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Sexual Precocity in a 16-Month-Old
' |4 x( }/ h; @Boy Induced by Indirect Topical
8 N8 I: m8 M" R- H/ v- \Exposure to Testosterone u' v7 B- o; a
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2 Z& `8 c+ K/ O6 v
and Kenneth R. Rettig, MD13 V g5 n( c3 I6 q( C z
Clinical Pediatrics
2 |5 C* b9 s$ [/ j2 Z1 ^ VVolume 46 Number 6
3 w2 p K5 w# A6 s9 {July 2007 540-543
# a! m* _# r; h& Z6 K% z© 2007 Sage Publications
$ T9 R k) ]# w5 d10.1177/0009922806296651! L I) A; A: ~% \8 {' v7 M& n
http://clp.sagepub.com
7 v1 `, N% [+ k( e E" rhosted at- E+ @. E# ]6 U! h) Z* @% A
http://online.sagepub.com
m0 ~6 R0 D1 l, _Precocious puberty in boys, central or peripheral,( _( R: b6 Y1 a* m' o1 o7 T% n! P
is a significant concern for physicians. Central$ s0 b- }; O0 d! K& U0 X( n. t
precocious puberty (CPP), which is mediated6 I. `' z% p5 |6 Z; V) r
through the hypothalamic pituitary gonadal axis, has
% ?5 J e0 ~, ~a higher incidence of organic central nervous system
: D) T! |8 }0 n2 Jlesions in boys.1,2 Virilization in boys, as manifested
2 C* e+ }# E% j0 f+ z5 `0 kby enlargement of the penis, development of pubic3 |% r. Y$ @3 D# |
hair, and facial acne without enlargement of testi-
7 ?0 W# e3 M7 E. f$ N$ Ncles, suggests peripheral or pseudopuberty.1-3 We
2 V9 ?! U A' {* @report a 16-month-old boy who presented with the
. W% v: g$ Q; t" uenlargement of the phallus and pubic hair develop-% Y6 [. o8 t& ` Y: F7 I, j
ment without testicular enlargement, which was due+ C5 ?" w' Q4 J7 m- [
to the unintentional exposure to androgen gel used by
) R5 O9 {" {1 u/ Gthe father. The family initially concealed this infor-' U+ T8 T2 {: q5 d, z8 O" F& m( f, l1 k
mation, resulting in an extensive work-up for this- ^1 t3 b: w A! }. R; c1 T
child. Given the widespread and easy availability of
: W% P, @) w' p- _, Dtestosterone gel and cream, we believe this is proba-9 m N' p5 M. U# b+ T
bly more common than the rare case report in the. ` X# Z T+ o) ?" B) C- f( s$ P) h
literature.41 f! |0 k# O' G1 Y
Patient Report
" @" z3 O- B3 S2 N$ EA 16-month-old white child was referred to the$ X0 t: H3 g K5 J9 f0 F, F0 s, i) c
endocrine clinic by his pediatrician with the concern
- D6 `/ ]/ r* O4 ~, v9 yof early sexual development. His mother noticed
) i# G& m, j1 b; r! \light colored pubic hair development when he was
- Y# Y8 s" M+ Y2 P& ^1 O. z$ TFrom the 1Division of Pediatric Endocrinology, 2University of W6 E% y, W' z: I
South Alabama Medical Center, Mobile, Alabama.
, v' A' X& W" n! f8 MAddress correspondence to: Samar K. Bhowmick, MD, FACE,
+ j( F3 R: d- U* Y; KProfessor of Pediatrics, University of South Alabama, College of
7 r; c; E$ r' L ~% b5 ]/ oMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
) `% d$ ~% T4 J2 l/ R4 D$ P3 }e-mail: [email protected].
& P: W( `. B/ @$ Z) v$ y! k1 ^about 6 to 7 months old, which progressively became2 {6 I8 Z; U6 n, R/ C& s
darker. She was also concerned about the enlarge-
4 x( b1 o% M. f4 O `( N" wment of his penis and frequent erections. The child
: | z9 G1 b5 i3 y+ o0 ^/ t# I5 Hwas the product of a full-term normal delivery, with
* ~; T! `* w, B$ {' O% Ra birth weight of 7 lb 14 oz, and birth length of) b; z+ R. N( v
20 inches. He was breast-fed throughout the first year
4 F! M& x( ?5 D! e, Q( E, I jof life and was still receiving breast milk along with2 g! z! j A( W! b- t8 w% G* {
solid food. He had no hospitalizations or surgery,- d* w3 Z6 z: h& i
and his psychosocial and psychomotor development6 ?; [! d y+ N, X5 K
was age appropriate., X8 a0 I1 M5 P7 h Y" x
The family history was remarkable for the father,
* q! {) s l# r8 v) e3 [9 l3 |5 Iwho was diagnosed with hypothyroidism at age 16,3 B9 L0 o g5 f5 V
which was treated with thyroxine. The father’s
4 L0 U' A5 h: M. ?# A% t$ Wheight was 6 feet, and he went through a somewhat
1 W+ y) S# t4 E4 I$ Eearly puberty and had stopped growing by age 14.' r, @$ f. H4 h |
The father denied taking any other medication. The0 y5 R6 m. B9 M# S' O$ k( J
child’s mother was in good health. Her menarche
2 Q+ ~( k4 |/ ]# ~was at 11 years of age, and her height was at 5 feet1 p4 o* z% E4 _8 V( b J) y& g9 w
5 inches. There was no other family history of pre-
8 v7 Z) s( T _cocious sexual development in the first-degree rela-4 Z7 M( P: V6 Q
tives. There were no siblings.
' i" e H" V1 A7 WPhysical Examination) K t: @3 R; v) Y* B
The physical examination revealed a very active,
; b4 H3 m8 N6 ?) |+ `playful, and healthy boy. The vital signs documented
$ C4 r# g0 h7 R- n1 I+ Ba blood pressure of 85/50 mm Hg, his length was
, s, F$ e5 q' @9 B$ r- p2 G90 cm (>97th percentile), and his weight was 14.4 kg
- O2 q2 t7 z0 d( c/ s(also >97th percentile). The observed yearly growth/ j$ R5 S/ _4 k0 I( x2 U$ o$ m
velocity was 30 cm (12 inches). The examination of
# M, o; L9 O+ `1 \the neck revealed no thyroid enlargement.
% J7 n4 X v7 ?7 l: G- z/ iThe genitourinary examination was remarkable for
+ C% J- {+ a2 _enlargement of the penis, with a stretched length of0 [! X- v5 A- Q& X7 @5 \
8 cm and a width of 2 cm. The glans penis was very well" b" [+ h& k/ O% x x& A
developed. The pubic hair was Tanner II, mostly around' v2 S5 u1 t' Q& S7 k" K+ r
540
3 p6 W/ a3 Q; @( R) h! [at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
+ R8 b# z9 U L3 l' t/ Vthe base of the phallus and was dark and curled. The
2 `. t4 b- i" S7 A/ i: `6 Ntesticular volume was prepubertal at 2 mL each.. w$ q3 w) j8 ^9 u
The skin was moist and smooth and somewhat
6 x0 p/ u5 ?9 A; d! B) m4 }9 }oily. No axillary hair was noted. There were no( d2 ?7 w7 O) V( c
abnormal skin pigmentations or café-au-lait spots.6 D6 C, k2 V6 _9 m& M6 Q
Neurologic evaluation showed deep tendon reflex 2+
/ c, [2 }* W7 D/ s" pbilateral and symmetrical. There was no suggestion! o6 A$ v: Z4 v5 `4 d' R
of papilledema.
6 B7 v$ k' _5 ^% g1 {% `5 KLaboratory Evaluation0 ]* N* n2 Z" ]& v+ H& D: `
The bone age was consistent with 28 months by
3 n! P# k5 p3 R* g7 kusing the standard of Greulich and Pyle at a chrono-
2 ^. u, c+ L. z- @4 y$ nlogic age of 16 months (advanced).5 Chromosomal; Z! L0 `; A: P# C2 q- _
karyotype was 46XY. The thyroid function test
* Q" p( t! M6 E! p7 V* V" vshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
& E9 b8 ^1 S2 j% J9 B" y G. E4 P/ _lating hormone level was 1.3 µIU/mL (both normal). x. v7 B5 v0 \
The concentrations of serum electrolytes, blood& Z% V0 r& v! S- @) q
urea nitrogen, creatinine, and calcium all were
9 F$ j8 A% n0 {8 h6 s1 Mwithin normal range for his age. The concentration
* ]* H) A: C( J0 Z; x) Hof serum 17-hydroxyprogesterone was 16 ng/dL
& w1 f$ @6 u& A" c- c6 M(normal, 3 to 90 ng/dL), androstenedione was 20
, R( G; K* J4 k K& ing/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
& T, m# g: b. E% H8 Fterone was 38 ng/dL (normal, 50 to 760 ng/dL),
9 s" U9 e H# R- l! h! Xdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
- a. H) V5 V6 s: _/ {49ng/dL), 11-desoxycortisol (specific compound S)
' i- G3 z/ J. W- z2 m0 M. jwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
. d6 e4 j) c% Y4 }" I: Ntisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total- W0 d+ u1 Z- C- @* p; O
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
5 o& ?5 h- q# aand β-human chorionic gonadotropin was less than9 K z5 a% M) W8 e7 ^& H: M
5 mIU/mL (normal <5 mIU/mL). Serum follicular
5 S; W" j* U* I$ i) Y wstimulating hormone and leuteinizing hormone( Y$ o6 t0 Z- C, e3 K1 j' T7 L
concentrations were less than 0.05 mIU/mL
/ Y$ j; _: o2 F- T( v1 o5 Z(prepubertal)." p4 a8 a% J% Z/ {; x
The parents were notified about the laboratory1 `+ @0 h! o `* z/ S5 u. ?
results and were informed that all of the tests were
3 T6 n1 u7 \2 \- n1 snormal except the testosterone level was high. The9 P- e' O0 z9 |" A; b y2 I) Y
follow-up visit was arranged within a few weeks to% I" h6 _% |% n$ q4 i1 _
obtain testicular and abdominal sonograms; how-$ _9 q7 W2 ~# i! B" n! r! }* K
ever, the family did not return for 4 months.) y( a9 [. G" }
Physical examination at this time revealed that the" Z# [- G% Y( H6 L
child had grown 2.5 cm in 4 months and had gained
9 V$ T3 j6 o6 u8 ]) I( I7 z8 q2 kg of weight. Physical examination remained# J+ N* ?$ {1 r
unchanged. Surprisingly, the pubic hair almost com-% v8 o* ?; Q" j4 S0 W
pletely disappeared except for a few vellous hairs at
2 T1 q8 U. K! |$ M# C* {+ z g) \' }9 athe base of the phallus. Testicular volume was still 2* U' @: F3 |* k6 O9 S9 C
mL, and the size of the penis remained unchanged.
6 |; H4 H' ?% E3 e/ RThe mother also said that the boy was no longer hav-
3 Q' b7 q1 F: m* L' wing frequent erections.
) g% v2 n1 c- a. F* B: ^" }/ XBoth parents were again questioned about use of5 w8 ~0 v4 a- v w4 |+ T
any ointment/creams that they may have applied to2 U I3 A7 E! q- A$ `8 ?
the child’s skin. This time the father admitted the
& b6 Z9 q4 {) m# ]) b2 ?1 `' iTopical Testosterone Exposure / Bhowmick et al 541
% ?: Y, z5 ?$ n' J6 huse of testosterone gel twice daily that he was apply-* w5 y0 s: S% T, p( Z8 ~
ing over his own shoulders, chest, and back area for
4 m3 _2 X s' V- Xa year. The father also revealed he was embarrassed
8 ?$ H4 J, c7 ^! {7 @to disclose that he was using a testosterone gel pre-3 l) [" _, k j( q& F9 ]
scribed by his family physician for decreased libido7 I; N# `; `1 o. n& {: ~# B
secondary to depression.
! M0 R0 [8 H% ~The child slept in the same bed with parents.0 y. V5 Z0 ?8 D5 Z5 q7 w4 {
The father would hug the baby and hold him on his
( g" o( c' r3 X- z9 G) xchest for a considerable period of time, causing sig-
+ }3 Z }1 h- W- R$ r5 q# tnificant bare skin contact between baby and father.3 J# L# H+ }0 I* W3 T
The father also admitted that after the phone call,
8 h3 X; X( ^! Y7 k+ R8 E+ Mwhen he learned the testosterone level in the baby
, g$ Y& ^0 B/ `. X# |3 m, Nwas high, he then read the product information% v; p3 W0 v* F! u t0 K/ ?6 D/ n
packet and concluded that it was most likely the rea-
0 J) U( M. T# O) ^% w$ Rson for the child’s virilization. At that time, they
+ E# g S7 l, j3 ndecided to put the baby in a separate bed, and the
4 _2 s3 Z: j/ R' [/ L+ e8 Qfather was not hugging him with bare skin and had* ^ E) H' y) H* i0 ?1 h/ M: t% G
been using protective clothing. A repeat testosterone
) A5 c1 L, _. [7 W1 Itest was ordered, but the family did not go to the
% q2 f, A& Y7 P1 {laboratory to obtain the test.
5 v5 b) w# T# J' m* s5 CDiscussion0 a- r. T X8 _1 G
Precocious puberty in boys is defined as secondary
; P, E6 J% B$ R0 w2 }. bsexual development before 9 years of age.1,4* U$ n$ @4 F. N: L2 y% G
Precocious puberty is termed as central (true) when
( X3 I6 W+ {) Z. Jit is caused by the premature activation of hypo-# [$ y$ m/ @" l1 d/ Q9 R
thalamic pituitary gonadal axis. CPP is more com- O! |; m7 |1 D) y% k/ U5 z' C
mon in girls than in boys.1,3 Most boys with CPP
, |8 k% [) h4 u7 Emay have a central nervous system lesion that is% G, K3 g3 k8 t+ a- I' m- A" Z# b
responsible for the early activation of the hypothal-
7 t7 Q. [ d* f3 N7 iamic pituitary gonadal axis.1-3 Thus, greater empha-; `- R! N4 p* M4 R! H9 a
sis has been given to neuroradiologic imaging in" o8 L, B+ P2 y' q# D* N
boys with precocious puberty. In addition to viril-
# D8 r _* ]. O9 e0 x5 `6 aization, the clinical hallmark of CPP is the symmet-
4 X1 p7 H# ~" h/ r/ ?8 j! orical testicular growth secondary to stimulation by
% g! k7 A* \* w& ^3 u7 mgonadotropins.1,3
7 `. F. ?/ V0 I j$ ~/ d- VGonadotropin-independent peripheral preco-
9 {* W1 S2 h1 Vcious puberty in boys also results from inappropriate# v! I5 f, S [9 n& W5 x8 a
androgenic stimulation from either endogenous or
5 U# R; \" \, J4 h, m5 @8 Jexogenous sources, nonpituitary gonadotropin stim-
1 f& x2 M/ f! Fulation, and rare activating mutations.3 Virilizing
9 h: Z! N! s& G2 Tcongenital adrenal hyperplasia producing excessive2 y* F; _% N/ |+ p8 x
adrenal androgens is a common cause of precocious% e$ D+ X' q( s9 Q7 S# d; }
puberty in boys.3,4 M0 w @! Y& v( F n: F9 N; z
The most common form of congenital adrenal' b G, c5 l- Z. B& a
hyperplasia is the 21-hydroxylase enzyme deficiency.
8 t$ f! J' ], J2 q. ?% DThe 11-β hydroxylase deficiency may also result in
3 D G: c) t* z r$ }' R$ v) [# G5 Pexcessive adrenal androgen production, and rarely,
! P' q1 Q2 I4 Z, `1 m3 Uan adrenal tumor may also cause adrenal androgen( P+ k3 c; U8 n! s! q; F0 y) W
excess.1,3 d$ ]7 q0 m5 [% K
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from7 p M( S3 L% Q
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# }& p) Y" E, o' o
A unique entity of male-limited gonadotropin-
; D1 `) c! b9 k, \+ kindependent precocious puberty, which is also known, a# X: W" P6 K( N9 \1 j ]
as testotoxicosis, may cause precocious puberty at a: }$ q+ ~1 J* T. M
very young age. The physical findings in these boys. x, ]3 l* @: [: a
with this disorder are full pubertal development,
9 r5 r' a M% \9 u9 |! mincluding bilateral testicular growth, similar to boys
2 A# X/ a- ^* R& \with CPP. The gonadotropin levels in this disorder+ \- D# g, f0 q; t H
are suppressed to prepubertal levels and do not show
/ z2 t( U6 [ Z# v G ipubertal response of gonadotropin after gonadotropin-- n/ E1 T: R. w2 y5 m! |2 a4 \" K
releasing hormone stimulation. This is a sex-linked
- G" N% q9 M$ U* j: ^: I, W5 s8 a4 [% bautosomal dominant disorder that affects only9 X8 Q7 g) n+ Q' e. g
males; therefore, other male members of the family
1 s$ I- d2 f. y/ ^- D& ^may have similar precocious puberty.3
7 G; C0 J* U6 uIn our patient, physical examination was incon-, ]9 C8 @& W3 J; q! r
sistent with true precocious puberty since his testi-
+ T% z, E+ q$ e' s7 Z0 ?$ _ L3 gcles were prepubertal in size. However, testotoxicosis
4 D6 L7 l! z5 E+ vwas in the differential diagnosis because his father" O& X& Q0 E5 e ^ E+ U
started puberty somewhat early, and occasionally,) B' F0 U" e( y8 ?
testicular enlargement is not that evident in the1 W9 n* N8 P6 O8 E/ N- O
beginning of this process.1 In the absence of a neg-* R6 P9 p( j/ y$ n, M: D
ative initial history of androgen exposure, our! q/ q% e( b; r2 @! n
biggest concern was virilizing adrenal hyperplasia,! |& v i' |) b2 l0 S
either 21-hydroxylase deficiency or 11-β hydroxylase) _5 C7 O- ^4 D5 T( _# Y
deficiency. Those diagnoses were excluded by find-0 Z6 v% s* w; e3 s0 a2 f5 z7 s# w6 h
ing the normal level of adrenal steroids.9 ^& R# F2 ?2 p# X
The diagnosis of exogenous androgens was strongly K# E$ ^6 B( m& v5 R {+ D5 ~
suspected in a follow-up visit after 4 months because! ~( x$ b0 G& v6 ?1 M
the physical examination revealed the complete disap-
# A2 D0 R; i, d- z% b0 Kpearance of pubic hair, normal growth velocity, and
& M# o5 N6 x2 K6 Ldecreased erections. The father admitted using a testos-
( h* n* Z/ q+ f5 x' w- T5 J+ vterone gel, which he concealed at first visit. He was* T+ J7 Z5 y8 x- k6 w
using it rather frequently, twice a day. The Physicians’
9 I2 X' O5 J* [9 _( b& GDesk Reference, or package insert of this product, gel or& m H% ~, Y, j5 w& t
cream, cautions about dermal testosterone transfer to- E; J: G5 U# \) {
unprotected females through direct skin exposure.
+ \, r# g* Z# N' fSerum testosterone level was found to be 2 times the9 b# i8 E* g9 t: B: \8 a
baseline value in those females who were exposed to% o6 r3 | @ e: |: M
even 15 minutes of direct skin contact with their male
! ~0 S! M6 X, ?partners.6 However, when a shirt covered the applica-
5 x; _5 E. S- ~tion site, this testosterone transfer was prevented.
f ]0 J. l, Z& \, r# X, f) IOur patient’s testosterone level was 60 ng/mL,
1 \; `' o0 n) I! @9 rwhich was clearly high. Some studies suggest that
- X* a: n6 P4 z) l' e6 H8 Q& Qdermal conversion of testosterone to dihydrotestos-# A* J( s% t7 M0 y
terone, which is a more potent metabolite, is more
# I" j$ u- \ |+ G! ~4 ^6 cactive in young children exposed to testosterone
. Q: W$ `% L7 v2 |- Iexogenously7; however, we did not measure a dihy- x) ^4 G2 }2 K7 p
drotestosterone level in our patient. In addition to
7 k, q1 ]2 n2 l) |! X8 \virilization, exposure to exogenous testosterone in
- m6 I% z& M8 G/ |$ _- {children results in an increase in growth velocity and# J! T# Z2 B. n4 W) N
advanced bone age, as seen in our patient.
+ |# R5 C1 ]$ {4 i# x8 g2 N6 R% J6 ZThe long-term effect of androgen exposure during
8 i* c! l& M5 Aearly childhood on pubertal development and final4 Y* O& G# {* B, e/ V5 s- r
adult height are not fully known and always remain
) d! w2 _# b4 f8 Z/ ~a concern. Children treated with short-term testos-
0 \- s5 D$ t3 G) i$ P% Mterone injection or topical androgen may exhibit some
# y N2 m3 y& y! w# B( tacceleration of the skeletal maturation; however, after( y8 S% A1 U# ]# z
cessation of treatment, the rate of bone maturation! l! g7 Y. d( [/ ~& q8 } d' k
decelerates and gradually returns to normal.8,90 ~: P& Y2 S7 ]# B7 X5 v
There are conflicting reports and controversy, g9 S' R8 M* M+ p: B, L
over the effect of early androgen exposure on adult
5 ?) a! [9 v) \penile length.10,11 Some reports suggest subnormal6 N2 A; H/ L/ s b
adult penile length, apparently because of downreg-. a/ B v# C1 i& o) p
ulation of androgen receptor number.10,12 However,- X. o; N( i2 L6 ^' V% I# l+ w, G* g
Sutherland et al13 did not find a correlation between
! T" `3 b+ ]) N- M) L: xchildhood testosterone exposure and reduced adult6 `" n- U) e! o& t0 N' v; w- W
penile length in clinical studies.
7 B! W2 i" Y. q" ANonetheless, we do not believe our patient is$ c [" ^6 j) }2 m
going to experience any of the untoward effects from
4 J; x7 O, v" e- k; mtestosterone exposure as mentioned earlier because$ [/ Z; N& N/ u; J/ h
the exposure was not for a prolonged period of time.
G+ z/ R5 v! Y! sAlthough the bone age was advanced at the time of
: i/ [6 }5 ?0 q( T! @2 H5 h0 fdiagnosis, the child had a normal growth velocity at
; M* u+ L, V5 o# Ethe follow-up visit. It is hoped that his final adult
- C( b5 a7 E- O4 d4 \2 _# f0 P/ E9 mheight will not be affected.
( @0 L, _$ i) { ZAlthough rarely reported, the widespread avail-& h2 Z% G) K. p3 ^3 y3 O
ability of androgen products in our society may L& u" A( P" i1 Z! k
indeed cause more virilization in male or female8 |0 l! l4 ^+ [3 p- t3 s, @) C5 E
children than one would realize. Exposure to andro-
0 `3 m8 t7 F) C% n+ }4 E2 h' Rgen products must be considered and specific ques-
; h. h$ }& d' a3 x" qtioning about the use of a testosterone product or
8 {# }. R p: |1 W! O! D( S+ k2 C2 hgel should be asked of the family members during
o& n5 P/ w8 cthe evaluation of any children who present with vir-. f7 r a: T' N* J5 x+ ?
ilization or peripheral precocious puberty. The diag-2 ]" o4 s$ o j8 p7 e
nosis can be established by just a few tests and by
$ q6 q) Q5 G) x2 v8 Q2 \) c( ?1 dappropriate history. The inability to obtain such a3 b# U; c- ^. I7 |. @0 S; N$ V
history, or failure to ask the specific questions, may
( z3 F; z! m9 r* ~: l% Kresult in extensive, unnecessary, and expensive; s/ V, ~3 c$ [- Y% \" F3 N
investigation. The primary care physician should be
5 E3 e; d7 L5 b- t6 K" Waware of this fact, because most of these children$ V1 L: N; n- q! W3 ?$ @$ B* a% X
may initially present in their practice. The Physicians’* c* x7 B% C) b, {
Desk Reference and package insert should also put a
1 k7 b4 ~) k7 a1 q; ]- [warning about the virilizing effect on a male or
S2 V8 L) O" v4 c% X5 Yfemale child who might come in contact with some-
4 X( w" L5 ]- u* E9 ione using any of these products.
- l; ~" z+ S( h& Z( d, y& u- J" Z9 r5 kReferences
# r- u; z1 B) ?1 x8 F" B8 C1. Styne DM. The testes: disorder of sexual differentiation" [4 c& L' `4 H' b# |$ n3 _ S
and puberty in the male. In: Sperling MA, ed. Pediatric
_) Q2 C( B( l! t; O: p3 v; _Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;) E, ^2 M! c8 ~ h
2002: 565-628.
+ ^, F" s* b6 J. a" G5 e3 I& o2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious4 e5 m' d3 E1 `( p
puberty in children with tumours of the suprasellar pineal |
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