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Sexual Precocity in a 16-Month-Old, K5 z7 |6 _1 c+ ]* N% o v
Boy Induced by Indirect Topical; K: w5 O, C3 U% \9 E# F; R K" Q
Exposure to Testosterone m9 s" j" E: d6 ]/ }( m
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
" j! F! Z* S) r1 e$ _& Oand Kenneth R. Rettig, MD1
( v$ `* v* J( T4 cClinical Pediatrics
1 c x* Y+ T; M$ {Volume 46 Number 64 _( S3 e& S( x" [% Q2 d
July 2007 540-543
/ {9 c+ c) F+ P5 \: t© 2007 Sage Publications
# [6 F' T' \/ I% w, w, c9 w$ ]10.1177/0009922806296651
* O5 f- U) @& e$ \; x% U6 \http://clp.sagepub.com
6 V8 Q% v- n+ n6 ihosted at6 a. A8 u, ?3 J$ m
http://online.sagepub.com
, c i1 i2 D8 F5 h. xPrecocious puberty in boys, central or peripheral,
8 x( Y1 W# m3 R' Eis a significant concern for physicians. Central
9 U; b6 C. d2 I; ]. P" sprecocious puberty (CPP), which is mediated
; L0 c' M8 s8 U0 r# ^through the hypothalamic pituitary gonadal axis, has. T- R- _3 ^3 j
a higher incidence of organic central nervous system
( ^6 E& p8 P+ K9 \( W% ?% ulesions in boys.1,2 Virilization in boys, as manifested
! q$ s5 B* n3 r; N. W+ nby enlargement of the penis, development of pubic2 m6 W( p& V" X7 H+ b( t5 X5 B: r
hair, and facial acne without enlargement of testi-7 p, V! |( I$ E) @- e2 a9 T
cles, suggests peripheral or pseudopuberty.1-3 We
1 H' [! x: j" A6 breport a 16-month-old boy who presented with the: a5 N& x! U* ~ G, o3 B# T. e
enlargement of the phallus and pubic hair develop-
! L) y5 f2 X/ iment without testicular enlargement, which was due" o* U% L# m& L% h% \+ |. D8 S/ ^# r
to the unintentional exposure to androgen gel used by" d t+ }+ B, s/ ]+ |7 ]
the father. The family initially concealed this infor-
0 W$ D* S1 Z) Z; I& Y4 qmation, resulting in an extensive work-up for this
' D e6 x m& M2 o: n |child. Given the widespread and easy availability of8 A) K, F( p) i6 A p
testosterone gel and cream, we believe this is proba-2 T- o0 {6 \; ^9 R/ o
bly more common than the rare case report in the
+ i% l1 X# b! y' Oliterature.4! j0 o5 S) G% F& k
Patient Report
9 N: E+ p' t: E: t0 sA 16-month-old white child was referred to the& k/ J& ~3 n9 w3 j
endocrine clinic by his pediatrician with the concern
4 v y F1 N5 xof early sexual development. His mother noticed1 Y3 O- s0 l1 `6 Q' x5 J7 T
light colored pubic hair development when he was
6 K$ w5 w# k( _2 ?+ I8 SFrom the 1Division of Pediatric Endocrinology, 2University of
' h- D$ Q# R- l! d5 s7 jSouth Alabama Medical Center, Mobile, Alabama.7 t& i0 W* H, r
Address correspondence to: Samar K. Bhowmick, MD, FACE,
! C, t# ?" T+ ZProfessor of Pediatrics, University of South Alabama, College of
0 ~8 k1 `+ A/ B+ |7 y- u; ?8 H4 BMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;/ X$ w" u: ?( I c. o
e-mail: [email protected].5 U* V. X) K# x& j. u h8 f# f
about 6 to 7 months old, which progressively became- B9 P3 H" L0 a( v) H! U
darker. She was also concerned about the enlarge-
9 H2 \* X4 H1 l, oment of his penis and frequent erections. The child
/ Y$ c& w, k' |( R7 c( Vwas the product of a full-term normal delivery, with
" t+ J1 [8 x1 }! I5 Fa birth weight of 7 lb 14 oz, and birth length of3 H# \# W8 P" I+ B
20 inches. He was breast-fed throughout the first year% F ]# G: H) Z5 o1 d" U
of life and was still receiving breast milk along with
9 {; ^: _, q2 J8 P0 B4 x/ t- Tsolid food. He had no hospitalizations or surgery,
7 L0 Y0 A, h7 C3 a k5 V* }) sand his psychosocial and psychomotor development
; u" b, r" S: kwas age appropriate.5 ?6 q( p* A1 q3 R! ~
The family history was remarkable for the father,
" Z: n8 r6 K" Z/ V4 a/ h' Twho was diagnosed with hypothyroidism at age 16,4 _; f8 q; Z' x
which was treated with thyroxine. The father’s
# ]: R9 M1 i6 h3 D- _1 h7 eheight was 6 feet, and he went through a somewhat
+ r- W: u# Z: X1 m% j) |early puberty and had stopped growing by age 14.
' Z2 J+ s" u4 |( @3 \The father denied taking any other medication. The; j4 o: B. Y7 A3 T/ A
child’s mother was in good health. Her menarche5 n- |$ f4 M4 N5 h$ q
was at 11 years of age, and her height was at 5 feet
+ Z" p8 n: I& g" Y) q- y& J$ Q5 inches. There was no other family history of pre-/ O8 Q: J Y5 Z- Y% r5 Y3 W
cocious sexual development in the first-degree rela-
/ g9 m+ g0 }. \' H5 ?! btives. There were no siblings.
- ~' _) Q& d) s7 bPhysical Examination' @) r& a+ x; E8 o& \6 L/ k
The physical examination revealed a very active,
& s- X9 e* |/ h) Y: }' Z, bplayful, and healthy boy. The vital signs documented) u8 r# F" h" [& B) G8 |
a blood pressure of 85/50 mm Hg, his length was: _3 I: `5 O9 U$ S' y8 m- K
90 cm (>97th percentile), and his weight was 14.4 kg
$ R8 _' e3 L8 O0 w5 @(also >97th percentile). The observed yearly growth3 x. e0 @+ b5 x! e- [+ T
velocity was 30 cm (12 inches). The examination of
. c: U* H5 ?& C% C! ^0 O! v3 xthe neck revealed no thyroid enlargement.. N5 O- u! |2 v4 W) ] g
The genitourinary examination was remarkable for
+ Q' C0 b, [* e% T6 V9 {enlargement of the penis, with a stretched length of. P& e7 F% o. ]
8 cm and a width of 2 cm. The glans penis was very well
0 J+ s" A5 X5 B! r- Mdeveloped. The pubic hair was Tanner II, mostly around
% Z/ }; f- e8 m/ `5 M1 D5406 ^! m) N6 D- ^; K+ W. E, _; r$ F
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
2 W1 r* \- A, S$ E! fthe base of the phallus and was dark and curled. The+ l5 u# B# @6 `7 H
testicular volume was prepubertal at 2 mL each.
7 Z5 D0 z+ S7 rThe skin was moist and smooth and somewhat
" x9 Z! v1 F. U: d% Q/ S7 Koily. No axillary hair was noted. There were no
A9 A% P" Z* w4 p9 {( s; Nabnormal skin pigmentations or café-au-lait spots.
7 R5 [: i$ V/ h4 JNeurologic evaluation showed deep tendon reflex 2+
# [ F) o* {5 F/ f1 ibilateral and symmetrical. There was no suggestion
8 e) G* m) ~) C' B2 D" {! }, d. Q' Zof papilledema.
5 b4 P$ | [# p7 l) ?* t/ @Laboratory Evaluation( G/ y3 H" s: x
The bone age was consistent with 28 months by
3 r5 C s( A9 Pusing the standard of Greulich and Pyle at a chrono-+ X$ c2 H X2 V* s( [, c& ~
logic age of 16 months (advanced).5 Chromosomal
7 d$ M3 d, M1 Dkaryotype was 46XY. The thyroid function test
9 @' X5 L9 g- ^/ Vshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
- t+ W& @- F7 ? A5 \lating hormone level was 1.3 µIU/mL (both normal).
?. F: P: Z \( C/ QThe concentrations of serum electrolytes, blood3 k0 E2 J! e8 X2 {- e
urea nitrogen, creatinine, and calcium all were1 R* p; U' K: F4 E
within normal range for his age. The concentration
& h: k6 Z8 o, A2 ]of serum 17-hydroxyprogesterone was 16 ng/dL4 E# Z2 n d& p0 k3 t
(normal, 3 to 90 ng/dL), androstenedione was 20
: C9 I5 j: D3 F; [0 Ong/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
" @( x% D: d/ ]% Rterone was 38 ng/dL (normal, 50 to 760 ng/dL),
# K; q( a- L7 a. y2 h! b+ u, gdesoxycorticosterone was 4.3 ng/dL (normal, 7 to- M# r1 q& z5 [! e
49ng/dL), 11-desoxycortisol (specific compound S)5 D- }2 C6 s! |+ A# Q1 v" {: s8 b
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
, Z) K- K# z3 g3 X8 ptisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total# m. w; O2 i) {- Q4 S2 M t. `
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
6 S V! L7 C7 V; d; ?. c4 Sand β-human chorionic gonadotropin was less than
3 G9 z0 X) Z4 k( e) B, x5 mIU/mL (normal <5 mIU/mL). Serum follicular8 m m2 f- [! [5 N
stimulating hormone and leuteinizing hormone9 }- r9 b- X8 Y" `2 r
concentrations were less than 0.05 mIU/mL/ t9 [3 z$ Z( K& q0 a
(prepubertal).$ P: O# D* p& \ ]* |' q
The parents were notified about the laboratory* A% }- O/ `# u% a7 q
results and were informed that all of the tests were/ i/ S% X" x! t- h- b' m
normal except the testosterone level was high. The
, e+ i1 I1 j9 m. |follow-up visit was arranged within a few weeks to/ y2 |; C4 s2 C0 s1 z1 m& I0 \
obtain testicular and abdominal sonograms; how-
$ h( `/ i9 c* E/ Pever, the family did not return for 4 months.
4 F) q5 X$ i) R' u. K) PPhysical examination at this time revealed that the
5 [0 M# W; m& s0 S" H& H; j/ pchild had grown 2.5 cm in 4 months and had gained* Q" A, j( T7 H& B
2 kg of weight. Physical examination remained1 P; |8 `# I. v# F3 j1 G1 S5 F/ m
unchanged. Surprisingly, the pubic hair almost com-
; l! b* c6 d4 J% I4 _5 M7 Lpletely disappeared except for a few vellous hairs at
8 i5 u; Y- k- bthe base of the phallus. Testicular volume was still 2
. Y1 g0 \+ w9 F6 C# h; GmL, and the size of the penis remained unchanged.' W/ y# S- D/ k, z- I! u4 x
The mother also said that the boy was no longer hav-
/ P! E2 L; j! G; o8 b( ~; [ing frequent erections.
; {) h, N" G0 K# U0 K* q6 P" uBoth parents were again questioned about use of
: q& B A4 l; iany ointment/creams that they may have applied to
0 A M1 x) D+ r. D8 Hthe child’s skin. This time the father admitted the
+ c! }; U/ g: Q2 T6 O" F* o5 xTopical Testosterone Exposure / Bhowmick et al 541
n) ^. r- ]- x/ l8 Kuse of testosterone gel twice daily that he was apply-
0 W- z4 `& G7 V2 M. Wing over his own shoulders, chest, and back area for5 F/ O& K) y5 ^
a year. The father also revealed he was embarrassed
. e7 T: W' H, q: B, u' Pto disclose that he was using a testosterone gel pre-5 {& j ?- U3 U* y3 x
scribed by his family physician for decreased libido
7 q! ]7 }! h. |secondary to depression. Y0 J) d* k2 Z+ _
The child slept in the same bed with parents., \6 j+ M# n1 s3 `6 r8 g4 {5 `
The father would hug the baby and hold him on his' b+ v) x' B" [9 A/ S$ S& T
chest for a considerable period of time, causing sig-3 }: j1 a4 v1 M2 N+ n3 T
nificant bare skin contact between baby and father.( a1 s# i* V9 R6 ?9 f# v7 ^
The father also admitted that after the phone call,
+ p; X! u) W0 Z: S2 z( swhen he learned the testosterone level in the baby# C$ C: ^" P( h! V0 [# u2 Y6 c" w
was high, he then read the product information
5 }% ^1 q7 f( |+ w7 p apacket and concluded that it was most likely the rea-9 w I" x- M: [3 X( [% X D
son for the child’s virilization. At that time, they
0 U+ U! ~- e5 |* r1 m. O2 qdecided to put the baby in a separate bed, and the
7 f+ v0 U: y S1 Vfather was not hugging him with bare skin and had
0 ~. f9 k4 c. v+ N; abeen using protective clothing. A repeat testosterone
& U) C# O) v4 ^7 r+ [test was ordered, but the family did not go to the5 g0 O- T( A, Y
laboratory to obtain the test.3 U! _4 \. k& m' W3 \. L1 i
Discussion
7 z" U4 D/ c% Q ?, }+ Y! u1 pPrecocious puberty in boys is defined as secondary
2 `7 j; \! Q7 ?' _sexual development before 9 years of age.1,4: Z, n4 }1 h9 z8 S7 [7 s
Precocious puberty is termed as central (true) when
! u7 H, j9 j# Eit is caused by the premature activation of hypo-
% K, N6 L4 }4 X% C3 ~thalamic pituitary gonadal axis. CPP is more com-$ V' W5 t5 P) R* F
mon in girls than in boys.1,3 Most boys with CPP6 B; G# C5 _' L& A; o
may have a central nervous system lesion that is" X T4 P/ G* G: `& N; S$ U
responsible for the early activation of the hypothal-
' }8 Z) s, d, I- R x4 zamic pituitary gonadal axis.1-3 Thus, greater empha-' {8 @9 {* ]) K: v2 C$ F: d' }/ Y
sis has been given to neuroradiologic imaging in% K7 E. \) ~$ p, C
boys with precocious puberty. In addition to viril-
/ W4 |, c# l( R( G& D1 H# bization, the clinical hallmark of CPP is the symmet-! s3 k7 k- x' V( l; K! _ N3 R
rical testicular growth secondary to stimulation by
! E( i. ?& y3 Kgonadotropins.1,3: a% V6 y$ y% C9 e% c$ X* r4 G
Gonadotropin-independent peripheral preco-* \0 `1 ?6 u: ~) J. w+ G/ Y
cious puberty in boys also results from inappropriate
c3 O* X s' I9 @" Aandrogenic stimulation from either endogenous or, W1 V( p: h0 B: F7 S _1 e3 l
exogenous sources, nonpituitary gonadotropin stim-
" p! S9 v# y0 W0 n7 Mulation, and rare activating mutations.3 Virilizing/ [ K [4 {( n' G' c+ l0 {- D. u
congenital adrenal hyperplasia producing excessive
: k* t* { S0 |1 `3 F. zadrenal androgens is a common cause of precocious6 g" b; W2 j) S
puberty in boys.3,4
7 Y* P7 V% c! i# XThe most common form of congenital adrenal6 w1 A* a3 Q6 [( N d
hyperplasia is the 21-hydroxylase enzyme deficiency.
4 M2 `5 `) H4 P u7 R3 J0 O8 ~; KThe 11-β hydroxylase deficiency may also result in
- g% W; u, K# ^) d K$ ?' hexcessive adrenal androgen production, and rarely,& F4 c8 c! n5 r* b- _
an adrenal tumor may also cause adrenal androgen
* P8 v" [& y* {* y# `% C/ eexcess.1,37 G9 J& a3 ^0 ^6 r& a6 [: P& G" q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
/ m- x: w# P6 |* p4 ]& y542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# Z" D( C8 p& r7 l' h$ k
A unique entity of male-limited gonadotropin-
0 B0 }% I5 C6 f3 t+ m% O/ pindependent precocious puberty, which is also known
3 |2 d* R# C, j# C, F! oas testotoxicosis, may cause precocious puberty at a
% Z& I9 E2 c: C" Dvery young age. The physical findings in these boys
2 C3 m* I- a/ r" }1 V }9 `with this disorder are full pubertal development,4 e7 b* t! r+ v
including bilateral testicular growth, similar to boys
6 r9 t' J. J1 y' r) Iwith CPP. The gonadotropin levels in this disorder- A6 j, S r" h, I7 G; I9 o; d$ G
are suppressed to prepubertal levels and do not show: `. W% ]5 k* y% h
pubertal response of gonadotropin after gonadotropin-
; K& h: v/ H% X) ?' U3 Oreleasing hormone stimulation. This is a sex-linked3 C% T0 D, L* A, V
autosomal dominant disorder that affects only
: P( s9 u5 `& D! V7 `8 h! O' Zmales; therefore, other male members of the family9 w8 b0 ]# D! B3 M! N7 r8 _; m
may have similar precocious puberty.3
' y6 u! I* I' M0 P0 m [+ F" p; yIn our patient, physical examination was incon-, k0 Q$ n# N2 u" }1 j2 Z
sistent with true precocious puberty since his testi-& O1 }$ _, N1 i$ w( E
cles were prepubertal in size. However, testotoxicosis
' B7 w+ E Z. ^was in the differential diagnosis because his father
4 x! m1 F' v8 t5 M( zstarted puberty somewhat early, and occasionally,
. I: n$ f( X3 Ttesticular enlargement is not that evident in the
6 h6 R! K" e" p. `: Kbeginning of this process.1 In the absence of a neg-
% ]: [2 c5 C) \" @" ^ative initial history of androgen exposure, our& K% S% \0 x; H' r& f
biggest concern was virilizing adrenal hyperplasia,, R0 h2 _% ?$ f+ k9 A( q7 t- W$ ~
either 21-hydroxylase deficiency or 11-β hydroxylase
& Q, g$ z3 f4 n9 i& Tdeficiency. Those diagnoses were excluded by find-0 h6 Q! g9 Q* p! w, J
ing the normal level of adrenal steroids.
3 d1 A4 |7 w. G! F, e& [The diagnosis of exogenous androgens was strongly
+ }1 o) g9 i& H V2 T9 Q" ? p9 m( esuspected in a follow-up visit after 4 months because% e8 v0 T5 F" A: T/ v
the physical examination revealed the complete disap-
; s9 s" D9 A8 p" x; P6 C+ ?3 Vpearance of pubic hair, normal growth velocity, and
+ ^* ~2 Z8 u9 b' mdecreased erections. The father admitted using a testos-& q5 [, H$ r" J0 x$ V
terone gel, which he concealed at first visit. He was
2 e$ T) M+ H# h% [* h n0 Vusing it rather frequently, twice a day. The Physicians’6 |- k" o# ?0 x2 p
Desk Reference, or package insert of this product, gel or
9 B# I. A* }! X- wcream, cautions about dermal testosterone transfer to
% k9 d1 H' e: C: k3 `' J& Iunprotected females through direct skin exposure.% \% ~. t0 p& R
Serum testosterone level was found to be 2 times the! a6 e/ i& ~7 F! `7 Q% }
baseline value in those females who were exposed to
6 g" k& l7 n' leven 15 minutes of direct skin contact with their male- T0 O3 A! o' V* |: f$ x4 _5 h: y
partners.6 However, when a shirt covered the applica-" z; q. q [/ o/ X. O
tion site, this testosterone transfer was prevented.
8 W/ U. y6 [1 xOur patient’s testosterone level was 60 ng/mL,# O* \3 E9 |) w
which was clearly high. Some studies suggest that8 x- d6 h! \% Q
dermal conversion of testosterone to dihydrotestos-
0 M6 d e% s% w- P2 p2 }) R7 S( ^terone, which is a more potent metabolite, is more
: E6 ?& s1 N: f2 t4 g! S) l6 factive in young children exposed to testosterone
; g% q& I m) T1 r& L5 texogenously7; however, we did not measure a dihy-2 F6 I0 A( z9 r" R# z6 F
drotestosterone level in our patient. In addition to% d; r! L# b3 \* A# s) _ m
virilization, exposure to exogenous testosterone in
& f+ J5 {' _: c2 H, p3 zchildren results in an increase in growth velocity and
$ U. ~9 ]: {5 Wadvanced bone age, as seen in our patient.; w9 c$ P: x/ e2 M
The long-term effect of androgen exposure during1 V3 p% M! N1 b1 G: J
early childhood on pubertal development and final6 ~6 G* E; g' o1 N
adult height are not fully known and always remain
% m W8 i N" t( n u3 ~a concern. Children treated with short-term testos-
8 z# P1 N- y; \& B8 _: Y7 Z/ cterone injection or topical androgen may exhibit some
! R) k& V! H" Z- J0 _acceleration of the skeletal maturation; however, after
" u- t1 ]+ B- N7 v9 |3 rcessation of treatment, the rate of bone maturation
0 |3 {/ C- u1 r0 Q. adecelerates and gradually returns to normal.8,9- Z2 p% j+ B" R+ S
There are conflicting reports and controversy
7 z% _) c. s' L4 P6 X' Dover the effect of early androgen exposure on adult; y: e0 y0 D% o4 p
penile length.10,11 Some reports suggest subnormal
. E! e2 e) z, ]adult penile length, apparently because of downreg-
3 A, s0 |- n1 ]' U; t7 B5 culation of androgen receptor number.10,12 However,
& ?( |* I' o; w0 T6 M9 }" XSutherland et al13 did not find a correlation between3 R9 X1 S. K4 m5 A
childhood testosterone exposure and reduced adult
2 k+ @4 @6 K% z' E9 J" Ypenile length in clinical studies., B% t8 I# ~/ p# Z l ]' w9 j
Nonetheless, we do not believe our patient is
5 _; E3 }7 X* j& Jgoing to experience any of the untoward effects from) o' @8 {9 e- F( o
testosterone exposure as mentioned earlier because
- a) |# e9 m, K& [. m; {the exposure was not for a prolonged period of time.
3 x; O0 n/ v U& [5 d0 gAlthough the bone age was advanced at the time of
5 I6 {$ y. `- T+ sdiagnosis, the child had a normal growth velocity at* d7 A6 t- { X2 t5 Y, i: X. G9 f
the follow-up visit. It is hoped that his final adult4 `, \4 g1 c) J
height will not be affected.% @- V, h# h1 ~- s0 ?
Although rarely reported, the widespread avail-
0 V' x3 U$ \+ s+ q* J$ K3 vability of androgen products in our society may; r, o' s8 Y8 a. Y7 k( `
indeed cause more virilization in male or female! u3 a2 a& |0 @' @* S8 q; y5 ?
children than one would realize. Exposure to andro-
; X4 c4 [& }, p6 f! ugen products must be considered and specific ques-, d Z$ R- ?8 g" P
tioning about the use of a testosterone product or
* g0 y+ _9 j: L6 wgel should be asked of the family members during
3 `* D* A/ a' d: Y& Q6 J2 w. tthe evaluation of any children who present with vir-
: x: \) {3 j d/ H9 x! o9 `ilization or peripheral precocious puberty. The diag-
3 c: s4 i: T j) ]1 E9 ynosis can be established by just a few tests and by
: ^! M6 D3 F8 i1 \/ w8 V! Jappropriate history. The inability to obtain such a
8 F7 m) h, G" ^history, or failure to ask the specific questions, may6 L% Y' M1 ~. t0 o: z: W
result in extensive, unnecessary, and expensive
7 Z: z4 _. ?0 d4 B; W) \investigation. The primary care physician should be
0 a( S' Y, {8 Kaware of this fact, because most of these children
+ h+ V1 A7 U! V) h9 Q7 f3 Amay initially present in their practice. The Physicians’
6 Q3 x1 v) C5 ^. q/ [& }+ x! [9 n, wDesk Reference and package insert should also put a( i& `8 G1 u X4 o- h5 Q
warning about the virilizing effect on a male or. {! }% _) h5 L3 O8 c0 G5 f
female child who might come in contact with some-
/ ]$ k) x7 Y% ~' ]one using any of these products.
2 n W- Z; p4 d' `References# T8 [) @& R; j$ m2 t) s7 r8 G
1. Styne DM. The testes: disorder of sexual differentiation" s# ~" V$ a3 l, n* [
and puberty in the male. In: Sperling MA, ed. Pediatric, ~/ n: n! T8 e3 z2 e
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
4 H5 W& {) Z+ h4 H/ ^( X! i2002: 565-628.9 r# u9 g% D+ K
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
- b$ O: ]# L. T& Q2 F! I6 vpuberty in children with tumours of the suprasellar pineal |
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