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Sexual Precocity in a 16-Month-Old4 T5 P6 C" N' d: m
Boy Induced by Indirect Topical i M- E V# E6 T' i% P8 O, n1 ~
Exposure to Testosterone
$ ^7 f) d. s& K% tSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
, q0 f8 ^& @7 q2 D2 ?5 Fand Kenneth R. Rettig, MD17 s" @8 _% m& c5 e) Q
Clinical Pediatrics
5 e* b. z! K! W* xVolume 46 Number 6) G" C) W9 f( B+ f$ s! j3 ?
July 2007 540-5430 Z7 R2 p& `5 N" R2 o4 t6 Z: k
© 2007 Sage Publications* t) C. `3 e. u' x4 r
10.1177/00099228062966517 @7 t4 O8 i- m* j
http://clp.sagepub.com
* R! i# O* u2 ]# o( y: }1 G( q7 A/ Dhosted at
( m3 y A' W- X4 |' L! D* Yhttp://online.sagepub.com
' q# r. P6 @8 Z3 a' cPrecocious puberty in boys, central or peripheral,
8 \+ I9 b! L' u: K: S: Jis a significant concern for physicians. Central
2 O6 h3 q/ n; V$ cprecocious puberty (CPP), which is mediated5 a; y% T8 |) P/ }. \8 q
through the hypothalamic pituitary gonadal axis, has. }- c' L+ j* h1 t4 w. q
a higher incidence of organic central nervous system
# n' P, C x t( ~7 olesions in boys.1,2 Virilization in boys, as manifested
% Y* m# _& Y# Q0 p# y3 uby enlargement of the penis, development of pubic
, g" r+ M: n7 J( t" D, @hair, and facial acne without enlargement of testi-9 B* G& e/ ?; I1 N, M; @! }
cles, suggests peripheral or pseudopuberty.1-3 We; J/ \& V ^+ L4 Y7 Y8 u6 _
report a 16-month-old boy who presented with the
5 y4 b3 ^8 u! Z. Ienlargement of the phallus and pubic hair develop-/ U6 ?- Z# X* I Z1 b* N
ment without testicular enlargement, which was due( |# [+ H9 Z) U- ?, t; n
to the unintentional exposure to androgen gel used by
* ^# {( u! e$ i; k5 i. rthe father. The family initially concealed this infor-4 u/ ^, p% a) j
mation, resulting in an extensive work-up for this
r9 s$ v# T- D. K, M7 H8 o& }; Wchild. Given the widespread and easy availability of' b: h+ t& p8 g1 e d9 o. D: ^ o
testosterone gel and cream, we believe this is proba-
6 Y3 z# R& K/ G, fbly more common than the rare case report in the5 J, Q) c# N. {
literature.4
: r/ p; h% L4 `6 d1 s p; u0 cPatient Report* g" b# U0 r- A, \0 j5 ?
A 16-month-old white child was referred to the
D; T' V% Y. j0 d/ G! s: iendocrine clinic by his pediatrician with the concern l8 l( `7 C' f% x0 O, r' K
of early sexual development. His mother noticed
) t) K' e" R1 l$ jlight colored pubic hair development when he was/ J7 ^7 G. B- k; j1 A9 t( e6 t
From the 1Division of Pediatric Endocrinology, 2University of
- j" i9 N; E. y( aSouth Alabama Medical Center, Mobile, Alabama.( K# Y" x9 _) u1 m o
Address correspondence to: Samar K. Bhowmick, MD, FACE,( ~6 O$ x- _6 X9 L: d% q
Professor of Pediatrics, University of South Alabama, College of
1 i3 I: m- ^5 {0 {Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
1 D, ]2 U0 a' p6 R' l2 ^( Ue-mail: [email protected].
y9 f0 B" ^+ B. h7 I$ Aabout 6 to 7 months old, which progressively became) ~, F3 W2 \! {5 C: o) H0 x
darker. She was also concerned about the enlarge-
! W* z3 z* E8 F0 K# bment of his penis and frequent erections. The child7 Z0 Y2 a, r) j% x: k
was the product of a full-term normal delivery, with
- C. _" i' n! t9 Ya birth weight of 7 lb 14 oz, and birth length of
' X1 [. M8 a! r, Q* A4 S6 k+ K20 inches. He was breast-fed throughout the first year: o* A7 f" v r1 C; I
of life and was still receiving breast milk along with$ l* s$ x3 ?, U! U- V7 N
solid food. He had no hospitalizations or surgery," i, G4 s+ w5 G* M+ g6 V% s
and his psychosocial and psychomotor development* F: e) R5 c' ]# z
was age appropriate.
a8 i j1 b0 o, I3 D5 CThe family history was remarkable for the father,. F. L! c9 {; k
who was diagnosed with hypothyroidism at age 16,
; E. J4 }* h9 N" \5 pwhich was treated with thyroxine. The father’s
6 p" z& D7 m* ` D4 r2 Qheight was 6 feet, and he went through a somewhat2 B8 k' m# V; J7 I# t
early puberty and had stopped growing by age 14.
( v! l( y# q, W; k$ a3 pThe father denied taking any other medication. The
: O% A, T8 _4 N/ w/ V" }, achild’s mother was in good health. Her menarche
" H( ^" D: H) n" \) owas at 11 years of age, and her height was at 5 feet, F! h% w/ e7 l0 u; b
5 inches. There was no other family history of pre-8 b& C# b4 G4 L% K8 Q
cocious sexual development in the first-degree rela-
" h" B& ~) H1 @( U8 Htives. There were no siblings.
5 V' L* U; O! ?( v2 A% p5 nPhysical Examination
; k7 e% D# y% cThe physical examination revealed a very active,
7 o& F# d7 Y) r; w0 Z6 z& iplayful, and healthy boy. The vital signs documented; d B% H9 W- v
a blood pressure of 85/50 mm Hg, his length was
0 J* S" }" t6 p, D) L, ~0 t90 cm (>97th percentile), and his weight was 14.4 kg% k0 }5 V7 d9 q/ ^" v6 B6 [2 n
(also >97th percentile). The observed yearly growth
8 A. M0 K, X6 h6 C; ~, R; I# J9 dvelocity was 30 cm (12 inches). The examination of$ q+ B; l5 n7 n& V
the neck revealed no thyroid enlargement.
\" X5 u7 r5 j+ AThe genitourinary examination was remarkable for: h- o- D8 r, `; Q% w4 J
enlargement of the penis, with a stretched length of/ C. V/ e- A& m% A- I @3 _
8 cm and a width of 2 cm. The glans penis was very well
1 D6 v* j0 Y; j( f+ N9 M) Rdeveloped. The pubic hair was Tanner II, mostly around
% X1 N& u D& i7 c540
, I9 ^. `% ^. r6 Z+ _at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from6 s5 Q: c, w1 R5 c( @
the base of the phallus and was dark and curled. The: K7 ^4 w1 t. w, [! L
testicular volume was prepubertal at 2 mL each.
2 c8 `9 R- ]0 V" fThe skin was moist and smooth and somewhat! G6 l4 L. V% e$ M& k
oily. No axillary hair was noted. There were no5 n+ X) t2 x% p$ o1 X" Z' k
abnormal skin pigmentations or café-au-lait spots.8 d' ~( l4 ^% w: g5 d4 S! ~- _
Neurologic evaluation showed deep tendon reflex 2+
* N! \' q& u$ n; zbilateral and symmetrical. There was no suggestion2 p5 s# e8 m3 K/ ^9 U+ v7 E$ W
of papilledema.) ~$ C7 D) J. T; `' z
Laboratory Evaluation
1 S6 U" \9 r j+ L& u4 cThe bone age was consistent with 28 months by9 N. w6 ?4 [# ^8 P6 L! a# v7 D) h
using the standard of Greulich and Pyle at a chrono-; j" F r- I3 S) W- n
logic age of 16 months (advanced).5 Chromosomal. F% B4 P( ]$ z
karyotype was 46XY. The thyroid function test
3 V0 d( L( b: k1 Z% A& M; F* gshowed a free T4 of 1.69 ng/dL, and thyroid stimu-( x% O. p* d) ?
lating hormone level was 1.3 µIU/mL (both normal).% |' H; w6 r% Y6 A" ]7 [; q7 w7 a0 h/ E% F
The concentrations of serum electrolytes, blood1 l, c! C5 `0 Y/ Z& r ]0 t
urea nitrogen, creatinine, and calcium all were4 j, r N8 I2 x7 B0 p; {
within normal range for his age. The concentration
% t1 v5 Z4 V- V" rof serum 17-hydroxyprogesterone was 16 ng/dL2 x' M% d+ U+ n0 A' {- a! v
(normal, 3 to 90 ng/dL), androstenedione was 20
8 T9 m7 H7 l! y. C/ ong/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
5 k. s4 c/ C3 ^6 Y. o: rterone was 38 ng/dL (normal, 50 to 760 ng/dL)," G% i* R# I; V W$ h8 Q
desoxycorticosterone was 4.3 ng/dL (normal, 7 to( K) U( Y0 f$ N% Y
49ng/dL), 11-desoxycortisol (specific compound S)
" p7 j0 A [ s' U6 S# e( Bwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! |5 ?2 w4 Z0 v8 Btisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total( T/ p: a: U& O# D
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
. H; r* f, f1 l* o mand β-human chorionic gonadotropin was less than' T R- A" v2 i X( @' h0 t# O
5 mIU/mL (normal <5 mIU/mL). Serum follicular. i) y! \+ F1 @" i! o
stimulating hormone and leuteinizing hormone5 V \# J8 ~6 t* I
concentrations were less than 0.05 mIU/mL1 `0 ?" z3 e# r3 e, X7 o$ O
(prepubertal).2 S5 y0 Z# K) H7 o6 Y$ e6 L i& y
The parents were notified about the laboratory0 v9 o' @# {3 o2 O
results and were informed that all of the tests were( {6 @0 ?1 |* h( I3 G1 V
normal except the testosterone level was high. The* w* m5 X. w9 ?4 C
follow-up visit was arranged within a few weeks to
: j3 ?3 _8 d1 `. P2 U( pobtain testicular and abdominal sonograms; how-
) w& A* L) x$ h6 ?! l% r# P& Xever, the family did not return for 4 months.1 k2 t! x1 |1 {# i2 A9 r
Physical examination at this time revealed that the# U( H# w, B- U; |
child had grown 2.5 cm in 4 months and had gained/ L" [; p9 {% i/ r7 v1 s, b
2 kg of weight. Physical examination remained
# S( V% B% X: m! }1 w0 k+ lunchanged. Surprisingly, the pubic hair almost com-
5 ?5 ]+ \' U8 U9 dpletely disappeared except for a few vellous hairs at0 g+ n* [& B2 {, |( M9 g6 Z& r* `: R4 T
the base of the phallus. Testicular volume was still 2
8 u: u9 q# o- k! v1 Z, gmL, and the size of the penis remained unchanged.
, Z. s3 ]/ E& A% T+ y1 _3 UThe mother also said that the boy was no longer hav-
3 R. T4 u( n, _& j( m. U9 Jing frequent erections.! g* V3 H- }, e0 Q m9 o
Both parents were again questioned about use of
) l E8 N' M ?; Wany ointment/creams that they may have applied to8 X4 h3 U$ U' T2 O& a( k
the child’s skin. This time the father admitted the
! e9 B- @. s1 @9 ATopical Testosterone Exposure / Bhowmick et al 541 v' m+ m+ i6 D
use of testosterone gel twice daily that he was apply-: ?- s) }' {; c' D; f$ X
ing over his own shoulders, chest, and back area for, ` Y* S* |+ D- P6 f7 L
a year. The father also revealed he was embarrassed
0 f7 F4 A5 s" P: w+ j1 Qto disclose that he was using a testosterone gel pre-
4 h5 ]7 c1 G' M6 r# @- F# {. d4 ?scribed by his family physician for decreased libido) g# K, R/ ^9 A0 B4 K) a( p
secondary to depression.
" F; N" l% [( j, \( v% ^The child slept in the same bed with parents.
. A8 y- @% y- S; c# X* |# F. W, M* OThe father would hug the baby and hold him on his( L* F) O4 e* }" f( n3 k( I
chest for a considerable period of time, causing sig-2 ?4 E& S% @1 i5 d* e! i
nificant bare skin contact between baby and father.
7 M* N. n8 s1 G+ T4 E2 W. y0 V. Z4 OThe father also admitted that after the phone call,, v; K- U7 {( g; k$ ]
when he learned the testosterone level in the baby) R' k! F& t: F
was high, he then read the product information1 _( f% D; n6 h) s% j4 ]
packet and concluded that it was most likely the rea-
u: A0 K! w1 G$ v" Eson for the child’s virilization. At that time, they% X, i, m W. G! z% e- g# V
decided to put the baby in a separate bed, and the3 r/ D4 q, b9 [! _ a4 N) G: |
father was not hugging him with bare skin and had6 v' }# {7 p+ g7 O& D. ~9 x
been using protective clothing. A repeat testosterone
5 `* f' k @" k2 d9 H- R0 }test was ordered, but the family did not go to the+ P. v5 z9 N2 c& t9 v+ \3 Z
laboratory to obtain the test.
7 `" f7 f- x/ E- k# ~/ DDiscussion
7 F6 X& U6 U' W3 zPrecocious puberty in boys is defined as secondary
6 D" ^/ K& G5 Z! ~9 ]- vsexual development before 9 years of age.1,4, s. ^% P. e" F7 z+ X
Precocious puberty is termed as central (true) when# H) x0 J* G- w& Z
it is caused by the premature activation of hypo-' ]) o4 U# T/ V6 z5 t4 j
thalamic pituitary gonadal axis. CPP is more com-
- r4 ?9 H/ T7 C& P" Mmon in girls than in boys.1,3 Most boys with CPP: N" {* C& ` O
may have a central nervous system lesion that is
V8 D$ q# _9 jresponsible for the early activation of the hypothal-
; ?! O& t, _# H; l! |+ l0 ?amic pituitary gonadal axis.1-3 Thus, greater empha-5 k( _* D0 G% O, |. ~2 G& J9 ^
sis has been given to neuroradiologic imaging in
9 x* k; ^: i# w1 U9 Rboys with precocious puberty. In addition to viril-
: x6 S/ J- @6 K tization, the clinical hallmark of CPP is the symmet-. K; G. Z- w. y4 p2 `
rical testicular growth secondary to stimulation by% B2 e5 E! g! k/ G2 h( q4 c$ ]
gonadotropins.1,3
9 w: O$ {! ]' W+ l8 v9 `& NGonadotropin-independent peripheral preco-# C- G, c& u8 T& u7 G+ E: B. R
cious puberty in boys also results from inappropriate- C7 A/ C% v8 P: \3 \" W% P9 d5 Z
androgenic stimulation from either endogenous or
5 U% [ Y u: c! U& h9 j8 Lexogenous sources, nonpituitary gonadotropin stim-) K4 P* z- A* a9 Z
ulation, and rare activating mutations.3 Virilizing% y. b2 M p9 L9 f
congenital adrenal hyperplasia producing excessive
& |, s& t* X& k: l' U1 i5 badrenal androgens is a common cause of precocious$ w$ `5 k- }$ o6 {2 j
puberty in boys.3,4, r# C" q& F: ~- k( j. V
The most common form of congenital adrenal" o3 i8 M$ `1 R! j* U! o
hyperplasia is the 21-hydroxylase enzyme deficiency.
& ]* z/ K6 B# M, F bThe 11-β hydroxylase deficiency may also result in9 b X+ b. t, R! |8 L
excessive adrenal androgen production, and rarely,& Q8 N1 A, F+ i+ _, o/ {2 l
an adrenal tumor may also cause adrenal androgen, l; e7 |; Y* s! [$ s3 `, Q( @
excess.1,3
9 i; g5 k. X6 A' ]at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
0 e" Y. g7 Q# ^' x542 Clinical Pediatrics / Vol. 46, No. 6, July 20075 x1 _' Q, z2 H! A
A unique entity of male-limited gonadotropin-9 r( u+ Q3 H. Y8 S: V
independent precocious puberty, which is also known
9 B3 p! W+ H6 B+ ias testotoxicosis, may cause precocious puberty at a. u/ b8 q3 Y Z( c
very young age. The physical findings in these boys7 g/ y7 \( H9 R) u* j H) n
with this disorder are full pubertal development,0 l6 G% Q) p; }3 b5 ^; F6 h, m |$ o" p
including bilateral testicular growth, similar to boys5 T* M* T4 T) E% J3 e/ {# |0 x* }) `
with CPP. The gonadotropin levels in this disorder+ t) T5 V( j5 b! i
are suppressed to prepubertal levels and do not show/ P& n: N8 ~, Z; y. X
pubertal response of gonadotropin after gonadotropin-% G9 m+ k5 w0 M6 O+ g7 ^' A
releasing hormone stimulation. This is a sex-linked9 F% ~. C9 P) l& j8 [! m' T
autosomal dominant disorder that affects only- I% d+ A! X7 t7 A3 f! ]" Q- K$ g
males; therefore, other male members of the family
U% G) u7 G2 tmay have similar precocious puberty.31 E3 b% P. e B- `) {
In our patient, physical examination was incon-1 t* y& M3 W) @$ \+ |
sistent with true precocious puberty since his testi-
; x3 [5 a5 P) t. p" Kcles were prepubertal in size. However, testotoxicosis
7 l9 }) n/ p. Q) U O' W: Rwas in the differential diagnosis because his father
, A, R# H# I9 i8 [) Xstarted puberty somewhat early, and occasionally,/ b; O& f/ W& z8 e0 G# [; _
testicular enlargement is not that evident in the
1 b: e" F9 n. ^beginning of this process.1 In the absence of a neg-$ T3 x# t$ m7 N; C6 V" [
ative initial history of androgen exposure, our
& T3 m }3 U) I# B& x& Dbiggest concern was virilizing adrenal hyperplasia,% K: J4 o8 `9 T: ^( ~9 G7 ?) Z
either 21-hydroxylase deficiency or 11-β hydroxylase
) D2 q6 s% ?' r+ ], ]' Gdeficiency. Those diagnoses were excluded by find-
* {: Q: Q/ @5 uing the normal level of adrenal steroids./ _, s- }* g5 D2 l6 L6 v
The diagnosis of exogenous androgens was strongly
0 h' {% J- @% o. [+ Q2 P: ususpected in a follow-up visit after 4 months because
' N# t( O* B$ A ]1 A6 Athe physical examination revealed the complete disap-8 z7 S( p4 V! `4 C* n( A* h9 \. K
pearance of pubic hair, normal growth velocity, and
4 {# F6 m9 b* W9 J* M5 F4 e" o4 kdecreased erections. The father admitted using a testos-5 Z; r+ i2 a4 {' ] }
terone gel, which he concealed at first visit. He was
; [8 Y3 D+ T! g: ^, F1 Ousing it rather frequently, twice a day. The Physicians’
- M/ d. q* ^+ B7 a# {& B' YDesk Reference, or package insert of this product, gel or2 I; Y& H" L4 d- T8 c) Q
cream, cautions about dermal testosterone transfer to
+ K2 @% g& |! m, Q% nunprotected females through direct skin exposure.
$ H* W; d! @7 B2 Q1 HSerum testosterone level was found to be 2 times the
+ K' e% d* Q8 t4 ?6 O3 t+ dbaseline value in those females who were exposed to0 J% a9 T1 o& P/ ?3 x* k: Q
even 15 minutes of direct skin contact with their male
+ n C4 |, }' i+ I# Ppartners.6 However, when a shirt covered the applica-
; d& b' H- G* F( ?tion site, this testosterone transfer was prevented.& t/ c* e7 e; V3 w2 z
Our patient’s testosterone level was 60 ng/mL,1 S: ~; |0 R3 H# ^: u) P) _
which was clearly high. Some studies suggest that8 A+ X$ O+ }( h: ?) N3 ^
dermal conversion of testosterone to dihydrotestos-6 \# s0 J& i5 S% a8 R
terone, which is a more potent metabolite, is more- J; k2 n2 G& I& \# d0 {
active in young children exposed to testosterone2 a+ C7 P2 S- o; P" o5 ?
exogenously7; however, we did not measure a dihy-
) z# ~7 e8 o0 G& E( Edrotestosterone level in our patient. In addition to: \! E- P! D$ q% [3 U5 {7 d
virilization, exposure to exogenous testosterone in3 N: K; D, i7 `( }
children results in an increase in growth velocity and
' }9 ?; U$ r: Z5 E$ E2 {% yadvanced bone age, as seen in our patient.6 d- {( j$ T3 J6 i( B) K
The long-term effect of androgen exposure during
* U9 H3 u T, l. R/ w0 bearly childhood on pubertal development and final y9 M$ g2 N* f8 S6 _
adult height are not fully known and always remain; u; g+ h; z# F L3 `
a concern. Children treated with short-term testos-
' w% p; ?# c2 Mterone injection or topical androgen may exhibit some
: L: p" P+ A( f5 s' Qacceleration of the skeletal maturation; however, after
( g2 U9 E5 k5 G% K0 ocessation of treatment, the rate of bone maturation# l J# _* v5 w* L$ ~4 K' a0 |' y9 K
decelerates and gradually returns to normal.8,9# i: t# h" I3 R7 ~
There are conflicting reports and controversy- S+ ~' z8 ]1 ]
over the effect of early androgen exposure on adult
* d( p; g9 K+ ^! ]8 Kpenile length.10,11 Some reports suggest subnormal! d Z) E. \- Z$ z
adult penile length, apparently because of downreg-
; I3 V8 s4 g8 E- \7 }ulation of androgen receptor number.10,12 However,
! y" N* @3 s' p6 W9 p. e2 X9 BSutherland et al13 did not find a correlation between/ M0 O7 l3 r2 O- N* }; v" Z( N; W" t
childhood testosterone exposure and reduced adult
' m. M+ |- H) ]& b& S- I) l7 `! Gpenile length in clinical studies.
* i8 Y& W* E6 X6 D/ ?- s5 xNonetheless, we do not believe our patient is0 ?( [' T* [. H. Z* f$ Q
going to experience any of the untoward effects from
# D9 ~) z4 {6 w$ z7 W; y& Q, Q6 xtestosterone exposure as mentioned earlier because! |, V8 p7 d3 J2 B' l
the exposure was not for a prolonged period of time.. Q. ]) g7 e y9 u. m' N- m* _" F" x
Although the bone age was advanced at the time of
5 t0 E0 @4 t8 G2 @* `diagnosis, the child had a normal growth velocity at
) _3 }8 g- {/ v0 X; v: P- V. kthe follow-up visit. It is hoped that his final adult
; [0 k# H& V" |3 w# u' J4 X9 sheight will not be affected.- R) A4 N: N: m
Although rarely reported, the widespread avail-
# d3 ~5 e' F4 z& Gability of androgen products in our society may
6 J2 @9 j0 I( _/ @indeed cause more virilization in male or female2 d. ^ z, l2 n1 P' v+ X9 f
children than one would realize. Exposure to andro-7 d7 f+ ~3 ?( q8 U4 k: x- K1 A: G# X
gen products must be considered and specific ques-3 ^4 |) v5 a F+ O; b
tioning about the use of a testosterone product or- w' E6 n; u) F7 i9 J/ Y* D
gel should be asked of the family members during# V+ @" R' Z' n/ A/ D* c% D* e' @3 [
the evaluation of any children who present with vir-' v- f3 F! i4 R
ilization or peripheral precocious puberty. The diag-
2 O9 C3 L# q G4 r! r3 Vnosis can be established by just a few tests and by! m5 K8 }, T# G) k. R- ^
appropriate history. The inability to obtain such a
1 j0 L8 `6 c: W u' Khistory, or failure to ask the specific questions, may0 V1 F# A0 s, I I" a
result in extensive, unnecessary, and expensive
2 G6 `" _! P p2 ^+ k% o0 |investigation. The primary care physician should be0 \" x5 k* |3 j
aware of this fact, because most of these children6 L; p; o( K' M. A9 [
may initially present in their practice. The Physicians’+ ^3 q% H6 V/ N2 D: ?. C$ D; s8 l' ^+ L
Desk Reference and package insert should also put a& e8 G( ?+ c3 X4 h: i
warning about the virilizing effect on a male or
6 {' t+ Y) K" y5 U, ]# Rfemale child who might come in contact with some-" U, k: K% Q) p2 Z
one using any of these products.
7 L/ {. S6 O$ _% S$ s# O* @. X& MReferences
5 ~ g' y: K+ A1. Styne DM. The testes: disorder of sexual differentiation
" m" A9 x# v8 G3 Eand puberty in the male. In: Sperling MA, ed. Pediatric' V9 N: d. I% T9 }! G- N
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
: T5 y! D" U6 H( E% ^2002: 565-628.- \3 {3 C5 S3 \( g) U
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious( Z) U- `. p8 r2 K7 D$ x5 G2 r A
puberty in children with tumours of the suprasellar pineal |
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