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Sexual Precocity in a 16-Month-Old
7 @7 V; Q1 d, m5 c( O. @, fBoy Induced by Indirect Topical. U: _& W+ ?5 v( O
Exposure to Testosterone3 C" ]0 R. ~& Y" M
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2: P- b7 m! w: K7 \
and Kenneth R. Rettig, MD1
+ p1 l0 b5 }( P/ GClinical Pediatrics
' y, l8 P5 i6 \4 Z) zVolume 46 Number 6& y! v) s3 e' O" ?2 G8 c( T
July 2007 540-543
. ?6 x$ l4 g5 ~; \+ Q© 2007 Sage Publications* H6 q# C7 M `$ I% b( v: z$ \1 R
10.1177/0009922806296651
4 N* k I5 k7 ]% {/ \http://clp.sagepub.com
& w! I) c! ?: Y$ w1 X1 chosted at9 x4 V( f7 O1 o
http://online.sagepub.com: K8 y; n3 p) A# D9 {8 m
Precocious puberty in boys, central or peripheral," I" E2 ?# b( o8 [$ O2 l
is a significant concern for physicians. Central! `) `5 Z! ]2 }+ ` v L
precocious puberty (CPP), which is mediated
$ s2 w; r4 D' K6 @9 i6 O/ J; qthrough the hypothalamic pituitary gonadal axis, has" ] ~2 I, l3 K- V' f
a higher incidence of organic central nervous system: C: V: R* ^$ @0 {8 ?) s
lesions in boys.1,2 Virilization in boys, as manifested
4 a- a! l% O( N2 O0 iby enlargement of the penis, development of pubic
) g0 o. L5 _5 \hair, and facial acne without enlargement of testi-
4 d/ x7 w! V$ N1 E/ Lcles, suggests peripheral or pseudopuberty.1-3 We. G' \$ z( P3 e! O1 W( @
report a 16-month-old boy who presented with the$ C0 d! w% {5 X( U7 v* ?4 r0 y
enlargement of the phallus and pubic hair develop-
' S8 F% M" r/ Tment without testicular enlargement, which was due2 l4 S! O) N( X( n/ p/ V
to the unintentional exposure to androgen gel used by2 H" P' `2 g ]7 n
the father. The family initially concealed this infor-
1 E: w6 k* k2 y! `mation, resulting in an extensive work-up for this x9 R- @1 Q; d
child. Given the widespread and easy availability of
0 C' i! z5 X: d otestosterone gel and cream, we believe this is proba-
9 k' N6 K' G6 o; @8 {7 J+ d5 ebly more common than the rare case report in the
+ ?& V& B, a3 j" D7 W, Y# dliterature.4
4 F0 S! V" W5 F# ?* b: IPatient Report. @4 [+ G- n, [, ?) i }
A 16-month-old white child was referred to the
- _ g( A' P+ b+ eendocrine clinic by his pediatrician with the concern
5 M, z5 Y. W Y5 l! t; Qof early sexual development. His mother noticed
( J$ T. J# M [5 C" alight colored pubic hair development when he was# K5 n7 N2 ?7 W( S
From the 1Division of Pediatric Endocrinology, 2University of6 d* h5 I: m: U+ O
South Alabama Medical Center, Mobile, Alabama.
8 N0 w [# \. {Address correspondence to: Samar K. Bhowmick, MD, FACE,% s' x! T- @8 G7 B* P9 e2 T) }0 ?
Professor of Pediatrics, University of South Alabama, College of3 K$ U' h7 X+ T+ R0 D- Y
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
: b% ~6 A: ^* le-mail: [email protected].
" L9 m4 M8 s2 q, q6 A! C, d5 e, s' xabout 6 to 7 months old, which progressively became9 H: S. L$ h. W' \% n$ \+ Q
darker. She was also concerned about the enlarge-
6 g/ m- v/ O9 R1 u% x# _5 iment of his penis and frequent erections. The child$ E- | o% d0 N& S8 d0 t
was the product of a full-term normal delivery, with6 v, {. {0 F# e" c7 X U
a birth weight of 7 lb 14 oz, and birth length of
/ G4 g. h8 \; \; g: |2 ?) v4 F20 inches. He was breast-fed throughout the first year% `( p. }% e5 y0 j" r+ u( x
of life and was still receiving breast milk along with( D- `6 [& K; c* ^' r
solid food. He had no hospitalizations or surgery," r8 T, x" [; x
and his psychosocial and psychomotor development
) E1 J Z" |! ~" Hwas age appropriate." G3 \- E& ]- A
The family history was remarkable for the father,
7 n' b! v# @) _# I! Y' g! c8 Uwho was diagnosed with hypothyroidism at age 16,% u9 U- Q |' b! l- Z. X
which was treated with thyroxine. The father’s
4 |9 M! O# b# l( a: Cheight was 6 feet, and he went through a somewhat
. J5 @# Z( G" W8 `0 gearly puberty and had stopped growing by age 14.( n% b; T; E8 s
The father denied taking any other medication. The* o* W( C1 O0 u* |
child’s mother was in good health. Her menarche7 z* ]" I, N3 s: m& s3 l
was at 11 years of age, and her height was at 5 feet# w% N% O& N5 m* P; D3 `
5 inches. There was no other family history of pre-2 Y3 p/ z1 A5 Q5 [: L6 ]6 A' u
cocious sexual development in the first-degree rela-( I( T. y/ V4 s( V( |' F
tives. There were no siblings.8 ]* t- F: W3 @) n8 k
Physical Examination) X: {& f9 J0 {
The physical examination revealed a very active, G/ r1 R) U! |! C. R9 d& r
playful, and healthy boy. The vital signs documented; Q6 {& E5 ~' R7 k
a blood pressure of 85/50 mm Hg, his length was9 L2 P: f. q1 p) ]+ Y
90 cm (>97th percentile), and his weight was 14.4 kg3 ?7 A( e) ?2 w V
(also >97th percentile). The observed yearly growth
% F9 \5 T8 J3 B9 n* G4 E. w6 Kvelocity was 30 cm (12 inches). The examination of' a$ E( i7 C% @1 Y5 l. X% R
the neck revealed no thyroid enlargement.8 s, s" ~. u) f. k6 V1 o
The genitourinary examination was remarkable for) X" z; g- B A, O' H% G
enlargement of the penis, with a stretched length of
( x( p1 _! H" M" `9 |( y2 Y3 H8 cm and a width of 2 cm. The glans penis was very well
% q' r/ l8 _. t, b" L# Zdeveloped. The pubic hair was Tanner II, mostly around% r6 h% O1 ^8 O2 P3 ?
540! r9 d* `' g( a/ E; S
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 w# q$ w$ g- o# t% @! ]/ [+ D- X6 x
the base of the phallus and was dark and curled. The
5 {3 V- R! f2 E1 Ltesticular volume was prepubertal at 2 mL each.
( Y1 ~$ I) M( y( nThe skin was moist and smooth and somewhat
e0 I$ Z8 ~: e0 G/ X! F( M$ noily. No axillary hair was noted. There were no: ?! Q7 N( V: K" m2 v
abnormal skin pigmentations or café-au-lait spots.6 O# x9 c8 H- v5 [) N6 o5 v- Q
Neurologic evaluation showed deep tendon reflex 2+
+ k( u1 z" X+ C5 C# L5 X8 Hbilateral and symmetrical. There was no suggestion
) o3 k1 ]1 c# c- w7 iof papilledema." ]7 \7 D9 @3 X
Laboratory Evaluation
/ _; Y: p9 t' P- IThe bone age was consistent with 28 months by5 W0 b- Z# k# p6 H2 l, K+ N; j
using the standard of Greulich and Pyle at a chrono-
9 \" y# q* m) f" b3 m1 B- m+ Llogic age of 16 months (advanced).5 Chromosomal
# D$ u& D; i) d# C4 I) hkaryotype was 46XY. The thyroid function test
5 p* k- q* F& [: v9 vshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
1 m3 [- c B5 \* Alating hormone level was 1.3 µIU/mL (both normal).3 @, _2 v( o2 x- l) j8 o& T+ H, c
The concentrations of serum electrolytes, blood) }0 V7 x) \- O6 w0 R) x$ p
urea nitrogen, creatinine, and calcium all were
+ m T Z7 e' ^within normal range for his age. The concentration% H2 h, @% q( V- F
of serum 17-hydroxyprogesterone was 16 ng/dL
) m# W4 t v- ](normal, 3 to 90 ng/dL), androstenedione was 20
. U# \9 @7 v; Jng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
9 x5 Q5 R" O2 aterone was 38 ng/dL (normal, 50 to 760 ng/dL),/ w5 T! N1 |! S( m
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
- E' F* N Q0 w( U% K6 g+ O49ng/dL), 11-desoxycortisol (specific compound S)
0 Y3 ~3 Z; ?( m( D) B! R" {# hwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-! v) t# y/ W5 X+ @9 }7 q& m
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total: B( f# U+ L. A ?, y/ E
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),' @4 i; v* `7 G; T+ _' c B
and β-human chorionic gonadotropin was less than7 t( M i5 [8 a. [/ R
5 mIU/mL (normal <5 mIU/mL). Serum follicular; V3 _# N* k% V" }3 L
stimulating hormone and leuteinizing hormone) G7 F2 o( M" z% B
concentrations were less than 0.05 mIU/mL
6 C# P' R" z( u# M0 E z& X(prepubertal).
$ f B% Q4 F; R g! j1 hThe parents were notified about the laboratory- [# j0 g( U4 b; Z* T8 s2 ^( O
results and were informed that all of the tests were
, P8 y& A5 ` Q5 f5 D) pnormal except the testosterone level was high. The
( |, u- u5 s$ \& g) afollow-up visit was arranged within a few weeks to
9 e/ c! K+ o: W9 iobtain testicular and abdominal sonograms; how-: @2 p1 |& @) I' c. y
ever, the family did not return for 4 months.
$ g% [) Y% h- j$ O5 h$ fPhysical examination at this time revealed that the6 ~; B: g, u% t5 w4 Q4 B, ~
child had grown 2.5 cm in 4 months and had gained
3 e$ @# A' @- V% o3 Y3 `2 kg of weight. Physical examination remained" m* `3 b( i3 d; \& o
unchanged. Surprisingly, the pubic hair almost com-
* A! ~& f" }. |+ fpletely disappeared except for a few vellous hairs at4 r3 P2 T3 o5 U3 f6 \ _) x1 H
the base of the phallus. Testicular volume was still 2
* i, d! S: M! N: V+ s' H' vmL, and the size of the penis remained unchanged.( _1 O `& k+ L7 m F! c
The mother also said that the boy was no longer hav-& f0 W2 l+ R5 n0 f; V i: Y4 c
ing frequent erections.5 `$ a, N& l3 [/ h# Z; m; h
Both parents were again questioned about use of' H: o9 K# n; X8 x- ]0 e* [
any ointment/creams that they may have applied to1 \0 e q3 G& k6 Y' J; r G
the child’s skin. This time the father admitted the
; q; z2 T% A1 n; t/ r' yTopical Testosterone Exposure / Bhowmick et al 541
* s0 D- k# F k5 W, X: u |! _use of testosterone gel twice daily that he was apply-" f% U# [* z l+ j7 V/ w1 L- m/ L
ing over his own shoulders, chest, and back area for8 t+ D; ?, S; P$ @1 q2 z5 `. _9 k
a year. The father also revealed he was embarrassed/ ?. G' r7 T- U5 ^' E0 b( U
to disclose that he was using a testosterone gel pre-% g9 q7 ?3 C. R3 m2 g1 s: T: I# L
scribed by his family physician for decreased libido
9 y3 A1 s' ^ H3 ^2 q; \( Zsecondary to depression.
3 d: e/ T4 T; ?( R; }( q. ?The child slept in the same bed with parents.5 u( c, q7 `8 U$ y
The father would hug the baby and hold him on his+ U9 ~1 e' [7 R* h# M0 t6 y
chest for a considerable period of time, causing sig-+ H5 Z8 j" l/ s. f3 u/ I. f( [
nificant bare skin contact between baby and father.
' s' U9 H) j# V9 H3 m0 g+ O, cThe father also admitted that after the phone call,
7 d: Z* }& |; Owhen he learned the testosterone level in the baby
- H6 F! T- I+ @7 c" Q c7 Ewas high, he then read the product information4 a6 z8 w( D# m5 s: p+ o* _
packet and concluded that it was most likely the rea-, z, w" N2 T7 r. n& |7 Q
son for the child’s virilization. At that time, they2 |) m" `& E3 Z& R
decided to put the baby in a separate bed, and the
4 F2 M1 m8 `: cfather was not hugging him with bare skin and had
) x; X5 Y5 D% j& ~, l& Nbeen using protective clothing. A repeat testosterone
* z9 m i) x7 _test was ordered, but the family did not go to the
! M* e8 F/ c6 \0 Glaboratory to obtain the test.
7 c d& e7 U! _9 V7 x) oDiscussion
+ N/ R' R' a- X) ?; R) T7 X/ q: {Precocious puberty in boys is defined as secondary/ \; f5 [& B+ Z$ P1 ]2 A
sexual development before 9 years of age.1,40 g$ C8 {6 v' |* s) m( Q
Precocious puberty is termed as central (true) when6 H g4 ?2 y& A4 [9 g7 t( d
it is caused by the premature activation of hypo-
T# ^/ i5 ]& K9 O. |7 W( Tthalamic pituitary gonadal axis. CPP is more com-
. {0 V% z$ a, e9 F3 ~6 F# M+ ^! n! }mon in girls than in boys.1,3 Most boys with CPP5 n! W* Q0 l0 P! Y' j* E" @/ {' y& R
may have a central nervous system lesion that is5 `" ~0 y: ^( ^" W9 ~- L
responsible for the early activation of the hypothal-0 E/ }9 Z* U+ x( C
amic pituitary gonadal axis.1-3 Thus, greater empha-
( Q" E6 W Z% x4 {! N) z1 X8 H. ~sis has been given to neuroradiologic imaging in5 m; l+ D0 \- t2 o. H! q
boys with precocious puberty. In addition to viril-
3 Y' L7 {) [; g, eization, the clinical hallmark of CPP is the symmet-7 E/ `( b/ ^4 }$ J
rical testicular growth secondary to stimulation by$ U6 F9 h6 x* L: T
gonadotropins.1,3
- S: n/ ~' }# ~: KGonadotropin-independent peripheral preco-
7 j2 I0 ^% B& q# k% m2 C# u; Y" ucious puberty in boys also results from inappropriate0 n8 j5 o9 s: Q+ x/ H
androgenic stimulation from either endogenous or4 j! F7 e1 x* }9 Q M
exogenous sources, nonpituitary gonadotropin stim-" w; i( q) T! h" c% d+ c8 t
ulation, and rare activating mutations.3 Virilizing4 o9 A; B4 h2 B% C2 H
congenital adrenal hyperplasia producing excessive
( U# L9 [2 W! L) ^5 P y7 Tadrenal androgens is a common cause of precocious
# J) Y6 E# l- O* H3 Zpuberty in boys.3,4# l$ |4 U! d" k& X h% W7 A" g
The most common form of congenital adrenal
5 n7 J; j* {' U" ~% K. ?2 |+ Ohyperplasia is the 21-hydroxylase enzyme deficiency.
$ T i* I, ~& R& @' {6 c! aThe 11-β hydroxylase deficiency may also result in
3 z0 L4 c6 p# Y( H) g+ z4 Iexcessive adrenal androgen production, and rarely,% ?1 w& Z' W1 H, D
an adrenal tumor may also cause adrenal androgen
! {+ T1 j0 n" f9 A4 jexcess.1,31 v" I% z( y. Q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from0 S( f9 D2 l: \6 P; R3 P% W" Z
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
{$ s4 Y% [) L: u4 u5 I% ]. yA unique entity of male-limited gonadotropin-# Y& o1 L& V5 X# a" t: i
independent precocious puberty, which is also known
3 h, f2 ~- y \+ V( fas testotoxicosis, may cause precocious puberty at a
" i7 \2 c. W) b: every young age. The physical findings in these boys
! @9 W) o5 x( U$ zwith this disorder are full pubertal development,
3 v9 |/ r0 s; O. Qincluding bilateral testicular growth, similar to boys( k1 i7 ^) d" b/ b
with CPP. The gonadotropin levels in this disorder& U) F: Y f8 n5 { r
are suppressed to prepubertal levels and do not show
. ~+ j V- a$ w1 ]* X- {! qpubertal response of gonadotropin after gonadotropin-
* t7 F* v; g4 [+ M, Ereleasing hormone stimulation. This is a sex-linked* u, u. N, `1 o6 X: }0 C6 @( F
autosomal dominant disorder that affects only
: h2 Y! k9 [7 H: X4 o# j9 Wmales; therefore, other male members of the family
) t, c, L6 A+ g/ k$ L4 kmay have similar precocious puberty.3
" N8 K+ }" I1 T: _1 ]In our patient, physical examination was incon-5 }; x2 p* ~; G1 L m* p$ P
sistent with true precocious puberty since his testi-
9 x7 a( a$ a7 j( k% ^cles were prepubertal in size. However, testotoxicosis* K0 j) e9 w6 \( T$ m6 U
was in the differential diagnosis because his father. l. J5 R8 F( W. d8 s8 P( n+ {0 ]
started puberty somewhat early, and occasionally,, Y1 _0 ~2 {: |
testicular enlargement is not that evident in the
5 N, a# W. g8 i; I5 ubeginning of this process.1 In the absence of a neg-
% W/ K9 k1 W0 s% n `; Kative initial history of androgen exposure, our' l9 E) j& c0 g6 k
biggest concern was virilizing adrenal hyperplasia,
3 K3 @ U% X% j5 h, w; \- k2 w+ g: Ceither 21-hydroxylase deficiency or 11-β hydroxylase
% {0 b. b7 e* e2 j0 L' g+ e7 Ndeficiency. Those diagnoses were excluded by find-
8 y! Z, c; v Y8 R) s/ T; k' w4 cing the normal level of adrenal steroids.
' `2 e4 Q8 v6 F3 n: D6 z9 `The diagnosis of exogenous androgens was strongly
# e. K2 ?, T+ @: t* `; wsuspected in a follow-up visit after 4 months because
% e. `9 m B2 f& Y5 hthe physical examination revealed the complete disap-# a! G! t0 ?0 q2 l4 w+ \1 W5 I
pearance of pubic hair, normal growth velocity, and
0 ?* j ]/ u; x: G5 ~/ Ndecreased erections. The father admitted using a testos-6 v1 O6 _0 n$ u0 T! w
terone gel, which he concealed at first visit. He was: n( R+ l9 C" `4 p6 B
using it rather frequently, twice a day. The Physicians’& O6 T; i# Z2 m- |# B5 @
Desk Reference, or package insert of this product, gel or/ p- o' u( l0 ?/ `3 l3 Z
cream, cautions about dermal testosterone transfer to" ]$ S0 m4 J4 n. y; D2 g; S
unprotected females through direct skin exposure.
5 j& u# `9 J: z, U& n; HSerum testosterone level was found to be 2 times the
: h9 P; @8 C7 mbaseline value in those females who were exposed to
8 }0 o3 B5 Y" P* D z% S# Heven 15 minutes of direct skin contact with their male4 j; H1 ?# \& \8 y, m
partners.6 However, when a shirt covered the applica-$ p$ \! A( b, d+ J
tion site, this testosterone transfer was prevented.; @* j: e6 \& l, f
Our patient’s testosterone level was 60 ng/mL,
& v r! M1 \5 t0 Ewhich was clearly high. Some studies suggest that
t- ]/ T) j. m2 ~! g6 |9 e1 x7 k# Vdermal conversion of testosterone to dihydrotestos-
% J. b& W# Y3 X$ ]2 wterone, which is a more potent metabolite, is more
. o& N; r1 a% @! ^- @active in young children exposed to testosterone+ u4 J; \# N4 y) p, s
exogenously7; however, we did not measure a dihy-
. T" O, E* t( f$ v5 Tdrotestosterone level in our patient. In addition to
% s( _; k% ~1 ]+ I0 U% gvirilization, exposure to exogenous testosterone in! _9 ~4 C9 F* w3 p% Q+ H
children results in an increase in growth velocity and; q `3 d# m% L* J! G ^) B/ M, r
advanced bone age, as seen in our patient.1 K3 w% e5 }, I3 `& d- Y
The long-term effect of androgen exposure during
0 g o6 W7 h) t: `8 |: learly childhood on pubertal development and final
/ B/ I3 Y9 O4 z9 \ A; K) xadult height are not fully known and always remain
. p$ x2 Z5 ^9 x$ @- ja concern. Children treated with short-term testos-
# K" l9 q& }6 O1 Z h P" Zterone injection or topical androgen may exhibit some
7 I' D* [: a8 v3 @; q% Qacceleration of the skeletal maturation; however, after- l8 k& y) \- }" n" |0 ~
cessation of treatment, the rate of bone maturation
U( ?' M+ a$ J5 [3 Fdecelerates and gradually returns to normal.8,9
7 t6 ?: C$ h+ H- n7 |There are conflicting reports and controversy% g5 u$ S& @1 E: F u3 a1 E: z8 Y
over the effect of early androgen exposure on adult5 d+ M$ z/ y9 |2 n
penile length.10,11 Some reports suggest subnormal
8 K$ E2 w$ A }- w, x+ s! \4 Nadult penile length, apparently because of downreg-
/ G/ H; c) H( U C! U, T% a% n: Yulation of androgen receptor number.10,12 However,
' ?5 S& N4 q3 C& ISutherland et al13 did not find a correlation between' O8 r. ~1 N; y8 ` I
childhood testosterone exposure and reduced adult6 ~6 l3 d; F8 Y1 s
penile length in clinical studies.( V' b: O. t! O3 V7 [# F7 M% p
Nonetheless, we do not believe our patient is
/ i0 @6 l7 {, p$ v; ]going to experience any of the untoward effects from
& q$ P& W/ m! u3 S: Ttestosterone exposure as mentioned earlier because7 y L& b8 m7 M' R2 |
the exposure was not for a prolonged period of time.
+ p+ Z/ I( s5 g. j, uAlthough the bone age was advanced at the time of
$ ?7 H( m; E* c) I& Wdiagnosis, the child had a normal growth velocity at" O- a, y. k" h% y' r4 F
the follow-up visit. It is hoped that his final adult
5 R. r: l9 T; W+ f* Bheight will not be affected.% p: j! i: }: `1 K! h" h5 |3 y) i
Although rarely reported, the widespread avail-
- j6 u. E$ a1 b- H) x8 E4 Cability of androgen products in our society may( N, O2 H5 L5 l+ f) I
indeed cause more virilization in male or female- v, U$ t6 I; a) ~" K, U) S% m# V
children than one would realize. Exposure to andro-. J5 j$ d* o6 z4 P3 L5 U
gen products must be considered and specific ques-. I8 T" }& z, f
tioning about the use of a testosterone product or& I! S! |* ?1 }) F( i9 |! i
gel should be asked of the family members during
# r9 c2 r6 m: W- j9 xthe evaluation of any children who present with vir-
! P# q3 W& P/ p8 l- J/ @4 R1 qilization or peripheral precocious puberty. The diag-+ B' z+ }2 Y O% _6 ^/ f8 V% ?1 L
nosis can be established by just a few tests and by
/ m, D8 F" b& _% f9 x$ tappropriate history. The inability to obtain such a+ D, W4 k( t0 [/ ^) ^
history, or failure to ask the specific questions, may
4 p6 Y5 @# F" P# L9 R' p# Y5 Wresult in extensive, unnecessary, and expensive
; b6 r/ h% @8 z0 I' U7 sinvestigation. The primary care physician should be
& {6 F3 o/ G! L. ~aware of this fact, because most of these children
- G7 ^$ F, L ]6 Emay initially present in their practice. The Physicians’$ u+ d( M3 W8 t" A
Desk Reference and package insert should also put a( f6 x s- g2 u+ ]) e" T( M7 g
warning about the virilizing effect on a male or% ^- k$ {% h$ ?! R: I2 S
female child who might come in contact with some-
& m& |* M2 L3 Aone using any of these products.
3 A) r" q, U& v o+ c* G& ~, _& _References+ q% U. e" I* ^$ d
1. Styne DM. The testes: disorder of sexual differentiation
( y3 r- y5 E# ?# y& s4 f( Yand puberty in the male. In: Sperling MA, ed. Pediatric- R0 g1 v' z+ P* z. n3 y( h- _
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;, f3 {9 K' a& S3 z/ q9 R$ p& F8 Y
2002: 565-628.
6 M" T& I4 k) d: f5 U2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious2 D. B0 f4 x5 l* ^! E5 g: q
puberty in children with tumours of the suprasellar pineal |
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