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Sexual Precocity in a 16-Month-Old
! P# d) I+ t$ R7 qBoy Induced by Indirect Topical
! J( f) ]6 [# m! G4 y& iExposure to Testosterone
x J8 E0 e0 o5 h2 z7 n- ~Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
8 ^# e. K% z w; t) B5 V1 I, pand Kenneth R. Rettig, MD1
& U: L! M. ^# p/ Z& f0 Z/ ~Clinical Pediatrics
' }- J, b9 m: d* B" [4 u( |; ~Volume 46 Number 62 ~" Z% L6 ~. f9 V: z
July 2007 540-543/ K, z8 J* j3 o4 e t
© 2007 Sage Publications
@ c( c+ d; [+ ]10.1177/0009922806296651
0 A8 e: a2 S0 j8 H) Bhttp://clp.sagepub.com% N6 p- }/ n, [" H3 n- ~% W/ n$ A6 p: ~
hosted at+ g- E+ ~" g7 p/ D* l4 l
http://online.sagepub.com/ w) N; D f" J- T' }7 e! O$ m- A; ~
Precocious puberty in boys, central or peripheral,0 E6 [2 K" ?+ ~% \! U y& r! ?
is a significant concern for physicians. Central
6 X& `( L; |& p, Zprecocious puberty (CPP), which is mediated, p7 W0 Q7 Q. X, y" X- q
through the hypothalamic pituitary gonadal axis, has
( l8 V- L% B9 i" _0 s/ xa higher incidence of organic central nervous system
1 d1 Q) N2 X2 q0 P( k# ilesions in boys.1,2 Virilization in boys, as manifested
# A1 V! a7 O0 gby enlargement of the penis, development of pubic; H7 {6 }2 E/ g9 q7 A, ?
hair, and facial acne without enlargement of testi- t: Z% x( T% l: \+ A
cles, suggests peripheral or pseudopuberty.1-3 We& s6 F! _' } A) p: e" b
report a 16-month-old boy who presented with the
9 {, E" W" O( W5 H0 z3 f$ X% senlargement of the phallus and pubic hair develop-( k% {& C6 h( O) g7 y7 G
ment without testicular enlargement, which was due
4 S* j4 H( a8 ~* }3 \to the unintentional exposure to androgen gel used by
4 x5 [# @" l' [" ]/ }! ]; J* Athe father. The family initially concealed this infor-8 y7 J" `6 _# N9 l
mation, resulting in an extensive work-up for this
: W8 y W; x% m; q# c+ X, r7 p, V; rchild. Given the widespread and easy availability of
4 {, E% Y6 I' k, Ytestosterone gel and cream, we believe this is proba- n2 F! m% t& H" @, r7 {
bly more common than the rare case report in the8 ~ C2 X/ E8 x# H m. k1 c, _
literature.4
0 ^8 i0 g) Y' s3 a5 {Patient Report* W. h% }0 S% ?+ i {; z
A 16-month-old white child was referred to the
8 C4 E) B8 Z% O+ o* Eendocrine clinic by his pediatrician with the concern
" g2 _% l9 i0 B; u4 [. t Jof early sexual development. His mother noticed% p5 |4 R, \; w# [9 [% Q Y
light colored pubic hair development when he was
' e, G4 G4 A7 p$ I8 d. iFrom the 1Division of Pediatric Endocrinology, 2University of
3 K8 b1 |/ K& { lSouth Alabama Medical Center, Mobile, Alabama.7 x: _- g( G; d/ m/ x+ }, X% v$ @
Address correspondence to: Samar K. Bhowmick, MD, FACE,4 ^+ G# h8 T6 x7 ?9 E P1 g
Professor of Pediatrics, University of South Alabama, College of1 s! D. a' H: Z3 U# a
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297; g3 y/ I% Q* R6 R6 V7 B
e-mail: [email protected].* W# W) Q5 j- d2 s
about 6 to 7 months old, which progressively became
3 d! d0 Q7 h! U M& d% idarker. She was also concerned about the enlarge-5 y$ x4 h0 r8 E" M# F2 X
ment of his penis and frequent erections. The child
4 W/ c0 n- g$ j+ Fwas the product of a full-term normal delivery, with
1 K/ Z/ i' g' l8 za birth weight of 7 lb 14 oz, and birth length of
" y7 E" A( m; `/ [. H5 Y7 ]+ Z$ c20 inches. He was breast-fed throughout the first year
1 J% y9 H! B% I5 xof life and was still receiving breast milk along with. z- Q1 }2 k6 \
solid food. He had no hospitalizations or surgery,
, W; j" b2 J" Wand his psychosocial and psychomotor development4 `& g# m; ?1 }
was age appropriate.
8 y& \2 T4 X5 _" sThe family history was remarkable for the father,% u; ?3 Y# J8 g Z& y5 |2 r
who was diagnosed with hypothyroidism at age 16,$ d$ v9 T) t( b' L& e6 s6 s& G
which was treated with thyroxine. The father’s
' z5 p9 m; c* {height was 6 feet, and he went through a somewhat
* X+ y; s% _3 T2 x1 O; l! Fearly puberty and had stopped growing by age 14.
) c% W3 Q7 S, w5 bThe father denied taking any other medication. The
4 |1 E4 k6 k# X% |: P* lchild’s mother was in good health. Her menarche$ {* R/ E4 }! V
was at 11 years of age, and her height was at 5 feet
' H9 B6 V( }/ Z {/ @5 inches. There was no other family history of pre-: n9 x0 p# p& ~8 {
cocious sexual development in the first-degree rela-/ e \# j6 I" Q( ?* @
tives. There were no siblings.7 p+ z4 d8 }1 G# B+ r( N& h5 g, |
Physical Examination- }5 a. b0 g3 G K% s5 e9 T
The physical examination revealed a very active,) T- X# w1 ? [" ~
playful, and healthy boy. The vital signs documented
! u: ^0 M* H- x7 [a blood pressure of 85/50 mm Hg, his length was3 Q8 W; G' a* a0 j# _# G
90 cm (>97th percentile), and his weight was 14.4 kg
5 {0 G5 a/ N \2 l( ~. A% o7 s(also >97th percentile). The observed yearly growth1 u! G! }, M+ V# t H! s: g
velocity was 30 cm (12 inches). The examination of
( M1 b$ n6 K& N" d' n+ Nthe neck revealed no thyroid enlargement.
% y+ L. L8 v% c$ hThe genitourinary examination was remarkable for
2 W0 T6 |0 B. S" e8 D2 h, _* Jenlargement of the penis, with a stretched length of
- w' C0 J- w" b' P8 cm and a width of 2 cm. The glans penis was very well
. _9 D; w& N2 B( ideveloped. The pubic hair was Tanner II, mostly around. s$ H0 g+ k% P
540
7 r4 \% ?0 y: N7 a& y! m0 Xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 b8 P+ s7 g1 Y
the base of the phallus and was dark and curled. The( e4 s6 I+ n) u) Y7 N$ a
testicular volume was prepubertal at 2 mL each." V1 T4 J' c' `0 L/ S: v, h
The skin was moist and smooth and somewhat8 V% z5 L/ w2 G
oily. No axillary hair was noted. There were no h9 C# W+ h. z
abnormal skin pigmentations or café-au-lait spots.
2 C5 y4 J/ n" ^4 d3 U( ]# `Neurologic evaluation showed deep tendon reflex 2+
* h. u' o! B" T! hbilateral and symmetrical. There was no suggestion( e, P' M+ y# d
of papilledema.; p! v: j. {& M
Laboratory Evaluation
8 q; ]/ |( ]. b! P, @The bone age was consistent with 28 months by
) r. w0 B1 @* yusing the standard of Greulich and Pyle at a chrono-
! Q# I. U) v" ?# E) P, Blogic age of 16 months (advanced).5 Chromosomal
! r" w" O- E! h5 z, n8 i. q1 zkaryotype was 46XY. The thyroid function test
5 |) ?; f, H' L7 Jshowed a free T4 of 1.69 ng/dL, and thyroid stimu-" B+ ~2 |4 K, W9 [
lating hormone level was 1.3 µIU/mL (both normal).4 z1 x: x% h3 y- v5 X1 z
The concentrations of serum electrolytes, blood( ]( w" o! h* S, g) U. K# [
urea nitrogen, creatinine, and calcium all were
4 B! x. r. ^) ]- D' {$ v( D8 |/ f) Twithin normal range for his age. The concentration
+ M/ { n [7 z8 O. Oof serum 17-hydroxyprogesterone was 16 ng/dL2 Y1 N6 |$ I& I& T; E$ h
(normal, 3 to 90 ng/dL), androstenedione was 20
5 g& E! b) r9 E @# @' `ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
5 f' i% n; u. c6 z- e2 R7 ?' tterone was 38 ng/dL (normal, 50 to 760 ng/dL),* F4 W2 T/ W: u0 J$ E
desoxycorticosterone was 4.3 ng/dL (normal, 7 to+ `% D( g" v( P$ O1 d* y! S
49ng/dL), 11-desoxycortisol (specific compound S)0 j( b: G9 t4 o! I5 @
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-" c9 V4 E0 ~5 X5 P& ^
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
: V9 L9 f, `: |4 [* Z P" }testosterone was 60 ng/dL (normal <3 to 10 ng/dL),. W# L) W' E# Z$ {8 w4 p1 }, v
and β-human chorionic gonadotropin was less than! j8 g5 U4 Z) T9 B9 V5 P J
5 mIU/mL (normal <5 mIU/mL). Serum follicular
, p! m- V/ Y! h1 U( Fstimulating hormone and leuteinizing hormone, I& G( [# p e& v6 ^* @9 c
concentrations were less than 0.05 mIU/mL
8 A; ^% }5 x6 H+ w(prepubertal).
' c$ h$ P' Q, [ ^7 C/ |* nThe parents were notified about the laboratory! X6 D! q/ L; P3 g
results and were informed that all of the tests were4 ~+ a# b; p2 Q6 S3 c* U
normal except the testosterone level was high. The
8 `1 z2 x0 @. W- D d% l% Pfollow-up visit was arranged within a few weeks to
' `6 c5 E) k* ^* Y. \6 bobtain testicular and abdominal sonograms; how-+ @9 A; D, H8 D7 u) Z# r2 t
ever, the family did not return for 4 months.
. f) b2 d0 n8 f# a+ p$ }5 tPhysical examination at this time revealed that the
9 h6 e# `- Y+ ~6 ]3 F, I: E1 Rchild had grown 2.5 cm in 4 months and had gained# u' _, s4 S+ ~2 @
2 kg of weight. Physical examination remained
. D/ P C5 u( F5 ~$ \* Eunchanged. Surprisingly, the pubic hair almost com-4 n6 v% R) g; P& _/ E3 l1 q- R; g
pletely disappeared except for a few vellous hairs at
. [$ e+ p" q1 Rthe base of the phallus. Testicular volume was still 2
! G3 _. Z$ i( `, o y6 }3 U2 pmL, and the size of the penis remained unchanged. f. `7 p- I& A* L, ]
The mother also said that the boy was no longer hav-( ^" M% e3 @; I% b
ing frequent erections. q5 E7 D5 W" E6 t
Both parents were again questioned about use of0 D# Q; n8 q4 T: @* H
any ointment/creams that they may have applied to
: R; Q! \- i7 pthe child’s skin. This time the father admitted the
$ y5 @: X- ~- }( [$ pTopical Testosterone Exposure / Bhowmick et al 5413 Q* Z& B4 G, t, ~2 z- J5 w
use of testosterone gel twice daily that he was apply-
+ [# `& J& ^/ V/ m3 [+ l* ring over his own shoulders, chest, and back area for- S3 E' `" q: r0 I( d
a year. The father also revealed he was embarrassed
4 P& Z6 l, Q1 m/ n) H8 |to disclose that he was using a testosterone gel pre-: [3 x+ i6 f( k; v
scribed by his family physician for decreased libido: C! F: m; ]+ D# }* I
secondary to depression.
5 p1 a# [( B; t' ?( `: qThe child slept in the same bed with parents.+ r8 t1 K: D2 a8 b& a- t
The father would hug the baby and hold him on his6 c. m' Y! W2 x; {
chest for a considerable period of time, causing sig-+ U, t; L9 ]- m; H7 V4 A
nificant bare skin contact between baby and father.3 y$ X1 T7 |. w& N% _; G
The father also admitted that after the phone call,
" p/ X! O- q" q# s4 \2 L, {when he learned the testosterone level in the baby
. n( e M- l# f: ^7 awas high, he then read the product information
2 e1 \" q! R% a, e/ Q/ n3 [* U- zpacket and concluded that it was most likely the rea-0 y8 B4 O8 u( F
son for the child’s virilization. At that time, they
" Z/ o3 Q) O" r) Z: Vdecided to put the baby in a separate bed, and the
1 w) Z. E j+ V Z6 Rfather was not hugging him with bare skin and had: g5 V( ^+ M8 k* k; K: @
been using protective clothing. A repeat testosterone
6 c. X0 n) q' B! Ytest was ordered, but the family did not go to the
: Y1 A: R8 w! L6 k3 L* llaboratory to obtain the test.6 a$ L d" f1 S: i% I
Discussion
K( A9 F5 q7 _7 kPrecocious puberty in boys is defined as secondary. {& W0 ?8 p# f& W
sexual development before 9 years of age.1,4. B3 x* r |* ?
Precocious puberty is termed as central (true) when0 j& }, B }7 |
it is caused by the premature activation of hypo-
W4 O% x( U4 l( F; Cthalamic pituitary gonadal axis. CPP is more com-
8 A: X( q" w J( ` l* emon in girls than in boys.1,3 Most boys with CPP
' Y" ]! {4 d0 U+ z1 o M# q4 F8 w; hmay have a central nervous system lesion that is
9 I* p( w3 b- f* Tresponsible for the early activation of the hypothal-* {( E i8 @+ Q0 S1 q+ N. {
amic pituitary gonadal axis.1-3 Thus, greater empha-0 C6 T/ G3 A4 e5 j
sis has been given to neuroradiologic imaging in' u( ^5 |6 Z4 L1 w# g2 H& R
boys with precocious puberty. In addition to viril-0 X7 Q6 @# n7 H% C# _
ization, the clinical hallmark of CPP is the symmet-/ ?& s8 C6 @$ h' c4 }
rical testicular growth secondary to stimulation by
3 B( w( p9 o5 k K8 M5 Kgonadotropins.1,3/ W: T7 n" f, W9 L% c
Gonadotropin-independent peripheral preco-
2 O7 F' K1 ~" g( Z4 s, i+ Mcious puberty in boys also results from inappropriate
0 D3 A6 v- [' Sandrogenic stimulation from either endogenous or
' K& r1 I u/ _- w) y6 Y7 rexogenous sources, nonpituitary gonadotropin stim-, F& h) }0 ?/ G' j$ S$ f
ulation, and rare activating mutations.3 Virilizing4 a3 w& d1 q/ O. C; v5 H* M
congenital adrenal hyperplasia producing excessive
1 I2 h" {, _, [% X9 s: Padrenal androgens is a common cause of precocious3 z3 W* d" q: Y2 Z* n; ~
puberty in boys.3,4/ N8 l/ d4 O8 p, P
The most common form of congenital adrenal
: R+ M) _% Z& I$ c# V1 Nhyperplasia is the 21-hydroxylase enzyme deficiency.
/ Y; A8 q' {1 h% u. x0 RThe 11-β hydroxylase deficiency may also result in7 n3 Q, `5 b- b% z! M+ N# N
excessive adrenal androgen production, and rarely,% t: D. Q3 Z6 T6 k0 O
an adrenal tumor may also cause adrenal androgen" H' C6 E0 U! v2 N7 F3 E
excess.1,3, Y# f }9 s# f& {
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, G4 m, A6 S, m: L6 I9 @9 o, w+ V
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; {) R. j: ?/ Z% F; W3 E$ FA unique entity of male-limited gonadotropin-- n4 W$ S2 n. r" D' V% R( M
independent precocious puberty, which is also known
" _, j. [; f2 b: r' z6 `6 Q4 \as testotoxicosis, may cause precocious puberty at a
; K/ }8 S M: w5 pvery young age. The physical findings in these boys
$ f0 _! e' a( c3 z8 R" Qwith this disorder are full pubertal development,
8 B3 V( ^& ]2 m/ P4 wincluding bilateral testicular growth, similar to boys
( T# i4 n6 g9 z+ Mwith CPP. The gonadotropin levels in this disorder _; d. p/ \' N8 K
are suppressed to prepubertal levels and do not show5 m& V$ R+ Z* A
pubertal response of gonadotropin after gonadotropin-
! X- d; K; d3 g1 r2 s0 }9 M# K) Oreleasing hormone stimulation. This is a sex-linked
& C6 d. @" T& s+ \/ R Sautosomal dominant disorder that affects only3 M: p7 {/ O. j' N2 ^' O; E, D$ v
males; therefore, other male members of the family. S, p. ?0 Z$ B
may have similar precocious puberty.3
( z: b1 |7 i* t9 Q6 {: H3 BIn our patient, physical examination was incon-
' M) [$ _% L. |) ssistent with true precocious puberty since his testi-4 M; l2 e$ C8 |5 m, G/ `
cles were prepubertal in size. However, testotoxicosis
6 C" y+ L2 ?8 Swas in the differential diagnosis because his father
0 l4 ]* p$ p( I% mstarted puberty somewhat early, and occasionally,
# o9 \7 ^( g n9 w& _testicular enlargement is not that evident in the
# o% G3 P! b4 A0 I" Wbeginning of this process.1 In the absence of a neg-
! W( z6 P; }/ Z. n! j7 |ative initial history of androgen exposure, our! q! o, W: _/ t) w, [. |
biggest concern was virilizing adrenal hyperplasia,
1 r2 x- O' O; k3 A: e" q! leither 21-hydroxylase deficiency or 11-β hydroxylase
' C1 ~ b1 G/ {& }( Y1 @/ ddeficiency. Those diagnoses were excluded by find-' _' T( u5 D7 G! N( y/ r% {
ing the normal level of adrenal steroids.
# T. N. u! y+ qThe diagnosis of exogenous androgens was strongly
( g7 r! e8 E& D0 zsuspected in a follow-up visit after 4 months because7 B* b6 C' w* Q9 z
the physical examination revealed the complete disap-
* {* \0 p+ Z; m$ e& k W: H* q4 t. \6 xpearance of pubic hair, normal growth velocity, and/ U* y+ r( m; z# r: E* _
decreased erections. The father admitted using a testos-
6 R. O ?$ b4 D$ K5 i* \terone gel, which he concealed at first visit. He was4 J0 q, C+ t' T, h# h
using it rather frequently, twice a day. The Physicians’7 S, l9 `3 c+ G9 Y2 _* P& ^
Desk Reference, or package insert of this product, gel or {* F/ F& h$ Q9 u7 v9 C1 a/ ~! l" D
cream, cautions about dermal testosterone transfer to; z: v) y/ L$ [( ~
unprotected females through direct skin exposure.
/ a% G" u. o9 @% W6 t# G; bSerum testosterone level was found to be 2 times the b8 r+ ~& ?% s9 a5 H
baseline value in those females who were exposed to
6 u) }' J: P. A, |- @even 15 minutes of direct skin contact with their male1 U* A5 v+ e) p& Y3 j
partners.6 However, when a shirt covered the applica-! B- q# g5 ~7 u' q, R' Z8 ~0 \5 r
tion site, this testosterone transfer was prevented.. u! x5 j Q" N5 Q
Our patient’s testosterone level was 60 ng/mL,0 O, |! m1 A( l6 o5 E
which was clearly high. Some studies suggest that
5 I! D5 z; o: F6 ?- G; t" ]dermal conversion of testosterone to dihydrotestos-& R) \! s; G* M' q" [
terone, which is a more potent metabolite, is more) S& d k+ T3 p" \1 |# G0 q" J
active in young children exposed to testosterone
; U( z/ Y# ?# Aexogenously7; however, we did not measure a dihy-: Y! h% a. K4 V+ |7 [
drotestosterone level in our patient. In addition to: r% ?3 c& y. R$ a* F5 J
virilization, exposure to exogenous testosterone in! a" Y$ Y0 m# s6 @+ e9 y3 }" f, o
children results in an increase in growth velocity and
: m4 |; i- C+ n" fadvanced bone age, as seen in our patient.
0 n, I/ h0 b- z0 y+ S9 t2 PThe long-term effect of androgen exposure during$ |8 D% o1 Q' u6 h5 j
early childhood on pubertal development and final7 c# I/ L* H" v4 Z5 J
adult height are not fully known and always remain9 | J" t1 [1 M( q* z) `
a concern. Children treated with short-term testos-
" B/ p6 W3 Q! F. g( Gterone injection or topical androgen may exhibit some
9 Z3 B8 X! Y7 s& T! y% {acceleration of the skeletal maturation; however, after' W0 Z! w" X2 q! E
cessation of treatment, the rate of bone maturation
* A* n2 p. {" [' b$ ~6 X8 Pdecelerates and gradually returns to normal.8,9+ r- i, S% F% \3 w
There are conflicting reports and controversy0 Q9 T: }* e2 w$ a
over the effect of early androgen exposure on adult( P- G- A1 p1 R L, {
penile length.10,11 Some reports suggest subnormal
# y' M# k& u) S0 O* S3 l) ~adult penile length, apparently because of downreg-
; T5 G1 }; ~. ~. Sulation of androgen receptor number.10,12 However,
! p/ j. P' P ^* R1 }Sutherland et al13 did not find a correlation between: L1 U; a6 a/ Z9 A
childhood testosterone exposure and reduced adult
1 M' h! E; j. z/ Ypenile length in clinical studies.
6 O" j6 ^4 M- K3 s. z7 _Nonetheless, we do not believe our patient is( f% a. f q ]! x6 `( r5 J
going to experience any of the untoward effects from
" }. V6 h! L# d3 b* utestosterone exposure as mentioned earlier because
0 k! r" {. D0 @+ R |$ P7 t4 Vthe exposure was not for a prolonged period of time.
+ r; S# I* ]" M& }Although the bone age was advanced at the time of
+ E( i0 R, I- g9 ~diagnosis, the child had a normal growth velocity at
; A, z! q$ i) c; i# G2 hthe follow-up visit. It is hoped that his final adult
1 P6 l& I/ m5 @: ?height will not be affected.# u; a& D( F0 v- s: Y, x/ p
Although rarely reported, the widespread avail-- h: Z! Y* w5 \' Q' p e; Q
ability of androgen products in our society may
7 \5 `! H- Y8 {3 x" S/ }indeed cause more virilization in male or female* X8 k9 G) M( _1 j/ D$ H* |+ Q1 x
children than one would realize. Exposure to andro-2 m1 d5 V% Q1 t
gen products must be considered and specific ques-( q. m! B' ~/ i" z) v% k I' Y' N
tioning about the use of a testosterone product or2 _% T+ U7 u* Z! L$ K. D/ |% n
gel should be asked of the family members during
9 V( h2 u- g* D! r `the evaluation of any children who present with vir-3 r, m: C. w0 m
ilization or peripheral precocious puberty. The diag-
8 M- J" m) l* e" Bnosis can be established by just a few tests and by2 j9 }$ |8 o: w3 N9 l- ?
appropriate history. The inability to obtain such a, \; `$ p- R7 H; j' O6 |
history, or failure to ask the specific questions, may
5 C- U8 f0 Q7 oresult in extensive, unnecessary, and expensive# S3 R! T. T3 ]( `% J# D, n
investigation. The primary care physician should be7 T# n/ i5 F/ G8 v
aware of this fact, because most of these children
U' n2 J6 Y9 b" X4 e. }; A9 ~$ R6 hmay initially present in their practice. The Physicians’$ Y/ K) d, ~( l
Desk Reference and package insert should also put a
0 U+ F6 M _' v/ {/ kwarning about the virilizing effect on a male or5 L0 a3 H( N+ T; c9 A
female child who might come in contact with some-
6 |" i7 b4 U* M: Z$ }one using any of these products.
5 s6 e \1 `" T1 A& C# O" ZReferences6 L' m5 W' [. k$ _+ i! ^$ e
1. Styne DM. The testes: disorder of sexual differentiation0 R# u7 b5 z: n) \) b
and puberty in the male. In: Sperling MA, ed. Pediatric& @7 {( o: `8 u* e
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; e2 P5 m: n. `# q c
2002: 565-628.- r# S3 s8 z7 f, B$ D
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% G! n! \+ j1 r! p2 P
puberty in children with tumours of the suprasellar pineal |
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