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Sexual Precocity in a 16-Month-Old
* u' s( O' P( \Boy Induced by Indirect Topical
" y9 I! p: |2 i. V, Q0 qExposure to Testosterone$ F* D4 r0 \% N) y9 U) e% j; U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
: w9 a9 G, u- j3 l# n+ kand Kenneth R. Rettig, MD1# d: f- ^. ^* ]9 w/ D+ w
Clinical Pediatrics
. O, O+ X( E- f- z; t. s6 zVolume 46 Number 6
3 M9 ]7 s/ d, f* XJuly 2007 540-543. L& N8 r8 @! H5 m
© 2007 Sage Publications8 \0 |4 P9 H. s' u% X
10.1177/0009922806296651
% h8 H/ S& b) k4 h8 fhttp://clp.sagepub.com
8 V* t* Y1 t$ Q% p6 z! dhosted at; m, |8 E6 ?; M& O( Y
http://online.sagepub.com* R& f% u6 B2 A. r
Precocious puberty in boys, central or peripheral,
4 T. z3 f. y" w$ F# \is a significant concern for physicians. Central8 O6 e3 G+ z) ~5 E) {! s$ F1 ~/ ~
precocious puberty (CPP), which is mediated; i i* M$ @- P
through the hypothalamic pituitary gonadal axis, has
; i e6 Q0 |8 k2 A) J1 W* l5 Xa higher incidence of organic central nervous system8 Q/ G7 H4 a7 m
lesions in boys.1,2 Virilization in boys, as manifested& m. i3 y, S$ x+ R v+ `2 g
by enlargement of the penis, development of pubic
' [/ P. q* Y$ Lhair, and facial acne without enlargement of testi-
2 h p* Q! A$ N8 ]: P8 xcles, suggests peripheral or pseudopuberty.1-3 We
0 a. q- ?; d" ]# N3 t+ a2 Xreport a 16-month-old boy who presented with the
9 z4 _; X0 |# V( Y2 [0 `5 b+ Lenlargement of the phallus and pubic hair develop-) W. ~* |/ _$ ]+ i1 t
ment without testicular enlargement, which was due X4 h W( V. j! n
to the unintentional exposure to androgen gel used by
" J# D6 u; y) G2 y# j& sthe father. The family initially concealed this infor-
G% d) C! z, z0 M+ qmation, resulting in an extensive work-up for this9 N' ?9 K1 f8 A
child. Given the widespread and easy availability of5 u R9 _8 d. j- H* [0 W1 E
testosterone gel and cream, we believe this is proba-
5 _/ x9 C) q. S9 Z1 j- fbly more common than the rare case report in the2 U, |" O# D% u% u% G
literature.4
7 R- q+ y A" R$ _6 \* @Patient Report" m7 _! E1 b" ^; x. B
A 16-month-old white child was referred to the
( v0 ]) X' L- v. k4 ~9 uendocrine clinic by his pediatrician with the concern6 |! f9 x! R. f# K% u# D( G! K# a
of early sexual development. His mother noticed
+ f% e$ u& | i# Z# P3 _light colored pubic hair development when he was3 T# X4 A1 e/ t0 j; X
From the 1Division of Pediatric Endocrinology, 2University of( u5 ~) i u+ q9 U! K# K
South Alabama Medical Center, Mobile, Alabama.
: n4 W% z5 y1 i' f0 k+ I4 WAddress correspondence to: Samar K. Bhowmick, MD, FACE,; c$ p8 X3 P, z' k6 v' T% r* y
Professor of Pediatrics, University of South Alabama, College of. |' Z8 H. |" h% T" g8 r+ ]
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
2 G {: g/ _! @$ k& {9 \3 c6 F, Ae-mail: [email protected].% b4 L$ f9 H6 _3 r6 _$ v2 q
about 6 to 7 months old, which progressively became8 L0 t6 O0 c( \% w6 q ? w6 ~& C+ ]
darker. She was also concerned about the enlarge-6 }4 b! E0 @! c1 o6 {" L
ment of his penis and frequent erections. The child+ o& P' g8 U! n8 b8 q! V2 M
was the product of a full-term normal delivery, with# V" W, l, U( i/ P& D: ?0 U
a birth weight of 7 lb 14 oz, and birth length of
+ a. C- y* O* D% o& E9 x% Y20 inches. He was breast-fed throughout the first year
8 p) Q# Q9 U# `! wof life and was still receiving breast milk along with
( [3 K4 d1 z7 J3 _solid food. He had no hospitalizations or surgery,2 b& A, I5 j- X9 _
and his psychosocial and psychomotor development
$ [5 K5 o4 v6 u3 wwas age appropriate.
4 S/ w* J+ F/ K5 a8 M' ^The family history was remarkable for the father,
% |( |+ u ]2 u3 xwho was diagnosed with hypothyroidism at age 16,
; N' N$ b' s6 C" q$ M R$ Gwhich was treated with thyroxine. The father’s
5 }: n! {; P: v u6 e: Sheight was 6 feet, and he went through a somewhat; W- i- S' R. k3 }) V2 `
early puberty and had stopped growing by age 14.
& l, O1 W( O5 @# i( A+ JThe father denied taking any other medication. The* Y0 W0 p/ w& t0 O1 m& O
child’s mother was in good health. Her menarche
. T3 X( e4 q3 d+ W- Kwas at 11 years of age, and her height was at 5 feet4 ]/ k" q4 F8 T1 r
5 inches. There was no other family history of pre-3 x* _4 \8 ~& T
cocious sexual development in the first-degree rela-$ Q# P2 [; x1 O
tives. There were no siblings.
' L1 X2 f3 B% t c! S0 K5 PPhysical Examination
) T# c+ U$ @) d& `! k* F4 QThe physical examination revealed a very active,
0 V; @5 j! B' n# ~7 wplayful, and healthy boy. The vital signs documented% ~# O2 a7 s J9 l
a blood pressure of 85/50 mm Hg, his length was
- [* `1 f, ~0 _! o. u+ ^90 cm (>97th percentile), and his weight was 14.4 kg0 E5 g2 e' S) |: E1 s0 U
(also >97th percentile). The observed yearly growth
- i- u/ E& r+ U" L7 evelocity was 30 cm (12 inches). The examination of6 O" _4 i8 h9 H) m# B
the neck revealed no thyroid enlargement.
$ e# t: V) T- r' _8 BThe genitourinary examination was remarkable for
. m: w2 _2 _! F: y1 r5 ^7 Denlargement of the penis, with a stretched length of
9 R0 j% }' r) R3 P) S8 cm and a width of 2 cm. The glans penis was very well8 m/ d" ]: @* C5 y* U5 B7 E) b
developed. The pubic hair was Tanner II, mostly around5 b& E. \" Z. I
540
, v$ o1 U% E: Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
+ j' l5 F1 M; U" ythe base of the phallus and was dark and curled. The
0 K! ^; D$ k( L9 ]3 Dtesticular volume was prepubertal at 2 mL each.6 s, W5 |' c' [& Y; m
The skin was moist and smooth and somewhat
9 r0 o0 q, F7 l$ r S. T0 toily. No axillary hair was noted. There were no
+ g% }: K# v8 }abnormal skin pigmentations or café-au-lait spots.
2 V% N, \9 z8 a& @Neurologic evaluation showed deep tendon reflex 2+
' p0 {' Y* ]& Zbilateral and symmetrical. There was no suggestion! R/ i( X: I' b$ ~( ^
of papilledema.. t1 m0 b: U4 r- h/ @8 g. q2 G
Laboratory Evaluation
+ t7 b) q* Y$ S, k0 \The bone age was consistent with 28 months by: i0 G! Q6 o5 W+ l$ h
using the standard of Greulich and Pyle at a chrono-# a$ l( U* M( L3 M* W! m
logic age of 16 months (advanced).5 Chromosomal" J! Z1 I/ H2 U
karyotype was 46XY. The thyroid function test
0 C$ X; E- i. s; C7 \' @showed a free T4 of 1.69 ng/dL, and thyroid stimu-
, x0 N. c# ]% ^3 d) R: m- hlating hormone level was 1.3 µIU/mL (both normal).
$ }* s R8 E6 e+ z3 j7 IThe concentrations of serum electrolytes, blood$ X8 i s$ B! a+ e6 n
urea nitrogen, creatinine, and calcium all were
% n: D1 J8 N% ~" V/ awithin normal range for his age. The concentration2 g3 K. O/ Y' R& h8 d6 Q, T+ L% R2 Q2 [
of serum 17-hydroxyprogesterone was 16 ng/dL
: K+ x: i9 {5 }; V. N a1 u(normal, 3 to 90 ng/dL), androstenedione was 20' }: d+ Y- u& y/ k
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-) t) ?3 v' ` x3 s* p2 E
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
# k4 T3 c* g Q5 ]; P0 Kdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
* Y) T L2 v! M49ng/dL), 11-desoxycortisol (specific compound S)
# b8 e9 Z" J0 p. Owas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-" V' I5 c! T3 X8 `
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
9 ^8 k0 v( V+ e- y! R c6 u ~* ^+ }4 Wtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
9 N6 m* ]' o5 u/ b. p1 m) j* u5 P7 Nand β-human chorionic gonadotropin was less than
9 z3 i& w3 }2 l, C/ y! h5 H- }5 mIU/mL (normal <5 mIU/mL). Serum follicular3 Z3 s7 q7 ]2 ^
stimulating hormone and leuteinizing hormone# Z- u. z6 f+ m! u* `
concentrations were less than 0.05 mIU/mL+ u% K! T' Q( p& g
(prepubertal).
3 m6 ^/ y v9 B$ u& M2 DThe parents were notified about the laboratory
) M/ H6 l( ^. ^+ D0 Fresults and were informed that all of the tests were" M2 z& V; x, f q- v; n7 B
normal except the testosterone level was high. The
7 h# V% A9 [+ h) Hfollow-up visit was arranged within a few weeks to6 t4 d5 D9 Z" ?; ^
obtain testicular and abdominal sonograms; how-$ _3 U( c0 l; r: A* Q8 H' q& T
ever, the family did not return for 4 months.+ o0 t$ D+ g- X) O
Physical examination at this time revealed that the/ P& f" k- ^6 x9 Y# H
child had grown 2.5 cm in 4 months and had gained
: @8 C, d" F* |3 X2 kg of weight. Physical examination remained9 a* P8 Q7 J% H1 v: ?
unchanged. Surprisingly, the pubic hair almost com-
3 o) m( H( ~* l( T# L6 I6 ]pletely disappeared except for a few vellous hairs at
$ ]1 R* d7 Y7 V% [7 Q( P% dthe base of the phallus. Testicular volume was still 2( P- a+ s( A" H/ E
mL, and the size of the penis remained unchanged.3 `; n/ l; x7 s: W2 \% n9 A
The mother also said that the boy was no longer hav-6 J: T# K0 ]5 Y* ^
ing frequent erections." ]4 Z M2 n ?- a- n. V- j
Both parents were again questioned about use of
2 g7 E! V$ ~' H \' f# ?any ointment/creams that they may have applied to# l V6 i* W( k' n; v
the child’s skin. This time the father admitted the0 K# {! K6 P/ z# m5 |4 g
Topical Testosterone Exposure / Bhowmick et al 541
# T! {& E- U+ i5 Euse of testosterone gel twice daily that he was apply-
9 a" d) `1 ` `: I* f* eing over his own shoulders, chest, and back area for
9 w: ~# S+ A) D2 P' n7 d8 ~& La year. The father also revealed he was embarrassed
2 x B& T9 f! @( Ito disclose that he was using a testosterone gel pre-
- J7 o. g$ q% `( Mscribed by his family physician for decreased libido! y" _( e% @9 m3 M4 i
secondary to depression.; ]. i6 I0 _6 ~6 Y3 L5 P
The child slept in the same bed with parents.+ |/ A, t: q8 j/ [2 X' g9 M
The father would hug the baby and hold him on his- f% x/ F h2 i: I. z* [
chest for a considerable period of time, causing sig-* L/ F& y: l: f
nificant bare skin contact between baby and father.
9 |6 G& n, M' y# M2 |! s. uThe father also admitted that after the phone call,0 l* U8 f# Q7 z2 ~
when he learned the testosterone level in the baby \) G' L+ F; _7 U- B/ K4 U& ]8 c
was high, he then read the product information
' H$ m5 f. n, T8 b' Hpacket and concluded that it was most likely the rea-$ ?+ D4 S6 {, T: r) o( t B
son for the child’s virilization. At that time, they
- q/ k' }& K# x% V# g. mdecided to put the baby in a separate bed, and the/ r( s) M4 F, V J/ a% g
father was not hugging him with bare skin and had
2 l4 \, {8 N8 x2 ?$ {been using protective clothing. A repeat testosterone& I' k% N/ P! t8 h# A! E; g
test was ordered, but the family did not go to the! h, }% w5 }* B4 }5 M+ s. I
laboratory to obtain the test.- w' t9 {! I+ F9 e0 B
Discussion( H1 ~: J# j4 p8 u) a$ o
Precocious puberty in boys is defined as secondary
9 O [ |4 \ Gsexual development before 9 years of age.1,4
7 e ?. r5 ]( wPrecocious puberty is termed as central (true) when" v7 p& U5 e( m) s0 b4 l
it is caused by the premature activation of hypo-$ h* e7 S1 g+ \4 a' U1 ^
thalamic pituitary gonadal axis. CPP is more com-) P% A) B" r) k/ G/ s3 K# }
mon in girls than in boys.1,3 Most boys with CPP
* j3 ~ P5 l' I2 q. s U' ?may have a central nervous system lesion that is" a5 G' p2 m- i. t( U
responsible for the early activation of the hypothal-
2 |# @" ?$ Z/ j2 w' Xamic pituitary gonadal axis.1-3 Thus, greater empha-6 |& d) O8 X. L0 v9 C3 S" H
sis has been given to neuroradiologic imaging in/ F. {% p5 q. k( e8 Y2 k% Z
boys with precocious puberty. In addition to viril-
1 y6 T# d% ]0 uization, the clinical hallmark of CPP is the symmet-
: L! F5 \+ h+ Y% m+ ^rical testicular growth secondary to stimulation by f& q, `, z' e( N9 n/ y: x
gonadotropins.1,3
U; C5 L- A b% S p3 [6 ~Gonadotropin-independent peripheral preco-1 f/ c* p! B3 A; m+ w
cious puberty in boys also results from inappropriate
7 _1 {8 O2 q* i4 D& randrogenic stimulation from either endogenous or0 G1 J) h- A5 W' _
exogenous sources, nonpituitary gonadotropin stim-
( m1 ^4 K% w) Julation, and rare activating mutations.3 Virilizing( g/ C9 ^4 E6 c0 p
congenital adrenal hyperplasia producing excessive) h8 {5 n( U- ?9 L, [7 I6 \2 C
adrenal androgens is a common cause of precocious3 [6 f" a g7 T
puberty in boys.3,4( M9 w4 b# Q+ f n7 G
The most common form of congenital adrenal
' b6 ]! d1 S( t' w7 D! U" m' Q0 khyperplasia is the 21-hydroxylase enzyme deficiency.
2 F6 V* J# w# ~The 11-β hydroxylase deficiency may also result in
( m; {. d7 ]: w' Q3 c" }excessive adrenal androgen production, and rarely,
# ~4 D( t( ]( m& zan adrenal tumor may also cause adrenal androgen
( R" Y9 Q! R( n8 v1 f7 Qexcess.1,3% D- q( c1 d Q: o/ n9 l
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% s6 W! n5 e$ g/ p) V
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007: A1 ], P9 p9 u9 G
A unique entity of male-limited gonadotropin-& v) {$ n, f! A- ^2 i. X, a
independent precocious puberty, which is also known- [5 i0 C+ M: g- m: Z& E
as testotoxicosis, may cause precocious puberty at a
1 K) X( s5 p4 l& h( f* Wvery young age. The physical findings in these boys
" e1 y" g7 G3 I) e! gwith this disorder are full pubertal development,
$ P* m T' m. R; N2 Qincluding bilateral testicular growth, similar to boys* T& }" G3 K0 r4 {
with CPP. The gonadotropin levels in this disorder
+ e( V/ a/ u3 ]( p0 ^2 _: ?are suppressed to prepubertal levels and do not show% T; C; I$ D- z* D. x7 W: s
pubertal response of gonadotropin after gonadotropin-
: b0 e: y7 [( Freleasing hormone stimulation. This is a sex-linked
# ]& Z+ N; w, {/ j( m8 R1 uautosomal dominant disorder that affects only! N. A1 ^* b% r! G7 y7 Z- E+ M! k8 q
males; therefore, other male members of the family* }! R J( Y3 k
may have similar precocious puberty.3
# Y; v0 I" J4 g' G# X6 U9 Z. wIn our patient, physical examination was incon-
9 A$ s1 @% J. s. Y2 usistent with true precocious puberty since his testi-
7 x U1 _0 n' O" ]/ lcles were prepubertal in size. However, testotoxicosis
9 g' s, Y1 w. W: lwas in the differential diagnosis because his father8 m; m; n: G9 F: F! u+ A
started puberty somewhat early, and occasionally,1 R" W+ [) P9 Y8 C E% A, e' q, w
testicular enlargement is not that evident in the. }1 L: k l# W
beginning of this process.1 In the absence of a neg-& m, y3 m" s0 U! t& }# j( |
ative initial history of androgen exposure, our
) K/ v# q: g5 y7 I- u' R9 ~, }2 O; Cbiggest concern was virilizing adrenal hyperplasia,3 r5 ]5 n u8 A: B. o" g! ?) K8 k- V
either 21-hydroxylase deficiency or 11-β hydroxylase3 |7 [; n( ^. s. S
deficiency. Those diagnoses were excluded by find-6 g$ i- A6 I, C1 S4 v. p: w
ing the normal level of adrenal steroids.
: l5 G1 {; ]: Z) [# qThe diagnosis of exogenous androgens was strongly
: Y" V& H6 }8 D7 P0 xsuspected in a follow-up visit after 4 months because
& N7 M1 k* M( ]+ F1 hthe physical examination revealed the complete disap-
+ E8 h) N* m0 v' p0 c9 d+ dpearance of pubic hair, normal growth velocity, and
( p! w9 o8 F6 A) c: p! i- }decreased erections. The father admitted using a testos-/ P, w; U6 V0 E( k9 f
terone gel, which he concealed at first visit. He was
: ]- {8 Z( j: @3 xusing it rather frequently, twice a day. The Physicians’
( L) D4 `9 u3 m8 J' |+ yDesk Reference, or package insert of this product, gel or
7 d7 \- a# z" B8 r; b/ W& mcream, cautions about dermal testosterone transfer to
[4 `7 B& s: v4 ^; h( g( [" b+ Hunprotected females through direct skin exposure.
2 D' l4 g. S2 S* P( T% J; HSerum testosterone level was found to be 2 times the
8 j# V" r F) qbaseline value in those females who were exposed to
; U# V' O" h' M3 ueven 15 minutes of direct skin contact with their male
) ^5 e b# ~7 r; m6 J/ O! q, Apartners.6 However, when a shirt covered the applica-
3 Z; J# e+ n6 u( M9 _tion site, this testosterone transfer was prevented.1 j2 A5 Q$ R& @3 U/ d1 J! c. c8 Y# k
Our patient’s testosterone level was 60 ng/mL,
7 g9 `4 b# F& `2 v6 ywhich was clearly high. Some studies suggest that
o# k6 `5 v% q0 i0 f/ C- jdermal conversion of testosterone to dihydrotestos-2 g3 L4 C5 G- R3 e
terone, which is a more potent metabolite, is more
8 i. o' G2 W' Y# [: Zactive in young children exposed to testosterone
w+ [3 F. U: ~- R* `4 Cexogenously7; however, we did not measure a dihy-
9 b8 z* i3 f( h8 Q/ u6 ?9 V* cdrotestosterone level in our patient. In addition to+ ]* v, C k* I( N' F$ d; N+ J/ F
virilization, exposure to exogenous testosterone in9 N7 B2 ~% Q+ w+ a( U, q
children results in an increase in growth velocity and" [0 n$ Q: O5 {. Z& V" C
advanced bone age, as seen in our patient.
6 |6 B, ?4 [' q/ B' z- cThe long-term effect of androgen exposure during
# M: ?! p( t' T3 rearly childhood on pubertal development and final
3 Y9 x7 a" V, B' F4 Yadult height are not fully known and always remain l! w! b; t! u6 t8 ^
a concern. Children treated with short-term testos-8 x) u, [4 M5 g0 j7 T2 P
terone injection or topical androgen may exhibit some
% C* A; f: ]. i- J4 oacceleration of the skeletal maturation; however, after
- M! c8 R8 ~) Kcessation of treatment, the rate of bone maturation# ~$ F0 n% _' a$ y+ p/ V
decelerates and gradually returns to normal.8,9! q* B' T6 }8 K+ P7 D
There are conflicting reports and controversy
* ~# Q3 e& ^ tover the effect of early androgen exposure on adult5 o$ x( B% @. I' M/ p- x- g
penile length.10,11 Some reports suggest subnormal7 c/ d( g* A2 B6 V0 f ^
adult penile length, apparently because of downreg-
2 L- n: m1 u, C1 Wulation of androgen receptor number.10,12 However,8 O7 I- p- f' k9 a/ ?
Sutherland et al13 did not find a correlation between# [* _+ o- j# [
childhood testosterone exposure and reduced adult" Y$ J, D7 Y3 @8 j( s
penile length in clinical studies.
3 q& I, C8 V O0 `% c; \; A- L. WNonetheless, we do not believe our patient is8 G; ]5 W7 u9 I! D# ?
going to experience any of the untoward effects from6 v" t5 D- i X5 E, U. {& t" R
testosterone exposure as mentioned earlier because
3 I' m' t9 B% S# Othe exposure was not for a prolonged period of time.9 |2 c5 c3 D' S Q
Although the bone age was advanced at the time of- e2 P/ J4 u: u. u
diagnosis, the child had a normal growth velocity at
# @1 S! y- i- V+ Hthe follow-up visit. It is hoped that his final adult
. i0 K Y- `2 K& d9 K* eheight will not be affected.- W x2 J* D4 e' F
Although rarely reported, the widespread avail-# R' U: I! H* R9 t ?; d/ x3 S
ability of androgen products in our society may
% N* _) l' o( D" J' Tindeed cause more virilization in male or female
- U. |1 a/ r2 ?2 I1 h: T+ P, g1 Echildren than one would realize. Exposure to andro-5 O- ?" ^' ?) P& B
gen products must be considered and specific ques-
8 A1 T% u, Y6 B- R: q: I: f4 [1 |tioning about the use of a testosterone product or
# @9 V2 g$ l4 N6 q3 T3 ]- x7 pgel should be asked of the family members during
/ T; X' d4 D5 Xthe evaluation of any children who present with vir-+ ^1 \& \& |4 K5 l7 w/ E
ilization or peripheral precocious puberty. The diag-2 x$ s3 ?9 c! _% P" C) ?( c) t
nosis can be established by just a few tests and by2 h% p, K, t/ H* \
appropriate history. The inability to obtain such a
5 _. z" e ^5 b! ]history, or failure to ask the specific questions, may- R! f+ h- s$ Y' x' L- A' e
result in extensive, unnecessary, and expensive; a' ?7 J* ]4 q( T0 L
investigation. The primary care physician should be
, Y0 _0 ?) @$ V- B, P: n; Y" Caware of this fact, because most of these children
7 C8 C1 I2 s/ J; m. B9 _ jmay initially present in their practice. The Physicians’
& i0 @$ \* B+ c" DDesk Reference and package insert should also put a
W# ?+ y" X) g* d/ @+ ]+ fwarning about the virilizing effect on a male or
U i- h+ W0 g6 e/ w1 Afemale child who might come in contact with some-0 @ u9 ^" N, P' {" r \
one using any of these products.9 G1 q# f. h$ O! ?) h' S
References" u0 Q+ v( z' j; W/ b. o' ~8 W
1. Styne DM. The testes: disorder of sexual differentiation
: |) X# m- V* e' Wand puberty in the male. In: Sperling MA, ed. Pediatric- [3 \; N5 _$ ?5 r+ N
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
, ^/ J+ c- V. g3 v& {2 a8 K2002: 565-628.
6 B. n( r) o. d: D# a+ a( p) Z2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious; T& r: G( ^% ^
puberty in children with tumours of the suprasellar pineal |
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