Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY Associate Editors: Tina L. Cheng, Baltimore, MD Joseph A. Zenel, Sioux Falls, SD Editor, In Brief: Henry M. Adam, Bronx, NY Consulting Editor, In Brief: Janet Serwint, Baltimore, MD Editor, Index of Suspicion: Deepak M. Kamat, Detroit, MI Consulting Editor Online and Multimedia Projects: Laura Ibsen, Portland, OR Editor Emeritus and Founding Editor: Robert J. Haggerty, Canandaigua, NY Managing Editor: Luann Zanzola Medical Copy Editor: Deborah K. Kuhlman Editorial Assistants: Kathleen Bernard, Melissa Schroen Editorial Office: Department of Pediatrics University of Rochester School of Medicine & Dentistry 601 Elmwood Avenue, Box 777 Rochester, NY 14642
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Publisher: American Academy of Pediatrics Michael J. Held, Director, Division of Scholarly Journals and Professional Periodicals
Pediatrics in Review姞 (ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098 Statements and opinions expressed in Pediatrics in Review威 are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an exclusive course of treatment or serve as a standard of medical care. Subscription price for 2011 for print and online/online only: AAP Fellow $177/ $135; Nonmember $222/$172; Allied Health or Resident $165/$111. Institutions call for pricing (866-843-2271). For overseas delivery, add $109. Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing offices. © AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved. Printed in USA. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to PEDIATRICS IN REVIEW威, American Academy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. Pediatrics in Review Print Issue Editorial Board Disclosures The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest before the confirmation of service of those in a position to influence and/or control CME content. All individuals in a position to influence and/or control the content of AAP CME activities are required to disclose to the AAP and subsequently to learners that the individual either has no relevant financial relationships or any financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial interest is defined as any entity producing, marketing, reselling or distributing health-care goods or services consumed by, or used on, patients. Each of the editorial board members, reviewers, question writers, PREP Coordinating Committee members and staff has disclosed, if applicable, that the CME content he/ she edits/writes/reviews may include discussion/reference to generic pharmaceuticals, off-label pharmaceutical use, investigational therapies, brand names, and manufacturers. None of the editors, board members, reviewers, question writers, PREP Coordinating Committee members, or staff has any relevant financial relationships to disclose, unless noted below. The AAP has taken steps to resolve any potential conflicts of interest. Disclosures ● Richard Antaya, MD, FAAP, disclosed that he participates in Astellas Pharma, US, Inc., clinical trials, speaker bureau and advisory board; and that he participates in the Novartis speaker bureau. ● Athos Bousvaros, MD, MPH, FAAP, disclosed that he has research grants from Merck and UCB; and that he is a paid consultant and on the speaker bureau for Millennium. ● Brian Carter, MD, FAAP, disclosed that he participates in the MedImmune speaker bureau. ● David N. Cornfield, MD, FAAP, disclosed that he has National Institutes of Health grants. ● Donald W. Lewis, MD, FAAP, disclosed that he is a consultant for and has a research grant from Astra Zeneca and Merck; and that he has research grants from Ortho McNeil, Lilly, Bristol-Myers Squibb, GlaxoSmithKline, and Boehringer Ingelheim Pharmaceutical. ● Blaise Nemeth, MD, MS, FAAP, has disclosed he has an unrestricted educational grant for fellowship from Biomet. ● Janet Serwint, MD, FAAP, disclosed that she receives a research grant from the Maternal and Child Health Bureau. ● Richard Sills, MD, FAAP, disclosed that he receives a research grant from Novartis.
contents
PediatricsinReview姞 Vol.32 No.6 June 2011 Articles
223
Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini, Robert L. Rosenfield
230
Speech and Language Development: Monitoring Process and Problems Susan McQuiston, Nancy Kloczko
240
Acid-Base Disorders Mara Nitu, Greg Montgomery, Howard Eigen
252 253
Cover Art Contest Visual Diagnosis: Swelling and Redness of the Fourth Toe in a 3-month-old Infant Charles O. Onyeama, Karla Vitale, Kenneth Cochran, Ginikanwa L. Onyeama
Index of Suspicion
257
Case 1: Status Epilepticus, Hypertension, and Tachycardia in a 5-year-old Boy Case 2: Cardiopulmonary Arrest During Gymnastics Practice in a Teenage Girl Case 3: Acute Renal Failure in a Teenage Boy Who Has Autism and Pica Case 1: Corey Chartan, Elizabeth Aarons Case 2: Aliva De, Steven Fishberger, John Messina Case 3: Ifrah Abdirahman, Steven Arora, Maisa Dekna, Keith K. Lau
Online-Only Article
e66
Abstract appears on page 256. Psychogenic Nonepileptic Seizures (Pseudoseizures) Hema Patel, David W. Dunn, Joan K. Austin, Julia L. Doss, W. Curt LaFrance, Jr, Sigita Plioplys, Rochelle Caplan
Pediatrics in Review威 is supported, in part, through an educational grant from Abbott Nutrition, a division of Abbott Laboratories, Inc.
Cover: The artwork on the cover of this month’s issue is by one of the winners of our 2009 Cover Art Contest, 6-year-old Anne C. of Woodbury, NJ. Anne’s pediatrician is Pierre Coant, MD.
Answer Key:
1. A; 2. E; 3. D; 4. E; 5. B; 6. E; 7. A; 8. D; 9. D; 10. B; 11. E; 12. D; 13. B
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Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini and Robert L. Rosenfield Pediatr. Rev. 2011;32;223-229 DOI: 10.1542/pir.32-6-223
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/32/6/223
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Article
adolescent medicine
Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini, MD,* Robert L. Rosenfield, MD*
Objectives
After completing this article, readers should be able to:
1. Explain how puberty is regulated by the hypothalamic-pituitary-gonadal axis. 2. Describe the hormonal interactions involved in pubertal development in boys and girls. Author Disclosure Drs Bordini and
Introduction
Rosenfield have
Puberty is a defining developmental stage of every child’s life, both physically and psychosocially. Concerns about the normalcy of pubertal development and menstrual patterns are among the most common questions posed to every physician caring for children. This article reviews the primary physiologic changes in the hypothalamicpituitary-gonadal (HPG) axis and in adrenal androgen and growth hormone (GH) production that underlie the normal pubertal milestones. Understanding of these changes allows interpretation of laboratory data in children suspected of having pubertal abnormalities. Puberty is the developmental stage during which a child becomes a young adult, characterized by the maturation of gametogenesis, secretion of gonadal hormones, and development of secondary sexual characteristics and reproductive functions. Adolescence is used widely as a generally synonymous term for puberty, but the term often is used to convey an added connotation of cognitive, psychological, and social change. Thelarche denotes the onset of breast development, an estrogen effect. Pubarche denotes the onset of sexual hair growth, an androgen effect. Menarche indicates the onset of menses and spermarche the appearance of spermatozoa in seminal fluid. Gonadarche refers to the onset of pubertal function of the gonads, which produce most of the sex hormones that underlie the pubertal changes in secondary sex characteristics. Adrenarche refers to the onset of the adrenal androgen production that contributes to pubarche.
disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
The Hormonal Axes Underlying Puberty The Hypothalamic-Pituitary-Gonadal Axis Normal puberty results from sustained, mature activity of the HPG axis. (1). The major hormones of the HPG axis are shown in Figure 1. In response to a single gonadotropinreleasing hormone (GnRH), the pituitary gland releases two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH is secreted by specialized neurons of the hypothalamus in a pulsatile fashion. Pituitary LH and FSH secretion consequently is pulsatile and can be sustained only in response to pulsatile GnRH signals. LH acts primarily on the specialized interstitial cells of the gonads to stimulate formation of androgens, and FSH acts primarily on the follicular/tubular compartment to stimulate formation of estrogen from androgen precursors, inhibin, and gametes. The function of the two compartments of the gonads is coordinated by paracrine regulatory mechanisms. Abbreviations The HPG axis is active during three phases of development: fetal, neonatal, and adult, with puberty being the ACTH: adrenocorticotropic hormone period of transition to mature function. Changes in GnRH DHEAS: dehydroepiandrosterone sulfate secretion underlie the changing activity of the HPG axis. The FSH: follicle-stimulating hormone sexually dimorphic patterns of sex hormone secretion during GH: growth hormone the prenatal and neonatal periods of HPG activity appear to GnRH: gonadotropin-releasing hormone play a role in programming sexually dimorphic patterns of HPG: hypothalamic-pituitary-gonadal behavior, metabolism, and neuroendocrine function in later LH: luteinizing hormone life. *Section of Adult and Pediatric Endocrinology, The University of Chicago Pritzker School of Medicine, Chicago, IL. Pediatrics in Review Vol.32 No.6 June 2011 223
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adolescent medicine
pubertal development
ingly active again in the late prepubertal period, as central nervous system restraint recedes, followed by an increasing tempo throughout puberty. The gonads account for the most important circulating estrogen (estradiol) and androgen (testosterone). Gonadal function accounts for more than 90% of estradiol production in the female (50% in the male) and more than 90% of testosterone production in the male (50% in the female) (Fig. 2). (4)(5)
Figure 1. The hypothalamic-pituitary-gonadal axis. Hypo-
thalamic neurons release gonadotropin-releasing hormone (GnRH) into the pituitary portal venous system, where it stimulates gonadotropin (luteinizing hormone [LH] and folliclestimulating hormone [FSH]) secretion. LH primarily stimulates specialized interstitial cells (theca cells in the ovary or Leydig cells in the testes) to secrete androgens. FSH primarily stimulates the ovarian follicle or seminiferous tubules to form estrogen, inhibin, and gametes (eggs or sperm). The interstitial and follicular/ tubular compartments act cooperatively through paracrine mechanisms to form estrogen and to regulate sex steroid and gamete development. Sex steroids exert endocrine closed-loop negative feedback effects on GnRH and gonadotropin secretion. Inhibin exerts negative feedback on FSH secretion. In mature females, a critical estradiol concentration for a critical duration exerts a transient positive feedback effect to stimulate the LH surge that initiates ovulation.
The HPG axis is established during the first trimester. Its activity in the second trimester contributes to the establishment of normal penile size and the inguinalscrotal phase of testicular descent. (2)(3) In the latter half of pregnancy, activity is suppressed by the high estrogens elaborated by the fetoplacental unit. The HPG axis promptly functions at a pubertal level in the newborn after withdrawal from maternal estrogens. This “minipuberty of the newborn” is subclinical, except for contributing to genital growth, acne, and transient thelarche in the neonate. HPG function subsequently comes under gradual central nervous system restraint at the end of the neonatal period. The axis is relatively, but not absolutely, dormant throughout childhood, particularly in girls, who have slightly higher FSH concentrations than boys and a few ultrasonographically visible ovarian follicles as evidence of this effect. The HPG axis becomes increas224 Pediatrics in Review Vol.32 No.6 June 2011
Figure 2. Simplified diagram of sex steroid production by
the adult adrenal glands, follicular phase ovaries, and testes. Blood production rates shown are the sum of direct secretion (heavy solid arrows) and peripheral formation from secreted precursors (dotted arrows). Several key steroidogenic enzyme activities expressed in these glands, such as sulfotransferase (SULT), 3-hydroxysteroid dehydrogenase (3), aromatase, and 17-hydroxysteroid dehydrogenase type 5 (17HSD5), are also expressed in peripheral tissues such as liver, fat, and skin. Type 3 17HSD (17HSD3) is only expressed in testes. Peripheral conversion from secreted androstenedione accounts for 50% of testosterone in women, and about 10% of estradiol and DHEAS similarly arise from circulating precursors. Estrone, the intermediate in the pathway from androstenedione to estradiol, is not shown. DHEAⴝdehydroepiandrosterone, DHEASⴝ dehydroepiandrosterone sulfate, A’DIONEⴝandrostenedione
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adolescent medicine
Adrenarche, the “Puberty” of the Adrenal Gland Adrenarche is actually a re-onset of adrenal androgen production. The fetal zone of the adrenal cortex elaborates large amounts of dehydroepiandrosterone sulfate (DHEAS), which is important as the major substrate for placental estrogen formation during pregnancy. This zone then regresses over the first several postnatal months. Adrenarche is the pseudopuberty of the adrenal gland that begins in mid-childhood as the zona reticularis of the adrenal cortex develops. (1) This zone has the capacity to form 17-ketosteroids, but not cortisol, in response to adrenocorticotropic hormone (ACTH), and DHEAS is the primary endpoint of this biosynthetic pathway. Consequently, although cortisol concentrations and the cortisol response to ACTH do not change from childhood to adulthood, DHEAS values gradually rise from mid-childhood until adulthood. This timeframe coincides approximately with the gonadal androgen production of true puberty, but adrenarche is an incomplete aspect of puberty that is independent of pubertal maturation of the HPG axis. The adrenal gland secretes more than 90% of DHEAS in children and women and more than 70% in adult men, while 50% of testosterone in the female and less than 10% of testosterone in the male is produced by the adrenal. (6) Adrenal androgen concentrations increase to a point sufficient to stimulate apocrine odor and mild acne after about 5 years of age and pubic hair growth after about 10 years of age (Table).
Interactions Between Pubertal Hormones and the Growth Hormone/Insulin-like Growth Factor-I Axis Pituitary GH secretion increases during puberty in response to sex steroids. (1) This rise in GH causes a rise in Table.
pubertal development
insulin-like growth factor-I concentrations to peaks in late puberty that are above those of adults, sometimes in the adult acromegalic range. Half of the characteristic pubertal growth spurt is due to the direct effect of sex steroids on epiphyseal growth and half to GH stimulation. Conversely, in accord with the general principle that everything grows better with GH, GH is necessary for optimal gonadotropin effects on gonadal growth and sex steroid effects on secondary sex characteristics. For example, selective GH resistance is characterized by small testes and micropenis, poor breast and sexual hair development, and absence of a pubertal growth spurt. (12)
Regulation of the Onset and Progression of Puberty There is no single “trigger” for puberty; rather, puberty results from a gradual increase in GnRH pulsatility that arises from maturation of central nervous system developmental programs that send inhibitory and stimulatory signals to GnRH neurons. (1) Puberty is associated with changing sensitivity of the neuroendocrine system to negative feedback by gonadal hormones. When GnRH secretory activity is low due to central nervous system inhibition in mid-childhood, it is inhibited by trace amounts of sex steroids. Increasing central activation during puberty permits sex steroids to rise to adult concentrations before exerting negative feedback effects. The major GnRH-inhibitory systems are GABAergic and opioidergic; the major excitatory systems involve glutamate and kisspeptin, with glial cells facilitating GnRH secretion. Kisspeptin is a hypothalamic neuropeptide discovered in the search for the molecular basis of hypogonadotropic hypogonadism; it acts as an important signal for pubertal GnRH release via GPR54, a G-protein coupled receptor located on GnRH neurons. It has been estimated that at least half of the varia-
Typical Early Morning Pubertal Hormone Blood Concentrations
Group
LH (IU/L)
FSH (IU/L)
Estradiol (pg/mL)
TT (ng/dL)
DHEAS (g/dL)
Prepubertal 1 to 5 yr Premenarchal females Postmenarchal females** Adult men***