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Sexual Precocity in a 16-Month-Old1 J2 t5 @9 Q- i
Boy Induced by Indirect Topical- F8 `( s7 T, ?- a' Z9 n- V2 }5 |
Exposure to Testosterone
( m' {8 v/ t* w" pSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2* ]! s. @$ M( ~
and Kenneth R. Rettig, MD1
5 N+ J2 N7 `& ^3 c# ZClinical Pediatrics
+ A$ l0 x. W" X' i* dVolume 46 Number 6
, I8 F( s4 `: V# h3 SJuly 2007 540-543
- ?7 `8 j+ ? K) ^© 2007 Sage Publications
' I- D$ E2 d& k10.1177/0009922806296651
8 d5 _' H; Y8 H! Bhttp://clp.sagepub.com7 M+ _6 T+ R) c6 T" g
hosted at3 s% S* y" C, a n$ F
http://online.sagepub.com
% n8 y7 t4 f& zPrecocious puberty in boys, central or peripheral,* V) d( K0 B$ ~
is a significant concern for physicians. Central
; @1 i5 z9 K0 Nprecocious puberty (CPP), which is mediated
5 ?- f, d# P. S" lthrough the hypothalamic pituitary gonadal axis, has
; a4 r* B& l$ u8 f6 t& Ea higher incidence of organic central nervous system$ _0 I" \4 ^4 Q
lesions in boys.1,2 Virilization in boys, as manifested. q8 J7 p' r0 _. K
by enlargement of the penis, development of pubic+ r) c; S$ o$ _9 f. v* n
hair, and facial acne without enlargement of testi-* ]1 m. W1 z5 _5 y) c
cles, suggests peripheral or pseudopuberty.1-3 We* I; k# x" C* v6 c8 Q/ U1 w
report a 16-month-old boy who presented with the
! f, E F4 \' q$ ^+ \6 k0 Genlargement of the phallus and pubic hair develop-
, M* [! a _, s0 Vment without testicular enlargement, which was due
& [+ t' h. c g5 P0 Fto the unintentional exposure to androgen gel used by, f. q0 G+ l0 x" `
the father. The family initially concealed this infor-
! L# L, h# R( D. s: [9 tmation, resulting in an extensive work-up for this
7 m5 o, a& V! C. w5 ]" [/ Cchild. Given the widespread and easy availability of
& Q: |. ^3 l, W. {testosterone gel and cream, we believe this is proba-
5 h- Q2 n0 W1 W3 Obly more common than the rare case report in the3 t( ^9 E! v N0 q& K0 A' Z. X4 I
literature.4
. w8 ?- E% J: f4 }Patient Report4 T' d |, Q8 x6 s* q0 X9 e
A 16-month-old white child was referred to the8 z6 a2 O: x9 ]" Y$ s3 B
endocrine clinic by his pediatrician with the concern
* B+ `. d; E2 h+ ~+ E% d: |0 H' Xof early sexual development. His mother noticed
( R6 N/ x* y+ S d1 ?! _light colored pubic hair development when he was
& v8 K) ]% j6 {2 m2 Y( RFrom the 1Division of Pediatric Endocrinology, 2University of" u. ~$ b. \2 Y, R& Z" G; N% I
South Alabama Medical Center, Mobile, Alabama.
! X. u0 A+ f- D- w8 C" XAddress correspondence to: Samar K. Bhowmick, MD, FACE,$ D5 ]' c; N1 C" D* z @! K
Professor of Pediatrics, University of South Alabama, College of
# M/ \ C7 V6 z2 k+ X8 [, ]Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
u0 z$ w( `- de-mail: [email protected]./ [; r2 S+ U$ {% p9 h) ^9 z$ V
about 6 to 7 months old, which progressively became N o6 Y6 J) X( N- R
darker. She was also concerned about the enlarge-
: [+ [! {9 @! N1 L# ?3 Gment of his penis and frequent erections. The child. ^$ B0 z: Q, L
was the product of a full-term normal delivery, with. O* g d* g3 B
a birth weight of 7 lb 14 oz, and birth length of
* H; f4 R s& P7 L' z20 inches. He was breast-fed throughout the first year
1 e* B( V9 _: |" _' t' p p3 hof life and was still receiving breast milk along with
) m+ K+ `, M& @: D& Ssolid food. He had no hospitalizations or surgery,
9 ~& t8 i9 h. e- O* Z7 F4 q7 [and his psychosocial and psychomotor development
# ] ^2 M2 r: P/ [% g- O0 pwas age appropriate.5 ?$ r/ j5 r0 o0 {) T- D' n, R0 R: u' J
The family history was remarkable for the father,, Y( u2 V' G. p( ~4 Q- {
who was diagnosed with hypothyroidism at age 16,
0 I7 B5 |& t) f0 U& h2 L. d" Fwhich was treated with thyroxine. The father’s" ^- l! @2 f. P0 H. ~
height was 6 feet, and he went through a somewhat* A Y7 Y& p7 v% P
early puberty and had stopped growing by age 14.
/ _& j( G) S* k1 GThe father denied taking any other medication. The) A5 z3 ]" X2 \: J, w8 j
child’s mother was in good health. Her menarche( O! O. l7 u' K2 M
was at 11 years of age, and her height was at 5 feet
5 Z7 ?: n( |, W2 M5 inches. There was no other family history of pre-+ R- Y0 v' K$ i% j2 L$ v# A
cocious sexual development in the first-degree rela-8 M3 x5 s, o! X% T) ]6 z/ m* k
tives. There were no siblings.
7 V" [: l$ g) _! q" I( h$ KPhysical Examination+ [- l! H* f* a3 F1 [2 }
The physical examination revealed a very active,9 h& @8 P6 ?; i5 U7 w- s
playful, and healthy boy. The vital signs documented# Y8 s3 X# J7 j' D
a blood pressure of 85/50 mm Hg, his length was7 @+ R* _3 M3 Z" I2 Z6 @
90 cm (>97th percentile), and his weight was 14.4 kg
4 O: k6 d3 I! \, b+ F4 u% Y J5 f(also >97th percentile). The observed yearly growth
% F2 H) @$ [& b( M/ S9 ?4 Ivelocity was 30 cm (12 inches). The examination of' } f. w( h6 r1 `2 e
the neck revealed no thyroid enlargement.# X8 S) R# [: U/ I+ J7 v4 q8 `) O
The genitourinary examination was remarkable for
# l. o. d1 J8 i5 D: w K% ~enlargement of the penis, with a stretched length of& ^# L5 `. h2 {) z& a0 n4 X
8 cm and a width of 2 cm. The glans penis was very well& M" s% ^1 ^5 A, e. ]2 Z) o/ g
developed. The pubic hair was Tanner II, mostly around3 y: J/ E- p" r5 @5 D4 B
540; R/ s. M$ S J* _5 L; U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from' d X0 M- {+ u$ O
the base of the phallus and was dark and curled. The4 ?- j3 B( X6 b4 o1 g5 w8 |$ G! c
testicular volume was prepubertal at 2 mL each.
, x( I3 ~% f+ TThe skin was moist and smooth and somewhat
1 o6 i% r/ A$ Foily. No axillary hair was noted. There were no3 a3 i+ i' f3 I, b7 ~( F' J
abnormal skin pigmentations or café-au-lait spots.+ f5 Z0 J$ P7 h
Neurologic evaluation showed deep tendon reflex 2+8 r& n3 G7 K8 M; T/ o% \- V
bilateral and symmetrical. There was no suggestion$ X D1 w( G; ]9 e: Y
of papilledema.
' x8 f l% P: Y& q$ A+ zLaboratory Evaluation6 C) K/ D9 h" p4 s
The bone age was consistent with 28 months by
2 q! ]: z* U- Z* \! Y# ^8 g: Yusing the standard of Greulich and Pyle at a chrono-' y9 c Z# E( k* u1 j, @
logic age of 16 months (advanced).5 Chromosomal
: z2 b8 N; ?# t; Z5 okaryotype was 46XY. The thyroid function test5 N- Z( l$ @9 v, ]. Y
showed a free T4 of 1.69 ng/dL, and thyroid stimu-) F' G- M d: S+ T5 z E
lating hormone level was 1.3 µIU/mL (both normal).
' K% l! E* k6 b" \The concentrations of serum electrolytes, blood
9 U2 J7 G4 X* A" L7 Ourea nitrogen, creatinine, and calcium all were9 p1 p+ h+ j4 \9 X
within normal range for his age. The concentration! Q( a% S& y. Y9 G
of serum 17-hydroxyprogesterone was 16 ng/dL1 r8 l; a+ a0 C( C
(normal, 3 to 90 ng/dL), androstenedione was 20
" t3 W& c. l) f7 e& M bng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
8 B. U% ]6 o0 ?+ dterone was 38 ng/dL (normal, 50 to 760 ng/dL),9 C0 v( |1 e5 S
desoxycorticosterone was 4.3 ng/dL (normal, 7 to; T X! o1 [9 e! J7 W' C8 p
49ng/dL), 11-desoxycortisol (specific compound S)$ k' n! |) m S' @' c
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-2 a! W3 a9 o- q
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
7 h) G3 n% T. t* i# `9 R1 Z( _' k/ atestosterone was 60 ng/dL (normal <3 to 10 ng/dL),: g( T' [6 x' L+ V4 a
and β-human chorionic gonadotropin was less than; o- M2 B0 {2 s8 F: \
5 mIU/mL (normal <5 mIU/mL). Serum follicular
4 l7 l; j4 r% L+ v$ k7 @# k8 Rstimulating hormone and leuteinizing hormone
' A. @+ z3 V3 V% `; p0 M3 aconcentrations were less than 0.05 mIU/mL
9 T) t/ {. c* a! q(prepubertal).
; h% Y# _1 k; x( TThe parents were notified about the laboratory% `! ^% f. u- L# C# k5 X3 `' a/ ^
results and were informed that all of the tests were- \$ w% y& A$ ]: w/ f6 a* f, K
normal except the testosterone level was high. The* M9 P" Z9 o4 g$ d" K3 V
follow-up visit was arranged within a few weeks to1 X/ h; a/ s1 p
obtain testicular and abdominal sonograms; how-( I6 a( t" e5 c& X4 N
ever, the family did not return for 4 months.8 R- O# p4 P. Z2 p8 s
Physical examination at this time revealed that the7 c5 J3 M+ _6 D: q* J& A! n9 ^
child had grown 2.5 cm in 4 months and had gained4 E' }' e$ s9 R( L$ |
2 kg of weight. Physical examination remained
) I0 Z, c2 I. `unchanged. Surprisingly, the pubic hair almost com-
; u" p& G7 o* Ppletely disappeared except for a few vellous hairs at
3 M* B$ E8 W8 s8 l8 {; m% Dthe base of the phallus. Testicular volume was still 2! T% Z% J; A ` z, ]: d" q
mL, and the size of the penis remained unchanged.3 i5 v" V+ H3 @+ q3 B& b z
The mother also said that the boy was no longer hav-
( J5 a" @5 I) b# p" zing frequent erections.
6 X, G' I9 }$ E( T7 OBoth parents were again questioned about use of% p; t4 T# J; B; O
any ointment/creams that they may have applied to
3 x* P0 z, t; D) S7 V8 Z6 e! |' hthe child’s skin. This time the father admitted the" M6 Q% ^4 w, l7 y: t
Topical Testosterone Exposure / Bhowmick et al 5419 }. X9 N" e# ]" i
use of testosterone gel twice daily that he was apply-
. ? T2 f; G( r' _' N% i8 D) `ing over his own shoulders, chest, and back area for
" O: ?$ J% a) U* R1 [( {( j# ha year. The father also revealed he was embarrassed
/ u/ t( }0 Y( ?7 q Kto disclose that he was using a testosterone gel pre-1 V1 R% Z1 n P5 R& q& k* b
scribed by his family physician for decreased libido3 ~+ a9 J) t3 ^* V* k1 |* x5 ]: N
secondary to depression.
) \: E; k# [; J+ }% T3 CThe child slept in the same bed with parents.
. G- X% o5 k6 BThe father would hug the baby and hold him on his
* ~ r& }# s$ [, g3 c+ Qchest for a considerable period of time, causing sig-
0 P) K( q) k- H, Anificant bare skin contact between baby and father.% N5 J- m& ~( l4 {
The father also admitted that after the phone call,' `8 B) l7 a$ y$ _
when he learned the testosterone level in the baby
1 }5 ^5 y1 o! \3 vwas high, he then read the product information6 D' ~# r" ~+ B* A
packet and concluded that it was most likely the rea-' e; y" b' z; D9 x! o$ G& i
son for the child’s virilization. At that time, they9 k4 c6 t3 K& W
decided to put the baby in a separate bed, and the6 E. y, N ~/ s* q. [, Q2 a
father was not hugging him with bare skin and had/ {4 J0 I/ D% d0 R8 ?
been using protective clothing. A repeat testosterone9 u n( Y/ c. |# J% Y" n* Z
test was ordered, but the family did not go to the
, j. {9 Y! s( Z/ _4 @$ }9 Y8 o4 Elaboratory to obtain the test.
4 d% Z: x& |2 [' iDiscussion# w# ]# c6 Y* v
Precocious puberty in boys is defined as secondary
$ V/ t; L" n7 C: Y) ?% t, u& m4 Bsexual development before 9 years of age.1,4; m9 O: J4 \0 q& ^! t/ z
Precocious puberty is termed as central (true) when
' A2 R6 s; x5 d pit is caused by the premature activation of hypo-1 S( B4 |& m9 ^" }7 _
thalamic pituitary gonadal axis. CPP is more com-
( g' e4 S l* b6 n- emon in girls than in boys.1,3 Most boys with CPP
$ C* Q9 p& A+ a7 r; b$ Y9 B; Rmay have a central nervous system lesion that is
' N; {3 k. ~% i9 O- I( T% ^responsible for the early activation of the hypothal-7 g0 e$ g( K9 C
amic pituitary gonadal axis.1-3 Thus, greater empha-
$ ]# g+ B" f: |+ M8 D3 d: Jsis has been given to neuroradiologic imaging in6 B* r. f- h, R# n( n" g
boys with precocious puberty. In addition to viril-
6 V3 j. `/ P0 b M- j7 f' S& c4 g1 Fization, the clinical hallmark of CPP is the symmet-4 ]; r$ U- B7 P& _
rical testicular growth secondary to stimulation by
% b6 e2 P* ~( A" E7 _gonadotropins.1,3
4 S b! w6 D6 r+ _- P( I6 |4 IGonadotropin-independent peripheral preco-
7 d8 U9 [# t, Y& x# Ecious puberty in boys also results from inappropriate( w' Q" G4 J# s: K9 Q
androgenic stimulation from either endogenous or
; t2 g4 i7 y9 r) ^/ @! N2 xexogenous sources, nonpituitary gonadotropin stim-1 u2 w" c0 U+ W+ C) H
ulation, and rare activating mutations.3 Virilizing
$ s) Q: z) ^0 ?" Wcongenital adrenal hyperplasia producing excessive, f5 X: m6 W( C: ]7 f
adrenal androgens is a common cause of precocious
9 ^2 J% v# q8 ~1 Apuberty in boys.3,4
# E' u0 p$ D2 z$ G' i" _The most common form of congenital adrenal
+ B2 [4 C2 z8 v A0 h' ahyperplasia is the 21-hydroxylase enzyme deficiency.
* M4 r8 N6 v! i4 v* JThe 11-β hydroxylase deficiency may also result in
6 p. v# S) `1 c: y2 D9 m% Wexcessive adrenal androgen production, and rarely,4 A, r# X# A3 n/ V& a3 l, s
an adrenal tumor may also cause adrenal androgen: Y& F+ c3 ^1 k) B! ~7 @
excess.1,37 t! m. o' k1 O; ], x
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from9 M9 P- G: m" E
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
) |- }/ W' ~2 C! |' B; x+ xA unique entity of male-limited gonadotropin-5 e7 [: f' S0 k
independent precocious puberty, which is also known
# {, `, Z+ v G% Yas testotoxicosis, may cause precocious puberty at a8 w: J, n# j$ [9 B" s- K! h
very young age. The physical findings in these boys3 W& H+ [! c" ]4 Y/ h; l6 v$ r
with this disorder are full pubertal development,
, ~- M" K; \, K5 _$ |% m4 m: u- Xincluding bilateral testicular growth, similar to boys
! t5 C V/ L. k6 ?$ |with CPP. The gonadotropin levels in this disorder
# m9 `. s0 b, S Eare suppressed to prepubertal levels and do not show, x" n) X8 I4 o3 C8 n3 R
pubertal response of gonadotropin after gonadotropin-
; k8 Q: J) B9 H3 |7 x/ creleasing hormone stimulation. This is a sex-linked# _- E3 w% R, v4 Y+ W& ~7 @9 W
autosomal dominant disorder that affects only
' k' I- m U, j( wmales; therefore, other male members of the family
: W# W" X9 W: l) \- Dmay have similar precocious puberty.3
" S7 O* m. f& v W3 C8 N2 b! d9 vIn our patient, physical examination was incon-" k2 b) p. W3 s9 F- R+ Y
sistent with true precocious puberty since his testi-
8 X. a+ C9 J4 R, L& t5 { Pcles were prepubertal in size. However, testotoxicosis
, H1 a% R( e% j/ ~) Dwas in the differential diagnosis because his father) R" q* H% N4 W/ s
started puberty somewhat early, and occasionally,
5 F1 m9 k- ]2 z* Ytesticular enlargement is not that evident in the$ ?7 Z. o! B- e) x3 o" s
beginning of this process.1 In the absence of a neg-
0 W, K" W6 T( o( ^, [7 I6 kative initial history of androgen exposure, our* _7 c' n0 [: w& r
biggest concern was virilizing adrenal hyperplasia,$ m1 e' V9 f. b- U
either 21-hydroxylase deficiency or 11-β hydroxylase3 F& \) S2 L/ M L: X
deficiency. Those diagnoses were excluded by find-) h& u$ A1 N' U
ing the normal level of adrenal steroids.) F" a, V4 _* x9 O
The diagnosis of exogenous androgens was strongly
+ Q* ]$ d5 t. g0 w- ^suspected in a follow-up visit after 4 months because
- H5 Q- H! f- @9 n' d6 n6 Qthe physical examination revealed the complete disap-
6 G7 b. A! g/ P+ @( ?3 z2 Lpearance of pubic hair, normal growth velocity, and
" u7 l. l8 Z& L m" jdecreased erections. The father admitted using a testos-( q% P% Q) N$ e* Z) `
terone gel, which he concealed at first visit. He was$ H& j) [% E! Q. L( D. k
using it rather frequently, twice a day. The Physicians’
3 p' T4 I5 r* V6 l- ?/ SDesk Reference, or package insert of this product, gel or
8 n5 `: `7 H; D+ Ccream, cautions about dermal testosterone transfer to
' W3 c1 D2 R! x( Aunprotected females through direct skin exposure.
2 B$ S* j- d9 C. ~( y* D' J, wSerum testosterone level was found to be 2 times the) O' m$ u6 {; I* K& u. W
baseline value in those females who were exposed to
0 S h7 W G5 S6 l9 Leven 15 minutes of direct skin contact with their male
& q! ]* q' _' U' o0 K) w! I) N+ g( Spartners.6 However, when a shirt covered the applica-6 s- s* G6 a6 Z* h* u6 |) G
tion site, this testosterone transfer was prevented.( ?+ n. x% t* ^- G" _5 m
Our patient’s testosterone level was 60 ng/mL,
) y9 }/ {. \. qwhich was clearly high. Some studies suggest that7 B I0 o7 g% x0 R8 O
dermal conversion of testosterone to dihydrotestos-) n2 g) n3 h3 r" r. r" f4 S M( p
terone, which is a more potent metabolite, is more# N3 H5 |# H( X& b
active in young children exposed to testosterone
& t8 m. h% l* A( oexogenously7; however, we did not measure a dihy-( ~! p& c ^9 U, F
drotestosterone level in our patient. In addition to
# D; [$ W( |5 j$ w$ Y# D/ G$ b5 Hvirilization, exposure to exogenous testosterone in
* @* b" Q: t+ Ichildren results in an increase in growth velocity and
* r' G% G1 d/ B/ Uadvanced bone age, as seen in our patient.
3 n8 \/ o4 w( AThe long-term effect of androgen exposure during5 y) u" m+ [/ x6 {0 B9 C% ]' R
early childhood on pubertal development and final$ @7 U. Q" _9 S; k* k
adult height are not fully known and always remain2 K" e* ?7 L( L0 I: [
a concern. Children treated with short-term testos-+ p. J% ]* _) W- P) e0 v" z+ F
terone injection or topical androgen may exhibit some
5 k1 @; }/ x" s+ R: {- B) gacceleration of the skeletal maturation; however, after
7 s9 g9 v) C$ _cessation of treatment, the rate of bone maturation2 ~. e# T" x1 [
decelerates and gradually returns to normal.8,9
: c( v+ X8 a& j/ _1 \ IThere are conflicting reports and controversy
* n( J2 a# _0 c5 S1 W7 Sover the effect of early androgen exposure on adult% _ a( c2 t" m- O }1 j
penile length.10,11 Some reports suggest subnormal3 j0 }! P q* K6 s* C2 x- _
adult penile length, apparently because of downreg-
' \. n6 `, i0 q5 |- e* fulation of androgen receptor number.10,12 However,# G* q! z9 Y$ I5 u2 o& A
Sutherland et al13 did not find a correlation between
4 y* j* v0 d! l$ P7 \childhood testosterone exposure and reduced adult# j2 P& J; k8 J7 n6 g
penile length in clinical studies.
6 n3 S- R. [! {4 a) O2 p/ d2 YNonetheless, we do not believe our patient is
" J4 V$ X: s6 e: w. pgoing to experience any of the untoward effects from
/ v% H7 H8 d! [testosterone exposure as mentioned earlier because
4 V4 F; r2 a+ S. A* ethe exposure was not for a prolonged period of time.& r7 T, _& {9 H( I6 \5 u0 M6 X) O
Although the bone age was advanced at the time of6 x9 {4 T5 L, r( d9 y! i- z! `
diagnosis, the child had a normal growth velocity at
: R& U3 }6 J3 g6 Xthe follow-up visit. It is hoped that his final adult& \* U3 c& `1 T
height will not be affected., w/ j5 p4 g" e- Z n
Although rarely reported, the widespread avail-
& a( k8 m3 a- i# J( N$ }/ Z5 G# dability of androgen products in our society may; E. L( ]: v- f- X
indeed cause more virilization in male or female6 ~5 h( I/ @9 m+ @6 z; [6 g
children than one would realize. Exposure to andro-4 A2 D! A% [% y; k& v
gen products must be considered and specific ques-
% S4 D6 Y9 \; I% btioning about the use of a testosterone product or, u3 y' a, I& B: F* K
gel should be asked of the family members during+ I" F( J; i2 I: h j+ t
the evaluation of any children who present with vir-/ I/ f5 ^$ w q& P
ilization or peripheral precocious puberty. The diag-7 w6 k! u; F( A$ L3 [0 E" ]
nosis can be established by just a few tests and by
T0 L) M- W- O6 ~$ k: }appropriate history. The inability to obtain such a' C T" A0 S5 _+ x
history, or failure to ask the specific questions, may
* r" k# Z3 _- V+ U9 y( E0 kresult in extensive, unnecessary, and expensive
$ n/ o9 h* G* I0 Q/ _investigation. The primary care physician should be$ w2 k. X: B3 t
aware of this fact, because most of these children5 h; u" C( l* B; t2 m
may initially present in their practice. The Physicians’$ H6 ?* t' w7 n/ h3 u
Desk Reference and package insert should also put a( a* }# ]+ U' v; e
warning about the virilizing effect on a male or* O1 c" a9 Q$ Z
female child who might come in contact with some-
6 ]' O0 A5 B- T. D) {one using any of these products.3 u* {- h! E- W% E9 S
References% |, b$ `' x# C$ ^4 F5 C* }- x( X5 f3 C ?
1. Styne DM. The testes: disorder of sexual differentiation
0 h* k; A$ R( r \, T7 tand puberty in the male. In: Sperling MA, ed. Pediatric
8 ?$ S) h7 R6 f6 s! v4 xEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;7 y( P2 B8 u" V) t
2002: 565-628.
6 G1 Y( F1 r# s& d9 y! N1 M2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
' J2 U/ x0 s3 x$ ^1 s9 M; X. gpuberty in children with tumours of the suprasellar pineal |
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