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Sexual Precocity in a 16-Month-Old
5 l5 a% F, j( Y3 A6 K+ TBoy Induced by Indirect Topical$ a; y8 n m% C6 u
Exposure to Testosterone
$ J+ ^9 ]$ \$ D, \. z) wSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
5 X( V$ P% o ^" w& Gand Kenneth R. Rettig, MD1' H7 ~8 S" D9 }1 ]4 f
Clinical Pediatrics5 j5 j- s8 i2 P/ K% |9 j- E
Volume 46 Number 61 X1 C% N0 n4 R9 S- v6 P7 m, H
July 2007 540-543
( t+ ]5 h) D7 B, p& R" K8 j& m z© 2007 Sage Publications3 ?/ g! s: D$ E4 e( |
10.1177/0009922806296651
4 M8 d" G6 b6 u/ Y) Khttp://clp.sagepub.com
$ ?/ F2 T# H" b; h% phosted at
; B! l. R8 w8 y1 V7 ~5 o( Xhttp://online.sagepub.com* g+ c$ X$ Y1 x6 Z
Precocious puberty in boys, central or peripheral,
" X6 P/ [4 T/ Z$ Y0 }. L% ^; _2 S5 lis a significant concern for physicians. Central
* X l$ M$ n, a! ]) \precocious puberty (CPP), which is mediated1 t6 T/ y( [9 _3 {# h
through the hypothalamic pituitary gonadal axis, has
7 Q; _7 @" [" g$ e9 V2 Va higher incidence of organic central nervous system
U$ S- `9 [5 h X7 x# flesions in boys.1,2 Virilization in boys, as manifested* k- G A3 x" D; m: |4 Q4 @
by enlargement of the penis, development of pubic
5 @) a/ P% N& ~& Ghair, and facial acne without enlargement of testi-
2 |* ^6 d9 [: X2 \' m- Pcles, suggests peripheral or pseudopuberty.1-3 We
( T! \3 N/ Y+ v' ]report a 16-month-old boy who presented with the m9 }4 r- M8 x/ A7 n! N( q9 z) y& O
enlargement of the phallus and pubic hair develop- Z: C$ n! i5 ^0 F- Y- g4 X
ment without testicular enlargement, which was due
' a+ T$ i9 ^ n# [8 k+ N- Zto the unintentional exposure to androgen gel used by& {5 Z2 W4 p5 Y" I- N
the father. The family initially concealed this infor-. q( u1 a% M/ P d' h+ v
mation, resulting in an extensive work-up for this6 b0 U- B8 o w, c- c j5 A
child. Given the widespread and easy availability of& m' o+ p* J [+ d+ W
testosterone gel and cream, we believe this is proba-" B2 U3 ]* y/ O8 `1 [5 A/ N5 \
bly more common than the rare case report in the8 a; L5 ~7 P8 _8 Z
literature.46 A; m; r2 ?# d. N" d% Z/ H9 _
Patient Report. G0 I+ _2 x7 c
A 16-month-old white child was referred to the- ~! ?& v0 s6 E0 I' r
endocrine clinic by his pediatrician with the concern* y# Y4 a1 N$ X7 b! A) o. S0 H) r
of early sexual development. His mother noticed
- X# d3 T1 Q4 F! t) }+ Glight colored pubic hair development when he was& E9 ~! N+ d8 h# j1 y9 i s) o
From the 1Division of Pediatric Endocrinology, 2University of
( z* m0 ?/ E: y9 t' K; M0 JSouth Alabama Medical Center, Mobile, Alabama.
6 k- F* l& K4 x! W6 B$ JAddress correspondence to: Samar K. Bhowmick, MD, FACE,# t* }9 ~# `; Y+ P& S
Professor of Pediatrics, University of South Alabama, College of
! |' a. h# ~' Q+ hMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;! `- o: v. w; u- v6 W Q; s& ~8 }& F" k
e-mail: [email protected]., f9 D8 F. h: A6 V* {
about 6 to 7 months old, which progressively became
: m/ J1 {- g/ Mdarker. She was also concerned about the enlarge-- D: m, _, P1 @7 S; G2 Y
ment of his penis and frequent erections. The child& `% v7 d2 ~2 T7 y) `
was the product of a full-term normal delivery, with* `% [! F+ q2 O+ ?6 |
a birth weight of 7 lb 14 oz, and birth length of
' ]2 s. S* p, b5 ~) a" }20 inches. He was breast-fed throughout the first year
1 \1 w, G9 c: v3 Mof life and was still receiving breast milk along with
' h7 K7 i: Z0 `5 r3 Csolid food. He had no hospitalizations or surgery,2 R) i- R8 K6 n- Q+ ?+ b
and his psychosocial and psychomotor development8 [# \& H8 V6 K* x
was age appropriate.' c4 n1 _0 T, ^# n: N3 |, m# U
The family history was remarkable for the father,* L* _/ h6 A C w V+ a
who was diagnosed with hypothyroidism at age 16,
- F. I) e' g* w! mwhich was treated with thyroxine. The father’s
- Z! A, X3 i, v6 d/ ^0 c8 ~height was 6 feet, and he went through a somewhat
/ Z- E4 `5 Y& {" p, Kearly puberty and had stopped growing by age 14.# g; A& b; u/ ^3 c7 _. P" [
The father denied taking any other medication. The7 u$ D5 d: ?$ a: c- B a3 ]
child’s mother was in good health. Her menarche
- h1 C* x4 j b& s* ^was at 11 years of age, and her height was at 5 feet
, O! X/ E4 F0 _' H5 inches. There was no other family history of pre-' x9 _1 L2 t7 w1 Z/ h' x2 L
cocious sexual development in the first-degree rela-
C4 y* x+ j. I) @+ Y' xtives. There were no siblings.& G# X6 h% o/ s P
Physical Examination
, E3 w0 M( N# R8 sThe physical examination revealed a very active,
% O3 w' c8 ~% j- ` [$ ?- Qplayful, and healthy boy. The vital signs documented3 Q* |% b) y0 w1 Y
a blood pressure of 85/50 mm Hg, his length was/ f( Z, Q) h; _1 r
90 cm (>97th percentile), and his weight was 14.4 kg0 a$ l; O0 s3 s* t! d; s# s
(also >97th percentile). The observed yearly growth
9 L4 a# M: p! P0 {' H9 [) d% nvelocity was 30 cm (12 inches). The examination of% d. m8 n. q$ g1 @
the neck revealed no thyroid enlargement.$ Y; q+ ]; h* k0 X2 n5 o2 z, s* a% L2 L
The genitourinary examination was remarkable for
; q, M2 A V% Uenlargement of the penis, with a stretched length of
4 B/ B: @8 Z, _6 h8 X! B; x8 cm and a width of 2 cm. The glans penis was very well
: R% J& [* Q8 |: \- U+ z2 n* Kdeveloped. The pubic hair was Tanner II, mostly around. A. U+ ?' |! K7 Q+ R; r* z
540* M# r4 ?9 B% z
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from+ J9 k" p( U7 N3 G! F) h: B
the base of the phallus and was dark and curled. The8 [( } a, L& q
testicular volume was prepubertal at 2 mL each.' @' E: X6 a j j7 M
The skin was moist and smooth and somewhat( t _3 w6 g( l
oily. No axillary hair was noted. There were no
* Q+ J) E- P, J$ w, l3 Tabnormal skin pigmentations or café-au-lait spots.
$ P8 S4 x1 h l0 K/ B6 r+ QNeurologic evaluation showed deep tendon reflex 2+ Y/ f& f- {3 k9 j" m: U$ b
bilateral and symmetrical. There was no suggestion
1 c$ d6 Y' f/ z: {of papilledema.3 }: W0 I* Y: d' g9 y! H
Laboratory Evaluation: C3 G( P) H0 A" o
The bone age was consistent with 28 months by
$ B5 F V0 D5 @3 Y3 N8 m+ vusing the standard of Greulich and Pyle at a chrono-8 Q/ k# J( B ^
logic age of 16 months (advanced).5 Chromosomal, W+ Y7 U7 [2 ]- Y
karyotype was 46XY. The thyroid function test R& _6 Y& u( R. l
showed a free T4 of 1.69 ng/dL, and thyroid stimu-- | c; K. k2 V! d
lating hormone level was 1.3 µIU/mL (both normal).
+ x- D% D9 E3 [: g' J8 k: AThe concentrations of serum electrolytes, blood& h- [( {5 x- f: y6 x
urea nitrogen, creatinine, and calcium all were
7 |) {$ k* S( f# z; J: p/ m! `5 Hwithin normal range for his age. The concentration# G: f7 W/ { O6 a
of serum 17-hydroxyprogesterone was 16 ng/dL# ?1 \, x% {- S) W# T: S' m9 E( v
(normal, 3 to 90 ng/dL), androstenedione was 20# l: h; p* l7 q" b$ R
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
: H2 v* u5 R* N3 K: X2 k; tterone was 38 ng/dL (normal, 50 to 760 ng/dL),; p7 A6 c1 _5 [# O2 S
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
! h4 l+ [; k& P4 v; `5 e* s49ng/dL), 11-desoxycortisol (specific compound S), @- r j+ c6 P9 o9 U
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
3 b$ P$ P) d ntisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
8 G8 K+ \( [- j. C& m. k4 s) N8 |testosterone was 60 ng/dL (normal <3 to 10 ng/dL)," N) I I/ w9 @3 S0 u {
and β-human chorionic gonadotropin was less than
* A6 O0 N$ d0 |# h! U5 mIU/mL (normal <5 mIU/mL). Serum follicular3 o5 O2 T: o% g/ h% h7 B
stimulating hormone and leuteinizing hormone
& ^7 _ _+ M/ `+ b& fconcentrations were less than 0.05 mIU/mL
9 E" d: u! R/ N R7 F, e(prepubertal).
" u+ |* k3 W6 ]8 k3 eThe parents were notified about the laboratory# b. k7 @- b1 c" J( X
results and were informed that all of the tests were
! y+ n6 b3 e' v" x8 y1 @normal except the testosterone level was high. The
" V* L; w, x( E6 _1 M3 ^1 v# ofollow-up visit was arranged within a few weeks to! i$ h! b7 `- |! j4 S
obtain testicular and abdominal sonograms; how-0 w3 y# P) T: S/ [. f+ c2 |) o
ever, the family did not return for 4 months.! K: o& d) @ T. c
Physical examination at this time revealed that the0 `: ]. S! I- ~1 ^. C
child had grown 2.5 cm in 4 months and had gained
3 ]1 S u) v0 i' p2 kg of weight. Physical examination remained
6 [# U; j4 N9 I/ Z2 `unchanged. Surprisingly, the pubic hair almost com-3 B/ Z( o% W/ z1 H6 ^
pletely disappeared except for a few vellous hairs at( F+ E; W+ C8 L1 N+ t5 [) x( B: w
the base of the phallus. Testicular volume was still 2/ M7 h2 Y& `6 L- }- |$ z
mL, and the size of the penis remained unchanged.
4 f) @" S- z0 y) |( q0 BThe mother also said that the boy was no longer hav-
. V/ x, t- Q B4 y- m2 |0 Iing frequent erections.0 X, d& N8 H x5 f+ u
Both parents were again questioned about use of4 b. ?, A+ M. w. ]
any ointment/creams that they may have applied to0 f$ } L+ p' T- t @
the child’s skin. This time the father admitted the7 J4 w& M3 L+ x
Topical Testosterone Exposure / Bhowmick et al 541" ~6 F2 O! O" e- y: ?
use of testosterone gel twice daily that he was apply-
# B+ K) i8 i7 P* |; cing over his own shoulders, chest, and back area for5 Z1 L. j! y- j1 P* [# F
a year. The father also revealed he was embarrassed
' u6 {& F6 l/ b2 I6 @* xto disclose that he was using a testosterone gel pre-
% Y5 R( Y* z! m' ^# O! Tscribed by his family physician for decreased libido
0 x; I9 y, q; ]; Usecondary to depression.
1 k; S2 n+ M9 Q& B6 X3 E% p5 XThe child slept in the same bed with parents.. `7 L# i# x" d3 L6 g* ?% b
The father would hug the baby and hold him on his
' F+ u) [1 O6 Q+ W- W fchest for a considerable period of time, causing sig-
& o- l, U/ J, o" }4 ynificant bare skin contact between baby and father.) k$ e+ r) p! p% |- x8 W3 A" y
The father also admitted that after the phone call,
9 l$ U6 w/ | H* U0 Dwhen he learned the testosterone level in the baby& C# l2 S% ^9 T6 @% s2 A
was high, he then read the product information
6 n3 j. w6 J, R) epacket and concluded that it was most likely the rea-
. j- a+ R% L$ j+ ?2 `5 oson for the child’s virilization. At that time, they* ]; R/ X1 g0 F
decided to put the baby in a separate bed, and the
3 [2 r! e+ s4 u% c3 d A3 a2 _1 ufather was not hugging him with bare skin and had
4 _. X! W4 z3 K* wbeen using protective clothing. A repeat testosterone" i, z* M+ q" i: f6 w# J5 D
test was ordered, but the family did not go to the
( _* \" J4 \+ V6 r8 G" }' Xlaboratory to obtain the test.% N5 y& K) J9 n6 y* q9 N, i0 `% g
Discussion6 M8 h0 T7 D# }
Precocious puberty in boys is defined as secondary
5 w: T6 O* q+ _) rsexual development before 9 years of age.1,4) W$ z' ?6 L& e+ Q" F2 d: J7 \
Precocious puberty is termed as central (true) when
" p% v' }6 ~; e$ Sit is caused by the premature activation of hypo-7 f" i5 U/ y& V! j0 u) J
thalamic pituitary gonadal axis. CPP is more com-. s# y4 A& m' O4 }
mon in girls than in boys.1,3 Most boys with CPP% g- S: m4 K0 ~3 v9 D* V- c
may have a central nervous system lesion that is
: n% k' c( v- @* r- Nresponsible for the early activation of the hypothal-
0 D& k: G2 F7 N# z7 ]7 O! ]amic pituitary gonadal axis.1-3 Thus, greater empha-+ J2 r. ^" t- L; _+ @9 u
sis has been given to neuroradiologic imaging in6 P' N3 @# ?8 c- V D
boys with precocious puberty. In addition to viril-
3 O( y$ P! c( U# M1 f, Qization, the clinical hallmark of CPP is the symmet-
1 m$ ^. Q; E$ X; B* ~rical testicular growth secondary to stimulation by
4 _% n' j4 F- ?' Cgonadotropins.1,3; f; a, L, j$ Y5 `
Gonadotropin-independent peripheral preco-$ K, {; n3 F! B
cious puberty in boys also results from inappropriate" Y' V$ ]5 a2 v- S
androgenic stimulation from either endogenous or
" q" q. O. A+ J4 d- Pexogenous sources, nonpituitary gonadotropin stim-7 _4 V$ z2 I. V$ w- w
ulation, and rare activating mutations.3 Virilizing+ x$ g' Y' }+ c/ n
congenital adrenal hyperplasia producing excessive7 c( u( E2 \+ n8 B- O# ^# G& [' \
adrenal androgens is a common cause of precocious& h3 H1 u$ p- }( M3 g& p
puberty in boys.3,4& }3 n# K+ c1 u* n! b
The most common form of congenital adrenal
2 S$ s( G+ W% b- Ghyperplasia is the 21-hydroxylase enzyme deficiency.
# `1 ` i3 t, O4 dThe 11-β hydroxylase deficiency may also result in/ T f: H7 ]' a% O
excessive adrenal androgen production, and rarely,2 S" I$ Z) j: ~ c: G
an adrenal tumor may also cause adrenal androgen5 ^/ s7 e+ E) I0 T! ~2 f: e: e1 w" S
excess.1,30 w4 T$ b! }3 `
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from. r( \) x ]; d
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
- V) B/ A6 h7 p8 I1 f5 q4 NA unique entity of male-limited gonadotropin-8 r! a* q2 g L( g
independent precocious puberty, which is also known
) O0 r- g$ \9 Y! A/ {5 N$ Tas testotoxicosis, may cause precocious puberty at a$ p' Y4 w% }; ^* J! k; n
very young age. The physical findings in these boys! c& O: D% {$ {; K, [. X3 S5 q
with this disorder are full pubertal development,
8 R: n" B' R4 W7 uincluding bilateral testicular growth, similar to boys
. B% }$ c) g$ cwith CPP. The gonadotropin levels in this disorder+ S6 o* b: o5 o: y, y$ Y
are suppressed to prepubertal levels and do not show
' e; J a ~( E7 j; ?' }pubertal response of gonadotropin after gonadotropin-
! _8 k7 E* o( {. m; u8 v4 q6 [releasing hormone stimulation. This is a sex-linked- C9 m$ f/ ?! U4 p7 Z
autosomal dominant disorder that affects only& U' t |4 {0 [3 c
males; therefore, other male members of the family" @# G t5 H* ~7 v' e$ q
may have similar precocious puberty.3
$ z [- a" ~% L# T8 j- N2 Z! qIn our patient, physical examination was incon-" p4 l+ n& d3 y8 t% q8 Q; h
sistent with true precocious puberty since his testi-
; G# G0 {/ v- f7 Z) ucles were prepubertal in size. However, testotoxicosis3 i: u5 m* s7 @: w% q- [0 [2 t
was in the differential diagnosis because his father
0 ^" y- x0 C! u$ ostarted puberty somewhat early, and occasionally,
( f* P% s/ b0 r" H5 `$ d3 @testicular enlargement is not that evident in the; y" y+ [6 I# ?; c
beginning of this process.1 In the absence of a neg-
; H( Z, }+ F6 k/ m. Aative initial history of androgen exposure, our" }9 S% Q" h3 F, _- h" G, z. D: L
biggest concern was virilizing adrenal hyperplasia,
' s) {1 V) x8 S. |6 ^$ Q! M3 geither 21-hydroxylase deficiency or 11-β hydroxylase
, p9 r% y( t" k9 s0 M' K8 ]7 Vdeficiency. Those diagnoses were excluded by find-
1 S5 R% Z$ J% b- hing the normal level of adrenal steroids.8 l5 m: G+ v3 c6 b
The diagnosis of exogenous androgens was strongly' W3 F& y3 r8 y( q# D- |( d" x
suspected in a follow-up visit after 4 months because
$ u% _8 `# M0 ?# b* j% I uthe physical examination revealed the complete disap-
4 G# X7 I; i" I% j5 l1 Q. ?3 \pearance of pubic hair, normal growth velocity, and/ Y6 S3 h" r2 d+ ~" i) A: \
decreased erections. The father admitted using a testos-
2 C4 x' B4 g8 j6 W( y; ^terone gel, which he concealed at first visit. He was7 k5 a) }; _( m
using it rather frequently, twice a day. The Physicians’" \) r# R0 U5 ^$ ^& @, n/ x
Desk Reference, or package insert of this product, gel or
- w, X( M Y( i5 l6 I/ s# M1 e5 Tcream, cautions about dermal testosterone transfer to5 q: a- w. O) c5 u: a8 @
unprotected females through direct skin exposure.6 M; g4 X% C- K, Q
Serum testosterone level was found to be 2 times the) O) @! f- y) Z$ }$ K- {
baseline value in those females who were exposed to
9 a6 [3 c e/ c3 l: _) ?( H, m) M {even 15 minutes of direct skin contact with their male! R; s0 [5 i) G. f
partners.6 However, when a shirt covered the applica-
) {$ B/ O9 S, `tion site, this testosterone transfer was prevented. d) X# J/ ]0 k2 P7 w
Our patient’s testosterone level was 60 ng/mL,, `( S: E/ W& ~$ v
which was clearly high. Some studies suggest that
* R( E# Z9 ~; U' Y* zdermal conversion of testosterone to dihydrotestos-
% D. g |5 h* j/ J- R1 vterone, which is a more potent metabolite, is more
0 ?9 \; Y- Z! Z0 v4 K/ mactive in young children exposed to testosterone
" r% m3 J8 i0 C" J% f7 e0 qexogenously7; however, we did not measure a dihy-
' d- H. H/ R; f9 b2 n3 ]& Kdrotestosterone level in our patient. In addition to
: N; ] ?0 t) O9 V0 {* D4 h$ |/ ]8 I$ U$ @virilization, exposure to exogenous testosterone in
" \! U4 E6 ?! X, U9 h# I0 E' Fchildren results in an increase in growth velocity and o9 \: F3 M" R& q5 H
advanced bone age, as seen in our patient.+ C# b/ [/ p# T
The long-term effect of androgen exposure during
: Y6 O% |5 @* t4 p( |/ B+ kearly childhood on pubertal development and final
! o1 n% W" L$ @' m8 cadult height are not fully known and always remain
, |' {' J# @) v' E2 Q4 ^- s7 ca concern. Children treated with short-term testos-
6 F" ?' Q# i. R; p# {9 dterone injection or topical androgen may exhibit some2 Z4 ~! H t$ o/ G2 J" I
acceleration of the skeletal maturation; however, after
' E6 l$ _. E$ l; U7 u( Jcessation of treatment, the rate of bone maturation2 \' }" e0 G0 a6 _) {
decelerates and gradually returns to normal.8,9
, p+ N$ }7 M- XThere are conflicting reports and controversy0 ~$ s# u9 f( ?8 X
over the effect of early androgen exposure on adult
0 ^% f7 A- I$ Y* Hpenile length.10,11 Some reports suggest subnormal
: q7 ]4 t7 m0 p& W* \4 g' T" E5 dadult penile length, apparently because of downreg-
/ Z* k, c' E' Dulation of androgen receptor number.10,12 However," ~3 D$ X3 W; A" D6 Y
Sutherland et al13 did not find a correlation between1 u8 I) \# A2 E# ?" n
childhood testosterone exposure and reduced adult$ m8 N6 @7 F; i& h/ ]# |9 x
penile length in clinical studies.; u: r. }7 ^& H$ O
Nonetheless, we do not believe our patient is
0 h) d, Y+ W4 S/ u$ bgoing to experience any of the untoward effects from- |& w3 C) z: B: f
testosterone exposure as mentioned earlier because
! C# H: D2 T" @+ y$ `. B/ @6 H3 othe exposure was not for a prolonged period of time.0 E/ s! u' w; {1 \3 S; {/ [$ c5 t
Although the bone age was advanced at the time of
2 `! R5 r9 {/ N4 adiagnosis, the child had a normal growth velocity at: M* M9 ]) `" B
the follow-up visit. It is hoped that his final adult7 O6 _- w$ x7 z
height will not be affected./ u5 u; W4 e1 J6 k" P$ X! d7 u
Although rarely reported, the widespread avail-
/ R4 m' D( q. G& @ability of androgen products in our society may6 A: h( c8 O$ I& V; J2 n2 B S
indeed cause more virilization in male or female! y$ G" `0 ^* S! G% U$ a
children than one would realize. Exposure to andro-
- Y/ R! o+ G% Jgen products must be considered and specific ques-" s5 j+ H" f! R; D& v; w2 ?
tioning about the use of a testosterone product or* L' s6 h: P( M7 ~2 C
gel should be asked of the family members during- e9 i* Y9 E& m3 X* ?6 W
the evaluation of any children who present with vir-8 a$ I o0 ?( V" z3 ]
ilization or peripheral precocious puberty. The diag-& h( O+ a9 S/ z
nosis can be established by just a few tests and by+ @# Z; ~- y' T7 Q# B
appropriate history. The inability to obtain such a) a& N% ?! G0 {8 v' z
history, or failure to ask the specific questions, may1 g3 R$ H* v8 ~" s( q' ]
result in extensive, unnecessary, and expensive
; W' Q, T3 g6 D1 @investigation. The primary care physician should be
2 q1 H/ E6 h4 k7 S9 X: g* o gaware of this fact, because most of these children
- |3 j6 P! Y- J" x1 R& Emay initially present in their practice. The Physicians’
; e4 K4 J7 e1 v$ S. c" [$ ?Desk Reference and package insert should also put a
' I- {4 g. L! K1 R! @6 {0 Wwarning about the virilizing effect on a male or; x" t9 ]8 d) D6 }0 R; I; W- Z
female child who might come in contact with some-8 K, b" W! l0 q/ \2 M
one using any of these products.
+ s; J I0 ^# J& L/ TReferences, H: _' X2 y8 T3 Y, |+ e, n0 W
1. Styne DM. The testes: disorder of sexual differentiation, K2 R, ~$ o& Z5 p* }' L+ a
and puberty in the male. In: Sperling MA, ed. Pediatric
7 q, V% @/ b6 P* w: f5 d0 @Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
4 V. I1 s; D9 K2 Q4 s- ?2002: 565-628.
9 c0 I- W9 p f. y. S2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
G7 v' l% b; l* k) Mpuberty in children with tumours of the suprasellar pineal |
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