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Sexual Precocity in a 16-Month-Old
1 O0 `( t6 y" V9 UBoy Induced by Indirect Topical
D5 D( [3 `+ P# y j+ {7 O; `+ r/ qExposure to Testosterone: K5 V2 B/ D- b: ~
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
- U9 B: v5 X, K( N, h# I/ Zand Kenneth R. Rettig, MD1
- Z$ a8 q& w" n5 I w pClinical Pediatrics$ ?3 U- B6 O+ Q, C
Volume 46 Number 6/ g8 l6 |6 x. N$ S4 r, T, {
July 2007 540-543# R: c/ H3 p4 n& E, W
© 2007 Sage Publications# n: Q5 }, W$ z) n+ t
10.1177/00099228062966518 s; E: G/ {7 a
http://clp.sagepub.com
( D) H9 Z j0 V3 ^8 ihosted at
) t# z" _ y. ^# z" J6 `/ }! {* R6 Fhttp://online.sagepub.com/ c2 Q7 m3 K3 R0 {$ C& R2 X
Precocious puberty in boys, central or peripheral,
9 h5 g) a$ H8 }9 L4 O6 nis a significant concern for physicians. Central
( U2 ^! l6 B$ t' P2 Nprecocious puberty (CPP), which is mediated
% {; ]+ A. X) U/ ~" hthrough the hypothalamic pituitary gonadal axis, has
) d5 O' Y( @. i7 H- r$ f Ga higher incidence of organic central nervous system
6 b* } ]9 _; T# n2 h# llesions in boys.1,2 Virilization in boys, as manifested
2 e% {: J- T4 n5 b1 @( Q+ ?3 hby enlargement of the penis, development of pubic
5 B! _/ H1 Y5 Ohair, and facial acne without enlargement of testi-
# o8 S/ k q. c7 Ycles, suggests peripheral or pseudopuberty.1-3 We% y3 l. g+ Q! W2 q
report a 16-month-old boy who presented with the
9 b7 R5 G- g/ o' N' D2 Zenlargement of the phallus and pubic hair develop-8 \1 Q" L y# M: L
ment without testicular enlargement, which was due
. N1 W% R, k) P, nto the unintentional exposure to androgen gel used by6 ?- ?8 t+ b5 {1 \7 C
the father. The family initially concealed this infor-
9 u) X0 A, ? e5 h" `0 ~5 G3 @mation, resulting in an extensive work-up for this, v/ c8 o; G8 a
child. Given the widespread and easy availability of4 D. T# W+ \& V3 X( b+ z, V1 j
testosterone gel and cream, we believe this is proba-; X' a1 M9 B4 E( y- E* z* C7 ]# T
bly more common than the rare case report in the
: @4 {. x2 K, B3 {( Hliterature.4
6 L3 b% d& H: ]/ Q( F8 hPatient Report; y3 {: t, ^# w6 F! i0 Z5 q
A 16-month-old white child was referred to the) x; E8 B' X: a
endocrine clinic by his pediatrician with the concern
5 _; d" D2 I5 Qof early sexual development. His mother noticed
. t# B2 `2 Z7 J' c) ?8 mlight colored pubic hair development when he was
4 |) B4 b. H$ ^) EFrom the 1Division of Pediatric Endocrinology, 2University of
- ~7 C z% ]( T' C" zSouth Alabama Medical Center, Mobile, Alabama.0 A1 B% Q; [2 k n
Address correspondence to: Samar K. Bhowmick, MD, FACE,. Y7 I Y% B; {6 \. h2 a
Professor of Pediatrics, University of South Alabama, College of, h9 h* F2 Q& @/ @, Q" U$ M$ f
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;0 n; k$ X$ ?% C; N! F* _! b
e-mail: [email protected].
4 U" l8 F/ B3 U0 u7 m: jabout 6 to 7 months old, which progressively became" g; X ?* o2 I$ `$ y( x: j$ ~
darker. She was also concerned about the enlarge-
3 ^3 Q8 e7 p0 c) d* Y3 }ment of his penis and frequent erections. The child
/ q) ?9 P5 o' S |( owas the product of a full-term normal delivery, with4 e% P9 q6 Q9 w
a birth weight of 7 lb 14 oz, and birth length of; \% n% ]! q/ K7 i5 a$ O) `
20 inches. He was breast-fed throughout the first year
" T9 f/ }$ T$ cof life and was still receiving breast milk along with3 ?4 v( O4 T8 V, I
solid food. He had no hospitalizations or surgery,
. ?7 G) k' h0 |3 `0 c% F; D) rand his psychosocial and psychomotor development6 K" u4 [2 x2 Z! t% T
was age appropriate.
2 X- ?, ?* ]7 \& G2 c: ^8 oThe family history was remarkable for the father,3 O0 G% F* }# E+ L) N4 K4 S/ L
who was diagnosed with hypothyroidism at age 16,& v3 [) Y4 H' D/ Y" @' _
which was treated with thyroxine. The father’s
+ z7 F3 [4 C# q& P. J' bheight was 6 feet, and he went through a somewhat
9 y! @0 H' P/ ?. R8 t8 R3 M: hearly puberty and had stopped growing by age 14.+ {) A9 t+ P# u2 Y# g9 X
The father denied taking any other medication. The
k* x1 ]9 L& h' p V! @child’s mother was in good health. Her menarche
7 n1 Y8 U) V# v( c( Bwas at 11 years of age, and her height was at 5 feet
I h; `# B$ i, o. C5 inches. There was no other family history of pre-2 k! v, i# F7 W, u, B# [
cocious sexual development in the first-degree rela-( u7 v7 H: W4 y( [% K* j
tives. There were no siblings.
- \$ I/ ^0 Z' H' D) {1 \Physical Examination' P+ G6 x! V' Y# |5 e
The physical examination revealed a very active,
7 Y0 W4 q7 p1 ~: tplayful, and healthy boy. The vital signs documented
0 b' F( s. ] Y! [- m& W0 U+ ra blood pressure of 85/50 mm Hg, his length was; T* S/ N$ r4 j6 J% B3 G
90 cm (>97th percentile), and his weight was 14.4 kg% ]# N n. B, x/ D
(also >97th percentile). The observed yearly growth
! b5 Q/ d, M3 A: f# D$ z+ q# zvelocity was 30 cm (12 inches). The examination of% C% g; W7 p& _
the neck revealed no thyroid enlargement.5 t: t* z3 S5 `1 d8 Z* o: `, o b6 u
The genitourinary examination was remarkable for* |* R* m4 q& a8 t7 I( ~
enlargement of the penis, with a stretched length of6 D( H; C" m4 {; Q( W& O. _# w6 P
8 cm and a width of 2 cm. The glans penis was very well; U- x% I. s" i7 C
developed. The pubic hair was Tanner II, mostly around# A& G7 H3 x+ v3 Y9 Z& ?4 l$ ]2 |
540
: L" B. g! D W, B) W, |at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from3 M, K0 w3 h! } d
the base of the phallus and was dark and curled. The
% M) H! w- O' {' etesticular volume was prepubertal at 2 mL each.2 S9 V% V' l+ g% g; j: z
The skin was moist and smooth and somewhat- A+ j y4 q# W' s& Q3 z* b
oily. No axillary hair was noted. There were no
, o1 d3 {+ r8 Uabnormal skin pigmentations or café-au-lait spots.
2 M- J) c& X# o, FNeurologic evaluation showed deep tendon reflex 2+
0 X0 y& B: h0 F1 ^bilateral and symmetrical. There was no suggestion
. D: z2 I" ^$ B3 O0 n0 Cof papilledema.
( w/ t- K# E' y6 g2 m: k+ k( ^* JLaboratory Evaluation# E2 V/ x9 i2 q" s+ p) G
The bone age was consistent with 28 months by
! h2 Z! D# [! e {2 f% iusing the standard of Greulich and Pyle at a chrono-
$ g; i0 s# h% R6 W3 i; Qlogic age of 16 months (advanced).5 Chromosomal8 U" N9 ]% e: j; x# h
karyotype was 46XY. The thyroid function test
! r; b5 y: W2 b2 l: w9 u3 }showed a free T4 of 1.69 ng/dL, and thyroid stimu-5 c; U2 C9 u; O
lating hormone level was 1.3 µIU/mL (both normal).
6 {& ^7 l) D, n. N+ D0 |The concentrations of serum electrolytes, blood% ]# b, d( V+ y3 \& H
urea nitrogen, creatinine, and calcium all were8 z1 O" a2 s9 A* I0 H9 r6 a. y
within normal range for his age. The concentration7 j0 M1 S- F3 U$ Y# t2 B/ ?5 ?% e$ ?5 @
of serum 17-hydroxyprogesterone was 16 ng/dL
, u/ D* _9 R* S3 P5 p* J* n4 Y( P6 @(normal, 3 to 90 ng/dL), androstenedione was 20
; m$ u! _3 k2 D7 \8 @ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-- F* {3 f8 ]7 `/ J" [, n
terone was 38 ng/dL (normal, 50 to 760 ng/dL),/ z- H& t- q5 ~$ S3 F
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
N" Q; `2 Z' X: i2 B9 }# ^# C49ng/dL), 11-desoxycortisol (specific compound S)
3 W! ~5 V7 j$ b! Rwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-$ q1 r) \. e% t. Q* Y& [
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total0 V2 [$ T3 `4 v) O9 |2 U. }% }
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
1 w% z9 @5 Q7 mand β-human chorionic gonadotropin was less than& a7 ?" b( i: a
5 mIU/mL (normal <5 mIU/mL). Serum follicular- Y$ z% K0 P. Y0 X, k' u/ R
stimulating hormone and leuteinizing hormone+ g/ f$ U5 m, [) Y) ^ e# t/ {
concentrations were less than 0.05 mIU/mL
6 k* ^, `$ I# L. e(prepubertal).6 R4 o. K) b5 O2 f8 ~8 O& n
The parents were notified about the laboratory
# P7 {, y" [# {. _6 H' D! h9 cresults and were informed that all of the tests were* p3 K0 W8 ?, H% t9 e
normal except the testosterone level was high. The$ P5 k; A2 p9 l* ^) S
follow-up visit was arranged within a few weeks to
0 g; Q; e, O8 {obtain testicular and abdominal sonograms; how-8 N6 C* Y6 R# w0 [; Q5 C( c i; B' Q$ c
ever, the family did not return for 4 months.9 v* q O6 d1 q
Physical examination at this time revealed that the6 v! i" O3 y" G! M4 H- E4 e% n
child had grown 2.5 cm in 4 months and had gained ^9 f$ {/ g/ m2 s. o" i
2 kg of weight. Physical examination remained. I+ t- s) |8 x8 o5 I9 t$ w. h
unchanged. Surprisingly, the pubic hair almost com-
9 K+ D) C" w+ e6 E- R- n7 ^pletely disappeared except for a few vellous hairs at
9 k6 T A( F* i0 Ythe base of the phallus. Testicular volume was still 29 X1 l. r+ q% k4 N% b
mL, and the size of the penis remained unchanged.- r+ Z+ _3 Y9 \5 [ A( d6 f$ e3 R, x
The mother also said that the boy was no longer hav-
& m8 A/ Y; k, s/ K ging frequent erections.
( T$ k! z* ^/ S/ L- b* o: f, s0 P! hBoth parents were again questioned about use of, M, P; }. g7 W: P: ~- _8 N; o
any ointment/creams that they may have applied to- r7 G! q8 E5 q* M+ t
the child’s skin. This time the father admitted the$ E* I: S) }# r' q( i
Topical Testosterone Exposure / Bhowmick et al 541
' Y- D1 N$ q$ r( w" ~* [use of testosterone gel twice daily that he was apply-
' |& X: D+ m$ Z6 a, {ing over his own shoulders, chest, and back area for
' M" s" P: r, M+ R6 Z+ W- Sa year. The father also revealed he was embarrassed
}' L5 R0 l- \0 H3 v2 Oto disclose that he was using a testosterone gel pre-0 I. }* ]+ B/ B% B( r6 m. @) p
scribed by his family physician for decreased libido
r) q* S! t \& Y% s: nsecondary to depression.3 x V9 h; L2 a! G8 s: k5 q
The child slept in the same bed with parents.
, _; ]: g$ E4 }The father would hug the baby and hold him on his
( q. l& M. F6 ]8 qchest for a considerable period of time, causing sig-. }9 F# C0 u# k; z3 O" b
nificant bare skin contact between baby and father.1 h2 E! V! I2 ^/ s; Z
The father also admitted that after the phone call,
( R. l5 R- R8 }# Z) @6 _. Mwhen he learned the testosterone level in the baby( ~+ f. h7 r" p/ L' u- S) Y X
was high, he then read the product information9 ]5 s# ]1 N6 q6 i7 y
packet and concluded that it was most likely the rea-
, n* r4 C4 A( z0 Uson for the child’s virilization. At that time, they" ~4 x3 A5 G* t3 P
decided to put the baby in a separate bed, and the7 c+ C0 w+ r+ Z4 E5 b
father was not hugging him with bare skin and had' A& e( c2 G/ K6 M2 D5 U& _8 J p9 j
been using protective clothing. A repeat testosterone
" j' k, G( @) wtest was ordered, but the family did not go to the
: _1 g$ c1 d3 o3 Q* l. xlaboratory to obtain the test.
# G5 W% S( a7 ~! K# ^( a" b$ NDiscussion
! L8 s/ e2 a+ U$ RPrecocious puberty in boys is defined as secondary; i1 o/ `0 g$ Z; |7 n8 E* t9 D
sexual development before 9 years of age.1,4
" n9 i4 V# K7 z J& APrecocious puberty is termed as central (true) when$ F8 E- n# _) i: t
it is caused by the premature activation of hypo-
% o6 f9 f i J" cthalamic pituitary gonadal axis. CPP is more com-: X T1 q4 o, @# a0 y8 W
mon in girls than in boys.1,3 Most boys with CPP
( S9 y; t, F9 J t, hmay have a central nervous system lesion that is M+ D& n7 \3 |! T5 L
responsible for the early activation of the hypothal-
* {# k$ L6 Y3 z2 Y! _7 wamic pituitary gonadal axis.1-3 Thus, greater empha-
6 u! Z. S% k0 T1 t; _, H [sis has been given to neuroradiologic imaging in/ t" A9 S( T* A8 C
boys with precocious puberty. In addition to viril-
) E$ L5 z/ p& ]ization, the clinical hallmark of CPP is the symmet-, P8 l# w( j# W3 x. k8 L) C
rical testicular growth secondary to stimulation by9 i4 q6 q) L6 b+ ^- b+ G5 k
gonadotropins.1,3
; N: J L+ Y. l" l( _5 s2 B# rGonadotropin-independent peripheral preco-3 n% R8 ^ W' v% `! [/ ?: Z
cious puberty in boys also results from inappropriate" Q. A+ n9 e) ~$ `2 D2 {
androgenic stimulation from either endogenous or" H/ z5 L B- W
exogenous sources, nonpituitary gonadotropin stim-
3 f" i) A6 T& s T. m( d3 N+ o6 qulation, and rare activating mutations.3 Virilizing
) z; I4 M+ g/ L4 `4 `+ ]& ]( Scongenital adrenal hyperplasia producing excessive
4 g& q. V; y+ Q! C# [% w. ~) oadrenal androgens is a common cause of precocious, o7 |$ m: j5 S% E6 \9 f
puberty in boys.3,4
# W' O& \/ |5 h% w/ s8 _The most common form of congenital adrenal0 @ o7 J$ w0 g+ x$ T
hyperplasia is the 21-hydroxylase enzyme deficiency.
" m. y9 X# C. OThe 11-β hydroxylase deficiency may also result in, ?8 \+ O6 H' T' e3 [ w
excessive adrenal androgen production, and rarely,
, H! r. G' z- ]+ c4 j* K9 Van adrenal tumor may also cause adrenal androgen7 f0 ]: B0 J- [% n6 v) E
excess.1,39 h1 O" A/ e$ b3 x2 u% ?- r" U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
) [& ]1 j* l+ E7 Q# k/ Z542 Clinical Pediatrics / Vol. 46, No. 6, July 2007% {) u& n" P9 x) c
A unique entity of male-limited gonadotropin-$ C8 K* c/ N' p2 F- l; f
independent precocious puberty, which is also known4 ]" d3 `& f, F. K; ~& A5 f
as testotoxicosis, may cause precocious puberty at a
( G! U, R9 ?- F( M2 T' jvery young age. The physical findings in these boys
, y4 Q6 O2 M1 ?2 W- A1 e* Qwith this disorder are full pubertal development,
* H- J4 Y9 {: tincluding bilateral testicular growth, similar to boys
( i0 S7 M) G9 I X6 h5 \; @with CPP. The gonadotropin levels in this disorder4 C( l1 N$ _, l5 o" A/ @+ _
are suppressed to prepubertal levels and do not show
) K5 s* l6 R* D2 f. Y' epubertal response of gonadotropin after gonadotropin-
% q# z* {& B, b+ |7 Treleasing hormone stimulation. This is a sex-linked
- A/ I8 z; {0 b6 p; D. y% y% D+ vautosomal dominant disorder that affects only
( q J$ V6 `3 [" r$ ]/ ]9 Gmales; therefore, other male members of the family
5 V0 A. M. f% ?7 imay have similar precocious puberty.37 \1 m- I! S5 o8 V) R0 M: ?3 i
In our patient, physical examination was incon-
0 n& m2 C a% L Q# z" w4 Tsistent with true precocious puberty since his testi-) H( i. U# d, Q: W- l0 D/ ? Z
cles were prepubertal in size. However, testotoxicosis& Y2 k# l+ B) J% t+ P
was in the differential diagnosis because his father
+ u( {$ O4 c6 s2 p4 ], wstarted puberty somewhat early, and occasionally,
, L* @0 Y( e3 O% btesticular enlargement is not that evident in the. ]: K% g9 d5 b. t, N6 k
beginning of this process.1 In the absence of a neg-
1 B5 @6 Y `& Iative initial history of androgen exposure, our
+ j2 ~6 P/ Q6 @biggest concern was virilizing adrenal hyperplasia,3 l- d5 Z) |3 [
either 21-hydroxylase deficiency or 11-β hydroxylase! m$ b6 c" F- q% B' w# }) M' p
deficiency. Those diagnoses were excluded by find-
V- u7 G v- |3 Uing the normal level of adrenal steroids.
7 A& j( _) y$ n. Z! v3 YThe diagnosis of exogenous androgens was strongly
, P0 z, B7 m+ ]* k isuspected in a follow-up visit after 4 months because8 p; i6 R/ C( H& |) k
the physical examination revealed the complete disap-1 ?) M; Z* ?6 @( V
pearance of pubic hair, normal growth velocity, and0 ]' i4 w7 b% ]1 H
decreased erections. The father admitted using a testos-2 y& E. ?0 [' \/ o+ B
terone gel, which he concealed at first visit. He was
; |9 Q$ ^. B% Kusing it rather frequently, twice a day. The Physicians’
+ M3 z1 Y: A7 S3 ]Desk Reference, or package insert of this product, gel or
+ \: Y; C6 a2 m* wcream, cautions about dermal testosterone transfer to' W$ x6 g7 L" M% h" J
unprotected females through direct skin exposure.6 g9 K& G7 f/ S# V1 x: x/ W; c
Serum testosterone level was found to be 2 times the @0 s' ]% @8 ^
baseline value in those females who were exposed to3 u7 m; H, ]! L
even 15 minutes of direct skin contact with their male
+ C; n }& q! U6 zpartners.6 However, when a shirt covered the applica-" n! \" p' X, Q" Z6 h0 _+ u
tion site, this testosterone transfer was prevented.
! v8 N. `' W; sOur patient’s testosterone level was 60 ng/mL,! B8 w" o) E2 p
which was clearly high. Some studies suggest that
! l& ]# A' v L1 [% k3 \dermal conversion of testosterone to dihydrotestos-
$ [& i2 j* Q$ s; I$ W% d" iterone, which is a more potent metabolite, is more# Z% w) j# C9 V; e
active in young children exposed to testosterone+ q; ~* ?$ o" z7 d8 |/ e" o/ [2 a
exogenously7; however, we did not measure a dihy-
# S% h& D6 F% p8 n0 k5 b% i5 mdrotestosterone level in our patient. In addition to
7 K) ^. B7 {: l: v/ M, V- Uvirilization, exposure to exogenous testosterone in7 X& t, h3 ?' Z! L1 H7 K" X0 ~
children results in an increase in growth velocity and5 o: b: ^4 P6 e% ]) S) h: K
advanced bone age, as seen in our patient.
! p+ e, ?" ~7 O: U# m6 i3 q5 o, fThe long-term effect of androgen exposure during
9 [. T, X, B0 xearly childhood on pubertal development and final2 T% \$ n4 m& B
adult height are not fully known and always remain
# W: B; X9 S4 N( V0 _a concern. Children treated with short-term testos-
_+ F/ d2 A h0 d3 \terone injection or topical androgen may exhibit some
' \ ~ s! D! i" T! }acceleration of the skeletal maturation; however, after
) o* M& G' p1 W; e0 Kcessation of treatment, the rate of bone maturation6 `/ P9 \. R( X* M( p+ l" H6 p
decelerates and gradually returns to normal.8,9
8 ?. d# M( |3 [( Y2 D" rThere are conflicting reports and controversy
& X7 v8 Z. S# D. Aover the effect of early androgen exposure on adult3 t. T2 w# @* O' M
penile length.10,11 Some reports suggest subnormal6 M4 K$ G; }/ e" `+ k7 J8 F
adult penile length, apparently because of downreg-% I( q! M; { V8 u
ulation of androgen receptor number.10,12 However," V) W" w* q5 F
Sutherland et al13 did not find a correlation between8 ~' d" L& _5 z
childhood testosterone exposure and reduced adult
$ Q% R: i( T5 j y, l Lpenile length in clinical studies.! }3 c! o3 w {, Q7 n/ y
Nonetheless, we do not believe our patient is
) P7 h6 c' K' egoing to experience any of the untoward effects from
9 O& S1 W; j; f8 i! U% a( Ftestosterone exposure as mentioned earlier because* h, W1 m: R/ A2 K, ^. G1 i
the exposure was not for a prolonged period of time.
" q8 K. Y5 N5 p. J5 M" C0 Z2 lAlthough the bone age was advanced at the time of
4 G9 \/ P/ K& c4 ^* D5 g! pdiagnosis, the child had a normal growth velocity at- [2 q+ ]2 o0 A$ U- p
the follow-up visit. It is hoped that his final adult( y" H9 K# v& T: v/ {, K- ]
height will not be affected.
, F( u% J: A& {/ Y0 O& A4 Z: @Although rarely reported, the widespread avail-
2 @! S# m; P+ o7 tability of androgen products in our society may
0 c2 C8 _# A1 ?; L) Z9 }+ |7 Jindeed cause more virilization in male or female Z1 A: v6 j" c
children than one would realize. Exposure to andro- f0 U* G* q, `$ J1 M. U" v* ]
gen products must be considered and specific ques-. \ R/ J3 ]+ s) n& Y9 y
tioning about the use of a testosterone product or
4 f, Z$ D1 H/ M7 r$ V9 ]. R; `gel should be asked of the family members during
" @! q7 Q! a7 Q* s( }% L5 Vthe evaluation of any children who present with vir-
! N, h) f* h) d& I& Q$ W! oilization or peripheral precocious puberty. The diag-1 K+ }' y# }+ |, x) [7 O% j: j) C+ Y' g
nosis can be established by just a few tests and by
# J+ i4 Z$ @' B Q# }6 Jappropriate history. The inability to obtain such a9 X# j8 |4 ]# m8 c3 h9 p
history, or failure to ask the specific questions, may
) R# V4 |& q ~5 ~" b) Uresult in extensive, unnecessary, and expensive
8 z1 P- q2 q Z% J" Rinvestigation. The primary care physician should be
- @+ q. b7 M7 Maware of this fact, because most of these children
/ p" \2 s( f7 m! z6 Z% Y! Mmay initially present in their practice. The Physicians’
( r/ T6 o% }5 r5 B0 \Desk Reference and package insert should also put a8 {( P; I e" U; x7 C# s
warning about the virilizing effect on a male or
9 X% z4 c0 y7 B& i1 x! Wfemale child who might come in contact with some-
7 Z! \. J7 q! j; Oone using any of these products.: Z; `4 k) d2 a {+ A- |
References* p r0 @0 u* N" k* _; Z7 q
1. Styne DM. The testes: disorder of sexual differentiation, m) b2 }) Y' S- R* G+ Z
and puberty in the male. In: Sperling MA, ed. Pediatric$ W3 j2 ?% p; ~, _
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;+ j+ i: B+ v# b1 |. A6 o2 d
2002: 565-628." t! @+ r# T1 {6 g
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious* i2 n8 e ] p
puberty in children with tumours of the suprasellar pineal |
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