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Sexual Precocity in a 16-Month-Old- g/ }" W( L; u+ C% E
Boy Induced by Indirect Topical5 V7 A9 `' M' G* D: s! g- @. f3 O
Exposure to Testosterone4 u2 B( F6 x$ _* w! c
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
- T. D" J& ~, T6 [. H' vand Kenneth R. Rettig, MD1; @/ u2 @+ A/ ]
Clinical Pediatrics9 w* a. p( B$ G$ ~
Volume 46 Number 6
- a0 c5 k% `' N2 j3 d3 v: d4 t/ zJuly 2007 540-543 K( K4 D2 J, C) ^( `( T
© 2007 Sage Publications% |+ F% u# q7 H! A
10.1177/0009922806296651
: f5 D- K5 o6 v: W- e1 K& Mhttp://clp.sagepub.com
F0 E+ h/ W& g3 t3 ]' e, \hosted at) R4 x/ v5 B* h7 d# [: r% Z! y
http://online.sagepub.com: g7 }$ E d* p
Precocious puberty in boys, central or peripheral,
( g% ?1 ?: H" S0 J r, y' r3 lis a significant concern for physicians. Central# @* m+ H# B' a/ |8 g' H
precocious puberty (CPP), which is mediated
& E: y: m- q1 K" N9 S0 lthrough the hypothalamic pituitary gonadal axis, has
# x5 d# j4 b2 Y7 N/ Na higher incidence of organic central nervous system
E9 n2 ?; r; z" glesions in boys.1,2 Virilization in boys, as manifested6 D7 c, t+ Z8 `$ l' o& z
by enlargement of the penis, development of pubic; x8 z# s4 f9 C5 D, G, f5 t5 S: }$ v
hair, and facial acne without enlargement of testi-
0 @- s& i. c5 P u) m1 C1 A5 Ocles, suggests peripheral or pseudopuberty.1-3 We
1 f6 r: z2 ]- nreport a 16-month-old boy who presented with the: j6 z6 ?6 N, A2 O6 W& D( [
enlargement of the phallus and pubic hair develop-
) V: o" Y1 z8 q$ H5 E# u& Ament without testicular enlargement, which was due9 f: z" [' \: e4 L! g0 a" C! E
to the unintentional exposure to androgen gel used by
4 D E- D$ p8 Y8 i/ gthe father. The family initially concealed this infor-' Y0 t1 b% ]9 |$ E7 G# v2 L7 t
mation, resulting in an extensive work-up for this
A# B! A$ S& W2 o; h+ J! b* N7 C6 r& achild. Given the widespread and easy availability of
9 D U$ g ?3 J- k8 }testosterone gel and cream, we believe this is proba-
# q9 u. A. g4 B" [+ }bly more common than the rare case report in the8 o* p. N8 B0 Z- e5 O4 \% a
literature.4! ]# ? R% l* j @
Patient Report
+ K; P: q# L3 j4 h1 l. U5 |$ `A 16-month-old white child was referred to the! E. J0 G7 B7 J5 l/ l. T' I
endocrine clinic by his pediatrician with the concern- @5 T4 {. y- \9 F; G$ G
of early sexual development. His mother noticed
4 Z; T/ U7 N2 O9 g8 o8 |light colored pubic hair development when he was- i7 H5 s4 l5 v$ t" ]
From the 1Division of Pediatric Endocrinology, 2University of. h' j& a/ C3 K: G, ]
South Alabama Medical Center, Mobile, Alabama.* Y( m/ o3 k% ?: p) D7 n
Address correspondence to: Samar K. Bhowmick, MD, FACE,% D* M9 V! ?) k' f; L& [$ v
Professor of Pediatrics, University of South Alabama, College of9 p% M8 F2 U3 n4 F0 N6 P5 Y
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
# d* r, }2 C1 U# ]e-mail: [email protected].
' W& F$ ^# `- Dabout 6 to 7 months old, which progressively became; S6 F5 ~& q8 G( v* w
darker. She was also concerned about the enlarge-/ P' s5 R6 e" \8 m
ment of his penis and frequent erections. The child
1 }# ?1 }& N: Qwas the product of a full-term normal delivery, with
8 e0 i( t/ ]/ @a birth weight of 7 lb 14 oz, and birth length of
/ d9 L" m8 s& }20 inches. He was breast-fed throughout the first year- r2 g& `7 e O0 y3 r4 U
of life and was still receiving breast milk along with4 p) Y8 w$ a* T! \
solid food. He had no hospitalizations or surgery,5 Y; x: k( [6 S6 \! \$ r7 f
and his psychosocial and psychomotor development5 Q* p8 p* i: O4 E
was age appropriate., Y2 t- k. i) Z' w
The family history was remarkable for the father,7 t+ m' d _) h! O z
who was diagnosed with hypothyroidism at age 16,% y+ @- M3 m4 `+ y
which was treated with thyroxine. The father’s/ q* j& l6 c. s+ J4 |# y4 G
height was 6 feet, and he went through a somewhat8 X B6 X& C$ i2 m; U0 O
early puberty and had stopped growing by age 14.
* \) ~4 \% B# w; p$ ^: LThe father denied taking any other medication. The2 O) U& F1 X0 B8 o; e2 c8 J
child’s mother was in good health. Her menarche
\8 r- T" _4 g) J- [/ b, iwas at 11 years of age, and her height was at 5 feet! y: b$ e' q+ l+ J% U/ a5 T
5 inches. There was no other family history of pre-
! {% Y! o& ]- I# p, q! k" Ccocious sexual development in the first-degree rela-+ l8 Q, u5 M, S
tives. There were no siblings.
* T/ l8 d! `/ {Physical Examination
4 N* o+ ]6 k! O- I4 ? e! a, hThe physical examination revealed a very active,( R' u$ I- n4 [" Y$ z( o) Q
playful, and healthy boy. The vital signs documented
. b1 o, _6 w6 Ka blood pressure of 85/50 mm Hg, his length was4 x J$ l1 G; W4 d! U J9 E- Z
90 cm (>97th percentile), and his weight was 14.4 kg
. z# a8 Y' b! s% k! H(also >97th percentile). The observed yearly growth" x- s; {) F$ C1 {7 k; v: m3 I7 h
velocity was 30 cm (12 inches). The examination of
( }' S( M; h% `, Nthe neck revealed no thyroid enlargement.
- \' ^! v6 q" \6 z& D7 S7 G5 {The genitourinary examination was remarkable for3 X0 @# u! w4 u7 y( `1 ]& |, w
enlargement of the penis, with a stretched length of( ]. q3 F1 @0 u3 F- @
8 cm and a width of 2 cm. The glans penis was very well
3 A: _8 Y8 _# J) q) b: L: N3 x/ Kdeveloped. The pubic hair was Tanner II, mostly around, K# M$ d, q* O" t7 g: A& L
540
1 t# P6 _$ M O r; I- f" H, Nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from$ c J; E- O& Y
the base of the phallus and was dark and curled. The
+ K4 P5 J, h& d0 O. c4 a5 ~testicular volume was prepubertal at 2 mL each.7 l7 z/ D3 g7 M9 H$ k8 C/ @+ T3 V9 u' X
The skin was moist and smooth and somewhat
! G% g1 Q% e1 hoily. No axillary hair was noted. There were no/ K+ H6 P2 c8 |8 s3 Y: x1 Y$ W' Y( o
abnormal skin pigmentations or café-au-lait spots.3 S0 d! `( t! k! F
Neurologic evaluation showed deep tendon reflex 2+# k0 z2 j' K: h9 f0 K
bilateral and symmetrical. There was no suggestion5 a8 O- j+ c2 g
of papilledema.2 R2 T* @7 K+ k9 w" C5 h" [( J
Laboratory Evaluation [2 S I, U4 I1 E+ \
The bone age was consistent with 28 months by& e" J+ _: Z1 ^5 S1 I
using the standard of Greulich and Pyle at a chrono-6 |) r, }3 {, a0 H3 F6 N
logic age of 16 months (advanced).5 Chromosomal
: l* q1 r* X, O# L Ikaryotype was 46XY. The thyroid function test
- x$ R) X& D- x, C/ l3 \showed a free T4 of 1.69 ng/dL, and thyroid stimu-, W. S/ Y. @% v* V4 N
lating hormone level was 1.3 µIU/mL (both normal).: w4 c U1 f% {: X! F* r
The concentrations of serum electrolytes, blood2 g7 U( T# I/ P) H
urea nitrogen, creatinine, and calcium all were# D9 |& n5 I! h* z
within normal range for his age. The concentration
" {3 a6 U# S) J! dof serum 17-hydroxyprogesterone was 16 ng/dL
& g8 J- o; Q, h2 T* ]: A0 A(normal, 3 to 90 ng/dL), androstenedione was 20
8 I8 b/ T' N3 J7 L% @ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
8 N+ D, D D( t6 G7 t xterone was 38 ng/dL (normal, 50 to 760 ng/dL),; j6 L! B& o7 G# D0 j: N3 W
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
# F0 \8 M1 s: v49ng/dL), 11-desoxycortisol (specific compound S)
) q" e6 r; q( \- Twas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-0 R; }7 m; x( x: l S3 q
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
5 m+ k' z" c! htestosterone was 60 ng/dL (normal <3 to 10 ng/dL),* M2 T# P% d7 @# \9 R
and β-human chorionic gonadotropin was less than! T7 A& I& v: a3 O6 y
5 mIU/mL (normal <5 mIU/mL). Serum follicular X8 P! q! ^ x$ J0 o
stimulating hormone and leuteinizing hormone% X' F2 ?4 Q5 n/ d
concentrations were less than 0.05 mIU/mL5 p9 T: g r" W# I& n: B
(prepubertal).
& B5 c9 G" d+ M- yThe parents were notified about the laboratory
5 |) K; f5 m+ i9 xresults and were informed that all of the tests were9 L% r+ E# A, Z) i% Z
normal except the testosterone level was high. The
9 I5 Q( Q; O4 C$ R1 n( efollow-up visit was arranged within a few weeks to+ N7 k' `! W: R7 r: [
obtain testicular and abdominal sonograms; how-
; q: c: t; j6 r8 a$ A3 Zever, the family did not return for 4 months." Y, }5 W5 @3 F
Physical examination at this time revealed that the( n8 }6 Z- d; C* @9 l
child had grown 2.5 cm in 4 months and had gained& x) T' }( t9 }+ m4 V
2 kg of weight. Physical examination remained
6 U4 m. `* @* Vunchanged. Surprisingly, the pubic hair almost com-( [% h1 D9 r+ l: c( N3 }0 b
pletely disappeared except for a few vellous hairs at+ z, f7 x$ K$ {$ [# I# z
the base of the phallus. Testicular volume was still 2( U+ |0 H/ J+ |- h
mL, and the size of the penis remained unchanged.
, X- u8 w. X8 |1 w- l* p' m1 ]/ eThe mother also said that the boy was no longer hav-
2 u1 W9 e- f/ m1 s7 Xing frequent erections.
. {& L- v/ i e* c4 ~3 E$ X5 BBoth parents were again questioned about use of
- [! ?- ?5 p: v6 }* H& z; Iany ointment/creams that they may have applied to
4 p& i o6 i) R1 hthe child’s skin. This time the father admitted the
8 {( j- g, }. c% ]8 s8 u# nTopical Testosterone Exposure / Bhowmick et al 5414 K% d$ z7 y4 F8 I
use of testosterone gel twice daily that he was apply-
6 n3 ?+ O" I7 x% d4 f: {ing over his own shoulders, chest, and back area for( E- H4 {) H0 b; ^2 z
a year. The father also revealed he was embarrassed
$ {: f5 W( D" O. Cto disclose that he was using a testosterone gel pre-
' t0 }) l" R; n' }* Rscribed by his family physician for decreased libido- h% Z" x8 b5 v! C+ f
secondary to depression.9 c/ |$ ]; @8 [0 y+ j4 Y2 i6 ?4 c
The child slept in the same bed with parents.! b& e" {3 F/ G( |
The father would hug the baby and hold him on his
: S) { j2 n' k- A3 Z0 h0 achest for a considerable period of time, causing sig-
) U2 k3 c) y$ z6 I% Onificant bare skin contact between baby and father.
' m/ E7 @0 ]+ t, rThe father also admitted that after the phone call,
- }3 ~+ g5 \; j/ p3 E; `when he learned the testosterone level in the baby
* i- }2 c) t u8 c% F' m! p- _was high, he then read the product information
, h+ [5 b. c% h. x4 e1 g2 P, npacket and concluded that it was most likely the rea-
1 [* q% c; z4 u# |, Z0 Hson for the child’s virilization. At that time, they
& [; |3 S! ^( a6 y4 L( xdecided to put the baby in a separate bed, and the
9 U' h$ M# c6 q! X/ t. Cfather was not hugging him with bare skin and had
7 r: a& P3 m' Ebeen using protective clothing. A repeat testosterone: X, P' Y9 O7 ?# F+ }
test was ordered, but the family did not go to the
3 y% ?4 U+ j6 n9 rlaboratory to obtain the test.$ h, Y" T @/ x' X
Discussion
4 W& M1 U6 S( R4 U& B f, c9 aPrecocious puberty in boys is defined as secondary* O X' v$ X7 U+ b4 Y' H
sexual development before 9 years of age.1,43 \! r# j% J7 H0 j* ?! A. j
Precocious puberty is termed as central (true) when
2 ] @5 U6 a$ Z' v0 {- @it is caused by the premature activation of hypo-. P5 Q4 K$ W2 V) v A
thalamic pituitary gonadal axis. CPP is more com-
: Y& O/ k W# P, i$ k0 P8 {mon in girls than in boys.1,3 Most boys with CPP
K, @, a) q" Bmay have a central nervous system lesion that is
- L. E7 E/ h! Xresponsible for the early activation of the hypothal-
1 Y T2 o# T0 pamic pituitary gonadal axis.1-3 Thus, greater empha-
7 P" w, L& _0 J- d% e+ Q. usis has been given to neuroradiologic imaging in
6 s$ i0 A8 f1 l, x) Wboys with precocious puberty. In addition to viril-
# ?: G$ J: M$ N* ]3 g& sization, the clinical hallmark of CPP is the symmet-) j( `" Z5 Q# t: `) G
rical testicular growth secondary to stimulation by7 {8 Y3 t' b f! {6 U) @+ C6 O3 A+ S
gonadotropins.1,3
+ Q- E+ }7 E( [0 O& y {Gonadotropin-independent peripheral preco-* V& `+ N5 h/ z& N5 Y- `
cious puberty in boys also results from inappropriate
) W; Z5 H* j* |" b) k" randrogenic stimulation from either endogenous or9 k/ G1 q$ R1 u' I' W( z3 w
exogenous sources, nonpituitary gonadotropin stim-/ u0 B+ `+ B$ c6 F& R
ulation, and rare activating mutations.3 Virilizing5 \) n* s$ l& a7 {
congenital adrenal hyperplasia producing excessive
) y+ K% ?6 ?2 \" h7 @+ madrenal androgens is a common cause of precocious5 |) K( V; B: K Q9 o/ e: Z5 x
puberty in boys.3,4: x7 m& g% r& c n/ W g. w, l
The most common form of congenital adrenal
5 D, s7 Q; t; e8 _, ihyperplasia is the 21-hydroxylase enzyme deficiency.
' o) u' X' S/ eThe 11-β hydroxylase deficiency may also result in0 |! h' e. R, v5 I6 k
excessive adrenal androgen production, and rarely,1 H; E3 {) f/ O8 D" `9 E6 s
an adrenal tumor may also cause adrenal androgen+ j+ W* n8 M, u L, A9 J
excess.1,3* m9 m" P" n9 ]/ @+ a6 w
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; Y+ b$ F) ]& m$ f
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
) n }' r- @0 ]/ l/ g, oA unique entity of male-limited gonadotropin-1 `- T3 i# g1 d( v+ ~
independent precocious puberty, which is also known
) t' ]/ m- B7 A# U& J4 Gas testotoxicosis, may cause precocious puberty at a0 h; \9 ~. N# B, Q* ]. ]7 e. A
very young age. The physical findings in these boys8 y/ [1 [% c) {& m
with this disorder are full pubertal development,. M% q& m: S! n8 D
including bilateral testicular growth, similar to boys; M4 ~9 T Q6 d9 ?# k. P: ~
with CPP. The gonadotropin levels in this disorder
/ {. a# m N% @1 r, zare suppressed to prepubertal levels and do not show
, {5 y1 i5 e! dpubertal response of gonadotropin after gonadotropin-7 Q- W7 w+ O) l8 o" z8 g8 t! O
releasing hormone stimulation. This is a sex-linked6 o" _' \% f6 \0 B
autosomal dominant disorder that affects only
( q8 l. i* X9 H9 X) m- @males; therefore, other male members of the family
8 b8 z# P+ p8 X- T( Z4 Xmay have similar precocious puberty.3
5 x: `8 }! C$ }In our patient, physical examination was incon-
6 }8 _' C7 P. `7 W- Gsistent with true precocious puberty since his testi-
; L5 P2 L6 u7 v8 @" @cles were prepubertal in size. However, testotoxicosis2 x l8 _/ `- {3 m% @/ Z/ b
was in the differential diagnosis because his father
9 f% j$ T6 k) R$ wstarted puberty somewhat early, and occasionally,4 b V: N3 C" u! n: G1 S
testicular enlargement is not that evident in the
/ p3 o B0 R1 Y; y0 j8 d7 xbeginning of this process.1 In the absence of a neg-
9 m' E v# M# v2 y1 @( wative initial history of androgen exposure, our8 @# r" T1 P! e6 Y0 }" E
biggest concern was virilizing adrenal hyperplasia,
1 h7 j; f9 f y, b P1 U$ H& oeither 21-hydroxylase deficiency or 11-β hydroxylase
6 I( B" Q/ A" |3 H2 {; jdeficiency. Those diagnoses were excluded by find-& h6 g6 r) m5 A! g% k- `
ing the normal level of adrenal steroids.
1 G" }# S. o. A0 R, b" Z* Y: EThe diagnosis of exogenous androgens was strongly
' z/ x( Q8 N5 `# w7 k/ L3 n# y/ Nsuspected in a follow-up visit after 4 months because3 r% V$ k! e) [6 }! v6 `1 z3 a9 `" v
the physical examination revealed the complete disap-
8 [+ \$ p# ?: `3 Ypearance of pubic hair, normal growth velocity, and
/ X$ q) V; f6 ldecreased erections. The father admitted using a testos-
8 A* d" [1 N: J( t; q' @* `9 I8 hterone gel, which he concealed at first visit. He was
8 \4 C& e) s: {' g+ rusing it rather frequently, twice a day. The Physicians’: U. F! Z; e9 P- V3 y
Desk Reference, or package insert of this product, gel or
7 c; P- N: y( g* Q/ q2 scream, cautions about dermal testosterone transfer to6 c7 c4 L8 l/ Q
unprotected females through direct skin exposure.
' ~! ~- B0 f c+ A0 a+ \Serum testosterone level was found to be 2 times the7 j% x8 U9 h% M6 I; z+ o
baseline value in those females who were exposed to- }/ ` v% k- w0 w
even 15 minutes of direct skin contact with their male; [5 Y/ F$ X2 N$ g, ] j( ^
partners.6 However, when a shirt covered the applica-# z I9 b2 g0 K2 `1 D- b8 X
tion site, this testosterone transfer was prevented.! O c- l5 v* @* r
Our patient’s testosterone level was 60 ng/mL,- G+ z! j8 I5 L) L# U
which was clearly high. Some studies suggest that L! e, H7 h, p5 R) i; K
dermal conversion of testosterone to dihydrotestos-
5 W( U4 _* f1 s+ G; Z: j5 Fterone, which is a more potent metabolite, is more) @9 A, d5 W6 E* n# Z6 j
active in young children exposed to testosterone
+ _+ @4 c |2 E+ m% Texogenously7; however, we did not measure a dihy-1 Q1 ~: Q3 `2 {+ j- v
drotestosterone level in our patient. In addition to
- b0 }: I T. U; R* Y- n" s* vvirilization, exposure to exogenous testosterone in
1 Z' S* E% w9 B8 J8 [* ^- }; [children results in an increase in growth velocity and" K7 d! G$ W$ ^. r7 U& O4 Z
advanced bone age, as seen in our patient.
" i! _- n+ q' A7 P: {6 \3 @+ o% l6 RThe long-term effect of androgen exposure during2 o# W' [5 ^4 |! c0 _! J
early childhood on pubertal development and final
: \- J9 _( ^6 T2 Ladult height are not fully known and always remain
5 b9 l- y+ q- X' l8 d4 Za concern. Children treated with short-term testos-! Q- d; m+ _( d" b( n
terone injection or topical androgen may exhibit some# x/ c: j! i+ q; g! X6 |
acceleration of the skeletal maturation; however, after
" T8 h+ K& T4 fcessation of treatment, the rate of bone maturation. x3 u; i6 F2 X. s3 e w. E
decelerates and gradually returns to normal.8,9* W4 ]' ~& [2 T/ y, I: E
There are conflicting reports and controversy: c2 i* w5 V# t7 p
over the effect of early androgen exposure on adult
3 E5 N# L1 q7 F- _& u% b jpenile length.10,11 Some reports suggest subnormal
1 K" V% s, u: F' v% b* dadult penile length, apparently because of downreg-
7 Q, d5 q: A' S( E0 o& q) E2 U$ j4 xulation of androgen receptor number.10,12 However,$ r7 Y) B C; M n- j+ t) @
Sutherland et al13 did not find a correlation between
" j V: _4 |8 K( uchildhood testosterone exposure and reduced adult
3 Z1 ]( [. u b v% V& |3 Hpenile length in clinical studies.- {$ U6 [5 |0 g9 g% g2 L, c
Nonetheless, we do not believe our patient is
, J% g1 o4 K* J) a- y2 C3 Fgoing to experience any of the untoward effects from5 H" [+ x3 {" D9 g2 @; b; g
testosterone exposure as mentioned earlier because
( g) q0 Y; B' Fthe exposure was not for a prolonged period of time.# h6 D7 X1 ]5 {% U) T
Although the bone age was advanced at the time of. x5 N0 ~) }# k, C/ m; T; P
diagnosis, the child had a normal growth velocity at. t9 {! E& h6 _/ U" [+ ^, H2 T
the follow-up visit. It is hoped that his final adult& K8 g# Z! ~ N5 C1 Z
height will not be affected.1 v- S9 @# i" f& P0 ~$ w/ M
Although rarely reported, the widespread avail-+ ?. `3 a$ @$ m& @
ability of androgen products in our society may
) A3 N8 b" O$ X( G+ X9 P0 U; Hindeed cause more virilization in male or female \1 J3 L2 n5 J3 w" _
children than one would realize. Exposure to andro-
. {& W d+ _- h+ D5 g8 g, [5 Agen products must be considered and specific ques-
; M% g7 ^( T% j, w# e2 q2 wtioning about the use of a testosterone product or
! n9 x5 G2 k$ y4 f7 n7 l ygel should be asked of the family members during1 J4 t- x1 L% w8 w( y
the evaluation of any children who present with vir- r; S% u4 F* ^& K; H: s. U
ilization or peripheral precocious puberty. The diag-) K3 N( t6 F3 R! b' A, `, I
nosis can be established by just a few tests and by
6 Y# F3 R/ e" j& z Y& Wappropriate history. The inability to obtain such a+ d! D0 O( \# i/ `
history, or failure to ask the specific questions, may2 J* B* j0 d+ l0 z2 t
result in extensive, unnecessary, and expensive7 C6 D# \1 E( \. j
investigation. The primary care physician should be
6 X$ X% i$ V) i9 y. Uaware of this fact, because most of these children
7 Z6 Q' {; L+ u3 umay initially present in their practice. The Physicians’
* W0 ]! l! F- Y% [0 L4 F2 W4 U2 U IDesk Reference and package insert should also put a
_6 Q% n& t7 t& {' [5 uwarning about the virilizing effect on a male or
2 b$ \* R I6 Y& y" q6 jfemale child who might come in contact with some-
; {+ ?8 l z& Y, g+ G( Uone using any of these products.$ D, y( o& _; @" V$ s8 D/ Y8 m3 L
References' g; [% D6 P' e7 B9 i
1. Styne DM. The testes: disorder of sexual differentiation
3 w* ~+ J3 t5 v: o% gand puberty in the male. In: Sperling MA, ed. Pediatric
; B5 z0 H0 {9 C3 ^Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;) u6 y7 @5 O/ q
2002: 565-628.
. e, f5 v1 M1 P2 y7 ^. \, H2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
7 f* p1 \$ _+ V) [% H- O5 p! | apuberty in children with tumours of the suprasellar pineal |
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