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Sexual Precocity in a 16-Month-Old
* n% d7 T1 U3 ~* nBoy Induced by Indirect Topical2 w, s+ L. F: ^% h( Q- }, u, K
Exposure to Testosterone6 h7 Y2 q3 Z+ O" w1 n
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2$ v* R+ f% {. I% e& b
and Kenneth R. Rettig, MD1
. W5 ?7 p: Z+ i! K: o. ~% uClinical Pediatrics; s) Q/ \7 g! ^7 ]
Volume 46 Number 60 J3 w% w* _! m; K8 W7 @* I
July 2007 540-543
$ r- w% {/ I2 c6 c, `/ b4 h© 2007 Sage Publications7 e# i/ `* c9 L, J5 B0 K
10.1177/0009922806296651
0 {6 A7 N4 x4 z4 p) [http://clp.sagepub.com3 C$ w R5 [7 H6 S) a
hosted at- t* _ y& `8 l' \ b/ b" l
http://online.sagepub.com
6 a! i/ O$ R7 H0 B7 M+ n. L- HPrecocious puberty in boys, central or peripheral,) n, X8 M. r( v. K0 C' }
is a significant concern for physicians. Central( k9 ^1 g7 R% C8 v1 z6 _4 B5 e M
precocious puberty (CPP), which is mediated
v8 p2 j" ]/ D5 E6 Q9 Mthrough the hypothalamic pituitary gonadal axis, has1 i2 G0 r/ ~+ j
a higher incidence of organic central nervous system
" _1 W l% @$ l; ~lesions in boys.1,2 Virilization in boys, as manifested
7 E& U" Q1 _; @by enlargement of the penis, development of pubic
% D* p" E1 e9 ~* V- w$ W: Jhair, and facial acne without enlargement of testi-" `' p O& n- t+ V, V5 ?
cles, suggests peripheral or pseudopuberty.1-3 We% h' I. ^4 Y6 o1 S, F
report a 16-month-old boy who presented with the4 S6 _& L9 Y1 N6 {
enlargement of the phallus and pubic hair develop-, m3 C0 _: |/ E$ n& O
ment without testicular enlargement, which was due; ^# Y+ e* c% R% C' J+ O1 B
to the unintentional exposure to androgen gel used by
- i0 ?$ \/ m1 S$ a' othe father. The family initially concealed this infor-, n( X$ T2 m' `$ E9 J4 g
mation, resulting in an extensive work-up for this
( `4 {5 A: C4 mchild. Given the widespread and easy availability of) H: ]1 e( J( W7 S4 C
testosterone gel and cream, we believe this is proba-3 w1 _1 Y% c8 y8 k( ~9 A' }
bly more common than the rare case report in the
' w$ k6 G6 E7 p0 q- W" yliterature.4) ?0 s- F4 l6 d, }
Patient Report% {0 o! Z, T' g) ]7 j
A 16-month-old white child was referred to the
) q! m# h7 M3 y8 n& S5 {endocrine clinic by his pediatrician with the concern- U( [ V. R1 Q# h7 L3 i, \3 J
of early sexual development. His mother noticed) s( e& Y4 p S9 v
light colored pubic hair development when he was
3 N4 I; l: C/ c. @From the 1Division of Pediatric Endocrinology, 2University of
( c3 A- k" w5 y9 _$ PSouth Alabama Medical Center, Mobile, Alabama.
" r/ l: Y8 A' N+ {Address correspondence to: Samar K. Bhowmick, MD, FACE,3 T& V( C1 b1 H+ o
Professor of Pediatrics, University of South Alabama, College of: Q0 F0 ^* j6 }
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! B; C2 b$ O3 d' \ @% p( ee-mail: [email protected].
L: D3 o& ]1 [0 z$ labout 6 to 7 months old, which progressively became0 I9 l/ x5 J3 J% V( J1 r5 v4 }7 E8 i
darker. She was also concerned about the enlarge-4 v! D+ U9 X% V" n4 u
ment of his penis and frequent erections. The child
, q$ q. C0 U" y0 E/ Awas the product of a full-term normal delivery, with# D* E" z4 \1 d
a birth weight of 7 lb 14 oz, and birth length of
* ]$ ^1 ^; Y2 T& X" W20 inches. He was breast-fed throughout the first year+ h3 h9 N0 F9 R$ `. G: v6 A$ Z' V" Y
of life and was still receiving breast milk along with5 ^8 d% |: N$ ~2 ?) w! z" K5 B9 p6 c X
solid food. He had no hospitalizations or surgery,! W2 o2 A! l4 ?* b
and his psychosocial and psychomotor development& ~/ @) i+ F* P6 E9 z2 E
was age appropriate.$ e" b; [: @4 ]' b2 U. G6 y
The family history was remarkable for the father,
9 A' W6 \3 V% x9 qwho was diagnosed with hypothyroidism at age 16,9 i& L+ J& o7 M; L& |* M8 O
which was treated with thyroxine. The father’s
2 g4 E% B5 K7 {3 Z9 |& g4 \height was 6 feet, and he went through a somewhat
, K- O* J8 p/ \" N/ i; Dearly puberty and had stopped growing by age 14.
7 M5 _, y6 m, ~) j; q- N) d! r6 YThe father denied taking any other medication. The$ g3 y3 V* {) u5 Z2 l& M
child’s mother was in good health. Her menarche$ R- X0 o. j6 ?" X
was at 11 years of age, and her height was at 5 feet
% Y# H# |* c H3 @" G5 inches. There was no other family history of pre-/ [4 Q: V- q2 P
cocious sexual development in the first-degree rela-
& w) C0 A/ U& ftives. There were no siblings.+ ? ?/ I2 F" F" s0 i
Physical Examination$ z: y6 ^: F( |5 _: f% H( V
The physical examination revealed a very active,
' u) n1 ^( F. K- G' zplayful, and healthy boy. The vital signs documented
# T6 z# F. Q9 F( X ka blood pressure of 85/50 mm Hg, his length was4 O* O9 K+ z v/ f
90 cm (>97th percentile), and his weight was 14.4 kg
4 c& c& w& T: U$ `(also >97th percentile). The observed yearly growth* y1 Z% B) Y; U9 I
velocity was 30 cm (12 inches). The examination of2 d4 \( n. W/ K/ Q
the neck revealed no thyroid enlargement.
$ M( s( K- l3 r- @* hThe genitourinary examination was remarkable for
4 Y8 w& I2 x- g0 c' cenlargement of the penis, with a stretched length of6 x. p8 k, o+ `# i6 ^
8 cm and a width of 2 cm. The glans penis was very well
% ~2 n6 F+ M! Rdeveloped. The pubic hair was Tanner II, mostly around
/ l( D( x. j$ k540: A9 \1 m- b; q1 |8 Y! U' S' q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; f3 k; C" `) g- u8 r3 P! ]" G
the base of the phallus and was dark and curled. The
" _! Q3 x/ Y" L; ]8 n) l" R4 rtesticular volume was prepubertal at 2 mL each.$ d! p6 n: K' S" V
The skin was moist and smooth and somewhat# |. m, H3 K: e( ~& s& N: R
oily. No axillary hair was noted. There were no
7 z- D/ j6 }* F( W% qabnormal skin pigmentations or café-au-lait spots.
; n3 u' p- V6 J: x- s2 s$ ?) RNeurologic evaluation showed deep tendon reflex 2+
8 \: B% \ U% [- Gbilateral and symmetrical. There was no suggestion: k9 ~8 Z7 p7 ~" P6 B+ G7 V
of papilledema.2 h- Y: f9 s' V8 n9 ~; |' Z
Laboratory Evaluation( O/ v2 q, W% Z, Y8 Q% @3 y
The bone age was consistent with 28 months by
9 g6 O$ N$ S! o1 @using the standard of Greulich and Pyle at a chrono-
- N' Q/ @# Q( h8 b) D$ L& alogic age of 16 months (advanced).5 Chromosomal
: D6 z- I" d6 u3 U) Q2 I% ?karyotype was 46XY. The thyroid function test4 |3 a- e7 l& R: {1 z# ]1 l
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
4 O3 N) B, \4 V! Xlating hormone level was 1.3 µIU/mL (both normal).
4 N2 T/ u8 {( uThe concentrations of serum electrolytes, blood9 e* V' S( O. ]; `3 r
urea nitrogen, creatinine, and calcium all were4 A; _ {; |5 L R3 Y. U
within normal range for his age. The concentration
4 R4 d3 u/ r" @8 E$ Eof serum 17-hydroxyprogesterone was 16 ng/dL- O1 r) I- x, M& _" o, o- Y
(normal, 3 to 90 ng/dL), androstenedione was 20
Y8 K( T0 b J8 `5 V* J3 G/ wng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
4 x8 \% K8 X9 U3 g" A- U+ rterone was 38 ng/dL (normal, 50 to 760 ng/dL),) p1 M! k: f5 c: Q7 S+ T
desoxycorticosterone was 4.3 ng/dL (normal, 7 to) E: ^+ | X( H5 [6 o: z# f) ^$ I6 X
49ng/dL), 11-desoxycortisol (specific compound S)+ A; l- A+ H1 f8 ?
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
, O6 M5 z( i. C8 Q+ u3 Otisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
5 n. r, `+ x( U5 n& H8 f* m& H# ^! H9 Htestosterone was 60 ng/dL (normal <3 to 10 ng/dL),' a( V) d& `/ M) q) d# O* X' @
and β-human chorionic gonadotropin was less than
9 [% p1 u5 i% S5 mIU/mL (normal <5 mIU/mL). Serum follicular4 {# V; M s$ C/ B6 {+ d4 }+ N3 M0 O* u
stimulating hormone and leuteinizing hormone
: }3 S# h4 u$ J" K, lconcentrations were less than 0.05 mIU/mL: c D+ l; m" f, k8 Y. ?: v& E$ Q
(prepubertal).
6 h, k! j! }" p( k, D8 B) F8 pThe parents were notified about the laboratory
' h% [/ p7 C. C- rresults and were informed that all of the tests were
. e6 p$ a5 X; {! F- h/ xnormal except the testosterone level was high. The
3 v& K% n; C) F# H- Sfollow-up visit was arranged within a few weeks to
3 t& d3 p1 R# S( d/ jobtain testicular and abdominal sonograms; how-0 V! m. g* V" J. I& W# k. K# L
ever, the family did not return for 4 months.
1 c4 E8 V E1 K& m9 V0 F1 K* _Physical examination at this time revealed that the, y9 T* O6 O+ h7 V' Y
child had grown 2.5 cm in 4 months and had gained
# e1 ^9 z5 z! n$ O0 U v+ R2 kg of weight. Physical examination remained" U. ?! |0 y7 d
unchanged. Surprisingly, the pubic hair almost com-; ^% y4 Q/ n* l. [, G6 b
pletely disappeared except for a few vellous hairs at( y! V+ A: o0 T' b; W
the base of the phallus. Testicular volume was still 2
/ j* d! X9 C& h1 [mL, and the size of the penis remained unchanged.
4 [+ E+ c0 \& a" a ZThe mother also said that the boy was no longer hav-7 j/ g4 f% q, V5 W6 u# a# {
ing frequent erections.
3 V% ]4 R& y$ n( w. R! }: A* HBoth parents were again questioned about use of
" J7 a4 J+ j7 p& E/ e9 p6 k( cany ointment/creams that they may have applied to
6 E# l1 E, U" y7 h9 ?the child’s skin. This time the father admitted the% \, p/ T+ K7 i5 [+ t8 X$ ?, N
Topical Testosterone Exposure / Bhowmick et al 5414 m# n8 x! @" i+ B+ }+ ]2 Y5 Q
use of testosterone gel twice daily that he was apply-
( `# u- F( w% m: aing over his own shoulders, chest, and back area for, \- G! T* ^ x0 F. ?
a year. The father also revealed he was embarrassed) f: A, x& f* e3 T' k
to disclose that he was using a testosterone gel pre-/ H) Q2 P; r( N. K: n
scribed by his family physician for decreased libido
' l2 w6 K& q/ a" i' jsecondary to depression.0 {* B* o( ?" o9 @
The child slept in the same bed with parents." C: D7 g0 w! a3 D+ n$ ^( o
The father would hug the baby and hold him on his
. F0 B0 h# o( r2 I: fchest for a considerable period of time, causing sig-% o6 j) ^# R- P. _
nificant bare skin contact between baby and father.& z2 s( n% k/ J) A4 B. n
The father also admitted that after the phone call,
9 _5 d- ~; G3 Z8 Z7 rwhen he learned the testosterone level in the baby$ _4 S) e l1 _
was high, he then read the product information% k Y* H( x2 X
packet and concluded that it was most likely the rea-
2 a9 p; \, z/ W9 C. ?1 lson for the child’s virilization. At that time, they
% a2 V4 [: n5 Tdecided to put the baby in a separate bed, and the' n$ }6 i2 u5 J% m" f# u
father was not hugging him with bare skin and had( E2 D, v; T: K* F; G/ }' B
been using protective clothing. A repeat testosterone
8 H- _0 ~, ?3 i- d% @$ z" c6 Ctest was ordered, but the family did not go to the
. R7 T; Z/ b3 M6 ilaboratory to obtain the test.
, |$ N& h; q: h& mDiscussion6 E, f! q V8 {! N
Precocious puberty in boys is defined as secondary
/ j1 @2 y3 ^+ Vsexual development before 9 years of age.1,4" g Y4 n/ J5 i0 P: L' ]
Precocious puberty is termed as central (true) when5 V* l: T' k r$ C
it is caused by the premature activation of hypo-+ a4 c9 W7 J- [( V
thalamic pituitary gonadal axis. CPP is more com-, c0 l5 Q& n( ^2 R: E, U+ \8 R
mon in girls than in boys.1,3 Most boys with CPP K2 k9 { }( A: m7 q
may have a central nervous system lesion that is
; g! e1 J( V$ j* f% \/ N1 B0 Eresponsible for the early activation of the hypothal-
4 ?, ?# A/ @7 q/ yamic pituitary gonadal axis.1-3 Thus, greater empha-
\- X M5 U! t* p; d3 E8 q4 D$ }+ o+ [sis has been given to neuroradiologic imaging in: q# h7 P! K) X5 {7 N6 ?+ k
boys with precocious puberty. In addition to viril-
2 e/ o+ t. D/ j F7 |( tization, the clinical hallmark of CPP is the symmet-0 U9 Q. M/ j" ^6 j. S& U. ~
rical testicular growth secondary to stimulation by+ M/ }7 {1 M' V' O! l% l
gonadotropins.1,3
6 R& X2 G# B: w. v' aGonadotropin-independent peripheral preco-6 W! K) {' a9 Y* K, c6 E
cious puberty in boys also results from inappropriate
# w$ M8 `/ Q- A Y0 Gandrogenic stimulation from either endogenous or9 D# N) F( n! S" |: p; a: y
exogenous sources, nonpituitary gonadotropin stim-6 @- r# p) H) b" A q* @5 {
ulation, and rare activating mutations.3 Virilizing& w1 T% y; G5 {, T1 y- P
congenital adrenal hyperplasia producing excessive4 J1 f$ c# U$ r H+ [; S; ]: {$ q) g# x
adrenal androgens is a common cause of precocious+ j9 i! e$ u) s9 B" ^8 _9 p
puberty in boys.3,4) W/ x8 e; v" ]9 H. i |+ m( D- v
The most common form of congenital adrenal
* z D2 Q! P/ q3 ?, M$ ohyperplasia is the 21-hydroxylase enzyme deficiency.2 S+ ~, I9 b1 ~ R4 k6 s
The 11-β hydroxylase deficiency may also result in
" }9 S1 [, S% z* T2 o+ y. \excessive adrenal androgen production, and rarely,
' _! g+ v f8 v5 ban adrenal tumor may also cause adrenal androgen
1 T. i! A% I( ^/ h' Wexcess.1,3, L- T# F) U( f. w; h
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! r' f$ o) Q" ^542 Clinical Pediatrics / Vol. 46, No. 6, July 20074 {5 b Y4 V+ \1 [( }( b* w
A unique entity of male-limited gonadotropin-- B: Z0 x$ d; Y8 [9 s2 u7 N
independent precocious puberty, which is also known
& G r0 `+ U! s7 ?6 B* ias testotoxicosis, may cause precocious puberty at a, s5 ^+ o% l% |* C1 V; ^
very young age. The physical findings in these boys5 z6 c; H2 P# j/ S' w
with this disorder are full pubertal development,
8 p# F$ F( {- s" s7 Fincluding bilateral testicular growth, similar to boys
! |# ]# H$ a7 U; b: Twith CPP. The gonadotropin levels in this disorder
) d$ a7 s; K3 [ T8 f2 {are suppressed to prepubertal levels and do not show
" A! W9 ^9 X: l* J* A# rpubertal response of gonadotropin after gonadotropin-
& W2 I- O9 Y( y2 mreleasing hormone stimulation. This is a sex-linked& H) d# m3 a5 B w
autosomal dominant disorder that affects only
E4 m1 o; y3 R/ L) }% Wmales; therefore, other male members of the family
- g2 {! y( b- g1 }may have similar precocious puberty.3
, g) Z ^. j a: N7 B6 mIn our patient, physical examination was incon-
$ a- D6 w, f5 msistent with true precocious puberty since his testi-% m z+ U8 s3 g' C9 A
cles were prepubertal in size. However, testotoxicosis
+ u' k) l8 ?! O3 w6 R1 Uwas in the differential diagnosis because his father
9 _& H/ i4 N, e ostarted puberty somewhat early, and occasionally," C( T3 X% y% F" k0 j
testicular enlargement is not that evident in the
% ~; ~6 Y6 y' P2 Cbeginning of this process.1 In the absence of a neg-
% L' f4 q2 B5 a0 N+ oative initial history of androgen exposure, our7 {- K* N1 p ^! u. j
biggest concern was virilizing adrenal hyperplasia,
, A- y, `& h) }! w; e) w, ieither 21-hydroxylase deficiency or 11-β hydroxylase
0 H9 V# l/ a0 i* n' G+ G) }deficiency. Those diagnoses were excluded by find-
6 p( S& F: n6 sing the normal level of adrenal steroids.& V# o: m: k% r1 E- A8 t: s. C) S
The diagnosis of exogenous androgens was strongly
3 |9 o' `6 x3 Z; Isuspected in a follow-up visit after 4 months because0 R' g/ j j& d8 [+ K
the physical examination revealed the complete disap-
& p, P+ J, c2 Y6 }pearance of pubic hair, normal growth velocity, and7 k8 [2 m' x" L8 I S
decreased erections. The father admitted using a testos-
9 \: V# B3 l) o6 Jterone gel, which he concealed at first visit. He was4 V. c7 Q+ V+ m+ n& F. O
using it rather frequently, twice a day. The Physicians’& f1 L1 q, F8 f* d2 G
Desk Reference, or package insert of this product, gel or
4 s; D- v; H& G8 Tcream, cautions about dermal testosterone transfer to# Q8 P. [" |, z; H
unprotected females through direct skin exposure.
. y# B3 |" O: V. gSerum testosterone level was found to be 2 times the( ]+ o F4 l8 @
baseline value in those females who were exposed to
0 x; I; [+ M! A; C8 j/ U4 R6 [even 15 minutes of direct skin contact with their male
( H- p I$ s* H; A" X Z- [partners.6 However, when a shirt covered the applica-, \' b$ }) y! E. G
tion site, this testosterone transfer was prevented.
! N/ I. u4 c2 b% x# iOur patient’s testosterone level was 60 ng/mL,' Q4 b! ?9 `- F# ?! ^0 P m
which was clearly high. Some studies suggest that
W, [) o8 |2 r( n$ R1 tdermal conversion of testosterone to dihydrotestos-3 M9 f0 u: f7 n4 @
terone, which is a more potent metabolite, is more/ K! r2 c1 e! u, p: h
active in young children exposed to testosterone
7 H9 { | `4 K6 vexogenously7; however, we did not measure a dihy-: D( g2 S# z" p1 m
drotestosterone level in our patient. In addition to5 d- g, r" r3 n0 I+ T, n
virilization, exposure to exogenous testosterone in7 c% i+ m$ D! F& m% W
children results in an increase in growth velocity and& ~; c3 b: ]. a$ e$ i! |
advanced bone age, as seen in our patient.0 {- I" q: J% L& _( F
The long-term effect of androgen exposure during4 E2 y2 |5 l7 o) X
early childhood on pubertal development and final0 Y$ }; x9 f% b
adult height are not fully known and always remain
) U4 p9 b7 h4 t# na concern. Children treated with short-term testos-& q5 i' k4 I7 ]! m9 i
terone injection or topical androgen may exhibit some
. n- l# U+ w" e: W3 v, n5 A5 u% c# dacceleration of the skeletal maturation; however, after. p( J& Z/ w7 e
cessation of treatment, the rate of bone maturation
7 O7 `2 F& X6 h8 U. Q! M0 D7 c. Sdecelerates and gradually returns to normal.8,9
# [. j- A6 \6 d3 D9 R1 O: jThere are conflicting reports and controversy' {+ X, S1 k) ?- ?8 [5 E
over the effect of early androgen exposure on adult
- l7 {4 L, P5 j+ u$ u! Mpenile length.10,11 Some reports suggest subnormal$ M7 `' P, X2 g1 F; o" O J
adult penile length, apparently because of downreg-* `# L2 h7 @( M- h" f
ulation of androgen receptor number.10,12 However,
5 n0 r, E1 g! K8 A3 lSutherland et al13 did not find a correlation between
8 }: c6 j! n- B8 P! O4 Achildhood testosterone exposure and reduced adult
$ k; z" c. d/ c8 z' |2 b- `2 dpenile length in clinical studies.
8 }: l2 f2 M1 n3 q) g4 fNonetheless, we do not believe our patient is
0 r5 F, [* b( e4 O% tgoing to experience any of the untoward effects from% o h* v. J5 o7 J' h, t
testosterone exposure as mentioned earlier because
% @$ Z: p" Y9 ]! a, Gthe exposure was not for a prolonged period of time.
6 w) j6 f$ q. i4 k5 tAlthough the bone age was advanced at the time of
! |9 h9 ^4 _2 l5 A. cdiagnosis, the child had a normal growth velocity at$ }3 Y- n. [6 W4 J
the follow-up visit. It is hoped that his final adult3 b1 w$ Y; W4 Y/ [: w$ n
height will not be affected.; T0 I% z) e& R3 W
Although rarely reported, the widespread avail-0 X! E3 P, f- _. s1 x1 l
ability of androgen products in our society may' H8 ?, A. d% G% s
indeed cause more virilization in male or female
- w0 ?- o7 q! C% g$ I# {children than one would realize. Exposure to andro-, d- O3 x1 @ l2 o, ~3 Y- {# j
gen products must be considered and specific ques-
/ F( C0 G! F R* ~tioning about the use of a testosterone product or& b. d1 D6 g% @% t2 U& @2 u
gel should be asked of the family members during9 q* u7 t: N0 G5 o9 ]* Y6 z- i
the evaluation of any children who present with vir-, ]6 j! o; j+ p" k
ilization or peripheral precocious puberty. The diag-
. H: t' J$ R6 F, Nnosis can be established by just a few tests and by
: X/ Q/ T% e: d& Cappropriate history. The inability to obtain such a
5 N3 P- H) {" qhistory, or failure to ask the specific questions, may
7 H: ~) R+ A5 a' nresult in extensive, unnecessary, and expensive- Y' c1 E' M4 M2 H/ B" {$ R* ^& `6 T
investigation. The primary care physician should be; t7 B6 O, G- c* j h5 S+ B S+ _
aware of this fact, because most of these children' m' _: _0 X7 r G, I8 K: t, | q
may initially present in their practice. The Physicians’
# e2 J: V- F( p" z0 J" {* J) u$ D; _& QDesk Reference and package insert should also put a' L( ?) X! Y8 p. @: g% u
warning about the virilizing effect on a male or
$ M$ f, E6 r- H, Mfemale child who might come in contact with some-
* k' n! k9 \% N) `one using any of these products.
7 q) e' @, | N4 ^+ ]References
- m8 i B5 a: I; u$ T* K& ?9 B1. Styne DM. The testes: disorder of sexual differentiation, w% G9 _9 H6 e. q4 B
and puberty in the male. In: Sperling MA, ed. Pediatric6 z6 t8 b# S F+ m/ a; g% }* }( d R
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
. W; s, a2 y- L' o! N( n2002: 565-628.
( g' |; J# F8 E: x7 J& u2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
3 Q4 L, z3 H+ bpuberty in children with tumours of the suprasellar pineal |
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