EARLY PUBERTY/SHORT STATURE
From Clinical Pediatrics, presented by the American Academy of Pediatrics, California Chapter 2
Mitchell E. Geffner, MD, Professor of Pediatrics, the Keck School of Medicine at the University of Southern
California, Los Angeles, and Research Faculty Member, The Saban Research Institute, Childrens Hospital Los
Angeles
| EARLY PUBERTY: NEW DEFINITIONS AND TREATMENT
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| Hypothalamic-pituitary-gonadal axis: mechanism of puberty starts in arcuate nucleus of hypothalamus (contains neurons
for gonadotropin-releasing hormone [GnRH]); GnRH descends through pituitary stalk (through vascular supply)
to anterior pituitary, where it stimulates gonadotrophs to produce luteinizing hormone (LH) and follicle-stimulating
hormone (FSH); LH and FSH travel to gonad to activate ovary or testicles
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| First detectable signs of puberty: girls—clinically, breast development; by ultrasonography (US), ovarian enlargement;
boys—enlargement of testicles; caveat—pubic hair appears before gonadal enlargement or breast development
in 15% of children
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| Pubertal tempo: pubertal development may start at normal time, but progress too rapidly, causing short stature; factors
that may alter pubertal tempo—low birth weight; rapid or excessive growth in early childhood; excessive dietary intake
(reflected by obesity); high-dose treatment of hypothyroidism; adoption (correct date of birth may not be known);
endocrine disruption (environmental causes; under study)
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| Definition of early puberty: development of secondary sexual characteristics in white girls <8 yr of age (<7 yr of age
in black girls); in boys <9 yr of age (unclear whether racial differences exist)
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| Causes of sexual precocity (overview): most importantly, normal variants; central—gonadotropin dependent;
peripheral—gonadotropin independent; primary ovarian, testicular, or adrenal problem
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| Normal variants: idiopathic precocious thelarche—onset most common at 2 or 3 yr of age, but may present at birth
(unilateral or bilateral; symmetric or asymmetric); cause unknown (in most cases, hormone levels normal); no other
signs of puberty (bone age not advanced or only slightly advanced); typically regresses without intervention (breasts
may persist, but without dramatic increase in size); idiopathic precocious adrenarche—occurs in girls more frequently
than boys; more common in obese girls and black girls; signs include pubic hair, axillary hair, odor, and acne;
presumed result of secretion of adrenal androgens; no virilization (absence of clitoromegaly, muscle development, and
temporal hair recession); bone age usually mildly advanced; in girls, no estrogen effects (ie, breast development or
menses)
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| Epidemiology of sexual precocity: estimated prevalence, 1 in 5000 to 10,000 children; idiopathic in 80% of affected
girls (diagnosis of exclusion); organic etiology responsible in ≤66% of affected boys
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| When central etiology likely: girl presents with estrogen and androgen effects (breasts and pubic hair); boy presents
with bilateral testicular enlargement; in both sexes, rapid height increase and significant bone age advancement
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| Neurofibromatosis type 1 (NF-1): associated with smooth-bordered café-au-lait spots and axillary freckles; in young
boy, testicular enlargement
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| Diagnosing sexual precocity: measure random LH and FSH levels; consider immunochemiluminescent assay (ICMA);
if hormone levels above normal prepubertal range, diagnosis made; sex steroid levels (estradiol in girls; morning testosterone
in boys; best method tandem mass spectrometry); if still uncertain, consider GnRH stimulation test (measures
LH response to GnRH; excessive rise in LH indicates central etiology); thyroid function tests to detect hypothyroidism;
human chorionic gonadotropin (hCG) production by tumors can cause sexual precocity in boys by stimulating
testicular development and testosterone production; 17α-hydroxyprogestrone (nonclassic adrenal hyperplasia) can
present with precocious puberty; if hormonal testing uncertain, pelvic US in girls to detect enlargement of ovaries; adrenal
US if adrenal tumor suspected (typically occurs in boys with small testicles and in setting of hyperandrogenism);
if central etiology suspected, order cranial MRI to rule out pathology
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Central Sexual Precocity
| Etiologies: abnormality affecting hypothalamic-pituitary axis (eg, benign hypothalamic hamartoma)
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| Treatment (GnRH analogues): mechanism of action—decrease gonadotropin secretion by downregulating pituitary
GnRH receptors; medications—leuprolide has longest history (monthly form most commonly used); intranasal formulation
(nafarelin) dosed twice daily; implantable medication may be available soon; effects of treatment—LH
and FSH decrease; testosterone decreases in boys (estradiol in girls; with no treatment, no change); plateau or slight
reduction in pubertal development (ie, testicular size, and breast and pubic hair stage); predicted adult height increased
with treatment
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Peripheral Sexual Precocity
| McCune-Albright syndrome: diagnostic triad—1) café-au-lait spots (irregular border); 2) polyostotic fibrous dysplasia
(replacement of normal bone with fibrous tissue); 3) multiple autonomous endocrinopathies; cause—mutation in
Gsα gene that occurs early in embryogenesis, and results in constitutive activation of adenylyl cyclase; mutation
blocks conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP), which shuts off receptor activity
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| Familial testotoxicosis: rare autosomal dominant disorder; precocious puberty typically manifests by 4 yr of age; does
not affect fertility; testosterone production begins as result of maturation of Leydig cells (disorder due to effect of mutation
in LH receptor gene on testicles); testes activated in absence of ligand
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| Medical treatment of pseudoprecocious puberty: do not use GnRH analogue (etiology not central); ketoconazole
(steroid-synthesis inhibitor that blocks formation of testosterone); other drugs inhibit synthesis of sex steroids, or
block their action, or block conversion of androgen to estrogen; spironolactone blocks androgen receptor
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| Exogenous androgen exposure (case): patient 2 yr of age; penis enlarged, pubic hair present, testicles small; testosterone
level 300 ng/dL; transcutaneous acquisition from “roughhousing” with father who used testosterone cream
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| NEW APPROACHES TO TREATMENT OF THE SHORT CHILD
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| Growth hormone (GH) mechanism of action: main pathway mediated by signal transducers and activators of transcription
(STATs), which cause cell stimulated by GH to manufacture 3 peptides, ie, insulin-like growth factor-1
(IGF-1), IGF binding protein-3 (IGFBP-3 [transport protein for IGF-1]), and acid-labile subunit (ALS [transport protein]);
GH produced by pituitary gland under hypothalamic control; GH action through GH receptor on liver—
causes liver to make 3 proteins (IGF-1, ALS, and IGFBP-3); ternary complex reaches target tissue (eg, cartilage);
alternatively—GH may bypass liver and go directly to cartilage, where it binds to GH receptor, causing IGF-1 to exit
cell and reenter, or enter adjacent cells through own receptor
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Pubertal GH Dosing for Growth Hormone Deficiency (GHD)
| Rationale: normally, endogenous GH secretion doubles during pubertal growth spurt; concomitantly, since IGF-1 mediates
GH action, IGF-1 production also increases during puberty; in both sexes, ≈15% of adult height achieved during
pubertal growth spurt
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| Effect on height standard deviation score (SDS; Mauras et al): traditional dose of 0.3 mg/kg per week compared to
0.7 mg/kg per week; height velocity and SDS comparable on entry; however, divergence over next 3 yr (higher-dose
GH group grew better and had better SD on average, compared to conventionally treated group); 4.7-cm difference in
gain at 2.3 times dose; approach higher-dose option carefully because of cost and theoretic risk for side effects
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Prader-Willi Syndrome (PWS)
| Also known as “H4O” syndrome: hypotonia (pre- and postnatal); hypogonadism (usually central); decreased mental
function (“hypomentia”); hyposomatotropism (GHD); obesity
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| Genetic basis: chromosome arm 15q (70% caused by paternal deletion; 25% by uniparental maternal disomy; <2%
from imprinting and other defects); if suspected, order DNA methylation test (not fluorescence in situ hybridization
[FISH])
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| GH therapy: rationale—in many patients, primary GHD related to generalized hypothalamic dysfunction; abnormal
body composition in PWS reflects GHD; GH treatment would decrease fat mass and increase lean body mass (LBM),
and improve physical function (early hypotonia and delayed motor milestones typical); additionally, GH may improve
low resting energy expenditure; effects—improved linear growth rate, LBM, and bone mineral density (BMD); decreased
fat mass; improved physical strength and agility; increased total energy expenditure and fat utilization; responses
diminish after first year but restored with adjustments in dose; complications—in studies, progression of
known complications of PWS (eg, scoliosis and glucose intolerance) not increased by GH; early reports of 14 deaths
of PWS children who received GH (deaths occurred soon after initiation of therapy in patients who were most obese;
relationship to GH unclear); indications—GH approved by Food and Drug Administration (FDA) at 0.24 mg/kg per
week for growth failure associated with proven PWS (GH testing not required)
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Small for Gestational Age (SGA) Without Growth Recovery to Fifth Percentile by 2 Yr of Age
| Treatment: patients not GH deficient; GH treatment normalizes stature and increases final height above baseline height
prediction (growth response dose-related); despite high dosing, treatment does not increase risk for metabolic syndrome
(however, untreated children at increased risk); GH therapy FDA-approved at doses up to 0.48 mg/kg per week
to treat former SGA infants who fail to show catch-up growth by 2 yr of age (GH testing not required)
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Idiopathic Short Stature (ISS; Studies by Lilly)
| Design: study 1—placebo compared to GH 0.22 mg/kg per week; study 2—dose-response study; 3 regimens compared
(0.24 mg/kg per week; 0.24 mg/kg per week for 1 yr, followed by 0.37 mg/kg per week; and 0.37 mg/kg per week
from start); on entry—average age 9.8 yr (average bone age 7.8 yr); GH stimulation test (mean peak 17.1 mg/mL;
normal ≈10.0 mg/mL); height velocity 4.3 cm/yr
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| Mean final height SDS: study 1—placebo group (-2.3); group that received 0.22 mg/kg per wk (-1.8); difference 3.7
cm; study 2 (0.24 vs 0.37 mg/kg per week)— lower-dose group (-1.7); at higher dose (-1.1); cross comparison—
high-dose group compared to placebo-treated group (7.3-cm difference)
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| Individual final height SDS (study 1 and study 2): -2.0 SDS low-end of normal; percentage achieving SDS above -
2.0 in placebo group, 36%; in 0.22-mg group, 55%; in 0.24-mg group, 71%; and in 0.37-mg group, 94%
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| Summary: 0.37 mg/kg per week—62% of subjects reaching final height gained >5 cm over baseline predicted height;
31% gained >10 cm over baseline; 94% >-2 SD; no additional or unique safety concerns; FDA-approved dose—0.37
mg/kg per week; treatment restricted to children >2.25 SD below mean for age and sex (shortest 1.2% of children)
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Short Stature Homeobox-Containing Gene Deficiency (SHOX-D)
| SHOX gene: located in pseudoautosomal region of X and Y chromosomes; encodes transcription factor; homeodomain
protein controls cartilage formation, and responsible for linear growth; mechanism of action unknown, but gene and
protein expressed in tissues that may contribute to cubitus valgus or increased carrying angle, short chin (retrognathia),
genu valgum, and other manifestations of Turner’s syndrome in girls
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| SHOX-D responsiveness to GH (study by Blum et al): control group—1) patients with SHOX deficiency who do
not get GH; treatment groups—2) children with Turner’s syndrome and SHOX-D; 3) patients with SHOX-D in absence
of Turner’s syndrome; results—GH stimulated similar rates of increase in children with SHOX-D only and
those with Turner’s syndrome; untreated patients showed little growth
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IGF-1 for Treatment of Growth Failure
| Indications: 1) severe primary IGF-1 deficiency (rare); manifests as Laron dwarfism (GH resistance) or 2) IGF-1 gene
mutation; GH therapy not helpful; administration of IGF-1 bypasses block and should foster growth; 3) GH gene deletion
in patients with neutralizing antibodies to GH
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| Criteria for use: height SDS ≤-3.0; basal IGF-1 SDS ≤3.0; normal or elevated GH levels (exception children with GH
gene deletion); exclude growth failure due to—secondary IGF-1 deficiency (most commonly, GHD; treat with GH);
malnutrition; hypothyroidism; chromosome abnormalities; chronic diseases; pituitary tumors; be sure that child not
taking GH or glucocorticoids; have child followed by pediatric endocrinologist
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| Growth response of children with GH resistance to IGF-1: children diagnosed with Laron syndrome or IGF-1 gene
deletion; in first year, growth with treatment ≈8 cm/yr vs ≈3 cm/yr before treatment; effect wanes but still beneficial
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| Side effects: hypoglycemia (drug best administered immediately before eating); preferential increase in size of lymphoid
tissues, eg, tonsils and adenoids; intracranial hypertension (pseudotumor cerebri; also reported with GH therapy);
slipped capital femoral epiphysis with GH and IGF-1; progression of scoliosis; rarely, allergic reactions
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Aromatase Inhibitors
| Male patient with mutation in estrogen receptors associated with tall stature and delayed bone age (case): at 24
yr of age, bone age 14 or 15 yr; physical development (pubic hair; slightly feminine body habitus); testosterone levels
high and estrogen levels low; in both sexes—testosterone converted to estradiol by enzyme (aromatase); patient had
aromatase gene mutation and did not produce estrogen; epiphyses not fused (estrogen important in fusion of epiphyses
and cessation of growth); aromatase converts testosterone to estradiol, and androstenedione to estrone
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| Hypothesis: aromatase inhibitor (by raising testosterone level) improves height in boys with short stature by preventing
formation of estrogens that lead to early fusion of epiphyses; drugs FDA-approved for treatment of estrogen-sensitive
cancer in adults (use in growth augmentation investigational)
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| Treatment with letrozole during adolescence increases near-final height in boys with constitutional delay of puberty
(Hero et al): 1-yr study; patients treated with testosterone and letrozole (oral), or testosterone and placebo;
mean final height—testosterone-with-placebo group, ≈170 cm; testosterone-and-letrozole group, ≈177 cm or 178 cm
(6.7-cm gain); height SDS—testosterone alone (improvement +0.8); combination (+1.4); candidacy for therapy unclear;
more research needed about potential side effects
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Suggested Reading
Blum WF et al: Growth hormone is effective in treatment of short stature associated with short stature homeobox-
containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab
92:219, 2006; Bowden SA, Germak JA: Klinefelter syndrome presenting with precocious puberty due to a human
chorionic gonadotropin (hCG)-producing mediastinal germinoma. J Pediatr Endocrinol Metab 19:1371, 2006; de
Vries L, Philip M: Children referred for signs of early puberty warrant endocrine evaluation and follow-up. J Clin
Endocrinol Metab 90:593, 2005; Franklin SL, Geffner ME: Precocious puberty secondary to topical testosterone
exposure. J Pediatr Endocrinol Metab 16:107, 2003; Geffner ME: Hypopituitarism in childhood. Cancer Control
9:212, 2002; Gesmundo R et al: Laparascopic management of ovarian cysts in peripheral precocious puberty of McCune-Albright
syndrome. J Pediatr Endocrinol Metab 19 Suppl2:571, 2006; Hero M et al: Treatment with the aromatase
inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty.
Clin Endocrinol (Oxf) 64:510, 2006; Ibanez L et al: Early puberty-menarche after precocious pubarche: relation to
prenatal growth. Pediatrics 117:117, 2006; Lee MM: Clinical practice. Idiopathic short stature. N Engl J Med
354:2576, 2006; Massart F et al: How do environmental estrogen disruptors induce precocious puberty? Minerva
Pediatr 58:247, 2006; Mauras N et al: High dose recombinant human growth hormone (GH) treatment of GH-deficient
patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative
Study Group. J Clin Endocrinol Metab 85:3653, 2000; Muir A: Precocious puberty. Pediatr Rev 27:373, 2006; Papadimitriou
A et al: Early growth acceleration in girls with idiopathic precocious puberty. J Pediatr 149:43, 2006;
Rapaport R: Idiopathic short stature. N Engl J Med 355:1178, 2006; Rosenbloom AL: Is there a role for insulin-like
growth factor-I in the treatment of idiopathic short stature? Lancet 368:612, 2006.
Educational Objectives
| The goal of this program is to improve management of precocious puberty and short stature through awareness of
current trends and treatment options After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Identify factors that may alter pubertal tempo.
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| 2. Recognize signs of early puberty.
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| 3. Evaluate current treatments for managing precocious puberty.
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| 4. Describe various etiologies of short stature in children.
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| 5. Employ newer approaches to treatment of the short child.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Geffner is a board
member of TAP Pharmaceuticals.
Acknowledgements
Dr. Geffner was recorded at Clinical Pediatrics, presented February 15-18, 2007, in Palm Springs, CA, by the American
Academy of Pediatrics, California Chapter 2. The Audio-Digest Foundation thanks Dr. Geffner and the Academy
for their cooperation in the production of this program.
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