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Sexual Precocity in a 16-Month-Old" a: w i1 j/ { n. _) M! R
Boy Induced by Indirect Topical
' L8 Q% w4 T# C+ b t9 n1 i8 W5 I% WExposure to Testosterone
( U \. ^2 B W8 P/ B3 X7 ZSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2, s/ {# ?) F' z% s! [2 c8 s
and Kenneth R. Rettig, MD1
6 ~" |8 {4 r3 W$ g L4 oClinical Pediatrics
: F' L/ t- ? a' u( Q3 {: ?3 NVolume 46 Number 6
/ I6 }" c9 L* w2 D" @July 2007 540-543
- B* q8 L, H# F2 w! i© 2007 Sage Publications6 g" ~$ M1 |* q- [
10.1177/0009922806296651
8 i/ S4 X- f# c* ehttp://clp.sagepub.com
3 I: f9 H3 w; q% @7 N+ Ghosted at
' y8 r# \6 @3 @1 [2 k- Ghttp://online.sagepub.com
A3 R5 n0 K- r" C" U, Q! lPrecocious puberty in boys, central or peripheral,
. S. {# K! A: ~* o5 s. M+ His a significant concern for physicians. Central7 r5 K/ |% y8 f% e# l! t4 o
precocious puberty (CPP), which is mediated
! _. j0 E) f4 b2 S' |through the hypothalamic pituitary gonadal axis, has
" j6 F/ V9 D7 d- ^) v2 W7 za higher incidence of organic central nervous system% `( N( b5 z. J9 {
lesions in boys.1,2 Virilization in boys, as manifested8 i' q! P- ]% B! T4 d- c
by enlargement of the penis, development of pubic& o; k2 X9 @/ ^% r/ z
hair, and facial acne without enlargement of testi-$ [7 I" R6 T& q. w7 M8 |
cles, suggests peripheral or pseudopuberty.1-3 We( L9 j. y" x d0 A/ _
report a 16-month-old boy who presented with the2 j0 p% p" m' _4 U, L
enlargement of the phallus and pubic hair develop-
6 @% D: p+ Y- xment without testicular enlargement, which was due& \4 C5 B& n% o4 S
to the unintentional exposure to androgen gel used by
% O, a' }+ s6 I- i6 Y' }% mthe father. The family initially concealed this infor-/ D6 ]# O8 g9 b& A
mation, resulting in an extensive work-up for this
& w( F4 W) a& pchild. Given the widespread and easy availability of
1 B/ P) b4 N' h, F! q% Etestosterone gel and cream, we believe this is proba-
- }! B$ i/ b, j* zbly more common than the rare case report in the
7 \9 ]/ N* Q+ s7 eliterature.4
$ v( B7 K) X, ]6 Q* F' rPatient Report( E( Y/ [- }0 B! ]3 f7 }* _# P1 O
A 16-month-old white child was referred to the, p5 ~: ^& p0 F/ j# _
endocrine clinic by his pediatrician with the concern" K& X' i. e" t3 U- s
of early sexual development. His mother noticed
3 L5 V7 J( N) ^" z/ P+ l. Blight colored pubic hair development when he was7 G6 M* Z5 ]- K6 { F' l% H3 h
From the 1Division of Pediatric Endocrinology, 2University of( E7 k9 ^' f- b% `2 `) g) y
South Alabama Medical Center, Mobile, Alabama.
5 M1 Z. [; Q7 D9 g) {4 F/ dAddress correspondence to: Samar K. Bhowmick, MD, FACE,/ U# a0 C$ f, ` R
Professor of Pediatrics, University of South Alabama, College of
' D E; a( Q- S1 S! n, kMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;* h* ^. G% T- K9 y; J$ r* b6 o J
e-mail: [email protected].9 `" g9 Z6 Q2 E" l# \0 t c
about 6 to 7 months old, which progressively became
$ W; f- G0 [) C8 G5 A+ Xdarker. She was also concerned about the enlarge-
: ?6 L! s6 k% \( ?- fment of his penis and frequent erections. The child O" @+ L' M$ e
was the product of a full-term normal delivery, with
* F1 s/ h4 ?: q' z# A4 La birth weight of 7 lb 14 oz, and birth length of$ B( v* H' c3 p" |
20 inches. He was breast-fed throughout the first year6 Z' }' d/ B& a+ w4 `
of life and was still receiving breast milk along with- A' T6 g( D7 l$ F; {
solid food. He had no hospitalizations or surgery,- a2 f9 Q2 R0 I, [
and his psychosocial and psychomotor development
* c' G m+ ~5 D6 D9 Ewas age appropriate.0 L, m [ P$ w8 m; F
The family history was remarkable for the father,% w3 ^' o+ R+ U2 p! z7 ^
who was diagnosed with hypothyroidism at age 16,
; \6 P3 H ?- O! N3 W6 Nwhich was treated with thyroxine. The father’s
0 G5 }! W1 V' y3 Q6 V" R9 T4 fheight was 6 feet, and he went through a somewhat
% O: O1 }& c3 T2 zearly puberty and had stopped growing by age 14.
2 K0 {9 j# Z+ |$ n/ ~# }The father denied taking any other medication. The
& }' E' u; L! w) r, |) echild’s mother was in good health. Her menarche
8 s& t7 E( w9 z- c! t% Gwas at 11 years of age, and her height was at 5 feet7 k# a: u- X( ?( J/ M6 K; u
5 inches. There was no other family history of pre-5 F8 L% u2 I0 Y4 A3 `/ i# r
cocious sexual development in the first-degree rela-& E. X( O" ^2 k1 f0 t0 Z
tives. There were no siblings.
' M! Q2 l, j# p' P4 o% }Physical Examination
8 T" D8 `4 ^8 a+ a' P, W7 |5 SThe physical examination revealed a very active,
0 R5 F) o4 @. I8 w. Y8 H: Splayful, and healthy boy. The vital signs documented9 `$ Y3 F/ u b1 m( N, M
a blood pressure of 85/50 mm Hg, his length was
$ P3 k1 b n9 F$ p* t6 ^3 x90 cm (>97th percentile), and his weight was 14.4 kg
, y0 ]6 ^. H4 e% b4 D7 B& m3 X7 t(also >97th percentile). The observed yearly growth/ _ J3 p9 G. |3 d# U- l
velocity was 30 cm (12 inches). The examination of' ^/ f% ]) F4 [
the neck revealed no thyroid enlargement.
2 X0 t; [, V c* y, Q0 Z0 pThe genitourinary examination was remarkable for
% g. U- _4 \( I: q/ @. W( \ A: Jenlargement of the penis, with a stretched length of2 @; X* s s3 i# u7 L; Y
8 cm and a width of 2 cm. The glans penis was very well, ? D' i% F" O& q* J
developed. The pubic hair was Tanner II, mostly around: p! p1 c: z4 B% i& j
540! z, }6 s# w: r) [+ p: p# M; V
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from: n! O) z3 l$ n2 z5 j4 h# }
the base of the phallus and was dark and curled. The
7 f4 k3 Q' _- p" q% G# W5 J Ltesticular volume was prepubertal at 2 mL each.8 a- h9 y9 Q5 i3 G5 b) q' O! C
The skin was moist and smooth and somewhat
8 ~8 Z) ?( A. l% ?* s& l. Hoily. No axillary hair was noted. There were no5 @* \( K @2 z
abnormal skin pigmentations or café-au-lait spots.
3 J w/ b3 _8 x! N: v/ fNeurologic evaluation showed deep tendon reflex 2+
6 j# H r0 T4 T) K/ bbilateral and symmetrical. There was no suggestion, g' Q( [' i& m. R
of papilledema.
( [, y Q; `8 G" H7 `' c1 HLaboratory Evaluation
e y3 v. h0 \' a" i# L/ iThe bone age was consistent with 28 months by, P. ^' D; v3 b3 W. Q' f
using the standard of Greulich and Pyle at a chrono-
6 O1 b! U$ b6 D$ @2 @logic age of 16 months (advanced).5 Chromosomal+ \1 @. L; F% k) }1 C4 X3 T# J( r
karyotype was 46XY. The thyroid function test
4 y! S) |4 x1 ~3 r) Xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
8 v' ]& C9 Y# R7 D. _2 \- m( klating hormone level was 1.3 µIU/mL (both normal).
( A$ v; ~+ R* S4 l. c( d+ c+ P$ jThe concentrations of serum electrolytes, blood
+ _9 f- F0 w/ k& durea nitrogen, creatinine, and calcium all were
0 b, P* U' I1 F5 a) E5 _% owithin normal range for his age. The concentration- X1 m; C& K4 B! E, s, D
of serum 17-hydroxyprogesterone was 16 ng/dL& P( M3 ]9 }+ T- R, [- V' G
(normal, 3 to 90 ng/dL), androstenedione was 20/ P5 c/ i% ]! v9 L$ V9 [
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-$ @6 ]5 q' z! t5 D9 D+ Z
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
" C1 Z- L1 K, O, V0 idesoxycorticosterone was 4.3 ng/dL (normal, 7 to
, }4 w$ A2 d& M) O) g3 b9 m( T49ng/dL), 11-desoxycortisol (specific compound S)4 q* S- a# C% n' S" X
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
) r/ e* s; O. g. m1 [; Ptisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total8 E' z3 @: A( D A( A
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
; Q6 A7 {+ h, Zand β-human chorionic gonadotropin was less than
: @8 y( s" E- U, J1 U5 mIU/mL (normal <5 mIU/mL). Serum follicular: p- V% L- P2 M6 }
stimulating hormone and leuteinizing hormone- P k9 i$ Y9 {7 K3 _
concentrations were less than 0.05 mIU/mL
7 y7 e& i& L0 @0 v6 w! w1 E(prepubertal)." `- f9 M& \( N- O/ ^$ p/ i9 X3 l# l
The parents were notified about the laboratory5 T# ^/ i4 j# x% a. ~
results and were informed that all of the tests were% ~7 Y1 }7 g! S$ Y" W3 S7 E ^
normal except the testosterone level was high. The+ a8 h, y5 f# n! I) z; M5 k& C
follow-up visit was arranged within a few weeks to* X( L7 s8 e/ c4 D8 v
obtain testicular and abdominal sonograms; how-# O: q6 X5 Q( _
ever, the family did not return for 4 months.+ z3 k6 p, Q/ V' r& v1 S" Q
Physical examination at this time revealed that the
9 S; R: S* s! v+ ochild had grown 2.5 cm in 4 months and had gained9 c" M; [! X$ I. e2 k" }
2 kg of weight. Physical examination remained
( G$ P7 ]9 X. s: ~unchanged. Surprisingly, the pubic hair almost com-) B, T5 r9 z; N O( }
pletely disappeared except for a few vellous hairs at* D6 V2 E- ~) n: y! r
the base of the phallus. Testicular volume was still 2
2 M! `' b. u S, L) V; kmL, and the size of the penis remained unchanged.( u8 V2 y! G) U
The mother also said that the boy was no longer hav-
# g7 U" e4 D" g2 Qing frequent erections.' G& Y% J u( s# t
Both parents were again questioned about use of
) D; p: j8 f. X9 x1 o1 i* ?any ointment/creams that they may have applied to1 [: J1 s% m7 x0 Y. }- r5 I
the child’s skin. This time the father admitted the4 o- Y2 i; l: ^! v B8 R
Topical Testosterone Exposure / Bhowmick et al 541
5 h$ T4 {) h+ K% m, E9 j C' muse of testosterone gel twice daily that he was apply-
, o/ |; [$ f7 Wing over his own shoulders, chest, and back area for& j" g. L P# W# W0 d" {1 j% \* Y
a year. The father also revealed he was embarrassed; S6 }" p J4 a1 v
to disclose that he was using a testosterone gel pre-
3 P- T% x: ]5 _& f. A6 j8 cscribed by his family physician for decreased libido
) b5 ] b: E: k4 _& m6 j6 Ssecondary to depression.2 i+ R3 I- f, z) `& R4 h% E
The child slept in the same bed with parents.
3 e1 C/ }3 ^9 v: iThe father would hug the baby and hold him on his: c9 O% J) P& s& W% Z. j
chest for a considerable period of time, causing sig-
+ K: P+ r) q Q2 U% t+ tnificant bare skin contact between baby and father.
+ ?5 @" _1 F& Z) c# {/ MThe father also admitted that after the phone call,
Y7 K, \# A$ v8 K6 n, ?+ R& Cwhen he learned the testosterone level in the baby+ p7 G8 \" T! k
was high, he then read the product information
: I, @+ Z Y; M( [) K, N% J3 u) Zpacket and concluded that it was most likely the rea-* F1 K" [2 }9 X' k
son for the child’s virilization. At that time, they
& i d0 _" ~" q% v1 a, h% g6 G9 edecided to put the baby in a separate bed, and the
) t* c3 a; J- Kfather was not hugging him with bare skin and had V3 h2 {" O3 |6 t; i2 @+ w8 B
been using protective clothing. A repeat testosterone
: m4 t6 j0 L+ N! mtest was ordered, but the family did not go to the
" W5 }0 s3 o& ^, ]laboratory to obtain the test.$ S3 V5 t& N! f5 d8 s( Y
Discussion
" H, C- @( g+ LPrecocious puberty in boys is defined as secondary
7 Q& J& x" D& f9 ]sexual development before 9 years of age.1,4
' |; v1 J; j1 G8 N# ^# nPrecocious puberty is termed as central (true) when* s4 R8 K- t8 @1 o* J
it is caused by the premature activation of hypo-
9 [+ c) U$ d4 Kthalamic pituitary gonadal axis. CPP is more com-
( m( f% T& C9 r, r# j3 Hmon in girls than in boys.1,3 Most boys with CPP
1 |/ B3 g( j- `/ y, W1 T: `may have a central nervous system lesion that is
( _% s5 W* t, k; S" W6 Mresponsible for the early activation of the hypothal-% v3 u( E @* |. F; F6 M& Z9 J# I
amic pituitary gonadal axis.1-3 Thus, greater empha-
5 w8 |% A, V! t; Ksis has been given to neuroradiologic imaging in) o3 }9 q: `1 k4 n
boys with precocious puberty. In addition to viril-7 e2 L0 w" Q2 Q& X
ization, the clinical hallmark of CPP is the symmet-
) D, M6 z1 G: w" P1 e2 O" Erical testicular growth secondary to stimulation by
) n$ i& Y5 o! C- H% U# ?gonadotropins.1,38 h* m9 h* f) E7 G
Gonadotropin-independent peripheral preco-; ]# q' M6 f) ?. F- Y) b+ g+ R0 i/ u, l
cious puberty in boys also results from inappropriate) X. k; [$ E+ M
androgenic stimulation from either endogenous or
2 w/ h- v& E1 K/ Hexogenous sources, nonpituitary gonadotropin stim-
7 e/ F. G- [* W1 p$ |2 }ulation, and rare activating mutations.3 Virilizing
5 d% C f& K0 ccongenital adrenal hyperplasia producing excessive4 e, ^1 m4 l# d, F, M
adrenal androgens is a common cause of precocious) A# d2 e: g; {. ?
puberty in boys.3,4
; K. |% u( k9 J; rThe most common form of congenital adrenal
+ [. m( x* X* W6 Shyperplasia is the 21-hydroxylase enzyme deficiency.5 i! g& Z% g& j( O
The 11-β hydroxylase deficiency may also result in
) ^, b. R$ @. u; q% S5 Nexcessive adrenal androgen production, and rarely,
, \9 L% v5 U" i( M5 ?an adrenal tumor may also cause adrenal androgen
( \# K$ Z, q& O; y; r+ E: Uexcess.1,3; S8 [: F6 S& \; |6 o9 r
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 I2 A% r7 c0 b. f, _& P542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
: K8 h4 W. J9 l- y5 _A unique entity of male-limited gonadotropin-
" F8 {* X7 b9 Pindependent precocious puberty, which is also known
4 C6 C- b2 j4 G$ oas testotoxicosis, may cause precocious puberty at a
2 J% }) Y7 q2 Z/ [very young age. The physical findings in these boys; O* N$ m+ J7 g, o( A+ L2 J
with this disorder are full pubertal development,: E( n* d8 v3 T5 q, H z3 T0 T$ q
including bilateral testicular growth, similar to boys0 H v& \, c/ \1 J7 B
with CPP. The gonadotropin levels in this disorder
3 |! [4 D6 |- W' Bare suppressed to prepubertal levels and do not show
9 Y4 m' s+ q0 M/ t: N. qpubertal response of gonadotropin after gonadotropin- }$ C0 K; |' g _
releasing hormone stimulation. This is a sex-linked8 h, q* U% ?# ^6 M- w' `7 J: c
autosomal dominant disorder that affects only$ c: ^6 w7 t F* B
males; therefore, other male members of the family
/ Z3 ? n( w/ B; p( o' c5 _! b2 Gmay have similar precocious puberty.3% b( }+ M) m4 ^/ a3 Z
In our patient, physical examination was incon-! {; s0 r5 G- ?" C& Q/ V. _2 b
sistent with true precocious puberty since his testi-, }$ S8 a9 u2 j# `6 r2 C
cles were prepubertal in size. However, testotoxicosis: Q2 m7 ~; {- Z1 ~! G: R6 m
was in the differential diagnosis because his father4 W) H0 w3 H; s
started puberty somewhat early, and occasionally,
1 t' z' Q1 e2 _3 b; L' Z, b* rtesticular enlargement is not that evident in the: r/ o' _9 `& Y
beginning of this process.1 In the absence of a neg-
9 O" V4 n& E1 y9 i& f# f5 Eative initial history of androgen exposure, our" A c4 O. l. V2 A! K0 c# c0 ?
biggest concern was virilizing adrenal hyperplasia,
. @4 ~: P+ a: o1 Yeither 21-hydroxylase deficiency or 11-β hydroxylase" l$ Y' J: F( c. j E
deficiency. Those diagnoses were excluded by find-
( D" A9 |; X+ F0 Hing the normal level of adrenal steroids.
& W+ C. b& r' N4 }* e/ hThe diagnosis of exogenous androgens was strongly4 s0 G* B2 ~. D5 ?: v6 G
suspected in a follow-up visit after 4 months because: Y. f2 Y2 F) q3 e* L: `/ E7 W
the physical examination revealed the complete disap-
( v Y; v0 g: X, n0 M- c( d/ Mpearance of pubic hair, normal growth velocity, and
9 Z7 R* C8 J. t$ ^5 D) Z* g; Cdecreased erections. The father admitted using a testos-- n, n0 Q1 Q& H. E' c3 \* C3 @$ a7 z
terone gel, which he concealed at first visit. He was* S2 U8 e9 L' |$ z! k% x. M2 H" _5 z6 `: _
using it rather frequently, twice a day. The Physicians’
" Q5 T$ H! g' o5 }$ y: q4 EDesk Reference, or package insert of this product, gel or. _- ~9 @) }3 q; \, J1 `) Y9 R; U6 t
cream, cautions about dermal testosterone transfer to
/ | B9 P' @% L& @. v: T1 Dunprotected females through direct skin exposure.
8 Z% m9 _3 w! c$ I5 @Serum testosterone level was found to be 2 times the. b1 Y6 z U7 }
baseline value in those females who were exposed to5 L! j2 T; N) r% a# g' d
even 15 minutes of direct skin contact with their male
; Z9 p' _2 d9 `partners.6 However, when a shirt covered the applica-# W2 j: a- c2 B% K. x; Z5 n
tion site, this testosterone transfer was prevented., U, D6 Y5 h, Z, W0 }% J
Our patient’s testosterone level was 60 ng/mL,
2 @+ c1 K5 X3 [3 T3 Owhich was clearly high. Some studies suggest that
% D, a0 o6 |& i W! @dermal conversion of testosterone to dihydrotestos-2 o# O- b/ @; l) [1 \
terone, which is a more potent metabolite, is more
' l7 V8 r! W& f9 e7 pactive in young children exposed to testosterone
/ a" Y) }# ?! @/ i7 N% pexogenously7; however, we did not measure a dihy-4 c; r m. D9 L7 z, J3 k9 N# _
drotestosterone level in our patient. In addition to
" t$ [9 G1 S! v4 \* X. zvirilization, exposure to exogenous testosterone in
6 b6 Y/ F5 P" k0 Gchildren results in an increase in growth velocity and3 j/ B3 w; H* ~ V# D
advanced bone age, as seen in our patient.
" i. }$ ]1 o% B7 LThe long-term effect of androgen exposure during
& \, n$ I2 ?3 I* T. N& G, jearly childhood on pubertal development and final2 v0 V' r x& t j
adult height are not fully known and always remain
9 v* m; Z L4 }" ^& p$ q+ R- aa concern. Children treated with short-term testos-
0 I$ K7 ~+ K/ Z. _5 p/ G3 f+ @/ fterone injection or topical androgen may exhibit some
: E+ V D3 ?4 v; vacceleration of the skeletal maturation; however, after4 f( _/ ^! Y W b) b
cessation of treatment, the rate of bone maturation
& M4 I) `$ M" ]decelerates and gradually returns to normal.8,9+ @3 i+ R8 u- w& c
There are conflicting reports and controversy9 D, e" L" k% C0 v7 p6 X+ l' @
over the effect of early androgen exposure on adult
+ p9 q( T! H8 f3 v- Wpenile length.10,11 Some reports suggest subnormal
% S# R. o: D% U( Vadult penile length, apparently because of downreg-
/ k! E4 M' g8 b; v) ?" Uulation of androgen receptor number.10,12 However,5 E* o) D' I; ?" n
Sutherland et al13 did not find a correlation between
% o/ v+ S, o' i! N, f* J2 B+ ochildhood testosterone exposure and reduced adult" l% X2 ]$ b4 A/ b. p$ g) p: k3 ?
penile length in clinical studies.
n* H6 s: P. \5 p& b2 e% g4 {. fNonetheless, we do not believe our patient is' A% ^5 H0 X- I, T' I- o" I) o
going to experience any of the untoward effects from4 P( e+ M; ~0 l
testosterone exposure as mentioned earlier because9 _0 S# ]6 t& W: g& ~& d' N
the exposure was not for a prolonged period of time.
4 w: p; S9 I3 t q1 M+ v; q( s7 \Although the bone age was advanced at the time of" z7 Q; y% b0 Q- T. d6 A
diagnosis, the child had a normal growth velocity at
6 L/ _8 l- u/ N& m7 Q- j: l; bthe follow-up visit. It is hoped that his final adult
4 `1 O1 H; g$ |$ `height will not be affected.
& [5 q5 k/ K o! o5 l! mAlthough rarely reported, the widespread avail-
3 f) p, Q$ m" ^3 ?* Y: Lability of androgen products in our society may2 D5 u1 A$ B% t- ~" q$ X2 o
indeed cause more virilization in male or female7 T/ h4 b: o/ P& `2 q8 j5 b+ }
children than one would realize. Exposure to andro- G1 @' Z5 c# G3 m" [* P! q; d1 @
gen products must be considered and specific ques-
) M0 o. X- q/ n+ X, ]tioning about the use of a testosterone product or
+ _# Q4 Z z1 n! Ygel should be asked of the family members during9 o+ J8 c2 u* @' w- g& o' n& M
the evaluation of any children who present with vir-
7 K8 ?9 P& a) G Bilization or peripheral precocious puberty. The diag-8 `% u( L/ N, ]9 V( ^7 M# I6 c
nosis can be established by just a few tests and by" C6 c6 G4 L# @ k O4 U' h
appropriate history. The inability to obtain such a
8 B, w1 J/ G0 s* [. l3 T7 Z) Jhistory, or failure to ask the specific questions, may; N3 e0 P& P* n" N
result in extensive, unnecessary, and expensive% z: B6 u$ `0 m7 @' f/ `/ P
investigation. The primary care physician should be3 g) ~+ v) i7 `: u" R- H
aware of this fact, because most of these children5 y' w( D( R1 T
may initially present in their practice. The Physicians’
, |5 j8 N% b6 H4 c+ bDesk Reference and package insert should also put a
5 f! N7 i- D+ w1 g, B7 r! hwarning about the virilizing effect on a male or
; k3 l* ?* t. X8 C: m' ]female child who might come in contact with some-
& y, c2 v; H6 F% z3 Z5 Sone using any of these products.
9 ?! }% q9 g4 n/ `( Q9 M9 G+ Y9 RReferences/ `0 F! U+ x$ I" {
1. Styne DM. The testes: disorder of sexual differentiation3 `7 Y$ @1 Q1 n) @/ u
and puberty in the male. In: Sperling MA, ed. Pediatric
$ p' [/ `# F% Q5 _+ r8 wEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
6 }8 X/ \+ k! Q& V7 o' I2002: 565-628., F0 T9 c' P3 v9 ~5 g
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
, k( z/ N$ }$ H) R8 m9 ppuberty in children with tumours of the suprasellar pineal |
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