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Sexual Precocity in a 16-Month-Old, L% _2 ^+ \7 J6 `1 U4 F% F
Boy Induced by Indirect Topical2 A% D' q6 b2 U! U( o* [5 d, x2 Q
Exposure to Testosterone3 t: O; w4 H+ H+ `6 ~" a
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
5 v2 A" f5 o6 k# S! Band Kenneth R. Rettig, MD1
8 [8 `3 n* v5 D6 u( x7 IClinical Pediatrics
3 d( i3 ~1 w0 F! d% S( g* |Volume 46 Number 6
8 \# m) t% O5 V% q) l; b4 W! \July 2007 540-543- n0 q. F" m6 f
© 2007 Sage Publications
% J. V/ a3 P5 p3 g/ J7 k$ D6 j10.1177/0009922806296651
. p9 ^: m4 m* M5 x6 m y& T2 qhttp://clp.sagepub.com
. g9 d! B& T2 y! h4 A" `- \hosted at
; ^8 _. l0 ~+ c6 @1 i5 z& Ihttp://online.sagepub.com
3 K/ e, ~0 a cPrecocious puberty in boys, central or peripheral,
+ |$ X) O- e( V3 fis a significant concern for physicians. Central) D8 ]* _" Y9 d4 c$ `
precocious puberty (CPP), which is mediated
$ e8 h8 K$ ~& A4 _7 M' mthrough the hypothalamic pituitary gonadal axis, has0 p% l$ L8 r$ l6 K1 `* E
a higher incidence of organic central nervous system
; e% x& L5 G0 F7 e) J; |, x' ^lesions in boys.1,2 Virilization in boys, as manifested
% n) W9 g8 j6 @" h/ S* a& G+ x6 qby enlargement of the penis, development of pubic: H4 J* p: R( ]3 e# h
hair, and facial acne without enlargement of testi- y2 E8 q, U% J/ H6 o% j
cles, suggests peripheral or pseudopuberty.1-3 We }; ?% N! T8 J" P% P: M7 M; i
report a 16-month-old boy who presented with the* q l( N$ H; z
enlargement of the phallus and pubic hair develop-
% Z. C: `+ i, \ment without testicular enlargement, which was due& R- U- q* {, Z) X& K
to the unintentional exposure to androgen gel used by
9 w: R3 i2 {: y' s8 i) S. Uthe father. The family initially concealed this infor-4 D# J: i: Y6 v0 H9 q
mation, resulting in an extensive work-up for this
; _) ^1 B2 ]% T; a& tchild. Given the widespread and easy availability of# ?5 \( M7 I- l' q
testosterone gel and cream, we believe this is proba-3 E2 @7 N! w( O8 ?0 N9 F
bly more common than the rare case report in the/ V% |% j( C! K5 x
literature.4
0 V, y' \+ A/ k# c' O7 N' oPatient Report9 b4 T" i1 M ?5 |$ G
A 16-month-old white child was referred to the8 V: t0 q4 ~& v
endocrine clinic by his pediatrician with the concern
$ \, P/ s9 C6 a k7 fof early sexual development. His mother noticed
9 ?- m3 a6 [& i/ Plight colored pubic hair development when he was8 w/ T' {5 q6 u" f7 S/ Z
From the 1Division of Pediatric Endocrinology, 2University of0 h7 g3 L/ m/ e5 ^4 r3 w
South Alabama Medical Center, Mobile, Alabama.0 Z. T8 d" K$ ^
Address correspondence to: Samar K. Bhowmick, MD, FACE,$ t) p1 B! `$ ~) t* p2 f( Y5 G
Professor of Pediatrics, University of South Alabama, College of
1 d$ o" P: I- `0 J2 n* PMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
- p" r* m6 o% @3 v2 m& P! q6 G- P' ]e-mail: [email protected].# `- I! W6 B! {: a0 p0 n1 o
about 6 to 7 months old, which progressively became
% |5 t" B5 q0 a7 h' H' j: Wdarker. She was also concerned about the enlarge-
& H* f3 E" z4 u8 p6 O- U; oment of his penis and frequent erections. The child& ^4 n7 K h% K1 F9 x1 J
was the product of a full-term normal delivery, with! Z( d8 c9 B2 V9 _& K n4 M
a birth weight of 7 lb 14 oz, and birth length of$ _2 Y3 a8 Q6 F1 F9 j
20 inches. He was breast-fed throughout the first year$ W, A0 n: ~: }9 X0 u8 \
of life and was still receiving breast milk along with% T" u, x5 \- d- A' @! W
solid food. He had no hospitalizations or surgery,$ ?& j. O7 d# m) r
and his psychosocial and psychomotor development
! D1 E$ S. _( `; m! G2 Q5 b Ywas age appropriate.- p& l" i8 r* q/ O5 i/ J/ G: N
The family history was remarkable for the father,
. i9 e* u; f( A W% i5 Iwho was diagnosed with hypothyroidism at age 16,
3 v( k8 p& W7 S2 u0 u1 b) Y# Bwhich was treated with thyroxine. The father’s
" d4 z: [* f+ ^" i) v$ e( f) k% eheight was 6 feet, and he went through a somewhat
+ d$ }9 b$ V" jearly puberty and had stopped growing by age 14.
/ P! k5 t9 g- \1 ~The father denied taking any other medication. The
# ^2 x- s/ S* C) s% @! j6 Achild’s mother was in good health. Her menarche% H9 ]4 ?! v K" y5 M' G
was at 11 years of age, and her height was at 5 feet: Q/ r# e/ L9 @. I
5 inches. There was no other family history of pre-
! M: q$ H' C! ~/ D4 z0 Z$ I. K" Wcocious sexual development in the first-degree rela-
2 U) f% v+ F a! Q/ P- G1 ntives. There were no siblings.# s j+ d2 Q; U/ k7 N: J! M
Physical Examination* y! b+ {: q; y2 G" Q9 [, F
The physical examination revealed a very active,
& j$ f8 ~, L1 S% Z( O/ f4 G) i0 {$ Nplayful, and healthy boy. The vital signs documented4 }+ N, s# g. X& s, _3 m( d
a blood pressure of 85/50 mm Hg, his length was' M, X% t1 c& V+ {6 l9 ~/ L1 ^' G
90 cm (>97th percentile), and his weight was 14.4 kg
5 T3 h+ k, @! g6 x(also >97th percentile). The observed yearly growth
+ b: g' N9 K1 ]$ Pvelocity was 30 cm (12 inches). The examination of& L* M8 ^" I5 B) o: D2 U1 U
the neck revealed no thyroid enlargement.
+ Z2 W% v5 }8 ]6 I' {The genitourinary examination was remarkable for: j! F5 f, E3 B0 y/ ^0 f0 N6 n( p
enlargement of the penis, with a stretched length of
! g x+ s* q$ k" P* Y- W8 cm and a width of 2 cm. The glans penis was very well% e F# x p6 c5 ~& E. W
developed. The pubic hair was Tanner II, mostly around
( U7 c+ M, x" e) f540
, F3 ]7 B0 G( P g* A+ u* g7 k3 J$ Iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# b+ Q( Y# D4 G" B& jthe base of the phallus and was dark and curled. The! b# Z& O! L n; y9 f
testicular volume was prepubertal at 2 mL each.
7 [4 V8 M9 n) O+ n/ L- HThe skin was moist and smooth and somewhat
# u' k( q! a4 s# e6 j+ F8 d# S9 M6 Zoily. No axillary hair was noted. There were no' t; N% U3 j6 E; R9 T0 w
abnormal skin pigmentations or café-au-lait spots.
: d* B6 l- p* FNeurologic evaluation showed deep tendon reflex 2+9 h- F& Q) G8 E
bilateral and symmetrical. There was no suggestion
+ ]) @# e% I4 vof papilledema.
: g0 X, a7 `: f5 v! a; I) PLaboratory Evaluation
! |6 X# k1 t& d( zThe bone age was consistent with 28 months by
0 M$ F" [7 `" z: m( ]# lusing the standard of Greulich and Pyle at a chrono-( X5 U( A2 Z2 Q: r h% o
logic age of 16 months (advanced).5 Chromosomal
) G4 H5 s" R) C. J6 V* `karyotype was 46XY. The thyroid function test
) k- D5 [: ~! ?' _9 g( G/ Oshowed a free T4 of 1.69 ng/dL, and thyroid stimu-& b( @+ ?; H4 p" {6 a) V
lating hormone level was 1.3 µIU/mL (both normal).
: W' p. H: h& R6 P1 FThe concentrations of serum electrolytes, blood" d+ e% D$ c) U7 S& P
urea nitrogen, creatinine, and calcium all were% ^: c8 _- Q) L% U- E) t0 O+ B% G+ [' d N
within normal range for his age. The concentration* G8 c# }8 p2 B5 q
of serum 17-hydroxyprogesterone was 16 ng/dL
V/ ?' C+ r/ {9 h: V r& ?7 l(normal, 3 to 90 ng/dL), androstenedione was 20, k1 P" ]3 e* z7 ]0 A9 G2 }
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-* ?. D. U- U( m* q; k2 g
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
8 n* u' r' F" b& Ddesoxycorticosterone was 4.3 ng/dL (normal, 7 to' O5 ~3 n# u8 a+ [
49ng/dL), 11-desoxycortisol (specific compound S)7 z* C+ G$ y! K0 l' |/ O
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-2 b: S% h: {* y2 e8 W7 V1 B
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
( e; c- x5 K3 f; w: l3 J. ^' q& qtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
- h0 U& A: l: A5 y3 Z3 N" ^! C1 {and β-human chorionic gonadotropin was less than2 H0 Z* o$ d3 d4 R1 r0 M l. I5 Q3 y
5 mIU/mL (normal <5 mIU/mL). Serum follicular
8 J* _* k, u/ }2 E6 ]stimulating hormone and leuteinizing hormone
, ?) N+ R/ n3 q1 _0 K$ ]0 Tconcentrations were less than 0.05 mIU/mL
2 R. D3 b8 ]0 Z, e) l5 z9 H# ?- B(prepubertal).
( s; P3 @9 Y3 V8 E! O( w& ZThe parents were notified about the laboratory
( S# y. k" z' o2 wresults and were informed that all of the tests were
- O! n. S! s) v, a' onormal except the testosterone level was high. The
4 k: O7 W$ ]5 P9 G5 Efollow-up visit was arranged within a few weeks to
1 N* D/ r s/ Fobtain testicular and abdominal sonograms; how-
& I# F: o! c7 F1 \+ X, @* Sever, the family did not return for 4 months.
# T7 y' U) @2 q9 p/ APhysical examination at this time revealed that the% u, E# p2 u0 y
child had grown 2.5 cm in 4 months and had gained
3 Z, G! [3 u! ~2 kg of weight. Physical examination remained
+ R h3 ~; ?% ~4 \unchanged. Surprisingly, the pubic hair almost com-
2 P+ |( y2 S5 s; R4 Wpletely disappeared except for a few vellous hairs at
; k3 q& [3 A# M8 X* h9 Wthe base of the phallus. Testicular volume was still 2
4 ], E8 B1 V9 h# z+ f5 I- t' }! Z! amL, and the size of the penis remained unchanged.
5 P1 k. @$ V1 T KThe mother also said that the boy was no longer hav-
! }! \2 j4 K Q }ing frequent erections.
6 s, q) G8 s( r x/ v8 I5 xBoth parents were again questioned about use of) I+ [& U# W2 M, \
any ointment/creams that they may have applied to' D! c% q5 F6 c
the child’s skin. This time the father admitted the
6 l5 \1 ]2 D- J. t$ vTopical Testosterone Exposure / Bhowmick et al 5412 V* B8 Q0 h1 j" n; ~! Q
use of testosterone gel twice daily that he was apply-& i/ M+ h6 t1 P* y3 n C |
ing over his own shoulders, chest, and back area for
$ E0 o. `, m/ ~4 xa year. The father also revealed he was embarrassed
3 t) L2 p& m# K! Q5 Eto disclose that he was using a testosterone gel pre-3 o5 ] K S1 y3 H' i- Y" c: S; E. o3 D
scribed by his family physician for decreased libido) A5 e6 M' T: Z$ c; @3 Z
secondary to depression.( a9 s: `" {+ [7 v& U2 ?- j
The child slept in the same bed with parents.+ }6 ?. J* v# H- H4 D5 w. M' n
The father would hug the baby and hold him on his
. ]; z3 J) k9 k; B nchest for a considerable period of time, causing sig- S& {! r# T! c( V( g, C# l+ _& \
nificant bare skin contact between baby and father.; L' L$ C U2 P; \
The father also admitted that after the phone call,
- M% }7 [" G) w |$ {9 lwhen he learned the testosterone level in the baby% ]: T" J: d/ z! X5 N& j
was high, he then read the product information6 R" U! r# V3 a& \, P A5 C
packet and concluded that it was most likely the rea-
9 k1 Z' E& g# u5 rson for the child’s virilization. At that time, they
* [# W7 O' O/ c6 [& T3 Zdecided to put the baby in a separate bed, and the0 l R0 ^. x; ?3 r
father was not hugging him with bare skin and had
1 M/ L7 x! R& ~) m2 H0 ^been using protective clothing. A repeat testosterone b" r2 s0 L% } Q( P2 I
test was ordered, but the family did not go to the
+ |1 M$ x- U4 }9 ~0 u) Hlaboratory to obtain the test.
, ~$ y& ^; F% |. GDiscussion
4 \$ C m' t0 m3 b, ePrecocious puberty in boys is defined as secondary
4 [/ a& P) U7 e0 ssexual development before 9 years of age.1,41 r+ w# s& Y: x6 k7 m5 \4 i1 O
Precocious puberty is termed as central (true) when
" r) `( Y- h. Z+ ]: H, ?it is caused by the premature activation of hypo-
$ g8 E$ V. \" Z* y2 }- w+ F0 ~# fthalamic pituitary gonadal axis. CPP is more com-
4 P/ |6 I0 z! J* omon in girls than in boys.1,3 Most boys with CPP
9 E3 s: w6 D) x+ g- Omay have a central nervous system lesion that is
. a. ^# K* d8 I, U. x+ \ i/ kresponsible for the early activation of the hypothal-
. R) Y, `+ R/ Famic pituitary gonadal axis.1-3 Thus, greater empha-3 m, N) B0 t! {: L0 o" U f
sis has been given to neuroradiologic imaging in
4 d* O- T0 a' wboys with precocious puberty. In addition to viril-. A- v" |4 t d/ k
ization, the clinical hallmark of CPP is the symmet-
; r( n- \1 {% i7 U1 p. f1 y) `rical testicular growth secondary to stimulation by3 Q8 [1 ^, B0 S# p
gonadotropins.1,3
; v! G. F. @5 O: U5 MGonadotropin-independent peripheral preco-
, ?! K- } H; xcious puberty in boys also results from inappropriate
. a# f* D7 S* P Jandrogenic stimulation from either endogenous or
. d' e2 m9 K# D. K& n" j( g' xexogenous sources, nonpituitary gonadotropin stim-# w3 \0 {% b3 K. z
ulation, and rare activating mutations.3 Virilizing2 R# \- _8 t4 t- ]; \3 J8 m
congenital adrenal hyperplasia producing excessive
. n4 s! m7 h8 C6 d, l F3 radrenal androgens is a common cause of precocious
# e% n( O% K" q! `puberty in boys.3,4
: K5 b; X( B, s8 SThe most common form of congenital adrenal' {0 K5 z9 c3 w& z Q& C
hyperplasia is the 21-hydroxylase enzyme deficiency.% u( b+ v8 Y* T$ M% @
The 11-β hydroxylase deficiency may also result in
- I6 ]# z+ [0 V0 G* k0 |' T" L9 Sexcessive adrenal androgen production, and rarely,
, d0 P0 ^3 d! _& o- u# qan adrenal tumor may also cause adrenal androgen
8 C+ g- Y, a, q* ? t1 R4 oexcess.1,3! J! _' o/ D. j! H* N
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 \& _6 c( |* i7 X
542 Clinical Pediatrics / Vol. 46, No. 6, July 20079 Z9 |9 e7 Y. Z! _* ?
A unique entity of male-limited gonadotropin-& J& {& t6 z ^
independent precocious puberty, which is also known
0 C" e* d% T" m& W; h; \) \as testotoxicosis, may cause precocious puberty at a
. M8 c) F3 T0 G, E& `' b( ]very young age. The physical findings in these boys& P1 ]0 l/ p) U1 n4 t
with this disorder are full pubertal development,+ Y0 o1 j$ h1 u
including bilateral testicular growth, similar to boys
1 \. N8 d: j4 }4 }with CPP. The gonadotropin levels in this disorder
9 Q% z2 A- f, T0 Q, D; X9 iare suppressed to prepubertal levels and do not show6 Z( d& M1 D Z& }, E! s3 |( e+ J
pubertal response of gonadotropin after gonadotropin-
+ p2 h! m$ I* u' m% Breleasing hormone stimulation. This is a sex-linked
$ S( d+ ^$ k; I+ u3 Bautosomal dominant disorder that affects only! x4 [& k c7 V8 t8 e& V- A
males; therefore, other male members of the family9 b6 G7 M! f6 k/ H7 E; J
may have similar precocious puberty.3
8 o2 g. f8 W4 b$ d, DIn our patient, physical examination was incon-
' r- ~- M! L5 V* L! [4 a- hsistent with true precocious puberty since his testi-
6 x* l7 Y) l* \: N& Ucles were prepubertal in size. However, testotoxicosis
3 `! G9 b- ? W6 W' d, L& J! Ewas in the differential diagnosis because his father
2 ^; m. |6 E6 d- `. x' t" \started puberty somewhat early, and occasionally,
8 M% T- j" ?1 X' ~5 G3 [testicular enlargement is not that evident in the% z3 l1 _9 B6 I* f0 ]
beginning of this process.1 In the absence of a neg-3 u) B* M6 y# b! o; [
ative initial history of androgen exposure, our* V, G$ W- M' o
biggest concern was virilizing adrenal hyperplasia,+ T$ j8 Z: o- t, ]/ a) R$ z
either 21-hydroxylase deficiency or 11-β hydroxylase E6 y: T4 c3 a2 z& h
deficiency. Those diagnoses were excluded by find-
. {% N* O( o0 m! w7 {6 Q# aing the normal level of adrenal steroids.& X/ y* |0 V' G# a
The diagnosis of exogenous androgens was strongly# b9 w: i: L' m4 T
suspected in a follow-up visit after 4 months because v- T! r6 g/ l, u9 K
the physical examination revealed the complete disap-
2 G) U6 I7 T; e9 A: X: ipearance of pubic hair, normal growth velocity, and
! q5 C& ~2 b% n1 O1 l L% y4 Kdecreased erections. The father admitted using a testos-0 F, \( i4 t, n; T5 e8 F7 |/ L
terone gel, which he concealed at first visit. He was" m3 r2 f* j# F8 i/ q3 V, Q
using it rather frequently, twice a day. The Physicians’: w! N& V" g4 _& a: H$ o: _0 a
Desk Reference, or package insert of this product, gel or
$ [. B, c1 l* J/ j0 R$ M0 @cream, cautions about dermal testosterone transfer to
/ I4 d) Q) a4 Vunprotected females through direct skin exposure.
. c r% S2 A: o* j- jSerum testosterone level was found to be 2 times the& \( p! ?. g- J8 m/ m: w
baseline value in those females who were exposed to
* d; t1 u: P/ seven 15 minutes of direct skin contact with their male
& |, @. t2 l2 q. z6 ?1 I( Npartners.6 However, when a shirt covered the applica-+ N, G ~: ?4 i
tion site, this testosterone transfer was prevented.
& ^4 `& e/ q$ \+ X" y$ ROur patient’s testosterone level was 60 ng/mL,
A q. }# |! m y. fwhich was clearly high. Some studies suggest that0 H( I6 e! [; x# V- |: j
dermal conversion of testosterone to dihydrotestos-& D ?7 Q2 `, F u' F+ u% g" Q
terone, which is a more potent metabolite, is more
3 q R/ S+ i% f$ Pactive in young children exposed to testosterone
. J, N; t; v( U! xexogenously7; however, we did not measure a dihy-
' i; a3 a, i- pdrotestosterone level in our patient. In addition to" C* Z% S0 h" @3 @
virilization, exposure to exogenous testosterone in6 L P" t. N8 O
children results in an increase in growth velocity and0 w+ @# P0 ~$ ^, v1 G! H, v
advanced bone age, as seen in our patient.
% e1 W4 X- p0 N, W0 A( c" }The long-term effect of androgen exposure during
( L2 s8 q: v! u; m7 G) T6 ?early childhood on pubertal development and final
, D/ l6 @ L! D! g1 H/ k% m- u$ Oadult height are not fully known and always remain( [- b, _7 s8 q
a concern. Children treated with short-term testos-
! Y: {* R1 L+ U6 G) Uterone injection or topical androgen may exhibit some/ B0 z9 Y9 V' k, i
acceleration of the skeletal maturation; however, after r! B8 D0 G# n1 }, ]1 f
cessation of treatment, the rate of bone maturation6 J7 b) q* V* r- ]9 j% h4 J
decelerates and gradually returns to normal.8,9" R1 G" o. M: B5 y3 `0 j4 m4 k$ M
There are conflicting reports and controversy
, X( c4 S" y/ t0 Iover the effect of early androgen exposure on adult6 h5 `, Q' M" ^% n1 d
penile length.10,11 Some reports suggest subnormal' |# o" x1 ?1 ~7 O' t
adult penile length, apparently because of downreg-
% v5 a7 \/ z! T6 F- Sulation of androgen receptor number.10,12 However,
$ W- [) ], \+ A* ~5 Q" VSutherland et al13 did not find a correlation between
% h3 H" r9 W2 _' g0 {childhood testosterone exposure and reduced adult& c9 f% X: ^1 `$ T; R4 k
penile length in clinical studies.9 I0 B/ s" j+ b2 M0 i6 b& m1 }
Nonetheless, we do not believe our patient is/ }3 r" v2 u, c! e$ o" L
going to experience any of the untoward effects from0 Y6 g2 U) F; K. L) S1 q3 u. ~
testosterone exposure as mentioned earlier because
- z" I7 _% q( B$ }# W6 uthe exposure was not for a prolonged period of time.
0 q, A" b$ }$ S& d$ B( R fAlthough the bone age was advanced at the time of
$ s, \' P' I: \+ t: Rdiagnosis, the child had a normal growth velocity at
3 x) P; \# h" z4 P' i! d8 j; C8 _0 g1 Jthe follow-up visit. It is hoped that his final adult
F) A2 j: d6 r+ _height will not be affected.! ~2 j5 h. h; G% c
Although rarely reported, the widespread avail-6 W! k( ~/ ~8 |0 U; X
ability of androgen products in our society may
7 t# Z) a* p* p" q/ ]- T! Hindeed cause more virilization in male or female o. v" r+ ?: l6 @
children than one would realize. Exposure to andro-
5 _5 ~# Q0 J( ngen products must be considered and specific ques-3 Q( Z4 _" s+ ]8 a8 ]+ F
tioning about the use of a testosterone product or
, s( G0 q( e! C0 ]% S, Mgel should be asked of the family members during/ y3 |9 I& \6 B5 U
the evaluation of any children who present with vir-
+ Z& t8 [, P# R+ E* H; |ilization or peripheral precocious puberty. The diag-9 }: m* M! D+ X# y* F
nosis can be established by just a few tests and by
7 I! X$ x: s( [+ `# Uappropriate history. The inability to obtain such a, X2 M3 E2 I7 A9 h1 y8 L) x- U
history, or failure to ask the specific questions, may
" Z4 `% S! k I( y- P! Z- \result in extensive, unnecessary, and expensive6 S* q0 u9 T7 \, n9 Y L
investigation. The primary care physician should be2 g9 U7 |0 t2 I& g2 C
aware of this fact, because most of these children
3 ]: K9 l' p. o$ J6 |may initially present in their practice. The Physicians’
% H4 p' z2 `& W4 f+ T2 x5 hDesk Reference and package insert should also put a
8 Z# |4 u4 \9 H' K& X& T- ~- }warning about the virilizing effect on a male or
# q, A$ v$ e) sfemale child who might come in contact with some-
0 w* {( r8 a' }; oone using any of these products.2 O p7 ?% K% z1 b
References1 G$ t8 G. J+ f; d6 `6 ?; ?" N, t
1. Styne DM. The testes: disorder of sexual differentiation$ I4 e. @% h% a* d% _6 q4 b! f K
and puberty in the male. In: Sperling MA, ed. Pediatric" s. J$ N e! k' m
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
1 }) B3 W$ ^$ W2 x2002: 565-628.2 V* a2 L3 E& I/ p9 [
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
0 |" N5 i8 Q& [6 ~2 jpuberty in children with tumours of the suprasellar pineal |
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