranged by anatomical systems, as in Edition 1. The format of these chapters has been revised somewhat to more consistently reflect the relevant embryology, epidemiology, molecular insights, and animal studies. The occurrence of each anomaly in various associations and syndromes is documented. The natural history, approaches to treatment, and prevention strategies are given in the final subsection of each entry. Acknowledgments

Edition 2 of Human Malformations and Related Anomalies has had the benefit of the editorial touches of associate and assistant editors. Kathy Sulik took responsibility for giving a consistent and contemporary view of the human embryology relevant to each section. Enid Gilbert-Barness edited the entries from a pathology perspective. Karen Buchanan attended to the myriad details necessary to facilitate communications between the authors and editors, organize the contents, and adhere to the schedule. To these colleagues and to each of the 42 contributing authors, we are indebted. Rachel Collins, Librarian at the William A. Klauber and Betty Jane Klauber Genetics Library, has provided searches, citation verification, and reprints. Patti Broome assisted in preparation and organization of the final manuscript copy. Preparation of Edition 2 of Human Malformations and Related Anomalies has given us the pleasure of working again with Jeffrey House and Edith Barry at Oxford University Press. They have been helpful, encouraging, and accessible throughout the process. Similar support has come from our clinical and laboratory colleagues at the Greenwood Genetic Center and the University of British Columbia. Appreciation is expressed to the host of clinicians and researchers worldwide who, through their observations and laboratory findings, have contributed new knowledge and insights sufficient to warrant production of the current edition. Participants in the David W. Smith Workshop on Malformations and Morphogenesis have been continual sources of information and insight. Their innumerable contributions to this edition are gratefully acknowledged. R. E. S. J. G. H.

Contents

Contributors

3. Systemic Vasculature

xiii

121

Lynne M. Bird and Kenneth Lyons Jones

Part I—Overview 1. Human Malformations and Related Anomalies

3

Roger E. Stevenson

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

Nomenclature 6 Classification and Coding 13 Genetic Causes of Malformations 14 Gene Mutations and Malformations 22 Environmental Causes of Malformations 33 Human Anomalies with Unknown Causes 58 Detection, Diagnosis, Evaluation, Management 58 Discussions with the Family 71

Part II—Cardiorespiratory Organs

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15

Interrupted Aortic Arch 121 Right Aortic Arch 123 Cervical Aortic Arch 125 Double Aortic Arch 125 Double-Lumen Aortic Arch 126 Incidental Anomalies of the Aortic Arch 127 Innominate Artery Variants 128 Subclavian Artery Variants 129 Patent Ductus Arteriosus 130 Coarctation of the Aorta 133 Persistent Left Superior Vena Cava 136 Inferior Vena Cava Variants 137 Miscellaneous Venous Variants 138 Deep Vein Abnormalities 139 Vascular Malformations 140

4. Lymphatic System

145

Judith E. Allanson

2. Heart

85

Angela E. Lin, John Belmont, and Sadia Malik

2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14

Heterotaxy 93 Single Ventricle 96 Conotruncal Defects 97 Atrioventricular Septal Defects 101 Right Ventricular Outflow Tract Obstructive Defects 103 Left Ventricular Outflow Tract Obstructive Defects 106 Atrial Septal Defects 112 Ventricular Septal Defects 113 Anomalies of the Pulmonary Veins 115 Abnormal Systemic Venous Connections 117 Anomalies of the Ductus Arteriosus 118 Aortopulmonary Window (Aortopulmonary Septal Defect) 119 Anomalies of the Coronary Arteries 119 Anomalies of the Pericardium 120

4.1 4.2 4.3 4.4 4.5

Primary Lymphatic Anomalies 146 Pulmonary Lymphangiectasia 161 Fetal Cystic Hygroma 163 Lymphangioma 169 Lymphangioleiomyomatosis 180

5. Spleen

183

Arthur S. Aylsworth

5.1 5.2 5.3

Polyasplenia 185 Positional Alterations of the Spleen 195 Accessory Spleens, Structural Variation, and Fusion to Other Organs 196

6. Lower Respiratory Organs

201

Laurie H. Seaver

6.1 6.2 6.3 6.4 6.5

Bifid Epiglottis 201 Laryngeal Atresia, Webs, and Stenosis Laryngotracheoesophageal Cleft 205 Tracheal Agenesis 206 Tracheal Stenosis 207

202

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Contents

6.6 6.7 6.8 6.9 6.10 6.11 6.12

Congenital Tracheal Cartilaginous Sleeve 209 Tracheoesophageal Fistula 209 Pulmonary Agenesis/Aplasia 209 Congenital Cystic Adenomatoid Malformation 211 Congenital Lobar Emphysema 213 Primary Pulmonary Hypoplasia 213 Congenital Diaphragmatic Hernia 214

9.11 Congenital Cataracts 316 9.12 Persistent Hyperplastic Primary Vitreous or Persistence of the Fetal Vasculature 318 9.13 Optic Nerve Hypoplasia 320 9.14 Morning Glory Disc Anomaly 322 9.15 Optic Pit 324 10. Ear

327

John C. Carey

Part III—Craniofacial Structures External Ear 7. Skull

221

John M. Graham, Jr.

7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22

Craniosynostosis 221 Kleeblattscha¨del 235 Wide Cranial Sutures 237 Anomalies of Fontanels 238 Cranial Dermal Sinus 242 Parietal Foramina (Includes Cranium Bifidum) 243 Wormian Bones 245 Scalp Vertex Aplasia 246 Thin Cranial Bones 248 Undermineralization of the Skull 248 Craniotabes 249 Thick Cranial Bones 251 Sclerosis and Hyperostosis of the Skull 254 Vertex Birth Molding 254 Breech Head (Bathrocephaly) 257 Other Cranial Deformations Due to Abnormal Fetal Presentation 258 Anomalies of the Sella Turcica 259 Anomalies of Foramen Magnum 260 Anomalies of the Other Basal Foramina and Canals 261 Basilar Impression 261 Cephalhematoma and Caput Succedaneum 262 Miscellaneous Anomalies of the Skull 264

8. Facial Bones

267

Karen Gripp and Luis Fernando Escobar

8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 9. Eye

Premature Metopic Sutural Synostosis 268 Orbital Hypotelorism 270 Orbital Hypertelorism 273 Midline Facial Skeletal Clefting 278 Absence and Hypoplasia of the Zygoma 280 Midface Retrusion and Hypoplasia 283 Agnathia 287 Micrognathia 288 Congenital Asymmetry of the Facial Skeleton 292

Anophthalmia 299 Microphthalmia and Typical Uveal Coloboma Cyclopia and Synophthalmia 302 Cryptophthalmos 303 Blepharophimosis 305 Other Anomalies of the Eyelids 306 Congenital Corneal Anomalies 309 Anterior Segment Dysgenesis 311 Peters Anomaly 313 Hypoplasia of the Iris (Aniridia) 314

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 10.21

Microtia/Anotia 331 Small Ear 335 External Auditory Canal Stenosis and Atresia Without Microtia 336 Cryptotia 338 Large Ear (Macrotia) 338 Polyotia 339 Duplication of the External Auditory Meatus 340 Synotia/Otocephaly 340 Low-set Ears 342 Posteriorly Rotated Ears 344 Lop/Cup Ear Anomaly 344 Protruding Ear 346 Stahl Ear 348 Mozart Ear 349 Darwinian Tubercle 350 Prominent Crus of the Helix 350 Lobular Defects 350 Auricular Tags 351 Auricular Pits 353 Ear Lob Creases/Pits 355 Deformation of the Auricle 356

Middle Ear

356

John C. Carey and Albert H. Park

10.22 Hypoplasia/Aplasia/Malformation of the Malleus 358 10.23 Fusion Defects of the Malleus 359 10.24 Hypoplasia/Aplasia/Malformation of the Incus 361 10.25 Fusion Defects of the Incus 362 10.26 Hypoplasia/Aplasia/Malformation of the Stapes 362 10.27 Congenital Fixation of the Stapes 363 10.28 Absence of the Oval Window 364 10.29 Congenital Cholesteatoma 364 10.30 Persistence of the Stapedial Artery 365 10.31 Highly Placed Jugular Bulb 365 Inner Ear 366 Daryl A. Scott and John C. Carey

297

Elias I. Traboulsi

9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10

329

John C. Carey, Albert H. Park, and Harlan R. Muntz

10.32 Vestibular Dysplasias 366 10.33 Prelingual Hearing Loss 369 300

11. Nose

373

M. Michael Cohen, Jr.

11.1 11.2 11.3 11.4 11.5 11.6

Arhinia 374 Unilateral Arhinia, Heminasal Aplasia Small Nose 375 Nostril Coloboma 376 Bifid Nose 376 Nostril Atresia 377

374

Contents

11.7 11.8 11.9 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 12. Lips

Choanal Atresia 377 Polyrrhinia 378 Proboscis 378 Noses of Distinction 381 Deviation of the Nasal Septum 386 Turbinate Deformity 386 Arrhinencephaly 386 Hemangioma of the Nose 386 Dermoid Cyst of the Nose 388 Glioma of the Nose 388 Encephalocele Involving the Nose 388 391

Marilyn Jones

12.1 12.2 12.3

Median Cleft Lip 393 Cleft Lip With or Without Cleft Palate (CL/P) 394 Cleft Palate 400

13. Tongue

ix

14.6 14.7 14.8 14.9 14.10

13.6 13.7 13.8 13.9 13.10 13.11 13.12 13.13

13.14 13.15 13.16 13.17 13.18 13.19 13.20 13.21 13.22 14.

Teeth

425

Rena N. D’Souza, Hitesh Kapadia, and Alexandre R. Vieira

14.1 14.2 14.3 14.4 14.5

Tooth Agenesis 431 Supernumerary Teeth 444 Microdontia 446 Macrodontia 451 Abnormalities of Tooth Shape 452

469

15. Brain

Alasdair G. W. Hunter

15.1 15.2 15.3 15.4 15.5

405

Aglossia, Hypoglossia, Microglossia 406 Absence of Lingual Frenulum 406 Macroglossia 407 Bifid Tongue 408 Fissured Tongue, Scrotal Tongue, Lingua Plicata 408 Glossopalatine Ankylosis (Ankyloglossum Superius) 409 Ankyloglossia: Tongue-tie, Partial Ankyloglossia, Total and Lateral Ankyloglossia 410 Median Rhomboid Glossitis 411 Double Tongue 412 Lingual Thyroid 413 Choristoma of Tongue: Enterogenous Cyst of Tongue 414 Choristoma of Tongue: Epidermoid Cyst of Tongue 416 Choristoma of Tongue: Cyst Lined with Respiratory Epithelium or Nonciliated Columnar Epithelium 416 Choristoma of Tongue: Brain Tissue in Tongue 416 Choristoma of Tongue: Chondroma and Osteoma 417 Congenital Dermoid Cyst 418 Hamartoma: Lymphangioma of the Tongue 419 Hamartoma of the Tongue: Hemangioma 420 Hamartoma of the Tongue: Mixed Type (Mesenchymoma) 420 Congenital Teratoma 421 Abnormal Tongue Movements and Excessive Mobility of the Tongue 421 Pigmented Fungiform Papillae and Other Lingual Pigmentations 423

463

Part IV—Neuromuscular Systems

Robert J. Gorlin

13.1 13.2 13.3 13.4 13.5

Dental Malocclusion 456 Enamel Dysplasia 458 Dentin Dysplasia 461 Cementum Dysplasia 463 Abnormalities of Tooth Eruption

15.6 15.7 15.8 15.9 15.10 15.11 15.12 15.13 15.14

Microcephaly 470 Megalencephaly 511 Aprosencephaly/Atelencephaly 525 Holoprosencephaly 528 Malformations of Cortical Development: Disorders of Neuronal and Glial Formation, Migration, and Maturation; Lissencephaly, Pachygyria, Polymicrogyria, Heterotopias, Ectopias, and Cortical Dysplasias 546 Agenesis of the Corpus Callosum 581 Cavum, Cysts, and Absence of the Septum Pellucidum and Cavum Vergae 604 Hydrocephalus 610 Colpocephaly 636 Hydranencephaly 639 Porencephaly 645 Cerebellar Anomalies 654 Cystic Malformations 677 Chiari Malformations 700

16. Brain and Spinal Cord

715

Alasdair G. W. Hunter

16.1

Disorders of Neural Tube Closure

17. Spinal Cord

715

757

Alasdair G. W. Hunter

17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8

Primary Tethered Cord 757 Neurenteric Malformations 762 Intraspinal (Nonneurenteric) Cysts 764 Syringomyelia 768 Split Cord Malformation (Diastematomyelia) and Diplomyelia 773 Myelocystocele 776 Anterior and Lateral Meningoceles 778 Tailgut Cyst 782

18. Muscle

783

Judith G. Hall

18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9

Generalized Abnormalities of Muscle Mass: Increased Muscle Mass 786 Generalized Abnormalities of Muscle Mass: Decreased Muscle Mass 788 Localized Abnormalities of Muscle 790 Aglossia 791 Facial Muscle Deficiency 791 Asymmetric Crying Facies 791 Deficiency of Eye Muscles 792 Deficiency of Esophageal Muscles 792 Defects of Pectoralis Muscles and Other Muscles of the Shoulder Girdle 793

x

Contents

18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18

Poland Anomaly 794 Poland-Mo¨bius Syndrome 795 Poland-Like Gluteal-Lower Leg Anomaly 796 Prune Belly Syndrome 797 Isolated Deficiency of Abdominal Muscles 799 Diaphragmatic Defects 799 Variations with Accessory Muscle Tissue 800 Muscle Atavisms 800 Muscle Abnormalities Associated with Chromosomal Disorders 801

21. Hands and Feet

935

David B. Everman

21.1 21.2 21.3 21.4

The The The The

Polydactylies 937 Syndactylies 954 Brachydactylies 968 Oligodactylies 984

22. Skeletal Dysplasias

997

Ju¨rgen Spranger

Part VI—Gastrointestinal and Related Structures Part V—Skeletal System 23. Ventral Wall of the Trunk 19. Pectoral Girdle, Spine, Ribs, and Pelvic Girdle

805

Louanne Hudgins and Keith Vaux

19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11 19.12 19.13 19.14 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 20. Limbs

Clavicular Hypoplasia/Aplasia 806 Clavicular Pseudarthrosis 807 Altered Shape and Other Abnormalities of the Clavicle 807 Sprengel Anomaly 807 Glenoid Hypoplasia 809 Anomalies of the Sternum 810 Pectus Excavatum/Pectus Carinatum 811 Rib Anomalies 812 Cervical Rib 813 Occipitalization of the Atlas 813 Aplasia/Hypoplasia of the Odontoid Process of the Axis 818 Segmentation/Formation Defects of the Vertebrae 819 Klippel-Feil Anomaly 821 Altered Vertebral Body Contour 823 Sagittal Clefts of the Vertebrae 825 Coronal Clefts of the Vertebrae 826 Spondylolysis and Spondylolisthesis 827 Sacral Agenesis 829 Anomalies of the Pelvic Bones 830 Developmental Dysplasia of the Hip 830 Coxa Vara 833 Coxa Valga 833 835

23.1 23.2 23.3

23.4 23.5 23.6 23.7 23.8

Sternal Defects 1025 Ectopia Cordis, Including Cantrell Pentalogy The Umbilicus: Congenital Anomalies and Variations in Configuration and Placement 1028 Umbilical Hernia 1031 Omphalocele 1034 Gastroschisis 1038 Exstrophy of the Bladder 1042 Exstrophy of the Cloaca 1046

Breasts

1049

23.9 23.10 23.11 23.12 23.13 23.14 23.15

Amastia and Hypomastia 1051 Enlarged Breasts 1053 Symmastia 1055 Supernumerary Breasts and Nipples Widely Spaced Nipples 1058 Gynecomastia 1059 Premature Thelarche 1063

24. Upper Gastrointestinal System

Pharynx 24.1

1065

24.2

1067

Fistulas, Sinuses, and Cysts: Branchial Clefts and Pouches 1069 Congenital Pharyngeal Diverticula 1071

Esophagus 24.3

Judith G. Hall

1055

H. Eugene Hoyme

20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 20.9 20.10 20.11 20.12 20.13 20.14

1027

Ellen Boyd and Roger E. Stevenson

Roger E. Stevenson

Limb Deficiencies 839 Synostosis 856 Constriction Rings 871 Duplications, Excessive Partitions, and Accessory Bones 876 Bowing of Long Bones 882 Short Stature 894 Tall Stature 900 Limb Overgrowth 902 Increased Bone Density 910 Decreased Bone Density 914 Osteolysis 916 Anomalies of the Patella 919 Hypermobile Joints 922 Arthrogryposis (Multiple Congenital Contractures) 925

1023

Cynthia Curry, Ellen Boyd, and Roger E. Stevenson

1071

Esophageal Stenosis, Atresia, and Tracheoesophageal Fistula 1073 24.4 Esophageal Webs and Rings 1076 24.5 Tubular Esophageal Duplications 1077 24.6 Enterogenous Cysts 1077 24.7 Esophageal Diverticula 1078 24.8 Heterotopic Gastric Mucosa in the Esophagus 1079 24.9 Congenital Short Esophagus 1079 24.10 Achalasia 1079 24.11 Chalasia 1080 Stomach 24.12 24.13 24.14 24.15

1081

Infantile Hypertrophic Pyloric Stenosis 1082 Microgastria 1084 Atresia and Stenosis of the Stomach 1084 True Diverticula of the Stomach 1085

Contents

24.16 24.17 24.18 24.19

Duplication of the Stomach 1086 Defects of Gastric Musculature 1086 Malposition of the Stomach 1087 Mucosal Heterotopia 1088

Duodenum

1089

24.20 24.21 24.22 24.23 24.24 24.25

Malrotation of the Duodenum 1090 Duodenal Stenosis and Atresia 1090 Duodenal Duplications 1092 Duodenal Diverticula 1093 Congenital Aganglionic Duodenum 1094 Extrinsic Vascular Obstruction of the Duodenum 1095 24.26 Congenital Paraduodenal Hernia through a Peritoneal Defect 1095

xi

28.6 28.7 28.8 28.9 28.10 28.11 28.12 28.13 28.14 28.15 28.16 28.17

Renal Dysplasia 1205 Familial Nephronophthisis/Medullary Cystic Disease 1215 Medullary Sponge Kidney 1217 Renal Cystic Disease Secondary to Obstruction Supernumerary Kidney 1222 Renal Ectopia 1223 Horseshoe Kidney 1228 Anomalies of the Bladder and Ureters 1232 Urachal Anomalies 1234 Urethral Agenesis or Atresia 1237 Posterior Urethral Valves and Urethral Stenosis 1241 Urethral Duplication 1247

29. Male Genital System 25. Small and Large Intestines

1097

Intestinal Agenesis 1099 Intestinal Atresia/Stenosis 1099 Duplications and Cysts 1103 Megacolon 1105 Malrotation 1109 Meckel Diverticulum 1111 Polyps 1111 Vascular Anomalies 1114

26. Rectum and Anus

1115

Cathy A. Stevens

26.1 26.2

Atresia of the Rectus and Anus Rectal Duplication 1122

27. Liver, Gallbladder, and Pancreas

1116

1123

Ian D. Krantz and Arthur S. Aylsworth

27.1 27.2 27.3

Anomalies of Liver Shape and Lobation 1127 Liver Dysplasia/Ductal Plate Malformations 1131 Intrahepatic Biliary Duct Atresia and Hypoplasia 1136 27.4 Agenesis of the Gallbladder 1139 27.5 Extrahepatic Biliary Atresia 1142 27.6 Cysts of the Biliary System 1145 27.7 Structural Variation and Miscellaneous Anomalies of the Gallbladder and Extrahepatic Ducts 1147 27.8 Pancreatic Agenesis 1150 27.9 Structural Variation and Anomalies of the Pancreas 1150 27.10 Pancreatic Cysts and Dysplasias 1154 27.11 Pancreatic Ectopia and Heterotopia 1157 Part VII—Urogenital System Organs 28. Urinary Tract

1161

Jane A. Evans

28.1 28.2 28.3 28.4 28.5

1251

Rick A. Martin

Eberhard Passarge and Roger E. Stevenson

25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8

1219

Renal Agenesis 1184 Renal Hypoplasia 1190 Cystic Diseases 1194 Autosomal Recessive (Infantile) Polycystic Kidney Disease 1197 Autosomal Dominant Polycystic Kidney Disease 1200

29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 29.9 29.10 29.11 29.12 29.13 29.14 29.15 29.16 29.17 29.18

Micropenis 1255 Hypospadias 1258 Epispadias 1261 Hidden or Concealed Penis 1262 Megalourethra 1263 Diphallia 1264 Aphallia 1265 Penoscrotal Transposition 1265 Ectopic/Accessory Scrotum 1267 Cryptorchidism 1267 Microorchia/Anorchia/Agonadism 1268 Polyorchidism (Supernumerary Testes) 1271 Ectopic Testis 1272 Male Pseudohermaphroditism and 46,XY Sex Reversal 1272 Wolffian Duct Malformations 1276 Persistent Mu¨llerian Ducts 1276 Splenogonadal Fusion 1277 Inguinal Hernia 1277

30. Female Genital System

1279

Leah W. Burke

30.1 Ovarian Dysgenesis 1281 30.2 Mixed Gonadal Dysgenesis 1284 30.3 Hermaphroditism 1286 30.4 Ambiguous Genitalia 1287 30.5 Mu¨llerian Aplasia 1291 Isolated Anomalies of the Mu¨llerian Structures 1294 30.6 Absence of the Fallopian Tube 1294 30.7 Incomplete Mu¨llerian Fusion 1294 30.8 Cervical Atresia 1297 30.9 Vaginal Atresia 1298 30.10 Transverse Vaginal Septum 1299 30.11 Longitudinal Vaginal Septum 1300 30.12 Agenesis of the Clitoris 1300 30.13 Isolated Hypertrophy of the Clitoris/Clitoromegaly 1301 30.14 Duplication or Bifidism of the Clitoris/Female Epispadias 1302 30.15 Labial Fusion 1303 30.16 Imperforate Hymen 1303 30.17 Absence/Hypoplasia of External Genitalia 1303 30.18 Hyperplasia, Duplication, and Inversion of External Genitalia 1304

xii

Contents

Part VIII—Other Systems and Structures 31. Cutaneous Structures

1307

Julie S. Prendiville

31.1

Skin Cysts, Sinuses, Dimples, Tags, Tails, and Clefts 1309 31.2 Aplasia Cutis Congenita 1311 31.3 Mosaicism and the Lines of Blaschko 1312 31.4 Cutaneous Hamartomas 1315 31.5 Disorders of Keratinization 1319 31.6 Epidermolysis Bullosa 1319 31.7 Developmental Disorders of Connective Tissue 1321 31.8 Vascular Malformations 1322 31.9 Pigmentation Anomalies 1329 31.10 Malformations of the Epidermal Appendages 32. Endocrine Organs

1333

35. Umbilical Cord

1339

32.3 32.4 32.5 32.6 32.7 32.8 32.9

Congenital Adrenal Hyperplasia 1346 Anterior Pituitary, Hypothalamus, and Disorders of Short Stature 1349 Parathyroid Gland: Calcium Sensing Receptor Defects 1353 Parathyroid Gland: Albright Hereditary Osteodystrophy 1353 Posterior Pituitary and Water Metabolism 1354 Thyroid and Thyroid Biosynthetic Defects 1354 Endocrine Tumor Syndromes 1355 Mendelian Disorders with Endocrine Abnormalities 1356 Chromosomal Disorders with Endocrine Features 1357

33. Asymmetry and Hypertrophy

1359

Omar Abdul-Rahman and H. Eugene Hoyme

33.1 33.2

Laterality Sequences 1361 Kartagener Syndrome 1363

Patterns of Asymmetric Growth 33.3 33.4 33.5 34. Twins

1413

Will Blackburn and Nelson Reede Cooley, Jr.

Amy Potter and John A. Phillips III

32.1 32.2

Incidence of Twinning 1382 Causes of Twinning 1383 Sex Ratio 1383 Growth 1384 Spontaneous Abortions 1385 Vanishing Twin 1385 Fetus Papyraceus 1388 Perinatal Morbidity and Mortality 1389 Vascular Anastomoses in Twin Placentas 1390 Twin–Twin Transfusion Syndrome 1391 Acardia 1394 Conjoined Twins 1396 Structural Defects 1401 Mirror Image Twinning 1404 Discordance 1404 Caution for Complex Disorders 1404

1365

Hemihyperplasia (Hemihypertrophy) 1366 Hemihypoplasia and Hemiatrophy 1369 Generalized Overgrowth 1372 1377

Mary C. Phelan and Judith G. Hall

Zygosity and Placentation 1377 Polar Body Twinning 1380 Animal Models of Twinning 1380 Determination of Zygosity 1381

35.1 35.2 35.3 35.4 35.5 35.6 35.7 35.8 35.9 35.10 35.11 35.12 35.13 35.14 35.15 35.16 35.17 35.18 35.19 35.20 35.21

Umbilical Cord Calcifications 1417 Umbilical Cord Amnion (Inclusion) Cysts 1418 Umbilical Cord Cysts and Remnant Anomalies of Allantoic Duct Origin 1419 Umbilical Cord Cysts and Remnants of Vitelline (Omphalomesenteric Duct) Origin 1421 Umbilical Cord Pseudocyst (Cystic Mucoid Degeneration) 1424 Umbilical Cord Disruption (Linear) 1425 Umbilical Cord Dimensional Abnormalities 1426 Umbilical Cord-to-Cord Entanglements 1434 Umbilical Cord Hematoma 1436 Umbilical Cord Hernia 1437 Anomalies of Umbilical Cord Insertion 1439 Umbilical Cord Knots 1441 Umbilical Cord Loops (‘‘Encirclement’’) 1443 Umbilical and Umbilical Cord Polyp 1445 Abnormalities of Umbilical Cord (Abdominal Wall) Position 1448 Antenatal Separation of the Umbilical Cord 1449 Abnormalities of Postnatal Umbilical Cord Separation 1450 Umbilical Cord Torsion (Twist) Abnormalities 1451 Umbilical Cord Helical Ulceration 1453 Umbilical Cord Neoplasms 1454 Vascular Anomalies of the Umbilical Cord 1457

Index to Tables of Malformations and Associated Syndromes 1473 Subject Index

1477

Contributors

Omar Abdul-Rahman, M.D. Division of Medical Genetics Department of Pediatrics Stanford University School of Medicine Stanford, California Judith E. Allanson, M.D. Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada Arthus S. Aylsworth, M.D. Department of Pediatrics University of North Carolina Chapel Hill, North Carolina John Belmont, M.D., Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas Lynne M. Bird, M.D. Department of Dysmorphology and Genetics Children’s Hospital San Diego, California

M. Michael Cohen, Jr., D.M.D., Ph.D. Oral and Maxillofacial Sciences Dalhousie University Halifax, Nova Scotia, Canada Cynthia Curry, M.D. Genetic Medicine Central California Fresno, California Department of Pediatrics University of California, San Francisco San Francisco, California Rena N. D’Souza, D.D.S., Ph.D. Department of Orthodontics, Dental Branch University of Texas Health Science Center Houston, Texas Luis Fernando Escobar, M.D. Medical Genetics and Developmental Pediatrics St. Vincent Hospital of Indianapolis Indianapolis, Indiana

Will Blackburn, M.D. Fairhope, Alabama

Jane A. Evans, Ph.D. Department of Biochemistry and Medical Genetics University of Manitoba Winnipeg, Manitoba, Canada

Ellen Boyd, M.D. Fullerton Genetics Center Asheville, North Carolina

David B. Everman, M.D. Greenwood Genetic Center Greenwood, South Carolina

Leah W. Burke, M.D. Division of Clinical Genetics University of Vermont College of Medicine Burlington, Vermont

Robert J. Gorlin, D.D.S., D.Sc. University of Minnesota School of Dentistry Minneapolis, Minnesota

John C. Carey, M.D. Division of Medical Genetics University of Utah Salt Lake City, Utah

John M. Graham, Jr., M.D., Sc.D. Medical Genetics Institute Steven Spielberg Pediatric Research Center David Geffen School of Medicine at UCLA Cedars Sinai Medical Center Los Angeles, California

xiii

xiv

Karen Gripp, M.D. DuPont Hospital for Children Wilmington, Delaware Judith G. Hall, M.D. Departments of Medical Genetics and Pediatrics UBC and Children’s and Women’s Health Centre of British Columbia Vancouver, British Columbia, Canada H. Eugene Hoyme, M.D. Division of Medical Genetics, Department of Pediatrics Stanford University School of Medicine Stanford, California Louanne Hudgins, M.D. Division of Medical Genetics, Department of Pediatrics Stanford University School of Medicine Stanford, California Alasdair G.W. Hunter, M.D. Children’s Hospital of Eastern Ontario Ottawa, Ontario, Canada Kenneth Lyons Jones, M.D. Division of Dysmorphology/Teratology University of California San Diego, California Marilyn Jones, M.D. Children’s Hospital San Diego, California Hitesh Kapadia, D.D.S. Department of Orthodontics University of Texas Health Science Center Houston, Texas Ian D. Krantz, M.D. Division of Human Genetics and Molecular Biology The Children’s Hospital of Philadelphia The University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Angela E. Lin, M.D. Genetics and Teratology Unit Massachusetts General Hospital Boston, Massachusetts Sadia Malik, M.D. Department of Cardiology Arkansas Children’s Hospital Little Rock, Arkansas

Contributors

Eberhard Passarge, M.D. Institit fu¨r Humangenetik Universita¨tklinikum Essen, Germany Mary C. Phelan, Ph.D. T.C. Thompson Children’s Hospital Chattanooga, Tennessee John A. Phillips III, M.D. Division of Medical Genetics Department of Pediatrics Vanderbilt University School of Medicine Nashville, Tennessee Amy Potter, M.D. Division of Endocrinology and Metabolism Department of Medicine Vanderbilt University School of Medicine Nashville, Tennessee Julie S. Prendiville, M.B. British Columbia’s Children’s Hospital University of British Columbia Vancouver, British Columbia, Canada Daryl A. Scott, M.D., Ph.D. Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas Laurie H. Seaver, M.D. Greenwood Genetic Center Greenwood, South Carolina Ju¨rgen W. Spranger, M.D. Greenwood Genetic Center Greenwood, South Carolina Cathy A. Stevens, M.D. Department of Pediatrics University of Tennessee College of Medicine Chattanooga, Tennessee Roger E. Stevenson, M.D. Greenwood Genetic Center Greenwood, South Carolina Elias I. Traboulsi, M.D. Division of Ophthalmology Cleveland Clinic Foundation Cleveland, Ohio

Rick A. Martin, M.D. St. Louis Children’s Hospital, Medical Genetics Washington University St. Louis, Missouri

Keith Vaux, M.D. Department of Pediatrics Division of Dysmorphology University of California, San Diego San Diego, California

Harlan R. Muntz, M.D. Department of Otolaryngology University of Utah Health Sciences Center Salt Lake City, Utah

Alexandre R. Vieira, D.D.S., Ph.D. Department of Pediatrics University of Iowa Iowa City, Iowa

Albert H. Park, M.D. Department of Otolaryngology University of Utah Health Sciences Center Salt Lake City, Utah

Part I Overview

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1 Human Malformations and Related Anomalies Roger E. Stevenson

M

alformations result from pathologic processes during the embryonic period. The pathologic processes may be inborn, extrinsic, or some combination of the two. There is a narrow period of vulnerability during which developmental processes may be affected adversely, since most human body structures are formed between the second and the eighth weeks of development. Some organs, such as the brain, continue to develop throughout fetal life and even after birth. The small period of vulnerability notwithstanding, a remarkably large number of conceptuses, perhaps the majority, fall victim to disturbances in normal developmental processes. In most instances, the malformed conceptuses or embryos fail to implant or die following implantation.1–17 A minority of these conceptuses continue to develop, but will result in infants born with malformations. In this book, the phrase ‘‘malformations and related anomalies’’ encompasses all types of fetal and embryonic processes that lead to the presence of structural anomalies at birth. In addition to those processes that interfere with normal formation of structures (malformations), there are disruptions (in which normally developing structures are damaged by in utero forces such as vascular accidents or amniotic bands), deformations (in which a normal structure is misshaped by internal or external mechanical forces), and dysplasias (in which cell structure, cell arrangement in tissue, or tissues are disorganized). Among liveborn infants, 2–3% will have major malformations that are detected at birth or in the initial weeks or months of life (Tables 1-1 and 1-2).18–29 Some major malformations escape early detection, but these covert malformations are usually found by age 5 years and equal the number (2–3%) found at birth.30 Some internal malformations fail to cause physiologic disturbance and may be found only incidentally during surgery, scans, radiographs, or autopsy. Among stillborn infants, 15–20% will have major malformations.31–34 An even higher rate of malformations is to be found among spontaneous abortions. All anatomic structures appear to be susceptible to malformations. The frequency with which different structures are The author gratefully acknowledges the contributions of Judith G. Hall, Patrick M. MacLeod, Dagmar Bauer-Hansmann, Mitchell S. Golbus, Richard J. Schroer, Robert A. Saul, and Golder N. Wilson to volume 1 of the first edition of Human Malformations and Related Anomalies, on which this Introduction is based.

found postnatally to be malformed varies significantly, depending to a significant degree on the physiologic impact of the malformation prenatally. Table 1-1 gives the birth prevalence for malformations of the major anatomic structures.22,23,35 Certain birth defects appear to be increasing (e.g., hypospadias and coarctation of the aorta), whereas others are declining in prevalence (e.g., neural tube defects and renal agenesis). Wide fluctuations in prevalence are seen in different locations around the world.35 Nowhere in medicine is a sympathetic and discerning ear more important than in the evaluation of the infant with a birth defect. The family may be devastated by the announcement that the anticipated ‘‘perfect baby’’ has or may have a significant defect. More and more often the anomaly is recognized prenatally. The evaluation must begin at the time the defect is recognized or suspected, although full evaluation may be postponed in some infants until birth or until the infant can be evaluated at a tertiary center if the anomaly is not life threatening. The ideal situation with non– life-threatening defects is that parent–infant bonding proceed without interruption and the infant be discharged from the hospital with the mother. In other circumstances, evaluation must be carried out more urgently. Certain anomalies, particularly cardiac and gastrointestinal anomalies, are potentially lethal if not treated immediately. Other lethal conditions for which no treatment is available need urgent diagnosis to plan appropriate management with the family. Some anomalies may not be life threatening, but evaluation is no less urgent. Notable among these is ambiguous genital development. Malformations have emerged as the most common cause of death during the first year of life in developed countries.36–38 With a preplanned protocol, evaluation of the infant with anomalies who dies can be carried out efficiently and with sensitivity to the family. The protocol should include complete examination, storage of appropriate samples (serum, urine, tissues), photographs, radiographs, and necropsy.39,40 Abortuses and stillborn infants can be evaluated under a similar protocol. Only with knowledge of the nature of the anomalies can accurate information on the cause of death and risk of recurrence be provided for the family. Clinicians attempt to assign causation in all human anomalies for the purpose of gaining a secure foundation for counseling and consideration of future preventive efforts. As desirable 3

Table 1-1. Prevalence of selected major malformations USA: Atlanta*

USA: California{

Canada{

High Prevalence Regionsx

Low Prevalence Regionsx

Rate

Trend

Rate

Rate

Trend

Anencephaly

3.6

;

3.7

2.1

;

Mexico South America

Italy South Africa

Spina bifida

3.8

;

4.3

6.3

;

Mexico South America

Spain England/Wales

Encephalocele

1.6

;

0.9

1.4

Mexico South America

Spain Norway

Hydrocephaly

8.1

;

3.5

7.1

South America France

England/Wales Spain

Anophthalmia/Microphthalmia

2.9

;

1.2

1.1

USA (Atlanta) Ireland (Dublin)

England/Wales Hungary

Anotia/Microtia

1.5

Mexico South America

Australia England/Wales

USA (Atlanta) Ireland (Dublin)

England/Wales

N. Netherlands France

Mexico England/Wales

USA (Atlanta) France

England/Wales South America

Ireland (Dublin) USA (Atlanta)

England/Wales Spain

Neural Tube Defects

;

3.3

Cardiac Defects Atrial septal defect

25.1

19.7

23.0

:

Ventricular septal defect

37.8

16.0

30.4

:

Tetralogy of Fallot

4.2

2.6

4.2

:

Transposition of great vessels

5.4

4.2

4.2

Truncus arteriosus

0.9

0.6

1.2

Hypoplastic left heart syndrome

3.0

2.5

2.9

Coarctation of aorta

5.1

:

4.0

4.8

Cleft Lip With or Without Cleft Palate

9.0

;

10.4

10.7

Norway Japan

South Africa Canada

Cleft Palate Without Cleft Lip

6.8

4.9

6.3

Malta Finland

South Africa

Esophageal Atresia/Stenosis With or Without Fistula

2.0

1.2

3.4

South America Ireland (Dublin)

England/Wales

Rectal and Large Intestinal Atresia/Stenosis

3.7

2.5

4.5

:

33.7

:

2.3

24.2

Israel Czech Republic

Australia Italy

Renal Agenesis/Hypoplasia

4.5

;

0.5

4.2

Canada Ireland (Dublin)

Hungary Mexico

Diaphragmatic Hernia

2.3

2.5

France Ireland (Dublin)

South Africa Mexico

Bladder Exstrophy

0.1

0.0

Mexico France

England/Wales Japan

Omphalocele

2.6

France South America

Spain England/Wales

Gastroschisis

2.2

4.2

Mexico South America

Spain South Africa

Limb Reduction Defects (Upper)

4.1

3.7

Limb Reduction Defects (Lower)

1.7

1.7

Canada France

South Africa Japan

Hypospadias/Epispadias

;

1.3

g g

: 6.6

4.6

(continued)

4

Human Malformations and Related Anomalies

5

Table 1-1. Prevalence of selected major malformations (continued) USA: Atlanta* Rate

USA: California{

Trend

Canada{

Rate

Rate

Trend

High Prevalence Regionsx

Low Prevalence Regionsx

Chromosome Aneuploidies Trisomy 13

1.5

1.1

1.2

:

Ireland (Dublin)

Hungary

Trisomy 18

2.5

1.8

2.1

:

Ireland (Dublin)

Hungary

Trisomy 21

12.5

10.1

12.4

Ireland (Dublin)

Hungary

*Malformation rates (1996–2000) birth to age 6 years per 10,000 livebirths reported by Metropolitan Atlanta Congenital Defects Program (5 Metropolitan Atlanta counties).22 { Malformation rates (1996–2000) birth to age 1 year per 10,000 livebirths reported by California Birth Defects Monitoring Program (8 counties).22 { Malformation rates (1991–1993) birth to age 1 year per 10,000 births reported by Canadian Congenital Anomalies Surveillance System (Alberta, Manitoba, and Ontario provinces).23 x

High and low prevalence regions from International Clearinghouse for Birth Defects Monitoring Systems.35

Additional prevalence information on specific malformations may be found in the appropriate chapters.

Table 1-2. Incidence of major and minor anomalies Location 18

Sample Size

Major Anomalies (%)

Minor Anomalies (%)

14.7

Marden et al., 1964

USA

4412

2.1

Myrianthopoulos and Chung, 197420

USA

53,257

7.1

Mehes, 198350

Hungary

4589

2.2

Merlob et al., 198529

Israel

3762

1.6

21.0

Leppig et al., 198951

USA

4305

3.8

40.7

CBDMP, 1994*26

USA

>500,000

2.9

–

Stoll, 199525

Europe

291,126

2.2

–

Queisser-Luft et al., 200224

Germany

30,940

6.9

35.8

7.26 17.2

*California Birth Defects Monitoring Program.

as that goal may be, it is not attainable in every case. The causes of many malformations and recognized syndromes simply are not known. This is the case for approximately 40% of malformations.41,42 Of the 290 malformation syndromes included in Jones’ Smith’s Recognizable Patterns of Human Malformations, 40 (14%) have unknown etiology.43 Assignment of causation of a malformation in one individual may not be possible although the cause of the same malformation is readily determined in other individuals. Lethality has posed a barrier to determining causation of certain malformations and patterns of malformations; sirenomelia and Proteus syndrome are examples (Fig. 1-1).44,45 These conditions generally occur as isolated cases within a family. Affected individuals either die early (sirenomelia) or fail to reproduce (Proteus syndrome). The possibilities that either represents a dominant phenotype caused by a new mutation, a multifactorial phenotype with a low recurrence rate, or a chromosomal disorder caused by submicroscopic deletion that has not been detected with current technology cannot be excluded. Hence, the causes of these conditions will remain unknown until one of these possibilities or another alternative is confirmed and the possible cause or causes can be sorted out.

If heritable factors, environmental factors, or some combination of the two are accepted as the only etiologic possibilities for human anomalies, then one assumes that birth defects of unknown etiology will eventually be explained in terms of one of these three possibilities. Should factors other than hereditary and environmental be identified, the new influence must be woven into the causation schema. Kurnit et al. have suggested that chance may play a significant role in the occurrence of major malformations.46 The field of developmental biology is advancing in remarkable ways. Many of the genes involved in organ formation have been identified in lower animals; these same genes turn out to be important and thus conserved in human development.194 These developmental genes are expressed in a hierarchical manner much like the clotting cascade. Complex controls cause transcription to occur in tissue-specific and time-specific manner during development. Although the precise roles for various molecular phenomena (e.g., alternative splicing, regulatory elements, polymorphisms, receptors, affectors, epigenetic modifications of DNA and histones, processing of RNA) in development are unknown, it is clear that current investigations are directed at delineating a complete molecular embryology. Specific defects in

6

Overview

Fig. 1-1. Sirenomelia (A) and Proteus syndrome (B), a malformation and malformation syndrome of unknown causation. Note that a minority of cases of sirenomelia occurs in infants of diabetic mothers, and some possible cases of Proteus syndrome have had PTEN mutations.

molecular pathways and networks of pathways are now recognized and give greater insight into the etiology of structural anomalies observed at birth. 1.1 Nomenclature Meaningful terminology is fundamental to communication and to most educational processes. The plethora of terms used to describe human morphologic alterations sometimes promotes but often complicates these processes. Understandably, students may be confused by the admixture of commonly used terms. Some provide true descriptions of the alteration (macrocephaly); some bear ethnic, rank, or national connotations (Roman nose); some are colored with mythological imagery (sirenomelia, cyclopia); some imply a specific pathogenesis (oligohydramnios sequence); some imply a specific etiology (warfarin embryopathy); and some give tribute to a discoverer (Meckel diverticulum). The same term can be used in a very restricted sense by one group while having a more generic meaning for the total scientific community. Terms most removed from description of the anatomic alteration are most variable and carry the greatest prospect for continued change in the future. A universally acceptable and permanent terminology for anomalies would appear utopian. No previous system has met with full acceptance. One problem is that the priorities of different groups dealing with congenital anomalies are not the same. Anthropologists, anatomists, radiologists, and pathologists focus on the description of the change; therapists, on the functional implications; embryologists and teratologists, on the mechanisms; and clinicians, on the diagnosis, cause, treatment, and prevention. In each of these areas, a jargon has arisen to serve the perceived requirements of the group. Sometimes the terms used by one group coincide with those used by colleagues with other emphases. In

other situations, the terms used by one group meet indifference or rejection by others. Exclusive claim cannot be placed on any terms, and no group can prohibit use beyond a specified definition. Anatomically based nomenclature for malformations and related structural anomalies emphasizes topography and morphology. The purposes are to identify the anatomic part involved and to describe the alteration of that part. In this system, the development of new terms to describe human malformations would appear unnecessary. Human anatomy does not change, and timehonored terms for each structure are available.47 Morphologic alterations of individual structures can also be defined with simple, biologically correct terms. Should new descriptive terms become desirable, they can be introduced without necessitating revision of the entire system. Because anatomic terms are the least likely to change, they are used in this book. Anatomic alterations include size, shape, symmetry, consistency, density, continuity, patency, color, and position changes. Some are readily determined by gross inspection. Others fall into a continuum nearer the normal than the extreme. Indeed, some can be separated from the normal only by arbitrary convention. As part of the evaluation of an infant or child with malformations, careful measurements of normal and abnormal structures are essential. Norms for every age from embryo to adult are available. Not infrequently disharmonic growth between structures exists in association with congenital malformations. For those structural changes that fall along a continuum, one expects 5% to fall outside 2 standard deviations (SD) of the mean for the population, 2.5% below 2 SD of the population norm, and 2.5% above 2 SD of the norm. It is of interest that this definition of normality results in an incidence of abnormal members among the continuous traits similar to the incidence of major malformations in the newborn population (Tables 1-1 and 1-2). Some continuous traits (e.g., color, density, and consistency) have no standardized measurements from which their norms and standard deviations can be determined. In the clinical setting, assessment of these features is almost invariably subjective. In an anatomically based nomenclature, no consideration is given to causation and pathogenesis, although in certain instances they may be coincidentally accommodated. Macrocephaly is used generically to describe large head of unknown cause and also to describe large head with large brain. Hydrocephaly is used to describe a large head due to ventricular enlargement. Hydrocephaly, however, does not necessarily imply head enlargement, since hydrocephaly can coexist with normal or even small head sizes. This type of duplicity and nuance is to be expected in any system of nomenclature and can be tolerated to some degree. Macrohydrocephaly or hydromacrocephaly to identify large head due to enlarged ventricles becomes too cumbersome. The terminology for anomalies based on morphologic alterations is derived from the Greek language, as introduced by Malacarne in 1798,48 but an increasing drift toward the use of Anglicized terms is evident. With English now being considered the universal scientific language, this trend will likely continue. A mix of English, Latin, and Greek terms will be found in the present text, with the choice of the term being based on familiarity and ease of flow. Malformations, Disruptions, and Deformations

Distinction between pathogenetically different types of structural abnormalities is indicated by the terms malformation, disruption, and deformation.49 Anomalies can be placed into one of these

Human Malformations and Related Anomalies

categories on the basis of the developmental stage during which the alteration took place, the process that caused the change, or the end result. Using these distinctions, malformations arise during the initial formation of a structure. The structure can have a faulty configuration, can be incompletely formed, or can fail to form altogether. Malformations are caused by genetic or environmental influences or by a combination of the two. They result from abnormal processes during the formation of the structures (i.e., during organogenesis). For most structures, organogenesis is complete by 8 weeks postfertilization. However, teeth, brain, and genitalia are notable among the many structures whose formation extends beyond 8 weeks. Disruptions result from abnormal processes that alter normally forming structures during or after formation. A wide range of morphologic changes can occur secondary to disruptions, including alterations of shape and configuration, division of parts not usually divided, fusion of parts not usually fused, and loss of parts previously present. The causes of disruptions are usually environmental, but genetic causes (e.g., genetically programmed loss of blood supply and inherited thrombophilias) are also possible. Mechanical forces can cause compression, hemorrhage, thrombosis, emboli, and other vascular impairments that damage formed structures. The term deformation indicates molding of a part through mechanical forces, usually over a prolonged period of time. Deformations result in loss of symmetry, altered alignment, abnormal positioning, and distorted configuration. They usually occur after organogenesis, often involve musculoskeletal tissues, and require no obligatory underlying tissue defect. Abnormal tissues may, however, be more susceptible to deformation. Deformations are usually reversible postnatally, depending on how long-standing they are and how much growth has occurred subsequent to the initial compressive effects. Deformations are usually due to external forces but can result from edema, which can exert intrinsic compressive forces. These criteria for designating a malformation or disruption have been modified from those set forth by Spranger et al., who represented an International Working Group on Nomenclature of Errors of Morphogenesis.49 According to their definitions, malformations are all genetic in etiology; disruptions occur during or after organogenesis; and deformations are caused only by extrinsic forces. The restriction of malformation to structural defects of genetic origin would appear unwarranted and contrary to historical usage. For instance, it seems entirely appropriate to consider the limb anomalies caused by teratogens such as thalidomide to be malformations since they occur during the period of morphogenesis. Although this tripartite schema was thoughtfully devised and allows for meaningful communication among many who work with human congenital anomalies, universal usage should not be anticipated. The term malformation will be used in a generic sense by many to indicate any structural alteration that occurs during the prenatal period. In defense of this general usage, both scientists and the public understand the general nature of the problem when the term is used. Likewise, the term deformity is used by orthopedists to indicate any anomaly of the skeleton often including problems arising during embryologic development. The value to geneticists of using malformation, disruption, and deformation according to the foregoing definitions is that it allows certain generalizations to be made about the causation, pathogenesis, prognosis, and recurrence of different types of anomalies. It also allows for a more accurate categorization of the structural

7

abnormalities, which improves the prospect of a correct diagnosis. Spranger et al.,49 also described a fourth category of dysplasias in which cellular or tissue disorganization is present. Major and Minor Anomalies

Major structural anomalies have medical and social consequences. The incidences of major defects appear highest among abortions, intermediate in stillborn infants, and lowest among liveborn infants. The incidence of major anomalies recognized at birth among liveborn infants is 2–3% in most series (Table 1-1).18–29 An equal number of additional major anomalies will be recognized by age 5 years (e.g., cardiac defects, absent kidney). This means that by 5 years of age, 1 in 20 or 5% of individuals are found to have a major defect in structural development. Considering the complexity of the developmental processes, it is surprising that the frequency of anomalies is not higher. An evolving understanding of prenatal (and postnatal) human development indicates that the biochemical basis of development and growth changes during different stages of development. A specific gene’s product may have quite different effects in different tissues and at different times in development. Furthermore, a gene, possibly with alternative splicing, is reused in different tissues at different times in development. This suggests that susceptibilities and predispositions to detrimental influences both intrinsic and extrinsic may be very different at different times in development and that the potential for curative or corrective measures will need to be time-in-development sensitive. The control of these processes (e.g., the switch from embryonic to fetal and adult hemoglobin) is still poorly understood. No individual major anomaly has a sufficiently high incidence in the population for it to be considered a structural polymorphism; that is, none has an incidence of greater than 1%. The monopodic, cyclopic, and other malformed races that exist in noncritical accounts of ancient writers must be viewed with skepticism. Minor anomalies are relatively frequent structural alterations that pose no significant health or social burdens (Tables 1-2 to 1-4).18,49–52 They are nonetheless important because their presence prompts a search for coexistent, more important structural anomalies. The presence of two or more minor anomalies is an indication that a major defect or syndrome may be present as well. Minor anomalies often provide critical clues that permit the diagnosis of a specific syndrome or a specific disorder having multiple anomalies. They can also provide a clue to the timing of an insult during prenatal development. Approximately 15% of newborn infants have one or more minor structural anomalies.18,20,24,29,50,51 A higher incidence may be found among premature infants, while babies with intrauterine growth retardation have an even higher rate. The risk of having a major birth defect increases with the number of minor defects present (Table 1-4). Infants free of minor defects have a low incidence (approximately 1%) of major malformations. Infants with one minor defect have a 3% risk of a major defect; those with two minor defects have a 10% risk of a major malformation; and those with three or more minor defects have a 20% risk of a major defect.18,50,51 No clear distinction exists between normal variation and minor anomalies or between minor anomalies and major anomalies. The determinations are often arbitrary. Holmes separates minor anomalies from normal variants by considering as normal those features that occur in 4% or more of the population.52 This is a fourfold greater incidence than the 1% usually required for a

8

Overview Table 1-3. Minor anomalies Cranium and Scalp

Face and Neck

Horizontal palmar crease (single)

Triple hair whorl

Synophrys

Bridged palmar crease

Absence of hair whorl

Flat bridge of nose

Single crease, finger V

Patent metopic suture

Prominent bridge of nose

Metopic fontanel

Hypotelorism

Skin tags (preauricular, ear lobe, others)

Sagittal fontanel

Hypertelorism

Parietal foramen

Nostrils anteverted

Flat occiput

Long nasal septum

Prominent occiput

Epicanthal fold

Frontal bossing

Iris freckles

Flat brow

Upward palpebral slant

Pigmented spots Hypopigmented spots Trunk

Short palpebral fissures

Extra nipples Single umbilical artery Umbilical hernia

Microtia

Cleft uvula

Darwinian point

Cleft lip microform

Darwinian tubercle

Cleft gum

Lack of helical folding

Long philtrum

Bridged concha

Short philtrum

Ear lobe crease

Smooth philtrum

Ear lobe notched

Microstomia

Ear lobe bifid

Macrostomia

Lop ear

Macroglossia

Cup-shaped ear

Microglossia

Retroverted ear

Broad alveolar ridge

Thickened helix

Micrognathia

Helix excessively folded

Webbed neck

Helix attached to scalp

Redundant neck skin

Sinuses

Ptosis

Branchial

Skin

Overlapping digits

Preauricular

Shoulder dimples

Prominent heel

Ear lobe

Sacrum dimples

Helical

Dimples over other bones

Pilonidal

Sole crease

Diastasis rectus Glandular hypospadias Shawl scrotum Vaginal tag Limbs

Cubitus valgus Tapered fingers Overlapping fingers Broad thumb, great toe Clinodactyly Nails hypoplastic Nails hyperconvex Increased space, toes Syndactyly, toes 2–3

Table 1-4. Concurrence of minor and major anomalies at birth in three series Percent With Major Malformations Marden et al., 196418 USA

Mehes, 198350 Hungary

Leppig et al., 198751 USA

0

1.4

1.2

2.3

1

2.9

3.8

3.7

2

10.8

12.5

6.7

90

26


3

Nevi

Downward palpebral slant

Ears

Number of Minor Malformations

Hemangioma

19.6

human polymorphism. The level of sensitivity to minor anomalies is set differently by different observers. The difference may partially explain the low incidence of minor defects (7.26%) reported by Myrianthopoulos and Chung for the Collaborative Study in the

United States and the high incidence (39%) reported by Leppig et al.20,51 Minor morphologic features give the most consistent clues to the diagnosis of many multi-anomaly syndromes. Prenatal alcohol syndrome and prenatal hydantoin syndrome, for example, are more commonly diagnosed by a pattern of minor morphologic features than on the basis of major malformations. Mehes50 has found the number of minor anomalies detected to be greatest at the time of birth, with a decrease in the detection of many features by age 1 year. This suggests that certain minor anomalies resolve or become obscured with growth and function. Downslanting palpebrae, horizontal palmar creases, asymmetric ears, preauricular skin tags, and clinodactyly are among those features with similar incidences at birth and at 1 year. A 50% or greater reduction in the prevalences of high-arched palate, low-set ears, and upslanting palpebral fissures occurs by 1 year. This contrasts with the increased detection of major defects during the first year of life.20

Human Malformations and Related Anomalies

Connectional Terms

Because multiple structural anomalies often occur together, a terminology that relates the components has developed.49,53–57 In connectional terminology, anatomic description of the anomalies has been largely abandoned because listing each anatomical feature of the composite becomes cumbersome. Greater emphasis is given to pathogenesis and causation. The terminology relating multiple anomalies has little consensus and great liability for change and perhaps for confusion. These problems have prompted attempts to develop a uniform nomenclature. Over several years, beginning in 1974, a series of workshops were held to construct a classification and nomenclature of congenital anomalies and other human morphologic changes.49,53,58 As new rules regarding nomenclature were published, there was disagreement, and the scientific community became embroiled in a debate.59–61 It would be premature to suggest that this debate has resulted in widely accepted terminology. An equivalent meeting dealing with terminology is reported to have been held among persons themselves affected with congenital anomalies, in London, in 1898.62 The term prodigies, which the participants are said to have found acceptable, has never been adopted in the medical field. Syndrome, association, complex, spectrum, sequence, field defect, and phenotype have all been used to describe some composite of anatomic features. Johannsen63 coined the term phenotype to encompass the outward manifestations produced by an individual gene. The nature of the gene itself was termed genotype. Genotype and phenotype can refer to a single gene and its manifestations (anatomic, biochemical, physiologic), to a related group of genes and their manifestations, or to the entire genetic constitution and all resulting hereditary features. In current usage, phenotype has become a general term for describing a composite of features without regard to the underlying cause. Consistent with this usage, environmental as well as genetic factors can contribute to the phenotype. This more general use of phenotype in many cases suggests that the cause of the features is uncertain or that multiple causes might produce this composite of manifestations. In some cases a modifier is added to indicate pathogenesis, for example, akinesia phenotype to indicate those features that are produced by absence of prenatal movement from any cause. Complex is a general term that is also used to indicate a composite of manifestations. Spectrum is sometimes used to describe entities with multiple features, particularly those in which prominent features can be expressed with considerable variation. Greater specificity is suggested by the term syndrome, which means a group of features seen together in multiple individuals, but it also implies that the composite of features has a common, specific etiology. Use of the term indicates that a specific diagnosis has been made and that the natural history and recurrence risk are known. A well-recognized exception is use of the term to include the multiple features found in several well-delineated disorders, such as Proteus syndrome and Sturge-Weber syndrome.45,64 While the etiologies of these two disorders have not been identified, a single specific etiology is suspected for each. In some branches of medicine, syndrome is used without the specificity suggested previously when used to describe structural anomalies. Association has been used in clinical genetics to identify the nonrandom concurrence of two or more anomalies that occur more frequently than expected by chance alone but for which no etiology has been demonstrated. VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies) association

9

is a well-known example in which the first letters of the anomalies are used to make an acronym. Use of association does not imply a specific diagnosis. Recognition of such statistically related anomalies prompts the search for other defects when one component of an association is noted. It also helps to develop a differential diagnosis for specific entities (in the case of VACTERL: trisomy 18, thrombocytopenia and absent radius, Fanconi anemia, etc). Empiric risks for recurrence may also be given for an association even though no cause for the association has been determined. Furthermore, it may allow for prognosis if no specific diagnosis is achieved. For example, the prognosis for intellectual development for individuals with VACTERL association is generally favorable. Sequence has been used by some to indicate a pattern of anomalies that results from a single primary anomaly or single mechanical factor.43,49 The anomaly or mechanical factor that initiates the sequence may produce multiple secondary anomalies or may produce a secondary anomaly that leads to a tertiary anomaly, and so forth, in cascade fashion. For example, in Pierre Robin sequence, severe micrognathia is the primary anomaly that causes secondary glossoptosis which obstructs palatal shelf closure resulting in a cleft palate. Furthermore, oligohydramnios sequence and fetal akinesia sequence have overlapping features and both are actually deformational processes. Although proposed to identify a pattern of anomalies having uniform pathogenesis (oligohydramnios sequence), in use sequence sometimes implies causation (athyreotic hypothyroidism sequence). Redundancy in using the term sequence when applied to specific disease states such as athyreotic hypothyroidism is obvious. Further confusion can arise because of the longstanding use of sequence for the arrangement of nucleotides and codons in the genome. Finite areas of embryonic tissue develop into multiple and hence related morphologic structures. Damage to or defects in the genes underlying these finite areas or developmental fields can result in multiple structural anomalies. Use of the developmental field concept helps to explain why certain malformations occur together. Designation and understanding of developmental fields require considerable knowledge of embryonic topography and the fate of the component cells, as well as the timing of gene expression and their gene products. To use the concept, an arbitrary time during embryogenesis must be selected at which the dimensions of the developmental field are established and from which the developmental potential of the field is predicted. A polytopic field defect is a pattern of multiple anomalies often in different body areas resulting from disturbance of a single developmental field. This suggests that a specific gene (which is defective) is expressed in multiple body areas, perhaps even at different times. The term monotopic field is used when the repertoire of a developmental field is limited to a single body area; monotopic field defect is used to describe the malformation (usually of a single anatomic structure) that results from a disturbance to that field.54,65,66 Holoprosencephaly with midline cleft palate represents one classical monotopic field defect. Many difficulties arise with the actual use of developmental field to define structural anomalies. Many who work with human anomalies are not facile in linking various anomalies to their precursor embryonic cells and the genes they express. Considerable overlap of developmental fields occurs, depending on the dimensions selected and on the embryonic age at which the field is thought to be established. If the concept were pushed to the ultimate, the zygote would have to be considered the primary field from which the entire embryo develops.

10

Overview

Multiple anomalies can also be related through the time period during which they develop. A single insult during embryogenesis may affect multiple unrelated structures that are forming at the time. Without evidence linking the pathogenesis of diverse and seemingly unrelated components of conditions with multiple features, these components have been considered ‘‘pleiotropic effects’’ of the underlying cause. Pinsky55 has advocated the grouping of discrete syndromes that share a large portion of major features into communities and classes. It was suggested that grouping on the basis of multiple features could assist recall of the member syndromes, bibliographic retrieval, and computer analysis. At the same time the grouping could stimulate ideas about pathogenesis that might apply to a group of disorders sharing similar morphologic features and biochemical developmental pathways. This system could further permit collective statements that would then apply to the group as a whole and more clearly define the similarities and differences of member syndromes. Merits aside, this polythetic system has been slow to gain popularity, in part because it has been presented more as a theoretical system than as a practical system to be readily understood and utilized. However, reexamination may be useful in light of key developmental genes and their pathways such as sonic hedgehog and the fibroblast growth factors and their receptors (e.g., hedgehog community, FGFR community). Naming

The naming of composite entities (syndromes, associations, phenotypes) follows no fixed rules nor has any committee assumed authority for naming. Authors and editors often designate a name in the initial description of an entity, or one arises in a subsequent review. For conditions of known etiology, names that acknowledge the cause would seem to be most appropriate (e.g., trisomy 13 syndrome, prenatal alcohol syndrome). This is not possible for many syndromes caused by single genes, several genes, or for conditions of unknown etiology. Several different approaches have been used in these cases. If the major components are few, their enumeration in the name is possible (hypertelorism–hypospadias syndrome). This can be misleading, however, when the identifying features are not present (e.g., absence of cryptophthalmos in the cryptophthalmos syndrome or absence of camptomelia in camptomelic dysplasia). When the major components are numerous, the name can become tiresome. Use of the first letters of the major features to form a unique acronym has been successful in several instances (e.g., LEOPARD syndrome, CHARGE syndrome).This approach offers the user assistance in recalling the primary features of the entities. Perhaps the most widely accepted practice in naming composite entities has been to use eponyms. Eponymic designation attempts to credit the individual(s) who first described an entity or who first recognized it to be a specific entity. Not uncommonly, earlier reports of an entity are overlooked or not recognized to be that entity, leading to competing names or to compound eponyms (e.g., de Lange syndrome versus Brachmann–de Lange syndrome). Problems are also encountered when a prolific investigator describes more than one entity (e.g., Fanconi anemia syndrome and Fanconi renotubular syndrome). When heterogeneity is found to exist in an established name, renaming becomes necessary (Lawrence-Moon-Bardet-Biedl syndrome now divided into Lawrence–Moon syndrome and Bardet–Biedl syndrome with several subtypes of Bardet–Biedl). These difficulties aside, the use

of eponyms appears well established and will likely be replaced only by naming according to etiology (based on the gene or the environmental insult responsible). The possessive form of eponyms has been dropped in this book in keeping with McKusick’s suggestion. One international committee has published reasonable guidelines regarding the naming of human anomalies.53 Their suggestions include the use of etiologic agents when known (e.g., trisomy 18 syndrome), and eponyms (e.g., Down syndrome) that are well established. Use of the initials of the patient’s family (e.g., BBB syndrome, FG syndrome) and acronyms (e.g., EMG syndrome) that bear no relation to clinical feature was discouraged by this committee. Timing of Structural Alterations

The timing at which an anomaly arises has some importance in descriptive terminology. Postnatal alteration of an anatomic part should be distinguished from prenatal alteration, and prenatal alteration during organogenesis should be distinguished from alteration after organogenesis. Congenital means present at birth. It gives no clue to pathogenesis and causation, nor does it imply development at any particular time during prenatal life. Hence, use of congenital with malformation, disruption, or deformation in the sense described here would be redundant. Congenital anomaly, congenital defect, or congenital abnormality would be more appropriate term combinations since their use would restrict the general terms anomaly, defect, and abnormality to those present at birth. These terms imply a structure problem without specifying the etiology—which can be useful at times. Embryonic staging as set forth by Mall,67 Streeter,68,69 and O’Rahilly70,71 use arbitrary subdivisions of the period from fertilization to the start of fetal life to provide a description of the topographic, morphologic, and cytologic changes that take place during human development. The stages are defined by the composite of morphologic features and hence show some variability in size and chronologic age and in the progress of any single anatomic feature. They infer nothing about the gene expression and flow of biochemical events underlying the morphologic events. The age of an embryo is given in days following ovulation. Embryonic (postovulation) age is thus 2 weeks less than menstrual age (days or weeks following onset of last menstrual period), which is commonly used to date pregnancies in obstetrics and neonatology. Fertilization generally occurs within 24 hours after ovulation, usually in the outer reaches of the fallopian tubes. The initial four stages of human development take place over the first 5 to 6 days and span the early series of divisions of the free-floating conceptus up to and including the early implantation process. In the latter half of this period the conceptus is called a blastocyst, a mass of cells with an internal cavity. The period is called the preimplantation period. Interest in the specific nature of human preimplantation has been highlighted by the increasing use of assisted reproductive technologies (ARTs). Implantation occurs during stages 4–5, which span the period 5.5 to 12 days. The embryonic disc becomes bilaminar (ectoderm and endoderm), with the amniotic cavity developing on the epidermal surface and the yolk sac developing on the endodermal surface during these stages. The phenotypic description of the developing embryo often ignores the placenta which is

Human Malformations and Related Anomalies

simultaneously going through significant morphologic and metabolic change. Stage 23 (56–60 days, or 8 weeks, postfertilization) was considered arbitrarily to end the embryonic period.70,71 The beginning of marrow formation in the humerus was a developmental landmark used to assist in identifying this stage. The first 8 weeks after fertilization, or weeks 2 to 8, are generally considered the period of embryogenesis. The embryo has taken the human form, and most organs are fully formed and located in their final position by the end of this time. Exceptions are external genitalia, abdominal wall, heart, and dental structures and, of course, the brain, which continues its development (partly in response to utilization of neuronal pathways) into childhood. The fetal period begins with week 9 and extends to delivery, usually 40 weeks from the last menstrual period and 38 weeks from fertilization. Growth and maturation of function are the major processes that occur during this period. However, as noted previously, formation of some structures continues into this time and may be influenced by mechanical and flow considerations as well as gene expression (e.g., the heart and joints). External genitalia do not complete differentiation until week 12; hair follicles do not form until week 12; the midgut does not return to the abdominal cavity from the body stalk until week 10; and teeth do not gain their definitive morphology until much later in fetal life. An interesting new field related to fetal determinants of adult health suggests that events during fetal life can have long lasting effects on metabolism later in life. For instance, intrauterine growth retardation is associated with the development of diabetes, coronary artery disease, and hypertension in adulthood. Prematurity is associated with hypertension in adulthood. The mechanisms by which fetal events influence adult health are not yet known.71a In the strict sense, malformations, as previously defined, occur during the period of organ formation. Most will occur during the first 8 weeks of embryogenesis, but exceptions to this are not uncommon in those structures that are still forming after 8 weeks. In general, disruptions and deformations occur following morphologic development and, hence, usually after 8 weeks postconception. Some terms are particularly useful in defining environmental influences that act during gestation and that alter morphology, function, or growth. Teratogen has been used with widely variable meanings.72–74 In this text a teratogen has three features. First, as its derivation (teratos ¼ monster, gen ¼ produce) suggests, the end result of a teratogenic influence will be a morphologic abnormality rather than a functional one (however, of course, both morphologic and functional changes can be expected). Second, teratogens are environmental rather than genetic influences (however, maternal inherited metabolic disorders can have a detrimental effect on the embryo/fetus as in maternal phenylketonuria). Third, teratogens exert their influence following fertilization and before delivery (although the effects may not be obvious at birth as in the case of prenatal diethylstilbestrol exposure). Teratogens have an effect primarily during the first 8 weeks of embryogenesis, causing malformations, but may act at a later point in pregnancy, causing disruptions or deformations as well (e.g., as is seen with maternal warfarin use). These late effects of teratogens can also include malformation of structures that gain their morphology after the usual 8 weeks of embryogenesis. Etiology and Pathogenesis

Etiology simply means cause. For all human anomalies, the etiologic possibilities are limited to genetic (single gene, multiple genes,

11

chromosomal) or environmental (mechanical, infectious, chemical) causes, or some combination of the two. Little regard for etiology is given when naming individual structural anomalies. Etiology can be found, however, in the names of many syndromes (e.g., trisomy 13 syndrome, prenatal alcohol syndrome, X-linked hydrocephaly syndrome). More recently epigenetic influences (not resulting from changes in the structure of DNA, but rather in the control and expression of the genes) have been recognized to play a role in embryonic and fetal development. Pathogenesis indicates the mechanism or process by which a feature is produced. Again, little indication of pathogenesis is incorporated into the names of individual structural anomalies, but considerable emphasis is given in the naming of entities with multiple features (e.g., early amnion rupture, oligohydramnios sequence). As more is learned about the role of gene expression (e.g., alternative splicing, control of genes by RNA and transcriptions factors) as well as specific types of mutations, new nomenclature may emerge as illustrated by McKusick’s new organization of OMIM.101 Histologic Modifiers

Histologic analyses permit the description of the cellular and tissue processes underlying certain morphologic alterations. When known, these processes can be used as descriptive modifiers or to imply pathogenesis75 as in the chondrodysplasias. Aplasia, Hypoplasia, Hyperplasia, and Dysplasia

Aplasia indicates absence of cellular proliferation, hence the absence of tissue mass and, consequently, of an organ or morphologic feature. Hypoplasia indicates insufficient cell proliferation, resulting in a deficiency of tissue mass and ultimately undergrowth of an organ or morphologic feature. Similarly, hyperplasia means excessive proliferation of cells, accumulation of excessive tissue mass due to the increased cell number, and overgrowth of an organ or morphologic feature. Dysplasia as used in clinical genetics implies disorganization of cell structure, disordered cell arrangement in tissues, and faulty tissue organization in an organ or morphologic feature. At the tertiary (organ) level, these terms are best used only when the underlying histology is known. ‘‘Hyperplasia of (an anatomic part)’’ has greatest meaning when it implies that the excessive mass is due to an excessive number of otherwise normal cells. Regrettably, hyperplasia is often used as a mere description of overgrowth without regard to or knowledge of the histology. Worse yet, it is sometimes used to identify the larger of two parts of apparent unequal size without knowledge of the histology of either. At some point in their natural history, many cells become aplastic, that is, they cease to proliferate. Such cells (and tissues) can respond to injury, numerical depletion, hormone stimulation, and increased workload only by increasing their size. Muscle hypertrophy is a well-known example. Other cells retain the ability to divide actively. Endothelium, epithelium, mucosa, cartilage, bone, and connective tissues contain cells that are being constantly replenished by mitosis. The ability to repair damage can be an important cellular response during embryogenesis.72 The point in development at which paralysis of the various human cell types occurs is unknown, as are the signals that deprive cells of their ability to divide. Presumably most cells retain the ability to divide throughout embryogenesis and for variable periods of time thereafter. Hence embryos have the ability to repair and recover from certain insults

12

Overview

as long as the entire anlage is not damaged and as long as there are adequate time and resources to complete the repair before further differentiation is required. Dysplastic cells have altered sizes, shapes, and cytostructures. To the pathologist, these abnormal cells are regressive, often induced by chronic inflammation or irritation, and may progress in a neoplastic direction. No such connotations accompany the term dysplastic when used to describe the cellular, tissue, and organ disorganization found in congenital structural anomalies. These forms of dysplastic change arise during development, are usually genetically determined, and do not progress to neoplasia. The inborn errors of the chondroosseous skeleton constitute a large group of disorders called dysplasias.76,77 Multiple bones are involved, showing microscopic and radiographic evidence of disturbed growth and structure. Chondrocytes, osteocytes, connective tissue, or noncellular matrix can be abnormal, and the transition from cartilage to bone is often disorganized.78 Clinically these skeletal dysplasias are manifested by short stature; abnormal alignment, growth, or symmetry of body segments; or, less commonly, specific malformations (e.g., cleft palate, polydactyly). Agenesis has been used to indicate the failure of an organ to form, and in general it implies aplasia rather than loss through atrophy or disruption. Dysgenesis can be used in a similar fashion to indicate anomalous structure due to disorganization of the component cells and tissues. Atrophy, Hypotrophy, Hypertrophy, and Dystrophy

Atrophy means the degeneration of cells, usually resulting in shrinkage of tissue mass and diminished size of the affected organ or morphologic feature. Like the -plasia terms, atrophy and other -trophy terms are applied at the cellular (primary), tissue (secondary), and organ (tertiary) levels. Atrophy can be characterized by smaller than normal cell size, accumulation of intracellular pigment granules, and replacement of parenchymal cells by fat or connective tissue. Hypotrophy indicates that cells fail to achieve a normal size, and hence tissues, organs, and morphologic features are under grown. Hypertrophy is the enlargement of cells and consequent enlargement of tissue masses, organs, or morphologic features. Dystrophy means a disturbance in cell or tissue growth caused by faulty nutrition. The term has been used most widely, however, for certain heritable conditions of muscle, eye, or nails (e.g., myotonic dystrophy, lattice dystrophy of the cornea, nail dystrophy). In these conditions dystrophy is used without implying that defective nutrition is the underlying pathogenesis. Again, at the tertiary (organ or gross morphology) level, it may not be possible to distinguish enlargement due to hypertrophy from enlargement due to hyperplasia or to distinguish small size due to hypotrophy from small size due to atrophy, hypoplasia, or dystrophy. These distinctions require knowledge of the histologic structure. Accumulation of intracellular or extracellular fluid may alter size without affecting any of the cellular processes. In the absence of histologic information, general terms can be used to describe alterations in tissue bulk; for example, enlarged muscle to incorporate both muscle hyperplasia and hypertrophy or small muscle to encompass the possibilities of atrophy, hypotrophy, hypoplasia, dystrophy, and dysplasia. For practical reasons, the structural anomalies included in this discussion are those that can be detected by clinical observation and gross measurement. It is acknowledged that there exist

domains of microscopic and submicroscopic structural anomalies that are no less important than those mentioned. Histologic appearance is discussed only when those findings appear fundamental to understanding the gross structural alteration. Terms with Negative Impact

In general, structural anomalies are viewed negatively by medical practitioners, affected individuals, and society. Insensitive terminology can further stigmatize those affected and can separate caretakers from affected individuals, those affected from family, and family from society. Terminology should be as neutral as possible while correctly identifying or defining the structural anomaly. The care needed in choosing words when dealing with families or affected members may be obvious. However, terms employed internally in science should also be chosen carefully since these terms find their way to families via medical records, news articles, and courtrooms. It should be acknowledged that some morphologic abnormalities are not viewed negatively by affected individuals. An example is an alteration in size caused by achondroplasia. In this circumstance it is not unusual to find affected persons who want achondroplasia to recur in their biologic offspring, because normal size is less desirable in these particular families.79 Terminology does not remain constant; the nuances and implications of terms change with the generations. Until the early 1900s monster and monstrosity were widely used terms in medical circles to describe malformations or other morphologic changes. Monster has now gained a different nuance, primarily because of its use in movies to depict scary creatures. The new usage does not adhere to either of the word’s origins (to show or to warn), but suggests that those who look abnormal may also act in destructive, frightening, and otherwise offensive ways. Although monster and monstrosity have been used from the first written records of human malformations and into the twentieth century, they have in this century disappeared entirely from medical terminology. Other terms have had only brief life spans. Examples from the five editions of Smith’s Recognizable Patterns of Human Malformations will suffice to illustrate.43,80 In a period of less than 30 years (edition 1, 1970 to edition 5, 1997), repeated changes can be found in the preferred terminology for morphologic entities. Potter’s syndrome (edition 1) changed to oligohydramnios tetrad (edition 2) and then to oligohydramnios sequence (editions 3–5). The preferred term for amniotic bands changed with each edition. Initially, amniotic band syndrome changed to amniotic band anomalads, then to early amnion rupture spectrum, then to early amnion rupture sequence, and finally to amnion rupture sequence. These changes arose from the attempt to add a pathogenetic implication to the identification of the entity. Social sensitivity demands discretion in terminology. Terms that are divisive, derogatory, negative, or degrading should be abandoned. Happy puppet syndrome has been replaced by Angelman syndrome; fetal face syndrome by Robinow syndrome; and elfin facies syndrome by Williams syndrome. A term in common use in the middle of this century, mongolism, or mongoloid idiot, as assigned by Langdon Down for a specific mental retardation syndrome, is discouraged in favor of trisomy 21 syndrome or Down syndrome.81 The designation funny-looking kid (FLK) may be viewed as derogatory by an affected child, family members, and care-takers. The term dwarfism to identify persons with disproportionate skeletal dysplasias has been discouraged for the same reason. Special child or special needs child has been used to indicate children with handicaps. Since

Human Malformations and Related Anomalies

all children are special, the use of this term for a child with a malformation appears inappropriate and patronizing. The designation of syndromes by the initial of the proband (G syndrome, BBB syndrome) has been advocated by Opitz et al.54 While intended to be neutral, this naming schema offers nothing to assist the user in remembering the syndrome, is liable for duplication, and has not found wide acceptance. Anomalad was suggested by Fraser and advocated by Smith53 to indicate a cascade of structural anomalies that derived from a single preceding anomaly or mechanical force. The term was debated for several years and has now disappeared, being replaced by some users with sequence. Polyanomaly has also been suggested to indicate multiple anomalies, specifically those that arise from the same pathogenesis. There is nothing to recommend this term over multiple congenital anomalies, and the term does not flow well. In the last decade, the field of developmental biology has made considerable progress in understanding embryologic development by using animal models. Yeast, flies, worms, and fish have contributed to defining the molecular pathways involved in development of various structures. The conservation of the genes (and gene families) involved is remarkable. This work has a direct effect on understanding human development, which for ethical reasons cannot be studied directly. However, most animal models do not have a fetal period similar to that in humans. The application of these new discoveries of developmental biology to human in utero development and to the historic systems of phenotypic descriptive classification has been relatively slow and will undoubtedly be challenging.

1.2 Classification and Coding Classification

The systematic arrangement of structural anomalies on the basis of morphologic, anatomic, etiologic, or other criteria has been attempted by many observers. The number of classification schemas attests to the likelihood that no system has been entirely satisfactory. Nonetheless, finding some order among human congenital anomalies has utility in assisting human memory and giving insights into the range and nature of human anomalies. A growing utility is now being found for computer retrieval of information. Some admixture between the classification schemas is to be expected in a brief accounting of the types of classifications used in the past. Classification by Cause

One of the oldest classification schemas, that set forth by Empedocles,82 was based on causation. Five causes for human anomalies were recognized: excess semen, deficiency of semen, slowness of movement of semen, abnormal movement of semen, and division of semen into separate parts. Pare´’s classification83 had 13 causes, including abnormalities of semen as well as mechanical injury, uterine compression, maternal impressions, and the supernatural. Cleland’s system, published in 1889, had six causation categories, three leading to anomalies with morphologic deficiencies and three leading to anomalies of excess.84 Classification by Morphologic Alteration

Eight types of morphologic alterations were the major entries in the system of St. Isidore in AD 60085: large size, small size, transformation

13

of a part, transformation of the whole body, transposition of a part, adhesion of parts, mixture of sexes, and the coexistence of multiple anomalies. These types were supplemented by two entries based on the precocious or delayed appearance of features. To this type of classification, Huber86 added union of parts usually separated and closed state of canals usually open. Isidore and Etienne St. Hilaire set forth an extensive classification schema based on alterations of morphology.87 All anomalies were assigned to a kingdom, and the kingdom was subdivided into four divisions, each of which was further subdivided into classes, orders, tribes, families, and genera. Classification by Regional Anatomy

Use of regional anatomy to arrange anomalies first appeared in the 1600s.88,89 The systems used by Taruffi,90 Lowne,91 and Ballantyne92 at the end of the nineteenth century utilized regional anatomy as well. These systems often incorporated subclassifications based on morphologic alteration (e.g., excess or deficiency of parts). Classification by System

Closely related to schemas based on regional anatomy is the use of anatomic systems to organize human anomalies. This variation is the basis of classifications used by Warkany93 in the classic Congenital Malformations, in the International Classification of Diseases (ICD), in the Cardiff and Centers for Disease Control modifications of the ICD, and in the Systematized Nomenclature of Medicine (SNOMED).94–97 Other Classifications

Several additional schemas are of historical interest. The earliest known system separated malformations into those that affected ordinary citizens and those that affected royal families. This was the only arrangement of anomalies to be found in the enumerations of human anomalies in the teratologic records of the Chaldeans.98 Other systems have used viability of affected individuals, time of occurrence during embryogenesis, and various mixtures of the several foregoing schemas.94,96,99,100 The ICD is now undergoing its tenth revision.94 The currently available clinical modification (ICD-9-CM, 2004) as published by the U.S. Government allots 20 categories with accompanying numerical codes for congenital anomalies. Considerable inconsistency has crept into this schema. Initially oriented to systems, there occur drifts into regional anatomy and major divergence into causation (chromosome anomalies) in the nineteenth category. An admixture of systems, specific diseases, specific syndromes, and processes appears in the twentieth category. The system, although having lost its consistency, is widely used because of its acceptance for epidemiologic studies and for insurance categorization; but it does not accommodate a listing of rare but specific anomalies. The British Pediatric Classification modifies the ICD system for anomalies by adding two additional numbers to the code, permitting a further specific subdivision of an ICD category.95 The Centers for Disease Control (CDC) has further modified the ICD and British systems by adding a sixth digit to the code.96 The addition of digits in the British and CDC modifications allows categories of defects to be subdivided into individual anomalies but fails to correct the admixing of causation, pathogenesis, regional anatomy, organ system, syndromes, and diseases in the original ICD system. The Systematized Nomenclature of Medicine has been produced by the American College of Pathologists97 based on their

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Overview

Systematized Nomenclature of Pathology. This schema utilizes seven sections to permit access from numerous perspectives: topography, morphology, etiology, function, disease, procedure, and occupation. Most useful in relation to structural anomalies are the topographic, morphologic, and etiologic fields. Other systems that deal with certain individual anomalies and syndromes include McKusick’s alphabetical listing of single gene disorders101,102 and Shepard’s alphabetical enumeration of environmental agents.103 Several computerized databases have been developed to assist the clinician in recalling information about entities having one or more morphologic characteristic. The two major systems, London Dysmorphology Database104 and POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations),105 require entry of the anatomic description (topography and morphology) of individual features and search for entities in which the feature(s) occur.

Table 1-5. Causes of anomalies among liveborn infants Cause

Percent Incidence

Genetic

15–25

Chromosome

10–15

Single gene

2–10

Multifactorial

20–25

Environmental

8–12

Maternal diseases

6–8

Uterine/placental

2–3

Drugs/chemicals

0.5–1

Twinning

0.5–1

Unknown

40–60

Coding

At present there is no comprehensive coding system that is specific for structural anomalies that occur in humans. A five-digit system would be required to assign a unique number to each of the numerous structural variants and anomalies. To add an indicator of the major etiologies would require an additional digit. A further multidigit hindcode would be necessary to link individual anomalies to the various syndromes, diseases, or associations of which they might be a feature. Development of a uniform coding system for human anomalies will undoubtedly be encouraged by the increasing reliance on electronic systems for storage, retrieval, and manipulation of data. 1.3 Genetic Causes of Malformations Current clinical and technological methods can determine the cause of approximately one-half of the anomalies found in newborn infants (Table 1-5). One-half of the identifiable causes are either wholly or partially genetic. The genetic content of egg and sperm brings to the conceptus all instructions necessary for the formation and function of a new life. Disturbances in the amount of genetic material (aberrations in chromosome number or structure) or in the nature of this material (mutations or epigenetic alterations of genes) may preclude normal formation, causing a wide range of malformations or other morphologic changes and an equally broad range of functional impairments. Experience in mammalian cloning and in human in vitro fertilization has indicated that the genetic content of the gametes (DNA) must go through an epigenetic process called ‘‘reprogramming.’’ This process involves methylation of the DNA and its histones, and possibly other epigenetic measures, in order for the early development of a zygote to occur in a normal way before implantation. Without this ‘‘reprogramming,’’ disorders involving genomic imprinting may occur with increased frequency. Chromosome Aberrations and Malformations

Over 75 years passed between Flemming’s observations of chromosomes in the epithelium of the human cornea (1882)106 and the first demonstration (by Lejeune in 1959107) of the chromosomal basis for a human malformation syndrome, although the link between chromosomes and malformations had been suggested in the interim. As early as the 1930s, Waardenburg and Bleyer independently predicted that nondisjunction of chro-

mosomes during meiosis, resulting in abnormal chromosome number, might be the cause of Down syndrome.108,109 Rapid refinement in tissue culture and metaphase preparation and agreement on nomenclature followed Tjio and Levan’s discovery in 1956 that the correct number of human chromosomes was 46.110 Within 3 years chromosome analysis became commonplace in laboratories throughout the world. The discovery of numerical chromosome aberrations followed (Table 1-6), opening an era when an answer to nearly all human maladies, but especially malformations and malformation syndromes, was sought in the chromosomes. A rich yield rewarded investigators who sought the explanation of spontaneous abortion in chromosome analysis.5,13,111–114 In 1961, Penrose and Delhanty demonstrated triploidy in a macerated fetus.112 In reports that followed, chromosome aberrations were found in approximately one-half of early spontaneous abortions. The 45,X karyotype was found most frequently, but tetraploidy, triploidy, and numerous other trisomies not seen in liveborn infants constituted a major portion of chromosomally abnormal abortuses (Table 1-7). Prenatal diagnosis of chromosome aberrations became possible in 1966, when Steele and Breg combined the technique of amniocentesis with culture of amniotic fluid cells.115 The reliability and safety of the combined procedures contributed to rapid acceptance of the techniques for pregnancies determined to be at increased risk of chromosome abnormalities and certain biochemical defects. The utility of chromosomes in expanding the understanding of malformation syndromes reached a plateau in the late 1960s. Table 1-6. Sequence of discovery of chromosome aberrations Year

Chromosome Aberration

1959

Trisomy 21; 45,X; 47,XXY

1960

Trisomy 18; trisomy 13

1961

47,XYY

1963

Del 5p

1965

Del 4p

1969

Fragile X

1971

Trisomy 8

1973

Trisomy 9

Human Malformations and Related Anomalies Table 1-7. Prevalence of chromosomal aberrations among spontaneous abortions Type of Aberration

Percent

All Chromosome Aberrations

40

Trisomies

20

T-16

8

T-13,15,21,22

2*

T-2,7,8,14,18

1*

T-4,9,10,20

0.5*

T-3,5,6,12,7

0.1*

T-1,11,19

90%

*60%

*20%