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Sexual Precocity in a 16-Month-Old
0 ^0 S' V% U& f- e YBoy Induced by Indirect Topical* F6 j' X: g/ x/ }) y5 V8 o6 z/ L/ C
Exposure to Testosterone
% z5 T0 R6 c. l$ A8 ^Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
1 H; \9 w8 D5 U* V" jand Kenneth R. Rettig, MD12 S. ~9 _' N l% M8 S
Clinical Pediatrics! i; P$ b5 F" k3 B+ N4 f/ W0 S! _
Volume 46 Number 6
( M1 S, |- }5 r2 z/ UJuly 2007 540-5431 h2 ?2 l% _1 E
© 2007 Sage Publications
' D" x+ r, D% ^$ a1 p* |10.1177/0009922806296651+ y0 @3 A* x! T
http://clp.sagepub.com
& u' |# k% G; l7 p/ C+ i2 ^2 Y3 Uhosted at
' u! H' R! B" d7 } \http://online.sagepub.com
" ]/ `' c ?8 t: qPrecocious puberty in boys, central or peripheral,
: S- l% p3 R& R* D/ r1 iis a significant concern for physicians. Central' I/ u* _' g1 r+ d
precocious puberty (CPP), which is mediated
/ F# R4 M" V( o; Y' ^* {through the hypothalamic pituitary gonadal axis, has
5 h, V: j; d* J v# Qa higher incidence of organic central nervous system6 h0 Z0 w/ M8 O4 a# F
lesions in boys.1,2 Virilization in boys, as manifested8 E0 s! N4 D2 O9 I) ~/ T
by enlargement of the penis, development of pubic7 Z+ _3 G- N+ @1 n# }
hair, and facial acne without enlargement of testi-
0 V8 I% \9 F7 B3 y" B5 zcles, suggests peripheral or pseudopuberty.1-3 We
h4 }, m) d- L! h, o# A% k; lreport a 16-month-old boy who presented with the0 D d7 K( T* \# `. f+ L
enlargement of the phallus and pubic hair develop-
" [% f( [, M3 d! Vment without testicular enlargement, which was due
2 y4 |; ?* H @) C# Mto the unintentional exposure to androgen gel used by5 L- P, u' \3 ~% r
the father. The family initially concealed this infor-
% S* u# c+ v. R9 [3 L6 y5 |mation, resulting in an extensive work-up for this
% ?- X' w0 W& i9 Mchild. Given the widespread and easy availability of
8 {# {' y* o# L: Ftestosterone gel and cream, we believe this is proba-" _# F, ]6 z% G8 ^+ N
bly more common than the rare case report in the
. N& z9 i& m* m- J7 D2 _# \# Kliterature.46 C. ?0 f9 ?- A) F
Patient Report7 |, o, `6 l# n( _9 P4 k' |
A 16-month-old white child was referred to the
: }: _% K, @6 Zendocrine clinic by his pediatrician with the concern
3 a1 K; T5 t' s7 _of early sexual development. His mother noticed+ ?4 m! _ L: ~7 Q5 k
light colored pubic hair development when he was
' H- I' D9 B: s2 h4 ?From the 1Division of Pediatric Endocrinology, 2University of2 c) A. j3 n5 K( h
South Alabama Medical Center, Mobile, Alabama.
" p% [1 p# g: g( {5 F- p2 yAddress correspondence to: Samar K. Bhowmick, MD, FACE,% t* S$ R( @9 ^! f/ a
Professor of Pediatrics, University of South Alabama, College of1 F. x7 U: _0 [
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;/ `. {$ H6 @/ G0 H2 g9 y
e-mail: [email protected].9 r- ?' E& Z7 v7 U; z. `
about 6 to 7 months old, which progressively became
) R( I* j2 d* t! r, bdarker. She was also concerned about the enlarge-1 m5 ^( {% w: i( Y
ment of his penis and frequent erections. The child, f. ~& h& b7 i
was the product of a full-term normal delivery, with
8 r: `5 Z" S/ W( | f6 S ~2 fa birth weight of 7 lb 14 oz, and birth length of' x3 z. s Q# `7 Z+ d, O. X/ t
20 inches. He was breast-fed throughout the first year9 ~! z& h, f- W0 v& _
of life and was still receiving breast milk along with: \9 _% S. O7 \* q; q% c+ @& P
solid food. He had no hospitalizations or surgery,
+ l6 w: V+ u4 L9 T( F& M5 R0 aand his psychosocial and psychomotor development! t) Z! h5 z7 C$ {* Y4 f
was age appropriate.) g `; @, ~+ b) Y/ J ?: Q/ j
The family history was remarkable for the father,
7 x5 @; b$ N2 Awho was diagnosed with hypothyroidism at age 16,
, Z, V2 w3 O1 \& T1 g. nwhich was treated with thyroxine. The father’s
) o0 T/ o' @* iheight was 6 feet, and he went through a somewhat4 ?! G" r( V( C0 a6 D6 F; G
early puberty and had stopped growing by age 14.
* {' d$ h2 Q1 c2 F" HThe father denied taking any other medication. The
2 W) I3 c) U6 Z# t- ~. ~/ c" Y" Jchild’s mother was in good health. Her menarche d L' j5 u# c
was at 11 years of age, and her height was at 5 feet
: f2 T( ?: u) d! ]5 inches. There was no other family history of pre-
+ G2 N; m! r' g; D) k* Gcocious sexual development in the first-degree rela-
$ P2 }# S% O5 C# p+ Jtives. There were no siblings.
, F8 m1 w3 A) _7 oPhysical Examination8 y9 T9 u/ r4 d; b
The physical examination revealed a very active, `7 W2 I0 J# J, k. r
playful, and healthy boy. The vital signs documented0 p [' P9 V) p3 E
a blood pressure of 85/50 mm Hg, his length was
7 m3 E p0 v$ L! {: X90 cm (>97th percentile), and his weight was 14.4 kg
" G8 g/ I- P3 d9 ?" e ^# F( X(also >97th percentile). The observed yearly growth% ^3 P1 H! f1 ]' J& L( e! ]
velocity was 30 cm (12 inches). The examination of7 n o/ A v% h$ g; C
the neck revealed no thyroid enlargement.- `" p$ O: `* S, e
The genitourinary examination was remarkable for. t2 ]8 j( p8 O
enlargement of the penis, with a stretched length of+ t. T% A4 c, v3 f0 B3 g0 L
8 cm and a width of 2 cm. The glans penis was very well
3 Y- b ?/ N$ q: \# U% Ydeveloped. The pubic hair was Tanner II, mostly around4 X6 L; k% {9 i7 G4 n0 o
540
1 z1 |7 F, J' s- V5 C. uat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% s6 _/ T% E; G2 S1 B6 t6 v
the base of the phallus and was dark and curled. The& `1 f# ]9 L% I/ d
testicular volume was prepubertal at 2 mL each.
! V; @! z0 s4 v9 J- W. |2 Z5 AThe skin was moist and smooth and somewhat1 F3 z6 f' r8 N, n8 s" w
oily. No axillary hair was noted. There were no) P/ W2 D, u" B0 I, r. p# G
abnormal skin pigmentations or café-au-lait spots.
9 K/ W% P) F, p s8 _Neurologic evaluation showed deep tendon reflex 2+
4 a0 x; H# @1 E5 Ubilateral and symmetrical. There was no suggestion
: Z6 y3 v) N/ w# ?! fof papilledema." y) H* E: _: H
Laboratory Evaluation: H2 I& u Z' j* X
The bone age was consistent with 28 months by3 g. A6 `' R5 N
using the standard of Greulich and Pyle at a chrono-& I0 L9 p; w2 q" }
logic age of 16 months (advanced).5 Chromosomal' a1 r E! f; T% f
karyotype was 46XY. The thyroid function test) J2 U Y6 `/ ]) }4 X4 t
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
# ~3 r# ^7 o3 {0 L5 r5 ]* C+ Slating hormone level was 1.3 µIU/mL (both normal).' S: e& g( R4 V8 m+ [
The concentrations of serum electrolytes, blood& }% S/ V+ ^. l0 A( c- s7 H
urea nitrogen, creatinine, and calcium all were
' @0 M2 e) n& L3 B) owithin normal range for his age. The concentration |# |1 `4 I8 z, @3 H+ b
of serum 17-hydroxyprogesterone was 16 ng/dL/ a7 v* M# N3 |' P4 k0 ~/ a
(normal, 3 to 90 ng/dL), androstenedione was 20
4 Z5 v. ^6 U* n) gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
! T4 f! `# d4 mterone was 38 ng/dL (normal, 50 to 760 ng/dL),( ]% n% m; h) s7 C3 f
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
- U" U4 U! o6 }0 J( P; R+ I7 Q49ng/dL), 11-desoxycortisol (specific compound S)
/ k2 n& e; H2 {; _) d: Twas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-) Q5 _; X V5 x8 d1 A5 h
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total0 l/ C9 A% g/ O# P& o
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),& B, X" h& F! i6 F
and β-human chorionic gonadotropin was less than
8 T$ L; A: Q4 o1 y5 mIU/mL (normal <5 mIU/mL). Serum follicular, y8 Q! g0 U' k9 K$ g/ m, N4 e
stimulating hormone and leuteinizing hormone& u% Y% ]' }1 W0 R. d2 L
concentrations were less than 0.05 mIU/mL# d7 ?! u2 _* |# {9 }/ x9 V
(prepubertal).
$ [* p8 n, a) h: TThe parents were notified about the laboratory
: {2 H; B: y: x- w; L o5 `results and were informed that all of the tests were
2 j3 n' E) G8 P H8 gnormal except the testosterone level was high. The5 d/ R6 [7 Q0 Q
follow-up visit was arranged within a few weeks to* f6 a0 X7 C0 l5 w' v4 i$ s
obtain testicular and abdominal sonograms; how-+ Y$ W2 y( O8 S; R
ever, the family did not return for 4 months.
9 U. ^; d3 M" Z+ B O/ rPhysical examination at this time revealed that the# ^9 W$ Y& ?, F- H: z5 i# F
child had grown 2.5 cm in 4 months and had gained: X9 C% v/ E! ?8 P: {& v
2 kg of weight. Physical examination remained
6 l% c7 w7 |: g) e& sunchanged. Surprisingly, the pubic hair almost com-1 r4 _7 L! h" }* M9 y A
pletely disappeared except for a few vellous hairs at
& p8 a7 z' w, u1 M: n0 c- p" S5 Athe base of the phallus. Testicular volume was still 2
" [# ^; a/ j! K/ W) Q' L& R& pmL, and the size of the penis remained unchanged.
$ Z+ `2 K/ n* T) PThe mother also said that the boy was no longer hav-
2 }) l# ]) T: Q Y; `% xing frequent erections.
4 {4 L+ [; ]9 I uBoth parents were again questioned about use of( V) L& w* B7 H
any ointment/creams that they may have applied to% x- Z7 m, U: C- h* K+ ?
the child’s skin. This time the father admitted the
: e7 Z! [4 [9 O, kTopical Testosterone Exposure / Bhowmick et al 541
) q0 E# ]/ d, Vuse of testosterone gel twice daily that he was apply-9 {2 f/ w9 ~4 P
ing over his own shoulders, chest, and back area for
/ E4 J* w8 S$ ?9 K- Ha year. The father also revealed he was embarrassed
4 C. L- m8 e( bto disclose that he was using a testosterone gel pre-
, P2 P- i/ L# F8 rscribed by his family physician for decreased libido
( w0 m* d# D8 a9 `secondary to depression.1 A" }5 D; z2 ^; c
The child slept in the same bed with parents.$ M. U& f" e# c4 T7 M
The father would hug the baby and hold him on his
4 s' f! O3 |& j- X3 bchest for a considerable period of time, causing sig-& h1 |) ~1 o) J
nificant bare skin contact between baby and father.
: N: I3 T% h6 \) M1 |3 t- jThe father also admitted that after the phone call,5 X1 B+ r3 t8 r6 _( P/ E
when he learned the testosterone level in the baby8 l; |3 o5 E( q
was high, he then read the product information* X% y4 d: f7 Y( v3 o q, d7 S. M
packet and concluded that it was most likely the rea-
2 A* ]5 H9 c5 c4 W+ ason for the child’s virilization. At that time, they
" p* {' _, h ~' R- w8 Ldecided to put the baby in a separate bed, and the, i2 Z }6 C4 r2 x8 s G" B/ @% u: o4 X
father was not hugging him with bare skin and had+ F* ~* x2 _# i
been using protective clothing. A repeat testosterone( L0 q$ P* [/ S' j$ g$ X0 p) K
test was ordered, but the family did not go to the& {- u. Y; y5 `( t/ E7 E" j
laboratory to obtain the test.
! u. b/ q" L! P% f" v4 }; oDiscussion
! y/ b% q5 D; u" OPrecocious puberty in boys is defined as secondary
6 ~6 H3 `9 |- H! Usexual development before 9 years of age.1,4" I0 |2 u7 X. ~& [# ?4 N
Precocious puberty is termed as central (true) when% }( D9 I$ Q6 D# j$ \. t
it is caused by the premature activation of hypo-
/ r# P+ L4 l7 n' P. Wthalamic pituitary gonadal axis. CPP is more com-+ e# h9 y# i6 A$ ?. q) }" m
mon in girls than in boys.1,3 Most boys with CPP. o1 R+ S% z# I, |1 }6 S- l& V+ W& v
may have a central nervous system lesion that is
( c3 q" K. X9 F/ _/ Jresponsible for the early activation of the hypothal-$ W6 A6 u2 G2 C" _3 k1 j( N4 c& C% [8 e
amic pituitary gonadal axis.1-3 Thus, greater empha-
/ A$ e9 Y2 O* N& q( _3 c) ~" zsis has been given to neuroradiologic imaging in! w5 z2 }+ z! _4 y% m; N
boys with precocious puberty. In addition to viril-/ x# y3 x0 s1 _2 r3 Q0 U
ization, the clinical hallmark of CPP is the symmet-
0 Z3 _0 ], O/ O9 ~* k! r' D3 Erical testicular growth secondary to stimulation by3 C, r0 a, N8 p) W. h! Q/ G
gonadotropins.1,3+ F- Z, O8 g& Z
Gonadotropin-independent peripheral preco-
. i% {5 D, i8 w$ icious puberty in boys also results from inappropriate: ^9 D( H1 F2 V
androgenic stimulation from either endogenous or
, L+ f& I1 \2 B% ~# g3 Rexogenous sources, nonpituitary gonadotropin stim-
8 a6 n2 ^: y4 _, Uulation, and rare activating mutations.3 Virilizing
. b5 t0 i- L, n( G6 Qcongenital adrenal hyperplasia producing excessive
- X) s' O% ]3 j# |( i/ Wadrenal androgens is a common cause of precocious
1 o' J" e8 k! f/ A7 mpuberty in boys.3,4
6 @, @6 b" p0 s, ]- [The most common form of congenital adrenal
/ g X: y. I+ i5 Ihyperplasia is the 21-hydroxylase enzyme deficiency.
! o$ E9 B ?2 Y+ t# ]0 XThe 11-β hydroxylase deficiency may also result in! V2 K3 U4 g5 [$ y$ S
excessive adrenal androgen production, and rarely,
0 A1 X; p% T, @8 Ran adrenal tumor may also cause adrenal androgen- T8 i* ^( Y$ @7 B% K- m
excess.1,3* c- J4 c3 E; Y% R
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
, N5 }: S- y: `! E( K5 ]) w542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
( o. ?/ |& w& |% FA unique entity of male-limited gonadotropin-, ]" Q+ l5 a$ k. l- q" M3 k
independent precocious puberty, which is also known' W% T! z* p( X: z9 [% v5 Q
as testotoxicosis, may cause precocious puberty at a5 P& f; w) D& O! r$ z3 @
very young age. The physical findings in these boys
h8 g* I& b, w" z7 Ewith this disorder are full pubertal development,
7 V& Z- C+ V. `5 W* W3 \7 R' X; Qincluding bilateral testicular growth, similar to boys
1 d; b/ N3 {% }* c8 {/ K* _+ Mwith CPP. The gonadotropin levels in this disorder7 g, A! ]' Y4 n' Q* v% x: t
are suppressed to prepubertal levels and do not show
( z$ @- k8 u* f! Wpubertal response of gonadotropin after gonadotropin-
2 }* b4 u4 x5 \: Q( creleasing hormone stimulation. This is a sex-linked
9 v" j# ^& H4 Rautosomal dominant disorder that affects only) G! K& i" f# ^; b8 g
males; therefore, other male members of the family" P$ j) |9 ?+ i, K8 z
may have similar precocious puberty.3
7 b! e6 A; C% K- E# N2 _6 M$ OIn our patient, physical examination was incon-
" |8 n9 ]4 K1 G& c, ?& F) c( Z% psistent with true precocious puberty since his testi-
/ ~# p+ C: d& O8 p7 I+ Dcles were prepubertal in size. However, testotoxicosis' G( ] f# M$ Q& Z# _
was in the differential diagnosis because his father% ^4 M1 S: N: r; ?3 X$ I w5 y
started puberty somewhat early, and occasionally,
- U* [/ p( ]% s4 ~7 T' A# I2 htesticular enlargement is not that evident in the6 \0 P" d/ d5 s' ]4 D
beginning of this process.1 In the absence of a neg-( {7 R. b0 @$ A# |2 f
ative initial history of androgen exposure, our% m9 q3 H& _" u1 i1 ]
biggest concern was virilizing adrenal hyperplasia,
/ B- d( A, U, O) Y8 s* \either 21-hydroxylase deficiency or 11-β hydroxylase
9 J# L# o+ L. ^- {deficiency. Those diagnoses were excluded by find-2 J2 u- J0 A) q; X' r' Y
ing the normal level of adrenal steroids.+ r* u" ?+ h0 W6 P; G; H+ D
The diagnosis of exogenous androgens was strongly
6 p5 Z- B& y- Lsuspected in a follow-up visit after 4 months because
' N) P# m) Y8 a, rthe physical examination revealed the complete disap-
* s7 K1 l3 O+ G* {& Rpearance of pubic hair, normal growth velocity, and
% F0 W# ~% p5 L/ ~; p+ Sdecreased erections. The father admitted using a testos-5 p+ M( I7 J9 p% `
terone gel, which he concealed at first visit. He was P0 [& x) e$ z2 v' {9 s
using it rather frequently, twice a day. The Physicians’
/ @" Z) P( U7 qDesk Reference, or package insert of this product, gel or
. Q. O% `/ w, Ocream, cautions about dermal testosterone transfer to
# M9 W/ k% Q p1 u. f6 |unprotected females through direct skin exposure.
1 J% [$ l" j0 h/ rSerum testosterone level was found to be 2 times the) @; S8 V& ?( G+ A2 s
baseline value in those females who were exposed to3 u% H: d) v' C
even 15 minutes of direct skin contact with their male
9 \& v5 u- e# K& dpartners.6 However, when a shirt covered the applica-
1 k6 F/ B! j' g i I: h0 K' V a' Btion site, this testosterone transfer was prevented.
/ A, J6 d) S. T5 X; |& O/ YOur patient’s testosterone level was 60 ng/mL, \4 L! |- U/ F4 F
which was clearly high. Some studies suggest that# O) V9 l' a" p0 t& X K- ]
dermal conversion of testosterone to dihydrotestos-; D {* M- m$ r) E- s
terone, which is a more potent metabolite, is more, u: s. k- U, b' Z2 ?
active in young children exposed to testosterone
( Y3 ?5 W$ a0 S; I6 W; q" C3 Pexogenously7; however, we did not measure a dihy-; Y8 w7 q9 H3 U& x4 ~) y5 ?
drotestosterone level in our patient. In addition to, n) W7 p' x( }8 w9 ~
virilization, exposure to exogenous testosterone in
8 q. x6 @/ `5 A X. A7 vchildren results in an increase in growth velocity and
/ B- {! V% V! Gadvanced bone age, as seen in our patient.
- r0 z# y* E8 }8 OThe long-term effect of androgen exposure during4 h& g; v% W) `. k
early childhood on pubertal development and final
v7 _! e5 H) {' N6 f5 I2 _. qadult height are not fully known and always remain0 h {: I& b! f, @1 N
a concern. Children treated with short-term testos-
/ x0 g1 l; |! i9 p* \: H: hterone injection or topical androgen may exhibit some+ ^9 [ ^( P, d. _
acceleration of the skeletal maturation; however, after" E4 w, P8 Y8 S
cessation of treatment, the rate of bone maturation, ]5 o/ D W" r3 i$ @+ Y, ^/ u: O
decelerates and gradually returns to normal.8,9
: Z3 R! [! t! G2 f8 G! uThere are conflicting reports and controversy) N2 V( a% u6 e
over the effect of early androgen exposure on adult [+ L7 t6 L. [2 Z# Z T, l& ~
penile length.10,11 Some reports suggest subnormal
. [( ]4 C1 e# @! i1 Iadult penile length, apparently because of downreg-
& W; o5 M, |+ W. O/ I- s/ {ulation of androgen receptor number.10,12 However,
8 |& E$ J$ C+ b y" i( ySutherland et al13 did not find a correlation between& {* \" d2 M# a7 N8 f: j
childhood testosterone exposure and reduced adult, I. d+ k! |5 M' i# x
penile length in clinical studies.
' z$ p7 L8 ~. L. H8 [1 MNonetheless, we do not believe our patient is' l/ q( l4 a0 u+ v! ?
going to experience any of the untoward effects from
) y/ `! v9 |$ btestosterone exposure as mentioned earlier because7 b* f4 U+ X0 b. ]/ F2 Y
the exposure was not for a prolonged period of time.$ O) X* i5 v, X- [" P/ z3 `. S3 f( S) `
Although the bone age was advanced at the time of
8 ~2 g" H) F& bdiagnosis, the child had a normal growth velocity at
S6 n8 c0 p! F" y: V6 }/ |the follow-up visit. It is hoped that his final adult
* b7 P I9 v& [3 S; rheight will not be affected." I, U6 h4 J; S- U( I2 P$ ^ _3 ~
Although rarely reported, the widespread avail-% h! M! F( r- `& a/ q% p
ability of androgen products in our society may: J, `+ L. K. k S& v" ^) `6 Y
indeed cause more virilization in male or female# h" S' \0 v, c$ o
children than one would realize. Exposure to andro-
3 j/ o$ h8 E9 z+ w6 }gen products must be considered and specific ques-
- [/ Z: u5 X5 o% W8 Q1 ~4 `tioning about the use of a testosterone product or, H8 \5 o4 _' S' _
gel should be asked of the family members during# m; _: N0 v" [
the evaluation of any children who present with vir-3 I$ S0 W5 R: I
ilization or peripheral precocious puberty. The diag- e: K$ C \) Y4 d0 m7 v
nosis can be established by just a few tests and by6 K7 G2 v0 z' M) m2 T5 j
appropriate history. The inability to obtain such a
# ]# z6 W* j8 u9 n; [history, or failure to ask the specific questions, may a* N- t0 s5 f; ^* A- I. X
result in extensive, unnecessary, and expensive) w e) \' A, R$ c M, O
investigation. The primary care physician should be+ F& Z8 |& g% p. d; G( _# r
aware of this fact, because most of these children
+ e; @$ F4 G6 f9 M" t1 H9 Z. E7 k0 \may initially present in their practice. The Physicians’9 w0 j4 C+ d. q: \# c( B. a" U: ?
Desk Reference and package insert should also put a; F& r) X5 @* o' J
warning about the virilizing effect on a male or; ^: s. j Q5 H9 f* ^5 k* X& S" a( i
female child who might come in contact with some-0 x* Z5 }& q8 s7 @0 |
one using any of these products.( k' [! N* f( t
References
8 X6 M( T5 o0 d2 T0 F5 q, {5 \1. Styne DM. The testes: disorder of sexual differentiation
( q5 v/ M3 e, T& O5 @+ L. C( f3 p. Y- x) iand puberty in the male. In: Sperling MA, ed. Pediatric
1 D4 u U) u I5 W0 b9 m. REndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
& w3 z8 a% D$ h: u8 U4 L2002: 565-628.$ [+ C0 P$ e. v, j: E5 ^
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
* P; W. A* i3 g+ Ppuberty in children with tumours of the suprasellar pineal |
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