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PDF Practical Algorithms in Pediatric Endocrinology DL
PDF Practical Algorithms in Pediatric Endocrinology DL
Algorithms in
Pediatric
Endocrinology
2nd, revised edition
Editor
Ze‘ev Hochberg, Haifa
32 Hirsutism
R.L. Rosenfield; F. Riepe; W.G. Sippell
34 Hyperandrogenemia
R.L. Rosenfield; F. Riepe; W.G. Sippell
Water and electrolytes Thyroid Carbohydrates
72 Rickets
D. Tiosano; Z. Hochberg
108 Index of Signs and Symptoms
74 Hypomagnesemia
112 Abbreviations
A.D. Rogol; Z. Hochberg
Contributors
Jean-Pierre Bourguignon, MD, PhD Ze’ev Hochberg, MD, PhD Robert L. Rosenfield, MD
CHU Sart Tilman Rambam Medical Center The University of Chicago
Liège, Belgium Technion – Israel Institute of Technology Children’s Hospital
Haifa, Israel Chicago, Illinois, USA
David B. Dunger, MD
Department of Paediatrics Ram K. Menon, MD Wolfgang G. Sippell, MD
University of Cambridge, Addenbrooke’s Hospital Children’s Hospital Universitäts-Kinderklinik
Cambridge, UK Pittsburgh, Pennsylvania, USA Kiel, Germany
Library of Congress Cataloging-in-Publication Data Disclaimer. The statements, options and data contained in this publi- All rights reserved. No par t of this publication may be translated into
Practical algorithms in pediatric endocrinology / cation are solely those of the individual authors and contributors and other languages, reproduced or utilized in any form or by any means,
editor, Ze’ev Hochberg. – 2nd, rev. ed. not of the publisher and the editor(s). The appearance of adver tise- electronic or mechanical, including photocopying, recording, micro-
p. ; cm. ments in the book is not a warranty, endorsement, or approval of the copying, or by any information storage and retrieval system, without
Includes bibliographical references and index. products or services advertised or of their effectiveness, quality or permission in writing from the publisher.
ISBN-13: 978-3-8055-8220-9 (softcover : alk. paper) safety. The publisher and the editor(s) disclaim responsibility for any
1. Pediatric endocrinology – Diagnosis –Decision making. 2. Decision injury to persons or property resulting from any ideas, methods, in- 1st edition: Practical Algorithms in Pediatric Endocrinology
trees. structions or products referred to in the content or advertisements . Editor: Z. Hochberg, Haifa
I. Hochberg, Z. [DNLM: 1. Endocrine System Diseases. 2. Adolescent. IV + 110 p., 52 graphs, 4 fig., 1 tab., spiral bound, 1999
3. Child. 4. Decision Trees. 5. Endocrine System Diseases – diagnosis. Drug Dosage. The authors and the publisher have exerted every effort ISBN 3–8055–6693–X
6. Infant. WS 330 P8949 2007] to ensure that drug selection and dosage set forth in this text are in
RJ418.P69 2007 accord with current recommendations and practice at the time of pub- © Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel
618.92’4 – dc22 lication. However, in view of ongoing research, changes in government (Switzerland)
2007012334 regulations, and the constant flow of information relating to drug ther- Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISBN 978–3–8055–8220 –9 (spiral bound: alk. paper) apy and drug reactions, the reader is urged to check the package insert ISBN978–3–8055–8220–9
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.
Introduction
The first edition of Practical Algorithms in Pediatric Several chapters include suggestions made by our experienced with a given problem, a prepared algo-
Endocrinology was compiled in 1998 and published in readers and, as before, I invite comments to correct rithm would provide a logical, concise, cost-effective
1999. In the 8 years between its publication and this any mistakes which may have occurred or to make any approach prepared by a specialist who is experienced
second edition, molecular endocrinology has changed improvements to the diagnostic algorithms we offer. with the given problem. It would also train a young
our clinical practices to a level unimaginable only a practitioner in medical reasoning. This book is, there-
I hope you will find this book helpful in managing the
decade ago. The colossal pace of discovery in both fore, aimed at an audience of general practitioners
children under your care.
basic and clinical endocrinology has changed not only or pediatricians who are not exposed on a daily basis
our understanding, but also our daily engagement with to pediatric endocrine problems. It would also aid
Ze’ev Hochberg, MD, PhD
patients and parents. trainees in pediatric endocrinology as they presume
April 2007, Haifa
familiarity with clinical problem-solving to make
The first edition has sold over 3,000 copies. It is a
rational choices in approaching a clinical dilemma.
tribute to the 12 contributors to the first edition in that it
has become a leading bedside source for general prac- Certainly, there is more than one way to approach a
titioners, pediatricians and pediatric endocrine fellows. Introduction to 1st edition clinical problem, and this book presents one such way
The same contributors responded willingly to revise for each problem, prepared by skilled, experienced
each of the 50 algorithms. Naturally, we have additional Textbooks of medicine are oriented by body systems, specialists in pediatric endocrinology. The algorithms
younger contributors who have grown to be among the by disease or by diagnoses. Yet, the practicing physi- were prepared through discussion and deliberation
new leadership in pediatric endocrinology worldwide. cian is encountered by a patient ’s complaint, by a symp- among the authors of this book. By no means should
tom, by a physical sign or by a laboratory abnormality, they be viewed dogmatically as the one and only ap-
The basic outline remains unchanged. Algorithms are
from which he is expected to proceed to diagnosis and proach. We paid special attention to simple passages,
practical tools to help us address diagnostic and
to plan management. The traditional medical approach rejecting groups of diagnoses first by history and
therapeutic problems in a logical, efficient and cost-
is through differential diagnosis by exclusion. Algo- physical examination, then by simple laboratory tests
effective fashion. The enormous success and sell-out
rithms provide a direct approach to breaking down long common to any clinical setting, and only finally, in
of the first edition confirmed that this approach was
list tables of differential diagnosis into smaller, more some cases, to more sophisticated laboratory means,
useful for clinicians caring for children with endocrine
manageable lists, as often a whole group of diagnoses which may require specialized proficiencies.
disorders.
can be excluded by a single or a group of signs, blood
The term ‘algorithm’ is derived from the name of the
As with any approach that attempts to simplify com- tests or imaging.
ninth century Arabic mathematician Algawrismi, who
plex problems, there will always be exceptions. Each
Practical Algorithms in Pediatric Endocrinology is also gave his name to ‘algebra’. His ‘algorismus’ indi-
algorithm must be used in the context of the individual
meant as a pragmatic text to be used at the patient’s cated a step-by-step logical approach to mathematical
findings of each patient under examination and in
bedside. It classifies common clinical symptoms, signs problem-solving. It is presented hereby to the medical
conjunction with the published literature. The clinician
and laboratory abnormalities as they present to us in practitioner in that same spirit.
1 must always be aware that any individual patient’s
daily practice. The experienced practitioner applies
presentation may be atypical enough, or confounded
step-by-step logical problem-solving for each patient Ze’ev Hochberg, MD, PhD
by concomitant disorders or complications, to render
individually. Decision trees prepared in advance April 1999, Haifa
our approaches invalid. In addition, advances in diag-
have the disadvantage of unacquaintedness with the
nosis and management can render current approaches
individual patient. Yet, for the physician who is less
obsolete.
Growth R.L. Hintz · Z. Hochberg Failure to thrive
6
14
1 – Precocious breast development is the occurrence of breast 7 – Pelvic ultrasound is a noninvasive method to evaluate 13– GnRH agonist therapy, particularly the long-acting forms
tissue before the chronological age of 8 years in a girl. A different morphology and size of the ovaries and the uterus. The ovaries of the given as i.m. injections every 4 weeks or every 3 months, is the treat-
age limit may have to be used in particular environmental and ethnic prepubertal child may normally have a few follicles or ‘microcysts’ ment of choice of CPP. The promoting effects on adult height are lim-
groups (e.g. Black Americans are about 1 year ahead of White Ameri- up to 4 mm in diameter. The volume of the prepubertal uterus should ited when PP started after 6 years but psychosocial aspects may still
cans); the reader should refer to the local standards and experience. be 2 ml (length 4 cm). Additional information comes from the provide an indication. Cyproterone or medroxyprogesterone show
In developed countries, the secular reduction in average timing of Doppler study of uterine vessel resistance. Early pubertal stages are less-specific and more-undesirable (glucocorticoid-like) effects.
puberty has apparently come to an end but the early age limits may associated with a reduced pulsatility index. Pelvic ultrasound is pref- They can be considered when adult stature is not an objective while
still further decrease. The epidemic of obesity has been incriminated. erable to the vaginal smear which provides an alternative but inva- arrest of puberty and menses is wanted, e.g. in the severely mentally
Alternative factors are the endocrine disrupters. The tempo of devel- sive method to assess estrogenization of the female genital tract. retarded.
opment is important information that can be obtained through a 3- to Plasma estradiol measurements are not reliable unless an assay sen-
6-month follow-up. This tempo is usually low and comparable to sitive to <10 pg/ml is used, and cyclic fluctuations must be taken into 14– PPP involves estrogens of ovarian, adrenal or exogenous
normal puberty in the early variants of physiological development. In consideration in interpreting the value. In some patients seen very origin. True sexual precocity may rarely be caused by intracranial
contrast, fast progression throughout pubertal stages may be seen early during puberty, pelvic ultrasound may not yet show evidence human CG-producing germ cell tumors. A rare form of PPP can be
in patients with precocious puberty of abnormal organic or idiopath- of an estrogenic effect while measurement of the gonadotropins will associated with severe juvenile hypothyroidism and is reversible un-
ic origin. provide evidence of CPP. der thyroxine substitution. The advanced hypothalamic maturation
resulting from PPP may secondarily cause CPP. Ovarian imaging can
2 – History is critical regarding disorders or symptoms orient- 8 – Gonadotropin secretion (FSH and LH) can be assessed in be initially obtained through pelvic echography, while reliable adre-
ing towards an organic CNS cause. In several countries, migration different ways. A classical manner is the measurement of plasma nal imaging usually requires a CT or MRI scan.
for international adoption has emerged as a new cause of precocious gonadotropins before,
puberty. 20 min, and 60 min after a bolus injection of GnRH at a dose of 1 µg/ 15– McCune-Albright syndrome results from tissue-specific
kg (max. 100 µg). Typically, the secretory response of FSH predomi- auto-activating mutation in the signaling G-protein system (constitu-
3 – Associated signs may involve pubic and axillary hair, nates while the LH response is low in premature thelarche. In con- tive mutation only observable in cells from affected tissues). It asso-
swelling of vulvar mucosa, vaginal discharge or bleeding. Sexual trast, LH response shows a characteristic pubertal increase in CPP ciates café-au-lait spots and dysplastic lesions of the long bones. Ca-
hair is often absent early. and the response of both FSH and LH is low in peripheral sexual pre- fé-au-lait spots are also observed in neurofibromatosis which can be
cocity. Some authors have suggested the use of urinary gonadotro- associated with CPP and adrenal tumors as well.
4 – Height velocity shows early and rapid acceleration under pin measurement as a convenient and reliable index. The critical is-
estrogen action. It should be calculated retrospectively (when data sue is the availability of normative values to interpret the data ob-
from school or medical records are available) or prospectively. In- tained from the laboratory. Selected reading
creased height velocity should be > the 90th centile (7–8 cm/year be-
tween 5 and 9 years of age). When height velocity is unexpectedly 9 – Premature thelarche is usually a self-limited condition but Feuillan P, Merke D, Leschek EW, Cutler GB Jr: Use of aromatase
low while the other findings indicate increased estrogen activity, GH may be the initial manifestation of CPP and requires clinical follow- inhibitors in precocious puberty. Endocrine-Related Cancer
deficiency could be associated with central precocious puberty, par- up of growth and pubertal development. 1999;6:303–306.
ticularly if there is any organic cause. Then, a prepubertal level of Himes JH: Examining the evidence for recent secular changes in
serum IGF-1 is suggestive and GH stimulation test should be consid- 10 – CNS imaging is required when gonadotropin secretion the timing of puberty in US children in light of increases in the
ered (see p. 6). Likewise, hypothyroidism should be ruled out since it shows a pubertal secretory pattern indicating hypothalamopituitary prevalence of obesity. Mol Cell Endocrinol 2006;254–255:13–21.
can account for sexual precocity and slow height velocity. maturation. Though optimal imaging of this region is provided by
MRI, a CT scan is informative as well. Lebrethon MC, Bourguignon JP: Central and peripheral isosexual
5 – BA (X-ray film of left hand and wrist read according to precocious puberty. Curr Opin Endocr Diab 2001;8:17–22.
standards such as Greulich and Pyle) advancement means at least 2 11 – Idiopathic CPP (or complete, true precocious puberty) is Parent AS, Teilmann G, Juul A, Skakkebaek N, Toppari J,
SDs ahead of chronological age (1–2 years depending on age). When diagnosed when the history, physical examination and imaging of Bourguignon JP: The timing of normal puberty and the age limits
increased estrogen secretion has occurred very recently, BA ad- the CNS do not indicate any possible etiology or mechanism. In girls, of sexual precocity: variations around the world, secular trends
vancement may not be significant initially. idiopathic CPP is about 4–5 times more common than organic CPP and changes after migration. Endocr Rev 2003;24:668–693.
which involves causes such as CNS tumors.
6 – Infantile mammoplasia is a self-limited early form of pre-
mature thelarche which may develop during the neonatal period or 12 – It is now recognized that there is a continuum of conditions
infancy. Follow-up involves assessment of breast development and between premature thelarche and idiopathic CPP, with partial evi-
15
growth rate every 3–6 months as well as bone maturation at 1- to dence of premature estrogenization besides breast development.
2-year intervals. If a persisting estrogenic effect is suspected, pelvic Such conditions involve the slowly progressive variants of CPP and
ultrasound will be requested. If ultrasound is prepubertal, no endo- advanced PP starting at borderline age, for which no treatment is
crine assessment is mandatory but follow-up is necessary. Indeed, usually required, although follow-up is necessary.
this condition may rarely be the initial manifestation of true sexual
precocity.
36
Adrenal F. Riepe · W.G. Sippell · Z. Hochberg Hypertension
54
68
76
1 – Newborn screening tests: The dried blood 4 – A thyroid image by ultrasound or scan with
Selected reading
specimen is collected by heel prick of the infant usu- technetium pertechnetate will confirm within 2 h, the
ally prior to discharge, preferably after 24 h of age to suspected diagnosis of these disorders: (a) ectopic American Academy of Pediatrics; Rose SR; Section
avoid a higher frequency of false-positive values. The thyroid dysgenesis and the life-long need for thyroxine on Endocrinology and Committee on Genetics,
three most common screening methods for congenital therapy; (b) athyreosis (in the absence of TSH-receptor American Thyroid Association; Brown RS; Public
hypothyroidism using dried blood specimens are: antibodies); (c) familial dyshormonogenesis with goi- Health Committee, Lawson Wilkins Pediatric
(a) primary TSH screen; (b) primary T4 screen with con- ter in the absence of iodine deficiency. The procedure Endocrine Society; Foley T, Kaplowitz PB, Kaye CI,
firmatory TSH on the lowest 5–20% of T4 values, and has no known risk and can be easily and accurately Sundararajan S, Varma SK: Update of newborn
(c) primary TSH and primary T4 screen. The measure- performed and interpreted by experienced pediatric screening and therapy for congenital hypothyroid-
ment of TSH and total T4 on every neonate provides nuclear medicine specialists. A scan to suggest the ism. Pediatrics 2006;117:2290–2303.
comprehensive screening for CH of primary and cen- presence of familial disease is important for genetic
Fisher D: Next generation newborn screening for
tral (hypothalamic-pituitary) etiology with the lowest counseling of the parents.
congenital hypothyroidism? J Clin Endocrinol
false-negative results. The addition of TBG screening
Metab 2005; 90:3797–3799.
on specimens with low T4 screening results reduces 5 – Undetectable serum thyroglobulin values
the number of false-positive rates on with low T4 confirm the absence of thyroid tissue or the diagnosis Fu J, Jiang Y, Liang L, Zhu H: Risk factors of primary
screening values. The use of tandem mass spectrom- of thyroglobulin synthetic defects in neonates or chil- thyroid dysfunction in early infants born to mothers
etry to measure al ong with many other analytes keeps dren with a eutopic thyroid, thyromegaly, or a normal- with autoimmune thyroid disease. Acta Paediatr
the cost of screening for CH as low or lower than the sized thyroid, and primary hypothyroidism. 2005;94:1043–1048.
other two programs. To date no valid and reproducible
Kempers MJ, Lanting CI, van Heijst AF, van
free T4 screening method is available, though very de- 6 – Neonates with low serum total and free T4
Trotsenburg AS, Wiedijk BM, de Vijlder JJ, Vulsma T:
sirable. and low, normal or mildly elevated serum TSH must
Neonatal screening for congenital hypothyroidism
be evaluated for hypothalamic-pituitary hypothyroid-
based on thyroxine, thyrotropin, and thyroxine-
2 – Maternal history and physical examination ism. Clinical features often seen in infants with con-
binding globulin measurement: potentials and
of the infant may disclose the etiology for abnormal genital hypopituitarism include: (a) unexplained hypo-
pitfalls. J Clin Endocrinol Metab 2006;91:3370–3376.
screening tests for hypothyroidism: (a) maternal auto- insulinemic hypoglycemia; (b) combined direct and
immune thyroid disease may be associated with trans- indirect hyperbilirubinemia; (c) midline facial and/or Knobel M, Medeiros-Neto G: An outline of inherited
placentally acquired TSH-receptor-blocking antibodies CNS birth defects, and (d) hypogonadism in male in- disorders of the thyroid hormone generating
that may induce transient primary congenital hypothy- fants (micropenis and testicular volume 1 ml). A serum system. Thyroid 2003;13:771–801.
roidism in the neonate; (b) maternal autoimmune thy- cortisol test is required before T4 therapy is started in
La Gamma EF, van Wassenaer AG, Golombek SG,
roid disease may be associated with transplacentally order to determine or exclude the presence of CRF-
Morreale de Escobar G, Kok JH, Quero J, Ares S,
acquired TSH-receptor-stimulating antibodies from ACTH-Adrenal Insufficiency. Infants with low cortisol
Paneth N, Fisher D: Neonatal thyroxine supplemen-
mothers with active Graves disease who are receiving values must be treated with hydrocortisone before T4
tation for transient hypothyroxinemia of prematu-
treatment with antithyroid drugs that cross the pla- therapy is initiated in order to prevent the induction of
rity: beneficial or detrimental? Treat Endocrinol
centa and may cause neonatal goiter with/without acute adrenal insufficiency.
2006;5:335–346.
transient primary hypothyroidism; (c) maternal iodine
deficiency or exposure of mother and/or neonate to Nelson JC, Wilcox RB: Analytical performance of
supraphysiologic amounts of iodide may cause tran- free and total thyroxine assays. Clin Chem
sient neonatal goiter and hypothyroidism. 1996;42:146–154.
Peter F: Thyroid dysfunction in the offspring of
3 – Serum free T4 should be measured by direct
mothers with autoimmune thyroid diseases.
dialysis or methods whose validity has been docu-
Acta Paediatr 2005;94:1008–1010.
mented in cord or neonatal serum specimens by cor-
relation with values obtained by direct dialysis. van Tijn DA, de Vijlder JJM, Verbeeten B Jr, Verkerk
PH, Vulsma T: Neonatal detection of congenital
hypothyroidism of central origin. J Clin Endocrinol
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77
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 391–404.
94