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Sexual Precocity in a 16-Month-Old) s" g, w8 m( w$ B7 R) _* p
Boy Induced by Indirect Topical
% S8 x0 t* n- I" wExposure to Testosterone w( b: A* y9 ~& J, c
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
2 C" I: q* ]- m+ iand Kenneth R. Rettig, MD1. A O$ @/ o: t4 d7 V5 c$ x0 f
Clinical Pediatrics
1 ?+ u! e( r! tVolume 46 Number 6" H. f7 r* ?, Y0 G( Y; Y6 c
July 2007 540-543. _7 D }! F8 }1 w0 d3 c
© 2007 Sage Publications+ }0 Y0 n- x1 M3 m g% Z4 X5 D* g
10.1177/0009922806296651
% d$ M1 {8 i1 L5 M3 ?) nhttp://clp.sagepub.com- @4 o* t1 c" i# i
hosted at9 U8 i& N7 a) s1 p U3 A9 B
http://online.sagepub.com4 O4 ^" _ T4 O
Precocious puberty in boys, central or peripheral,( e, B$ b8 Y7 q* q
is a significant concern for physicians. Central6 m- w; `1 J' |4 P
precocious puberty (CPP), which is mediated
; l# y ]! C3 s7 l) [# Ythrough the hypothalamic pituitary gonadal axis, has
5 }2 \. x/ @1 p( J+ P9 za higher incidence of organic central nervous system
r( G1 ?3 A7 _0 C9 e( C" ?lesions in boys.1,2 Virilization in boys, as manifested; M8 m$ B3 }+ i$ D
by enlargement of the penis, development of pubic. A7 d: A7 r: k) k( g6 Q" b
hair, and facial acne without enlargement of testi-
( n$ @( @; v7 j% g4 _. qcles, suggests peripheral or pseudopuberty.1-3 We
) h# `$ L# T: [2 O0 hreport a 16-month-old boy who presented with the
; ~+ n0 m- j; L! P$ i2 fenlargement of the phallus and pubic hair develop-
' q/ U+ j; F, W% D( pment without testicular enlargement, which was due" I8 ^2 F P; y5 [7 D
to the unintentional exposure to androgen gel used by
/ v, U, Q6 [& g- k6 M+ Z) Sthe father. The family initially concealed this infor-
' i+ E. a4 s- j( cmation, resulting in an extensive work-up for this- ?; A1 X4 _, I( [: w8 T# p8 i
child. Given the widespread and easy availability of l8 a, J. q8 j
testosterone gel and cream, we believe this is proba-
+ V( g2 Q# d3 {1 y. x x8 g0 zbly more common than the rare case report in the
3 v% p! U: p3 Q/ g( w* N' [% v# ]literature.4
2 {1 [) t2 O3 _, @" S6 ^5 tPatient Report' f; k) [5 \* z1 M2 Z
A 16-month-old white child was referred to the2 U, S6 O: }5 S1 m. j! U6 Z6 B% Y+ e
endocrine clinic by his pediatrician with the concern% F% X* a/ w0 k3 ^( i6 C
of early sexual development. His mother noticed: D; t) A5 Q' q& b, o
light colored pubic hair development when he was
- h! U+ }0 H+ T4 o% l$ b0 LFrom the 1Division of Pediatric Endocrinology, 2University of$ o4 \; S$ }" I& z
South Alabama Medical Center, Mobile, Alabama.
/ P5 z6 ?+ L; b# kAddress correspondence to: Samar K. Bhowmick, MD, FACE,3 X5 D, r [2 u x5 t' E5 [7 R
Professor of Pediatrics, University of South Alabama, College of
3 {- `" l5 b3 ]% O0 CMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 f7 E2 R( j+ v6 K! ?. Z' P
e-mail: [email protected].
* `) ?6 @7 a( eabout 6 to 7 months old, which progressively became
1 v9 a! \$ U* K/ b, B1 ]darker. She was also concerned about the enlarge-
0 V5 ^; O$ Z+ b4 nment of his penis and frequent erections. The child! H" Q! L1 e" Z; m
was the product of a full-term normal delivery, with: w# U( B: `' c! _5 R
a birth weight of 7 lb 14 oz, and birth length of! ~. b4 | b( x( p3 E* b- I
20 inches. He was breast-fed throughout the first year& G6 C" j3 m: l" i+ N/ F M
of life and was still receiving breast milk along with
4 i- K+ H1 k( }* {7 _solid food. He had no hospitalizations or surgery,9 c7 q' C+ ?, @4 X3 Q
and his psychosocial and psychomotor development1 i* |' R1 i" T5 I, g$ H
was age appropriate.
. Q6 d* }9 B5 r" ?The family history was remarkable for the father,
2 W9 H9 d% v- {! X4 Fwho was diagnosed with hypothyroidism at age 16,2 p9 Y2 V3 R; f! D
which was treated with thyroxine. The father’s
1 ~ Z1 M k% l1 eheight was 6 feet, and he went through a somewhat7 s9 K; m/ o# D
early puberty and had stopped growing by age 14.
$ q2 ]) e# v! B3 R5 EThe father denied taking any other medication. The
4 f- q% f5 Q7 ~2 @child’s mother was in good health. Her menarche
( o% F1 D2 V, ]# Q% g/ K. Wwas at 11 years of age, and her height was at 5 feet
z. C- F' Z% ]+ I @3 g5 }6 V+ m5 inches. There was no other family history of pre-
0 N# u% e( d5 f7 u! n$ kcocious sexual development in the first-degree rela-
# f; W; ?( k' d1 \% |; x5 _/ B3 \tives. There were no siblings.
( t0 v% C) c& a) P3 T6 \2 ?Physical Examination
i! T# x2 q7 A5 OThe physical examination revealed a very active,
6 @: m- m7 C4 Y' k! Uplayful, and healthy boy. The vital signs documented
( i2 M) G* ?) P4 Z5 P( Ha blood pressure of 85/50 mm Hg, his length was
$ |8 _3 O @" n' U90 cm (>97th percentile), and his weight was 14.4 kg6 B3 E! b. p6 M
(also >97th percentile). The observed yearly growth0 j) Y" a, z" @4 s+ p
velocity was 30 cm (12 inches). The examination of5 @+ Y$ a- B4 F* ]( L" h* |
the neck revealed no thyroid enlargement." ?9 H& l+ r- [6 j
The genitourinary examination was remarkable for3 c3 z/ u; n, r s# ~
enlargement of the penis, with a stretched length of
2 z! \& H$ Q2 N7 u$ ?8 cm and a width of 2 cm. The glans penis was very well
A# C( S" J& z Y7 I7 Rdeveloped. The pubic hair was Tanner II, mostly around8 B$ u$ D4 _ l, Y
540; s9 @: Q9 p0 b5 Q3 _
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 p' k: `1 O4 T' O, Sthe base of the phallus and was dark and curled. The
+ @. s# Z9 J. n! f: Q4 v: xtesticular volume was prepubertal at 2 mL each.5 k, j( x5 I7 Z: [* P
The skin was moist and smooth and somewhat6 D e/ L/ B) ~( A* C" Q
oily. No axillary hair was noted. There were no( ]6 B! o3 Q5 q' k4 b
abnormal skin pigmentations or café-au-lait spots., V, W) f# D# |5 E# ]+ B
Neurologic evaluation showed deep tendon reflex 2+
* [- C9 E! R. u! |4 `bilateral and symmetrical. There was no suggestion
3 x1 o( ~5 d: p6 @5 V( Kof papilledema.
. d8 X$ }! M' A7 [* VLaboratory Evaluation1 F1 [6 U+ a$ b# n. N1 f
The bone age was consistent with 28 months by
- q, J3 z% ~+ x) |using the standard of Greulich and Pyle at a chrono-
6 k8 i& t' b# s" ^logic age of 16 months (advanced).5 Chromosomal
- n6 v+ M" D5 z3 {- Okaryotype was 46XY. The thyroid function test- r. m2 s4 R. ]5 W4 @; p
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
# {2 }$ | w4 v/ R+ ulating hormone level was 1.3 µIU/mL (both normal).; L4 ^( W. C4 k5 A) J
The concentrations of serum electrolytes, blood3 D( J- A- ^* J6 a
urea nitrogen, creatinine, and calcium all were, F9 W4 s- S' A: ~
within normal range for his age. The concentration
6 o; K6 ~6 S' [+ Mof serum 17-hydroxyprogesterone was 16 ng/dL& w% f4 ~ k& z
(normal, 3 to 90 ng/dL), androstenedione was 20* ~2 t6 X* P4 A4 |
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-8 k- W. A& j# Q. ~5 ]- w
terone was 38 ng/dL (normal, 50 to 760 ng/dL),' C! F) Z1 x/ |4 e, L
desoxycorticosterone was 4.3 ng/dL (normal, 7 to* t7 R- u: D2 \/ K
49ng/dL), 11-desoxycortisol (specific compound S) v5 H4 ^" R, j! K/ c
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-- R, B5 c' K9 A( O1 e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total; g! j3 `8 }+ Y) q3 [0 A% \4 v
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),, ~( W' \8 H- \4 D) Q) {" k* n
and β-human chorionic gonadotropin was less than9 c, [6 x% b& Q+ O" V0 n
5 mIU/mL (normal <5 mIU/mL). Serum follicular% q/ X9 r$ w0 y% z J0 j
stimulating hormone and leuteinizing hormone3 B" D5 b. ^9 a W
concentrations were less than 0.05 mIU/mL
4 R% ~0 b, Q2 a; P(prepubertal).# z+ y; n, A% p, Q& l6 f8 t |
The parents were notified about the laboratory$ V0 z$ C5 r |0 ~7 D0 t
results and were informed that all of the tests were1 ^7 @; \3 @( e) R, x. z
normal except the testosterone level was high. The
N" c9 h& w2 o3 l d+ T4 _# Ufollow-up visit was arranged within a few weeks to8 c- R% R8 m1 C2 ]5 F5 D
obtain testicular and abdominal sonograms; how-7 ~# ?# S( w$ i
ever, the family did not return for 4 months.
2 O. ]. i6 _; N) i: |Physical examination at this time revealed that the4 a( Z; T# O( x. f' w$ Y S
child had grown 2.5 cm in 4 months and had gained. c! N; K7 a7 Q0 P" v
2 kg of weight. Physical examination remained0 l4 d( z4 {" W( f4 O
unchanged. Surprisingly, the pubic hair almost com-( w3 x0 q1 `$ C
pletely disappeared except for a few vellous hairs at
: Z( F: Y" N3 X# ythe base of the phallus. Testicular volume was still 2+ w( D8 G: f8 g
mL, and the size of the penis remained unchanged.; J( s e+ Z$ D1 @
The mother also said that the boy was no longer hav-
" x% `) J& H8 k1 A" g! n$ `9 g" Jing frequent erections.
8 k( B- e4 r# {0 Z- ~0 EBoth parents were again questioned about use of
I3 a+ p, c: `9 V- T7 Dany ointment/creams that they may have applied to
8 e" |; B" n$ Vthe child’s skin. This time the father admitted the5 d+ e3 Z4 V) F
Topical Testosterone Exposure / Bhowmick et al 541$ `0 _. K2 O8 K/ ~% v
use of testosterone gel twice daily that he was apply-' G6 E( ~1 Z x+ [* [/ a; P
ing over his own shoulders, chest, and back area for
1 D- ~ ?+ D, V! U! K- S7 Q! N: |( Ca year. The father also revealed he was embarrassed5 O2 d! N) C4 ]8 Y7 `1 M( @2 l$ G
to disclose that he was using a testosterone gel pre-. ]6 |3 \9 v5 V. \
scribed by his family physician for decreased libido( O6 a j* R- X0 _
secondary to depression.
9 @% W# @* K3 r* Y* V7 T) V% ZThe child slept in the same bed with parents.. k( P0 F* G% q9 l8 j
The father would hug the baby and hold him on his. @+ ?6 n1 V: _" V
chest for a considerable period of time, causing sig-4 ]9 M" l T, q2 d* j; Z# g% V `
nificant bare skin contact between baby and father.: K2 r" W( q( K8 r/ l% P" h( x8 n
The father also admitted that after the phone call,
$ P Z4 c5 W0 ]; M0 ~% Zwhen he learned the testosterone level in the baby
" R1 m' a, Z+ l M% Nwas high, he then read the product information
/ _: Y' s* ^& g- s1 Zpacket and concluded that it was most likely the rea-: f/ b1 u: L% r0 {
son for the child’s virilization. At that time, they# H. e& ~4 X+ j6 _* D
decided to put the baby in a separate bed, and the
' X6 l$ o X. Cfather was not hugging him with bare skin and had- i) Y0 l0 J/ w' s; o
been using protective clothing. A repeat testosterone
0 Q" ^% ]! G |+ q' T8 [test was ordered, but the family did not go to the
0 q3 r( I; A% C4 s4 Y! n k- jlaboratory to obtain the test.
; ^2 g r! |9 a6 uDiscussion: b% v6 [3 _3 y% N
Precocious puberty in boys is defined as secondary2 q0 |6 m$ T. W7 q+ \( i
sexual development before 9 years of age.1,4
' z5 p; D$ R( B$ n# iPrecocious puberty is termed as central (true) when% l c0 P4 {: b: o
it is caused by the premature activation of hypo-, \& l9 ^0 l5 e! K# F) x) p
thalamic pituitary gonadal axis. CPP is more com-
6 ^: D9 t) {, C! I, c+ bmon in girls than in boys.1,3 Most boys with CPP# [) u: B' M& y6 R
may have a central nervous system lesion that is0 s, x: w t0 s- D
responsible for the early activation of the hypothal-
% x7 A; a) c* x. Famic pituitary gonadal axis.1-3 Thus, greater empha-
6 t- x- S0 Q; W, J0 [sis has been given to neuroradiologic imaging in
( g% C& R' Y; I# o* w1 k! P: ~boys with precocious puberty. In addition to viril-
, z3 g! V5 G4 k( v. g# Z; jization, the clinical hallmark of CPP is the symmet-# s* [, A' i" p, l; ?- h! R% b
rical testicular growth secondary to stimulation by$ {" |# V! f1 @+ m. n, L D
gonadotropins.1,3; X) @2 {/ s$ n# r+ |
Gonadotropin-independent peripheral preco- I7 |% r1 _% G+ r$ [ X& x
cious puberty in boys also results from inappropriate
! p+ N& A5 m- {androgenic stimulation from either endogenous or2 }, t1 c$ E0 Z% u4 o$ ~- t* W
exogenous sources, nonpituitary gonadotropin stim-
! m1 j, \ d0 J+ z) Lulation, and rare activating mutations.3 Virilizing; X o( U. `2 c8 Q' ]) S
congenital adrenal hyperplasia producing excessive
: y& H. Z% k2 q# Y! s+ z) ^adrenal androgens is a common cause of precocious
, A8 d; G) e* f& b- Vpuberty in boys.3,4
4 v$ A B8 p/ m0 e# cThe most common form of congenital adrenal
) P3 x2 I! u+ nhyperplasia is the 21-hydroxylase enzyme deficiency.
# Z r- ?) \# z, p# |The 11-β hydroxylase deficiency may also result in
' [( U% z6 H. @$ B2 Dexcessive adrenal androgen production, and rarely,
0 n4 b+ v G3 |0 Z4 w* F1 Qan adrenal tumor may also cause adrenal androgen- R* k- S5 B. g, D* w4 [
excess.1,3
7 P& C5 z9 }3 R1 W& Mat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from g. P3 x+ M* ~4 T% G9 R' ~
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007$ d; Y0 _1 C4 O& u2 L
A unique entity of male-limited gonadotropin-
0 G" B) I" G$ ~! r V, xindependent precocious puberty, which is also known
; w0 m) _. J/ T6 n1 B; E' C- Vas testotoxicosis, may cause precocious puberty at a
1 |! D7 I' s6 y, Dvery young age. The physical findings in these boys
$ Q. H7 l) e# X$ A; pwith this disorder are full pubertal development,, j$ O; b. `' X- R. }5 ^8 K* R% P
including bilateral testicular growth, similar to boys2 ^! ~0 \+ m( Q7 v$ y
with CPP. The gonadotropin levels in this disorder
8 a2 A# T7 f' q' Oare suppressed to prepubertal levels and do not show E; h4 y; r9 n/ b
pubertal response of gonadotropin after gonadotropin-5 Z: ^7 t* | ]3 f
releasing hormone stimulation. This is a sex-linked2 y3 t; `0 H- ?4 t
autosomal dominant disorder that affects only
/ M4 o" P5 j0 J1 D; y% Q4 Nmales; therefore, other male members of the family
& q1 k) \) G' W% }# Amay have similar precocious puberty.35 e5 _$ D- U7 u3 B" j
In our patient, physical examination was incon-
- E# Q7 \2 L6 B/ I# F: lsistent with true precocious puberty since his testi-! _# \( q1 ?6 k- _; {
cles were prepubertal in size. However, testotoxicosis
8 U& n- X }7 B' u' J8 Ywas in the differential diagnosis because his father
/ F4 H* V5 V- J) r: L+ rstarted puberty somewhat early, and occasionally,8 {4 z! P4 u- I, l
testicular enlargement is not that evident in the
$ {/ C5 @/ X9 t5 L& Z; B4 U' m5 mbeginning of this process.1 In the absence of a neg-
+ R1 \. `3 \' t% ^( {ative initial history of androgen exposure, our* C$ S+ S' u5 u2 h8 r5 p* s& K/ {
biggest concern was virilizing adrenal hyperplasia,
! ^, Z( @5 |! C' seither 21-hydroxylase deficiency or 11-β hydroxylase O* O8 _( Q4 `" w
deficiency. Those diagnoses were excluded by find-
2 u; ~0 y0 O- ]' v5 E: Jing the normal level of adrenal steroids.
* v$ [0 C1 L' O9 N6 JThe diagnosis of exogenous androgens was strongly* l0 K7 X. z* K9 C- U1 F
suspected in a follow-up visit after 4 months because! J# o+ D. @7 y
the physical examination revealed the complete disap-. n# g% ~& g7 K, q# ]; {
pearance of pubic hair, normal growth velocity, and
, A3 Q4 X9 k! B; [1 v: Hdecreased erections. The father admitted using a testos-* j3 T2 f% G* t6 J! {; E
terone gel, which he concealed at first visit. He was) s6 r }- R% B4 S6 |
using it rather frequently, twice a day. The Physicians’' |' t/ I5 q7 f; a( l. U' C" O
Desk Reference, or package insert of this product, gel or
2 I; Y1 [. F8 U' Z8 _+ ^- ~cream, cautions about dermal testosterone transfer to) W0 F0 L; t. R2 w k3 z) c- h: X
unprotected females through direct skin exposure.% D& c. J9 _7 n4 s9 C; H% A
Serum testosterone level was found to be 2 times the6 x2 l% E& y7 G* i
baseline value in those females who were exposed to
* A: G5 e, ^& q) w5 Ceven 15 minutes of direct skin contact with their male7 }, [0 t7 X6 S9 I4 n. U
partners.6 However, when a shirt covered the applica-, r6 V; x( G# i9 R1 P% t7 V
tion site, this testosterone transfer was prevented.$ X" b' y6 y7 H3 Y* _
Our patient’s testosterone level was 60 ng/mL,4 f: D/ K: d/ S
which was clearly high. Some studies suggest that( ^3 `4 d1 J7 Q a7 V
dermal conversion of testosterone to dihydrotestos-
" ?2 B! B" R3 ^7 s: Aterone, which is a more potent metabolite, is more
' @1 ~5 W6 k( V* @active in young children exposed to testosterone
Z3 o: \9 b6 o: N$ Z9 Nexogenously7; however, we did not measure a dihy-9 E, q1 ]9 Y; l+ `; u7 _
drotestosterone level in our patient. In addition to
1 f& I, x, i! s/ f: N8 qvirilization, exposure to exogenous testosterone in! k/ w6 y4 f- H1 Y6 w& @+ J
children results in an increase in growth velocity and, d! X {( K/ l
advanced bone age, as seen in our patient.
* |; Y0 Y) D- b2 N; ?- t+ u+ @- c6 m: c% jThe long-term effect of androgen exposure during
, ?8 \8 z7 c# z4 q5 vearly childhood on pubertal development and final
! v" S+ o R( c. b$ m3 f8 qadult height are not fully known and always remain
, M9 U/ O9 r, R" Oa concern. Children treated with short-term testos-0 m) w8 i: u8 P$ ~+ @% f4 d' n
terone injection or topical androgen may exhibit some
3 |% [" N$ M4 M7 Tacceleration of the skeletal maturation; however, after" ~ ?5 H4 t" @7 S
cessation of treatment, the rate of bone maturation; Y6 P; y2 I* p: y
decelerates and gradually returns to normal.8,9
D& C [8 U$ L/ x, W. VThere are conflicting reports and controversy
* y, f4 y' ?7 Q& [4 T' P5 T+ }over the effect of early androgen exposure on adult
4 \: V5 q$ N$ apenile length.10,11 Some reports suggest subnormal( L' n' C7 l3 o- c
adult penile length, apparently because of downreg-
6 X: P" [ O' b7 L: dulation of androgen receptor number.10,12 However,8 N& i) C- W; v" F
Sutherland et al13 did not find a correlation between
) k% m5 W7 s$ n+ O6 i* N" rchildhood testosterone exposure and reduced adult
2 [$ f1 a8 F1 L1 B) t Ipenile length in clinical studies.
3 Z- c1 X9 c& W: {. i# dNonetheless, we do not believe our patient is
( X% C+ [7 O. u; q4 r9 t, m0 `. Ngoing to experience any of the untoward effects from
( G- |/ j) Z; a" A Y# Y$ @6 N. g0 Dtestosterone exposure as mentioned earlier because6 {) k7 I4 X1 E. Z6 h
the exposure was not for a prolonged period of time.% U5 a1 @9 x! p- {/ O: n
Although the bone age was advanced at the time of2 g( L E, g# y
diagnosis, the child had a normal growth velocity at
/ }# O- H& O0 I$ F* U8 Gthe follow-up visit. It is hoped that his final adult
; v( j( J6 C( P, e1 F4 B- Rheight will not be affected.5 Y, W1 H4 S8 S8 |& n5 N+ `9 H
Although rarely reported, the widespread avail-! S _8 U. h3 S2 y8 ]* d9 B% w
ability of androgen products in our society may# N' M) Y* ]2 }2 \% I4 S/ V& q
indeed cause more virilization in male or female
% D2 {- y& {* y' ^children than one would realize. Exposure to andro-
* z8 D' O8 X8 ^gen products must be considered and specific ques-
7 J6 Z! v( P/ T |' ytioning about the use of a testosterone product or
; O$ I0 E" } F% g) |& Egel should be asked of the family members during( }5 ^% d4 R7 Q' C0 H
the evaluation of any children who present with vir-
: I+ L$ l9 c7 g6 Silization or peripheral precocious puberty. The diag-
7 q, O* l0 y; w! f3 ]( h2 @6 u& x) jnosis can be established by just a few tests and by
) i: V; }5 Z9 {& L% |* Xappropriate history. The inability to obtain such a. z8 u9 |% V# j3 u
history, or failure to ask the specific questions, may
5 D/ ~* D$ L- @" l" I' Lresult in extensive, unnecessary, and expensive
9 D" @& y& ]( Ainvestigation. The primary care physician should be
5 L3 a! |* |: k8 J: o& aaware of this fact, because most of these children2 ~# [" f9 v4 v3 b- L. k& \
may initially present in their practice. The Physicians’3 L, C! y5 }( B
Desk Reference and package insert should also put a& t; t, o# T% c! \5 ] O; e, Q2 w. k( l
warning about the virilizing effect on a male or
, t# X$ x/ B/ a3 k3 ?" d$ Mfemale child who might come in contact with some-
$ A B7 X/ J7 Gone using any of these products.: [2 ~4 V8 ~1 k: b+ F! Q$ Q6 k
References, w" |3 P: D, R2 ?0 f
1. Styne DM. The testes: disorder of sexual differentiation
$ s' ~4 N, q# R( t& l* T6 uand puberty in the male. In: Sperling MA, ed. Pediatric
6 c/ C+ I ]7 o! AEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
8 J' ]) c- u; ^+ {2002: 565-628." p1 k2 S5 A9 ~0 z- g3 y. W3 z
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
& v, D7 V( p4 O9 l1 }" Lpuberty in children with tumours of the suprasellar pineal |
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