Practical

Algorithms in
Pediatric
Endocrinology
2nd, revised edition

Editor
Zeev Hochberg, Haifa

53 graphs, 7 figures and 3 tables, 2007

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 Contents
Contributors Puberty Intersex

1 Introduction 14 Precocious breast development 36 Micropenis at age 1 year to puberty

Z. Hochberg in a girl M. Ritzn; R.L. Hintz
J.-P. Bourguignon; R.L. Rosenfield
38 Micropenis in a newborn
16 Precocious genital development M. Ritzn; R.L. Hintz
Growth in a boy 40 Hypospadias/virilization
J.-P. Bourguignon; R.L. Rosenfield M. Ritzn; R.L. Hintz
2 Failure to thrive
18 Precocious pubarche 42 Cryptorchidism
R.L. Hintz; Z. Hochberg
J.-P. Bourguignon; R.L. Rosenfield A.D. Rogol; Z. Hochberg
4 Short stature
20 Gynecomastia 44 Turner syndrome
R.L. Hintz; M. Ritzn
N. Zuckerman-Levin; Z. Hochberg; R.L. Hintz; Z. Hochberg
6 Growth hormone treatment R.L. Rosenfield
R.L. Hintz; J.-P. Bourguignon
22 Delayed or absent testicular
8 Tall stature development Adrenal
N. Zuckerman-Levin; Z. Hochberg; M. Ritzn J.-P. Bourguignon; R.L. Rosenfield

10 Overweight and obesity/ 24 Delayed or absent breast 46 Hypertension

Infantile obesity development F. Riepe; W.G. Sippell; Z. Hochberg
Z. Hochberg; A.D. Rogol J.-P. Bourguignon; R.L. Rosenfield
48 Cushing syndrome
12 Brain irradiation 26 Primary amenorrhea and A.D. Rogol; Z. Hochberg
A.D. Rogol; D.B. Dunger abnormal genital anatomy 50 Congenital adrenal hyperplasia
R.L. Rosenfield
(CAH) in the newborn period
28 Secondary amenorrhea or M. Ritzn; R.L. Hintz
oligomenorrhea 52 Congenital adrenal hyperplasia
R.L. Rosenfield
(CAH) presenting after the newborn
30 Anovulatory disorders period
R.L. Rosenfield; J.-P. Bourguignon M. Ritzn; R.L. Hintz

32 Hirsutism
R.L. Rosenfield; F. Riepe; W.G. Sippell

34 Hyperandrogenemia

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R.L. Rosenfield; F. Riepe; W.G. Sippell

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Water and electrolytes Thyroid Carbohydrates

54 Polyuria 76 Congenital hypothyroidism 94 Hypoglycemia

N. Zuckerman-Levin; Z. Hochberg; A.D. Rogol T.P. Foley, Jr.; F. Pter M.A. Sperling; O. Escobar; R.K. Menon;
D.B. Dunger
56 Hyperhydration 78 Juvenile hypothyroidism
W.G. Sippell; Z. Hochberg F. Pter; T.P. Foley, Jr. 96 Hyperglycemia
D.B. Dunger; O. Escobar; R.K. Menon;
58 Dehydration 80 Hyperthyroidism M.A. Sperling
W.G. Sippell; Z. Hochberg F. Pter; T.P. Foley, Jr.
98 Prediabetes and prediction of
60 Hypernatremia 82 Neonatal hyperthyroidism diabetes
W.G. Sippell; Z. Hochberg T.P. Foley, Jr.; F. Pter
D.B. Dunger; O. Escobar; R.K. Menon;
62 Hyponatremia 84 Goiter M.A. Sperling
W.G. Sippell; Z. Hochberg T.P. Foley, Jr.; F. Pter 100 T2DM
64 Hyperkalemia 86 Thyroid nodules in children and D.B. Dunger; O. Escobar; R.K. Menon;
M.A. Sperling
F. Riepe; W.G. Sippell; Z. Hochberg adolescents
T.P. Foley, Jr.; F. Pter 102 Type 1 diabetes mellitus
66 Hypokalemia
D.B. Dunger; O. Escobar; R.K. Menon;
F. Riepe; W.G. Sippell; Z. Hochberg 88 Thyroid carcinoma
M.A. Sperling
T.P. Foley, Jr.; F. Pter
104 Maturity-onset diabetes of youth
90 Hypothyroxinemia
Calcium metabolism (MODY)
T.P. Foley, Jr.; F. Pter
M.A. Sperling; O. Escobar; R.K. Menon;
92 Hyperthyroxinemia D.B. Dunger
68 Hypercalcemia F. Pter; T.P. Foley, Jr.
D. Tiosano; Z. Hochberg 106 Diabetic ketoacidosis
D.B. Dunger; O. Escobar; R.K. Menon;
70 Hypocalcemia M.A. Sperling
D. Tiosano; Z. Hochberg

72 Rickets
D. Tiosano; Z. Hochberg
108 Index of Signs and Symptoms
74 Hypomagnesemia 112 Abbreviations
A.D. Rogol; Z. Hochberg

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 Contributors
Jean-Pierre Bourguignon, MD, PhD Zeev Hochberg, MD, PhD Robert L. Rosenfield, MD
CHU Sart Tilman Rambam Medical Center The University of Chicago
Lige, Belgium Technion Israel Institute of Technology Childrens Hospital
Haifa, Israel Chicago, Illinois, USA

David B. Dunger, MD
Department of Paediatrics Ram K. Menon, MD Wolfgang G. Sippell, MD
University of Cambridge, Addenbrookes Hospital Childrens Hospital Universitts-Kinderklinik
Cambridge, UK Pittsburgh, Pennsylvania, USA Kiel, Germany

Oscar Escobar, MD Ferenc Pter, MD, PhD, DSc Mark A. Sperling, MD

Childrens Hospital Buda Childrens Hospital and Policlinic Childrens Hospital
Pittsburgh, Pennsylvania, USA Budapest, Hungary Pittsburgh, Pennsylvania, USA

Thomas P. Foley, Jr., MD Felix Riepe, MD Dov Tiosano, MD

University of Pittsburgh Universitts-Kinderklinik Meyer Childrens Hospital
Pittsburgh, Pennsylvania, USA Kiel, Germany Haifa, Israel

Raymond L. Hintz, MD Martin Ritzn, MD, PhD Nehama Zuckerman-Levin, MD

Stanford University Medical Center Karolinska Hospital Rambam Medical Center
Stanford, California, USA Stockholm, Sweden Haifa, Israel

Alan D. Rogol, MD, PhD

University of Virginia
Health Science Center
Charlottesville, Virginia, USA

Library of Congress Cataloging-in-Publication Data
Practical algorithms in pediatric endocrinology /
editor, Zeev Hochberg. 2nd, rev. ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-3-8055-8220-9 (softcover : alk. paper)
1. Pediatric endocrinology Diagnosis Decision making. 2. Decision
trees.
I. Hochberg, Z. [DNLM: 1. Endocrine System Diseases. 2. Adolescent.
3. Child. 4. Decision Trees. 5. Endocrine System Diseases diagnosis.
6. Infant. WS 330 P8949 2007]
RJ418.P69 2007
618.924 dc22
2007012334
Disclaimer. The statements, options and data contained in this publi-
cation are solely those of the individual authors and contributors and
not of the publisher and the editor(s). The appearance of advertise-
ments in the book is not a warranty, endorsement, or approval of the
products or services advertised or of their effectiveness, quality or
safety. The publisher and the editor(s) disclaim responsibility for any
injury to persons or property resulting from any ideas, methods, in-
structions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort
to ensure that drug selection and dosage set forth in this text are in
accord with current recommendations and practice at the time of pub-
lication. However, in view of ongoing research, changes in government
regulations, and the constant flow of information relating to drug ther-
All rights reserved. No part of this publication may be translated into
other languages, reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying, recording, micro-
copying, or by any information storage and retrieval system, without
permission in writing from the publisher.
1st edition: Practical Algorithms in Pediatric Endocrinology
Editor: Z. Hochberg, Haifa
IV + 110 p., 52 graphs, 4 fig., 1 tab., spiral bound, 1999
ISBN 380556693X
Copyright 2007 by S. Karger AG, P.O. Box, CH4009 Basel
(Switzerland)
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel

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ISBN 9783805582209 (spiral bound: alk. paper) apy and drug reactions, the reader is urged to check the package insert ISBN 9783805582209
for each drug for any change in indications and dosage and for added
warnings and precautions. This is particularly important when the rec-
ommended agent is a new and/or infrequently employed drug.

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The first edition of Practical Algorithms in Pediatric
Endocrinology was compiled in 1998 and published in
1999. In the 8 years between its publication and this
second edition, molecular endocrinology has changed
our clinical practices to a level unimaginable only a
decade ago. The colossal pace of discovery in both
basic and clinical endocrinology has changed not only
our understanding, but also our daily engagement with
patients and parents.
The first edition has sold over 3,000 copies. It is a
tribute to the 12 contributors to the first edition in that it
has become a leading bedside source for general prac-
titioners, pediatricians and pediatric endocrine fellows.
The same contributors responded willingly to revise
each of the 50 algorithms. Naturally, we have additional
younger contributors who have grown to be among the
new leadership in pediatric endocrinology worldwide.
The basic outline remains unchanged. Algorithms are
practical tools to help us address diagnostic and
therapeutic problems in a logical, efficient and cost-
effective fashion. The enormous success and sell-out
of the first edition confirmed that this approach was
useful for clinicians caring for children with endocrine
disorders.
As with any approach that attempts to simplify com-
plex problems, there will always be exceptions. Each
algorithm must be used in the context of the individual
findings of each patient under examination and in
conjunction with the published literature. The clinician
1 must always be aware that any individual patients
presentation may be atypical enough, or confounded
by concomitant disorders or complications, to render
our approaches invalid. In addition, advances in diag-
nosis and management can render current approaches
obsolete.
Introduction
Several chapters include suggestions made by our
readers and, as before, I invite comments to correct
any mistakes which may have occurred or to make any
improvements to the diagnostic algorithms we offer.
I hope you will find this book helpful in managing the
children under your care.
Zeev Hochberg, MD, PhD
April 2007, Haifa
Introduction to 1st edition
Textbooks of medicine are oriented by body systems,
by disease or by diagnoses. Yet, the practicing physi-
cian is encountered by a patients complaint, by a symp-
tom, by a physical sign or by a laboratory abnormality,
from which he is expected to proceed to diagnosis and
to plan management. The traditional medical approach
is through differential diagnosis by exclusion. Algo-
rithms provide a direct approach to breaking down long
list tables of differential diagnosis into smaller, more
manageable lists, as often a whole group of diagnoses
can be excluded by a single or a group of signs, blood
tests or imaging.
Practical Algorithms in Pediatric Endocrinology is
meant as a pragmatic text to be used at the patients
bedside. It classifies common clinical symptoms, signs
and laboratory abnormalities as they present to us in
daily practice. The experienced practitioner applies
step-by-step logical problem-solving for each patient
individually. Decision trees prepared in advance
have the disadvantage of unacquaintedness with the
individual patient. Yet, for the physician who is less
experienced with a given problem, a prepared algo-
rithm would provide a logical, concise, cost-effective
approach prepared by a specialist who is experienced
with the given problem. It would also train a young
practitioner in medical reasoning. This book is, there-
fore, aimed at an audience of general practitioners
or pediatricians who are not exposed on a daily basis
to pediatric endocrine problems. It would also aid
trainees in pediatric endocrinology as they presume
familiarity with clinical problem-solving to make
rational choices in approaching a clinical dilemma.
Certainly, there is more than one way to approach a
clinical problem, and this book presents one such way
for each problem, prepared by skilled, experienced
specialists in pediatric endocrinology. The algorithms
were prepared through discussion and deliberation
among the authors of this book. By no means should
they be viewed dogmatically as the one and only ap-
proach. We paid special attention to simple passages,
rejecting groups of diagnoses first by history and
physical examination, then by simple laboratory tests
common to any clinical setting, and only finally, in
some cases, to more sophisticated laboratory means,
which may require specialized proficiencies.
The term algorithm is derived from the name of the
ninth century Arabic mathematician Algawrismi, who
also gave his name to algebra. His algorismus indi-
cated a step-by-step logical approach to mathematical
problem-solving. It is presented hereby to the medical
practitioner in that same spirit.
Zeev Hochberg, MD, PhD
April 1999, Haifa
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 Growth R.L. Hintz Z. Hochberg Failure to thrive

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 Evaluation The key to the initial evaluation of
failure to thrive is a careful history
and determination of the auxological
parameters. Prompt diagnosis
and intervention are important
for preventing malnutrition and
developmental sequelae.
History Birth history and past growth
Family history of height and
development
Nutrition
Evidence of systemic disease
Physical Any evidence of systemic disease or
examination malnutrition
Anomalies suggestive of chromo-
somal disease
U/L ratio (or sitting height) and span
Laboratory T4, TSH, BUN or creatinine, ESR, CO2,
CBC and others as indicated
Markers of absorption
Metabolic testing (amino acids,
organic acids, etc.)
Chromosomes in infants with
anomalies
IGFBP-3
3 ogy, ed 4. London, Blackwell, 2001, pp 124139.
Growth
1 Failure to thrive in children is solely based
on anthropometrical indicators, with weight gain as
the predominant choice of indicator and cut off around
the 5th percentile. The syndrome of failure to thrive
occurs in infants under the age of 2 and is most com-
mon in the first year of life. It may occur either with or
without poor linear growth. If poor weight gain is the
predominant problem then maternal-child interaction,
nutritional or gastrointestinal problems are more like-
ly. If poor height gain is the predominant feature then
an endocrine or skeletal disorder is more likely. A de-
crease in the growth of head size usually develops sig-
nificantly after the onset of the decrease in growth in
weight and height. If the decrease in head circumfer-
ence is predominant, it suggests the presence of a pri-
mary CNS disease, particularly if the infant is develop-
mentally delayed. Many infants cross height percen-
tiles during the first 18 months of age depending on
their genetic background. If the shift in percentiles is
inappropriate for the infants genetic background or
persists after 18 months, a careful evaluation is neces-
sary.
2 If the infant has significant failure to gain
weight, a careful evalution is necessary. By far the
most common causes of failure to thrive syndrome are
malnutrition and maternal deprivation. These diagno-
ses are best suspected by a careful history, backed up
by careful observation and a trial of feeding the infant.
Evaluation by a social worker can be most helpful in
diagnosing maternal deprivation.
3 Many infants can be classified as having a
non-organic failure to thrive by a careful history and
physical examination. Further follow-up by medical
personnel and social workers is necessary, and if the
failure to thrive persists further laboratory evaluation
may be necessary. About 25% of normal infants will
shift to a lower growth percentile in the first 2 years of
life and then follow that percentile; this should not be
diagnosed as failure to thrive.
4 Not infrequently malnutrition and maternal
deprivation are found in combination as a cause of fail-
ure to thrive. Correction of the cause of the malnutri-
tion and psychosocial intervention are necessary.
5 If the history and physical examination are
suggestive of a genetic cause, the presence of a meta-
bolic disorder or a specific syndrome, then chromo-
R.L. Hintz Z. Hochberg
somes, metabolic testing and long bone X-rays may
lead to a specific diagnosis and treatment. The evalua-
tion of the U/L segment, sitting height and span, and
auxological measurements of mid-limb segments ver-
sus total limb segments can be especially helpful.
6 Laboratory evaluation may include electro-
lytes to screen for renal tubular acidosis or diabetes
insipidus (see p. 54), measurements of calcium, phos-
phorus and vitamin D to rule out rickets (see p. 72) or
other disorders of mineral metabolism, markers of Gl
absorption such as carotene and vitamin levels, a sedi-
mentation rate to screen for a chronic inflammatory
process, T4 and TSH to determine thyroid function,
and IGFBP-3 to screen for GHD (see p. 4). If there is a
history of steatorrhea, measurement of antiendome-
sial antibodies and sweat chloride are indicated.
7 Frequently, the underlying cause of the
failure to thrive syndrome remains unclear, and an
empiric trial of nutritional therapy by a person experi-
enced in feeding infants along with careful observa-
tion and support of the family is necessary.
8 If physical examination and history are unre-
vealing, screening tests for endocrine, Gl or metabolic
disorders are frequently necessary. Any specific diag-
nosis should be treated appropriately.
9 The diencephalic syndrome includes clinical
characteristics of severe emaciation, normal linear
growth, and normal or precocious intellectual devel-
opment in association with central nervous system
tumors.
Selected reading
Fleischman A, Brue C, Poussaint TY, Kieran M,
Pomeroy SL, Goumnerova L, Scott RM, Cohen LE:
Diencephalic syndrome: a cause of failure to thrive
and a model of partial growth hormone resistance.
Pediatrics 2005;115:e742e748.
Hintz RL: Disorders of size and shape; in Brook CGD,
Hindmarsh PC (eds): Clinical Paediatric Endocrinol-
Krugman SD, Dubowitz H: Failure to thrive.
Am Fam Physician 2003;68:879884.
Failure to thrive
 Growth R.L. Hintz M. Ritzn Short stature

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 Evaluation The key to the initial evaluation of
short stature is a careful history and
determination of the auxological
parameters.
History Birth history and past growth
Family history of height and
development
Evidence of systemic disease
Nutrition
Physical Any evidence of systemic disease or
examination malnutrition
Anomalies suggestive of
chromosomal disease
U/L ratio (or sitting height) and span
Laboratory T4, TSH, BUN or creatinine, ESR,
CO2, CBC and others as indicated
Bone age
Chromosomes in females, or in
males with significant anomalies
IGF-1, IGFBP-3, and basal GH
GH provocative testing (or GH
endogenous secretion)
1 Children who have growth failure over a sig-
nificant period of time develop short stature. This is
defined as absolute height which is <2 SDS for age,
and/or a linear growth velocity consistently <1 SDS
for age.
2 Children with Ht >2 SDS and/or Ht velocity
>0 SDS for age are probably normal.
3 If the child has significant short stature and/
or decreased growth rate (Ht <2.5 SDS for age, Ht
velocity <1 SDS), and no evidence of hypothyroidism,
systemic disease, or malnutrition, then an abnormality
of the GH/IGF axis should be considered.
4 If IGF-1 or IGFBP-3 <1 SDS below the mean
for age, GH/IGF axis dysfunction is likely and further
investigation of the GH/IGF axis is indicated. This may
include the measurement of GHBP, basal GH, IGF-2,
IGFBP-2, GH provocative testing or GH secretion
studies to further document the abnormality in the
GH/IGF axis.
5 If the GH peak <10 g/l, in a polyclonal RIA,
or an equivalent lower value in a two-site GH assay,
the diagnosis of classic GH deficiency is made. It is im-
portant to use a GH assay that has been well validated
and standardized, and that the variability in GH assays,
testing, and normal responses be recognized. A W/U
for other pituitary deficiencies and a head MRI should
be done to establish the cause and degree of hypotha-
lamic/pituitary disease. GH treatment is indicated (see
p. 6).
7 Children with Ht 2 to 2.5 SDS and/or Ht
velocity 1 to 0 SDS for age should be carefully ob-
served and may require further testing.
8 If IGF-1 or IGFBP-3 levels >1 SDS below the
mean for age, GH/IGF axis dysfunction is unlikely.
Nonhormonal causes of short stature should be recon-
sidered, and the child should be followed prospective-
ly for the rate of growth.
9 If the basal GH is elevated or GHBP is less
than 2 SDS below the mean, the patient has GH insen-
sitivity syndrome. This includes Laron syndrome and
variants, malnutrition and chronic disease. Treatment
with IGF-1 is likely to be effective.
Selected reading
Dunger DB, Ong KK: Endocrine and metabolic
consequences of intrauterine growth retardation.
Endocrinol Metab Clin North Am 2005;34:597615.
Lee MM: Clinical practice. Idiopathic short stature.
N Engl J Med 2006;354:25762582.
Rosenfeld RG, Hwa V: Toward a molecular basis
for idiopathic short stature. J Clin Endocrinol Metab
2004;89:10661067.

6 If the GH peak >10 g/l, the diagnosis is un-

clear. Some possibilities include GH insufficiency, idio-
pathic short stature, partial GH insensitivity, and mal-
nutrition. Careful clinical follow-up is indicated, and
GH treatment may be considered.

Growth R.L. Hintz M. Ritzn Short stature

 Growth R.L. Hintz J.-P. Bourguignon Growth hormone treatment

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 Evaluation The key to the initial evaluation for
GH treatment is a careful history and
physical examination.
History Birth history and past growth
Family history of height and
development
CNS lesion or history of CNS
irradiation or surgery
Evidence for systemic disease
Nutrition
Use of medications influencing
growth, such as glucocorticoids
Genetic forms
Physical Any evidence of systemic disease or
examination malnutrition
Anomalies suggestive of
chromosomal disease
U/L ratio (or sitting height) and span
Laboratory T4, TSH, BUN or creatinine, ESR, CO2,
CBC and others as indicated
BA
Chromosomes in female, or in male
with anomalies
IGF-1, IGFBP-3, GHBP and basal GH
GH provocative testing (or GH
endogenous secretion)
Gene mutations (Pit-1, )
1 The commonly approved indications for GH
treatment are for children with significant short stature
due to inadequate GH secretion; adults with GH defi-
ciency and changes in body composition, energy level,
7 strength and metabolism; children with Turner syn-
drome and poor growth, and chronic renal failure with
slow growth rate and intrauterine growth retardation
(IUGR). The commonly recommended daily dose of
GH vary depending on the conditions.
Growth
2 A child with significant short stature and/or
decreased growth rate (Ht <2.5 SDS for age, Ht veloc-
ity <1 SDS) and/or a history of CNS lesions or irradia-
tion treatment, or an adult with a history of childhood-
onset GH deficiency or an acquired pituitary/hypotha-
lamic disorder should be tested for the ability to se-
crete GH by one or several standardized methods. Se-
rum IGF-1 and/or IGFBP-3 are helpful screening tests
of GH secretion. If GH secretion is below normal (see
footnote 5) then the diagnosis of GH deficiency is
made, imaging of the brain and evaluation of other
pituitary hormones should be completed, and GH
treatment instituted.
3 Patients with diagnosed Turner syndrome
(see p. 44), short stature, and open epiphyses can be
treated with GH without the necessity of testing GH
secretion.
4 Children with slow growth due to chronic
renal failure or IUGR can also be treated with GH with-
out the necessity of testing of GH secretion.
5 It is important that any hypothyroidism be
diagnosed and adequately treated before testing for
GH deficiency is carried out. IGF-1 and IGFBP-3 levels
are valuable screening tests for inadequate GH secre-
tion in childhood. Values of IGF-1 above 1 SDS for age
in children essentially rule out GH deficiency, and val-
ues of IGF-1 and IGFBP-3 below 2 SDS strongly sug-
gest an abnormality of GH secretion or action. How-
ever, there are many causes of low IGF-1 levels in addi-
tion to GH deficiency, such as malnutrition and chronic
disease. IGF-1 and IGFBP-3 levels are less helpful in the
diagnosis of adult GHD. Provocative GH testing in chil-
dren uses many standardized protocols. A peak value
of GH in two provocative tests below 10 g/l in a poly-
clonal GH RIA (or equivalent lower value in two-site
GH assays) is consistent with GH deficiency in a child.
Sex hormone priming may be needed in cases of con-
stitutional delay of growth and puberty to distinguish
this normal variant from GH deficiency. The recom-
mended GH provocative test in adults is insulin hypo-
glycemia and the diagnostic level is below 3 g/l.
6 A child with GH secretion not consistent
with the diagnosis of classic GH deficiency, but with
significant short stature and persistently low growth
rate for age may still be considered for a trial of GH
treatment, especially if there is a history of hypotha-
lamic-pituitary disease or cranial irradiation.
R.L. Hintz J.-P. Bourguignon
7 During GH therapy, occurrence of side ef-
fects has been reported in <1% of the patients, includ-
ing benign acute intracranial hypertension and Legg-
Calv-Perths disease. Assessment is required in pa-
tients complaining about headaches or leg pain and
limp. The dose of GH can be adjusted to obtain a
growth response with IGF-1 levels or free IGF-1 index
(IGF-1/IGF-BP3 ratio) in the upper normal range for
age.
8 After completion of growth on GH treatment
in a GH-deficient patient, the question has to be ad-
dressed whether or not GH replacement should be fur-
ther provided in adulthood. In patients with isolated
and idiopathic forms of GH deficiency, retesting (ITT)
after several weeks of treatment withdrawal is impor-
tant since 1/2 to 2/3 patients will exhibit normalized GH
response to ITT.
Selected reading
Molitch ME, Clemmons DR, Malozowski S, Merriam
GR, Shalet SM, Vance ML: Endocrine Societys
Clinical Guidelines Subcommittee: Stephens PA:
Evaluation and treatment of adult growth hormone
deficiency: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2006;91:
16211634.
Thomas M, Massa G, Craen M, de Zegher F,
Bourguignon JP, Heinrichs C, De Schepper J,
Du Caju M, Thiry-Counson G, Maes M: Prevalence
and demographic features of childhood growth
hormone deficiency in Belgium during the period
19862001. Eur J Endocrinol 2004;151:6772.
Thomas M, Massa G, Maes M, Beckers D, Craen M,
Franois I, Heinrichs C, Bourguignon JP, in collabo-
ration with the BSGPE: Growth hormone secretion
in patients with childhood-onset GH deficiency:
retesting after one year of therapy and at final
height. Horm Res 2003;59:715.
Growth hormone treatment
 Growth N. Zuckerman-Levin Z. Hochberg M. Ritzn Tall stature

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 1 Children and adolescents with Ht over 23
SDS above the mean height for age are considered
tall.
2 The impression of long extremities is mag-
nified by poor muscular mass and arachnodactyly.
Caused by fibrin deficiency, autosomal-dominant (ex-
amine parents) Marfan syndrome is manifested also
by eye and heart abnormalities, and requires continu-
ous follow-up by a cardiologist.
3 The Bailey-Pinneau tables are the best
method to predict adult height in patients with tall stat-
ure.
4 The decision on growth-reducing therapy is
to be made by the patient and her/his parents. The
medical information to be presented by the physician
should address current knowledge of the physical and
mental benefits and risks of the two options: tall stat-
ure or high-dose sex steroid therapy with rapid devel-
opment of secondary sex characteristics. The long-
term detrimental effects on fertility in girls should be
mentioned. The efficacy of androgen therapy in boys
is doubtful, whereas the efficacy of estrogen and pro-
gestative therapy in girls is good, provided that thera-
py is given until complete closure of all growth plates.
5 The normal arm span is not to exceed the
childs Ht + 5 cm. For sitting height and U/L ratio
(upper and lower from the symphysis), consult nomo-
grams. Most very tall normal individuals have long
extremities.
6 Accelerated growth is observed in cerebral
gigantism (Sotos syndrome) only in the first 2 years of
life, followed by normal growth rate and normal final
height. Facial features may resemble acromegaly and
mental retardation is variable. Sotos syndrome is
caused by haploinsufficiency of NSD1.
Growth
7 Beckwith-Wiedemann syndrome results
from overexpression of IGF-2, caused by mutation in
chromosome 11p15.5, and manifests as big babies
with organomegaly, omphalocele and hyperinsulin-
emic hypoglycemia.
8 Patients with isolated glucocorticoid defi-
ciency due to inactivating mutations of the ACTH re-
ceptor are tall in childhood, and their BA is advanced.
9 Neurofibromatosis may be associated with
unexplained tall stature or with optic glioma and gi-
gantism in the absence of pituitary adenoma. Gigan-
tism may start as early as the 1st year of life.
10 Patients with aromatase deficiency or estro-
gen receptor defects have much delayed bone matura-
tion and continue to grow into their 3rd decade of life.
11 Androgen insensitivity syndrome is an
X-linked recessive disorder caused by mutations in the
androgen receptor.
12 Homocystinuria can be diagnosed by a sim-
ple urinary nitroprusside test.
13 Klinefelter syndrome (incidence 1/500!) and
individuals with karyotypes XYY and XXYY may
cause tall stature even before puberty, and develop
disproportionate long extremities during puberty. The
number of X chromosomes correlates with height.
14 Eunuchoid habitus is present in hypo-
gonadism.
15 Nonendocrine obesity manifests with accel-
erated height velocity, advanced bone age, early pu-
berty and normal adult height.
N. Zuckerman-Levin Z. Hochberg M. Ritzn
16 Gigantism caused by GH excess before
epiphyseal closure is rare. It may be due to a GH-
secreting pituitary adenoma (MRI) or to an ectopic
GHRH-secreting pancreatic carcinoma (CT scan). GH
excess may be seen in McCune-Albright syndrome
and in multiple endocrine neoplasia type 1. Serum GH
is insuppressible by a glucose load or TRH. GH profile
at 20-min intervals over at least 8 h will show no return
to nadir serum GH of <2 g/l. Elevated IGF1/IGFBP3
levels are helpful for diagnosis.
17 Growth acceleration is seen in prolonged
untreated patients with hyperthyroidism. The bone
age is advanced.
Selected reading
Drop SL, De Waal WJ, De Muinck Keizer-Schrama
SM: Sex steroid treatment of constitutionally tall
stature. Endocr Rev 1998;19:540558.
Kant SG, Wit JM, Breuning MH: Genetic analysis of
tall stature. Horm Res 2005;64:149156.
Kurotaki N, Imaizumi K, Harada N, et al: Haploinsuf-
ficiency of NSD1 causes Sotos syndrome.
Nat Genet 2002;30:365366.
Radivojevic U, Thibaud E, Samara-Boustani D,
Duflos C, Polak M: Effects of growth reduction ther-
apy using high-dose 17beta-estradiol in 26 constitu-
tionally tall girls. Clin Endocrinol 2006;64:423428.
Venn A, Bruinsma F, Werther G, Pyett P, Baird D,
Jones P, Rayner J, Lumley J: Oestrogen treatment to
reduce the adult height of tall girls: long-term ef-
fects on fertility. Lancet 2004;364:15131518.
Tall stature
 Growth Z. Hochberg A.D. Rogol Overweight

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 1 Of the various sophisticated tools for measurement of
obesity, height and weight are among the most accurate. Over-
weight and obesity are now mostly defined by the body mass index
[BMI = wt (kg)/ht2 (m2)]. We recommend the use of age-related BMI
reference as they match the adult cutoffs of BMI over 25 (overweight)
and 30 (obesity) at age 18 years [Cole TJ, et al: BMJ 2000;320:1240
1243]. BMI may not be accurate in very tall or short children. The
variability in the timing of pubertal onset in girls influences the refer-
ence population for adiposity.
32
Males 30
30
28
Body mass index
Body mass index
26 25
24
22
20
18
16
0 2 4 6 8 10 12 14 16 18 20
Age (years)
Endocrine consequences of obesity include low serum GH
2
and normal IGF-I; T3 levels may be increased; in the male serum tes-
tosterone is decreased and estrogen increased, in the female both
estrogen and androgen increase; insulin resistance. Also, survey lip-
id profile, biochemical profile, liver enzymes and ultrasonography,
glucose and insulin while fasting can be considered as first-line in-
vestigations. Oral glucose tolerance test (OGTT) to exclude IGT or
type 2 DM is indicated in individuals at high risk to develop type 2
DM or IGT (family history of T2DM, or metabolic syndrome).
Feminine (gynoid or peripheral) distribution is predomi-
3
nantly peripheral or lower body obesity and develops early in life;
probably before birth. Masculine (or android) distribution is predom-
inantly of central pattern and develops around age 6 years. Central
pattern is associated with increased risk for cardiovascular morbid-
ity. Glucose intolerance develops in patients with obesity onset at 6,
and more so when acanthosis nigricans is present.
4 Familial obesity can be related to known genetic diseases,
unknown genetic factors, family eating habits or a combination of all.
The success rate of weight reduction is lower in familial obesity.
5 In hypothyroidism obesity is due to decreased energy ex-
penditure. Delayed bone age (see pp. 76, 78).
6 Truncal obesity with reduced height velocity are the main
11 signs. There is no indication that cortisol levels in obese individuals
are abnormal. Hypercortisolism can be proven by an overnight dexa-
methasone suppression test (20 g/kg at 11 p.m., followed by serum
cortisol at 8 a.m.). Specific etiology is further diagnosed by low-dose
dexamethasone suppression test, CRH stimulation test, and by imag-
ing (see p. 48).
Growth
7 Growth retardation and mild truncal obesity may be the 17 Autosomal recessive. Onset of obesity is at 12 years of
only signs. In more severe deficiency the syndrome is more com- age. Stature is normal or short. Polydactyly, retinitis pigmentosa
plete. With GH therapy obesity subsides rapidly (see p. 6). with early night blindness and hypogonadism are usually present.
Mild renal failure and urinary concentrating defect.
8 In Albrights osteodystrophy obesity is mild to severe.
19 Autosomal recessive. Characteristic facial and limb dys-
9 Onset of obesity at late prepuberty (mean age 6 years), morphism with normal growth and mild mental retardation.
menstrual disorder, hirsutism and acne raise the suspicion of PCO
syndrome (see p. 32). Restraint of obesity ameliorates virilization 19 Onset of obesity is at mid-childhood, after a history of
32 (see p. 32). neonatal hypotonia. Narrow hands and feet with characteristic faces.
Females
30
28 10 Several phenothiazines, antidepressants, valproate and 20 Serum leptin is positively correlated with the degree of
26 carbamazepine and glucocorticoids (at doses above replacement) obesity. Leptin deficiency responds to leptin therapy.
24
increase body weight.
22
21 Beckwith-Wiedemann syndrome is manifested as macro-
20
11 Birth, casualty or surgical trauma of the hypothalamus as somia, visceromegaly, neonatal hyperinsulinemic hypoglycemia and
18
16
well as hypothalamic tumors may lead to uncontrollable appetite. postnatal gigantism. Large muscle mass, including macroglossia,
0 2 4 6 8 10 12 14 16 18 20 MRI is indicated. and thick subcutaneous fat develop. There is an increased suscepti-
Age (years)
bility to malignancies.
12 Obesity with growth retardation are occasional signs of
craniopharyngioma. More often, morbid obesity develops after par- 22 Macrosomia in infants of diabetic mothers is due to hyper-
tial or complete removal of craniopharyngioma. These children mani- insulinemia and resolves within weeks.
fest obesity and normal growth despite low GH levels and subnormal
responses to GH secretagogues.
Selected reading
13 This is the most common nutritional disease of affluent
civilizations. Normal growth, slightly advanced bone age and familial Lustig RH: Pediatric endocrine disorders of energy balance.
tendency are evident during childhood. Early puberty is common. Rev Endocr Metab Disord 2005;6:245260.
Psychoaffective disturbances are common, which may be the pri- Skelton JA, DeMattia L, Miller L, Olivier M: Obesity and its
mary component, or a secondary consequence. Secondary morbid- therapy: from genes to community action. Pediatr Clin North Am
ity includes hyperinsulinemia and glucose intolerance, hyperlipid-
2006;53:777794.
emia, hypertension, non-alcoholic fatty liver disease (NAFLD), non-
alcoholic steatohepatitis (NASH), coronary heart diseases, sleep ap- Speiser PW, Rudolf MCJ, Anhalt H, Camacho-Hubner C, Chiarelli F,
nea, hirsutism. Overfeeding in an infant can be qualitative (fat) or Eliakim A, Freemark M, Gruters A, Hershkovitz E, Iughetti L,
quantitative. Regurgitation and vomiting are common. Krude H, Latzer Y, Lustig RH, Hirsch-Pescovitz O, Pinhas-Hamiel O,
Rogol AD, Shalitin S, Sultan C, Stein D, Vardi P, Werther G,
14 Molecular genetic analysis is not essential for the diagno- Zadik Z, Zuckerman-Levin N, Hochberg Z: Childhood obesity.
sis of obesity but should be considered if a child presents with mor- J Clin Endocrinol Metab 2005;90:18711887.
bid obesity (BMI >4 SD above the age-related mean), with a history
of marked hyperphagia and with early-onset obesity; serum leptin
concentrations can be determined and genetic analysis of key candi-
date genes considered.
15 Onset of obesity is at 14 years of age. Small chubby
hands and feet and infantile hypotonia are characteristic. Mental re-
tardation hinders dietary therapy. Confirm by cytogenetic or DNA
search for microdeletions on chromosome 15. Serum GH and IGF-I
are low. GH therapy may be beneficial.
16 Children with this autosomal-recessive disease have nor-
mal growth and mental development. Onset of obesity is at 25 years
of age. Hypogonadism in males only.
Z. Hochberg A.D. Rogol Overweight
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 1 Including craniospinal axis.
2 Careful surveillance for growth and adoles-
cent development every 6 months.
3 The greater the amount of the biological ef-
fective dose to the hypothalamic area, the greater is
the likelihood of disruption of the GnRH-gonadotropin-
gonadal axis both precocious, especially with irradia-
tion at a younger age, and delayed puberty. There is a
hierarchy of sensitivity of the individual axes to the
effects of irradiation: GH > TSH > ACTH > gonadotro-
pins. Long-term follow-up is mandatory.
4 Note age-appropriate growth rates and
stage of adolescent development. Accelerated growth
from sex steroids alone can occur. Occasionally sub-
clinical ACTH deficiency may develop. Formal testing
as adulthood is approached may be prudent.
13
Growth A.D. Rogol D.B. Dunger
Selected reading
Brauner R, Rappaport R: Precocious puberty
secondary to cranial irradiation for tumors distant
from hypothalamo-pituitary area. Horm Res
1985;22:7882.
Gleeson HK, Shalet SM: The impact of cancer
therapy on the endocrine system in survivors of
childhood brain tumors. Endocr Rel Cancer 2004;11:
589602.
Gurney JG, Ness KK, Stoval M, Wolden S,
Punyko JA, Neglia JP, Mertens AC, Packer RJ,
Robison LL, Sklar CA: Final height and body mass
index among adult survivors of childhood brain
cancer. J Clin Endocrinol Metab 2003;88:47314739.
Lustig, RH, Post SR, Srivannaboon K, Rose SR,
Danish RK, Burghen GA, Xiong X, Wu S, Merchant
TE: Risk factors for the development of obesity in
children surviving brain tumors. J Clin Endocrinol
Metab 2003;88:611616.
Brain irradiation
 Puberty J.-P. Bourguignon R.L. Rosenfield Precocious breast development in a girl

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 1 Precocious breast development is the occurrence of breast
tissue before the chronological age of 8 years in a girl. A different
age limit may have to be used in particular environmental and ethnic
groups (e.g. Black Americans are about 1 year ahead of White Ameri-
cans); the reader should refer to the local standards and experience.
In developed countries, the secular reduction in average timing of
puberty has apparently come to an end but the early age limits may
still further decrease. The epidemic of obesity has been incriminated.
Alternative factors are the endocrine disrupters. The tempo of devel-
opment is important information that can be obtained through a 3- to
6-month follow-up. This tempo is usually low and comparable to
normal puberty in the early variants of physiological development. In
contrast, fast progression throughout pubertal stages may be seen
in patients with precocious puberty of abnormal organic or idiopath-
ic origin.
2 History is critical regarding disorders or symptoms orient-
ing towards an organic CNS cause. In several countries, migration
for international adoption has emerged as a new cause of precocious
puberty.
3 Associated signs may involve pubic and axillary hair,
swelling of vulvar mucosa, vaginal discharge or bleeding. Sexual
hair is often absent early.
4 Height velocity shows early and rapid acceleration under
estrogen action. It should be calculated retrospectively (when data
from school or medical records are available) or prospectively. In-
creased height velocity should be > the 90th centile (78 cm/year be-
tween 5 and 9 years of age). When height velocity is unexpectedly
low while the other findings indicate increased estrogen activity, GH
deficiency could be associated with central precocious puberty, par-
ticularly if there is any organic cause. Then, a prepubertal level of
serum IGF-1 is suggestive and GH stimulation test should be consid-
ered (see p. 6). Likewise, hypothyroidism should be ruled out since it
can account for sexual precocity and slow height velocity.
5 BA (X-ray film of left hand and wrist read according to
standards such as Greulich and Pyle) advancement means at least 2
SDs ahead of chronological age (12 years depending on age). When
increased estrogen secretion has occurred very recently, BA ad-
vancement may not be significant initially.
6 Infantile mammoplasia is a self-limited early form of pre-
mature thelarche which may develop during the neonatal period or
infancy. Follow-up involves assessment of breast development and
15 growth rate every 36 months as well as bone maturation at 1- to
2-year intervals. If a persisting estrogenic effect is suspected, pelvic
ultrasound will be requested. If ultrasound is prepubertal, no endo-
crine assessment is mandatory but follow-up is necessary. Indeed,
this condition may rarely be the initial manifestation of true sexual
precocity.
Puberty
7 Pelvic ultrasound is a noninvasive method to evaluate
morphology and size of the ovaries and the uterus. The ovaries of the
prepubertal child may normally have a few follicles or microcysts
up to 4 mm in diameter. The volume of the prepubertal uterus should
be 2 ml (length 4 cm). Additional information comes from the
Doppler study of uterine vessel resistance. Early pubertal stages are
associated with a reduced pulsatility index. Pelvic ultrasound is pref-
erable to the vaginal smear which provides an alternative but inva-
sive method to assess estrogenization of the female genital tract.
Plasma estradiol measurements are not reliable unless an assay sen-
sitive to <10 pg/ml is used, and cyclic fluctuations must be taken into
consideration in interpreting the value. In some patients seen very
early during puberty, pelvic ultrasound may not yet show evidence
of an estrogenic effect while measurement of the gonadotropins will
provide evidence of CPP.
8 Gonadotropin secretion (FSH and LH) can be assessed in
different ways. A classical manner is the measurement of plasma
gonadotropins before,
20 min, and 60 min after a bolus injection of GnRH at a dose of 1 g/
kg (max. 100 g). Typically, the secretory response of FSH predomi-
nates while the LH response is low in premature thelarche. In con-
trast, LH response shows a characteristic pubertal increase in CPP
and the response of both FSH and LH is low in peripheral sexual pre-
cocity. Some authors have suggested the use of urinary gonadotro-
pin measurement as a convenient and reliable index. The critical is-
sue is the availability of normative values to interpret the data ob-
tained from the laboratory.
9 Premature thelarche is usually a self-limited condition but
may be the initial manifestation of CPP and requires clinical follow-
up of growth and pubertal development.
10 CNS imaging is required when gonadotropin secretion
shows a pubertal secretory pattern indicating hypothalamopituitary
maturation. Though optimal imaging of this region is provided by
MRI, a CT scan is informative as well.
11 Idiopathic CPP (or complete, true precocious puberty) is
diagnosed when the history, physical examination and imaging of
the CNS do not indicate any possible etiology or mechanism. In girls,
idiopathic CPP is about 45 times more common than organic CPP
which involves causes such as CNS tumors.
12 It is now recognized that there is a continuum of conditions
between premature thelarche and idiopathic CPP, with partial evi-
dence of premature estrogenization besides breast development.
Such conditions involve the slowly progressive variants of CPP and
advanced PP starting at borderline age, for which no treatment is
usually required, although follow-up is necessary.
J.-P. Bourguignon R.L. Rosenfield Precocious breast development in a girl
13 GnRH agonist therapy, particularly the long-acting forms
given as i.m. injections every 4 weeks or every 3 months, is the treat-
ment of choice of CPP. The promoting effects on adult height are lim-
ited when PP started after 6 years but psychosocial aspects may still
provide an indication. Cyproterone or medroxyprogesterone show
less-specific and more-undesirable (glucocorticoid-like) effects.
They can be considered when adult stature is not an objective while
arrest of puberty and menses is wanted, e.g. in the severely mentally
retarded.
14 PPP involves estrogens of ovarian, adrenal or exogenous
origin. True sexual precocity may rarely be caused by intracranial
human CG-producing germ cell tumors. A rare form of PPP can be
associated with severe juvenile hypothyroidism and is reversible un-
der thyroxine substitution. The advanced hypothalamic maturation
resulting from PPP may secondarily cause CPP. Ovarian imaging can
be initially obtained through pelvic echography, while reliable adre-
nal imaging usually requires a CT or MRI scan.
15 McCune-Albright syndrome results from tissue-specific
auto-activating mutation in the signaling G-protein system (constitu-
tive mutation only observable in cells from affected tissues). It asso-
ciates caf-au-lait spots and dysplastic lesions of the long bones. Ca-
f-au-lait spots are also observed in neurofibromatosis which can be
associated with CPP and adrenal tumors as well.
Selected reading
Feuillan P, Merke D, Leschek EW, Cutler GB Jr: Use of aromatase
inhibitors in precocious puberty. Endocrine-Related Cancer
1999;6:303306.
Himes JH: Examining the evidence for recent secular changes in
the timing of puberty in US children in light of increases in the
prevalence of obesity. Mol Cell Endocrinol 2006;254255:1321.
Lebrethon MC, Bourguignon JP: Central and peripheral isosexual
precocious puberty. Curr Opin Endocr Diab 2001;8:1722.
Parent AS, Teilmann G, Juul A, Skakkebaek N, Toppari J,
Bourguignon JP: The timing of normal puberty and the age limits
of sexual precocity: variations around the world, secular trends
and changes after migration. Endocr Rev 2003;24:668693.
203.64.11.45 - 1/29/2015 6:38:40 PM
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 Puberty J.-P. Bourguignon R.L. Rosenfield Precocious genital development in a boy

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 1 Precocious genital development is the in-
crease in penile length before the chronological age of
9 years in a boy. A different age limit may have to be
used in particular environmental and ethnic groups;
the reader should refer to the local standards and
experience. In a prepubertal boy aged 49 years,
mean stretched penile length is 6 cm (normal range:
48 cm). Usually, other signs of androgen action such
as pubic hair development and changes in scrotal size,
texture and pigmentation are seen as well. Notewor-
thy, precocious puberty is much less frequent in boys
than in girls.
2 Increased height velocity means >6.57.5
cm/year between 5 and 9 years of age and advanced
BA means 2 SDS ahead of chronological age, which
represents 12 years depending on age. When in-
creased androgen secretion has occurred very recent-
ly, these effects may not be obvious.
3 Macroorchidism without virilization may
result from severe hypothyroidism where markedly
elevated thyrotropin (TSH) secretion might stimulate
the FSH receptor. This rare condition is reversible un-
der thyroxine substitution. Another condition which
may associate mental retardation and macroorchidism
is the fragile X syndrome.
4 Testicular volume estimate using Prader or-
chidometer is normally 3 ml (longest axis <2.5 cm) in
a prepubertal boy. In the physiological sequence of
male pubertal changes, an increase in testicular vol-
ume usually precedes onset of penile growth.
17
Puberty
5 Testosterone should be measured in a sam-
ple obtained early in the morning since the pubertal
increase in serum levels resulting from the sleep-as-
sociated increase in gonadotropin secretion is best
observable at that time. Normal prepubertal levels are
<1 nmol/l (1 nmol/l = 289 ng/ml).
6 17-OH-progesterone should be measured in
the early morning as well since circadian variations in
serum levels peak at that time. Normal levels should
not exceed 2 nmol/l (1 nmol/l = 330 ng/l).
7 For discussion about gonadotropin secre-
tion, see p. 14.
8 Though optimal imaging of this region is
provided by the MRI scan, a computerized tomography
scan is informative as well.
9 Organic CPP is more frequent than idiopath-
ic CPP in boys (as opposed to girls).
10 GnRH agonist therapy is very effective in
boys with CPP.
11 Testotoxicosis, also named familial male-
limited pseudoprecocious puberty, is an autosomal-
dominant or sporadic disorder resulting from constitu-
tively activating point mutation in the LH/hCG receptor
gene. DNA analysis may confirm the mutation. Alter-
natively, activating mutation in the stimulatory subunit
of the G protein system may be involved. This disor-
der, as the others associated with PPP, may second-
arily trigger CPP.
J.-P. Bourguignon R.L. Rosenfield
12 Ketoconazole is an inhibitor of several steps
in the biosynthesis of adrenal and gonadal steroids,
while spironolactone is an antiandrogen. Aromatase
inhibitors are used as well.
13 Tumors secreting hCG may be seen in boys
with some increase in testicular size, as well as in boys
with testes of prepubertal size. CG-secreting tumors
are usually localized in the liver. CNS tumors such as
pinealomas or dysgerminomas may also secrete the
-subunit of hCG. -FP is another marker of those tu-
mors. hCG-producing tumors have also been localized
in the mediastinum.
14 Exogenous androgens and anabolic steroids
are a rare cause of peripheral precocious puberty.
15 Testicular imaging can be initially obtained
using echography with computerized tomography or
MRI scan for confirmation purposes. Ultrasound imag-
ing of the adrenals is not very reliable and a computer-
ized tomography scan will usually be required.
16 CAH and its diagnosis and treatment are
discussed in the chapter on precocious pubarche
(p. 18) and in a specific chapter (p. 52). A rare disorder
which can mimic nonclassical CAH and causes PPP
is generalized resistance to glucocorticoids.
Selected reading
Lebrethon MC, Bourguignon JP: Central and
peripheral isosexual precocious puberty. Curr Opin
Endocr Diab 2001;8:1722.
203.64.11.45 - 1/29/2015 6:38:40 PM
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Downloaded by:
Precocious genital development in a boy
 Puberty J.-P. Bourguignon R.L. Rosenfield Precocious pubarche

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 1 Precocious pubarche is defined as the oc-
currence of pubic hair before the chronological age of
8 years in a girl and 9 years in a boy. Axillary hair may
be associated with pubic hair or may be isolated. It is
different from hypertrichosis which involves overall
body hair as seen particularly in some ethnic groups
or during treatment with drugs such as phenytoins.
2 Virilization involves any of the following
signs: clitoral hypertrophy in girls; changes in scrotal
size, texture and pigmentation and increased penile
size in boys. Microcomedones and changed body
odors are commonly associated in both sexes.
3 The growth curve should be drawn using
retrospective or prospective data from school or medi-
cal records. Height velocity should be calculated as
cm/year. Growth acceleration is indicated by a change
in centile channel of height and height velocity which
should increase above the 90th centile (6.58 cm/year
between 5 and 8 years of age). When previous height
data are not available, a 3- to 6-month follow-up is
warranted.
4 Bone age is assessed using an X-ray film of
left hand and wrist. The reading should be primarily
based on radial and cubital epiphyses, metacarpals
and phalanges, with reference to standards such as
that of Greulich and Pyle. At 78 years of age, a signifi-
cant advancement of bone age (2 SDS ahead) equates
2 years ahead of chronological age.
5 DHEAS is the sulfated form of DHEA, a 5
androgen which is predominantly of adrenal origin in
normal conditions. The circulating level of DHEAS is
low between 0.5 and 6 years (<30 g/dl, according to
most assays). Then, due to adrenarche, it starts in-
creasing gradually till the age of 16 years, at which
time it is >80 g/dl (average 120; upper limit 250 g/dl
in girls and 400 g/dl in boys). This increase is consis-
tent with adrenarche (100 nmol/l = 3.9 g/dl).
6 Serum androstenedione is a 4 androgen of
mixed adrenal and gonadal origin. It is mainly pro-
duced by the adrenal gland (during adrenarche) until
puberty (gonadarche) after which the gonads account
19 for two thirds of the production. The circulating level is
low between 0.5 and 6 years. Normal levels between 6
and 9 years should be below 75 ng/dl in both sexes
according to most assays that use preparatory chro-
matography (1 nmol/l = 28.7 ng/dl).
Puberty
7 Testosterone is a 4 androgen of mixed ad-
renal and gonadal origin. It is mainly produced by the
adrenal gland (during adrenarche) until gonadarche,
after which the ovaries account for half in girls and the
testes for 95% in boys. The circulating level should be
below 30 ng/dl between 0.5 and 9 years of age in both
sexes (1 nmol/l = 28.9 ng/dl).
8 17-OHP is the substrate of 21-hydroxylase in
the cortisol biosynthetic pathway. This steroid shows
normal circadian variations with peak levels obtained
around 8:00 a.m. which is the best time for blood sam-
pling to measure 17-OHP. In a prepubertal subject, the
serum levels should be below 120 ng/dl (1 nmol/l = 33
ng/dl).
9 Premature adrenarche is characterized by
levels of DHEAS and, to a lesser extent, androstenedi-
one in the early pubertal range with normal testoster-
one and 17-OHP levels. This is a benign condition not
requiring any treatment. It requires follow-up because
some of these patients, particularly those with DHEAS
over 140 g/dl or androstenedione over 75 ng/dl, will
later develop PCOS. There is some evidence that in
subjects born with intrauterine growth retardation,
premature adrenarche could be part of a spectrum of
disorders throughout life including ovarian hyperan-
drogenism (see p. 32), reduced sensitivity to insulin
and metabolic syndrome.
10 Nonclassic CAH is a late expression of a
mild deficit in adrenal enzymes involved in steroid bio-
synthesis. The most frequently affected enzyme is
21-OHD. After premature adrenarche, nonclassic CAH
is the most common diagnosis in a patient with preco-
cious pubarche.
11 The ACTH stimulation test consists of i.v.
injection of 0.1 mg of short-acting tetracosactide (8:00
a.m., fasting state) and blood collection before injec-
tion and after 60 min for measurement of cortisol and
17-OHP. In normal subjects, the peak level of 17-OHP
should not exceed 650 ng/dl. Levels higher than 1,200
ng/dl are required for diagnosis of nonclassic CAH.
12 Hydrocortisone replacement therapy should
be given in a daily dosage of 1020 mg/m2 divided into
34 daily doses using the least effective dose to nor-
malize 17-OHP serum levels and the rates of growth
and bone maturation.
J.-P. Bourguignon R.L. Rosenfield
13 Genetic counseling is warranted in nonclas-
sic CAH which is an autosomal-recessive disorder.
When available, molecular biology studies of 21-OHD
gene are helpful.
14 Typically, adrenal tumors result in elevated
DHEAS levels while ovarian tumors cause elevated
serum levels of 4 to a greater extent than 17-OHP.
15 The dexamethasone suppression test con-
sists of administration of 20 g/kg of dexamethasone
every 6 h for 36 days and study of serum cortisol and
androgen levels. Nonsuppressibility of serum andro-
gen levels indicates a non-adrenal origin or an autono-
mous tumor.
16 Adrenal-ovarian imaging can be easily ob-
tained through ultrasonography. This technique has,
however, a limited sensitivity, particularly for adrenal
tumors, and a CT or MRI scan may be required in the
absence of any echographic anomaly if the suspicion
of virilization is high.
17 For discussion about sexual precocity in
boys, see p. 16.
18 Exogenous androgens are a rare cause of
virilization. The use of anabolic steroids may also
cause premature development of pubic hair.
Selected reading
Rosenfield RL: Identifying children at risk of
polycystic ovary syndrome. J Clin Endocrinol Metab
2007;92:787796.
Witchel SF: Puberty and polycystic ovary syndrome.
Mol Cell Endocrinol 2006;254255:146153.
203.64.11.45 - 1/29/2015 6:38:40 PM
Kainan University
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Precocious pubarche
 Puberty N. Zuckerman-Levin Z. Hochberg R.L. Rosenfield Gynecomastia

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 1 Obesity often causes prominent breasts that
do not contain a core of true breast tissue (adipomas-
tia). Ultrasound may sometimes be useful to distin-
guish between ambiguous and true breast tissue. Un-
like true gynecomastia, pseudogynecomastia is not
associated with pain or tenderness. However, forma-
tion of E1 by aromatization of precursors in fat tissue
may cause coincidental true gynecomastia. The de-
gree of gynecomastia correlates with BMI. Other
causes of pseudogynecomastia are mastitis (charac-
terized by extreme tenderness) or breast tumor (sug-
gested by bloody discharge or hard and/or irregular
consistency of the breast).
2 The causes of gynecomastia can be summa-
rized as being estrogen excess, androgen deficiency,
or androgen/estrogen imbalance. Estrogen exposure
may be transcutaneous (e.g. body lotion exposure via
sexual contacts), by ingestion (phytoestrogens), or by
inhalation (marijuana). Anabolic steroids, including
testosterone, may cause gynecomastia. Androgen an-
tagonists capable of causing hypogonadism include
spironolactone, ketoconazole and omperazole. Radio-
therapy and radiomimetic drugs like cyclophospha-
mide, which cause hypogonadism, bring about gyne-
comastia.
3 Chronic liver disease is associated with de-
creased estrogen clearance, elevated SHBG and de-
creased free testosterone.
4 Thyrotoxicosis is associated with increased
extraglandular aromatase activity, increased SHBG,
decreased free testosterone and elevated estrogen to
testosterone ratio.
5 Family history is occasionally helpful in
indicating one of the familial disorders noted below.
More often, a positive family history is simply helpful
in emphasizing the normalcy of the most common
cause of breast enlargement, physiologic pubertal
gynecomastia.
6 Gynecomastia with no pubic hair indicates
estrogenic activity only, while the presence of pubic
hair suggests androgen activity.
21
7 Feminizing disorders should be character-
ized for their pattern of hormone secretion with
respect to steroid intermediates (e.g. progesterone,
17-hydroxyprogesterone, androstenedione, dehydro-
epiandrosterone). This will permit early detection of
recurrence in case a tumor is diagnosed and removed.
Puberty
8 Feminizing tumors are of testicular (Leydig,
Sertoli, germ cell tumor) or adrenal origin. Hyperpig-
mentation of the lips or family history of colon cancer
should suggest Peutz-Jeghers syndrome, in which
feminization is due to Sertoli cell tumors of the testes
which are often bilateral. Feminizing testicular tumors
may be unilateral, in which case the contralateral testis
is small.
Adrenal feminizing tumors are often associated with
increased 17-ketosteroid production and mild viriliza-
tion, with small testes.
9 E1 and E2 mass units may be converted to SI
units by multiplying by 3.72 (pm).
10 Imaging study of choice for adrenals is com-
puted tomography (CT), and for testes ultrasonogra-
phy or MRI.
11 Aromatase excess syndrome (familial aro-
matization excess) is an autosomal-dominant disorder
caused by a gain-of-function mutation in the aroma-
tase gene. It is characterized by gynecomastia, prema-
ture growth spurt, advanced bone maturation, de-
creased adult height and disproportionate elevation of
serum estrogens with normal androgen levels. Mas-
tectomy is indicated.
12 The testes typically grow through pubertal
stages ahead of pubic hair; reversal of this pattern sug-
gests the testes to be inappropriately small. Occasion-
ally, there is modest asymmetry of the testes at the
onset of puberty, but marked asymmetry suggests an
underlying mass.
13 Normal FSH levels do not rule out gonado-
tropin deficiency. To convert testosterone mass units,
multiply by 0.0347 (nm).
14 Karyotype is indicated to distinguish Kline-
felter syndrome from other causes of primary hypogo-
nadism, such as orchitis.
15 hCG-secreting tumors can arise from tes-
ticular or extragonadal germ cell tumors, dysgermino-
mas of the gonads or CNS, or hCG-secreting hepato-
blastoma. Those of the testes can be so small as to be
detectable only by spermatic vein catheterization.
16 Congenital adrenal hyperplasia due to 11-
OHase deficiency has on occasion been reported to
present with gynecomastia.
N. Zuckerman-Levin Z. Hochberg R.L. Rosenfield
17 Gynecomastia occurs in most boys during
puberty, and is by far the most frequent cause of ado-
lescent gynecomastia. It is typically transient and mild,
lasting less than 3 years. Occasionally, pubertal gyne-
comastia reaches proportions found normally only in
mid-adolescent females (macromastia). When this
occurs, it will persist.
18 Treatment for gynecomastia. Plastic surgery
through a periareolar incision by an experienced plas-
tic surgeon is definitive. There is no effective standard
drug therapy: antiestrogens and aromatase inhibitors
may have a limited effect, and dihydrotestosterone
cream has been reported to be effective, but experi-
ence is limited. Testosterone replacement therapy is
indicated when hypoandrogenism is persistent, but
this may aggravate the gynecomastia.
19 The clinical phenotype of gynecomastia,
hypospadias and/or cryptorchidism is similar in partial
androgen insensitivity syndrome, 17-ketosteroid re-
ductase deficiency, and in 5-reductase 2 deficiency.
Determination of plasma steroid intermediates is indi-
cated. The ratio of urinary metabolites of dihydrotes-
tosterone to testosterone makes the diagnosis of 5-
reductase deficiency. In 17-ketosteroid reductase defi-
ciency androstendione levels are elevated. However, a
definitive distinction between these entities depends
upon mutation analysis.
Selected reading
Carlson HE, Kane P, Lei ZM, Li X, Rao CV:
Presence of luteinizing hormone/human chorionic
gonadotropin receptors in male breast tissues.
J Clin Endocrinol Metab 2004;89:41194123.
Grumbach MM, Auchus RJ: Estrogen: consequenc-
es and implications of human mutations in synthe-
sis and action. J Clin Endocrinol Metab
1999;84:46774694.
Startakis CA, Vottero A, Brodie A, Kirschner LS,
DeAtkine D, Lu Q, Yue W, Mitsiades CS, Flor AW,
Chrousos GP: The aromatase excess syndrome is
associated with feminization of both sexes and
autosomal dominant transmission of aberrant P450
aromatase gene transcription. J Clin Endocrinol
Metab 1998;83:13481357.
203.64.11.45 - 1/29/2015 6:38:40 PM
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Gynecomastia
 Puberty J.-P. Bourguignon R.L. Rosenfield Delayed or absent testicular development

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 1 Delayed testicular development means absence of puber-
tal changes in testicular volume (3 ml, Prader orchidometer) in a
boy after 13.514 years of chronological age. A different age limit
may have to be used in particular environmental and ethnic groups;
the reader should refer to the local standards and experience.
2 A history of radio- or chemotherapy or orchidopexy may
indicate primary testicular failure. Bilateral cryptorchidism or anos-
mia may suggest gonadotropin deficiency. Chronic disorders such
as celiac disease may cause secondary and temporary delay of pu-
berty. History may also point to a familial factor with delayed men-
arche or growth spurt in parents and siblings. This is consistent with
the observation that genetic factors determine over half of the vari-
ance in pubertal timing and suggests a simple familial delay if the
parent condition was ultimately spontaneously resolved.
3 The signs of virilization of the male genitalia involve in-
crease in penile size, occurrence of pubic hair and changes in scrotal
size, pigmentation and texture. Because testicular enlargement usu-
ally precedes the signs of virilization, these signs are expected to be
absent in boys with prepubertal testes. In many patients seen for
delayed puberty, a pubertal testicular volume can be detected at the
first exam. Pubarche while the testes are still small may indicate ei-
ther adrenarche or early puberty (gonadarche).
4 Height velocity is reduced and stature usually short in dis-
orders involving GH deficiency, as is often the case in constitutional
delay of growth and puberty (CDGP). CDGP and gonadotropin-defi-
cient patients may be genetically tall or short, but height velocity
falls after about 11 years of age, when they fail to enter puberty. Stat-
ure may be tall in genetic disorders associated with primary gonadal
failure such as in Klinefelter syndrome. Height velocity is reduced (as
opposed to weight velocity) in Cushing syndrome. Weight excess is
also observed in some genetic syndromes (e.g. Prader-Willi) result-
ing in hypogonadism. Substantial gynecomastia suggests hypogo-
nadism. Bone age is frequently and variably delayed. It does not pro-
vide a key to differential diagnosis while it can be informative regard-
ing growth potential, anticipation of the onset of neuroendocrine pu-
berty in CDGP, and interpretation of whether prepubertal gonadotro-
pin levels are inappropriate for the degree of delay.
5 The gonadotropin secretion (FSH and LH) assessed
through a single basal determination can be increased (particularly
FSH) in primary gonadal failure. When ultrasensitive assays are
used, basal levels >0.6 U/l suggest CDGP rather than gonadotropin
deficiency. In the other instances, dynamic testing procedures such
23 as the classical administration of synthetic GnRH (1 g/kg i.v.) are
required. In some boys with CDGP, a pubertal pattern of response
(LH predominating over FSH) can be observed. A prepubertal re-
sponse is seen in some patients with CDGP as well as in gonadotro-
pin deficiency. Therefore, follow-up of the patient is often warranted
before a definitive diagnosis can be made.
Puberty
6 Serum testosterone levels should be preferably measured
using blood obtained in the early morning, around 8:00 a.m. when
testosterone secretion is physiologically increased by the sleep-as-
sociated elevation of gonadotropin secretion which occurs early dur-
ing puberty. While a pubertal level of testosterone >30 ng/dl (1 nmol/
l) suggests of CDGP, a low level is consistent with primary or second-
ary hypogonadism but does not exclude CDGP.
7 Primary testicular failure may result from different condi-
tions (testicular torsion, orchitis, surgical excision, congenital defi-
ciency, etc.). Hypoandrogenism requires testosterone replacement
therapy. Using long-acting testosterone esters (e.g. enanthate or cy-
pionate) injected i.m., we currently recommend to start treatment at
1314 years of age with administration of 50 mg every 4 weeks for the
first 6 months; this is one-eighth of the adult replacement dose. We
then double the dose progressively at 6-month intervals to attain the
adult replacement regimen, i.e. 200 mg every 2 weeks. These prepa-
rations result, however, in nonphysiologic variations in serum testos-
terone levels and will hopefully be replaced by transdermal patches
or gels capable of delivering the small testosterone doses optimal for
the induction of puberty.
8 Isolated gonadotropin deficiency may be caused by differ-
ent etiologies (genetic or sporadic, idiopathic or organic). The fea-
tures of Kallmann syndrome such as anosmia or hyposmia only de-
tectable through olfactometry should be looked for. Gonadotropin
deficiency may also occur in syndromes which will be suspected
from findings at physical examination such as obesity, hypotonia,
and mental retardation (Prader-Willi) or obesity and polydactyly
(Laurence-Moon-Biedl). Since hyperprolactinemic states may ac-
count for gonadotropin deficiency, serum prolactin (PRL) levels
should be assessed. Genetic studies can be considered including
KAL, FGFR1 and the recently described GPR54.
9 Elevated serum PRL may result from a PRL-secreting pitu-
itary adenoma, functional stalk section from a suprasellar tumor, or
hypothyroidism. Additional W/U includes TRH testing and CNS imag-
ing.
10 Multiple pituitary hormone deficiency can involve second-
ary hypogonadism whereas isolated GH deficiency can be associated
with delayed puberty secondary to the overall delayed process of
growth and maturation, particularly when diagnosis is late in the ad-
olescent period. Determination of serum levels of T4, IGF-1 and PRL
are useful as a first diagnostic approach. Priming of GH secretion
with exogenous sex steroids (50 mg of long-acting testosterone ester
i.m. 1 week before testing) may be critical for a correct diagnosis of
GH deficiency in patients with delayed puberty. Further details on
assessment of pituitary function are proposed on pp. 4, 76.
J.-P. Bourguignon R.L. Rosenfield Delayed or absent testicular development
11 In most patients with pituitary hormone deficiency, CNS
imaging is necessary to rule out organic causes (particularly tumors)
in the hypothalamopituitary region. A MRI scan may provide more
information than a computerized tomography scan.
12 For the treatment of gonadotropin-deficient patients, we
use testosterone initially. When an increase in testicular size and
spermatogenesis are desired, these may be achieved through the
administration of gonadotropins, recombinant forms becoming
available. In patients with isolated GH deficiency, GH therapy (see
p. 6) will usually result in spontaneous pubertal development.
13 Constitutional or temporary delay of puberty is by far
the most common condition with delayed testicular development.
A temporary treatment using i.m. injections of long-acting testoster-
one esters in a monthly dose of 50 mg given for 6 months can be
proposed. This may be particularly helpful when psychosocial dis-
tress resulting from CDGP is obvious.
14 Primary germinal failure involves genetic disorders such
as Klinefelter syndrome (XXY karyotype) as well as effects of irradia-
tion or cytostatic drugs. In some patients, Leydig cell function shows
some impairment and low serum testosterone levels require replace-
ment therapy.
15 Cushing syndrome can be diagnosed initially through
assessment of free cortisol in 24-hour urine and dexamethasone
suppression test (see p. 48).
Selected reading
Dunkel L: Use of aromatase inhibitors to increase final height.
Mol Cell Endocrinol 2006;254255:207216.
Sedlmeyer IL, Palmert MR: Delayed puberty: analysis of a large
case series from an academic center. J Clin Endocrinol Metab
2002;87:16131620.
203.64.11.45 - 1/29/2015 6:38:40 PM
Kainan University
Downloaded by:
 Puberty J.-P. Bourguignon R.L. Rosenfield Delayed or absent breast development

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 1 Delayed breast development means ab-
sence of breast tissue development in a girl after 13
13.5 years chronological age. A different age limit may
have to be used in a particular environmental or under
ethnic conditions; the reader should refer to the local
standards and experience. The presence of pubic hair
should be evaluated but pubarche can occur under the
action of adrenal androgens independent of ovarian
maturation.
2 A history of radio- or chemotherapy or sur-
gery for femoral hernia may point to primary ovarian
failure. Anosmia is suggestive of gonadotropin defi-
ciency. A history of chronic disorders such as rheu-
matic, celiac or inflammatory bowel disease and he-
molytic anemias will suggest secondary and tempo-
rary delay of puberty. Anorexia nervosa or anorexia
resulting from fear of obesity are additional causes of
temporary delay. Athletes, particularly dancers and
gymnasts, are at risk for delayed puberty. History may
also point to a familial factor with delayed menarche
or growth spurt in parents and siblings. This is consis-
tent with the observation that genetic factors deter-
mine over 50% of the variance in pubertal timing and
suggests a simple familial delay if the parent condition
was ultimately spontaneously resolved.
3 Height velocity (and stature) should be eval-
uated using appropriate growth charts. Specific charts
for Turner patients are available as well. Height veloc-
ity is usually normal in patients with gonadotropin de-
ficiency until puberty is delayed, at which time growth
rate may slow; these patients may or may not be short
prepubertally. Bone age (BA) is frequently and variably
delayed. It does not provide a key to differential diag-
nosis, although it can be informative regarding growth
potential and in anticipating the onset of neuroendo-
crine puberty.
4 Dysmorphic features of Turner syndrome
should be carefully looked for. In some patients, only
a few mild signs or even no signs can be recognized
(see p. 44). Then, the karyotype will be the only way to
diagnosis. Among Turner girls, up to 1/4 may develop
some degree of puberty spontaneously.
25
Puberty
5 The gonadotropin secretion (FSH and LH)
assessed through a single basal determination be-
comes increased (particularly FSH) in primary ovarian
failure and Turner syndrome once neuroendocrine pu-
berty begins, which is ordinarily at a BA of 1011
years. In the other instances, dynamic testing proce-
dures such as the classical administration of synthetic
GnRH (1 g/kg i.v.) are required. In some girls with
constitutional delay of puberty and growth (CDGP), a
pubertal pattern of response (LH predominating over
FSH) can be observed. A prepubertal response is seen
in some patients with CDGP as well as in gonadotropin
deficiency. Therefore, follow-up of the patient is often
warranted before a definitive diagnosis can be made.
6 Primary ovarian failure may result from au-
toimmune disorder, cytotoxic drugs or irradiation.
Rare causes include inactivating mutation of gonado-
tropin receptor or hereditary premature menopause
resulting from point mutation of the X chromosome.
Disorders of protein glycosylation may cause elevated
immunoreactive gonadotropins while there is no pri-
mary ovarian failure. In a patient with normal stature
and hypergonadotrophic hypogonadism of no known
etiology, a karyotype study is recommended to rule
out Turner syndrome.
7 Isolated gonadotropin deficiency may in-
volve different etiologies. Genetic studies can be con-
sidered including KAL, FGFR1 and the recently de-
scribed GPR54. Since hyperprolactinemic states may
account for hypogonadism, serum PRL levels should
be assessed. Some of these patients will be found to
have PRL-secreting adenoma which will be document-
ed through imaging of the hypothalamic-pituitary re-
gion. In gonadotropin-deficient patients, replacement
therapy is required using estrogens initially and subse-
quently adding progestin. We recommend starting
with about one-tenth to one-eighth of the adult re-
placement dose of estrogen. This equates with a start-
ing dose of depot (intramuscular) estradiol (E2) 0.20.4
mg/month, transdermal E2 6.25 g daily, oral micron-
ized E2 0.25 mg daily, or daily oral ethinyl E2 0.1 g/kg
during the first 612 months of treatment and then in-
creasing gradually to an adult dose over 2 years. Cyclic
administration of a low-dose estrogen-progestin prep-
aration can be used for the 3rd year in order to obtain
menstruations.
J.-P. Bourguignon R.L. Rosenfield
8 Multiple pituitary hormone deficiency can
involve secondary hypogonadism whereas isolated
GH deficiency can be associated with delayed puberty
secondary to the overall delayed process of growth
and maturation, particularly when diagnosis is late, in
the adolescent period. Determination of serum levels
of T4, IGF-1 and PRL are useful as a first diagnostic ap-
proach. Isolated low T4 may suggest hypothyroidism
(primary or secondary) as a cause of delayed puberty.
Priming of GH secretion with exogenous sex steroids
(3050 g of ethinyl estradiol per day orally, for 3 days
before testing) may be critical for a correct diagnosis
of GH deficiency in patients with delayed puberty (see
pp. 4, 78).
9 CNS imaging is necessary to rule out or-
ganic causes (particularly tumors) in the hypothalamo-
pituitary region in most patients with pituitary hor-
mone deficiency. A MRI scan may provide more infor-
mation than a computerized tomography scan.
10 Constitutional or temporary delay of puber-
ty is less common in girls than in boys. Some family
history of CDGP may exist. Follow-up should confirm
spontaneous pubertal development. When puberty is
delayed in girls due to chronic disease, food restriction
(fear of obesity) or intensive physical training, pubertal
development may resume after appropriate therapy of
the underlying disease or restoration of normal food
intake or reduction of physical training. In some CDGP
girls, temporary estrogen therapy may be considered.
Long-term outcome of bone mineral content is a mat-
ter of concern in girls with delayed puberty.
11 Turner syndrome usually benefits from
appropriate treatment using GH and sex steroids (see
p. 44).
Selected reading
Lee JM, Appugliese D, Kaciroti N, Corwyn RF,
Bradley RH, Lumeng JC: Weight status in young
girls and the onset of puberty. Pediatrics 2007;119:
e624e630.
Rosenfield RL, Kiess W, de Muinck Keizer-Schrama S:
Physiologic induction of puberty in Turner syn-
drome with very low-dose estradiol. Int Congr Ser
2006;1298:7179.
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Delayed or absent breast development
 Puberty R.L. Rosenfield Primary amenorrhea and abnormal genital anatomy

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 Primary amenorrhea is defined as absence of a spon-
taneous menstrual period by 15 years of age, which is
approximately 2.5 SD later than average in North
America. Menarche is delayed in children with consti-
tutionally delayed puberty; the normal span between
the onset of breast development and menarche aver-
ages 2.3 1.0 (SD) years. The normal age of menarche
varies, however, among ethnic groups and with eco-
nomic status. There are little if any persisting secular
changes in developed countries.
1 Prime among the causes of primary amen-
orrhea are a variety of chronic disorders that retard or
attenuate growth if they occur prior to epiphyseal fu-
sion. The work-up should be initiated with history and
examination, a chronic disease panel (complete blood
count and differential, sedimentation rate, comprehen-
sive metabolic panel, celiac panel, thyroid panel, corti-
sol and insulin-like growth factor-I levels, and urinaly-
sis), and, if the adolescent is not sexually mature, a
bone age radiograph.
2 Breast development ordinarily signifies the
onset of pubertal feminization. However, mature
breast development does not assure ongoing pubertal
estrogen secretion (see next algorithms).
3 Underweight is defined as body fat 15% or
less of body mass; this generally corresponds to BMI
<10th percentile.
4 Amenorrhea associated with low body fat
and stress can be due to eating disorders or excessive
physical activity relative to caloric intake. BMI is low in
anorexia nervosa, a symptom complex consisting of
amenorrhea, voluntary starvation, and a self-delusion-
al disturbance in the perception of body fatness. How-
ever, BMI may not accurately reflect body fat in serious
athletes (e.g., dancers, gymnasts, runners), who have
a disproportionately great muscle mass, or bulimia
nervosa.
27
Puberty
5 FSH is preferentially elevated over LH in pri-
mary ovarian failure. However, lack of FSH elevation
rules out primary ovarian failure only when the bone
age is appropriate for puberty (11 years or more). The
most common cause of primary amenorrhea due to
primary ovarian failure is gonadal dysgenesis due to
Turner syndrome. An increasing number of girls cured
after a previous oncology condition have ovarian defi-
ciency secondary to chemotherapy. The work-up of
primary ovarian failure is considered in detail in the
next algorithm (Secondary amenorrhea and oligomen-
orrhea).
6 A low (prepubertal) LH level is more often
found in delayed puberty and gonadotropin deficiency
than a low FSH level.
7 Constitutional delay of puberty, an extreme
variation of normal, closely mimics congenital gonad-
otropin deficiency. History and examination may yield
clues to the presence of hypogonadotropic hypogo-
nadism, such as evidence of hypopituitarism (midline
facial defect, extreme short stature) or anosmia (Kall-
manns syndrome). Random LH levels in hypogonado-
tropic patients are typically below 0.15 IU/l, but often
overlap those of normal pre- and midpubertal chil-
dren. The GnRH test, measuring the gonadotropin re-
sponse to a 50- to 100-g bolus, in the premenarchial
teenager strongly suggests gonadotropin deficiency if
the LH peak is less than 7.0 IU/l by monoclonal assay.
However, the GnRH test has limitations because of
overlap between hypogonadotropic and normal teen-
ager responses. GnRH agonist testing (e.g. leuprolide
acetate injection 10 g/kg s.c.) may discriminate bet-
ter. It may not be possible to definitively establish the
diagnosis of gonadotropin deficiency until puberty
fails to begin by 16 years of age.
8 Plasma total testosterone is normally about
2070 ng/dl (0.72.4 nM), but varies somewhat among
laboratories.
R.L. Rosenfield
9 Androgen resistance is characterized by a
male plasma testosterone level (when sexual matura-
tion is complete), male karyotype (46, XY), and absent
uterus. External genitalia may be ambiguous (partial
form) or normal female (complete form).
10 The differential diagnosis of hyperan-
drogenism is shown in a following algorithm.
11 Vaginal aplasia in a girl with normal ovaries
may be associated with uterine aplasia (Rokitansky-
Kustner-Hauser syndrome). When the vagina is blind
and the uterus aplastic, this disorder must be distin-
guished from androgen resistance and, if the external
genitalia are ambiguous, other disorders of sexual dif-
ferentiation (intersex).
12 Differential diagnosis of secondary amenor-
rhea is given in the next algorithm.
Selected reading
Rosenfield RL: Puberty in the female and its disor-
ders; in Sperling M (ed): Pediatric Endocrinology,
ed 3. Philadelphia, Saunders, 2002, chap 16,
pp 455518.
Timmreck LS, Reindollar RH: Contemporary issues
in primary amenorrhea. Obstet Gynecol Clin North
Am 2003;30:287302.
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Primary amenorrhea and abnormal genital anatomy
 Puberty R.L. Rosenfield Secondary amenorrhea or oligomenorrhea

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 Secondary amenorrhea is defined as absence of men-
ses for 3 months or more after the occurrence of men-
arche. Many anovulatory disorders which cause sec-
ondary amenorrhea may alternatively cause oligo-
menorrhea (fewer than 10 periods a year) or dysfunc-
tional uterine bleeding. Adolescents require special
consideration because about half of their menstrual
cycles are anovulatory in the first 2 years of menarche,
and a mature menstrual pattern is not expected until 4
years after menarche. If irregular menstrual cycles per-
sist for 2 years after menarche, there is a 50% prob-
ability of ongoing menstrual abnormalities.
The same disorders that typically cause secondary
amenorrhea can also cause primary amenorrhea if the
disorder is sufficiently severe or early in onset.
1 Mature secondary sex characteristics are
characteristic because the occurrence of menarche
indicates a substantial degree of development of the
reproductive system.
2 Diverse disorders of many systems cause
anovulation. History may reveal excessive exercise,
symptoms of depression, gastrointestinal symptoms,
radiotherapy to the brain or pelvis, or rapid virilization.
Physical findings may include hypertension (forms of
congenital adrenal hyperplasia, chronic renal failure),
short stature (hypopituitarism, Turner syndrome,
pseudohypoparathyroidism), abnormal weight for
height (anorexia nervosa, obesity), decreased sense of
smell (Kallmanns syndrome), optic disc or visual field
abnormality (pituitary tumor), cutaneous abnormali-
ties (neurofibromatosis, lupus), goiter, galactorrhea,
hirsutism, or abdominal mass.
29
Puberty
3 In the absence of specific symptoms or
signs to direct the work-up, laboratory evaluation for
chronic disease should be performed and include:
complete blood count and differential, sedimentation
rate, comprehensive metabolic panel, celiac panel,
thyroid panel, cortisol and insulin-like growth factor-I
levels, and urinalysis.
4 Patients missing only a small portion of an
X-chromosome may not have the Turner syndrome
phenotype. Indeed, among 45,X patients the classic
Turner syndrome phenotype is found in less than one-
third (with the exception of short stature in 99%). Ovar-
ian function is sufficient for about 10% to undergo
some spontaneous pubertal development and for 5%
to experience menarche. If chromosomal studies are
normal and there is no obvious explanation for the hy-
pogonadism, special studies for fragile X premutation
and autoimmune oophoritis should be considered.
5 Autoimmune ovarian failure may be associ-
ated with tissue-specific antibodies and autoimmune
endocrinopathies such as chronic autoimmune thy-
roiditis, diabetes, adrenal insufficiency, and hypopara-
thyroidism. Ovarian biopsy is of no prognostic or ther-
apeutic significance. Nonendocrine autoimmune dis-
orders may occur, such as mucocutaneous candidia-
sis, celiac disease, and chronic hepatitis. Rare gene
mutations causing ovarian insufficiency include ste-
roidogenic defects that affect mineralocorticoid status
(17-hydroxylase deficiency is associated with miner-
alocorticoid excess and lipoid adrenal hyperplasia
with mineralocorticoid deficiency) and mutations of
the gonadotropins or their receptors.
6 History may provide a diagnosis, due to can-
cer chemotherapy or radiotherapy, for example. Chro-
mosomal causes of premature ovarian failure include
X-chromosome fragile site and point mutations. Other
genetic and acquired causes include gonadotropin-
resistance syndromes such as LH or FSH receptor mu-
tation, pseudohypoparathyroidism, and autoimmu-
nity. A pelvic ultrasound that shows preservation of
ovarian follicles carries some hope for fertility.
R.L. Rosenfield
7 Withdrawal bleeding in response to a 5- to
10-day course of progestin (e.g. medroxyprogester-
one acetate 10 mg HS) suggests an overall estradiol
level over 40 pg/ml. However, this is not entirely reli-
able, so in the interest of making a timely diagnosis it
is often worthwhile to go directly on to the further
studies.
6 A thin uterine stripe suggests hypoestro-
genism; a thick one suggests endometrial hyperplasia,
as may occur in polycystic ovary syndrome.
9 A single cycle of an OCP containing
3035 g ethinyl estradiol generally suffices to induce
withdrawal bleeding if the endometrial lining is intact.
10 The differential diagnosis of other anovula-
tory disorders continues in the next algorithm.
Selected reading
Rosenfield RL: Puberty in the female and its disor-
ders; in Sperling M (ed): Pediatric Endocrinology,
ed 3. Philadelphia, Saunders, 2002, chap 16,
pp 455518.
Veldhuis JD, Roemmich JN, Richmond EJ,
Bowers CY: Somatotropic and gonadotropic
axes linkages in infancy, childhood, and the
puberty-adult transition. Endocr Rev 2006;27:
101140.
203.64.11.45 - 1/29/2015 6:38:40 PM
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Secondary amenorrhea or oligomenorrhea
 Puberty R.L. Rosenfield J.-P. Bourguignon Anovulatory disorders

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 1 Anovulatory disorders should be consid-
ered in any girl with unexplained secondary amenor-
rhea or oligomenorrhea, irregular menstrual bleeding,
short cycles, or excessive menstrual bleeding. The
work-up should be initiated as indicated in the previ-
ous algorithm, with history and examination, a chronic
disease panel, pregnancy test, and gonadotropin lev-
els.
2 Once breast development has matured, the
breast contour does not substantially regress when
hypoestrogenism develops. Hypoestrogenism is sug-
gested if plasma estradiol is persistently <40 pg/ml in
an assay sensitive to <10 pg/ml; however, a single es-
tradiol level may be misleading because of cyclic or
episodic variations (1 pg/ml = 3.67 pmol/l).
3 Baseline gonadotropin levels may not be
low in gonadotropin-deficient patients, especially
according to polyclonal antibody-based assays. GnRH
testing is usually performed by assaying LH and FSH
before and 0.51.0 h after the administration of 1g/kg
GnRH intravenously. GnRH agonist testing may alter-
natively be performed by administering 10 g/kg leu-
prolide acetate subcutaneously and assaying LH and
FSH at 4 h to assess gonadotropin reserve and at 24 h
to assess the ovarian steroid response to endogenous
gonadotropin release.
4 Baseline gonadotropin levels may be nor-
mal as the ovary begins to fail, as in menopause, but
an exaggerated FSH response to GnRH and subnormal
E2 response to the gonadotropin elevation induced by
acute GnRH agonist challenge are characteristic. The
further work-up is shown in the previous algorithm.
5 Responses to GnRH may vary from nil to
normal in gonadotropin deficiency. Normal LH and
FSH responses in the presence of hypoestrogenism
indicate inadequate compensatory hypothalamic
GnRH secretion.
6 Gonadotropin deficiency may be congenital
or acquired, organic or functional. Congenital causes
include midline brain malformations or specific ge-
netic disorders such as Prader-Willi syndrome, Bradet-
31 Biedl syndrome, or Kallmann syndrome. Kallmanns,
the association of anosmia with gonadotropin defi-
ciency, occurs in both the X-linked and autosomal-re-
cessive forms. Special MRI views often demonstrate
absence of the olfactory tracts. Acquired gonadotropin
Puberty
deficiency may be secondary to a variety of organic
CNS disorders, including hypothalamic-pituitary tu-
mor, radiation damage, and empty sella syndrome.
Autoimmune hypophysitis is a rare disorder, some-
times accompanying a polyendocrine deficiency syn-
drome. The prototypic form of functional gonadotro-
pin deficiency is anorexia nervosa. Idiopathic hypogo-
nadotropic deficiency may sometimes occur in fami-
lies with anosmia, suggesting a relationship to Kall-
manns syndrome.
7 Dysfunctional uterine bleeding or menor-
rhagia not controlled by progestin or OCP therapy ad-
ditionally requires a pelvic ultrasound examination (for
genital tract tumor or feminizing tumor), coagulation
work-up (which includes platelet count, prothrombin
time, thromboplastin generation test, and bleeding
time), and consideration of the possibility of sexual
abuse.
8 The equivalent of 4 miles per day or more is
generally required before body fat stores fall to the
point where amenorrhea occurs. Either physical or
psychosocial stress may cause amenorrhea.
9 Hyperandrogenism differential diagnosis is
outlined in the next algorithm.
10 Mild forms of stress disorders associated
with low body fat (anorexia nervosa, bulimia nervosa,
and athletic amenorrhea) may cause acquired hypo-
thalamic amenorrhea, discussed next, rather than
frank gonadotropin deficiency. The low body fat con-
tent of athletic amenorrhea may not be reflected by
weight for height because of high muscularity. There-
fore, dual photon absorptiometry scan may be useful
in documenting body fat below 15%. Patients with an-
orexia nervosa may become amenorrheic before or
when weight loss begins, indicating an important psy-
chological component to the etiology. Obesity also is
associated with anovulatory cycles; the mechanisms
are not well understood, but are to some extent prob-
ably mediated by peripheral formation of estradiol and
testosterone.
R.L. Rosenfield J.-P. Bourguignon
11 Hypothalamic amenorrhea is a diagnosis of
exclusion. It is a form of partial gonadotropin deficien-
cy in which baseline estrogen secretion is normal, but
a pre-ovulatory LH surge cannot be generated. It may
result from organic CNS disorders. Functional hypo-
thalamic amenorrhea may be undernutrition- or
stress-related or idiopathic. It may be secondary to
chronic illness or result from obesity or diverse types
of endocrine dysfunction. Research studies show sub-
normal LH pulsatility or estrogen-induceability of the
LH surge.
12 Hyperprolactinemia is heterogeneous in its
presentation. Galactorrhea is found in half. Some have
normoestrogenic anovulation; this may be manifest as
hypothalamic anovulation, hyperandrogenism, dys-
functional uterine bleeding, or short luteal phase. On
the other hand, some are hypoestrogenic; these do not
have galactorrhea.
13 Hyperprolactinemia may be caused by pro-
lactinomas, which secrete excess prolactin, or may be
secondary to interruption of the pituitary stalk by large
hypothalamic-pituitary tumors or other types of CNS
injury. The latter cause variable pituitary dysfunction,
which may include complete gonadotropin deficiency
and various manifestations of hypopituitarism, includ-
ing secondary hypothyroidism.
14 Drugs, particularly neuroleptics of the phe-
nothiazone or tricyclic type, may induce hyperprolac-
tinemia. In macroprolactinemia, a variant molecule or
autoantibody formation causes a falsely elevated
prolactin level on direct immunoassay, but there is
no physiologic consequence to the macroprolac-
tinemia since the biologically available prolactin level
is normal.
Selected reading
Gillam MP, Molitch ME, Lombardi G, Colao A:
Advances in the treatment of prolactinomas.
Endocr Rev 2006;27:485534.
Minjarez DA: Abnormal bleeding in adolescents.
Semin Reprod Med 2003;21:363373.
Rosenfield RL 2002 Puberty in the female and
its disorders. In: Sperling M (ed) Pediatric Endocri-
nology, ed 3, Chap 16, Saunders, Philadelphia,
203.64.11.45 - 1/29/2015 6:38:40 PM
pp 455518.
Kainan University
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Anovulatory disorders
 Puberty R.L. Rosenfield F. Riepe W.G. Sippell Hirsutism

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 1 Hirsutism is excessive sexual hair growth on
the spectrum found in men and is a risk factor for
hyperandrogenism. It must be distinguished from
hypertrichosis, excessive hair growth in a nonsexual
pattern, which does not have a hormonal basis. A
small amount of sexual hair growth in a male pattern
is normal (Ferriman-Gallwey score <8). Risk assess-
ment for hyperandrogenemia includes more than the
degree of hirsutism. Androgen excess is not necessar-
ily expressed as hirsutism: acne vulgaris, seborrhea,
pattern alopecia, hyperhidrosis, or hidradenitis suppu-
rativa are cutaneous hirsutism equivalents and may
be alternative signs of hyperandrogenism. In some
hyperandrogenic cases, there is no cutaneous symp-
tomatology (cryptic hyperandrogenism). If the risk
factors shown next are present, even in the absence of
hirsutism, androgen excess should be considered.
2 Medications that cause hirsutism include
anabolic or androgenic steroids (consider in athletes
and patients with endometriosis or sexual dysfunc-
tion). Valproic acid, an antiepileptic drug, raises testos-
terone levels.
3 Mild hirsutism in the absence of the risk
factors shown is likely to be idiopathic and to respond
to cosmetic or dermatologic therapy. Therefore, it is
reasonable to embark on these treatments without an
endocrine evaluation.
4 Acne vulgaris of early onset or unresponsive
to ordinary dermatologic measures, including anti-
biotic therapy, or pattern balding is similarly a risk
factor for hyperandrogenism.
5 Neoplasm risk is suggested by sudden on-
set, rapid progression, virilization, or an abdominal or
pelvic mass.
33
Puberty
6 Menstrual irregularity is present in most
polycystic ovary syndrome (PCOS), which is the cause
of most hyperandrogenism. Acanthosis nigricans
and central obesity may be the presenting complaint.
They are linked to the insulin resistance that is often
associated with PCOS.
7 The most common hyperandrogenic endo-
crine disorder other than PCOS in adolescents is
nonclassic congenital adrenal hyperplasia (CAH).
Risk is increased if family history is positive or in
certain ethnic groups, such as Ashkenazi Jews (preva-
lence 1:27), Hispanics (1:40), and Slavics (1:50).
8 Cosmetic therapies include bleaching,
shaving, and waxing. Dermatologic therapies include
topical eflornithine and laser treatment. Oral contra-
ceptive pill (OCP) treatment is a useful and effective
adjunct if hirsutism is more than minimal.
9 Idiopathic hirsutism, i.e. hirsutism unex-
plained by hyperandrogenemia, may be mimicked by
otherwise asymptomatic idiopathic hyperandro-
genism, which may be due to atypical polycystic ovary
syndrome or abnormal peripheral metabolism of pro-
hormones.
10 A random sample for plasma total testoster-
one is a reasonable screening test if reliable assess-
ment of free testosterone is not available. At 8:00 a.m.
during the mid-follicular phase of the menstrual cycle
(days 410), the normal upper limit for plasma total
testosterone is typically about 60 ng/dl (2.1 nM) for
postmenarcheal adolescents when determined by a
specialty laboratory. The upper limit of normal for
plasma free testosterone under these conditions is
9 pg/ml (32 pM) in our laboratory; unfortunately, the
methodology for plasma-free or bioavailable testoster-
one yields method-specific norms. Special reference
values apply for pre-menarcheal girls.
R.L. Rosenfield F. Riepe W.G. Sippell
11 A high-normal testosterone level may not
reflect a hyperandrogenic state if drawn after the early
morning, because of diurnal variation, or if only the
total testosterone is initially assayed, since the plas-
ma-free testosterone can be high when total testoster-
one is normal because sex hormone-binding globulin
(SHBG), the major determinant of the bioavailable
testosterone, is commonly low in hyperandrogenic
women.
12 An early morning plasma-free testosterone
determined by a specialty laboratory is indicated on
days 410 of the menstrual cycle or during a period of
amenorrhea when the plasma testosterone is high-
normal in patients with moderate or severe hirsutism,
if features suggestive of other disorders are present
or emerge, or if the response to cosmetic-dermato-
logic therapy is unsatisfactory. Simultaneous assay of
17-hydroxyprogesterone is indicated in subjects at
high risk for CAH, which is suggested by a level over
150 ng/dl (4.5 nM) and virtually assured by a level over
1,200 ng/dl (36 nM).
13 Because testosterone undergoes episodic
and cyclic changes in addition to diurnal ones, recheck
is indicated if the course is progressive or risk factors
emerge.
14 Hyperandrogenism with a polycystic ovary
or menstrual irregularity in the absence of drug use,
neoplasm, or other endocrinopathy meets standard
criteria for the diagnosis of PCOS. Therefore, ultrason-
ic imaging of the ovaries and adrenal glands is usually
advisable. See next algorithm for potential further
work-up to determine the source of androgen excess.
Selected reading
Azziz R: The evaluation and management of hirsut-
ism. Obstet Gynecol 2003;101(5 Pt 1):9951007.
Rosenfield RL: Hirsutism and the variable response
of the pilosebaceous unit to androgen. J Investig
Dermatol Symp Proc 2005;10:205208.
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Hirsutism
 Puberty R.L. Rosenfield F. Riepe W.G. Sippell Hyperandrogenemia

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 1 The association of testosterone elevation
with otherwise unexplained anovulatory symptoms
(see algorithms on Secondary amenorrhea and An-
ovulatory disorders) or a polycystic ovary fulfills stan-
dard diagnostic criteria for polycytic ovary syndrome
(PCOS), which in its various forms accounts for about
8090% of adolescent hyperandrogenism.
Determination of the source of excess androgen often
permits a positive diagnosis of the characteristic PCOS
type of functional ovarian or adrenal hyperandro-
genism (FOH or FAH) and rules out rare disorders that
mimic PCOS.
2 Dexamethasone is given in a dose of
1 mg/m2 in four divided doses (0.5 mg q.i.d. in adult)
for 4 days and plasma cortisol, free testosterone,
17-hydroxyprogesterone (17-OHP), and dehydroepi-
androsterone sulfate (DHEAS) are measured on the
morning of the 5th day after the final dexamethasone
dose. For individuals weighing 100 kg or more, dexa-
methasone is given for 7 days. The test should be
performed when amenorrheic or in the follicular phase
of menstrual cycle.
3 Dexamethasone suppression of ACTH-
dependent adrenal function normally causes plasma
total testosterone to fall below 35 ng/dl (1.2 nM), free
testosterone below 8 pg/ml (28 pM), DHEAS to fall by
75% to below 80 g/dl (2.1 M), and 17-OHP to fall
to less than 50 ng/dl (1.5 nM). Total testosterone is not
as discriminating a criterion as the free testosterone
(unfortunately, a method-dependent criterion) or
17-OHP criteria. Subnormal androgen suppression
with normal adrenocortical suppression indicates a
source of androgen other than an ACTH-dependent
adrenal one.
4 Normally cortisol falls below 1.5 g/dl (45 nM).
5 Subnormal cortisol suppression is most
often due to noncompliance with taking the dexameth-
asone tablets. Cushings syndrome is an infrequent
cause of hyperandrogenism and requires a more de-
finitive work-up. Hyperandrogenism has been report-
ed in the rare conditions of cortisol resistance and
cortisone reductase deficiency.
35
6 Ultrasonographic visualization of the ovaries
by the vaginal route yields better definition than by the
abdominal route, but this is not a generally acceptible
technique in the virginal child. An adolescent polycys-
Puberty
tic ovary is defined as one with a volume greater
than 10.8 ml or maximal area over 5.5 cm2 or with
10 or more follicles in the maximum plane.
7 True hermaphroditism patients may only
have a clearly elevated plasma testosterone level in
response to a midcycle LH surge, hCG, or GnRH
agonist test.
8 The baseline pattern of plasma androgens
may yield a clue to the type of tumor. A DHEAS level
over 700 g/dl (19 M) is suspicious of an adrenal tu-
mor. In the absence of a high DHEAS, disproportionate
elevation of the ratio of plasma androstenedione to
testosterone or elevated 17-hydroxyprogesterone is
typical of a virilizing tumor. Poor dexamethasone
suppressibility of testosterone and/or DHEAS is very
suggestive of adrenal tumor. CT scan of the abdomen
may be indicated in such cases.
9 Virilizing adrenal rests of the ovaries may
complicate PCOS; they may resemble a polycystic
ovary.
10 PCOS is a symptom complex with various
combinations of hirsutism or its cutaneous equiva-
lents, anovulation, and central obesity. A polycystic
ovary is a classic diagnostic criterion, but is not neces-
sary for the diagnosis. Nonclassic PCOS includes
anovulatory hyperandrogenic girls who lack a poly-
cystic ovary. Most have the typical PCOS type of
functional ovarian hyperandrogenism on dexametha-
sone suppression or GnRH agonist testing.
11 Therapy for PCOS/FOH is symptomatic.
Hirsutism can be arrested and menses normalized by
cyclic administration of oral contraceptives if the
source of androgen excess is FOH/PCOS, unless there
is coexisting adrenal androgen excess (see Functional
adrenal hyperandrogenism below). Regression of
hirsutism may require therapy with anti-androgens.
Isolated menstrual irregularity can be managed by
cyclic medroxyprogesterone acetate administration.
Obesity is treated with a diet and exercise program.
When infertility becomes an issue, referral should be
made to a reproductive endocrinologist.
12 The standard ACTH test is performed by
infusing 250 g ACTH124 intravenously over a period
of one minute and obtaining a blood sample before
injection and 1 h later.
R.L. Rosenfield F. Riepe W.G. Sippell
13 Congenital adrenal hyperplasia (CAH)
cannot be confirmed upon mutation analysis unless
the steroid intermediates immediately prior to the
enzyme block rise over 5 SD above average in re-
sponse to ACTH. For 17-OHP, this is over 1,200 ng/dl
(36.4 nM), for DHEA this is over 3000 ng/dl (104 nM) in
late adolescence (see p. 50, 52).
14 Primary functional adrenal hyperandrogen-
ism (FAH) is a term for idiopathic, ACTH-dependent
(dexamethasone-suppressible), adrenal hyperan-
drogenism in which modest rises in DHEA, 17-OHP,
etc. do not meet the criteria for the diagnosis of CAH. It
is often found in atypical PCOS.
15 Idiopathic hyperandrogenemia is distin-
guished from idiopathic hirsutism. About 8% of chron-
ic hyperandrogenemia remains unexplained after an
intensive investigation, which includes GnRH agonist
testing to detect the occasional case of ovarian hyper-
androgenism that is not detected by the dexametha-
sone test.
16 Low-dose prednisone as a single bedtime
dose of 5.07.5 mg typically selectively suppresses
adrenal androgen secretion without causing adrenal
atrophy. However, because adrenal atrophy may
occur in occasional patients, the patient should peri-
odically be checked to be sure 8 a.m. plasma cortisol is
over 10 g/dl. Hydrocortisone treatment (7.5 mg/m2
body surface) may be more favorable before reaching
final height in adolescent girls. Dexamethasone
dosage cannot be as finely tuned as prednisone or
hydrocortisone dosage, and so dexamethasone is
more prone to cause long-lasting striae and obesity. In
primary FAH patients (footnote 28), insulin sensitizer
therapy with drugs such as metformin or troglitazone
may lower androgens moderately. If a trial of low-dose
prednisone for FAH due to atypical PCOS does not
normalize menses within 4 months or improve hirsut-
ism within 6 months, the patient should be treated as
for ordinary PCOS.
Selected reading
Buggs C, Rosenfield RL: Polycystic ovary syndrome
in adolescence. Endocrinol Metab Clin North Am
2005;34:677705.
203.64.11.45 - 1/29/2015 6:38:40 PM
Rosenfield RL: Clinical practice. Hirsutism N Engl J
Med 2005;353:25782588.
Kainan University
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Hyperandrogenemia
 Intersex M. Ritzn R.L. Hintz Micropenis at age 1 year to puberty

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 1 In this context, micropenis is defined as be-
ing more than 2 SDS below the mean length for age
(penile length <2.54 cm, measured stretched from the
pubic bone to the tip of the glans).
2 Micropenis might be secondary to panhypo-
pituitarism or severe isolated GH deficiency, with or
without hypogonadotropic hypogonadism. Therefore,
evaluation of growth rate is essential after 1 year of
age. Note that isolated hypogonadotropic hypogonad-
ism will also cause delay in growth in adolescence.
MRI examination of the hypothalamus and pituitary
may reveal hypoplasia of the anterior pituitary and/or
dislocation of the posterior (bright spot) pituitary, or
agenesis of the corpus callosum, septo-optical dyspla-
sia or agenesis of the olfactory lobe.
3 Testosterone substitution (see below)
should be instituted at as young an age as possible,
along with cortisol, thyroxine and GH.
4 Isolated GHD generally does not cause mi-
cropenis. If so, very severe GHD (GH gene deletion?)
should be suspected.
5 Complete GH insensitivity due to GH recep-
tor defects regularly goes with small penis.
6 Normal growth rate makes GH deficiency
unlikely, but hypogonadotropic hypogonadism should
be ruled out by a GnRH test, if the boy is prepubertal.
7 Chromosomal mosaicism involving the sex
chromosomes can cause micropenis, but this is gener-
ally combined with hypospadias (see that decision
tree). More than two X chromosomes (48,XXXY or
49,XXXXY) will hamper testicular development to an
extent that will cause micropenis.
37
Intersex
8 Simple cryptorchidism is generally not as-
sociated with micropenis. Dysgenetic testes may have
enough function to allow increased T after hCG stimu-
lation.
9 Testicular atrophy (sometimes erroneously
called aplasia) may cause micropenis, if the testes
have disappeared early during gestation. Measure-
ment of antimllerian hormone and inhibin B in blood
may be helpful in diagnosis of absent testes.
10 Some patients with Kallmann syndrome
may have hyposmia rather than anosmia, and occa-
sionally bilateral cryptorchidism may be present.
11 Irrespective of the underlying cause, a short
course of testosterone treatment could be tried in all
patients with micropenis. The effect seems to be bet-
ter the younger the boy is, and there may also be less
risk of undue BA acceleration at younger ages. Testos-
terone enanthate, 2550 mg i.m. per month for a total
of three injections, will generally cause some in-
creased penile growth without undue acceleration of
bone age. However, it is uncertain if an initial gain in
penile length is maintained into adulthood. Transder-
mal DHT or T has also been reported to be effective
[Choi et al: J Urol 1993;150:657660]. If GH deficiency
is diagnosed, GH substitution is important as a syner-
gistic agent to T.
12 Partial androgen insensitivity due to muta-
tions of the androgen receptor gene may in rare cases
manifest itself as micropenis, although hypospadias
(see that decision tree) is more common. Patients with
mutations that cause decreased affinity between the
androgen and its receptor may show some response
to excess testosterone or dihydrotestosterone treat-
ment.
Penile length (cm)
Mean ( 2 SDS) penile length in relation to age. The black dots
are values calculated from the data included in the appendix
of the paper of Schonfeld [1943]. The lines represent curves of
approximate fit.
M. Ritzn R.L. Hintz
Selected reading
Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL:
Congenital hypogonadotropic hypogonadism and
micropenis: effect of testosterone treatment on
adult penile size why sex reversal is not indicated.
J Pediatr 1999;134:579583.
Feldman KW, Smith DW: Fetal phallic growth and
penile standards for newborn male infants.
J Pediatr 1975;86:395398.
Lee PA, Mazur T, Danish R, Amrheim J, Blizzard RM,
Money J, et al: Micropenis. I. Criteria, etiologies and
classification. Johns Hopkins Med J 1980;146:
156163.
Migeon CJ, Berkovitz GD, Brown TR: Sexual differ-
entiation and ambiguity; in Kappy MS, Blizzard RM,
Migeon CJ (eds): Wilkins: The Diagnosis and Treat-
ment of Endocrine Disorders in Childhood and
Adolescence, ed 4. Springfield, Thomas, 1994,
pp 573681.
Schonfeld WA: Primary and secondary sex charac-
teristics. Am J Dis Child 1943;65:535.
Tuladhar R, Davis PG, Batch J, Doyle LW: Establish-
ment of a normal range of penile length in preterm
infants. J Paediatr Child Health 1998;34:471473.
Zenaty D, Dijoud F, Morel Y, Cabrol S, Mouriquand P,
Nicolino M, et al: Bilateral anorchia in infancy:
occurrence of micropenis and the effect of testos-
terone treatment. J Pediatr 2006;149:687691.
+2 SD
16
14
Mean
12
10 2 SD
8
6
4
2
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Age (years)
203.64.11.45 - 1/29/2015 6:40:59 PM
Kainan University
Downloaded by:
Micropenis at age 1 year to puberty
 Intersex M. Ritzn R.L. Hintz Micropenis in a newborn

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 1 Micropenis in this context means a normally
shaped but small penis at birth (stretched penile
length, from the pubic bone to the tip of the glans, is
less than 22.5 SDS below the mean, corresponding to
1925 mm) [Feldman and Smith, 1975]. Severe hypo-
spadias (see p. 40).
2 Since micropenis may be a feature of hypo-
pituitarism, which, unless diagnosed and treated, may
cause severe hypoglycemia with brain damage, it is
mandatory to monitor blood glucose in any newborn
with micropenis.
3 It is important to get a blood sample for T
assay during the first day(s) of life, to catch the nor-
mally high levels immediately after birth. GH test
could be glucagon, L-dopa, or other provocation test,
or frequent blood sampling. Do not use insulin! IGF-1
levels are difficult to evaluate at this age low levels
do not prove GH deficiency. GnRH test is optional at
this stage. MRI examination of the hypothalamus and
pituitary may reveal hypoplasia of the anterior pitu-
itary and/or dislocation of the posterior (bright spot)
pituitary, or agenesis of the corpus callosum, septo-
optical dysplasia or agenesis of the olfactory lobe.
4 Boys with isolated GH deficiency may have
small penis, but generally not micropenis. If so, severe
GHD (GH gene deletion?) should be considered.
5 GH insensitivity is very rare, and will prob-
ably not be diagnosed at birth, unless a sibling with
this disease is known. However, it is important to illus-
trate that GH is needed for normal penile growth.
6 After the first months of age, the T produc-
tion has decreased so that an evaluation of Leydig cell
function requires stimulation with hCG (100 IU/kg i.m.,
with measurement of T before and 4 days later). Nor-
mal antimllerian hormone and inhibin B in blood also
indicates the presence of testes (Sertoli cells).
39
Intersex
7 Testicular dysgenesis is most often caused
Selected reading
by sex chromosome abnormalities (e.g. 45,X/46,XY),
which will cause hypospadias rather than micropenis Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL:
with normal shape. Congenital hypogonadotropic hypogonadism and
micropenis: effect of testosterone treatment on
8 Bilateral cryptorchidism requires treatment, adult penile size why sex reversal is not indicated.
preferably by surgery. hCG treatment is effective in J Pediatr 1999;134:579583.
only 1520% of the boys, but can be used as a pro-
Feldman KW, Smith DW: Fetal phallic growth
longed hCG test and, if positive, the increased T pro-
and penile standards for newborn male infants.
duction during a 4- to 5-week course of hCG may also
J Pediatr 1975;86:395398.
stimulate penile growth. However, hCG treatment may
cause apoptosis of germ cells. Lee PA, Mazur T, Danish R, Amrheim J, Blizzard RM,
Money J, et al: Micropenis. I. Criteria, etiologies
9 Also (erroneously) called testicular aplasia. and classification. Johns Hopkins Med J 1980;146:
Depending on when during fetal life the testes van- 156163.
ished, penile growth may be normal or very small.
Migeon CJ, Berkovitz GD, Brown TR: Sexual differ-
entiation and ambiguity; in Kappy MS, Blizzard RM,
10 Partial androgen insensitivity may in rare
Migeon CJ (eds): Wilkins: The Diagnosis and Treat-
cases manifest itself as micropenis, although hypo-
ment of Endocrine Disorders in Childhood
spadias (see p. 40) is more common. Patients with mu-
and Adolescence, ed 4. Springfield, Thomas, 1994,
tations of the androgen receptor gene that cause de-
pp 573681.
creased affinity between the androgen and its recep-
tor may show some response to excess testosterone Tuladhar R, Davis PG, Batch J, Doyle LW: Establish-
or dihydrotestosterone treatment. ment of a normal range of penile length in preterm
infants. J Paediatr Child Health 1998;34:471473.
11 Treatment will generally result in further
Zenaty D, Dijoud F, Morel Y, Cabrol S, Mouriquand P,
penile growth, with the main purpose of giving a male
Nicolino M, et al: Bilateral anorchia in infancy:
appearance through childhood. However, there are no
occurrence of micropenis and the effect of testos-
follow-up data on neonatally treated boys with micro-
terone treatment. J Pediatr 2006;149:687691.
penis into adulthood. Suggested treatment: testoster-
one enanthate, 25 mg i.m. once a month, to a total
of three injections. Transdermal DHT has also been
reported to be effective [Choi et al: J Urol 1993;50:
657660].
12 Many of the boys with micropenis will never
get an etiological diagnosis. However, it is important
to do a thorough W/U, since underlying disease may
require treatment.
203.64.11.45 - 1/29/2015 6:40:59 PM
Kainan University
Downloaded by:
M. Ritzn R.L. Hintz Micropenis in a newborn
 Intersex M. Ritzn R.L. Hintz Hypospadias/virilization

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 1 Hypospadias can also be called deficient
male differentiation or female virilization or unclear
sex differentiation in individual cases it may be dif-
ficult to determine the sex of the child. Therefore,
these items will be treated together.
2 PCR detection of X and Y specific markers is
the most rapid way to identify the type of sex chromo-
somes, but a full karyotype should also be requested.
3 The incidence of hypospadias is about 1/300
boys, and in most cases no etiology can be shown
even after extensive work-up. Therefore, it is reason-
able to exclude the most common (and least severe)
forms, the glandular and distal penile forms from fur-
ther work-up [Prader stage V, see fig. 1 and Collu et al.
(eds): Paediatric Endocrinology. New York, Raven
Press, 1981, p. 491, for explanation of Prader stages].
Moderate forms of hypospadias without cryptorchi-
dism should be referred directly to a urologist, who
can council on possible surgical intervention.
4 It is important to draw a blood sample for T
assay during the first day(s) after birth, before the
physiological decline of T levels has occurred.
5 Decreased T production in combination with
hypospadias may have many different etiologies: Dys-
genic testes or one of several enzymatic defects in T
synthesis. See below under 9.
6 High or normal T levels in blood of a boy
with hypospadias suggest AIS (Morris syndrome, tes-
ticular feminization) or 5-reductase deficiency. How-
ever, negative events during the first trimester of preg-
nancy (delayed fetal T production?) might hypotheti-
cally cause hypospadias in spite of later normal T pro-
duction and sensitivity. It is difficult to establish AIS in
the newborn: An hCG stimulation test might be used
both to investigate the T production capacity and its
action on target organs (reddening and volume in-
crease of penis and scrotum, nitrogen retention). After
the newborn period, the androgen-induced decrease
in SHBG levels might help in diagnosing AIS. Direct
study of the androgen receptor gene is useful, but may
need sequencing of several exons, since a large num-
41 ber of different mutations have been shown.
7 5-Reductase (type II) deficiency causes
poor masculinization of males that are most often giv-
en a female sex at birth. At puberty, masculinization
will proceed when 5-reductase type I is expressed.
Intersex
8 In order to define the steroidogenic block, or
even the presence or absence of a testis, a short-term
stimulation of Leydig cells with a bolus dose of hCG
(500 IU i.m.; T and precursors are measured before
and 4 days after the injection) might be needed.
9 Defective function of enzymes needed for T
synthesis include: (1) StAR deficiency: defective trans-
port of cholesterol into the mitochondria, causing defi-
ciency of all steroid hormones. (2) P450c17 deficiency:
inability to hydroxylate pregnenolone, and to cleave
the side chain of 17-OH-pregnenolone to DHEA. This
will result in deficiency in glucocorticoids and sex hor-
mones, but an excess of mineralocorticoids. (3) 3-
HSD deficiency: subnormal production of all steroid
hormones, including T, but excess DHEA is formed,
which may virilize females. (4) 17-Hydroxysteroid oxi-
doreductase deficiency: prevents conversion of 4 to T.
10 Complete lack of testicular differentiation
will result in completely female genitalia. However, it is
possible that incomplete inactivation of genes impor-
tant to testicular differentiation (e.g. SRY, the Wilms
tumor 1 gene or SOX-9 [campomelic dysplasia] genes)
might result in incomplete male differentiation sec-
ondary to deranged testicular differentiation.
11 Other forms of sex chromosome mosaicism
can also be found in hypospadias, such as 46,XY/
46,XX, 45,X/46,XY/47,XXX, and others.
12 Follow-up through puberty is mandatory,
since testicular tumors are very frequent (3040%?).
Testicular biopsy should be performed early and late
in puberty, to look for cancer or carcinoma in situ
(CIS). If unilateral CIS is found in a male, gonadectomy
should be performed. If bilateral, irradiation for the
purpose of irradiating CIS cells should be considered.
In females with a Y chromosome, gonadectomy
should be done before puberty, after thorough coun-
seling.
13 Congenital adrenal hyperplasia (CAH)
should always be ruled out in virilized 46,XX girls by
measuring 17-OHP, androstendione and DHEAS. All
forms of CAH cannot be listed here.
14 Once CAH is ruled out, laparoscopy can be
used to localize and identify gonads, uterus and fallo-
pian tubes. Ultrasound examination of newborns re-
quires large experience.
M. Ritzn R.L. Hintz
15 See also Congenital adrenal hyperplasia in
the newborn (p. 50).
16 Maternal virilization can be iatrogenic, or
depend on an adrenal or ovarian tumor. If the signs of
androgen excess disappear soon after birth in mother
and child, a placental source of androgens should be
suspected.
17 A complete deficiency of aromatase activity
will prevent estrogen production, and cause accumu-
lation of the immediate precursors 4 and T. This will
cause virilization of female fetuses and the mother, a
condition which disappears at delivery, only to recur in
puberty when the sex hormone production is reacti-
vated.
18 Feminizing surgery should be performed
during the first year of life, if needed. E2 substitution
starts in early adolescence.
19 See Congenital adrenal hyperplasia (p. 52).
Selected reading
Conte FA, Grumbach MM: The pathophysiology,
genetics, nosology and diagnosis of male
pseudohermaphroditism; in Hughes IA (ed):
Sex Differentiation: Clinical and Biological Aspects.
Front Endocrinol 1996;20:151172.
Hughes IA, Houk C, Ahmed SF, Lee PA: LWPES
Consensus Group: ESPE Consensus Group:
Consensus statement on management of intersex
disorders. Arch Dis Child 2006;91:554563.
Fig. 1. Typing of the degree of virilization of the external geni-
203.64.11.45 - 1/29/2015 6:40:59 PM
talia of females as proposed by Prader [1958]. In type I, the only
abnormality is a slight enlargement of the clitoris. In type V, there
is a markedly enlarged phallus with a penile urethra.
Kainan University
Downloaded by:
Hypospadias/virilization
 Intersex A.D. Rogol Z. Hochberg Cryptorchidism

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 1 Undescended testes are to be distinguished
Selected reading
from retractile testes. Retractile testes may have in-
Ferlin A, Siminato M, Bartoloni L, Rizzo G,
creased incidence from 2 to 6 years.
Betella A, Dottorini T, Dellapiccola B, Foresta C:
The INSL3-LGR8/GREAT ligand-receptor pair in
2 Measure LH and FSH values. Distinction be-
human cryptorchidism. J Clin Endocrinol Metab
tween hypergonadotropic and normal is straightfor-
2003;88:42734279.
ward. With most assays distinction between normal
and hypogonadotropic is not possible. Hudson JM, Hasthorpe S, Heyns CF: Anatomic and
functional aspects of testicular descent and cryptor-
3 Some advocate laparoscopic evaluation chidism. Endocr Rev 1997;18:259280.
rather than a GnRH or hCG therapeutic trial, since
many testes that descend with hormonal therapy will
re-ascend and require orchidopexy.

4 Idiopathic cryptorchidism is rarely caused

by a mutation in the insulin-like-3 gene (INSL3; OMIM
146738) as well as in the leucine-rich repeat protein-
containing G protein-coupled receptor-8 gene (LGR8;
OMIM 606655). These genes are active in testicular
descent.

5 Kallmann, Lawrence-Moon-Bardet-Biedl,
Prader-Labhardt-Willi and many others less com-
monly.

6 May be pan-hypopituitary or isolated go-

nadotropin deficiency.

43

203.64.11.45 - 1/29/2015 6:40:59 PM

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Intersex A.D. Rogol Z. Hochberg Cryptorchidism
 Intersex R.L. Hintz Z. Hochberg Turner syndrome

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 Evaluation The key to the initial evaluation for 1 The diagnosis of Turner syndrome should
Turner syndrome is a careful history be considered in any newborn female with edema,
and physical examination. and female at any age with significant short stature
and/or delayed puberty, primary or secondary amen-
History Neonatal history, especially orrhea, or infertility even if the patient does not have
lymphedema any history or physical findings suggestive of Turner
Past growth syndrome. Turner syndrome specific growth charts for
Frequent otitis media assessment of growth and prediction of adult stature
Congenital heart disease or kidney are useful.
malformation
2 A chromosome examination is necessary to
Physical Minor anomalies suggestive of diagnose Turner syndrome. This is usually done on
examination Turner syndrome peripheral lymphocytes, but sometimes chromo-
Pubertal status somes from other tissues may be necessary to estab-
lish the diagnosis. At least 40 cells have to be analyzed.
Laboratory Chromosomes If the chromosomes are normal, the patients should
T4, TSH, BUN and others as indicated receive further evaluation for other causes of short
Bone age stature, delayed puberty, or primary or secondary
E2 and FSH amenorrhea as indicated.
Ultrasound of pelvis, kidneys,
heart and aorta 3 If the chromosomes show an abnormality of
the X chromosome, the diagnosis of Turner syndrome
is made. Additional evaluation should include E2 and
FSH, bone age, and ultrasound of the pelvis, kidneys
and heart. If Y chromosomal material or markers (i.e.
SRY or centromer FISH) are found, gonadectomy may
be necessary. Patients with spontaneous menopause
should be counseled about possibilities for pregnancy
and genetic risks, and the development of an early
menopause. Abnormalities of the kidney, heart, or aor-
ta must be treated appropriately.
4 If the Turner patient has poor growth, sig-
nificant short stature (Ht <2 SDS) and unfused epiph-
yses (BA <13 years), therapy with GH for the short stat-
ure should be considered. Other treatment options
include counseling, oxandrolone, estrogens, and plas-
tic surgery.
5 Increased incidence of thyroiditis.
6 In a prepubertal female, the presence of
ovaries on ultrasound and/or a low FSH level indicates
the potential of ovarian function and the patient should
be observed for the development of the clinical signs
of spontaneous puberty. In addition, serial determina-
45 tion of FSH levels may be helpful.
Intersex R.L. Hintz Z. Hochberg
7 A leading cause of death in Turner syn-
drome is the development of dissecting aneurysm of
the aorta. Echocardiography is repeated periodically;
watch for dilating aortic root. Other complications of
Turner syndrome include recurring ear infections, hy-
percholesterolemia, glucose intolerance, obesity, au-
toimmune thyroiditis, and skin conditions.
8 Hearing problems are the single most im-
portant determinant of quality of life in Turner syn-
drome.
Selected reading
Bannink EM, Raat H, Mulder PG, de Muinck Keizer-
Schrama SM: Quality of life after growth hormone
therapy and induced puberty in women with Turner
syndrome. J Pediatr 2006;148:95101.
Bondy CA: Care of girls and women with Turner
syndrome: a guideline of the Turner syndrome
study group. J Clin Endocrinol Metab 2007;92:1025.
Carel JC, Elie C, Ecosse E, Tauber M, Leger J, Cabrol
S, Nicolino M, Brauner R, Chaussain JL, Coste J:
Self-esteem and social adjustment in young women
with Turner syndrome-influence of pubertal man-
agement and sexuality: population-based cohort
study. J Clin Endocrinol Metab 2006;91:29722979.
Hintz RL, Attie KM, Compton PG, Rosenfeld RG:
Multifactorial studies of GH treatment of Turner
syndrome: The Genentech National Cooperative
Growth Study; in Albertsson-Wikland K, Lippe B
(eds): Turner Syndrome in a Life-Span Perspective.
Amsterdam, Elsevier, 1995, pp 167173.
Saenger P, Wikland KA, Conway GS, Davenport M,
Gravholt CH, Hintz R, Hovatta O,Hultcrantz M,
Landin-Wilhelmsen K, Lin A, Lippe B, Pasquino AM,
Ranke MB, Rosenfeld R, Silberbach M: Recommen-
dations for the diagnosis and management of
Turner syndrome. J Clin Endocrinol Metab 2001;86:
30613069.
203.64.11.45 - 1/29/2015 6:40:59 PM
Kainan University
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Turner syndrome
 Adrenal F. Riepe W.G. Sippell Z. Hochberg Hypertension

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 1 Reference data for arterial blood pressure
are age, sex and population dependent use your lo-
cal national percentile curves. Preferably, use 24-hour
blood pressure profile.
2 PRA reference range depends on age, pos-
ture, fluid and electrolyte balance.
3 Similarly, plasma aldosterone levels depend
on age, posture, fluid and K+ vs. Na + balance. In young
infants, direct (nonextractive, nonchromatographic)
radioimmunoassays are not sufficiently reliable.
8 High aldosterone with low (suppressed) re-
nin = primary hyperaldosteronism, with hypokalemia,
hyperkaliuria and metabolic alkalosis.
9 Start with overnight (short-term) dexameth-
asone suppression test. In most instances, long-term
tests (low and high dose) are required.
10 In children very rare: APA of adrenal glo-
merulosa cells (Conn syndrome). Somewhat more
common: IHA with normal adrenals or with bilateral
adrenal (micronodular) hyperplasia (see pp. 66, 67).
Selected reading
Newman KD, Ponsky T: The diagnosis and manage-
ment of endocrine tumors causing hypertension in
children. Ann NY Acad Sci 2002;970:155158.
Pappadis SL, Somers MJ: Hypertension in adoles-
cents: a review of diagnosis and management.
Curr Opin Pediatr 2003;15:370378.
Varda NM, Gregoric A: A diagnostic approach for
the child with hypertension. Pediatr Nephrol
2005;20:499506.

4 Hyporeninemic hypoaldosteronism with 11 In this rare, autosomal-dominant disorder

hypertension and hypokalemia.
5 Rare autosomal-recessive disorder due to
defective oxidation of cortisol to cortisone by 11-HSD
caused by gene mutations. Unmetabolized cortisol
binds to renal mineralocorticoid receptor, inducing
hypertension and hypokalemia. Same clinical and lab-
oratory pattern in Liddle syndrome (defective renal
tubular Na+ transport; triamterene corrects hypokale-
mia) and in excessive ingestion of liquorice (glycyrrhe-
tinic acid inhibits 11-HSD activity).
6 With deficiency of sex steroid (c male pseu-
dohermaphroditism in XY, lack of puberty and primary
amenorrhea in XX) and cortisol production. Hyperten-
sion due to DOC and aldosterone excess.
7 With androgen excess (c precocious pseu-
dopuberty), cortisol deficiency and hyporeninemic
hypoaldosteronism. Hypertension due to DOC excess.
Highly specific plasma (multisteroid analysis) and/or
urinary steroid methods required. Confirmation of di-
agnosis by mutational DNA analysis of CYP11B1 gene
(see p. 52).
(also called DSH), aldosterone secretion is continu-
ously (without escape) stimulated by ACTH. It is
caused by a chimeric recombination of the CYP11B1
(11-hydroxylase) and CYP11B2 (aldosterone syn-
thase) tandem genes on chromosome 8q, leading to
abnormal expression of CYP11B2 in the adrenal zona
fasciculata with increased production of the mineralo-
corticoids 18-OH-S, 18-OH-cortisol and 18-oxocortisol
(see also pp. 66, 67).
12 Secondary hyperaldosteronism (renin al-
ways high) with hypertension may be due to tumors of
renin-producing cells (primary reninism) in the juxta-
glomerular apparatus, in Wilms tumors or in extrare-
nal malignant tumors (paraneoplastic syndrome). Al-
ternatively, it may be the consequence of renovascular
malformation (secondary reninism), severe renal fail-
ure (anephric state) after renal transplantation, in se-
vere genitourinary tract obstruction and in pheochro-
mocytoma.
13 Pheochromocytoma is rare in childhood.
When located in the adrenal medulla, it secretes epi-
nephrine and norepinephrine. Extramedullary tumors
secrete norepinephrine only. The metabolic syndrome
resembles diabetes mellitus.

47

Adrenal F. Riepe W.G. Sippell Z. Hochberg Hypertension

 Adrenal A.D. Rogol Z. Hochberg Cushing syndrome

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 1 Central obesity; growth failure; drug history;
hirsutism, buffalo hump, striae.
2 Fat distribution is central; extremities may
be normal or thin. Normal growth rate excludes Cush-
ing disease in children, other than in adrenal cortical
carcinoma, when some may have a normal or rapid
growth rate very early in course of disease because of
androgen release.
3 There is lack of agreement among experts
how to demonstrate hypersecretion of cortisol as well
as somewhat different criteria for the diagnosis of CS.
If two 24-hour collections are normal for urinary free
cortisol, two bedtime salivary cortisol levels are within
normal limits, or an overnight 1 mg dexamethasone
suppression test is normal CS is quite unlikely. The
low-dose dexamethasone suppression test is not es-
sential once hypercortisolism is proven.
4 Young children with adrenocortical carci-
noma may have early excessive linear growth and evi-
dence of excessive androgen (masculinizing) or estro-
gen (feminizing) secretion.
5 Transsphenoidal surgery is preferred and
should be done at centers with expertise in pituitary
neurosurgery.
Selected reading
Dias R, Storr HL, Perry LA, Isidori AM, Grossman AB,
Savage MO: The discriminatory value of the low-
dose dexamethasone suppression test in the inves-
tigation of paediatric Cushings syndrome. Horm
Res 2006;65:159162.
Findling JW, Raff H: Cushings syndrome: important
issues in diagnosis and management. J Clin Endo-
crinol Metab 2006;91:36463753.
Joshi SM, Hewitt RJ, Storr HL, Rezajooi K, Eliamushi
H, Grossman AB, Savage MO, Afshar F: Cushings
disease in children and adolescents: 20 years of ex-
perience in a single neurosurgical center. Neurosur-
gery 2005;57:281285.
Kanter AS, Diallo AO, Jane JA, Jr, Sheehan JP,
Asthagiri AR, Oskouian RJ, Okonkwo DO,
Sansur CA, Vance ML, Rogol AD, Laws ER Jr:
Single-center experience with pediatric Cushings
disease. J Neurosurg 2005;103(5 suppl):413420.
Magiakou MA, Chrousos GP: Cushings syndrome in
childhood and adolescence: current diagnostic and
therapeutic state. J Clin Invest 2002;25:181194.

6 Bilateral inferior petrosal sinus sampling

(BIPSS) is technically demanding, especially in chil-
dren and young adolescents. It depends virtually en-
tirely on the skill of an interventional radiologist and a
team that works with children. Administration of ovine
CRH may improve the diagnostic accuracy in distin-
guishing an ACTH gradient side-to-side.

7 Fluorine-18-fluorodeoxyglucose PET is ex-

perimental, but promising.

49

Adrenal A.D. Rogol Z. Hochberg Cushing syndrome

 Adrenal M. Ritzn R.L. Hintz Congenital adrenal hyperplasia (CAH) in the newborn period

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 1 Neonatal screening for elevated 17-OHP
may reveal 21-OHD in a boy that has not yet developed
any clinical symptoms. Even after confirmation of high
17-OHP levels in blood, it is advisable to perform mu-
tation analysis in order to subclassify into severe
forms (these children will, however, have developed
symptoms of failure to thrive, dehydration and salt
loss before the DNA analysis is finished), moderately
severe and mild forms. The moderately severe forms
need very low doses of hydrocortisone during the first
year of life, the mild forms can initially be followed
without substitution therapy, although under close
supervision and glucocorticoid substitution during
periods of stress.
2 By far the most common form of CAH is due
to deficiency in 21-hydroxylase (21-OHD). Very rare
forms, such as deficiency in side chain cleavage, 17-
hydroxylase and StAR enzymes will not be mentioned
here. Most girls with severe forms of CAH will present
at 515 days of age with virilization noted at birth,
vomiting, failure to thrive and dehydration. Boys easily
escape early diagnosis, and may be misinterpreted as
gastroenteritis. However, maintained diuresis in spite
of dehydration should raise suspicion of CAH. Girls
with CAH are often initially assigned male sex. CAH
must be ruled out in bilateral cryptorchidism!
3 Hyponatremia may also occur in moderately
severe forms of 21-OHD (simple virilizing forms) if the
child is under stress.
Other causes of abnormal sex differentiation will be
dealt with elsewhere.
4 There is no sharp limit between severe (salt
losing) and moderate (simple virilizing) forms. Mild
(nonclassical) forms are generally not detected until
after the neonatal period.
5 If available, mutation analysis of the 21-OH
gene should be done in all cases. Generally, there is a
good correlation between phenotype and genotype in
this disorder. Genotyping is of special value when
evaluating boys that are picked up by neonatal screen-
ing and treated before they have developed salt loss.
51
Adrenal
6 If the child is in no stress, the dose of hydro-
Selected reading
cortisone can be about 15 mg/m2 from the start. If in
stress, the initial dose should be 3 or 4 times higher Clayton P, Miller WL, Oberfield SE, Ritzn EM,
during the first week, then taper down to a mainte- Sippell WG, Speiser PW, Joint ESPE/LWPES Work-
nance dose. During the first year of life, the glucocorti- ing Group: Consensus statement on 21-hydroxylase
coid dose should be the lowest that still allows normal deficiency from the European Society for Paediatric
general well-being, no increased vomiting, normal Endocrinology and the Lawson Wilkins Pediatric
weight gain, even if 17-OHP levels in blood are above Endocrine Society. J Clin Endocr Metab 2002;87:
normal. This generally translates into 47 mg hydro- 40484053/Horm Res 2002;58:188195 (jointly
cortisone per day, divided into three doses. Attempts published).
to normalize 17-OHP blood levels will result in over-
Flck CE, Miller WL: P450 oxidoreductase deficien-
substitution. If renin levels are elevated, fludrocorti-
cy: a new form of congenital adrenal hyperplasia.
sone (initially 2550 g/day) is given. Addition of salt
Curr Opin Pediatr 2006;18:435441.
(0.5 g 23) to the diet often stabilizes the situation
during the first 1 or 2 years. Some pharmacies provide Speiser PW, White PC, New Ml: Congenital adrenal
taste-covered salt (individual grains are covered to hyperplasia; in James VH (ed): The Adrenal Gland.
eliminate the taste of salt until dissolved) that facili- Comprehensive Endocrinology, revised ser.
tates salt administration. New York, Raven Press, 1992, pp 371372.
Thiln A, Woods KA, Perry LA, Savage MO,
7 Lower urinary tract obstruction in a neonate
Wedell A, Ritzn EM: Early growth is not increased
may cause salt loss and imitate CAH.
in untreated moderately severe 21-hydroxylase
deficiency. Acta Paediatr 1995;84:894898.
8 A steroid pattern resembling both 21- and
17-hydroxylase deficiency (moderately elevated 17- Wedell A, Thiln A, Ritzn EM, Stengler B,
OHP and subnormal androgen levels) may be caused Luthman H: Mutational spectrum of the steroid
by a partial deficiency of P450 oxidoreductase (POR). 21-hydroxylase gene in Sweden: implications for
The phenotype is variable, but generally shows under- genetic diagnosis and association with disease
masculinization of boys and virilization of girls. It is manifestation. J Clin Endocrinol Metab 1994;78:
often but not always combined with skeletal abnor- 11451152.
malities (Antley-Bixler syndrome).
9 If genitalia are ambiguous, it should be con-
sidered as a medical urgency and the parents should
bring their child to a competent team of experienced
pediatric endocrinologist, surgeon, psychiatrist and
geneticist within the first day after birth. Prolonged or
hesitant management during the first days might ham-
per future acceptance of the child by the family. Par-
ents need full information on the future treatment of
the child. Feminizing surgery should, if needed, be per-
formed at about 6 months of age. Additional surgery
may be needed when the girl is able to be fully co-op-
erative, after age 1517. A written instruction to in-
crease the dose of glucocorticoids in case of somatic
stress (gastroenteritis, surgery, anesthesia, fever; tem-
perature >38C, double dose; >39C, triple dose; if last-
ing for more than 3 days, or if the child is lethargic:
contact doctor!) should be given to the parents.
M. Ritzn R.L. Hintz Congenital adrenal hyperplasia (CAH) in the newborn period
 Adrenal M. Ritzn R.L. Hintz Congenital adrenal hyperplasia (CAH) presenting after the newborn period

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 1 The clinical picture is that of a child with
signs of androgen excess. Girls show pubic hair, oily
skin, acne, apocrine sweat odor (skin puberty), accel-
erated linear growth and some clitoromegaly. Boys
will have early skin puberty, rapid growth and ad-
vanced genital maturation for age, but not testicular
growth.
Girls with severe forms of CAH will probably have
been picked up in the neonatal period, unless they are
so virilized that they have been assigned male sex.
They will not be included in this diagnostic flow sheet.
See CAH in the newborn period (p. 50).
2 If baseline 17-OHP level in blood is border-
line normal, a bolus injection of ACTH, measuring 17-
OHP before and after 1 h can yield more information
However, there is overlap between normal individuals
and nonclassical forms, between nonclassical and
mild forms, and between mild and severe forms (see
figure).
3 Premature adrenarche is here used as the
biochemical finding of elevated adrenal androgens,
mostly DHEA and its sulfate. The clinical correlate is
premature skin puberty (pubic hair, oily skin, apocrine
sweat odor, acne) without signs of gonadal puberty
(breast enlargement in girls, testicular growth in boys).
The underlying cause of premature adrenarche may
be specific, as in mild forms of CAH, but most often
remains unexplained (idiopathic). A family history of
plentiful general hair growth is often found.
4 Adrenal tumor in childhood is a rare but im-
portant differential diagnosis in isolated skin puberty.
Clinically, it may be impossible to distinguish from
simple premature adrenarche of late forms of CAH.
Occasionally, the tumor produces both glucocorticoids
that produce Cushing syndrome and androgens, most-
ly DHEA. Adrenal tumors most often produce a spec-
trum of adrenal steroids, including precursors, which
can be demonstrated by gas chromatography/mass
spectrometry of extracted urinary steroids.
5 Severe forms will have been diagnosed ear-
lier due to salt loss and dehydration. Females with
moderately severe forms can have a variable degree of
53 virilization at birth, sometimes escaping diagnosis. At
age 1824 months, growth rate will increase, pubic
hair develop and virilization proceed. Males will often
be diagnosed due to increased penile size and linear
growth.
Adrenal
6 Nonclassical (mild) forms of 21-OHD may
Selected reading
not have any symptoms during childhood. Borderline
early signs of androgen excess may have passed un- Clayton P, Miller WL, Oberfield SE, Ritzn EM,
noticed, until work-up in adulthood for infertility and Sippell WG, Speiser PW (Joint ESPE/LWPES working
hirsutism (females), or partial adrenal insufficiency group): Consensus statement on 21-hydroxylase
during stress (males and females). deficiency from the European Society for Paediatric
Endocrinology and the Lawson Wilkins Pediatric
7 11-OHD is rare in Northern Europe, but Endocrine Society. J Clin Endocr Metab
constitutes about one third of all CAH in the Middle 2002;87:40484053/Horm Res 2002;58:188195.
East. Hypertension is the clinical hallmark that distin-
Merke DP, Bornstein SR: Congenital adrenal hyper-
guishes this from 21-OHD, but this is not always pres-
plasia. Lancet 2005;365:21252136.
ent, especially not in the neonatal period. Boys may
show gynecomastia if compliance with treatment is Wedell A, Thiln A, Ritzn EM, Stengler B, Luthman
poor. Urinalysis will show increased tetrahydro deriva- H: Mutational spectrum of the steroid 21-hydroxy-
tives. lase gene in Sweden: Implications for genetic
diagnosis and association with disease manifesta-
8 Mutation analysis has become a very useful tion. J Clin Endocrinol Metab 1994;78:11451152.
tool in the diagnosis of both 21-OH and 11-OHD, and
might be used instead of extensive hormone analyses.
The genotype/phenotype correlation is generally good
in 21-OHD.
9 In moderately severe 21-OHD salt loss may
not be clinically evident. However, elevated renin level
in blood indicates that the capacity to produce miner-
alocorticoids is subnormal, and less glucocorticoids
are needed if a small dose (0.050.1 mg/m2) of fludro-
cortisone is added.
10 Conventionally, hydrocortisone treatment is
begun when 21-OHD has been diagnosed. However,
some adult men with mild forms of 21-OHD are diag-
nosed only because of family work-up, without having
presented other symptoms than a somewhat early pu-
berty and shorter stature than expected for family.
Stimulated 17-OHP (nmol/l)
Therefore, it can be argued whether, depending on the
clinical situation, daily glucocorticoid treatment might
1,000
be withheld, and only used in situations of stress. The Severe 21-OHD
long term side effects of daily glucocorticoid medica-
tion might outweigh the benefits. In women, however, 100 Mild 21-OHD
even mild 21-OHD might contribute to infertility and Heterozygotes for 21-OHD
hirsutism. 10 Unaffected
11 Some patients with 11-OHD remain hyper-
tensive even during adequate glucocorticoid treat- 1 10 100 1,000
ment. Spironolactone may then be added to counter- Baseline 17-OHP (nmol/l)
act excess mineralocorticoids.
Nomogram showing the approximate relation between 17-OHP
blood levels before (baseline) and 1 h after i.v. injection of ACTH
(stimulated) in unaffected individuals and patients that are
heterozygotes or affected with mild (nonclassical) or severe
(congenital) 21-OHD. Modified from New et al., J Clin Endocrinol
Metab 1983;57:323.
M. Ritzn R.L. Hintz Congenital adrenal hyperplasia (CAH) presenting after the newborn period
 Water and electrolytes N. Zuckerman-Levin Z. Hochberg A.D. Rogol Polyuria

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 1 Confirm complaint by 24-hour fluid intake and urinary vol-
ume. Polyuria is defined as urinary volume >4 ml/kgh.
2 Wolfram syndrome, type 1 diabetes (T1D) with DI, optic
atrophy and deafness, is caused by mutation in the wolframin gene.
Diabetes mellitus is characterized by increased effective ECF osmo-
lality, due to cell membrane impermeability to glucose. Bardet-Biedl
syndrome patients have retinitis pigmentosa, mental retardation,
deafness, hypogonadism, polydactyly, obesity and diabetes mellitus.
Part of this phenotype is shared by Alstrom syndrome patients who
also have T2D.
3 Potassium deficiency nephropathy occurs with prolonged,
severe hypokalemia and results in the loss of urinary concentration
ability.
4 Osmolality is to be measured in fresh urine and plasma.
The relationship of P/U osmolality is to be read from the nomogram.
Patients with DI are found right of the normal area, and patients with
SIADH are on its left.
5 When Posm is >300 mOsm/kg and the corresponding Uosm
is low according to the nomogram, the diagnosis of DI is very likely.
Random plasma AVP measurements are of little value and levels
should be measured during dynamic testing. AVP is normal or in-
creased in nephrogenic DI during water deprivation and is low in cen-
tral DI.
6 Vasopressin test can be conducted with i.v. desmopressin
(0.03 g/kg). Urine is collected at 1 h, +30 min and +60 min for os-
molality. A Uosm increase of >20% at either of the latter samples is
normal. In central DI, Uosm increases by 50%.
7 X-Iinked recessive nephrogenic DI results from mutations
of the vasopressin V2 receptor. On a vasopressin test, both Uosm,
plasminogen activator and coagulation factors VIII and von Wille-
brand fail to rise in the affected male. Females may have varying re-
sponses.
8 Autosomal-recessive nephrogenic DI results from muta-
tions of the water channel aquaporin-2. On a vasopressin test, plas-
minogen activator and the coagulation factors VIII and von Wille-
brand rise normally.
9 Mannitol and glycerol cause osmotic diuresis. Lithium,
demeclocycline and methoxythirane cause vasopressin resistance.
10 No specific therapy exists. The combination of low Na diet
and thiazide diuretics reduces GFR.
14 Hypertonic NaCl infusion test is used to diagnose partial
pituitary DI. It requires close supervision by an experienced physi-
cian. After a water-load of 600 ml/m2, volume is maintained constant
by q. 30 min oral replacement of urinary volume. 5% saline is infused
at 0.05 ml/kgmin and Uosm is measured q.15 min. The OT is calcu-
lated at real time to avoid prolonged infusion. Do not infuse beyond
Posm = 310 mOsm/kg.
15 The normal OT is 287 2 mOsm/kg. It is shifted upward in
chronic hypodipsia and downward in chronic hyperdypsia.
16 Essential hypernatremia results from an upwards reset-
ting of the OT, along with defective thirst sensation, altered osmotic
trigger for ADH release or both. The non-osmotic release of ADH ap-
pears intact, and these patients are generally euvolmeic. This rare
complication of head trauma requires vasopressin replacement ther-
apy.
17 Partial DI can result form upwards resetting of the OT with
normal maximal Uosm, from vasopressin insufficiency with normal
OT but subnormal maximal Uosm or from a combination of both.
18 Desmopressin is the treatment of choice for all types of
central DI. Oral or nasal administration are advocated for most pa-
tients, and the intravenous route is used in unconscious patients.
19 If MRI is not diagnostic on the first visit, repeat yearly for 5
years, as Langerhans cell type histiocytosis or germ-cell tumors may
become MRI-evident over that period.
20 CNS tumors that cause central DI are most commonly dys-
germinoma (measure hCG, -fetoprotein in serum or cerebral fluid),
craniopharyngioma, and tumors of the third ventricle floor.
21 Langerhans cell type histiocytosis. DI can be the sole
symptom, or as part of a triad with ptosis and osteolytic bone le-
sions. On MRI, the pituitary stalk appears thickened. Chemotherapy
is indicated.
22 Polyuria may be masked by associated ACTH deficiency
and relative water retention. Upon steroid therapy, polyuria reveals
itself. DI can occur after a trauma or pituitary/suprasellar surgery.
23 Genetic DI (familial central DI) has been reported to result
from mutations of the neurophysin domain of the AVP gene. Trans-
mission is usually dominant (examine the parents), but also reces-
sive cases were described. On MRI the bright spot of the posterior
pituitary disappears over time.
24 Hypertonicity will ordinarily not develop as long as free
26 Continue dehydration test to prove normal urinary concen-
tration. Patients with dipsogenic DI continue to drink while their
Uosm drops. A careful (beware of hyponatremia) monitoring of
drinking water will show that after 2 days of desmopressin adminis-
tration, polydipsia will sustain, while a normal subject would reduce
his fluid intake.
27 Whether these patients have a hypothalamic lesion affect-
ing the osmoreceptors is unknown. Hypercalcemia may contribute to
polyuria.
28 Cerebral salt wasting occurs post CNS injury. Patients are
hyponatremic due to excessive loss of sodium in the urine without an
increase in body fluids.
29 Hypercalcemia interferes with the action of vasopressin on
the collecting tubules, suppressing the expression of aquaporin-2.
Proximal tubular function may be impaired, causing sodium loss. In
chronic hypercalcemia deposits of calcium-phosphate salt may
cause interstitial nephritis, nephrocalcinosis and superimposed he-
maturia and UTI.
Selected reading
Asai T, Kuwahara M, Kurihara H, Sakai T, Terada Y, Marumo F,
Sasaki S: Pathogenesis of nephrogenic diabetes insipidus by
aquaporin-2 C-terminus mutations. Kidney Int 2003;64:210.
Knoers NV, Deen PM: Molecular and cellular defects in nephro-
genic diabetes insipidus. Pediatr Nephrol 2001;16:11461152.
Leger J, Velasquez, Garel C, Hassan M, Czernichow P: Thickened
pituitary stalk on magnetic resonance imaging in children
with central diabetes insipidus. J Clin Endocrinol Metab 1999;84:
19541960.
Maghnie M, Cosi G, Genovese E, et al: Central diabetes insipidus
in children and young adults. N Engl J Med 2000;343:9981007.
1,400
1,200
1,000
800 SIADH

Uosm
11 NSAID block PG synthesis and interfere with the vicious access to water is ensured and the thirst mechanism is intact, even
55 circle of polyuria increasing PG, which enhances polyuria. The ben- with urinary concentration defects. In infants, beware of excessive 600

efit from NSAID is not completely documented. fluid provision.

400
12 Identification of the mutation in both X-linked and autoso- 25 The dehydration test calls for hourly P/Uosm determina-
mal-recessive nephrogenic Dl allows for genetic counseling. tion and patient weighing. It requires special precaution and supervi- 200 DI Relation of Posm to Uosm in various
sion, and should be discontinued when P/Uosm relationship is clear- states of hydration. Adapted from
13 Once the diagnosis of pituitary DI is established, a search 0 Moses AM, Streeten DHP: Harrisons
ly normal or abnormal, or when Uosm >310 mOsm/kg.
for its etiology is required by MRI imaging. Langerhans cell type his- 276 280 284 288 292 296 Principles of Internal Medicine.
tiocytosis and germ cell tumors are the most common etiologies. Posm New York, McGraw-Hill, 1998.

Water and electrolytes N. Zuckerman-Levin Z. Hochberg A.D. Rogol Polyuria

 Water and electrolytes W.G. Sippell Z. Hochberg Hyperhydration

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 1 Expanded extracellular space contains ad-
ditional salt. It occurs with sea water drowning, when
infants or children are fed too much salt erroneously,
e.g. with hypertonic saline infusions, in Cushing syn-
drome and Conn syndrome.
2 Most common form, particularly in infants
(receiving adult infusion treatment).
3 Volume expansion of extracellular space.
Occurs in mild cardiac insufficiency, nephrotic syn-
drome, renal failure, liver cirrhosis.
4 Pure water intoxication. Occurs in insuffi-
cient diuresis (renal failure) or freshwater drowning.
Selected reading
Burford AE, Ryan LM, Stone BJ, Hirshon JM, Klein
BL: Drowning and near-drowning in children and
adolescents: a succinct review for emergency phy-
sicians and nurses. Pediatr Emerg Care
2005;21:610616.
Moritz ML, Ayus JC: Prevention of hospital-acquired
hyponatremia: a case for using isotonic saline. Pedi-
atrics 2003;111:227230.
Ruth JL, Wassner SJ: Body composition: salt and
water. Pediatr Rev 2006;27:181187.

5 Most often due to overload of hypotonic in-

fusions and in SIADH (ADH excess) when urinary os-
molality is high (see p. 54).

57

Water and electrolytes W.G. Sippell Z. Hochberg Hyperhydration

 Water and electrolytes W.G. Sippell Z. Hochberg Dehydration

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 1 Relatively more water than electrolytes is
lost. It occurs in infants with diarrhea and pyrexia,
dehydration fever, diabetes insipidus (see p. 54) and
anorexia.
2 Loss of water and electrolytes in the same
ratio as in the extracellular space. It occurs in diarrhea,
vomiting and acute volume depletion leading to shock.
3 Relatively more electrolytes than water are
lost. It occurs in diarrhea in older children and adults,
adrenal insufficiency, renal salt loss (see p. 62).
59
Water and electrolytes W.G. Sippell Z. Hochberg
Selected reading
Armon K, Stephenson T, MacFaul R, Eccleston P,
Werneke U: An evidence and consensus based
guideline for acute diarrhoea management.
Arch Dis Child 2001;85:132142.
Hartling L, Bellemare S, Wiebe N, Russell K, Klassen
TP, Craig W: Oral versus intravenous rehydration
for treating dehydration due to gastroenteritis
in children. Cochrane Database Syst Rev 2006:19;3:
CD004390.
Steiner MJ, DeWalt DA, Byerley JS: Is this child
dehydrated? JAMA 2004;291:27462754.
Dehydration
 Water and electrolytes W.G. Sippell Z. Hochberg Hypernatremia

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 1 E.g. in comatose patients during anesthesia.
2 In neonates check incubator temperature!
3 E.g. diabetes mellitus.
4 Central or renal (see p. 54).
5 E.g. lithium (see p. 55).
6 This often occurs with pyrexia (hyperpy-
retic toxicosis).
Selected reading
Christensen JH, Rittig S: Familial neurohypophyseal
diabetes insipidus an update. Semin Nephrol
2006;26:209223.
Jackson RV, Lafferty A, Torpy DJ, Stratakis C: New
genetic insights in familial hyperaldosteronism. Ann
NY Acad Sci 2002;970:7788.
Moritz ML, Ayus JC: Disorders of water metabolism
in children: hyponatremia and hypernatremia. Pedi-
atr Rev 2002;23:371380.

7 Main feature is hypokalemia and metabolic

alkalosis.

8 Only mild hypernatremia (without escape!)

and no potassium wasting.

9 Mostly due to administration of hypertonic

solutions (i.v., oral, rectal).

10 Most often caused by mother or nurse mix-

ing up salt and glucose/sucrose when preparing infant
feed.

11 Abnormal osmoreceptor control of ADH

secretion, often with hypodipsia or adipsia (see p. 54).

12 E.g. dysgerminoma, craniopharyngeoma,

histiocytosis X.

61

Water and electrolytes W.G. Sippell Z. Hochberg Hypernatremia

 62


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 1 If plasma/serum sodium is below 130
mmol/l. Normal range in neonates 132147, infants ^6
months 129143, children 66 months 132145 mmol/l.
Below 120 mmol/l: threat of convulsions and shock.
Pseudohyponatremia occurs with elevated serum
osmolality (above 295 mOsm/kg), due either to hyper-
lipidemia or hyperproteinemia or to hyperglycemia
(hyperosmolar).
2 Plasma (not serum) osmolality is best mea-
sured by an osmometer, but can be assessed by the
formula:
Osmolality [mOsm/kg] = 2 Na + + glucose + urea
(+ ethanol, etc.) [mmol/l]
or simpler = 2 (Na + + 5) [mmol/l].
Normal range is only available in comparison to the
simultaneous urine osmolality (see p. 54)
3 Evaluate hydration clinically: weight change,
skin turgor, anterior fontanel, mucous membranes,
peripheral edema, (orthostatic) blood pressure, jugu-
lar venous distention, etc. See also Hyperhydration
(p. 56) and Dehydration (p. 58).
4 When the kidney is the source of abnormal
fluid and electrolyte loss, sodium reabsorption is im-
paired even in the presence of volume depletion and
hyponatremia.
5 Lack of mineralocorticoid (decreased Na +
reabsorption) and/or decreased glucocorticoid levels
(impaired water excretion, cf. point 9) account for salt
wasting in Addison disease, salt-losing CAH, congeni-
tal adrenal hypoplasia and congenital hypoaldosteron-
ism.
6 Lack of mineralocorticoid effect (with &&
aldosterone, & PRA) is seen in aldosterone resistance
= pseudohypoaldosteronism, in transient renal imma-
turity in premature infants and in various renal (tubu-
lar) malformation (polycystic kidney disease, etc.) or
dysfunction (chronic pyelonephritis) disorders result-
ing in renal salt loss.
7 Diuretic (ab)use is the most common cause
of hyponatremia in the volume-depleted adult patient.
63 In children it is common with thiazide diuretics.
8 Hyponatremia in the setting of extrarenal
volume loss results from enhance vasopressin release.
Excretion of water is impaired even in the presence of
active sodium reabsorption by the kidney.
Water and electrolytes
9 Primary polydypsia is either habitual (some-
Selected reading
times mother induced) or psychogenic (older children
with eating disorders) or due to brain dysfunction (ex- Adrogue HJ: Consequences of inadequate
clude Dl with hypothalamic lesion). Water deprivation management of hyponatremia. Am J Nephrol
test and desmopressin (dDAVP) test are normal (in 2005;25:240249.
long-standing cases only after several days of treat-
Holliday MA, Friedman AL, Segar WE, Chesney R,
ment) (see pp. 54, 55).
Finberg L: Acute hospital-induced hyponatremia in
children: a physiologic approach. J Pediatr
10 Glucocorticoids inhibit both ACTH and vaso-
2004;145:584587.
pressin release. Conversely, patients with isolated glu-
cocorticoid deficiency may have a profound impair- Pham PC, Pham PM, Pham PT: Vasopressin excess
ment in water excretion due to vasopressin excess. and hyponatremia. Am J Kidney Dis 2006;47:
Cortisol replacement corrects hyponatremia and in- 727737.
creases vasopressin release.
11 Hyponatremia associated with hypothyroid-
ism is more frequently seen in older children. It is due
to impaired renal water excretion and retention of wa-
ter in myxedematic tissues, resulting in an increase in
total body water, whereas plasma volume is normal or
slightly reduced.
12 Syndrome of inadequately increased ADH
secretion (vasopressin excess) due to loss of inhibitory
input via the baroceptor system and/or disturbed vol-
ume receptor and osmoreceptor function. Most com-
mon in mechanically ventilated premature infants. Oc-
curs also in encephalitis, pulmonary disease and with
drug treatment (vincristine, cyclophosphamide, chlor-
propamide and other sulfonylureas, NSAID, opiates,
tricyclic antidepressants, haloperidol, etc.).
Diagnosis Plasma hypo-osmolality and oliguria
with increased urine osmolality. PRA
low/suppressed, serum aldosterone
usually unsuppressed.
Treatment Fluid restriction. In severe cases with
convulsions, confusion or coma,
hypertonic saline (+ furosemide) is
needed.
13 & Urinary sodium loss due to decreased
GFR + decreased tubular Na + reabsorption. Also &
ADH release.
14 Spot urine sodium concentration is reliable
in older infants and children only. Low urinary sodium
concentration due to increased Na+ reabsorption due
to decreased renal perfusion due to decreased effec-
tive arterial blood volume. This leads to & ADH re-
lease which further contributes to hyponatremia.
W.G. Sippell Z. Hochberg Hyponatremia
 Water and electrolytes F. Riepe W.G. Sippell Z. Hochberg Hyperkalemia

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 1 Oversupplementation by i.v. fluids or paren-
Selected reading
teral nutrition.
Evans KJ, Greenberg A: Hyperkalemia: a review.
2 See pp. 50, 52. J Intens Care Med 2005;20:272290.
Geller DS: Mineralocorticoid resistance. Clin Endo-
3 X-Linked, due to DAX-1 mutations, usually
crinol (Oxf) 2005;62:513520.
combined with pubertal failure (isolated gonadotropin
deficiency). Mattsson C, Young WF Jr: Primary aldosteronism:
diagnostic and treatment strategies. Nat Clin Pract
4 Rare autosomal-recessive enzyme deficien- Nephrol 2006;2:198208.
cy of terminal aldosterone biosynthesis, also termed
CMO deficiency. Can be differentiated into 2 types by
specific determination of plasma 18-OH-corticoste-
rone and/or DNA analysis.

5 Hyperkalemia is more pronounced in auto-

somal-recessive PHA (type-1, multi-organ sodium loss
due to mutations in the epithelial sodium channel
(ENaC) than in dominant PHA (type 2 renal sodium
loss, due to mutations in WNK1 or WNK4 genes).

65

Water and electrolytes F. Riepe W.G. Sippell Z. Hochberg Hyperkalemia

 66
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 1 In these conditions there is usually pro-
Selected reading
longed vomiting (e.g. pyloric stenosis), excessive na-
sogastric reflux/aspirate, profuse (severe) diarrhea Gennari FJ: Disorders of potassium homeostasis.
and enterostomy losses. Hypokalemia and hyperkalemia.
Crit Care Clin 2002;18:273288.
2 A group of complex renal tubulopathies due
to mutations in electrolyte channels. Frequently with Landau D: Potassium-related inherited tubulopa-
& renin, & aldosterone, normal blood pressure due to thies. Cell Mol Life Sci 2006;63:19621968.
concomitant renal Na + loss and hypovolemia. Tubular
loss of K+.

3 In children very rare: aldosterone-producing

adenoma (Conn syndrome). Somewhat more com-
mon: idiopathic hyperaldosteronism with normal ad-
renals or with bilateral adrenal (micronodular) hyper-
plasia (see also pp. 46, 47).

4 In this rare, autosomal-dominant disorder

(also called dexamethasone-suppressible hyperaldo-
steronism), aldosterone secretion is continuously
(without escape) stimulated by ACTH. It is caused by a
chimeric recombination of the CYP11B1 (11-OHase)
and CYP11B2 (aldo synthase) tandem genes on chro-
mosome 8q, leading to abnormal expression of
CYP11B2 in the adrenal zona fasciculata with increased
production of the mineralocorticoids 18-OH-S, 18-OH-
cortisol and 18-oxo-cortisol (see also pp. 46, 47).

5 Rare autosomal-recessive disorder due to

defective oxidation of cortisol to cortisone by 11-
HSD-2 gene mutations. Unmetabolized cortisol binds
to renal mineralocorticoid receptor, inducing hyper-
tension and hypokalemia. Same clinical and laboratory
pattern in Liddle syndrome (defective renal tubular
Na+ transport; triamterene corrects hypokalemia) and
in excessive ingestion of liquorice (see also pp. 46, 47).

6 Occurs during recovery from major tissue

damage, e.g. major surgery, malnutrition or during
treatment of diabetic coma (insulin administration).

7 Most often due to insufficient enteral or i.v.

supplements.

67

Water and electrolytes F. Riepe W.G. Sippell Z. Hochberg Hypokalemia

 Calcium metabolism D. Tiosano Z. Hochberg Hypercalcemia

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 * Neonatal hypercalcemia is referred to by an asterisk.
Idiopathic infantile hypercalcemia is transient and of-
ten considered as part of Williams syndrome, with
varying combinations of mental retardation, elfin faces
and supravalvular aortic stenosis. Other rare causes in
infancy include extensive subcutaneous fat necrosis
and the blue diaper syndrome.
1 The definition of hypercalcemia is age de-
pendent: Total serum calcium concentration in prema-
ture infants of >9.2 mg/dl (2.3 mmol/l); in full-term in-
fants >10.4 mg/dl (2.6 mmol/l); in children and adoles-
cents >10.8 mg/dl (2.7 mmol/l). Ionized calcium in pre-
mature infant is >5.8 mg/dl (1.5 mmol/l); in full-term
infants >5.0 mg/dl (1.3 mmol/l); in children and adoles-
cents >5.0 mg/dl (1.3 mmol/l).
2 Hypercalcemic crisis manifest with dehydra-
tion, hypertension and convulsions or coma. It may
develop when serum calcium exceeds 14 mg/dl (3.5
mmol/l), and such high serum levels have to be con-
sidered as a pending crisis. Intravenous 0.9% NaCI
with furosemide is the treatment of choice, and
bisphosphonate, glucocorticoids and calcitonin may
be added. In life-threatening crisis peritoneal dialysis
or hemodialysis has been advocated.
3 Children are more susceptible than adults to
hypercalcemia of immobilization. Hypertension is an
additional feature in such patients. In cases of immobi-
lization with malignancy the latter may be the major
factor.
4 Hyperthyroidism induces bone resorption
with hypercalcemia and suppressed PTH. Hypercalce-
mia was also reported in hypothyroidism, and attrib-
uted to increased sensitivity to vitamin D.
5 Thiazide may cause hypercalcemia due to
increased renal reabsorption of calcium and increased
calcium-binding protein. Hypervitaminosis A after in-
7 Hypercalcemia of adrenal insufficiency re-
sults from enhanced renal and intestinal reabsorption
due to deficiency of the calcium-suppressing gluco-
corticoids. Volume contraction and increased serum
calcium-binding protein contribute as well. Hypercal-
cemia is also an unusual manifestation in pseudohy-
poaldosteronism.
8 In the recovery phase from acute renal fail-
ure hypercalcemia may be observed for a short period
of time due to increased PTH.
9 In a spot urine, the normal calcium/creati-
nine ratio is age dependent.
10 A nonsymptomatic autosomal-dominant
condition of parathyroid insensitivity to the normal
suppressive effect of calcium on PTH secretion, due to
dominant mutations in the calcium calcium-sensing
receptor (CaSR). One of the parents may be affected.
* The homozygous condition is characterized by se-
vere often lethal neonatal hyperparathyroidism.
11 Serum phosphate levels are age dependent
(see Rickets, p. 72 algorithm). Tubular reabsorption of
phosphorus (TRP) is calculated from the ratio of phos-
phorus to creatinine clearance (see Rickets, p. 72 al-
gorithm).
12 Hypophosphatemia per se may induce hy-
percalcemia by way of stimulating calcitriol synthesis.
* ln newborn infants P needs to be added to parenteral
nutrition. Preterm infants may develop phosphate de-
pletion when given human milk.
13 PTHrp is produced by several types of tu-
mors. Immobilization and bone invasion by the tumor
may contribute. This condition is the major cause of
hypercalcemic crises.
14 Serum P is usually reduced, but may be nor-
15 MEN needs to be considered in any child
with hyperparathyroidism. The autosomal-dominant
nature of MEN-1 and MEN-2 inheritance requires ex-
amination of both parents and siblings. 90% of pa-
tients with MEN-1 have a parathyroid hyperplasia,
along with pituitary adenoma and/or pancreatic tumor.
In MEN-2, medullary thyroid carcinoma and pheochro-
mocytoma are the main features, and chief-cell hyper-
plasia is sometimes associated.
16 Activating mutation of the PTH receptor is
characterized by hypercalcemia, increased bone re-
sorption and delayed cartilage differentiation.
17 Hypervitaminosis D does not occur unless
,millions of units of vitamin D are taken.
* Absorptive hypercalcemia has been attributed to
increased sensitivity to normal amounts of vitamin D
in some infants, although this mechanism has not
been confirmed and serum calcitriol is normal.
18 The granulomatous tissues (i.e. sarcoidosis)
generate calcitriol.
Selected reading
Bilezikian JP, Silverberg SJ: Clinical practice:
asymptomatic primary hyperparathyroidism.
N Engl J Med 2004;350:17461751.
Goodman WG: Calcium-sensing receptors.
Semin Nephrol 2004;24:1724.
Jacobs TP, Bilezikian JP: Clinical review:
rare causes of hypercalcemia. J Clin Endocrinol
Metab 2005;90:63166322.
Rodriguez Soriano J: Neonatal hypercalcemia.
J Nephrol 2003;16:606608.

Urinary calcium/creatinine
1.0
gestion of 50,000 units per day or more may induce mal. The Skeletal erosion is best evident in the phalan- 0.9
enhanced bone resorption that may be severe enough ges and clavicle, but may be lacking. Sporadic cases 0.8
to develop into nephrocalcinosis and renal failure. Alu- result from either adenoma or chief-cell hyperplasia. 0.7

(mg/mg)
minum in patients with chronic renal disease binds Treatment is surgical. 0.6
phosphate and may increase calcitriol levels. * Hypocalcemia of a pregnant mother with hypopara- 0.5
69 * Thiazide, vitamin A and lithium ingested during ges- thyroidism will stimulate the fetal parathyroid gland 0.4
tation may cause neonatal hypercalcemia. and will result in a transient form of hyperparathyroid- 0.3
0.2
ism. Inherited hyperparathyroidism (see 10) may be
0.1
6 Alkalosis of any cause interferes with renal evident in infancy. 0
calcium excretion. In the milk-alkali syndrome alkalosis
is associated also with increased calcium intake in the 0 2 4 6 8 10 12 14 16
form of milk or CaCO3. Age (years)

Calcium metabolism D. Tiosano Z. Hochberg Hypercalcemia

 Calcium metabolism D. Tiosano Z. Hochberg Hypocalcemia

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 Diagnosis and therapy are related to the following
variables
(1) Age of the patient
Neonatal-early, days 13: premature, maternal dia-
betes or preeclampsia, RDS.
Neonatal-late, days 410: cows milk hyperphos-
phatemia, maternal hypercalcemia.
Infantile to 34 months: nutritional rickets.
Di George syndrome, pseudohypopara-
thyroidism 1a.
Childhood: pseudohypoparathyroidism 1b.
(2) Serum Pi
High Pi: renal failure or hypoparathyroidism.
Low Pi: vitamin D or Mg deficiency.
(3) General clinical status
Syndrome, infiltrative, autoimmune, renal, liver,
malabsorption, bone diseases, drugs, alcohol.
(4) Duration of hypocalcemia
Chronic (cataracts, basal ganglia calcification): hy-
poPTH.
*Neonatal hypocalcemia.
Early neonatal hypocalcemia results from prematurity,
birth asphyxia or maternal diabetes. Transfusion of
citrated blood results in decreased ionized calcium
with normal total calcium levels.
1 The definition of hypocalcemia is age de-
pendent (see Hypercalcemia, p. 68). If symptomatic,
treat with 10% calcium gluconate solution 0.5 ml/kg
infused in 510 min. If symptoms persist, repeat this
dose.
The effect of hypoalbuminemia can be corrected by
using the formula:
Corrected serum Ca (mg/dl) = Measured serum Ca
(mg/dl) + 0.8*[4 measured albumin (mg/dl)].
2 Conditions associated with malabsorption
and including malabsorption of vitamin D include: ce-
liac disease, cystic fibrosis, biliary cirrhosis, pancreatic
insufficiency and chronic pancreatitis, intestinal by-
pass, laxative abuse. They all lead to malabsorptive
rickets (see Rickets. p. 72).
71
Calcium metabolism
3 See Rickets. p. 72.
4 Anticonvulsant drugs see Rickets. p. 72.
Other forms of iatrogenic hypocalcemia include blood
transfusions with either EDTA or citrate, excessive use
of fluoride, colchicine, ketoconazole and pentamidine,
bisphosphonate, calcitonin, mithramycin, gallium ni-
trate and foscarnet.
5 Anticonvulsants during pregnancy have
been reported to cause neonatal hypocalcemia.
6 Urinary calcium is age-dependent; see
Hypercalcemia p. 54 .
7 Gain of function mutations of the calcium-
sensing receptor (CaSR) cause autosomal-dominant
hypocalcemia with hyperalciuria. Therapy is required
only if hypocalcemia is symptomatic.
8 Serum PTH levels need to be related to the
concurrent serum calcium. High PTH is the normal re-
sponse to hypocalcemia and, therefore, normal PTH
in a patient with hypocalcemia indicates relative hypo-
parathyroidism.
9 The diagnosis of hypoparathyroidism re-
quires low calcium, high phosphate and no bone dis-
ease on X-ray. HypoPTH may be postsurgical, a part of
a polyglandular autoimmune disease, or secondary to
infiltrative diseases (thalassemia major, hemochroma-
tosis, Wilson disease, metastatic carcinoma), neck
irradiation or idiopathic. Treatment with i.v. (if hypocal-
cemia is symptomatic) or oral calcium is to be fol-
lowed by 1-OHD or calcitriol.
* Hypoparathyroidism of the newborn results from
congenital malformations (aplasia or Di George
syndrome), hereditary disorder (X-linked or autoso-
mal-recessive) and GCMB mutations.
10 Cataracts and calcifications of basal ganglia
indicate chronicity of the disease.
D. Tiosano Z. Hochberg
11 Pseudohypoparathyroidism results from
peripheral resistance to PTH. In type 1 PHP dominant
G protein gene mutation, with or without Albright os-
teodystrophy, is of early childhood onset and can be
found in one of the parents. There is no stimulation of
either cAMP or phosphaturia by PTH. In type 2 PHP,
cAMP increases after PTH but no phosphaturia results.
12 * Hypercalcemia of the pregnant mother will
suppress fetal parathyroid gland and will result in a
transient form of hypoparathyroidism.
13 See Hypomagnesemia, p. 74.
Selected reading
Aggarwal R, Upadhyay M, Deorari AK, Paul VK:
Hypocalcemia in the newborn. Indian J Pediatr
2001;68:973975.
Bastepe M, Juppner H: GNAS locus and pseudo-
hypoparathyroidism. Horm Res 2005;63:6574.
Ding C, Buckingham B, Levine MA: Familial isolated
hypoparathyroidism caused by a mutation in the
gene for the transcription factor GCMB. J Clin Invest
2001;108:12151220.
Umpaichitra V, Bastian W, Castells S: Hypocalcemia
in children: pathogenesis and management.
Clin Pediatr (Philad) 2001;40:305312.
Hypocalcemia
 Calcium metabolism D. Tiosano Z. Hochberg Rickets (neonatal rickets)

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 * Neonatal rickets does not show the typical radiological rachitic 11 Due to decreased serum vitamin D-binding globulin, the 20 Mg-AI-OH chelates intestinal phosphorus.
changes. As secondary hyperparathyroidism may develop late, it clearance of vitamin D is accelerated, leading to increased loss of vi- * Neonatal rickets has been reported.
may show as a combined rickets and hypoparathyroidism. It is re- tamin D. Treatment is with increasing doses of vitamin D. Only when
ferred to by an asterisk. associated with renal failure, 1-OHD or calcitriol need to be used. 21 * lnfantile rickets may result from P deficiency.

1 The term rickets applies to children only, and the disease
is defined by changes in the growth plate, whereas adults with the
same defects have osteomalacia. The diagnosis is based on X-rays
and increased bone-derived alkaline phosphatase.
2 Serum calcium levels are age dependent: Total serum cal-
cium concentrations are 7.29.2 mg/dl (1.82.3 mmol/l) in premature
infants, 810.4 mg/dl (22.6 mmol/l) in full-term infants, and 8.710.8
mg/dl (2.22.7 mmol/l) in children and adolescents. Ionized calcium
is 5.25.8 mg/dl (1.31.5 mmol/lin premature infants), 4.05.0 mg/dl
(1.01.3 mmol/l) in full-term infants, and 4.65.0 mg/dl (1.11.3 mmol/
l) in children and adolescents.
3 Serum PTH levels need to be related to the concurrent se-
rum calcium. High PTH is the normal response to hypocalcemia and,
therefore, normal PTH in a patient with hypocalcemia indicates rela-
tive hypoparathyroidism.
4 During the first 3 months of life rickets may develop with-
out secondary hyperparathyroidism, and result in hypocalcemia and
hyperphosphatemia with high bone-derived alkaline phosphatase
levels.
12 Hepatic rickets and defective 25-hydroxylation of vitamin
D may develop in biliary atresia or biliary cirrhosis.
13 Anticonvulsant drugs may cause hypocalcemia, mostly in
institutionalized children who also have limited exposure to sunlight
or in malnourished children. Phenytoin interferes with intestinal cal-
cium absorption and calcium release from bone. Barbiturates induce
vitamin D catabolism. Other forms of iatrogenic hypocalcemia in-
clude blood transfusions with either EDTA or citrate, excessive use of
fluoride, colchicine, ketoconazole and pentamidine, bisphosphonate,
calcitonin, mithramycin, gallium nitrate and foscarnet. Alcohol in-
creases vitamin D catabolism. Malnutrition contributes to this rachit-
ic syndrome.
14 Serum phosphate levels are age dependent.
TRP is calculated from the ratio of phosphorus to creatinine clear-
ance. In this ratio urinary volume and the time are reduced, and the
calculation can be made for a spot urine and serum measurements of
creatinine and phosphorus:
TRP = [1 (Up Scr)/(Ucr Sp)]*100. Normal values are 8090%. The
renal threshold-concentration of P, TmP/GFR can be derived from the
TRP and the serum phosphate.
Selected reading
Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW:
Genetic evidence that the human CYP2R1 enzyme is a key vitamin
D 25-hydroxylase. Proc Natl Acad Sci USA 2004;101:77117715.
Jan de Beur SM, Levine MA: Molecular pathogenesis of hypo-
phosphatemic rickets. J Clin Endocrinol Metab 2002;87:24672473.
Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M,
Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM,
Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ,
Glorieux F, Vikkula M, Juppner H, Strom TM: DMP1 mutations in
autosomal recessive hypophosphatemia implicate a bone matrix
protein in the regulation of phosphate homeostasis. Nat Genet
2006;38: 12481250.
Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-
Rakover Y, Wagenstaller J, Tiosano D, Gershoni-Baruch R,
Albers N, Lichtner P, Schnabel D, Hochberg Z, Strom TM:
Hereditary hypophosphatemic rickets with hypercalciuria is
caused by mutations in the sodium-phosphate cotransporter
gene SLC34A3. Am J Hum Genet 2006;78:193201.

5 Vitamin D-resistant rickets type II, results from defective
vitamin D receptor or postreceptor mechanisms. This is the only
type of rickets associated with very high serum 1,25(OH)2D. In mild
cases or early diagnosis oral calcium may be sufficient, but in more
severe cases calcium has to be administered i.v.
6 In chronic renal failure, when over 75% of renal function is
lost, defective 1-hydroxylation of 25(OH)D may cause rickets.
7 Vitamin D-dependent rickets type 1 results from inherited
defect of 1-hydroxylation of 25(OH)D.
15 Hypophosphatemic rickets includes several clinical entities Wolpowitz D, Gilchrest BA: The vitamin D questions: how much do
that can be characterized by the levels of 1,25(OH)2D. In the presence you need and how should you get it? J Am Acad Dermatol
of hypophosphatemia alone 1-hydroxylase activity is enhanced, but 2006;54:301317.
if FGF23 levels are also elevated, it will hold up 1-hydroxylase activ-
ity and will result with inappropriate for the low Pi low 1,25(OH)2D
levels. Thus, inappropriately low 1,25(OH)2D levels indicates height
FGF23 levels.
16 Renal tubular functions include for that matter HCO3, glu-
cose, uric acid and amino acid excretion.
17 Therapy with phosphorus and calcitriol or 1-OH vitamin

Urinary calcium/creatinine
8 Vitamin D deficiency may occur when exposure to sunlight D. The aim of therapy is to normalize phosphorus levels. 1.0
is inadequate or vitamin D is not supplied. 0.9
0.8
18 Patients demonstrate normocalcemic hypercalciuric rick- 0.7

(mg/mg)
9 Calcium deficiency may occur in severe malnourishment, ets with low serum P and hyperphosphaturia. Serum 1,25(OH)2D is 0.6
and is common in Sub-Saharan Africa where children have a low cal- appropriately high and, thus, vitamin D preparations are contraindi- 0.5
cium diet reach in the calcium absorption competitive inhibitors phy- cated and would result in nephrocalcinosis. Heterozygotes have hy- 0.4
73 tate and oxalate. percalciuria only. 0.3
0.2
10 Malabsorption syndromes that affect fat-soluble vitamins 19 Syndromes associated with Fanconi tubulopathy include 0.1
include celiac disease, chronic small-bowel disease and pancreatic 0
Wilson disease, Lowe disease, tyrosinemia, glycogen storage dis-
insufficiency. ease and cystinosis. Phosphaturia and calciuria may be aggravated 0 2 4 6 8 10 12 14 16
by renal tubular acidosis. Age (years)

Calcium metabolism D. Tiosano Z. Hochberg Rickets (neonatal rickets)

 Calcium metabolism A.D. Rogol Z. Hochberg Hypomagnesemia

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 1 History is a most important element, espe-
cially of gastrointestinal or renal tubular injury; symp-
toms of muscular twitching and tremor; may have
numbness and tingling.
2 Assay plasma concentration; hypocalcemia
and potassium depletion are frequent manifestations
of magnesium deprivation. Red cell magnesium levels
may also be a measure of magnesium depletion.
3 Small for gestational age.
4 Give less over next few days (0.10.5 mEq/
kg day).
5 Bartters syndrome refers to a group of dis-
orders that are unified by autosomal-recessive trans-
mission of impaired salt reabsorption in the thick as-
cending limb of Henle with pronounced salt wasting,
hypokalemic metabolic alkalosis and hypercalciuria.
Its features include short stature, hyperactive renin-
angiotensin system, lack of effect of angiotensin on
blood pressure, renal salt wasting, an increase in renal
prostaglandin production and (variable) hypomagne-
semia. Gitelman syndrome is considered a variant that
has hypokalemic alkalosis in conjunction with hypo-
calciuria and hypomagnesemia.
75
Calcium metabolism
The Gitelman variant is caused by a mutation in the
Selected reading
thiazide sensitive Na-Cl co-transporter, SLC12A3,
OMIM 600968. The Bartter syndrome may be due to Knoers NVAM, de Jong JK, Meij Ic, Lamert PWJ,
mutations in several genes: antenatal type 1 (OMIM Van Den Heuvel J, Bindels RJM: Genetic renal disor-
601678) is due to loss of function mutations in the bu- ders with hypomagnesemia and hypocalciuria.
mentanide-sensitive Na-K-2Cl cotransporter NKCC2 J Nephrol 2003;16:293296.
(SLC12A1, OMIM 600839; the antenatal type 2 is due to
Shaer AJ: Inherited primary renal tubular hypokale-
loss of function mutations in the ATP-sensitive K chan-
mic alkalosis: a review of Gitelman and Bartter
nel, ROMK, KCNJ1, OMIM 600359, and the type 3 syn-
syndromes. Am J Med Sci 2001;322:316332.
drome is due to mutations in the kidney chloride chan-
nel B gene, CLCNKB (OMIM 602023). Topf JM, Murray PT: Hypomagnesemia and
hypermagnesemia. Rev Endocr Metab Dis 2003;4:
FXYD2; OMIM 601814. Dominant negative mutation in 195206.
the gene encoding the Na+, K(+)-ATPase gamma sub-
unit leading to a defective routing of protein which
does not reach the plasma membrane
Claudin 16; CLDN 16; OMIM 603959. Essential in the
paracellular pathway for Mg reabsorption and is ex-
pressed in the thick ascending limb of Henle and in the
distal convoluted tubule. Most of the mutant proteins
are retained in the endoplasmic reticulum.
6 Irrespective of cause, magnesium is neces-
sary for PTH secretion as well as end organ action.
A.D. Rogol Z. Hochberg Hypomagnesemia
 Thyroid T.P. Foley, Jr. F. Pter Congenital hypothyroidism

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 1 Newborn screening tests: The dried blood
specimen is collected by heel prick of the infant usu-
ally prior to discharge, preferably after 24 h of age to
avoid a higher frequency of false-positive values. The
three most common screening methods for congenital
hypothyroidism using dried blood specimens are:
(a) primary TSH screen; (b) primary T4 screen with con-
firmatory TSH on the lowest 520% of T4 values, and
(c) primary TSH and primary T4 screen. The measure-
ment of TSH and total T4 on every neonate provides
comprehensive screening for CH of primary and cen-
tral (hypothalamic-pituitary) etiology with the lowest
false-negative results. The addition of TBG screening
on specimens with low T4 screening results reduces
the number of false-positive rates on with low T4
screening values. The use of tandem mass spectrom-
etry to measure along with many other analytes keeps
the cost of screening for CH as low or lower than the
other two programs. To date no valid and reproducible
free T4 screening method is available, though very de-
sirable.
2 Maternal history and physical examination
of the infant may disclose the etiology for abnormal
screening tests for hypothyroidism: (a) maternal auto-
immune thyroid disease may be associated with trans-
placentally acquired TSH-receptor-blocking antibodies
that may induce transient primary congenital hypothy-
roidism in the neonate; (b) maternal autoimmune thy-
roid disease may be associated with transplacentally
acquired TSH-receptor-stimulating antibodies from
mothers with active Graves disease who are receiving
treatment with antithyroid drugs that cross the pla-
centa and may cause neonatal goiter with/without
transient primary hypothyroidism; (c) maternal iodine
deficiency or exposure of mother and/or neonate to
supraphysiologic amounts of iodide may cause tran-
sient neonatal goiter and hypothyroidism.
3 Serum free T4 should be measured by direct
dialysis or methods whose validity has been docu-
mented in cord or neonatal serum specimens by cor-
relation with values obtained by direct dialysis.
77
Thyroid
4 A thyroid image by ultrasound or scan with
technetium pertechnetate will confirm within 2 h, the
suspected diagnosis of these disorders: (a) ectopic
thyroid dysgenesis and the life-long need for thyroxine
therapy; (b) athyreosis (in the absence of TSH-receptor
antibodies); (c) familial dyshormonogenesis with goi-
ter in the absence of iodine deficiency. The procedure
has no known risk and can be easily and accurately
performed and interpreted by experienced pediatric
nuclear medicine specialists. A scan to suggest the
presence of familial disease is important for genetic
counseling of the parents.
5 Undetectable serum thyroglobulin values
confirm the absence of thyroid tissue or the diagnosis
of thyroglobulin synthetic defects in neonates or chil-
dren with a eutopic thyroid, thyromegaly, or a normal-
sized thyroid, and primary hypothyroidism.
6 Neonates with low serum total and free T4
and low, normal or mildly elevated serum TSH must
be evaluated for hypothalamic-pituitary hypothyroid-
ism. Clinical features often seen in infants with con-
genital hypopituitarism include: (a) unexplained hypo-
insulinemic hypoglycemia; (b) combined direct and
indirect hyperbilirubinemia; (c) midline facial and/or
CNS birth defects, and (d) hypogonadism in male in-
fants (micropenis and testicular volume 1 ml). A serum
cortisol test is required before T4 therapy is started in
order to determine or exclude the presence of CRF-
ACTH-Adrenal Insufficiency. Infants with low cortisol
values must be treated with hydrocortisone before T4
therapy is initiated in order to prevent the induction of
acute adrenal insufficiency.
T.P. Foley, Jr. F. Pter
Selected reading
American Academy of Pediatrics; Rose SR; Section
on Endocrinology and Committee on Genetics,
American Thyroid Association; Brown RS; Public
Health Committee, Lawson Wilkins Pediatric
Endocrine Society; Foley T, Kaplowitz PB, Kaye CI,
Sundararajan S, Varma SK: Update of newborn
screening and therapy for congenital hypothyroid-
ism. Pediatrics 2006;117:22902303.
Fisher D: Next generation newborn screening for
congenital hypothyroidism? J Clin Endocrinol
Metab 2005;90:37973799.
Fu J, Jiang Y, Liang L, Zhu H: Risk factors of primary
thyroid dysfunction in early infants born to mothers
with autoimmune thyroid disease. Acta Paediatr
2005;94:10431048.
Kempers MJ, Lanting CI, van Heijst AF, van
Trotsenburg AS, Wiedijk BM, de Vijlder JJ, Vulsma T:
Neonatal screening for congenital hypothyroidism
based on thyroxine, thyrotropin, and thyroxine-
binding globulin measurement: potentials and
pitfalls. J Clin Endocrinol Metab 2006;91:33703376.
Knobel M, Medeiros-Neto G: An outline of inherited
disorders of the thyroid hormone generating
system. Thyroid 2003;13:771801.
La Gamma EF, van Wassenaer AG, Golombek SG,
Morreale de Escobar G, Kok JH, Quero J, Ares S,
Paneth N, Fisher D: Neonatal thyroxine supplemen-
tation for transient hypothyroxinemia of prematu-
rity: beneficial or detrimental? Treat Endocrinol
2006;5:335346.
Nelson JC, Wilcox RB: Analytical performance of
free and total thyroxine assays. Clin Chem
1996;42:146154.
Peter F: Thyroid dysfunction in the offspring of
mothers with autoimmune thyroid diseases.
Acta Paediatr 2005;94:10081010.
van Tijn DA, de Vijlder JJM, Verbeeten B Jr, Verkerk
PH, Vulsma T: Neonatal detection of congenital
hypothyroidism of central origin. J Clin Endocrinol
Metab 2005;90:33503359.
Van Vliet G, Polak M: Thyroid disorders in infancy;
in Lifshitz F (ed): Pediatric Endocrinology, ed 5.
New York, Informa Healthcare, 2007, vol 2, Section
III: Thyroid Disorders, chap 16, pp 391404.
Congenital hypothyroidism
 Thyroid F. Pter T.P. Foley, Jr. Juvenile hypothyroidism

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 1 History of surgery or irradiation in the neck
region, iodine deficiency or excess, natural or synthet-
ic substances blocking thyroid hormonogenesis, infec-
tions, etc., as well as cold intolerance, constipation,
bradycardia, decreased pulse pressure, cool, dry and
pigmented skin, mild obesity despite decreased appe-
tite, retardation of growth, fall of intellectual achieve-
ment, delayed (rarely precocious) puberty or irregular
menses, possible galactorrhea could be informative.
2 The most sensitive finding of hypothyroid-
ism is elevation of the TSH level. In cases of moder-
ately elevated TSH levels increased TSH stimulation in
TRH test may confirm the suspected diagnosis of mild
forms.
3 The damage of the hypothalamopituitary
region by tumor or other infiltration, inflammation,
irradiation, etc., can result in secondary or/and tertiary
hypothyroidism. Besides the image techniques such
as computerized tomography scan or MRI, the deter-
mination of the reserve for other pituitary hormones,
such as GH, ACTH, LH and FSH can confirm the diag-
nosis.
4 Some forms of hypothyroidism can mani-
fest after the neonatal period and not be detected by
newborn screening with or without enlargement of
thyroid.
5 Ultrasonography is recommended espe-
cially in the regions with iodine deficiency. This nonin-
vasive and safe examination of echotexture may help
the early diagnosis of chronic thyroiditis to avoid the
iodine therapy in these cases.
79
Thyroid
6 Chronic lymphocytic thyroiditis presents
Selected reading
anytime after age 6 months with growth retardation
and the symptoms and signs of hypothyroidism. All of Foley TP Jr, Malvaux P, Blizzard RM: Thyroid
the diagnostic tests for chronic lymphocytic thyroid- disease; in Kappy MS, Blizzard RM, Migeon CJ (eds):
itis: the noninvasive ultrasonography (hypoechoden- Wilkins: The Diagnosis and Treatment of Endocrine
sity), thyroid antibodies in serum or cytology of the Disorders in Childhood and Adolescence, ed 4.
thyroid can give false (positive/negative) results in io- Springfield, Thomas, 1994, pp 457533.
dine-deficient areas; in this case the correct diagnosis
Rivkees SA: Hypothyroidism and hyperthyroidism
needs positivity at least in two tests.
in children; in Pescovitz OH, Eugster EA (eds): Pedi-
atric Endocrinology: Mechanisms, Manifestations,
7 Mild, late onset forms of congenital hypo-
and Management. Philadelphia, Lippincott Williams
thyroidism, or drug-induced cases, hypothyroidism
& Wilkins, 2004, pp 508521.
after irradiation or surgery of thyroid, transient sub-
acute thyroiditis, etc., can lead to acquired hypothy- Svenson J, Ericsson UB, Nilsson P, et al: Levothyrox-
roidism in children. ine treatment reduces thyroid size in children and
adolescents with chronic autoimmune thyroiditis. J
8 Inborn errors of hormone synthesis (dyshor- Clin Endocrinol Metab 2006;91:17291734.
monogenesis) with goiter (rarely without goiter) may
Van Vliet G: Hypothyroidism in infants, children, and
be in form of thyroid resistance to TSH, defect of io-
adolescents: acquired hypothyroidism; in Braver-
dine transport into the thyroid cells, defect of iodine
man LE, Utiger RD (eds): The Thyroid, ed 9. Philadel-
oxidation to elemental iodine (a special subgroup by
phia, Lippincott Williams & Wilkins, 2005, pp 1041
the name of Pendred syndrome is hypothyroid goiter
1047.
with sensorineural deafness), inability of iodinated
tyrosines to couple to thyroxine, disturbed synthesis Willgerodt H, Keller E, Bennek J, Emmrich P: Diag-
and degradation of thyroglobulin and deiodinase de- nostic value of fine-needle aspiration biopsy of thy-
fect of iodotyrosines. Despite increased radioiodine roid nodules in children and adolescents. J Pediatr
uptake of the thyroid (except the two first forms) these Endocrinol Metab 2006;19:507515.
patients have hypothyroidism. Therapy: in the defects
of trapping and deiodination: iodine supply, in other
forms: L-T4 replacement.
9 Partial peripheral resistance to thyroid hor-
mones is extremely rare. Clinical hypothyroidism with
hormonal euthyroidism (very rarely) may be caused
by selective peripheral resistance to thyroid hor-
mones.
F. Pter T.P. Foley, Jr. Juvenile hypothyroidism
 Thyroid F. Pter T.P. Foley, Jr. Hyperthyroidism

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 1 Positive family history, change of behavior (nervousness),
tremor, weight loss despite increased appetite, lessening of school
achievement, uncoordinated movements, heat intolerance, restless
sleep, nocturia, increased pulse pressure, vitiligo, and alopecia can
be typical. From the original triad (tachycardia, goiter, exophthalmos)
describing Graves disease, the least common is ophthalmopathy. It
is relatively mild in positive cases; the severe form is extremely rare.
In such children with increased clinical activity score and severity of
ophthalmopathy the therapy is not solved.
2 Both T3/FT3 and T4/FT4 level could be informative. T3/FT3
increases first but some commercial tests for FT3 may give a false
high level! T3/T4 ratio may be above 20. T4/FT4 is also elevated.
3 TSH is suppressed (decreased with supersensitive meth-
od). If not, TSH level does not increase in the TRH test.
4 Subacute thyroiditis is rarely seen in childhood (fever, ten-
derness or pain of the thyroid gland, malaise). The ESR, WBC, serum
2- and -globulin levels may be elevated. In spite of hyperthyroid
hormone results, radioiodine uptake of thyroid is low! Therapy see
Goiter (p. 84). It can start with a thyrotoxic phase followed by euthy-
roid and mild hypothyroid phases. The final prognosis is good.
5 Acute or chronic overdose/ingestion of thyroid hormone
preparations cause usually mild symptoms of thyrotoxicosis with
fever, tachycardia, hyperactivity, irritability, vomiting and diarrhea. T3
level remains normal, Tg and thyroid radioiodine uptake decrease,
especially in chronic ingestion. The overdose of thyroid hormone
has to be discontinued in these cases.
99m
6 Tc or 123I are used for thyroid scan in childhood.
7 The autonomous thyroid nodule is relatively rare (less
than 10% of thyrotoxic patients in children and adolescents) and
sometimes clinically euthyroid. Can be associated with other dis-
eases (e.g. McCune-Albright, Cushing syndrome) and can be single
or multiple (see Thyroid nodules, p. 86, for a detailed view).
8 Anti Tg and anti TPO antibodies seem to indicate damage
of thyroid tissue; TSI or TSAb have a central role in the pathogenesis
of Graves disease. The most common commercial test for TRAb
measures both TSH receptor-stimulating and -inhibiting antibodies.
9 In cases of bad tolerance of drugs (toxicity), in therapy re-
sistance, if the goiter is very large (airway obstruction, dysphagia) or
81 nodule(s) develop(s) in the gland, in the case of bad compliance one
of the definitive therapies has to be chosen. After (near)-total thy-
roidectomy the patients usually become hypothyroid. The relapse
rate is very low.
Thyroid
10 Among the definitive treatment methods, the earlier,
cheaper, more pleasant one is radioiodine therapy. The topic of dis-
cussion is the theoretical risk of radiation. Relatively high (ablative)
doses of radioiodine should be administered. This method is more
accepted in the USA than in Europe; however, the number of centers
using this form of treatment is increasing. These patients become
hypothyroid too.
11 Methimazole, carbimazole, thiamazole and PTU are the
most common antithyroid drugs (the first three are practically inter-
changeable). PTU inhibits conversion of T4 to T3 but its half-life is
much shorter (ca. one-fourth) than the others. The toxicity of these
drugs is similar (rash, arthralgia, fever, agranulocytosis, etc.) and the
cross-sensitivity of the two types of thionamides is up to 50%. It is
possible to administer antithyroid drugs alone (monotherapy) or in
combination with L-T4. Important aim is not to cause hypothyroidism
during antithyroid therapy (Follow-up: T3, T4 later on TSH.)
12 -Adrenergic blocking agents are helpful regardless of the
form of thyrotoxicosis: propranolol has some decreasing effect to the
5-monodeiodination too.
13 Autosomal-dominant or sporadic non-autoimmune thyro-
toxicosis due to germline mutations in the TSH receptor. May be pos-
itive family history, thyrotoxic symptoms without ophthalmopathy.
DNA analysis for germline mutations (see Neonatal hyperthyroid-
ism, p. 82). Treatment: in mild form ATD but mostly definitive thera-
py (surgery or radioiodine independently of age).
14 There are several definitions for the term Hashitoxicosis.
So: co-existence of chronic lymphocytic thyroiditis and Graves dis-
ease (both antithyroid- and TSH receptor antibodies are positive)
[Brown RS, Huang S: The thyroid and its disorders; in Brook Ch, Clay-
ton P, Brown RS (eds): Clinical Pediatric Endocrinology, ed 5. Oxford,
Blackwell, 2005, pp 241, 247]. These patients need a lower dose of an
antithyroid drug and do not need definitive therapy because of the
self-limited thyroiditis component of the disease.
15 Molar ratio of -subunit and TSH is calculated.
16 Pituitary resistance to thyroid hormone could be selective
or part of generalized resistance (see Hyperthyroxinemia, p. 92). In
the selective form, the thyrotrophic activity is resistant to thyroid hor-
mones but can be inhibited by glucocorticoids and dopaminergic
agents. This is the only form of thyrotoxicosis without suppression of
TSH. -Blocker and hormonally inactive, chemically thyroid hor-
mone-like preparations (D-T4, triiodothyroacetic acid Triac) could be
useful for therapy.
F. Pter T.P. Foley, Jr. Hyperthyroidism
17 Thyroid storm (hyperpyrexia, extreme tachycardia, con-
gestive heart failure, severe nausea, diarrhea, agitation, delirium,
etc.) is extremely rare in children. Therapy: -blockers (propranolol
i.v.), acetaminophen rather than aspirin (which can increase free hor-
mone level), PTU (in part blocking T4 to T3 conversion) or methima-
zole + iodine (iodinated contrast agents or Lugol solution), possible
steroids.
Selected reading
Beck-Pecoz P, Persani L, LaFranchi S: Safety of medications and
hormones used in the treatment of pediatric thyroid disorders.
Pediatr Endocrinol Rev 2004;2(suppl 1):124133.
Brown RS, Huang S: The thyroid and its disorders; in Brook Ch,
Clayton P, Brown RS (eds): Clinical Pediatric Endocrinology, ed 5.
Oxford, Blackwell, 2005, pp 208253.
Dallas JS, Foley TP Jr: Hyperthyroidism; in Lifshitz F (ed):
Pediatric Endocrinology, ed 5. New York, Informa Healthcare,
2007, pp 415442.
Foley TP Jr, White C, New A: Juvenile Graves disease: the
usefulness and limitations of thyrotropin receptor antibody
determinations. J Pediatr 1987;110:378386.
Hung W, Sarlis NJ: Autoimmune and non-autoimmune hyper-
thyroidism in pediatric patients: a review and personal commen-
tary on management. Pediatr Endocrinol Rev 2004;2:2138.
LaFranchi SH, Hanna ChE: Graves disease in the neonatal period
and childhood; in Braverman LE, Utiger RD (eds): The Thyroid, ed
9. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 10491059.
Lal G, Ituerte Ph, Kebebew E, et al: Should total thyroidectomy
become the preferred procedure for surgical management of
Graves disease? Thyroid 2005;15:569574.
Peter F: Hyperthyroidism and puberty; in Pinchera A, Mann K,
Hostalek U (eds): The Thyroid and Age. Schattauer, Stuttgart-
New York, 1998, pp 179190.
Rivkees SA: The management of hyperthyroidism in children with
emphasis on the use of radioactive iodine. Pediatr Endocrinol Rev
2003;1(suppl 2):212222.
 Thyroid T.P. Foley, Jr. F. Pter Neonatal hyperthyroidism

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 1 The maternal and family history will most likely provide
valuable information as to the cause of neonatal goiter with hyper-
thyroidism. The most common etiology, neonatal Graves disease, is
caused by transplacental transport of maternally derived TSH recep-
tor-stimulating antibodies from mother to fetus. The mother may or
may not be clinically thyrotoxic, but will have a history of autoim-
mune thyroid disease and usually an abnormal thyroid gland on ex-
amination. Women with a history of Graves disease treated by thy-
roid ablation using radioiodine therapy or near total thyroidectomy
very likely are receiving thyroxine therapy to maintain clinical euthy-
roidism or, if treatment is inadequate, hypothyroidism. However,
these patients still may produce TSH receptor-stimulating antibodies
to cause neonatal Graves disease.
Another cause of neonatal hyperthyroidism is non-immune-medi-
ated thyrotoxicosis caused by a germline mutation of the gene that
codes for the TSH receptor, causing constitutive activation of the re-
ceptor throughout the thyroid gland and goiter, hyperthyroidism and
thyrotoxicosis. The family history usually does not disclose history
of a similar disease.
Families having the syndrome of thyroid hormone resistance with
predominately pituitary resistance causing hyperthyroidism and thy-
rotoxicosis infrequently present with neonatal hyperthyroidism.
Since these diseases are usually transmitted via an autosomal-domi-
nant mode of inheritance, the family history should contribute perti-
nent information as to the diagnosis.
2 The history of previous cases of neonatal thyrotoxicosis in
a family should provide sufficient information to differentiate be-
tween transient neonatal Graves disease, the permanent thyrotoxi-
cosis of non-immune-mediated neonatal thyrotoxicosis and resis-
tance to thyroid hormone.
3 The clinical presentation of neonatal hyperthyroidism may
mimic that of narcotic withdrawal in an addicted newborn and moth-
er, or various types of congenital cardiac arrhythmias with tachycar-
dia. In infants with neonatal hyperthyroidism, the thyroid gland is
almost invariably increased in volume and should be easily identified
on palpation. Ocular signs of thyrotoxicosis with prominence of the
eyes and stare are usually seen in neonatal Graves disease and usu-
ally with exophthalmus, but other causes may be associated with the
appearance of exophthalmus. Other signs in the neonate include
wasting, small for gestational age, generalized enlargement of the
reticuloendothelial system (generalized lymphadenopathy, hepato-
megaly and splenomegaly), agitation, hyperkinesis, hyperthermia
and, rarely, disseminated intravascular coagulopathy.
83
Thyroid
4 The treatment of maternal Graves disease with antithyroid
drugs, usually using PTU, will inhibit the fetal thyroid unless concen-
trations of PTU as low as 50100 mg/day can effectively control the
disease. Inhibition of the fetal thyroid causes fetal and neonatal goiter
and elevation of serum TSH in the first 3 days after birth. Since PTU is
rapidly metabolized by the neonate, the inhibition of thyroid function
disappears and neonatal thyroid function returns to normal. However,
after delivery in those infants with high titers of TSH receptor antibod-
ies, the metabolism of PTU will cause the release of inhibition of thy-
roid hormone synthesis during the first 2 days of life, and neonatal
hyperthyroidism may begin to progress beginning as early as the sec-
ond or third day of age. The infant subsequently will present with
neonatal hyperthyroidism and thyrotoxicosis, requiring treatment.
5 Patients at risk for neonatal hyperthyroidism may initially
be clinically euthyroid. They should not be treated until clinical thyro-
toxicosis has developed and is confirmed by laboratory studies; also,
the onset may be delayed in rare instances as late as 46 weeks after
birth. Usually, clinical thyrotoxicosis is present at birth, or in infants
born to mothers treated with antithyroid drugs, on days 37 after
birth once the antithyroid drug is metabolized. It is important to re-
member that a history of maternal autoimmune thyroid disease, ei-
ther Hashimoto thyroiditis or Graves disease, may cause transient
goiter and neonatal thyroid dysfunction as hypothyroidism, euthy-
roidism or hyperthyroidism.
6 The most important initial therapy for the neonate with
moderate-to-severe thyrotoxicosis regardless of etiology is -adren-
ergic blockade using propranolol to control the exaggerated adrener-
gic receptor responses, and a sodium or potassium iodide solution
that inhibits the release of preformed thyroid hormones. The thyroid
of the newborn is very sensitive to the inhibiting effects of iodide, and
its use is very effective in infants with neonatal Graves disease since
the disease is transient and may be controlled with propranolol and
iodide alone. Since the effect of iodide is very efficient and rapid in
onset, serial monitoring of thyroid function is important for early
identification of the normalization of serum free thyroxine and T3 con-
centrations prior to the subsequent rise of serum TSH. At this time the
iodide dose needs to be tapered while thyroid function is monitored.
7 The measurement of TSH receptor antibodies, TSH, free T4
and T3 should provide adequate information to differentiate the
causes of neonatal hyperthyroidism. In neonatal Graves disease,
concentrations of TSH will be undetectable, TSH receptor antibodies
will be present and concentrations of the free and total iodothyro-
nines will be elevated. In non-immune-mediated neonatal thyrotoxi-
cosis, TSH receptor antibodies will be negative, TSH will be undetect-
able and the concentration of iodothyronines will be increased. In the
syndrome of thyroid hormone resistance with thyrotoxicosis, the to-
tal and free iodothyronine concentrations will be increased, the TSH
receptor antibodies will be negative and the serum TSH concentra-
tion will be in the normal range or, rarely, slightly elevated.
T.P. Foley, Jr. F. Pter Neonatal hyperthyroidism
8 The preferable method to measure TSH receptor antibod-
ies (TRAb) is the TBII assay. This method requires the least volume of
serum, the most rapid turnaround time, and accurately reflects the
activity in serum. The test does not discriminate between TSH recep-
tor-stimulating antibodies and TSH receptor-blocking antibodies;
however, the clinical presentation of the infant and thyroid function
tests determine if the neonate has either Graves disease with unde-
tectable TSH values and high iodothyronine concentrations, or pri-
mary hypothyroidism with increased TSH values and normal or low
iodothyronine concentrations; these data will define whether the in-
fant has TSH receptor-stimulating or -blocking antibodies. In rare
cases, the disease will be polyclonal and may have a population of
both a stimulating and blocking antibody. The expression of the clini-
cal disease would be dependent upon the affinity of the respective
antibodies for the TSH receptor and the concentration or quantity of
TSH receptor antibody that reaches the fetus transplacentally.
9 TSH and FT4 for the development of clinical thyrotoxicosis
and/or goiter.
10 Taper medications as clinical signs subside, and maintain
normal thyroid function test values.
Selected reading
Dallas JS, Foley TP Jr: Hyperthyroidism; in Lifshitz F (ed):
Pediatric Endocrinology, ed 5. New York, Informa Healthcare, 2007,
vol 2, Section III: Thyroid Disorders, chap 18, pp 415442.
Fisher DA: Neonatal hyperthyroid screening.
J Pediatr 2003;143:285287.
Fu J, Jiang Y, Liang L, Zhu H: Risk factors of primary thyroid
dysfunction in early infants born to mothers with autoimmune
thyroid disease. Acta Paediatr 2005;94:10431048.
Hung W, Sarlis NJ: Autoimmune and non-autoimmune hyper-
thyroidism in pediatric patients: a review and personal commen-
tary on management. Pediatr Endocrinol Rev 2004;2:2138.
Peter F: Thyroid dysfunction in the offspring of mothers with
autoimmune thyroid diseases. Acta Paediatr 2005;94:10081010.
Polak M, Legac I, Vuillard E, Guibourdenche J, Castanet M, Luton D:
Congenital hyperthyroidism: the fetus as a patient. Horm Res
2006;65:235242.
Sinclair D: Clinical and laboratory aspects of thyroid autoanti-
bodies. Ann Clin Biochem 2006;43:173183.
 Thyroid T.P. Foley, Jr. F. Pter Goiter

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84

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 * The italicized texts are important in iodine-deficient 6 Juvenile chronic lymphocytic thyroiditis
Selected reading
(or borderline) areas; otherwise (e.g. in the USA) the does not need L-T4 therapy with euthyroidism and
evaluation of diffuse goiter starts with the tests of thy- without significant enlargement of the thyroid neces- Delange F, Benker G, Caron Ph, Eber O, Ott W,
roid hormones, TSH, and thyroid antibodies. sarily, but follow-up is essential to control the develop- Peter F, et al: Thyroid volume and urinary iodine in
ment of hypothyroidism or/and considerable goiter. European schoolchildren: standardization of values
1 Classification of goiter-size stages: stage 0, for assessment of iodine deficiency. Eur J Endocri-
no goiter; stage I, goiter palpable but not visible, and 7 Simple (nontoxic, colloid) or idiopathic goi- nol 1997;136:180187.
stage II, goiter visible when the neck is in normal posi- ter without positive immunological parameters and
Fisher DA: Thyroid disorders in childhood and
tion [Indicators for Assessing Iodine Deficiency Disor- iodine deficiency is better to treat with L-T4 than to wait
adolescence; in Sperling MA (ed): Pediatric Endocri-
ders and Their Control through Salt lodination, Docu- for possible spontaneous regression (except the close-
nology. Philadelphia, Saunders, 2002, pp 198199.
ment WHO/NUT/94.6, p. 16]. The clinical assessment ly controlled cases). In iodine deficiency without au-
of grade I goiters is much too inaccurate by palpation toimmune phenomena the iodide treatment as well Hegeds L: Thyroid ultrasonography as a screening
(misclassification can be 40%!). Thyroid volumetry by as combined treatment with L-T4 and iodide may lead tool for thyroid disease (Guest editorial). Thyroid
ultrasonography is more precise. to reduction of thyroid volume superior compared to 2004;14:879880.
the effects of L-T4 alone.
Huang SA: Thyromegaly; in Lifshitz F (ed): Pediatric
2 Neonatal goiter with euthyroidism or hypo-
Endocrinology, ed 5. New York, Informa Healthcare,
thyroidism is rare and in the great majority of cases is Clinically, it may be difficult to differentiate
8
2007, pp 443454.
self-limited (high-dose antithyroid drug therapy of the between acute suppurative thyroiditis and abscess of
mother, iodine deficiency or excess, etc.), possible the thyroglossal duct. Fistula as a remnant of the Zimmermann MB, Molinari L, Spehl M, Weldinger-
dyshormonogenesis (see p. 72). Large goiter can fourth pharyngeal pouch can predispose to suppura- Toth J, Podoba J, Hess S, Delange F: Towards a con-
cause obstruction of the airway; it improves by elevat- tive thyroiditis. The fever, enlarged thyroid, mostly uni- sensus on reference values for thyroid volume in
ed position of the neck. lateral anterior cervical pain, later some erythema in iodine-replete schoolchildren: results of a workshop
the painful area and regional lymphadenopathy sup- on interobserver and inter-equipment variation in
3 Family history; nutritive factors: iodine defi- port the diagnosis. Besides the laboratory findings of sonographic measurement of thyroid volume. Eur J
ciency, goitrogens (natural, thiocyanate, flavonoids, an inflammatory process there are normal values re- Endocrinol 2001;144:213220.
cassava through thiocyanate, etc.; synthetic: phenol, lating to thyroid except for the thyroid scanning with
Zimmermann MB, Hess SY, Molinari L, De Benoist B,
aliphatic hydrocarbon derivatives, etc.), iodine excess reduced radioactivity over the suppurative area or
Delange F, Braverman LE, et al: New reference
through drugs containing iodine (e.g. amiodarone), sometimes moderately elevated T3 and T4 levels. Ther-
values for thyroid volume by ultrasound in iodine-
perchlorate, salicylate, diphenylhydantoins, phenothi- apy is antimicrobial and surgical.
sufficient schoolchildren: a WHO/NHD Iodine
azine, sulphonylurea, etc., antithyroid drugs blocking
Deficiency Study Group report. IDD Newslett
thyroid hormonogenesis.
2003;19:6264.
4 The analysis of thyroid volume and struc-
ture by ultrasonography is a much more precise and
Table 1. Upper limit of normal thyroid volume measured by ul-
objective method than the inspection and palpation.
trasonography in iodine-replete children aged 615 years as
Upper limit of normal thyroid volume measured by a function of age
ultrasonography in iodine-replete boys and girls aged
615 years was proposed on the basis of a European Age Thyroid volume, ml
survey [WHO and ICCIDD: Recommended normative boys girls
values for thyroid volume in children aged 615 years.
1 2 3
Bull WHO 1997;75:9597]. However, there are several 6 years 5.4 3.8 2.91 5.01 2.843
potential sources of inter-observer and/or inter-equip- 7 years 5.7 4.0 3.29 5.9 3.26
8 years 6.1 4.3 3.71 6.9 3.76
ment error in thyroid ultrasound. Smaller normal volu- 9 years 6.8 4.8 4.19 8.0 4.32
metric values were found in a parallel study of four 10 years 6.8 5.5 4.73 9.2 4.98
independent experts and the former data were adjust- 11 years 9.0 6.4 5.34 10.4 5.73
ed with a correction factor generated in this control 12 years 10.4 7.4 6.03 11.7 6.59
85 study. Recently brand new reference values were pro- 13 years 12.0 13.1
14 years 13.9 14.6
posed but these were not confirmed yet (see table). 15 years 16.0 16.1

5 Thyroid antibodies to thyroid peroxidase 1

Delange et al [1997]; 2 Zimmermann et al [2001];
and thyroglobulin are measured routinely. 3
Zimmermann et al [2003[.

Thyroid T.P. Foley, Jr. F. Pter Goiter

 Thyroid T.P. Foley, Jr. F. Pter Thyroid nodules in children and adolescents

Thyroid nodules in Isolated thyroid nodule

children and adolescents Family history

Physical examination
86
Clinically euthyroid
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 1 Patients with multiple thyroid nodules (multinodular goi-
ter) and no exposure to ionizing radiation are managed similarly to
the patient with an isolated thyroid nodule; multiple thyroid nodules
are infrequent in iodine-sufficient populations of children except for
those with autoimmune (chronic lymphocytic) thyroiditis.
2 The family history is important to determine the presence
of autoimmune thyroid diseases, benign or malignant thyroid neo-
plasia, other tumors and syndromes associated with thyroid neopla-
sia, or multinodular goiter with or without iodine deficiency. The his-
tory and physical examination of the patient usually differentiate the
patients who are euthyroid and thyrotoxic.
3 During an initial evaluation of a child or adolescent with an
isolated or multiple thyroid nodules, the measurement of serum thy-
roid function tests and thyroid antibodies are recommended. If thy-
roid function tests support the diagnosis of primary hypothyroidism
and/or if high titers of thyroid antibodies are detected, indicative of
autoimmune thyroiditis, further studies are usually not indicated.
Thyroxine therapy should be started in those patients with primary
hypothyroidism. Both TPOAb and TGAb should be measured since
1020% of children with autoimmune thyroiditis have either, but not
both antibodies present, and in 8090%, both antibodies are posi-
tive; very rarely do children with clinical thyroiditis, such as a nodular
thyroid gland, have negative antibodies. Alternatively, the TPO anti-
body could be measured, and only if no TPO antibodies are detected
should TGAb be subsequently tested. To exclude autoimmune thy-
roiditis, both TPOAb and TGAb are undetectable. Though the pres-
ence of low titers of TPOAb and/or TGAb are seen infrequently in
children and adolescents with papillary and follicular thyroid cancer,
their presence does not exclude underlying neoplasia.
4 When thyroid function studies are normal and thyroid anti-
bodies are negative, a thyroid ultrasound-guided FNA biopsy should
be the next test. The ultrasound determines whether the mass is sol-
id or cystic, and the FNA Biopsy defines the cytology as malignant,
suspicious, follicular, indeterminant or benign. If malignant, suspi-
cious or follicular, surgery is indicated; if indeterminant, a repeat
FNA should be performed; if benign, a repeat FNA biopsy should be
performed if the nodules enlarges.
When thyroid function tests suggest hyperthyroidism and the
nodule(s) is/are either solid or solid with cystic components, 99mTC
or 123I scan determines whether or not the nodule is hyperfunction-
ing and if uptake by normal thyroid tissue is suppressed by excessive
secretion of thyroid hormones by the adenoma. A hypofunctioning
(cold) nodule in children with normal thyroid function should be ex-
87
Thyroid
cised after a pre-operative FNA biopsy is performed to determine, if
Selected reading
possible, a pre-operative diagnosis to assist the surgeon in the extent
of surgery. In children with a cold nodule on radionuclide imaging, a Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ,
serum calcitonin value should be obtained. If elevated, DNA analysis Mazzaferri EL, McIver B, Sherman SI, Tuttle RM: Management
for the ret-protooncogene mutations in medullary carcinoma of the guidelines for patients with thyroid nodules and differentiated
thyroid (MCT) should be obtained; a FNA biopsy should be per- thyroid cancer. Thyroid 2006;16:109142.
formed prior to surgical excision even if the CT value is normal.
Degnan BM, McClellan DR, Francis GL: An analysis of fine-needle
aspiration biopsy of the thyroid in children and adolescents.
5 Children with a family history of MCT or an elevated CT
J Pediatr Surg 1996;31:903907.
value must be tested for a mutation in the ret protooncogene. If the
mutation is present, regardless of age, the patient has MCT, should Fogelfeld L, Wiviott MBT, Shore-Freedman E, et al: Recurrence of
have a total thyroidectomy and be evaluated for metastatic disease. If thyroid nodules after surgical removal in patients irradiated in
a child has a thyroid nodule and an elevated CT, but no mutation is childhood for benign conditions. N Engl J Med 1989;320:835.
found, the patient should have a pentagastrin stimulation test and
Foley TP Jr, Contis G, Vashchilin G, Rak S, Borisov GI, Kirienko L,
FNA biopsy. If the CT response to pentagastrin is abnormal, the pa-
Mykulske HT, Dumanovska MV, Levchenko PU, Galinsky YY:
tient should have a total thyroidectomy; if the CT response is normal,
Thyroid screening of children at high risk for thyroid neoplasia
the patient should have surgical excision of the nodule and lobe of
after the Chernobyl accident: a preliminary report. The 3rd
the thyroid.
International Conference on Health Effects of the Chernobyl
Accident: Results of 15-Year Follow-Up Studies. Int J Radiat Med
6 Patients with a solitary thyroid nodule and clinical thyro-
2002;4:5966.
toxicosis should have serum thyroid function but do not need thyroid
antibody determinations if the remainder of the thyroid gland is nor- Halac I, Zimmerman D: Thyroid nodules and cancers in children.
mal on palpation. Endocrinol Metab Clin North Am 2005;34:725744.
Huang SA: Thyromegaly; in Lifshitz F (ed): Pediatric Endocrinol-
7 Patients with a suppressed TSH and normal or elevated
ogy, ed 5. New York, Informa Healthcare, 2007, vol 2, section III:
serum T3 should have a serum free T3 measurement. Elevated serum
Thyroid Disorders, chap 19, pp 443454.
free T3 with normal total T3 may be seen in children and adolescents
with hyperthyroidism associated with a hyperfunctioning thyroid Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S,
nodule; these patients, when evaluated on a radionuclide thyroid Nardi F, Panunzi C, Rinaldi R, Toscano V, Pacella CM: Risk of
scan, will have no radionuclide uptake in the remaining thyroid tissue malignancy in nonpalpable thyroid nodules: predictive value of
if the autonomous nodule is secreting excessive amounts of thyroid ultrasound and color-Doppler features. J Clin Endocrinol Metab
hormones. In this situation, the nodule is usually greater than 2.5 cm 2002;87:19411946.
in diameter, the patient usually has clinical symptoms and signs of
Sclabas GM, Staerkel GA, Shapiro SE, Fornage BD, Sherman SI,
thyrotoxicosis, and serum TSH is usually suppressed below the nor-
Vassilopoulou-Sellin R, Lee JE, Evans DB: Fine needle aspiration of
mal range or undetectable. With this presentation, surgical excision
the thyroid and correlation with histopathology in a contemporary
of the nodule is indicated.
series of 240 patients. Am J Surg 2003;186:702709; discussion
709710.
8 In patients with a hyperfunctioning thyroid nodule on ra-
dionuclide scan and radionuclide uptake by the remaining normal
thyroid tissue, the size of the nodule is usually less than 2.5 cm in di-
ameter, the patient is usually clinically euthyroid, and the serum TSH
is usually in the low-normal or below-normal concentration, but mea-
surable. In this clinical situation the size of the nodule and thyroid
function tests should be monitored at 6-month intervals and thyroid
ultrasound every 12 years, especially if there is evidence of an en-
largement of the nodule. Should the size of the nodule increase, the
uptake over thyroid tissue disappear, and/or clinical thyrotoxicosis
develop, surgical excision is indicated.
T.P. Foley, Jr. F. Pter Thyroid nodules in children and adolescents
 Thyroid T.P. Foley, Jr. F. Pter Thyroid carcinoma

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 1 Thyroid carcinoma during childhood and adolescence
usually, though not invariably, presents as a solitary, asymptomatic
thyroid mass or nodule. Infrequently more than one nodule is identi-
fied, especially in children who have a previous exposure during fetal
life, infancy or childhood to ionizing radiation. The family history of
thyroid cancer is extremely important since the inherited forms of
medullary thyroid carcinoma are transmitted by an autosomal-domi-
nant mode of inheritance; in addition, familial forms of papillary thy-
roid carcinoma occur infrequently.
2 The thyroid nodule or nodular thyroid gland may be the
initial presentation of autoimmune (Hashimoto) thyroiditis, and the
disease needs to be excluded by thyroid function and thyroid anti-
body tests. However, it must be remembered that patients with thy-
roid carcinoma may have a low titer of thyroid antibodies but normal
thyroid function tests.
3 With experienced thyroid cancer histopathologists, a FNA
biopsy is very reliable as an initial diagnostic test when thyroid func-
tion tests are normal. Since FNA biopsies are usually performed with
guidance by thyroid ultrasound, a separate thyroid ultrasound image
usually in not necessary since thyroid cysts will be easily seen. Thy-
roid imaging studies may assist in the differentiation of the etiology
of the thyroid nodule when autoimmune thyroiditis has been exclud-
ed. If thyroid function tests are normal, thyroid ultrasound is ob-
tained to differentiate between a pure thyroid cyst and either a solid
thyroid mass or a cystic mass with solid components which may
have the appearance of thyroid carcinoma on ultrasound. When thy-
roid function tests suggest hyperthyroidism, the imaging procedure
should be a thyroid scan using either 99mTc or 123I to determine if the
nodule is hyperfunctioning or not. When a thyroid ultrasound is het-
erogeneous and suggestive of thyroid carcinoma, a FNA biopsy of
the dominant or largest thyroid nodule is indicated.
4 The FNA biopsy distinguishes benign and malignant dis-
ease when used in the evaluation of thyroid nodules. When a FNA
biopsy is reported as follicular, current cytology cannot distinguish
benign or malignant follicular neoplasma, and the mass must be
treated as a malignant thyroid cancer. Similarly, when the FNA bi-
opsy is reported as suspicious, the mass must be considered ma-
lignant. These uncertain cytologic interpretations indicate that an
excisional biopsy or lobectomy should be performed; if malignancy
is confirmed on permanent sections, then a completion thyroidec-
tomy is performed. The usual plan of management for a FNA biopsy
that is reported to be an indeterminant or inadequate specimen, a A multicenter clinical trial suggests that children and adolescents
repeat FNA biopsy, or if other findings are suspicious of malignancy,
89 an excisional biopsy should be performed. The larger the mass, the
sooner the FNA biopsy should be repeated. Patients with a FNA bi-
opsy report as benign should be monitored closely; if the mass en-
larges, another FNA biopsy should be performed.
Until there are more accurate cytologic tests on FNA specimens from
children and adolescents, the test can only be considered definitive
Thyroid
when the report indicates that the biopsy is malignant or suspicious
Selected reading
for malignancy. Prior to excision of a solid thyroid mass that does not
accumulate radioiodine, the FNA is indicated to provide the surgeon Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ,
with guidance in the operative procedure if the FNA is malignant or Mazzaferri EL, McIver B, Sherman SI, Tuttle RM: Management
suspicious for malignancy. guidelines for patients with thyroid nodules and differentiated
thyroid cancer. Thyroid 2006;16:109142.
5 Patients with benign thyroid neoplasia who have been ex-
Demers LM, Spencer CA: www.nacb.org The National Academy of
posed to ionizing radiation should be treated with thyroxine therapy
Clinical Biochemistry Laboratory Support for the Diagnosis and
since studies indicate a decrease in the recurrence of thyroid neopla-
Monitoring of Thyroid Disease.
sia. Exposures to ionizing radiation from therapeutic procedures or
other sources such as the environment (i.e. Chernobyl) are associ- Halac I, Zimmerman D: Thyroid tumors in children; in Lifshitz F
ated with increased risks for thyroid diseases (thyroiditis, benign (ed): Pediatric Endocrinology, ed 5. New York, Informa Healthcare,
neoplasia and papillary thyroid carcinoma). The younger the age at 2007, vol 2, section III: Thyroid Disorders, chap 20, pp 455473.
exposure and the greater the radiation dose, the higher the risk.
Hoe FM, Charron M, Moshang T Jr: Use of the recombinant human
TSH stimulated thyroglobulin level and diagnostic whole body
6 Children and adolescents with a diagnosis of papillary thy-
scan in children with differentiated thyroid carcinoma. J Pediatr
roid carcinoma with metastasis, multifocal papillary thyroid carci-
Endocrinol Metab 2006;19:2530.
noma, follicular carcinoma and medullary carcinoma should have a
total thyroidectomy with preservation or reimplantation of parathy- Hung W, Sarlis NJ: Current controversies in the management of
roid tissue. For patients with papillary and follicular thyroid carcino- pediatric patients with well-differentiated nonmedullary thyroid
ma, surgery should be followed by radioiodine ablative therapy, and cancer: a review. Thyroid 2002;12:683702.
thyroxine therapy is tittered to maintain serum TSH values sup-
Kloss RT, Mazzaferri EI: Thyroid carcinoma; in Cooper DS (ed):
pressed between 0.1 and 0.5 mU/l. The patient should be monitored
Medical Management of Thyroid Disease. New York,
with serum thyroglobulin levels using the same experienced and reli-
Marcel Dekker, 2001, chap 6, p 229.
able laboratory, TSH by third generation assays and free T4 to assure
adequacy of thyroxine therapy and suppressed or undetectable se- Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F,
rum thyroglobulin levels. A rise in serum thyroglobulin while the pa- Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD,
tient receives exogenous thyroxine suppressive therapy would indi- Lee S, Davies TE, Arafah BM, Ladenson PW, Pinchera A:
cate recurrent disease and radioiodine image studies would be indi- A Consensus report of the role of serum thyroglobulin as a
cated either after discontinuation of thyroxine therapy or with syn- monitoring method for low-risk patients with papillary thyroid
thetic TSH, or Thyrogen treatments. carcinoma. JCEM 2003;88:14331441.
NCCN Clinical Practice Guidelines in Oncology: www.nccn.com
7 Since medullary thyroid carcinoma is inherited as an auto-
National Comprehensive Cancer Network.
somal-dominant trait and the genetic mutations in the ret protoonco-
gene are known, all suspected patients should be tested; if positive, Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S,
siblings of affected patients should have DNA examined for muta- Nardi F, Panunzi C, Rinaldi R, Toscano V, Pacella CM: Risk of
tions. Whenever the mutation is identified, total thyroidectomy is in- Malignancy in nonpalpable thyroid nodules: predictive value of
dicated at diagnosis. After total thyroidectomy, patients with medul- ultrasound and color-doppler features. J Clin Endocrinol Metab
lary carcinoma of the thyroid should be monitored by serum calcito- 2002;87:19411946.
nin levels in the basal state and following an infusion of pentagastrin;
Rachmiel, M, Charron M, Gupta A, Hamilton J, Wherrett D, Forte V,
residual disease and early recurrence can be identified whenever se-
Daneman D: Evidence-based review of treatment and follow-up of
rum CT values increase above the normal range when performed
pediatric patients with differentiated thyroid carcinoma. J Pediatr
soon after surgery.
Endocrinol Metab 2006;19:13771393.
with a solitary well-differentiated papillary carcinoma and no locally
invasive or metastatic disease can be successfully treated with a lo-
bectomy including the isthmus of the thyroid. These patients must be
treated with L-thyroxine therapy to suppress TSH at or below the nor-
mal range for age, and should be monitored with thyroid ultrasound
of the remaining lobe and serum thyroglobulin. There are as yet no
long-term follow-up studies to determine if recurrent disease devel-
ops after this form of therapy.
T.P. Foley, Jr. F. Pter Thyroid carcinoma
 Thyroid T.P. Foley, Jr. F. Pter Hypothyroxinemia

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 1 Total T4 determinations are no longer useful
tests of thyroid function since the free T4 measure-
ments are now valid and cost-effective when mea-
sured by direct dialysis or by analog methods using
commercially available materials.
2 Since certain analog free T4 methods may
provide false-positive values in certain clinical syn-
dromes (non-thyroidal illness or euthyroid sick syn-
drome) in the presence of certain drugs and clinical
states with abnormal thyroxine-binding proteins. In
these situations, the free T4 by the direct dialysis meth-
od is the definitive gold standard method to accu-
rately measure the free thyroxine in serum.
91
Thyroid T.P. Foley, Jr. F. Pter
Selected reading
Djemli A, Van Vliet G, Belgoudi J, Lambert M,
Devin EE: Reference intervals for free thyroxine,
total triiodothyronine, thyrotropin and thyroglobin
for Quebec newborns, children and teenagers.
Clin Biochem 2004;37:328330.
Foley TP Jr: Hypothyroidism. Pediatr Rev 2004;25:
94100.
Huang SA: Hypothyroidism; in Lifshitz F (ed): Pediat-
ric Endocrinology, ed 5. New York, Informa Health-
care, 2007, vol 2, section III: Thyroid Disorders,
chap 17, pp 405414.
Nelson JC, Wang R, Asher DT, Wilcox RB: Underesti-
mates and overestimates of total thyroxine concen-
trations caused by unwanted thyroxine-binding pro-
tein effects. Thyroid 2005;15:1215.
Rabin CW, Hopper AO, Job L, Peverini RL, Clark SJ,
Deming DD, Nelson JC, Vyhmeister NR: Incidence of
low free T4 values in premature infants as deter-
mined by direct equilibrium dialysis. J Perinatol
2004;24:640644.
Hypothyroxinemia
 Thyroid F. Pter T.P. Foley, Jr. Hyperthyroxinemia

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 1 Free T4 determined by the analog-based 7 Increased binding capacity (serum concen- 1 Total T4 determinations are no longer useful
Selected reading
method may give false high results in case of in- tration) or binding affinity of transthyretin may result tests of thyroid function since the free T4 measure-
creased T4 binding by serum proteins. The equilibrium in elevated T4 (but not the T3) level. Camargo
ments Netovalid
are now U, Rubin R: Thyroxine binding
and cost-effective when mea-
dialysis or two step coated tube methods seem to be globulin
sured in neonates
by direct dialysisand children.
or by West
analog J Medusing
methods
more precise. In the case of free binding sites for T3, 8 Familial dysalbuminemic hyperthyroxin- 2001;175: 306.
commercially available materials.
the T3 RU can be decreased. emia is caused by an unusually high affinity of serum
Elmlinger MW, Kuhnel W, Lambrecht HG, et al:
albumin for T4 (not for T3). 2 Since certain analog free T4 methods may
Reference intervals from birth to adulthood of
provide false-positive values in certain clinical syn-
serum thyroxine, triiodothyronine, free T3, free T4,
2 Thyroid hormones circulate bound to thy- 9 Endogenous antibodies against T4 can cause dromes (non-thyroidal illness or euthyroid sick syn-
thyroxine-binding globulin and thyrotropin.
roid binding proteins: TBG, TBPA or transthyretin and elevation of the T4 level (in immunoassay it can be spu- drome) in the presence of certain drugs and clinical
Clin Chem Lab Med 2001;39:973979.
albumin. The binding affinity of TBG for T4 is higher rious!). states with abnormal thyroxine-binding proteins. In
than for T3 and it is of TBPA much higher than of albu- Fisher
these DA: Disorders
situations, of the
the free thyroid
T4 by in thedialysis
the direct newborn
min for T4. The binding capacity of albumin is the high- 10 Insufficiency of 5-deiodination in the very and infant;
method indefi
is the Sperling
nitive MA (ed):
gold Pediatric
standard Endocri-
method to ac-
est but because of its other functions as a transporter, rare clinical syndrome of type 1 iodothyronine-deio- nology,measure
curately ed 2. Philadelphia, Saunders,
the free thyroxine 2002,
in serum.
the TBG and TBPA are the most important thyroid hor- dinase deficiency can also conduce to increased T4 pp 161186.
mone transporters. level.
Nelson JC, Wang R, Asher DT, Wilcox RB: Under-
estimates and overestimates of total thyroxine con-
3 Elevated levels of TBG (normal values de- 11 Some drugs used mainly in adults (amioda-
centrations caused by unwanted thyroxin-binding
pendent on age and used method) may be congenital rone, amphetamines, heparin, iodine contrast agents,
protein effect. Thyroid 2005;15:1215.
occurring in 1:5,4001:40,000 subjects. propranolol) can elevate T4 level by impaired 5-mono-
deiodination and decreased conversion of T4 to T3
4 Endogenous estrogens increase TBG con- (drug I).
centration also by increasing sialylation and prolong
its metabolic half-life (pregnancy, neonatal period). 12 Generalized resistance to thyroid hormones
(because of mutation in thyroid hormone receptor
5 In infectious and chronic active hepatitis genes) is not effective in all of the tissues and clinical
(and in all forms of acute hepatocellular insult) TBG signs and symptoms can observe according to the de-
level may increase through its sialylation. gree of resistance, may be clinical euthyroidism. The
laboratory test results are hyperthyroid except the nor-
6 Exogenous estrogens, oral contraceptives mal or elevated basal TSH level and similar TSH re-
increase T4 level by elevating TBG concentration sponse in the TRH test.
(drug II).

93

Thyroid F. Pter T.P. Foley, Jr. Hyperthyroxinemia

 Carbohydrates M.A. Sperling O. Escobar R.K. Menon D.B. Dunger Hypoglycemia

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 1 Symptoms of neuroglycopenia (lethargy, lassitude, twitch-
ing, tremulousness, loss of consciousness, seizures) and activation
of the autonomic nervous system (sweating, shaking, trembling,
tachycardia, anxiety, and hunger).
2 Bedside glucose meters measure whole blood glucose.
Whole blood glucose is 1015% higher than corresponding plasma
or serum glucose. All bedside methods have a 1015% vulnerability.
3 Blood glucose <40 mg/dl (<2.2 mm) is confirmatory, <55
mg/dl (<3 mm) is highly suspicious.
4 Check other potential causes such as hypocalcemia, hy-
pomagnesemia, hyponatremia or primary neurological disorder.
5 If the rapidly determined bedside glucose measurement is
<70 mg/dl (<4.0 mm), a formal laboratory blood glucose measure-
ment is warranted. If this formal blood glucose measurement is <55
mg/dl (<3.0 mm), W/U should continue for hypoglycemia.
Have sample processed promptly to separate plasma/serum.
6 History of prematurity, SGA, maternal diabetes, persistent
neonatal jaundice, family history, nutritional intake, drug ingestion.
Physical examination should focus on features such as macrosomia,
hepatomegaly, microphallus, and syndromic features seen in disor-
ders such as Beckwith-Weidemann or leprechaunism.
7 Ketonuria usually indicates the presence of ketonemia.
Under certain circumstances measurement of ketone bodies -hy-
droxybutyrate) in the blood may be helpful in confirming the pres-
ence of ketonemia.
8 Urine for non-glucose-reducing substances will be
Clintest-positive but Clinstix-negative because the latter is glucose-
specific.
9 Patients with hyperinsulinemism commonly develop hy-
poglycemia within 68 h of initiation of fasting. A glucagon challenge
of 50 g/kg evokes a glucose response of >40 mg/dl (>2.2 mm) above
baseline in patients with hyperinsulinism, reflecting the presence of
adequate hepatic glycogen and intact enzymatic pathways.
10 Diazoxide, octreotide, surgical treatment. Genetic counsel-
ing should be given for risk of recurrence. Mutational analysis of
genes that regulate insulin secretion, such as those involved in the
ATP-regulated potassium channel, KCNJ11 (Kir 6.2), ABCC8 (Sur1)
95 and GDH (glutamate dehydrogenase) as well
Carbohydrates
as some others such as GCK (glucokinase), is now available to aid
diagnosis and genetic counseling. If medical management with
agents such as diazoxide, octreotide, plus frequent feedings fails to
control hypoglycemia, surgery must be considered and should, if
available, be preceded by PET scanning with 18F-L-Dopa to distin-
guish focal from the diffuse forms to guide appropriate surgical exci-
sion.
11 Factitious hyperinsulinism is a form of child abuse that
commonly involves those with access to insulin and syringes such as
medical paraprofessional staff or family members of patient with in-
sulin-requiring diabetes mellitus.
12 If total plasma carnitine is <30 mol/l, urine should be
checked for organic acidosis which is generally elevated in the vari-
ous forms of fatty and oxidation defects. Management consists of
educating parents to avoid fasting without glucose supplements (ge-
netic counseling for risks of recurrence is recommended).
13 Evaluation for enzymatic defects in glycogen metabolism
and gluconeogenesis usually requires determination of enzymatic
activity in blood or tissue, specifically liver tissue. Increasingly, mo-
lecular diagnostic tests are becoming available. The presence of (lac-
tic) acidosis, e.g. pH <7.35 and/or anion gap 15 mEq/l, may be help-
ful.
14 Ketotic hypoglycemia is now diagnosed less frequently
and is listed last as a diagnosis of exclusion, though it remains an im-
portant consideration. Generally, these will be former SGA infants
who may still be small for age. Hypoglycemia typically occurs during
an intercurrent febrile illness and after two or more missed meals.
The presence of ketones in the urine distinguishes these cases from
defects in fatty acid oxidation, which typically do not have ketones in
the blood or urine. Frequent feedings of glucose-containing carbon-
ated beverages and, if indicated, anticipatory i.v. glucose infusion (5
10 mg/kg min for 510 h) may avoid hypoglycemia. Patients family
should be educated to test urine for ketones and if positive to initiate
the measures outlined above.
15 These infants are often SGA, may have perinatal stress or
asphyxia, caesarean delivery, and more frequently are male. The
cause of the hypoglycemia is hyperinsulinism responsive to frequent
feedings and/or diazoxide with spontaneous resolution by a median
of 6 months. The mechanism of hyperinsulinism has not been identi-
fied [see Hoe FM et al., 2006].
M.A. Sperling O. Escobar R.K. Menon D.B. Dunger
Selected reading
Daly LP, Osterhoudt KC, Weinzimer SA: Presenting features of
idiopathic ketotic hypoglycemia. J Emerg Med 2003;25:3943.
Dekelbab BH, Sperling MA: Hypoglycemia in newborns and
infants. Adv Pediatr 2006;53:522.
de Lonlay P, Simon-Carre A, Ribeiro MJ, Boddaert N, Giurgea I,
Laborde K, et al: Congenital hyperinsulinism: pancreatic
[18F]fluro-L-dihydroxyphenylalanine (DOPA) positron emission
tomography and immunohistochemistry study of DOPA
decarboxylase and insulin secretion. J Clin Endocrinol Metab
2006;91:933940.
Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA,
Stanley CA: Clinical features and insulin regulation in infants with
a syndrome of prolonged neonatal hyperinsulinism. J Pediatr
2006;148:207212.
Hussain K, Aynsley-Green A, Stanley CA: Medications used in the
treatment of hypoglycemia due to congenital hyperinsulinism of
infancy (HI). Pediatr Endocrinol Rev 2004;2:163167.
Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H,
Hussain K, et al: Noninvasive diagnosis of focal hyperinsulinism of
infancy with [18F]-DOPA positron emission tomography. Diabetes
2006;55:1318.
Shin YS: Glycogen storage disease: clinical biochemical, and
molecular heterogeneity. Semin Pediatr Neurol 2006;13:115120.
Sperling MA, Menon RK: Differential diagnosis and management
of neonatal hypoglycemia. Pediatr Clin North Am 2004;51:
703723.
Stanley CA: Carnitine deficiency disorders in children. Ann NY
Acad Sci 2004;1033:4251.
Stanley CA: Parsing ketotic hypoglycemia Arch Dis Child
2006;91:483486.
Wolfsdorf JI: Understanding protein-sensitive hypoglycemia.
J Pediatr 2006;149:4752.
Hypoglycemia
 Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Hyperglycemia

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 1 Drugs are an unusual cause of hyperglyce-
mia in childhood but the etiology is usually clear.
2 Hyperglycemia as an incidental finding dur-
ing stress is common. In those children who are seri-
ously ill and require either high dependency, or inten-
sive care, hyperglycemia is a result of the endocrine
and metabolic response to stress and is unlikely to be
indicative of incipient T1DM. Hyperglycemia during
minor illness may be suggestive of a predisposition to
T1DM or of MODY and should be investigated further.
3 The diagnosis of type 1 diabetes mellitus is
usually relatively straightforward (see T1DM) and is
the most common underlying cause of hyperglycemia
in children. Where diabetes is secondary to another
variety of other medical conditions such as cystic fi-
brosis, the etiology is usually obvious and may even
be anticipated, e.g. oral glucose tolerance tests may be
performed routinely in children with cystic fibrosis
from puberty onwards to screen for CF-related diabe-
tes.
4 True T2DM is no longer rare in the pediatric
population but the incidence may be increasing sec-
ondary to the increasing incidence of obesity. The con-
dition is characterized clinically by obesity and there is
often a family history of obesity and/or T2DM and cer-
tain ethnic groups such as the Pima Indians are at in-
creased risk.
5 MODY is a rare cause of diabetes in children
but should be considered in individuals without the
expected type 1 diabetes presentation. The phenotype
can be extremely variable but affected individuals are
lean, may be negative for autoantibody screening and
there is often a family history of diabetes. The diagno-
sis should be suspected where presentation of diabe-
tes is before 25 years of age in at least one, but ideally
two, family members with an autosomal-dominant
pattern of inheritance and in individuals with negative
autoantibodies or low insulin requirements several
years from diagnosis. Please see the MODY algorithm
for more details.
97
Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling
6 An oral glucose tolerance test should be
performed if either T2DM, MODY or the pre-diabetic
state are thought likely. Blood should be taken for glu-
cose levels, HbA1c and islet cell antibodies. The WHO
define impaired glucose tolerance as a 2-hour plasma
glucose value of between 7.8 and 11.1 mmol/l and dia-
betes as either a fasting glucose of 67.0 or 611.1
mmol/l at 120 min after oral glucose load. Blood can
also be taken for autoantibodies, insulin and C-peptide
concentrations to aid diagnosis. Once the diagnosis
has been made, see the appropriate algorithms for
management.
Selected reading
Expert Committee on the Diagnosis and Classifica-
tion of Diabetes Mellitus: Report of the expert com-
mittee on the diagnosis and classification of diabe-
tes mellitus. Diabetes Care 1997;20:11831197.
Fagot-Campagna A, Saaddine JB, Flegal KM, Beck-
les GL: Third National Health and Nutrition Exami-
nation Survey. Diabetes, impaired fasting glucose,
and elevated HbA1c in US adolescents: the Third
National Health and Nutrition Examination Survey.
Diabetes Care 2001;24:834837.
Matyka K, Beard F, Appleton M, Ellard S, Hattersley
A, Dunger DB: Genetic testing for maturity onset
diabetes of the young in childhood hyperglycaemia.
Arch Dis Child 1998;78:552554.
Vaxillaire M, Froguel P: Genetic basis of maturity-
onset diabetes of the young. Endocrinol Metab Clin
North Am 2006;35:371385.
Hyperglycemia
 Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Prediabetes and prediction of diabetes

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 1 Prediabetes is defined here as a state of carbohydrate me-
tabolism that does not meet the criteria for diagnosing diabetes mel-
litus in children. Impaired fasting glucose (IFG) and impaired glucose
tolerance (IGT) are considered to be prediabetic states as they confer
increased risk for the development of diabetes. Both IFG and IGT are
defined within the new diagnostic criteria released by the American
Diabetes Association in June 1997. IFG is defined as a fasting glu-
cose between 110 and 125 mg/dl. IGT is defined as an OGTT 2-hour
blood glucose level between 140 and 199 mg/dl. Prediabetic states
are usually not accompanied by symptoms such as polyuria, poly-
dipsia, weight loss or vaginal yeast infection in girls. These individu-
als may be destined to develop diabetes and they may have harbin-
gers of progressive insulin deficiency manifested by consistent and/
or progressive impairments of first-phase insulin response (sum of 1
min plus 3 min value in plasma is <5th percentile for age) after a
pulse if i.v. glucose; islet cell antibodies (ICA), insulin autoantibodies
(IAA), glutamic acid decarboxylase antibodies (GAD 65) and insuli-
noma-associated phosphatase-2 antibodies (IA-2); or other autoanti-
bodies to pancreatic islet antigens suggestive of pancreatic -cell
destruction or genetic mutations in genes known to be associated
with diabetes in relatives.
2 First-degree relative is considered to be a sibling, parent or
child.
3 ICA, determined by indirect immunofluorescence using
standardized reagents provided by the Juvenile Diabetes Foundation
(JDF), hence, expressed in JDF units, is highly predictive of develop-
ment of diabetes. However, difficult standardization of method has
hampered widespread clinical use.
Glutamic acid decarboxylase autoantibodies (GAD65) found in 70
90% of prediabetic and type 1 diabetics. More prevalent in older chil-
dren and late onset type 1 diabetics.
IA-2 autoantibodies found in 5075% of type 1 diabetics at or prior to
onset of disease. More prevalent in younger patients and associated
with rapid progression of the disease.
IAA present in ~100% of young children (<5 years) before the clinical
onset of IDDM. This antibody correlates with younger age and with
more rapid progression of IDDM in the preclinical phase.
4 If the subject is participating in a longitudinal research
study, a repeat ICA determination may be performed 1 year later.
However, yield of repeated ICA determination is low and does not
appear to justify periodic testing if two determinations, 1 year apart,
are negative.
99 5 The statistics quoted here are based on the report by
Verge et al [Diabetes 1996;45:926933]. FPIR should be done if the
ICAs are positive and in the context of an ongoing investigation. This
test is not presently established as a practice standard.
Carbohydrates
6 Obesity, acanthosis nigricans, hirsutism and features of
PCOS are often manifestations of insulin resistance, sometimes as-
sociated with mutations in the insulin receptor.
7 OGTT is performed after an overnight fast of 1012 h fol-
lowing at least 3 days of normal carbohydrate intake. The recom-
mended glucose dose is 1.75 g/kg, up to a maximum of 75 g. Blood
samples are obtained at 0, 0.5, 1, 2 and 3 h after glucose ingestion for
measurement of glucose and insulin in selected cases, e.g. suspect-
ed MODY where some forms have insulinopenia and, hence, may
require insulin replacement therapy. Criteria for diagnosing diabetes
mellitus or impaired glucose tolerance are the following:
8 Educating patients about symptoms such as increased
thirst and fluid intake (polydipsia), increased urination (polyuria),
weight loss or vaginal yeast infection is important so as to treat clini-
cal diabetes before the patient decompensates to ketoacidosis. Pa-
tients also may be taught to periodically test urine for glucosuria
and, if present, to report to the physician for evaluation and manage-
ment.
9 Individuals with certain disorders may have an increased
risk to develop special forms of diabetes mellitus which cannot be
classified as type 1 diabetes mellitus or type 2 diabetes mellitus.
Awareness of this will help clinicians perform an early diagnosis and
provide appropriate and timely therapy. Two such conditions include
cystic fibrosis and organ transplants. CFRD (cystic fibrosis-related
diabetes) and PTDM (post-transplant diabetes mellitus) are recog-
nized entities. CFRD occurs as a result of declining insulin secretion
due to fibrosis of the pancreas, frequently complicated by a compo-
nent of insulin resistance related to infection-induced stress and ste-
roid treatment. PTDM is usually the result of the effect of immuno-
suppressive agents and steroids which may act through different
mechanisms including decreased insulin secretion, increased insulin
resistance or direct toxic effect on the -cell. Cyclosporin and tacroli-
mus are known to cause PTDM. Mycophenolate mofetyl (MMF) and
sirolimus are less well understood. Asparaginase is known to induce
hyperglycemia and pancreatitis. High-dose steroids lead to hyper-
glycemia through the induction of insulin resistance.
Diagnostic criteria for diabetes mellitus [ADA, 1997]
Symptoms* of diabetes plus random plasma glucose =>
200 mgdl (11.1 mmol/l)
or
Fasting plasma glucose => 126 mg/dl (7.0 mmol/l)
or
Two-hour plasma glucose during the OGTT => 200 mg/dl (11.1 mmol/l)
*Symptoms include polyuria, polydipsia, and unexplained weight loss
with glucosuria and ketonuria.
D.B. Dunger O. Escobar R.K. Menon M.A. Sperling
Diagnostic criteria for potential prediabetic states [ADA, 1997]
Impaired fasting glucose (IFG): fasting glucose between 110 and
125 mg/dl (6.16.9 mmol/l)
Impaired glucose tolerance (IGT): Two-hour plasma glucose during the
OGTT between 140 and 199 mg/dl (7.811.0 mmol/l)
Selected reading
American Diabetes Association: Report of the Expert Committee
on the Diagnosis and Classification of Diabetes Mellitus, 1997.
Diabetes Prevention Trial Type 1 Diabetes Study Group: Effects
of insulin in relatives of patients with type 1 diabetes mellitus.
N Engl J Med 2002;346:16851691.
Fajans SS, Bell GI, Bowden DW, Halter JB, Polonsky KS:
Maturity onset diabetes of the young (MODY). Diabet Med
1996;13(suppl 6):S9095.
Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and
clinical pathophysiology of maturity-onset diabetes of the young.
N Engl J Med 2001;345:971980.
Gabir MM, Hanson RL, Dabelea D, et al: The 1997 American
Diabetes Association and 1999 World Health Organization criteria
for hyperglycemia in the diagnosis and prediction of diabetes.
Diabetes Care 2000;23:11081112.
Gale EA, Bingley PJ, Emmet CL, et al: European Nicotinamide
Diabetes Intervention Trial (ENDIT): a randomised controlled
trial of intervention before the onset of type 1 diabetes. Lancet
2004;363:910.
Hoffmeister PA, Storer BE, Sanders JE: Diabetes mellitus in long-
term survivors of pediatric hematopoietic cell transplantation.
J Pediatr Hematol Oncol 2004;26:8190.
Moran A: Cystic fibrosis-related diabetes: an approach to
diagnosis and management. Pediatr Diabetes 2000;1:4148.
Penfornis A, Kury-Paulin S: Immunosuppressive drug-induced
diabetes. Diabetes Metab 2006;32:539546.
Pietropaolo M, Shui Y, Libman IM, et al: Cytoplasmic islet cell
antibodies remain valuable in defining risk of progression to type
1 diabetes in subjects with other cell autoantibodies. Pediatr
Diabetes 2005;6:184192.
Sperling MA: Diabetes mellitus; in Sperling M (ed): Pediatric
Endocrinology, ed 2. Philadelphia, Saunders, 2002, pp 323366.
Prediabetes and prediction of diabetes
 Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling T2DM

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 1 In 1997, the American Diabetes Association
recommended new diagnostic criteria (see below) and
a new classification of diabetes based on etiopatho-
genesis and not on therapeutic response. The two
main types of diabetes are type 1 diabetes and type possible to classify type 2 diabetes according to the
2 diabetes. The terms IDDM and NIDDM should be
abandoned. Type 1a diabetes is a disorder character-
ized by insulin deficiency as a result of the autoim-
mune destruction of the -cells, whereas type 2 diabe-
tes is characterized by insulin resistance with relative
but progressive insulin deficiency. There is a strong
genetic predisposition and certain ethnic groups such
as Pima Indians, Pacific Islanders, African-Americans
and, possibly, individuals from other groups, appear to
be at greater genetic risk, especially when associated
with obesity. The majority of individuals with type 2
diabetes mellitus are obese.
2 A diagnosis of diabetes mellitus can be
made if there are typical symptoms such as polyuria,
polydipsia, weight loss in the presence of a random
plasma glucose of 200 mg/dl or higher (11.1 mM or
higher). Also, if a fasting plasma glucose is 126 mg/dl
or higher (7.0 mM or higher), a diagnosis of diabetes is
established. Finally, if the plasma glucose is 200 mg/dl
or higher (11.1 mM or higher) at 2 h during the OGTT, a
diagnosis of diabetes is considered to be established.
Impaired fasting glucose is said to be present if the
fasting plasma glucose is >110 mg/dl (6.1 mM) but <126
mg/dl (7.0 mM). Impaired glucose tolerance is said to
be present if the fasting glucose remains <126 mg/dl
(7.0 mM) and the 2-hour plasma glucose during the
OGTT is <200 mg/dl (11.1 mM) but >140 mg/dl (7.7 mM).
Such abnormalities may herald the evolution of type 2
diabetes mellitus.
3 Even in children, obesity is present in at
least 60% of patients diagnosed as having type 2 dia-
betes mellitus. Acanthosis nigricans, hirsutism, and
features of PCOS are often associated with insulin re-
sistance and hence hyperinsulinemia which, in sus-
ceptible individuals, may lead to diabetes if pancreatic
-cell secretory reserve falters over time. Hyperten-
sion has also been demonstrated to be an associated
finding in those with type 2 diabetes, presumably a
reflection of insulin resistance with obesity. The high
101 preponderance of certain ethnic backgrounds in pre-
disposing to type 2 diabetes in children and adoles-
cents has been commented on above.
Carbohydrates
4 Polymorphisms in the genes of KCNJ11,
PPARG and TCF7L2 have been recently described and
found to predispose to type 2 diabetes in several large
studies. As genetic defects become defined, it will be
Diabetes Prevention Program. N Engl J Med
genetic defect rather than through our current broad
clinical category.
5 In the absence of physical stigmata com-
monly associated with type 2 diabetes as outlined
above, it is appropriate to consider a child to be in
evolving type 1 diabetes or MODY and to proceed as
outlined in greater detail in the algorithm for MODY or
for pre-diabetes.
6 Management of the child-adolescent with
type 2 diabetes mellitus is difficult and challenging.
Initial treatment with insulin is a common practice, es-
pecially in patients who present with severe metabolic
decompensation at onset (occasionally even in the
hyperosmolar nonketotic status or even in diabetic
ketoacidosis). Prompt implementation of lifestyle in-
tervention (dietary and exercise recommendations) is
of utmost importance. The use of oral agents, mainly
metformin, the only oral agent currently approved by
the US Food and Drug Administration for use in chil-
dren, has gained great acceptance in the management
of type 2 diabetes in youth and is not infrequently used
as the first line of treatment along with diet and exer-
cise. Improvement of insulin sensitivity as a result of
weight loss and improved fitness may allow weaning
and eventual discontinuation of pharmacologic thera-
py (insulin/metformin) in selected patients. Other oral
agents not currently approved for use in children in-
clude sulfonylureas, thiazolidinediones, glitinides and
glucosidase inhibitors. Orlistat, a lipase inhibitor and
sibutramine, an appetite suppressant, may be used for
treatment of obesity and thereby to stave off T2DM.
D.B. Dunger O. Escobar R.K. Menon M.A. Sperling
Selected reading
Florez JC, Jablonski KA, Bayley N, et al: TCF7L2
polymorphisms and progression to diabetes in the
2006;355:241250.
Franks PW, Looker HC, Kobes S, et al: Gestational
glucose tolerance and risk of type 2 diabetes in
young Pima Indian offspring. Diabetes 2006;55:
460465.
Gungor N, Arslanian S: Pathophysiology of type 2
diabetes mellitus in children and adolescents: treat-
ment implications. Treat Endocrinol 2002;1:359371.
Jacobson-Dickman E, Levitsky L: Oral agents in
managing diabetes mellitus in children and adoles-
cents. Pediatr Clin N Am 2005;52:16891703.
Polonsky KS, Sturis J, Bell GI: Non-insulin-depen-
dent diabetes mellitus: a genetically programmed
failure of the beta cell to compensate for insulin re-
sistance. N Engl J Med 1996;334:777783.
Sperling MA: Diabetes mellitus; in Sperling MA (ed):
Pediatric Endocrinology, ed 2. Philadelphia, Saun-
ders, 2002, pp 323366.
Weedon MN, McCarthy MI, Hitman G, et al: Combin-
ing information from common type 2 diabetes risk
polymorphisms improves disease prediction. PLoS
Med 2006;3:e374.
Weiss R, Taksali SE, Caprio S: Development of type
2 diabetes in children and adolescents. Curr Diab
Rep 2006;61826187.
Yeckel CW, Taksali SE, Dziura J, et al: The normal
glucose tolerance continuum in obese youth: evi-
dence for impairment in beta-cell function indepen-
dent of insulin resistance. J Clin Endocrinol Metab
2005;90:747754.
T2DM
 Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Type 1 diabetes mellitus

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 1 Diagnosis is usually straightforward see
Selected reading
Hyperglycemia (p. 96).
Acerini CL, Williams RM, Dunger DB: Metabolic im-
2 Early management. Comprehensive patient pact of puberty on the course of type 1 diabetes.
education package by specialist team including nurse Diabetes Metab 2001;27:S19S25.
specialist, dietician, physician, play specialist and psy-
Diabetes Control and Complications Trial Research
chologist where available. In pre-pubertal children, be
Group: The effect of intensive treatment of diabetes
aware of the risk of significant asymptomatic hypogly-
on the development and progression of long-term
cemia particularly overnight. Insulin therapy can be
complications in insulin-dependent diabetes
given as a mixture of long- and short-acting prepara-
mellitus. N Engl J Med 1993;329:977986.
tions either twice or three times daily. By adolescence
aim for a basal bolus regime with carbohydrate count- Eugster EA, Francis G, Lawson-Wilkins Drug and
ing. Consider continuous infusion of insulin via pump Therapeutics Committee: Position statement: Con-
in motivated families where conventional therapy is tinuous subcutaneous insulin infusion in very young
failing or where there are significant problems with children with type 1 diabetes. Pediatrics 2006;118:
hypoglycemia. e1244e1249.
Holl RW, Swift PG, Mortensen HB, Lynggaard H,
3 Aim for HbA1c below 7.5% and remember
Hougaard P, Aanstoot HJ, Chiarelli F, Daneman D,
that reference ranges vary between assays and cen-
Danne T, Dorchy H, Garandeau P, Greene S,
ters. Targets should be based on local assay and local
Hoey HM, Kaprio EA, Kocova M, Martul P,
normal range. Measure every 34 months.
Matsuura N, Robertson KJ, Schoenle EJ, Sovik O,
Tsou RM, Vanelli M, Aman J: Insulin injection
4 Annual screening. T4, TSH, and celiac screen
regimens and metabolic control in an international
recommended from early childhood. Height and
survey of adolescents with type 1 diabetes over
weight should be monitored regularly. Perform annual
3 years: results from the Hvidore study group. Eur J
urine albumin creatinine ratio, retinal photography
Pediatr 2003;162:2229.
and blood pressure annually from the beginning of
puberty. Peveler RC, Bryden KS, Neil HA, Fairburn CG,
Mayou RA, Dunger DB, Turner HM: The relationship
5 Puberty: be aware of the impact of physi- of disordered eating habits and attitudes to clinical
ological changes; increased insulin resistance which outcomes in young adult females with type 1 diabe-
can require up to 1.52.0 U/kg day to counteract. In tes. Diabetes Care 2005;28:8488.
girls there is a risk of excessive weight gain and poly-
cystic ovarian syndrome in late adolescence. During
adolescence there may be problems with compliance;
eating disorders, insulin omission (particularly in girls
to manipulate weight) and brittle diabetes resulting in
recurrent admissions.

6 Need for: (1) counseling; (2) early surveil-

lance complications (significance of microalbuminuria
during puberty not proven); (3) careful transfer: par-
ent-child, pediatric-adult clinics.

103

Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Type 1 diabetes mellitus
 Carbohydrates M.A. Sperling O. Escobar R.K. Menon D.B. Dunger Maturity-onset diabetes of youth (MODY)

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 * Alternatively known as monogenic diabetes of youth
= MODY
1 MODY is a genetically and clinically hetero-
geneous subtype of DM characterized by early onset
between the ages of 9 and 30 years, autosomal-domi-
nant inheritance and a primary defect in insulin secre-
tion. Because it is not always a form of non-insulin-
dependent diabetes (previously known as NIDDM but
now referred to as T2DM), we prefer the designation of
monogenic diabetes of youth rather than the term
maturity-onset diabetes of youth, which we believe is
misleading (because at least 2 forms are insulin de-
pendent from the outset), though established in the
literature. To date, some 6 MODY genes have been
identified. MODY 1 results from a mutation in the he-
patic nuclear factor (HNF) 4- gene located on the long
arm of chromosome 20. MODY 2 is due to a mutation
in the gene for glucokinase located on the short arm of
chromosome 7. MODY 3 is due to a gene mutation for
HNF1- located on the long arm of chromosome 12.
MODY 4 is due to gene mutation in the insulin promot-
er factor (IPF)-1 gene located on the long arm of chro-
mosome 13 the gene is also known as PDX-1 (pan-
creas duodenum homeobox). MODY 5 is due to a gene
mutation in HNF-1 located on chromosome 17. MODY
6 is due to a gene mutation on chromosome 2 known
as NeuroD1 and also as BETA2. With the exception of
MODY 2 which is due to a mutation in an enzyme that
renders the -cells less sensitive to glucose and hence
decreased insulin secretion at usual glucose concen-
trations, the remaining identified genes are transcrip-
tion factors that regulate insulin secretion or pancreas/
-cell development. There is phenotypic heterogene-
ity between different mutations of MODY subtypes
and within MODY pedigrees. Strict criteria for the diag-
nosis of MODY include DM which may be entirely in-
sulin dependent or treated with oral (sulfonylurea)
drugs in at least three generations with autosomal-
dominant transmission and diagnosis before age 25
30 years in at least one affected subject.
2 By definition, the absence of a family history
suggestive of autosomal-dominant inheritance makes
a diagnosis of MODY virtually untenable although new
mutations may occur. In such circumstances, the ap-
105 pearance of diabetes in a relatively young person
would most likely represent evolving type 1 diabetes
and, therefore, evaluation for markers of autoimmu-
nity is warranted. Milder, slowly evolving type 1 diabe-
tes could be confused with type 2 diabetes.
Carbohydrates
3 In the absence of markers of autoimmunity,
and with a negative history, a milder form of DM or a
prolonged honeymoon phase in a younger person
should be evaluated for common risk factors for T2DM
such as the presence of obesity, membership in ethnic
groups susceptible to T2DM or factors responsible for
secondary diabetes. Please refer to the separate algo-
rithm on T2DM and Pre-diabetes for more details.
4 Refer to relevant algorithm for type 1 or type
2 diabetes mellitus (see p. 100).
5 Once the more common type A insulin re-
sistance has been excluded, then inappropriately high
insulin levels in the presence of mild-to-moderate dia-
betes should raise the possibility of insulin resistance
due to a gene mutation of insulin itself, rendering the
molecule less effective. Patients with gene mutations
in the insulin gene may also appear to have autoso-
mal-dominant transmission. If suspected, the plasma
insulin must be evaluated for structural defects via
chromatographic elution patterns or other means, in-
cluding molecular diagnostics such as gene sequence
alterations, if available. Insulin receptor abnormalities
also may present with high insulin levels but without
structural defects or gene abnormalities in the insulin
molecule.
6 Mutations in the glucokinase gene respon-
sible for MODY 2 result in mild, chronic hyperglycemia
due to relatively milder reductions in pancreatic -cell
response to glucose. As a result, in the majority of af-
fected subjects, this is usually a relatively mild form of
diabetes with mild fasting hyperglycemia and im-
paired glucose tolerance. Homozygous mutations of
the glucokinase gene result in neonatal diabetes mel-
litus. Likewise, patients with mutations in the IPF-1/
PDX-1 gene may sometimes be treated with oral hypo-
glycemic agents, but may need insulin.
7 Patients affected with mutations in HNF4-,
HNF1-, HNF1- and NeuroD1-BETA2, show more se-
vere abnormalities of carbohydrate metabolism vary-
ing from impaired glucose tolerance to severe diabe-
tes and often progressing from mild to severe form
over time. About one-third of these subjects become
insulin-requiring and are prone to develop vascular
complications. Investigative studies demonstrate a
more severe form of insulin secretory defect in pa-
tients with MODY 1, and MODY 3 through MODY 6 as
compared to patients with MODY 2. In general, pa-
tients with MODY 2 and defects in the glucokinase
M.A. Sperling O. Escobar R.K. Menon D.B. Dunger
gene may demonstrate normal insulin responses to i.v.
glucose when blood glucose concentrations are main-
tained at >7 mM or higher. By contrast, patients with
the other listed forms of MODY have more severe im-
pairment of insulin secretion and this defect cannot be
overcome by priming with glucose infusion.
8 Distinction between the present forms of
MODY has clinical relevance in counseling because of
the lesser likelihood of vascular complications in MO-
DY 2, and the possibility of treating some of the other
forms (MODY 1, 3 and 4) by oral agents which induce
near-normal insulin secretion including an incretin
effect and maintenance of near-normal HbA1c concen-
trations. In time, some may need to be treated appro-
priately, with insulin, if necessary, in patients with MO-
DY 1, 3 and 4. Molecular analyses for the currently
known gene mutations in MODY 1 through MODY 4
are now available for routine clinical use to facilitate
diagnosis and management. New gene defects caus-
ing MODY are likely to be identified.
Selected reading
Fajans SS, Bell GI, Polonsky KS: Molecular mecha-
nisms and clinical pathophysiology of maturity-
onset diabetes of the young. N Engl J Med 2001;345:
971980.
Fajans SS, Bell GI: Phenotypic heterogeneity
between different mutations of MODY subtypes
and within MODY pedigrees. Diabetologia
2006;49:11061108.
Gloyn AL: Glucokinase (GCK) mutations in hyper-
and hypoglycemia: maturity-onset diabetes of the
young, permanent neonatal diabetes, and hyper-
insulinemia of infancy. Hum Mut 2003;22:353362.
Maturity-onset diabetes of youth (MODY)
 Carbohydrates D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Diabetic ketoacidosis

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 1 Diagnosis: Usually not difficult, but the com-
bination of hyperglycemia, acidosis and ketones must
be found. Severe metabolic acidosis in the absence of
hyperglycemia (or other obvious causes of acidosis
such as renal failure) raises the possibility of sepsis
(Gram-negative), lactic acidosis (glycogen storage dis-
ease type I), alcoholic ketoacidosis, aspirin overdose
and other inborn error of metabolism (propionic acide-
mia, methyl-malonic acidemia).
2 Coma at admission: True coma at admission
is rare (less than 10%), but conscious level may be im-
paired at presentation. If the child presents with coma
other possible causes must be considered (DKA may
have been precipitated secondarily). Cerebral edema
(a rare but devastating complication of DKA) may oc-
cur early in the disease, before any intravenous treat-
ment has been given.
3 Fluid resuscitation: The priority is to restore
the circulating volume. Please follow local protocol or
refer to the recently published international consensus
statement on the management of DKA in children for
details. Treat shock with fluid boluses 10 ml/kg 0.9%
sodium chloride or Ringers lactate solution. Reassess
clinical parameters of shock (heart rate, blood pres-
sure, capillary refill time) after each bolus. In severe
acidosis, where the pH is below 7.0, cautious use of
bicarbonate may be considered according to the local
protocol and following discussion with the physician
with overall responsibility for the patients care.
4 Dehydration: To evaluate the degree of de-
hydration the usual clinical signs should be used, but
overestimation may occur; a good correlation with the
degree of dehydration in young children has been
found with capillary refill time. Unless there is evi-
dence of shock, with capillary refill time longer than
3 s, estimate degree of dehydration as 5%.
107
Carbohydrates
5 Fluid requirements: The volume of fluid to
Selected reading
be replaced is based on the deficit (degree of dehydra-
tion) plus the maintenance (basal 24-hour require- Charfen MA, Fernandez-Frackelton M: Diabetic keto-
ment), ongoing losses should be replaced if signifi- acidosis. Emerg Med clin North Am 2005;23:609
cant. The debate over how long fluids should be re- 628
placed (24, 36 or even 48 h) is still ongoing; rapid infu- Dunger DB, Sperling MA, Acerini CL, Bohn DJ,
sion of large volumes of fluids has been proposed as a Daneman D, Danne TPA, Glaser NS, Hanas R, Hintz
risk factor for the development of cerebral edema, al- RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI:
though this has not been shown definitively. Currently, ESPE/Lawrence Wilkins Consensus Statement on
the advice is to replace the deficit over 48 h with close Diabetic Ketoacidosis in Children and Adolescents.
monitoring of pH, glucose and plasma electrolytes. Paediatrics 2004;113:133140.
Isotonic solution is used initially as the administration
Edge JA, Roy Y, Bergomi A, Murphy NP, Ford-
of hypotonic solutions may be associated with a de-
Adams ME, Ong KK, Dunger DB: Conscious level in
crease of plasma sodium concentration which also has
children with diabetic ketoacidosis is related to
been associated with a risk of development of cerebral
severity of acidosis and not to blood glucose con-
edema. Add 20 mmol/l KCl to every 500-ml bag of flu-
centration. Pediatr Diabetes 2006;7:1115.
id. Commence 0.9% saline and once the glucose has
fallen below 12 mmol/l, administer 0.45% saline 5% Lebovitz HE: Diabetic ketoacidosis. Lancet
dextrose. 1995;345:767772.
Insulin therapy: In the mildly dehydrated patient who
Rosenbloom AL: Hyperglycemic crises and their
is tolerating oral fluids, subcutaneous insulin may be
complications in children. J Pediatr Endocrinol
considered initially. In patients with moderate-to-se-
Metab 2007;20:518.
vere acidosis and dehydration who are not tolerating
oral fluids, commence 0.1 U/kg/h i.v. If the rate of fall of Saavedra JM, Harris GD, Song L, Finberg L: Capillary
blood glucose exceeds 5 mmol/l/h, consider reducing refilling (skin turgor) in the assessment of dehydra-
to 0.05 U/kg/h. tion. AJDC 1991;145:296298.
Monitor plasma electrolytes and blood gases closely,
with bedside glucose testing at least hourly.
6 Cerebral edema: This rare but devastating
complication of diabetic ketoacidosis is almost exclu-
sively a condition of childhood. The pathophysiology
is still not completely understood. It usually occurs
between 4 and 12 h from the start of treatment. The
clinical signs are variable: gradual deterioration and
worsening of conscious level from admission or more
commonly a gradual general improvement followed
by sudden neurological deterioration. It requires
urgent recognition and intervention; the treatment of
choice is mannitol, which must be given within 5 or
10 min of the initial deterioration in neurological func-
tion. Early admission in ICU, intubation and hyper-
ventilation is required, as hyperventilation together
with early mannitol has been shown to improve
outcome.
D.B. Dunger O. Escobar R.K. Menon M.A. Sperling Diabetic ketoacidosis
 Index of Signs and Symptoms
A Abdominal pain 106 Athyreosis 76 Conn syndrome 56, 66
108 Acanthosis nigricans 32, 98, 100 Autonomous nervous system, activation 95 Convulsions 63
Acne 11, 32, 53 Autosomal-dominant inheritance 104 Corneal drying 81
Adipomastia 21 Coronary heart diseases 11
Adrenal hyperandrogenism,
primary functional 32, 34
B Bardet-Biedel syndrome 54
Bartter syndrome 66, 74
Cortical suppression normal 34
Cortisol resistance and metabolic defects 34
Adrenal hyperplasia, congenital Beckwith-Wiedemann syndrome 8, 10, 94 Craniopharyngioma 10
after newborn period 52 Bicarbonaturia 62 Cryptorchidism 22, 38, 42
in newborn period 50 Blue diaper syndrome 69 Cushing
nonclassical 18, 34 Body disease 48
Adrenal insufficiency 58, 62 fat, redistribution 48 syndrome 10, 22, 32, 34, 48, 56
Adrenal rests 34 mass index 10
Adrenal tumor 16
Adrenarche 18, 52
odors, changed 19
Bone age 6, 14, 18, 52
D Dehydration 50, 58, 106
fever 58
Adrenocorticotropic hormone, insensitivity 8 advanced 16 hypertonic 60
African-American 100 Brain Diabetes
Albright osteodystrophy 11 damage 39 drug-induced 98
Albumin 68 irradiation 12 insipidus 58, 60
Aldosteronism 46, 66 Breast(s) central 54
Alopecia 32 bloody discharge 21 dipsogenic, partial, pituitary 54
Alstrm syndrome 10, 54 development maternal 94
Amenorrhea delayed or absent 24 maturity-onset of the young 96, 98, 100, 104
athletic, hypothalamic 30 precocious 14 mellitus 54, 100, 104
primary, secondary 28, 44 hard 21 immune-mediated 96, 98, 100, 104
Androgen(s) irregular consistency 21 non-immune-mediated 96, 98, 100
excess, signs 53 Burns 60 Type 1 100, 102
exogenous 16 Type 2 98, 100
insensitivity, incomplete 36, 38 C Calcium levels Diabetic ketoacidosis 106
insensitivity syndrome 8 serum 72 Diabetic mother 10
resistance 26 urine 72 Diarrhea 58
suppression 34 Calcium receptor defects 70 chronic 74
normal 34 Caloric intake 10 profuse 66
subnormal 34 Cardiac arrest 64 Diencephalic syndrome 2
Anorexia 24, 58, 60 Cardiac insufficiency, mild 56 Diuresis, insufficient 56
nervosa 25, 29 Carpenter syndrome 10 Diuretic (ab)use 63
Anosmia 22, 24, 31 Central nervous system lesion 6 Diuretic excess 62
Anovulation 29, 32 Chemotherapy 74 Dyshormonogenesis of thyroid 76, 78, 84, 85
Anovulatory disorders 30 Chorionic gonadotropin-secreting
Anthropometry 2
Aortic stenosis, supravalvular 69
syndrome, human 14
tumors 16
E Ear lobe fissures 94
Eating disorder 30
Apocrine sweat odor 53 Clitoral hypertrophy 19 Edema, female newborn 44
Appetite, uncontrollable 11 Clitoromegaly 52 Electrolytes, urea 106
Aromatase isolated, vaginal fusion 26 Elfin faces 69
deficiency 9, 40 Coarctation 46 Enterostomy losses 66

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inhibitors 16 Cohen syndrome 10 Estradiol 30
Aromatization excess, familial 20 Coma 106 Estrogen
Athlete 24 Confusion 106 deficiency, insensitivity 8
Athletic amenorrhea 26, 30 Conscious level, reduced 106 receptor defects 9

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 Ethnic background 100 isolated 22 Hypercalcemia 54, 68
high risk for diabetes 100 organic 30 neonatal 68
Ethnic groups 19 secretion 17 Hypercalcemic crisis 68
Eunuchoid habitus 9, 22 Graves disease 80 Hypercortisolism 11
Euthyroid 82 maternal, neonatal 82 Hyperglycemia 96, 100, 102
hyperthyroxinemia 92 Growth mild/moderate 100
Exophthalmos 80 abnormal 12 severe 100
acceleration 9, 19, 52 Hyperhidrosis 32
F Failure to thrive 2 hormone Hyperhydration 56
Fanconi syndrome(s) 66, 70, 72 deficiency 6, 10, 12, 38 Hyperinsulinemia 11, 94
Fat childhood 6 Hyperkalemia 64
distribution 10 classic 4 Hyperlipidemia 11
subcutaneous 69 insensitivity 36, 38 Hypernatremia 60
Feminizing disorders 21 excess 8 essential 54
Fever 80, 84 insensitivity 38 Hyperosmolar nonketotic state 100
Fibrous dysplasia 72 syndrome 4 Hyperphosphatemic rickets
First-degree relative treatment 6 autosomal-dominant 72
type 1 diabetes mellitus 98 normal 36 autosomal-recessive 72
type 2 diabetes mellitus 98 rate 8 calciuria 73
Fluid poor 44 Hyperpigmentation 52
depletion 58 rate, reduced 6 Hyperplasia, congenital adrenal 16, 64
overload 56 poor 6 Hyperprolactinemia 32
requirements 107 retardation 11 Hypertension 11, 46, 52
resuscitation 107 slow 36 renovascular 46
Fragile X syndrome 17 velocity, declining 48 Hyperthermia, malignant 64
Fructose intolerance 94 Gynecomastia Hyperthyroidism 8, 15, 68, 80, 84
false 20 neonatal 82
G Galactorrhea 31 idiopathic prepubertal 20 Hyperthyroxinemia 90, 92
Gastrointestinal injury 75 autoantibody-associated 92
Genetic counseling 19 H Hair, axillary, pubic 19 familial dysalbuminemic 92
Genital anatomy, abnormal 26 Hashitoxicosis 80 Hypertrichosis 32
Genital development, precocious, boy 16 Heart Hyperventilation 60
Genitalia disease, congenital 45 Hypocalcemia
ambiguous 50 failure, congestive 62 neonatal 70
internal, abnormal 32 Hearing 44 late 74
Germinal failure, primary 22 Height velocity 4 severe 74
Gigantism, cerebral 8, 9 decreased 22, 23, 24 Hypodipsia 60
Glucocorticoid deficiency 62 increased 8, 14, 15, 16, 18 Hypoglycemia 9, 10
isolated 9 normal 8, 14, 18, 22, 24 infants and children 94
Glucocorticoids 7 Hemodialysis 60 Hypogonadism 8
Glucose 38 Hepatocellular insult, acute 92 congenital 28
determination, rapid 94 Hermaphrodite, true 40 primary, other 20
intolerance 11 Hirsutism 11, 30, 32, 98, 100 Hypokalemia 54, 66
Glucose blood idiopathic 31 Hypomagnesemia 70, 74
fasting 96 Histiocytosis X 55 Hyponatremia
random 96 Homocystinuria 8 hypervolemic 62
109 Glucosuria 60 21-Hydroxylase deficiency hypovolemic 62
Glycosuria 102 mild 52 normovolemic 62
Goiter 29, 76, 80, 82, 84 moderate 52 Hypoparathyroidism, maternal 70
Goitrogens 84 secondary 46, 60 Hypopituitarism 39

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Gonadotropin Hyperandrogenemia 32, 34 Hypophosphatemic rickets 72
deficiency 24, 26 Hyperandrogenism, idiopathic 32, 34 Hypospadias 37, 38, 40
idiopathic 30

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Index of Signs and Symptoms
 Index of Signs and Symptoms

Hypothyroidism 7, 1012, 14, 16, 62, 84 M McCune-Albright syndrome 14 polycystic 34

acquired, other types 78 Macroglossia 94 Overweight 10
congenital 76, 90 Macro-orchidism, without virilization 16
hypothalamic pituitary 90 Macrosomia, no maternal diabetes 94 P Panhypopituitarism 3638
juvenile 78, 90 Malabsorption 70, 72 Parents, tall, non-tall 8
primary 30 Malnutrition 2 Penile length, mean, stretched 17
110 secondary, tertiary 76, 78 short gut syndrome 74 Penis
Hypothyroxinemia 90 Mammoplasia, infantile 14 large 19, 52
Marfan syndrome 8 size, increase 23
I Iatrogenic reasons 20, 56, 60, 62, 66, 68, 70 Maternal deprivation 2 Peutz-Jeghers syndrome 21
Ileus 66 Menstrual disorder 11 Pheochromocytoma 46
Immobilization 68 Mental retardation 69 renal 46
Incubator temperature 60 Micropenis 36, 38, 42, 94 Phosphate deficiency 72
Infant Mineralocorticoid excess 46, 66 Pima Indian 100
diabetic mother 74 5-Monodeiodinase, generalized deficiency 92 Pituitary
feed, mistake in preparing 60 Mumps orchitis 21 disorder 6
Infertility 44 Muscular twitching 75 multiple, hormonal deficiency 92
Inflammatory bowel disease 27 tumor 30
Insulin N Nasogastric reflux/aspirate 66 Pituitary/hypothalamic disease 6
exogenous (factitious hypoglycemia) 94 Neonatal goiter 84 Polycystic ovaries syndrome 10, 19, 32, 98, 100
requirements 102 Neonatal rickets 72 atypical 34
Insulinoma 94 Neonatal thyrotoxicosis 82 classical 34
Intersex 26, 34, 40 Nephrotic syndrome 56, 62, 70 nonclassical 34
Intestinal absorption defect 74 Neurofibromatosis 8 Polydipsia 102, 106
Intrauterine adhesions 28 Neuroglycemia 95 primary 62
Iodine Newborn screening tests 76 Polyuria 54, 102, 106
deficiency 76, 84 Nonpathogenetic stigmata 28 Poor length gain 2
exposure 76 Nystagmus 94 Prader-Willi syndrome 10
Prealbumin (transthyretin) hyperthyroxinemia 92
J Jansens metaphyseal dysplasia 68 O Obesity 10, 30, 32, 48, 58, 100 Precocious pubarche 18
Jaundice 94 infantile 10 Prediabetes, prediction of diabetes 98
mild truncal 11 Pregnancy 28
K Kallmann syndrome 29, 36 simple 10 test positive 26
Ketoacidosis 100, 102, 106 Oily skin 53 Prematurity 94
Ketonemia 94 Oligomenorrhea 28, 29 Prolactin 30
Ketones, smell of 106 Omphalocele 9 Prolactinoma 22
Ketonuria 62, 94 Optic glioma 9 Pseudogynecomastia 21
acidemia 106 Orchidopexy 22 Pseudohypoaldosteronism 64
Ketotic hypoglycemia 94 Orchitis 20 Pseudohypocalcemia 70
Kidney malformation 45 torsion 22 Pseudohypoparathyroidism 10, 70
Klinefelter syndrome 9, 20 Organomegaly 9 Psychological problems 102
Osmolality 62 Psychological stress 2, 29
L Laurence-Moon-Biedl syndrome 10 Osteomalacia Puberty 8, 102
Laxative abuse 66 tumor-induced 72 abnormal 12
Leptin 10 Osmotic diuresis 62 delayed 42
Lethargy 106 Otitis media 45 idiopathic central precocious 14
Liddle syndrome 46 Ovaria 28, 30 infantile central precocious 14
Lipodystrophy, total 8 Ovarian/adrenal tumor 34 organic central precocious 14
Liquorice abuse 66 Ovarian cyst/tumor 14 peripheral (pseudo)precocious,

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Liver Ovarian failure, primary 24, 28 central (true) precocious 16
cirrhosis 56, 62 Ovarian hyperandrogenism, functional 32 precocious, delayed 12
disease 20, 70 Ovaries true, precocious 8
chronic 21 not polycystic 34 Pubic hair 53
Lymphedema 45 absent, present 20

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development 17
 R Rachitic bone changes 73 T T4-binding protein abnormality 76 Thyrotoxicosis
Radiation Tachycardia 80, 82, 94 biochemical 92
exposure 88 Tall stature clinical 86, 92
no exposure 88 familial 8 factitia 80
Renal disease 54 unexplained 9 non-immune-mediated 83
Renal failure 56, 62, 70 Testes Tingling 75
acute 74 small 10, 38 Toxicosis, hyperpyretic 58
Renal insufficiency, chronic 60 retractile, vanishing 42 Tremor 75
Renal tubular injury 75 two prepubertal 16 Tremulousness 94
Respiration deep-sighing, Kussmaul 106 Testicular atrophy 36, 38 Turner syndrome 24, 44
Rheumatic disease 25 Testicular development, delayed or absent 22 Type 1 diabetes mellitus 100, 102
Rickets 70 Testicular dysgenesis 38 Type 2 diabetes mellitus 98, 100
calcitriol-resistant, vitamin D-dependent, Testicular failure, primary 22
hypophosphatemic, hepatic 72
hypoparathyroidism 72
Testicular volume 17
bilateral increase, unilateral increase 16
U Undernutrition 30
Undervirilized boy 40
neonatal 72 Testosterone-binding globulin Underweight 26
X-Iinked hypophosphatemic, autosomal-recessive deficiency 76 Urinary tract infection 50
hypophosphatemic with calciuria 72 increased concentration 92 severe 96
Rokitansky syndrome 26 Testotoxicosis 16 Uterine bleeding, dysfunctional 29
Thelarche, premature 14
S Salt-losing nephropathies 62
Salt loss, renal 58
Thyroglossal duct, abscess 85
Thyroid
V Vagina
blind, isolated 26
wasting, cerebral 54 adenoma 88 congenital absence 27
Sarcoidosis 54 toxic 86 Vaginal aplasia 26
Scrotal size, texture, pigmentation 17, 19, 23 carcinoma 86, 88 Ventricular fibrillation 64
Sea water intoxication 60 cyst, isolated 86 Vitamin D 25-hydroxylase deficiency 72
Seborrhea 32 disease 82 Virilization 18, 40
Seizure 94 ectopic 76 absent, partial or adult, but small testes 22
Sex eutopic 76 girl 40, 50
characteristics, secondary 9 hormone(s) maternal 41
chromosome disorders 8 generalized resistance to 92 rapid 29
differentiation 39 partial peripheral resistance 78 Vomiting 50, 58, 106
Sexual precocity, central, peripheral 18 pituitary resistance 80 prolonged 66
Shock 63, 106 medullary carcinoma 86
volume depletion, acute 58 nodule(s) 84 W Water depletion 60
Short stature 4, 6, 23 autonomous 80 Weakness 106
female 44 children, adolescents 86 Weight 46
idiopathic 4 clinically euthyroid 86 gain
Sleep apnea 11 multiple 87 poor 2
Small for gestational age 74, 94 storm 80 rapid 48
Sodium overload 60 tender/painful swelling 84 loss 102, 106
Steroidogenic block(s), 28 tenderness 80 Williams syndrome 68
Steroids, exogenous 14 Thyroid-stimulating hormone receptor Wolfram syndrome 54
Sweatiest 62 activating mutation 80
Sweating 94 Thyroid-stimulating hormone-secreting pituitary
adenoma 80
X X chromosome defects 28
111 Thyroiditis
autoimmune, with hypothyroidism 88
(juvenile) chronic lymphocytic 78, 80, 84, 87
increased incidence 45

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subacute 80, 84
suppurative 84

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Index of Signs and Symptoms
 Abbreviations
4 = Androstenedione FPG = Fasting plasma glucose PCR = Polymerase chain reaction
112 ACTH = Adrenocorticotropic hormone FPIR = First-phase insulin response PE = Physical examination
ADH = Alcohol dehydrogenase FSH = Follicle-stimulating hormone PG = Prostaglandin
AIS = Androgen-insensitivity syndrome PPP = Peripheral precocious puberty
AME = Apparent mineralocorticoid excess GAD = Glutamic acid decarboxylase PRA = Plasma renin activity
APA = Aldosterone-producing adenoma GH = Growth hormone PRL = Prolactin
ATPO = Antithyroid peroxidase GHBP = Growth hormone-binding protein PTH = Parathyroidhormone
GHD = Growth hormone deficiency PTHrp = PTH-related protein
BA = Bone age GHRH = Growth hormone-releasing hormone PTU = Propylthiouracil
BMI = Body Mass Index GI = Gastrointestinal
BUN = Blood urea nitrogen GnRH = Gonadotropin-releasing hormone RDS = Respiratory distress syndrome
RU = Resin uptake
CAH = Congenital adrenal hyperplasia hCG = Human chorionic gonadotropin
CBC = Complete blood count HNF = Hepatocyte nuclear factor S = Serum
CDGP = Constitutional delay of growth and 11-HSD = 11-Hydroxysteroid dehydrogenase SDS = Standard deviation score
puberty Ht = Height SGA = Small for gestational age
CF = Cystic fibrosis SHBG = Sex-hormone-binding globulin
CG = Chorionic gonadotropin IAA = Insulin autoantibodies SIADH = Syndrome of inappropriate ADH secretion
CHO = Carbohydrate ICA = Islet cell antibodies
CIS = Carcinoma in situ IGF-1 = Insulin-like growth factor T = Testosterone
CMO = Corticosterone methyl oxidase IGFBP = IGF-binding protein TBG = Thyroxin-binding globulin
CPP = Central precocious puberty IGT = Impaired glucose tolerance TBPA = Thyroxin-binding prealbumin
CRH = Corticotropin-releasing hormone IHA = Idiopathic hyperaldosteronism T1DM = Type 1 diabetes mellitus
CT = Calcitonin T2DM = Type 2 diabetes mellitus
CVP = Central venous pressure JDF = Juvenile Diabetes Foundation TGAb = Thyroglobulin antibody
THE = Tetrahydrocortisone
DCCT = Diabetes complications and LH = Luteinizing hormone THF = Tetrahydrocortisol
control trial THS = Tetrahydro-11-deoxycortisol
DDAVP = 1-Deamino-d-arginine vasopressin MCT = Medullary carcinoma of thyroid TPOAb = Thyroid peroxidase antibody
DHEAS = Dehydroepiandrosterone sulfate MCV = Mean corpuscular volume TRAb = Thyrotropin receptor antibodies
DHT = Dihydrotestosterone MEN = Multiple endocrine neoplasia TRH = Thyrotropin-releasing hormone
DI = Diabetes insipidus MODY = Maturity-onset diabetes of the young TRP = Tubular resorption of phosphones
DKA = Diabetic ketoacidosis MRI = Magnetic resonance imaging TSAb = Thyroid-stimulating antibodies
DOC = Deoxycorticosterone TSH = Thyroid-stimulating hormone
DSH = Dexamethasone-suppressible nl = Normal TSHR = Thyroid-stimulating hormone receptor
hyperaldosteronism NOCAH = Nonclassical adrenal hyperplasia TSI = Thyroid-stimulating immunoglobulin
NSD1 = Nuclear receptor set domain containing
E1 = Estrone protein 1 gene U = Urinary
E2 = Estradiol NSAID = Nonsteroidal anti-inflammatory drugs U/L = Upper/lower
ECF = Extracellular fluid UFC = Urinary free cortisol
ERG = Electroretinography OGTT = Oral glucose tolerance test URTI = Upper respiratory tract infection
ESR = Erythrocyte sedimentation rate OHD = Hydroxylase deficiency UTI = Urinary tract infection
OHP = Hydroxyprogesterone
F = Follicular OT = Osmotic threshold W/U = Work-up

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FAH = Functional adrenal hyperandrogenism WBC = White blood cell count
FNA = Fine-needle biopsy P = Plasma
FOH = Functional ovarian hyperandrogenism PCO = Polycystic ovary
-FP = -Fetoprotein PCOS = Polycystic ovary syndrome

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