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Sexual Precocity in a 16-Month-Old; \6 N- P7 k+ T
Boy Induced by Indirect Topical
/ i" W' c. h6 K/ U6 @9 IExposure to Testosterone0 K3 l. ?+ V. e& l1 y% b
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2/ f& j" t: C' b& c. c
and Kenneth R. Rettig, MD1# E/ c7 `7 y- L. _9 k% b
Clinical Pediatrics6 H1 T, w7 H$ K0 A, [" A$ S- Q4 U3 ]
Volume 46 Number 62 ]& z) b) N" G8 y8 m: v! k" H! Z" f
July 2007 540-543; f0 `/ Q3 M; C. o( M& O$ K
© 2007 Sage Publications
5 K. F; ?0 A" p& f+ T10.1177/0009922806296651% R- M- g/ m+ [% h" ]" D
http://clp.sagepub.com2 b+ R$ j) c Z- V, B8 @( ^
hosted at5 Y' z3 I( }8 i6 u J8 o9 }: D
http://online.sagepub.com" v8 I6 a) m% q; G1 n
Precocious puberty in boys, central or peripheral,
/ B7 C) f* R+ ]- P4 @. |0 h$ Zis a significant concern for physicians. Central: \" k s5 y; K8 o1 v+ |# o( L
precocious puberty (CPP), which is mediated) T' V2 @1 ^, r3 [# i
through the hypothalamic pituitary gonadal axis, has) G: G, r1 E) i, w
a higher incidence of organic central nervous system
+ W, j0 _/ ^( Q# _; L, olesions in boys.1,2 Virilization in boys, as manifested
, a9 r% @! p; A* S4 n {; K |8 Sby enlargement of the penis, development of pubic
$ q: F3 @# y& Y# u" w* Whair, and facial acne without enlargement of testi-) u" g% S' k! r; U6 O' k6 \2 t; v x
cles, suggests peripheral or pseudopuberty.1-3 We
`0 w# P6 H. x! Jreport a 16-month-old boy who presented with the
3 B% Y# o8 {3 v5 |9 p! h- d( o; Uenlargement of the phallus and pubic hair develop-& e* m( y/ _! w3 ~0 o# S# Z# F
ment without testicular enlargement, which was due
; L, E/ m6 z8 J9 k% Lto the unintentional exposure to androgen gel used by$ I; k* S& x' J) y$ I, q# i: x% _
the father. The family initially concealed this infor-2 X7 D0 q! ~% c0 |# [6 E
mation, resulting in an extensive work-up for this% c7 x; \4 r+ v" O' @; t* U
child. Given the widespread and easy availability of. K. G( a9 I" H1 C% [
testosterone gel and cream, we believe this is proba-
8 W8 ^6 e' B! {4 L( w1 R# ibly more common than the rare case report in the
3 H! G7 T! l+ R/ }5 Kliterature.4
' }: T" C. o# ~% i) \Patient Report. V* ]6 w. S. m7 O* i% K
A 16-month-old white child was referred to the- z* m/ g+ X! Y
endocrine clinic by his pediatrician with the concern
6 L& G4 a. x) E& W1 s" rof early sexual development. His mother noticed
! s8 j. p2 k) h1 Y* \8 p2 S9 Wlight colored pubic hair development when he was# Z: Y+ l+ n5 R3 t
From the 1Division of Pediatric Endocrinology, 2University of
, m4 F1 R L' f6 \( W1 y* XSouth Alabama Medical Center, Mobile, Alabama.9 p) c( ]9 k( N2 H6 G, p9 L
Address correspondence to: Samar K. Bhowmick, MD, FACE,1 O* R8 J' }5 o! y5 _ J: _
Professor of Pediatrics, University of South Alabama, College of3 B0 y2 V0 {$ |0 N8 Y
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
$ U7 P# i* s" u# Y( |: F$ ~e-mail: [email protected].. s1 Q) x1 P; D7 s/ s" I+ d
about 6 to 7 months old, which progressively became8 v0 b2 Z7 n @6 y3 B
darker. She was also concerned about the enlarge-) W) t" z" S2 q# d0 @
ment of his penis and frequent erections. The child1 j! ~! d, x' a% S U
was the product of a full-term normal delivery, with
3 q! {& R0 V) ?0 K/ Z, S8 m2 Za birth weight of 7 lb 14 oz, and birth length of
9 y0 b- U% ~" e2 R0 ^ ?2 Y20 inches. He was breast-fed throughout the first year8 I! d0 ]. X/ O' _
of life and was still receiving breast milk along with
5 v& Y& E& e: T7 M5 N2 W: Isolid food. He had no hospitalizations or surgery,
7 m. L# y' F, C6 wand his psychosocial and psychomotor development
) E9 I2 C2 t* E1 |. E# Lwas age appropriate.8 h! q( V# ]) \6 r
The family history was remarkable for the father,, k; |9 a. s* c/ s
who was diagnosed with hypothyroidism at age 16,8 i) X. E4 C9 @' G+ [+ q
which was treated with thyroxine. The father’s
1 v+ h9 l+ ?" U* D& Zheight was 6 feet, and he went through a somewhat
% B' G, Z" X6 X H' _3 Jearly puberty and had stopped growing by age 14.: d4 [5 {$ n. n6 ?+ X, h5 X
The father denied taking any other medication. The" W( Q8 n, k+ D4 d
child’s mother was in good health. Her menarche, R( ?9 x) y4 D! k( |
was at 11 years of age, and her height was at 5 feet
0 x: }9 ?' }) {1 M, w, _- j5 inches. There was no other family history of pre-7 M6 Z- B& x! u) \# M4 \3 }
cocious sexual development in the first-degree rela-
- M: Y! Y3 w. etives. There were no siblings., u, `0 @9 t+ n; J) g7 R
Physical Examination* g/ h( v$ B# ^4 B: `
The physical examination revealed a very active,
0 ~1 W! l) G) ]0 l$ f0 ~, Dplayful, and healthy boy. The vital signs documented
1 i9 g3 T' K) {3 G' ^ ta blood pressure of 85/50 mm Hg, his length was
, U9 u# D+ U N* s- T. N90 cm (>97th percentile), and his weight was 14.4 kg' F; [$ Q! x6 l8 J6 Y$ d
(also >97th percentile). The observed yearly growth
, e/ w8 d, r, i8 `7 hvelocity was 30 cm (12 inches). The examination of% E" k' ~5 q$ s( d- }0 `6 K
the neck revealed no thyroid enlargement.
$ u7 F, S& f% y l- i; iThe genitourinary examination was remarkable for! O7 J; @' y) B. v! [8 [
enlargement of the penis, with a stretched length of
" p: H' a2 ~4 A: _8 [8 cm and a width of 2 cm. The glans penis was very well6 `' ?7 ~2 q+ _/ ?" K# p" _* s( C
developed. The pubic hair was Tanner II, mostly around
. w' G( G* c- y4 C, {' a/ @4 M9 [: a540
3 s! x) X5 v9 p" [- c0 Uat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
: q& S) F; c, c% v9 o# Athe base of the phallus and was dark and curled. The
' S3 B3 R& D, y/ w- h: \. |testicular volume was prepubertal at 2 mL each.' `4 j( K* F& ` H+ }7 ~
The skin was moist and smooth and somewhat( ^. b3 u/ _6 S) n, B1 s! i+ f
oily. No axillary hair was noted. There were no
& Q; k x" c$ ~2 S& e5 Dabnormal skin pigmentations or café-au-lait spots.$ D/ z, I7 X$ c6 ?
Neurologic evaluation showed deep tendon reflex 2+
+ z- k, c9 V5 N t' w" ebilateral and symmetrical. There was no suggestion
?* W* X: g: y- T, E% z0 oof papilledema.
9 v2 _8 s2 v9 K; ]- LLaboratory Evaluation: L F. ?% V2 \& i5 \
The bone age was consistent with 28 months by6 H, j$ }. _! W6 Z
using the standard of Greulich and Pyle at a chrono-( R& B0 v% n. ^- O7 e; I
logic age of 16 months (advanced).5 Chromosomal
( i1 q4 J+ s! ]+ vkaryotype was 46XY. The thyroid function test4 L# W, r$ h4 V/ S; k) O
showed a free T4 of 1.69 ng/dL, and thyroid stimu-: ?: z& `' e- ?! q
lating hormone level was 1.3 µIU/mL (both normal).
- C6 Q3 y; L$ ]8 x% A BThe concentrations of serum electrolytes, blood
9 r$ p# j# e& [urea nitrogen, creatinine, and calcium all were
- I& n/ G5 l# `" J6 q; rwithin normal range for his age. The concentration
7 s. D9 G8 u. lof serum 17-hydroxyprogesterone was 16 ng/dL
2 z3 i* b2 W: g2 [# ^" e(normal, 3 to 90 ng/dL), androstenedione was 20
. W; ^) l+ ^1 K1 e3 |4 e0 S$ I2 bng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
( i3 b0 S+ J/ G6 ]! Xterone was 38 ng/dL (normal, 50 to 760 ng/dL),
) D; ]0 i+ U( l8 D) Jdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
( D4 |. `, x$ I49ng/dL), 11-desoxycortisol (specific compound S)
7 i6 |; b5 ~" Y/ Pwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-' Z% D6 f% r$ C( e3 }8 j
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
+ p' h- g6 A: k' k2 ctestosterone was 60 ng/dL (normal <3 to 10 ng/dL),; X( _* W+ W: I. ]( B6 O1 r# l+ z
and β-human chorionic gonadotropin was less than* B4 m o R/ ~' F2 U! D I/ K
5 mIU/mL (normal <5 mIU/mL). Serum follicular: ^; Z5 f0 j8 M
stimulating hormone and leuteinizing hormone4 ? [& Q2 V* M& ?( N
concentrations were less than 0.05 mIU/mL8 `' L, C2 w' V! B$ B0 Z
(prepubertal).( P S( f( ` A. `0 M+ H
The parents were notified about the laboratory
X3 k3 |- X" _# K) zresults and were informed that all of the tests were6 R% Y$ m" P; m7 K8 \3 h" U4 \
normal except the testosterone level was high. The) P9 M3 V. G% ~ Q( v: z0 O% @
follow-up visit was arranged within a few weeks to. R- R' J% Q5 r* \% @& I7 ?, ~0 o
obtain testicular and abdominal sonograms; how-
) m6 ^1 v1 Y( H+ B# T, [ever, the family did not return for 4 months.
7 P" `. @7 b* Q/ J0 J% pPhysical examination at this time revealed that the1 E A" `7 C/ j# Z6 i5 h
child had grown 2.5 cm in 4 months and had gained
4 {) k) y+ F- x3 |- A- E2 kg of weight. Physical examination remained
7 Z) g$ P8 A" Q/ {& t8 v8 p, gunchanged. Surprisingly, the pubic hair almost com-' o5 v4 O7 A) I2 w. H& B! q" s
pletely disappeared except for a few vellous hairs at
, p5 h3 J# J8 X, @+ othe base of the phallus. Testicular volume was still 2
5 i$ Z$ u7 d2 d8 i1 k" ImL, and the size of the penis remained unchanged.2 ^6 g. ? c E4 `) o
The mother also said that the boy was no longer hav-6 \# t; T" X. n$ g
ing frequent erections.
% Y6 j+ n0 P& e! Y9 b0 pBoth parents were again questioned about use of
/ H$ {4 U2 `( F) C0 aany ointment/creams that they may have applied to
. Z* m/ m, U! V. tthe child’s skin. This time the father admitted the
; i9 X$ p k/ W, p8 ~Topical Testosterone Exposure / Bhowmick et al 541
# i* B1 q4 J" _; w& Nuse of testosterone gel twice daily that he was apply-
. P/ W" C- q9 q" ning over his own shoulders, chest, and back area for
) h" i5 K5 {! p7 \& la year. The father also revealed he was embarrassed3 L( P; o7 v6 I! z# b0 F
to disclose that he was using a testosterone gel pre-
7 z) F1 p5 `& `# `scribed by his family physician for decreased libido( R8 m; k' l/ z' C, n+ J- n$ C
secondary to depression.$ ?! @7 B/ l9 P! B/ s' e
The child slept in the same bed with parents.
" O! S1 |3 {- h, H: RThe father would hug the baby and hold him on his
u# d; s* g g& X) |7 [chest for a considerable period of time, causing sig-
( g2 h1 { T1 ?0 m+ j# C. Lnificant bare skin contact between baby and father.- \- N; C% M' Y* {. `7 K: Z5 R
The father also admitted that after the phone call,* N, i6 m6 ]" e& q* t$ }% B3 t0 m
when he learned the testosterone level in the baby
* [- s9 H% c0 L6 ewas high, he then read the product information: @/ Q. p- h( q2 C# U
packet and concluded that it was most likely the rea-# {4 M/ n3 a, I- V
son for the child’s virilization. At that time, they
; m7 F; `/ E6 n V' r# a6 _; zdecided to put the baby in a separate bed, and the
: j! P/ l5 V: o- G5 ^5 S/ D% ~: _father was not hugging him with bare skin and had; |3 R5 f- Z+ J. f$ d5 L
been using protective clothing. A repeat testosterone
+ A" |- R" \' ?% F8 `( w2 ltest was ordered, but the family did not go to the
+ V5 x! x ?/ H1 ~& m1 ?laboratory to obtain the test.
2 V, u! f) H8 m- R. D" k3 A6 LDiscussion, g: k0 X; U% J$ u
Precocious puberty in boys is defined as secondary
3 i& Q5 @- k6 Usexual development before 9 years of age.1,4% ?8 M) M! b' ~% @! p" `) ] b9 J
Precocious puberty is termed as central (true) when
$ `& O: U$ x' |it is caused by the premature activation of hypo-
) } M" g5 Z3 J; p0 dthalamic pituitary gonadal axis. CPP is more com-
0 V7 G( |7 u" Z9 Bmon in girls than in boys.1,3 Most boys with CPP5 |( E7 S& B# b, |
may have a central nervous system lesion that is
4 ^( \2 O: c T1 vresponsible for the early activation of the hypothal-1 N; }/ J; q$ h B
amic pituitary gonadal axis.1-3 Thus, greater empha-7 e) }1 c2 E" U, l ~5 K" u: |' J
sis has been given to neuroradiologic imaging in
, ]2 Y: X O ?+ ]$ X. J( I) ^& w& Hboys with precocious puberty. In addition to viril-$ s9 `! B) R( I3 K% k4 V6 Q0 `' ^$ b
ization, the clinical hallmark of CPP is the symmet-
* H p" V* R# S4 Z- g3 ?% _, g brical testicular growth secondary to stimulation by v" f d8 [ c% L* u) G
gonadotropins.1,3
- ~0 w# ~0 ~) S: Q' }Gonadotropin-independent peripheral preco-
; m9 Y4 l( x5 _cious puberty in boys also results from inappropriate+ J7 R9 E9 ^8 \& P5 i* V
androgenic stimulation from either endogenous or
$ p* J$ k) Z! V+ C1 D9 ]; Lexogenous sources, nonpituitary gonadotropin stim-+ H; N" }: W* ^
ulation, and rare activating mutations.3 Virilizing. ?" s( U; o3 @( ], ^' c8 ]7 j
congenital adrenal hyperplasia producing excessive- S" X% M# e& |. c0 A
adrenal androgens is a common cause of precocious/ p3 r) Z( d0 t% f' G+ s2 k
puberty in boys.3,4' I- ]3 t8 F, X# r& c) G
The most common form of congenital adrenal8 Q# o% {3 n/ H+ z( i, ?
hyperplasia is the 21-hydroxylase enzyme deficiency.
; X7 [5 c7 l5 }The 11-β hydroxylase deficiency may also result in4 O+ V% [ B: s* V' Q2 p- q( [
excessive adrenal androgen production, and rarely,
8 [9 i+ M7 V5 [an adrenal tumor may also cause adrenal androgen
, X. H: f0 S5 X: T7 B6 Dexcess.1,3% z+ M) x9 r- z1 L5 ?1 ~& N8 `' Z
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 v w9 R4 A }1 y) h5 E
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
/ h9 g2 Z; Y- ]8 `( Y- o( kA unique entity of male-limited gonadotropin-& O& C" A9 N0 t
independent precocious puberty, which is also known+ }% c; d5 G7 r- {
as testotoxicosis, may cause precocious puberty at a7 P# `$ @& |. A0 H- ]8 z* d
very young age. The physical findings in these boys7 i* c. z6 |, t* u% r7 _
with this disorder are full pubertal development,: t8 Q2 e" |. F: b
including bilateral testicular growth, similar to boys6 T9 \) x* g* O8 r6 O: C$ t
with CPP. The gonadotropin levels in this disorder
% x; m) J( L( A' x6 q2 Fare suppressed to prepubertal levels and do not show2 P/ D. n2 ~3 O! r+ R1 n% V P
pubertal response of gonadotropin after gonadotropin-/ }) y8 s9 N/ x7 P
releasing hormone stimulation. This is a sex-linked" ^8 N. n- |+ n! V
autosomal dominant disorder that affects only3 c; h! s& ?; Q
males; therefore, other male members of the family
2 _7 u% Y9 h: D& C0 wmay have similar precocious puberty.37 G$ r1 w, j, ]9 {, o3 G
In our patient, physical examination was incon-
; E# U) q( {9 K5 `, m' U, ]% zsistent with true precocious puberty since his testi-/ @4 t" L- j" S9 A1 r
cles were prepubertal in size. However, testotoxicosis+ `/ I1 \# h$ J! x
was in the differential diagnosis because his father, G" _! a G' a; H
started puberty somewhat early, and occasionally,
) Y: n0 m. n8 g$ H( [$ d9 ctesticular enlargement is not that evident in the
. t3 l! I* v4 zbeginning of this process.1 In the absence of a neg-
& d; X8 e( P- fative initial history of androgen exposure, our
h( W0 e5 @7 m3 d1 ]" W, |biggest concern was virilizing adrenal hyperplasia,6 _* S+ A( t' W( P" e) w; z. X
either 21-hydroxylase deficiency or 11-β hydroxylase' O0 e& D1 Z: Y: s. I) \( r
deficiency. Those diagnoses were excluded by find-
9 ^$ O A( L* Uing the normal level of adrenal steroids.
! a: W! _4 X" X% U9 A' h4 F2 HThe diagnosis of exogenous androgens was strongly
! z5 R$ P* r4 B6 L9 P! t, V6 psuspected in a follow-up visit after 4 months because
, m, m3 G, W$ o- I- ^" v5 K* w* |+ s4 Nthe physical examination revealed the complete disap-. u: p% {- o/ x. v( f
pearance of pubic hair, normal growth velocity, and
; W. ? N0 e. F2 n$ [! X5 ~decreased erections. The father admitted using a testos-
2 |. d! z/ o4 xterone gel, which he concealed at first visit. He was+ d8 k1 m: ], U+ P
using it rather frequently, twice a day. The Physicians’) v& T2 _+ @7 A: L6 s1 K
Desk Reference, or package insert of this product, gel or
5 j1 r2 _9 d6 m* W' }+ r2 [cream, cautions about dermal testosterone transfer to
) L6 w4 c- ?$ T8 _4 N# V& Kunprotected females through direct skin exposure.
% i' f* L6 D0 D6 g4 SSerum testosterone level was found to be 2 times the1 a G. A+ r( {
baseline value in those females who were exposed to
* [3 {. B8 Z" c: leven 15 minutes of direct skin contact with their male2 l" F! L5 F0 c! S, s; ~
partners.6 However, when a shirt covered the applica-5 n2 {; W. t ~& M' B
tion site, this testosterone transfer was prevented.; H/ P A) V9 G5 S3 p
Our patient’s testosterone level was 60 ng/mL,8 N: H& i8 [$ k. k8 Q. w
which was clearly high. Some studies suggest that
2 c+ O& k n7 |* {8 @- l0 ]dermal conversion of testosterone to dihydrotestos-
7 @( {2 L' q/ k- C1 Xterone, which is a more potent metabolite, is more
& L: ~( w) G Mactive in young children exposed to testosterone0 N5 y) m% S2 ?) W! W# p! I
exogenously7; however, we did not measure a dihy-& _# }) R' M- k/ f7 t4 y. L* m
drotestosterone level in our patient. In addition to+ g) E4 b% F% o+ o4 E0 K1 B
virilization, exposure to exogenous testosterone in/ j: N9 L6 C2 m) g& R: w7 E/ H
children results in an increase in growth velocity and
* `' d1 k# W6 g# T. }$ O/ ?advanced bone age, as seen in our patient.
* {, Q( }1 _2 u8 h" j. O" @The long-term effect of androgen exposure during- T% t3 H' |+ T9 n' f2 u" X) `
early childhood on pubertal development and final
1 M1 e" U6 E9 x9 G+ Madult height are not fully known and always remain
! v4 U [. {- [1 } Ha concern. Children treated with short-term testos-9 k+ x, G; @. O( Y9 H
terone injection or topical androgen may exhibit some
6 [9 e" q% t/ z0 \2 f* t5 ^/ ]* gacceleration of the skeletal maturation; however, after
" T7 ]- m. X( P, E# p# K6 Bcessation of treatment, the rate of bone maturation# V3 d. o* F+ `0 [" i. I
decelerates and gradually returns to normal.8,9
& ?( Z5 M, L E5 kThere are conflicting reports and controversy/ K" ]( c! K+ I6 `5 s& F
over the effect of early androgen exposure on adult
! U& Q% l7 I" |$ K$ w, cpenile length.10,11 Some reports suggest subnormal, t. {) m: C4 l; E1 ~& A4 O1 m6 b
adult penile length, apparently because of downreg-
9 r8 @4 C* U+ S3 uulation of androgen receptor number.10,12 However,
- R2 R! D% z2 p; @Sutherland et al13 did not find a correlation between: A; x5 F& d$ b* l0 s
childhood testosterone exposure and reduced adult
' h, v/ Q1 z m* ]. }. h" Epenile length in clinical studies.5 b; P1 T# d( G# s% g, T
Nonetheless, we do not believe our patient is" D0 \! E/ t; y) ^, i# A
going to experience any of the untoward effects from
, {) c" k' L3 K, u3 _ M. N& @testosterone exposure as mentioned earlier because6 b2 } ?, p5 j
the exposure was not for a prolonged period of time.
% N( ~5 t5 {3 k% Q$ u( GAlthough the bone age was advanced at the time of3 H; }6 a1 w6 j" y' J
diagnosis, the child had a normal growth velocity at
9 j* P/ T8 P9 a1 ~/ Athe follow-up visit. It is hoped that his final adult. v0 a; Q" \: J( a: }: V
height will not be affected.
+ q( c$ j% M/ L1 C0 L6 jAlthough rarely reported, the widespread avail-; Q3 Y+ C& [0 ?. G
ability of androgen products in our society may; c) S% C( ^( g6 F
indeed cause more virilization in male or female
7 W: @3 Z9 }' i6 |3 }1 R+ m- kchildren than one would realize. Exposure to andro-
( t; p- |' B6 @- h5 e' kgen products must be considered and specific ques-
: t1 ^) J. o* Y9 a. f! ntioning about the use of a testosterone product or: t% V5 T4 ?/ ^9 v9 b6 n0 t* W
gel should be asked of the family members during
7 i6 T# D' G$ g# `the evaluation of any children who present with vir-
) }( t0 O3 j( c" ]ilization or peripheral precocious puberty. The diag-
( ?& ?' p# u- W# nnosis can be established by just a few tests and by
( G: r* R2 P- H/ R, C& q4 P# p/ |5 Oappropriate history. The inability to obtain such a
8 x& q; _0 C* c1 H* Xhistory, or failure to ask the specific questions, may
1 m) `/ Q5 R! K, b. Uresult in extensive, unnecessary, and expensive
$ x: _, n6 _, }2 m$ M# m) Yinvestigation. The primary care physician should be
, ]/ ] d' G5 c. vaware of this fact, because most of these children
3 S4 g+ E6 ~' J* Smay initially present in their practice. The Physicians’
9 i( T, L9 Z; I& \% V' k# ZDesk Reference and package insert should also put a* p1 y) T4 @% Y, Y- e" R
warning about the virilizing effect on a male or3 `- f' T- f6 p. F7 E2 C ^: s
female child who might come in contact with some-
. F5 f8 I4 n6 g- `one using any of these products.
( R! v9 ]' k4 S. z# tReferences
8 ^: w+ g# O2 H! e* q6 u5 N, d: x3 s1. Styne DM. The testes: disorder of sexual differentiation
' n! e* X$ w. _9 @4 s0 M) K- Qand puberty in the male. In: Sperling MA, ed. Pediatric
% [3 L6 M3 b6 Q$ gEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;0 `* ~5 l4 h% L' i3 `
2002: 565-628.8 B8 F$ o! v7 S
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious$ I% z0 { j8 y) e6 T; M6 \9 w
puberty in children with tumours of the suprasellar pineal |
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