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Sexual Precocity in a 16-Month-Old2 V* e! U5 { N) i$ |$ o/ ]
Boy Induced by Indirect Topical
5 Q9 c" v6 m7 b, MExposure to Testosterone
' z6 h _. i9 rSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
0 s( v9 V1 l/ q$ `and Kenneth R. Rettig, MD1; x1 r, x, g. w( ?6 h2 q
Clinical Pediatrics. |+ P- n- B, e! n: c
Volume 46 Number 64 G* F/ N3 Q( c* F5 C
July 2007 540-543
- b8 t! F, z( D* w* ^3 Z% o© 2007 Sage Publications& ^+ {+ a; m O. T: i( r- @
10.1177/0009922806296651! c3 k6 i2 @& {
http://clp.sagepub.com, F1 a$ z# r, c/ c. z/ X ^6 J
hosted at
9 ]6 K S( }+ v) j0 m8 n& k* A) z a' ]http://online.sagepub.com
! P/ G/ D4 G1 @: V* y3 YPrecocious puberty in boys, central or peripheral,: @' |& y0 F* t9 l8 \- t0 k# s- Z+ y
is a significant concern for physicians. Central
/ |4 g$ ?5 v" A2 S3 `& r1 }precocious puberty (CPP), which is mediated
! M+ V7 _7 b# G9 Vthrough the hypothalamic pituitary gonadal axis, has
0 [% \- r- W1 ` i3 W2 |9 La higher incidence of organic central nervous system
% R& b2 \( J. U. T/ J6 v0 O0 _9 {lesions in boys.1,2 Virilization in boys, as manifested
; l; R) Y4 M5 J( jby enlargement of the penis, development of pubic, A$ o- x5 v @: P
hair, and facial acne without enlargement of testi-0 j2 f3 Z0 O0 Y# y7 ?! z! k
cles, suggests peripheral or pseudopuberty.1-3 We
o; S3 r/ e4 z/ R- ^report a 16-month-old boy who presented with the
& K3 D3 z& \9 h2 m. cenlargement of the phallus and pubic hair develop-
* ~+ V0 {# W* P- C$ zment without testicular enlargement, which was due
0 ]0 N& Q5 J' i1 O8 {to the unintentional exposure to androgen gel used by2 r- t8 D8 F/ C _
the father. The family initially concealed this infor-( W {# r# @' K! K" Z. |5 R
mation, resulting in an extensive work-up for this
# E0 S/ o9 i% M3 f. k0 D$ @child. Given the widespread and easy availability of. \) G' G, s" V' ~$ p# V; k, u( `
testosterone gel and cream, we believe this is proba-: Y, C0 t0 H3 y! A% ~( {3 R( h
bly more common than the rare case report in the
* z$ p$ |/ d6 `, Kliterature.4
8 h: c$ o; `( k$ v! \Patient Report! B" v: R9 e7 b- R$ M' B" n4 i6 E, ?
A 16-month-old white child was referred to the
; Y `5 [' s4 r+ M+ fendocrine clinic by his pediatrician with the concern3 ^5 d+ R; R9 N% V" L( m5 g
of early sexual development. His mother noticed) S! d. @! l4 @/ w" {
light colored pubic hair development when he was& p. t) Z q) U0 m$ ?
From the 1Division of Pediatric Endocrinology, 2University of& o, p# }7 \' M1 l+ q
South Alabama Medical Center, Mobile, Alabama.4 e: v8 T3 M% J5 ]* s, f
Address correspondence to: Samar K. Bhowmick, MD, FACE, \- }, J" R0 L5 P2 h& H0 c
Professor of Pediatrics, University of South Alabama, College of6 i5 W5 x& _- j0 n7 x
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
- y6 n* y9 } ^( C se-mail: [email protected].5 G O$ `! W4 u! d- d
about 6 to 7 months old, which progressively became- W; K! p0 h4 \
darker. She was also concerned about the enlarge-
( u& W, O% b" p4 J1 {/ Z9 T" Mment of his penis and frequent erections. The child1 s# g% e2 j5 K: Y, h% \
was the product of a full-term normal delivery, with* M. U$ Z; X- O4 w5 Y# \
a birth weight of 7 lb 14 oz, and birth length of
* { q/ A# e0 D" }20 inches. He was breast-fed throughout the first year) m( f4 b1 O7 A! E y6 ^! s
of life and was still receiving breast milk along with/ d- ]( ]4 u% F' k% F* J
solid food. He had no hospitalizations or surgery,$ E# F1 ]1 f8 C3 g' r; y: r
and his psychosocial and psychomotor development
2 g1 O' O2 V( S# F |- h6 N! @was age appropriate.
; e, B" S/ D- X; ]The family history was remarkable for the father,
! h g- k) H' F9 iwho was diagnosed with hypothyroidism at age 16,
. g' X& n/ J; V& x: p$ b* y- a- ]which was treated with thyroxine. The father’s1 h$ n) u0 v* ^, S4 N
height was 6 feet, and he went through a somewhat
4 O* D' A+ G. v/ {early puberty and had stopped growing by age 14.
5 Z* r- G( j/ O- [! v' y4 g) sThe father denied taking any other medication. The/ O" }" b+ a4 K! q) I0 C
child’s mother was in good health. Her menarche
, K( p- Q; \' ]* Fwas at 11 years of age, and her height was at 5 feet
* q* W$ T5 G3 o1 W5 inches. There was no other family history of pre-+ |% w& j2 s2 z S' a' ^* D9 o
cocious sexual development in the first-degree rela-
7 H3 _" D! B9 L* N1 B9 Ltives. There were no siblings.
9 O1 f) T W5 G" }Physical Examination
; K+ i- w3 P1 K1 AThe physical examination revealed a very active,
& w, [5 ?; B$ M; j5 }; mplayful, and healthy boy. The vital signs documented5 Z) m) k$ v& f: [1 u) e
a blood pressure of 85/50 mm Hg, his length was
$ x4 T" p! s! x2 o4 w! |3 z90 cm (>97th percentile), and his weight was 14.4 kg
5 t. V U5 s9 d3 L(also >97th percentile). The observed yearly growth( e4 p3 v6 }2 F) v
velocity was 30 cm (12 inches). The examination of5 R' N8 [( j% G8 r: m) d
the neck revealed no thyroid enlargement.
. M2 s3 N/ K/ |$ ^" ^4 E3 w( N# mThe genitourinary examination was remarkable for
8 T) [; Z \0 w# J- g7 [5 E9 Henlargement of the penis, with a stretched length of
0 H! V5 _3 _& W% n2 a0 R8 cm and a width of 2 cm. The glans penis was very well$ d1 w" w# ^! V
developed. The pubic hair was Tanner II, mostly around% E5 Y0 q! _' P- W
5407 H- R0 |2 J0 X' l0 q* N
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, O. M7 O K, a" L& h/ V
the base of the phallus and was dark and curled. The5 h# U e. g6 W% c
testicular volume was prepubertal at 2 mL each.
6 f' x$ F% C! h4 yThe skin was moist and smooth and somewhat6 ?3 x9 C& H3 x+ I
oily. No axillary hair was noted. There were no: n) E+ s: H5 ?# d$ @; V
abnormal skin pigmentations or café-au-lait spots.
* P4 y% q+ z. G8 i) aNeurologic evaluation showed deep tendon reflex 2+* Z+ _8 b: V: A3 A1 S
bilateral and symmetrical. There was no suggestion- c: o* z1 C- v, C
of papilledema.- N! ?8 s0 E9 o7 t! z7 `9 x. \6 A
Laboratory Evaluation
" q- y' g0 j3 S) @; mThe bone age was consistent with 28 months by
| n: J( t/ z' c- z6 {6 _# Musing the standard of Greulich and Pyle at a chrono-
- T% T( G" L8 Q; Q" zlogic age of 16 months (advanced).5 Chromosomal% r' [$ ~$ R1 |/ b" S& l" |
karyotype was 46XY. The thyroid function test
7 a- b* o$ F/ V) e. S2 xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
) b/ R5 u- r1 W+ blating hormone level was 1.3 µIU/mL (both normal)." L8 M2 D* K Y% g
The concentrations of serum electrolytes, blood) b/ i* ^, M9 I3 D- b2 @
urea nitrogen, creatinine, and calcium all were4 m. ?$ O$ P* S, i x
within normal range for his age. The concentration
; P7 q, `5 S* U$ C4 Rof serum 17-hydroxyprogesterone was 16 ng/dL/ j1 D1 q$ g& o& \; ~
(normal, 3 to 90 ng/dL), androstenedione was 20
8 }* s8 o) l: h) J% @ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
. o/ b# q& I8 O' e; Y9 j9 C( {terone was 38 ng/dL (normal, 50 to 760 ng/dL),. ^* B' e; F, w( C) u2 d# }
desoxycorticosterone was 4.3 ng/dL (normal, 7 to, Q/ N1 e% {* o8 c
49ng/dL), 11-desoxycortisol (specific compound S)9 h1 X. V+ u3 L5 q
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
/ I9 Y) G# C# S' R* utisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total% ]$ q' I' s: F h- i* x& e
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),+ L- o6 I; Y" Q3 ~7 Q
and β-human chorionic gonadotropin was less than
6 M3 Q& d6 {) F0 ] S0 ~; L! w5 mIU/mL (normal <5 mIU/mL). Serum follicular
5 f& V! C/ h2 c' b' M5 u2 Lstimulating hormone and leuteinizing hormone
" h- f; y" H% ~ `: @* `) Pconcentrations were less than 0.05 mIU/mL
5 m7 _" H; y0 T(prepubertal).0 W S) F# x$ t, s9 |
The parents were notified about the laboratory
1 [& B* H% J7 k- Wresults and were informed that all of the tests were* s8 M0 u& l; l
normal except the testosterone level was high. The. @# k V3 }' c6 I
follow-up visit was arranged within a few weeks to! N; M3 f4 g$ K8 X% q$ d& e
obtain testicular and abdominal sonograms; how-* r/ l; a& m8 h; N: {7 `
ever, the family did not return for 4 months.
: ~+ m6 k( ?% h3 @Physical examination at this time revealed that the
) r8 T b5 M( `9 O1 m7 x, M; Fchild had grown 2.5 cm in 4 months and had gained- |+ Q( M" }. Y: j' t+ P+ E
2 kg of weight. Physical examination remained
# |" M1 ?6 l( _1 punchanged. Surprisingly, the pubic hair almost com- D! b, g4 B; x# f, p5 E" e
pletely disappeared except for a few vellous hairs at$ ~; _' M _% i
the base of the phallus. Testicular volume was still 2. g" y4 q( P1 `& G0 P( Y/ ^
mL, and the size of the penis remained unchanged.
5 b* e; N8 ~$ n, dThe mother also said that the boy was no longer hav-
# i) a( {9 C" ~& J: y2 K+ c/ wing frequent erections.5 Q S( l- r# p4 _( m) W$ F' f
Both parents were again questioned about use of/ M2 U% b8 L/ t) c7 x7 V& ]
any ointment/creams that they may have applied to2 u. K( V- W! J2 N
the child’s skin. This time the father admitted the, a0 o/ Z+ [' M8 `4 |
Topical Testosterone Exposure / Bhowmick et al 541% ?8 Q' d$ R3 H+ e! W2 t- ^
use of testosterone gel twice daily that he was apply-
! y, l$ R8 ? W( Q$ uing over his own shoulders, chest, and back area for; K2 Q4 u! e- q4 O
a year. The father also revealed he was embarrassed: c) T0 R. ?3 H( b* O) R! b
to disclose that he was using a testosterone gel pre-
! Q9 v/ M7 D Q8 m: sscribed by his family physician for decreased libido
* f6 L d* t' s) I3 Fsecondary to depression.
- W# T( j2 ]) z$ E, b6 BThe child slept in the same bed with parents.: t1 j# h) t e. s. S, ]+ E0 A
The father would hug the baby and hold him on his
% r* y+ v! p+ W4 c- B5 M: \chest for a considerable period of time, causing sig-
% H' Q' N/ l* W# fnificant bare skin contact between baby and father.& j/ C2 Q) r) y' w/ Y5 t# ~
The father also admitted that after the phone call,# J; _- Y- y. T: M+ X9 G/ [
when he learned the testosterone level in the baby7 p, A2 i: b# L/ O7 ^+ Z
was high, he then read the product information
2 K) g* f& Y* P, u6 dpacket and concluded that it was most likely the rea-6 k1 @7 _ T2 _& U
son for the child’s virilization. At that time, they: p. n9 p: d/ f# I$ |, w
decided to put the baby in a separate bed, and the
. S x% ?" Y! x9 Hfather was not hugging him with bare skin and had* H2 A% w8 m2 \7 b- |
been using protective clothing. A repeat testosterone
% ^+ L/ x8 X( i, F& l8 c [test was ordered, but the family did not go to the. j* q/ `& H/ b
laboratory to obtain the test." w8 E1 p& T; w; W; ^3 Y
Discussion
5 r W! B( Z0 u! W' t2 J& Q2 QPrecocious puberty in boys is defined as secondary
( S6 n! j. ?$ z7 |5 D" ?8 asexual development before 9 years of age.1,4
1 \6 A B( z% QPrecocious puberty is termed as central (true) when
# j3 w" ~ D0 J! H `; W0 O1 S1 Cit is caused by the premature activation of hypo-+ P' U1 b3 C& |$ F& P m+ X
thalamic pituitary gonadal axis. CPP is more com-
& G" Y2 k2 N( D9 b! e/ }, Hmon in girls than in boys.1,3 Most boys with CPP; S9 \) s% b5 s
may have a central nervous system lesion that is
3 W0 }( h/ m5 ?% K) s2 G9 w, Dresponsible for the early activation of the hypothal-
0 g3 B/ a h+ N5 \+ \8 ?8 Iamic pituitary gonadal axis.1-3 Thus, greater empha-
( h( w) N# {- S1 t" r- t! isis has been given to neuroradiologic imaging in
( v+ h- n' j' Iboys with precocious puberty. In addition to viril-$ i' O$ o J2 {' }# c! E
ization, the clinical hallmark of CPP is the symmet-
3 B: A s3 s- t2 I. ]# C3 }rical testicular growth secondary to stimulation by
% F( R" d% b4 {+ [/ fgonadotropins.1,3: A2 b6 D6 W1 u0 p
Gonadotropin-independent peripheral preco-, F. o/ ~. `8 f' h$ a
cious puberty in boys also results from inappropriate! M& H7 f2 G6 d
androgenic stimulation from either endogenous or
$ G1 g8 h5 A9 o% s4 aexogenous sources, nonpituitary gonadotropin stim-
% s: a0 M% A* i3 x# E) fulation, and rare activating mutations.3 Virilizing
3 A' v' n0 a ?) J; G% qcongenital adrenal hyperplasia producing excessive: l" r. S/ _' Y5 X4 ^( \
adrenal androgens is a common cause of precocious
) T0 ~: b" h# n# K# c5 Xpuberty in boys.3,4" ^2 h; P& G6 S) h) J
The most common form of congenital adrenal
2 K5 k9 J8 _1 thyperplasia is the 21-hydroxylase enzyme deficiency.
- u' T o8 e* J0 p- `The 11-β hydroxylase deficiency may also result in
% c; l* T) K/ J1 e% D% Cexcessive adrenal androgen production, and rarely,
7 s* s. |* }4 qan adrenal tumor may also cause adrenal androgen( c& X( Q `7 i1 q+ n8 y0 B' e
excess.1,36 m% ~- B' {5 [) d
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ o+ K% j! P- o542 Clinical Pediatrics / Vol. 46, No. 6, July 2007 q6 g& {5 {) |* f" Z) d
A unique entity of male-limited gonadotropin-
0 a! |$ G' J: |) l; G3 qindependent precocious puberty, which is also known
. z6 I3 j( p1 y9 H$ ]/ [as testotoxicosis, may cause precocious puberty at a
9 K; q o$ L5 fvery young age. The physical findings in these boys
6 {" p w. p' T+ Swith this disorder are full pubertal development, o" k0 v. U3 S! r/ y
including bilateral testicular growth, similar to boys
- O) {5 c, v) E# n. @2 G5 wwith CPP. The gonadotropin levels in this disorder" P' C# F. ]3 M; m- {
are suppressed to prepubertal levels and do not show
, G4 i% `' \9 T, ]7 g( q+ ^% X! z. \pubertal response of gonadotropin after gonadotropin-6 f& P5 x( {* y! }$ Y. y
releasing hormone stimulation. This is a sex-linked; j; V& I; p4 {( G
autosomal dominant disorder that affects only% t5 q; c9 j4 ~! z1 e! V/ B' m7 y+ ~
males; therefore, other male members of the family
& p) w3 l5 i$ K$ F, pmay have similar precocious puberty.37 j6 e8 t4 [9 `1 n
In our patient, physical examination was incon- q5 ^) P9 N/ ]( M/ b2 {
sistent with true precocious puberty since his testi-1 t. B6 y o4 _* n, t
cles were prepubertal in size. However, testotoxicosis
# m& o e0 g7 O1 S( _. ?was in the differential diagnosis because his father
: F$ ~( L+ }! A# R6 U/ fstarted puberty somewhat early, and occasionally,3 m$ w; q4 P5 z& C3 ?$ z9 u" {' S
testicular enlargement is not that evident in the
! n8 ?2 `7 m; ]beginning of this process.1 In the absence of a neg-
& u+ Y' W5 E, ?9 s( `ative initial history of androgen exposure, our5 y- r, c- f. J
biggest concern was virilizing adrenal hyperplasia,& E4 v4 [- b4 }! ?& V) h
either 21-hydroxylase deficiency or 11-β hydroxylase- N. G m- h, h2 K$ k6 }# d
deficiency. Those diagnoses were excluded by find-2 c/ l5 V% ?$ U2 \
ing the normal level of adrenal steroids.
# J9 {3 v6 D4 cThe diagnosis of exogenous androgens was strongly
$ y" @4 T- N/ csuspected in a follow-up visit after 4 months because( H* ?1 Z. B4 ?
the physical examination revealed the complete disap-
" X- K; `# u# b5 ~8 d4 F0 P- Hpearance of pubic hair, normal growth velocity, and
0 \& C3 j7 z( rdecreased erections. The father admitted using a testos-
+ H8 c' B. @ Z! I( |0 Fterone gel, which he concealed at first visit. He was
8 f- P7 a4 V+ R0 [6 Vusing it rather frequently, twice a day. The Physicians’8 E/ |# @& {: K. t7 d7 g3 e6 x' D2 M
Desk Reference, or package insert of this product, gel or' N) ^5 ]2 z* f
cream, cautions about dermal testosterone transfer to
7 E" U7 \; ]$ S7 b$ k& P- a J' }unprotected females through direct skin exposure.
8 R% V- M' [) A) a2 \7 x& }6 aSerum testosterone level was found to be 2 times the
t8 ]. R' n, ybaseline value in those females who were exposed to0 b3 b- B' i5 c, K
even 15 minutes of direct skin contact with their male
% Q! K! N: K1 P, h/ x$ H/ {+ Y8 r; fpartners.6 However, when a shirt covered the applica-3 @ I( m" q8 J8 U* _4 r+ I* L
tion site, this testosterone transfer was prevented.% C+ J1 x: X' ~: X5 I
Our patient’s testosterone level was 60 ng/mL,
0 I7 g& ^0 o+ B* G9 Ywhich was clearly high. Some studies suggest that/ ~1 d4 N2 t* m
dermal conversion of testosterone to dihydrotestos-
- x" r* i1 i6 Kterone, which is a more potent metabolite, is more5 ~. Q4 b( Z: |4 ^. _/ T
active in young children exposed to testosterone# R- F/ `1 N3 z# X- p0 j+ G
exogenously7; however, we did not measure a dihy-
5 }7 w: y, f( R# N0 ^$ h. O4 Ydrotestosterone level in our patient. In addition to( X# r/ U' H |. `+ L- M. V' F% W
virilization, exposure to exogenous testosterone in$ T _; A$ _5 c0 x
children results in an increase in growth velocity and/ Y% h( S$ ]0 {; k3 l" H, Q
advanced bone age, as seen in our patient.
( Q a( ]- [5 L9 K8 CThe long-term effect of androgen exposure during
! a% }0 f# X6 k; rearly childhood on pubertal development and final
6 i' s I2 X2 C2 [adult height are not fully known and always remain
% y4 ]3 P0 Y# ~4 B9 [9 C1 ?. U" m! E6 pa concern. Children treated with short-term testos-: `/ |, E9 ~4 ~
terone injection or topical androgen may exhibit some5 |/ O- B3 t0 u E3 c" S9 Q
acceleration of the skeletal maturation; however, after
# I3 `/ W `7 K8 {: \6 V' Ncessation of treatment, the rate of bone maturation) Y$ Y( s; e. x. E
decelerates and gradually returns to normal.8,9/ k3 E1 S# U* c7 ?" z' P
There are conflicting reports and controversy: _, |2 x% U1 k/ t8 r
over the effect of early androgen exposure on adult
6 [1 p9 `9 i- M9 `) g; Tpenile length.10,11 Some reports suggest subnormal
! H1 ^+ w, k/ W* l* t; l, j1 \adult penile length, apparently because of downreg-
3 u6 v; f# y) Q7 e0 y' l( r$ aulation of androgen receptor number.10,12 However,7 v; X* C2 t+ h; V. N& C
Sutherland et al13 did not find a correlation between
4 S* j6 \% N _/ E% mchildhood testosterone exposure and reduced adult( k! Z, U$ u9 j2 P8 A& Z: p
penile length in clinical studies.
# V, H+ M o9 K2 T" bNonetheless, we do not believe our patient is
1 d7 a6 _4 I+ j4 J0 {! P7 B* fgoing to experience any of the untoward effects from
5 R' y$ {2 \/ N3 Stestosterone exposure as mentioned earlier because
% H9 [( _# n7 X! z+ Dthe exposure was not for a prolonged period of time.0 y+ @( Y, v( _9 c2 A+ c
Although the bone age was advanced at the time of9 f! T7 l5 D& s5 d2 b
diagnosis, the child had a normal growth velocity at3 n7 a( c! U5 x& |% G- B* E4 R
the follow-up visit. It is hoped that his final adult
. _' A! ]7 P/ Y: n; uheight will not be affected.% P) I' f9 U! D( T
Although rarely reported, the widespread avail-/ m/ k( c# }9 k4 Z8 @
ability of androgen products in our society may
l$ n1 p- w [' k; X/ X8 _" pindeed cause more virilization in male or female% Y \6 W) m7 S- A
children than one would realize. Exposure to andro-0 U a g" R5 [) r6 p( E$ r
gen products must be considered and specific ques-% |( M5 p/ V g$ J+ u3 u6 h; e
tioning about the use of a testosterone product or
+ i6 Y" Z/ M, `/ Pgel should be asked of the family members during
6 R0 f1 ?8 q3 pthe evaluation of any children who present with vir-
. G5 }+ S' T5 Lilization or peripheral precocious puberty. The diag-, K/ A; ]- D1 J" c2 C+ d
nosis can be established by just a few tests and by
4 Z" [3 T2 r+ [, H ^' }, Iappropriate history. The inability to obtain such a$ U/ Z3 J8 v2 ~$ S& U" f. _( t
history, or failure to ask the specific questions, may l/ D$ J1 d k$ @1 j
result in extensive, unnecessary, and expensive7 l0 r' p8 n7 P- Y* E. E2 n
investigation. The primary care physician should be
: _( i8 H' ~; _8 B3 iaware of this fact, because most of these children3 }5 G: _; \: Y6 G0 [
may initially present in their practice. The Physicians’' ~; K, f, G, q9 f
Desk Reference and package insert should also put a/ F/ g& W2 e; Q# w
warning about the virilizing effect on a male or) H3 u4 Y }1 j' X; r4 Q
female child who might come in contact with some-9 [5 U L" f, a9 z
one using any of these products./ }/ h) Z5 E) ^" _4 U& J2 z
References
% a: A" l/ T& m) x- I1. Styne DM. The testes: disorder of sexual differentiation' C2 L% _9 g9 c! |2 d* T6 Y
and puberty in the male. In: Sperling MA, ed. Pediatric
" M4 w% [8 E* R$ Q' R% MEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
( Q3 s& z E6 Z# c2002: 565-628.# n4 n; w S3 i) l( K
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
& m' k3 M: D- v5 npuberty in children with tumours of the suprasellar pineal |
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