Pediatric Endocrinology

897 Pages·2008·23.573 MB·English

by  Mark A. Sperling

1600 John F. Kennedy Blvd.
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Philadelphia, PA 19103-2899
PEDIATRIC ENDOCRINOLOGY, THIRD EDITION ISBN: 978-1-4160-4090-3
Copyright © 2008, 2002, 1996 by Saunders, an imprint of Elsevier Inc.
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Notice
Knowledge and best practice in this fi eld are constantly changing. As new research and experience
broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or
appropriate. Readers are advised to check the most current information provided (i) on procedures
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sibility of the practitioner, relying on their own experience and knowledge of the patient, to make
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any use of the material contained in this book.
The Publisher
Library of Congress Cataloging-in-Publication Data
Pediatric endocrinology / [edited by] Mark A. Sperling. — 3rd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4160-4090-3
1. Pediatric endocrinology. I. Sperling, M.
[DNLM: 1. Endocrine System Diseases. 2. Child. 3. Infant. WS 330
P3712 2008]
RJ418.P42 2008
618.92’4—dc22
2007041424
Acquisitions Editor: Judith Fletcher
Developmental Editor: Colleen McGonigal
Project Manager: Bryan Hayward
Design Direction: Ellen Zanolle
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
FM_i-xvi-X4090.indd Sec3:ii 3/15/08 7:15:24 PM
To my parents, who gave and sustained my life; to my wife, Vera, “woman of valor”;
and our children, Lisa and Steven, Jonathan and Shoshana, and grandchildren,
Jacob, Benjamin, Tzvi, Sydney, Rebecca, and Julian, who provide
meaning, joy, and continuity to our lives.
FM_i-xvi-X4090.indd Sec3:iii 3/15/08 7:15:24 PM
Foreword to the First Edition
The aim of the editor and contributors to this volume is endocrinology. A glance at the roster of contributors to
to establish an effective bridge between the surging prog- this volume may well provide insight into why; many
ress in biomedical science and the clinical practice of who are responsible for the dramatic advances in the
pediatric endocrinology. Half a century ago the biochem- laboratory also pursue active clinical careers.
ical elucidation of the structure and subsequent synthesis This volume includes many new sections that were
of steroid hormones provided the basis for a revolution not presented in previous texts devoted to clinical pedi-
in the diagnosis and treatment of a number of endocrine atric endocrinology. It will serve as a valuable reference
and nonendocrine disorders; that era was soon followed for family physicians, internists, pediatricians, and other
by a succession of fundamental discoveries: structure of health professionals, covering as it does the gamut of
peptide hormones, identifi cation of releasing hormones information from basic molecular biology to practical
from the brain, rapid and precise assay methods, and considerations in the diagnosis and treatment of pediatric
synthesis of peptide hormones by molecular biological endocrine disorders.
techniques, to name but a few.
In no fi eld has laboratory science been more effec- Solomon A. Kaplan, MD
tively translated into clinical progress than in pediatric
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Preface
This third edition of Pediatric Endocrinology bears wit- pediatric endocrinologists. Likewise, management of
ness to the ongoing advances in this fi eld, bringing to- dyslipidemias in children and adolescents is of increas-
gether basic and clinical science and scientists for a ing importance as data accumulate on the effectiveness
deeper understanding of endocrine problems in infants and safety of lipid lowering agents in reversing intimal
and children, their diagnosis and their evidence-based changes and delaying or preventing the consequences
treatment. No area of inquiry has been more impacted by of atherosclerosis.
the contribution of molecular biology, sophisticated imag- As in previous editions, the book is divided into seam-
ing, and computer science to discover new knowledge, less sections. First, there is an introductory section on
apply it, and manage it. There is not a single topic in this molecular endocrinology and endocrine genetics, recep-
edition in which discoveries in the past fi ve years have tor transduction cascades, and the complexity of normal
not occurred to provide new insights on old problems. To homeostasis as exemplifi ed by the paradigm of bone min-
incorporate these comprehensive discoveries without sig- eral metabolism. Three chapters on endocrine disorders
nifi cantly changing scope, size. and cost, it was necessary in newborns follow cover the topics of ambiguous geni-
to realign some of the chapters. Hence, the chapters on talia, hypoglycemia, and abnormalities of thyroid func-
“Organization and Integration of the Endocrine System” tion. These, together with calcium disorders, form the
and “Imaging in Pediatric Endocrinology” have been re- most common endocrine problems in the newborn nurs-
luctantly removed in this edition; the former is addressed ery for which endocrine consultation is sought. A series
in detail in more fundamental texts which approach en- of chapters on specifi c disorders in childhood follows,
docrinology as the science of cell-to-cell communication including thyroid, growth, posterior pituitary, diabetes
via chemical messengers. In so doing, they blur previous mellitus, hypoglycemia, the adrenal cortex, pheochromo-
concepts of hormones as chemical messengers produced cytoma and multiple endocrine neoplasias, puberty in the
in a single organ with specifi c effects on a limited number female, Turner syndrome, disorders of the testes, disor-
of other cell types. Instead, the newer understanding of ders of calcium and bone mineral metabolism, autoim-
endocrinology incorporates signal transduction cascades mune polyglandular syndromes, disorders of energy bal-
in various cell types in response to circulating messengers ance, and lipid disorders in children and adolescents.
as diverse as cytokines into the family of “hormones.” Finally, the chapter on laboratory methods in pediatric
The expanding horizons of sophisticated imaging endocrinology is included because of the importance of
could not be limited to a single chapter without compro- understanding the methodologies used in correct and ap-
mising depth and quality; where relevant, appropriate propriate interpretation of test results. Each chapter has a
references are provided in specifi c chapters, best exem- comprehensive bibliography, which, like all modern hard
plifi ed by the use of 18-[F] L-DOPA positron emission paper texts, may be somewhat out of date by the time of
tomography (PET) scanning to distinguish focal from dif- publication.
fuse hyperinsulinemia. From an editor’s point of view, it has been a pleasure
Taking the place of these realigned chapters is a new to welcome new contributors from Europe and Israel to
chapter on dyslipidemias and an expanded chapter on the list of recognized authorities in their respective fi elds;
energy homeostasis and its disorders. These metabolic the text is enriched by their expertise and so too will be
topics were deemed to be essential inclusions for this its readers.
book, refl ecting the importance of the epidemic of obe- For any oversight, omissions, or errors, we extend our
sity and its consequences in pediatric populations apologies with request for indulgence and forgiveness
throughout the developing and developed world, and from our readers. As always, we welcome your input to
the signifi cant time commitment to management by improve the value of this book.
Mark A. Sperling
Pittsburgh, Pennsylvania
Spring 2008
vii
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Acknowledgments
I gratefully acknowledge the contributions and support of provided invaluable secretarial assistance. I thank Elsevier
each of the authors, who are my colleagues and friends. and their staff for their support; it has been a pleasure
Our post-doctoral trainees, residents, and students pro- working with them to bring this third edition to print.
vided constructive critique. Ms Kathy Wypychowski
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Contributors
John C. Achermann, MD Frank B. Diamond, Jr., MD
Wellcome Trust Senior Research Fellow in Clinical Professor of Pediatrics
Science University of South Florida College of Medicine
Developmental Endocrinology Research Group Tampa, Florida
Clinical and Molecular Genetics Unit All Children’s Hospital
UCL Institute of Child Health St. Petersburg, Florida
University College
London, United Kingdom Charis Eng, MD, PhD
Sondra J. & Stephen R. Hardis Chair in Cancer Genomic
Steven D. Chernausek, MD Medicine
Professor of Pediatrics Chair and Director, Genomic Medicine Institute
Department of Pediatrics Director, Center for Personalized Genetic Healthcare
University of Oklahoma Health Sciences Center Cleveland Clinic Foundation
Oklahoma City, Oklahoma Cleveland, Ohio
Pinchas Cohen, MD Delbert A. Fisher, MD
Professor of Pediatrics Professor Emeritus
CMRI Edith Kinney Gaylord Chair Pediatrics and Medicine
Director, CMRI Diabetes & Metabolic Research Center David Geffen School of Medicine at UCLA
UCLA School of Medicine Los Angeles, California
Director, Division of Endocrinology
Mattel Children’s Hospital at UCLA Christa E. Flück, MD
Los Angeles, California Assistant Professor
Pediatric Endocrinology and Diabetology
David W. Cooke, MD University Children’s Hospital Bern
Associate Professor Bern, Switzerland
Department of Pediatrics
Division of Pediatric Endocrinology Russel Grant, PhD
The Johns Hopkins University School of Medicine Director of Mass Spectrometry
Baltimore, Maryland LabCorp
Calabasas Hills, California
Sarah C. Couch, PhD, RD
Associate Professor Annette Grueters, MD
Department of Nutritional Sciences Professor of Pediatrics and Endocrinology
University of Cincinnati Charite Children’s Hospital
Cincinnati, Ohio Humboldt University
Berlin, Germany
Steven Daniels, MD, PhD
Professor and Chairman Michael J. Haller, MD
Department of Pediatrics Assistant Professor of Pediatrics
University of Colorado School of Medicine Department of Pediatrics
The Children’s Hospital University of Florida
Denver, Colorado Gainesville, Florida
Diva D. De León, MD Ieuan A. Hughes, MD, FRCP
Assistant Professor of Pediatrics Professor of Paediatrics
Division of Endocrinology University of Cambridge School of Clinical Medicine
Children’s Hospital of Philadelphia Department of Paediatrics
Philadelphia, Pennsylvania Addenbrooks Hospital
Cambridge, United Kingdom
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xiv CONTRIBUTORS
Sharon J. Hyman, MD Sally Radovick, MD
Fellow, Pediatric Endocrinology and Diabetes Professor of Pediatrics
Mount Sinai School of Medicine Director, Division of Pediatric Endocrinology
New York, New York The Johns Hopkins University School of Medicine
Baltimore, Maryland
David R. Langdon, MD
Clinical Associate Professor of Pediatrics Robert Rapaport, MD
University of Pennsylvania School of Medicine Emma Elizabeth Sullivan Professor
Division of Endocrinology Director, Division of Pediatric Endocrinology and
The Children’s Hospital of Philadelphia Diabetes
Philadelphia, Pennsylvania Mount Sinai School of Medicine
New York, New York
Peter A. Lee, MD, PhD
Professor, Department of Pediatrics Alan M. Rice, MD
Penn State College of Medicine Assistant Professor and Division Director
Staff Attending Physician, Department of Pediatrics Pediatric Endocrinology and Diabetes
MSHershey Medical Center University of Nevada School of Medicine
Hershey, Pennsylvania Las Vegas, Nevada
Professor, Department of Pediatrics
Indiana University School of Medicine Scott A. Rivkees, MD
Attending Physician, Department of Pediatrics Professor and Associate Chair
Riley Hospital for Children Chief Section of Developmental Endocrinology and
Indianapolis, Indiana Biology
Department of Pediatrics
Robert H. Lustig, MD Yale University School of Medicine
Professor of Clinical Pediatrics New Haven, Connecticut
Division of Endocrinology
Department of Pediatrics Allen W. Root, MD
University of California Professor of Pediatrics
San Francisco, California Department of Pediatrics
University of South Florida College of Medicine
Joseph A. Majzoub, MD Tampa, Florida
Chief, Division of Endocrinology All Children’s Hospital
Children’s Hospital Boston St. Petersburg, Florida
Thomas Morgan Professor of Pediatrics
Professor of Medicine Ron G. Rosenfeld, MD
Harvard Medical School Senior Vice-President for Medical Affairs
Boston, Massachusetts Lucile Packard Foundation for Children’s Health
Palo Alto, California
Ram K. Menon, MD Professor of Pediatrics
Professor of Pediatrics Stanford University
Professor of Molecular and Integrative Physiology Stanford, California
Director, Division of Endocrinology Professor of Pediatrics
Department of Pediatrics Oregon Health & Science University
University of Michigan Medical School Portland, Oregon
Ann Arbor, Michigan
Robert L. Rosenfi eld, MD
Walter L. Miller, MD Professor of Pediatrics and Medicine
Professor of Pediatrics The University of Chicago Pritzker School of Medicine
Chief of Endocrinology Section of Pediatric Endocrinology
University of California Chicago, Illinois
San Francisco, California
Paul Saenger, MD
Louis J. Muglia, MD, PhD Professor of Pediatrics
Alumni Endowed Professor of Pediatrics Albert Einstein College of Medicine
Washington University Medical School Bronx, New York
Director, Division of Pediatric Endocrinology and
Diabetes
St. Louis Children’s Hospital
St. Louis, Missouri
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CONTRIBUTORS xv
Desmond A. Schatz, MD Massimo Trucco, MD
Professor of Pediatrics Hillman Professor of Pediatric Immunology
Department of Pediatrics Head, Division of Immunogenetics
University of Florida Children’s Hospital of Pittsburgh
Gainesville, Florida Rangos Research Center
University of Pittsburgh
Mark A. Sperling, MD Pittsburgh, Pennsylvania
Professor and Chair Emeritus
Department of Pediatrics Stuart A. Weinzimer, MD
University of Pittsburgh School of Medicine Associate Professor of Pediatrics
Division of Endocrinology, Metabolism, and Diabetes Division of Pediatric Endocrinology and Diabetes
Mellitus Yale Medical School
Children’s Hospital of Pittsburgh New Haven, Connecticut
Pittsburgh, Pennsylvania
Ram Weiss, MD
Charles A. Stanley, MD Assistant Professor of Pediatrics
Professor of Pediatrics Hadassah Hebrew University School of Medicine
University of Pennsylvania School of Medicine Ein Kerem, Israel
Director, Division of Endocrinology and Diabetes
Children’s Hospital of Philadelphia William E. Winter, MD
Philadelphia, Pennsylvania Professor
Departments of Pediatrics and Pathology, Immunology,
Mark Stene, PhD and Laboratory Medicine
Director, Laboratory Operations University of Florida
Quest Diagnostics Gainesville, Florida
West Hills, California
Selma Feldman Witchel, MD
Constantine A. Stratakis, MD, DSc Associate Professor
Chief, Section on Endocrinology and Genetics (SEGEN) Department of Pediatrics
Director, Pediatric Endocrinology Training Program University of Pittsburgh
DEB, NICHD, NIH Children’s Hospital of Pittsburgh
Bethesda, Maryland Pittsburgh, Pennsylvania
William V. Tamborlane, MD
Professor of Pediatrics
Yale University School of Medicine
Director, Division of Endocrinology and Diabetes
Department of Pediatrics
New Haven, Connecticut
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C H A P T E R
1
Molecular Endocrinology
and Endocrine Genetics
Ram K. Menon, MD • Massimo Trucco, MD
• Constantine A. Stratakis, MD, DSc
Introduction Molecular Basis of Pediatric Endocrinopathies
Basic Molecular Tools Defects in Peptide Hormones
Isolation and Digestion of DNA and Southern Genomic Deletions Causing Human
Blotting Endocrine Disease
Restriction Fragment Length Polymorphism Point Mutations
and Other Polymorphic DNA Studies Defects in Peptide Hormone Receptors
Polymerase Chain Reaction Insulin Receptor
RNA Analysis Growth Hormone Receptor
Detection of Mutations in Genes Recombinant DNA Technology and Therapy
Direct Methods of Pediatric Endocrine Diseases
Indirect Methods Concluding Remarks
Positional Genetics in Endocrinology
The Principles of Positional Genetics
Positional Cloning of Endocrine Genes
Expression Studies: Microarrays and SAGE
Chromosome Analysis and Molecular
Cytogenetics
Outline of Methods
Applications
Future Developments
Introduction mon laboratory techniques, and some examples of the
recent advances made in clinical pediatric endocrinologic
The study of the endocrine system has undergone a dra- disorders—with an emphasis on endocrine genetics.
matic evolution in the last two decades, from the tradi-
tional physiologic studies that had dominated the fi eld for
many years to the discoveries of molecular endocrinology Basic Molecular Tools
and endocrine genetics.1,2 At the current time, the major
impact of molecular medicine on the practice of pediatric
ISOLATION AND DIGESTION OF DNA
endocrinology relates to diagnosis and genetic counseling
AND SOUTHERN BLOTTING
for a wide variety of inherited endocrine disorders.
In contrast, the direct therapeutic application of this The human chromosome comprises a long double-
new knowledge is still in its infancy. This chapter is an stranded helical molecule of DNA associated with differ-
introduction to basic principles of molecular biology, com- ent nuclear proteins.3,4 Because DNA forms the starting
1
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