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Sexual Precocity in a 16-Month-Old
( p; s5 c* @; \& o! f4 ]3 }Boy Induced by Indirect Topical
6 k! H5 a, c. @/ ?4 R/ j: t# pExposure to Testosterone: y& I7 c% T! y- R
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2+ M" g+ x# ~- l8 Z7 g3 K) S
and Kenneth R. Rettig, MD1% E5 j+ u. \8 Q S' \9 K
Clinical Pediatrics* }$ ^% q" [; {$ V, }, a
Volume 46 Number 6
" l$ R, V0 j- q6 m1 ~8 s" G4 OJuly 2007 540-543/ q, X: N% p( P E: a
© 2007 Sage Publications
7 Y! I# E$ J' M7 P C, ?10.1177/0009922806296651
, y5 n! L F# q2 W7 xhttp://clp.sagepub.com/ }. \& d0 g- ?) ?$ p" V
hosted at
/ ~, x8 L @/ J5 \# c# M4 n! rhttp://online.sagepub.com! u8 j6 \0 T+ G. b* J
Precocious puberty in boys, central or peripheral,% _3 \3 Q5 [$ P
is a significant concern for physicians. Central
: Z- X/ X+ ]7 H$ G7 _8 q% @5 J: cprecocious puberty (CPP), which is mediated
! C; T" a% C. G! ?3 k# [through the hypothalamic pituitary gonadal axis, has6 b2 c8 {8 |* X) ~
a higher incidence of organic central nervous system
/ P6 A! O2 ~3 ^( ?+ G" {) alesions in boys.1,2 Virilization in boys, as manifested
0 p$ d J+ W# j4 r$ L( x( Qby enlargement of the penis, development of pubic
' H. ^7 J' {/ x) ahair, and facial acne without enlargement of testi-" v* {: T. F4 K% l
cles, suggests peripheral or pseudopuberty.1-3 We
4 k4 W" M5 A1 I( e1 preport a 16-month-old boy who presented with the
8 Y, Q Y' P) G3 Z1 _ {- cenlargement of the phallus and pubic hair develop-
+ g0 A% W! _1 e! a fment without testicular enlargement, which was due0 S9 N$ m6 O, p" Y% M
to the unintentional exposure to androgen gel used by
; `- s+ z2 {% jthe father. The family initially concealed this infor-/ W/ j8 a4 y" v( s
mation, resulting in an extensive work-up for this
I/ ?+ m6 G, ?' Vchild. Given the widespread and easy availability of
; _4 T9 I, z8 [8 ], F& [testosterone gel and cream, we believe this is proba-+ T! J8 G2 I9 N5 C' I0 {6 [" m
bly more common than the rare case report in the
3 t1 J7 \5 E. r& M& eliterature.4! C. @# Y" |6 ?8 L
Patient Report
9 h( x3 \( c- fA 16-month-old white child was referred to the. J$ @# J) [) ]7 w+ R
endocrine clinic by his pediatrician with the concern
9 m9 r7 f/ }: }1 ]) |6 ~2 rof early sexual development. His mother noticed9 F* K& H0 H& g
light colored pubic hair development when he was* b! g; Y) R& R" W( d/ ?. u4 b
From the 1Division of Pediatric Endocrinology, 2University of
$ {9 Q, x8 O. B- H3 d5 tSouth Alabama Medical Center, Mobile, Alabama.- V, C8 @) `* i6 l- V. u3 [0 q& z
Address correspondence to: Samar K. Bhowmick, MD, FACE,
4 Y% o& P9 w' K, QProfessor of Pediatrics, University of South Alabama, College of
% }% ^4 {9 I) O7 o' I1 m9 pMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
0 ?5 `: l8 N6 s* M8 H# m3 b' C* S* {e-mail: [email protected].
6 b; L. t' j( N6 M3 uabout 6 to 7 months old, which progressively became
/ P. [7 j. L& F: k/ f8 Edarker. She was also concerned about the enlarge-
# D4 Q1 t+ y# u9 f& _1 F. Dment of his penis and frequent erections. The child
, i1 P( V, S# A' B/ M% W- W! [& p! xwas the product of a full-term normal delivery, with
2 e3 s* E# o3 U3 z; k8 H$ wa birth weight of 7 lb 14 oz, and birth length of& d6 C4 y5 Z# a% q
20 inches. He was breast-fed throughout the first year
* k8 U" n$ C2 k3 K }, p, v* S* Hof life and was still receiving breast milk along with3 s' C, L* y6 M1 |, b. k
solid food. He had no hospitalizations or surgery," S) ]# H. T K* N, A
and his psychosocial and psychomotor development
, Z- s/ E$ f: R# E# uwas age appropriate.8 }; P$ E8 z4 C
The family history was remarkable for the father,0 W/ o0 J: g# _( n
who was diagnosed with hypothyroidism at age 16,1 o) o- H9 F' e% O- w6 i
which was treated with thyroxine. The father’s
/ {8 {* \, [/ F! O- eheight was 6 feet, and he went through a somewhat) `0 f3 G; `; E' h, X. e
early puberty and had stopped growing by age 14.
# s) j# I" ^; A! W, L& j* I/ pThe father denied taking any other medication. The
" y( Q* v N$ M8 cchild’s mother was in good health. Her menarche
0 Y! y$ K I: n5 Uwas at 11 years of age, and her height was at 5 feet4 ]5 J% R% ]6 k- Y0 k/ z
5 inches. There was no other family history of pre-! b' L1 l' {3 E+ l$ G- ?* V" \ h
cocious sexual development in the first-degree rela-
5 s3 N4 N5 G$ Z5 M7 Ztives. There were no siblings.4 m/ `* `" S: h* M4 I1 x+ e+ W4 [
Physical Examination: n& T3 s$ c, P
The physical examination revealed a very active,1 r- l q1 v: m
playful, and healthy boy. The vital signs documented# t% X. r5 C( ^9 O: N: n: u3 j. L
a blood pressure of 85/50 mm Hg, his length was9 U3 i4 J7 \* F3 m" G4 N) T
90 cm (>97th percentile), and his weight was 14.4 kg8 C$ X1 O' F" V8 Y3 S
(also >97th percentile). The observed yearly growth' o' r" I/ D! A9 C' v1 d) O
velocity was 30 cm (12 inches). The examination of: j/ M1 r: t: C* A" ~$ `: X
the neck revealed no thyroid enlargement.& Z; N9 m; l7 B( W& m
The genitourinary examination was remarkable for
: f4 x) k/ f. u, k; henlargement of the penis, with a stretched length of
$ p& W. x- {+ r% y9 B k8 cm and a width of 2 cm. The glans penis was very well
4 n# R2 X4 L6 W4 V+ v$ B2 y tdeveloped. The pubic hair was Tanner II, mostly around! x7 a# y0 `) z+ {5 R2 j
540
6 X$ p- c" N7 P) B8 f, U! @6 tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 B; C( A) L8 V1 H& Cthe base of the phallus and was dark and curled. The* A! b3 n1 Z* k& i' n3 Z9 D
testicular volume was prepubertal at 2 mL each.
, Z( W4 g& s6 b- P7 G; ?5 qThe skin was moist and smooth and somewhat- G! Y# a3 Q5 I. ]/ U: v
oily. No axillary hair was noted. There were no
2 a% j7 w, C) V" m7 M6 J q, Babnormal skin pigmentations or café-au-lait spots.& A% i4 e4 u0 V$ h
Neurologic evaluation showed deep tendon reflex 2+
2 z6 x6 I& P+ W! C9 L6 e6 E; rbilateral and symmetrical. There was no suggestion
) m! X0 ^, k! ~0 ?9 H! Y0 Mof papilledema.
$ S% p. Y8 f$ ^# @2 kLaboratory Evaluation, C" y) m' p8 p- `$ a0 S, L
The bone age was consistent with 28 months by
# M; s) \/ j$ J" o+ K1 lusing the standard of Greulich and Pyle at a chrono-$ t% C* A/ g6 Q4 W. M
logic age of 16 months (advanced).5 Chromosomal
( g g3 |( G) jkaryotype was 46XY. The thyroid function test7 S" ~! H3 h# X# J! X
showed a free T4 of 1.69 ng/dL, and thyroid stimu-0 i7 [9 w5 {' {1 S. N
lating hormone level was 1.3 µIU/mL (both normal).
" p. N, f* ^" o1 D6 iThe concentrations of serum electrolytes, blood
0 g S' X0 p& G% j3 U# e# ]urea nitrogen, creatinine, and calcium all were
) I0 ]1 c; ^' M1 ~+ Z, z' owithin normal range for his age. The concentration
/ b, s9 T! p8 [of serum 17-hydroxyprogesterone was 16 ng/dL
; \; R2 g5 d4 A5 L(normal, 3 to 90 ng/dL), androstenedione was 207 z4 D9 y) n* D3 @
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
% u4 ^8 q& N0 U2 Oterone was 38 ng/dL (normal, 50 to 760 ng/dL),' ~2 d( d3 c( _* V
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
( n: y2 Q4 K: V49ng/dL), 11-desoxycortisol (specific compound S)! i: d$ E+ e6 k% V7 \
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
- v; P. U$ n5 X2 p) X2 d2 ^% ptisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
5 O% Q D4 r4 m4 c5 s& ttestosterone was 60 ng/dL (normal <3 to 10 ng/dL),3 N. n0 D( a' j/ `5 b# L$ m
and β-human chorionic gonadotropin was less than* ]+ ?8 Q$ c/ E1 a ^. p+ T, M$ G
5 mIU/mL (normal <5 mIU/mL). Serum follicular* f" ], Q5 ]# M% M
stimulating hormone and leuteinizing hormone7 F) Q2 Z# A, c/ y. c
concentrations were less than 0.05 mIU/mL
: N! o& u9 u0 Z- ~1 o(prepubertal).( L2 x% l( p+ \
The parents were notified about the laboratory
1 [% x# X& k5 P( lresults and were informed that all of the tests were, ^+ R9 ]8 b" B3 N* u) w
normal except the testosterone level was high. The
1 _0 C3 ^4 g9 H6 c# [' H5 g- Xfollow-up visit was arranged within a few weeks to
* H. H, ]0 _- m' v5 p/ jobtain testicular and abdominal sonograms; how-% b+ k0 k# B) O# B! c
ever, the family did not return for 4 months.& i! g' f+ v4 [$ C- A! ` n
Physical examination at this time revealed that the
1 [2 u- b. y" V: {# K# w1 ~child had grown 2.5 cm in 4 months and had gained; H' U. C- U" p& a7 c! w
2 kg of weight. Physical examination remained
5 {0 j3 N+ m, ^& [3 R, g: R6 sunchanged. Surprisingly, the pubic hair almost com-
6 ~( ?7 p7 {$ |" [' G0 k+ ypletely disappeared except for a few vellous hairs at
- s6 o8 `/ x. y* c0 u0 Dthe base of the phallus. Testicular volume was still 29 [ D8 r' c4 @" E
mL, and the size of the penis remained unchanged.
' I+ @0 @, G( \$ n8 SThe mother also said that the boy was no longer hav-
" M, c6 q1 s5 T( eing frequent erections.
! V( l! W; a2 O0 Q- _* ZBoth parents were again questioned about use of8 w- ?5 w8 G( A8 {, E5 q
any ointment/creams that they may have applied to+ H( o0 J* i8 y- L% P7 E
the child’s skin. This time the father admitted the/ p( G/ D) [" }; {% K( N4 k
Topical Testosterone Exposure / Bhowmick et al 541
* h1 ~4 i8 g9 w( P' K- t8 w2 \use of testosterone gel twice daily that he was apply-- B! r* D! K6 ^* X5 F+ c3 J
ing over his own shoulders, chest, and back area for
* j; Q5 U) `: p- I5 u$ Ca year. The father also revealed he was embarrassed
+ J/ T+ o; R1 ^to disclose that he was using a testosterone gel pre-
% V6 s, |! X, z0 i' Zscribed by his family physician for decreased libido. j$ l' _3 N6 H9 R \: f5 h3 T
secondary to depression.
! ]2 N6 c! F) S1 |$ n! ~/ D- [5 HThe child slept in the same bed with parents.. E) U( ?6 O" X# a7 R; o
The father would hug the baby and hold him on his
0 e7 t; [' n& R* Schest for a considerable period of time, causing sig-
2 b- R' H# d& T2 g: e5 d% Lnificant bare skin contact between baby and father.) q, s% D. G6 e
The father also admitted that after the phone call," R) d5 u6 |" {; X! a
when he learned the testosterone level in the baby
/ L8 t* M/ r S( {4 v7 z: W8 ^was high, he then read the product information: M0 L- @% i7 v& ]
packet and concluded that it was most likely the rea-
) \4 S- `. d2 @son for the child’s virilization. At that time, they
9 a7 J U0 f5 E7 S' z6 _decided to put the baby in a separate bed, and the/ p2 |5 l# V4 [3 v
father was not hugging him with bare skin and had
! w% d U# [* w) abeen using protective clothing. A repeat testosterone
) T3 H. D* z# W( _test was ordered, but the family did not go to the
* }7 x9 G0 Z) D" claboratory to obtain the test.! F' x0 l8 o4 {
Discussion
) q& B7 F+ [6 ?2 OPrecocious puberty in boys is defined as secondary& L- V: R9 e; k5 U5 U
sexual development before 9 years of age.1,4
( V$ W k# b4 i& x8 ZPrecocious puberty is termed as central (true) when
! y! p/ H8 |9 O3 ^0 ?it is caused by the premature activation of hypo-; o) }0 F8 p( U, Q: [" v, F
thalamic pituitary gonadal axis. CPP is more com-5 ?9 x/ U3 E# {: l" Q2 _' U/ r
mon in girls than in boys.1,3 Most boys with CPP! y6 @/ u: m8 i$ {! r
may have a central nervous system lesion that is
2 h" F: p- G- X3 z0 X, l7 C Eresponsible for the early activation of the hypothal-
0 E e% M7 Z; m6 Camic pituitary gonadal axis.1-3 Thus, greater empha-
6 p- l% X. j4 x3 Hsis has been given to neuroradiologic imaging in6 e6 m \) `& S) I& |4 M. i& l
boys with precocious puberty. In addition to viril-
M: o8 `; W4 J8 }ization, the clinical hallmark of CPP is the symmet-# Q+ a, D0 E; W$ P* o
rical testicular growth secondary to stimulation by1 f, \# r3 E8 L/ W6 h( a
gonadotropins.1,3
: d% w5 t3 A2 ?! u9 LGonadotropin-independent peripheral preco-1 n" c- D3 R, B6 J& `
cious puberty in boys also results from inappropriate
6 w6 e: f! D5 ~2 sandrogenic stimulation from either endogenous or3 s* c) y, B" o) G) E1 N
exogenous sources, nonpituitary gonadotropin stim-: C! M r# T# f* r3 ^$ a3 }
ulation, and rare activating mutations.3 Virilizing
# D9 t9 R3 b" y4 F* D& R8 h$ Acongenital adrenal hyperplasia producing excessive
1 k0 y* i6 z& ?& M& jadrenal androgens is a common cause of precocious
b" ]3 }1 O2 Mpuberty in boys.3,4
% G+ K3 P3 Z+ k3 `% pThe most common form of congenital adrenal9 q# M6 O$ a- i. U" v
hyperplasia is the 21-hydroxylase enzyme deficiency." Y5 I% a. R( ?' N1 M) t) W, {
The 11-β hydroxylase deficiency may also result in2 g. W$ |; u+ S: R
excessive adrenal androgen production, and rarely,& Z. ~; [( Y! `
an adrenal tumor may also cause adrenal androgen6 u" r( d: g; h m, u8 j& V
excess.1,3
; @7 E0 M' I! p, Q: g* t9 jat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
1 @# R+ H8 j! d+ P# L' s0 Z542 Clinical Pediatrics / Vol. 46, No. 6, July 2007& L7 c' H; L. E. g
A unique entity of male-limited gonadotropin-) {+ |+ D) o( N3 k+ Z2 N
independent precocious puberty, which is also known$ Y" p( C7 x. A$ i+ ?$ M' r4 Y
as testotoxicosis, may cause precocious puberty at a$ m) L5 V8 o0 w2 f
very young age. The physical findings in these boys, R, V. T" r/ I7 ]! |
with this disorder are full pubertal development,
. Y% I, s+ Z9 [including bilateral testicular growth, similar to boys
% c/ B8 l, X- b8 v6 v( B7 Mwith CPP. The gonadotropin levels in this disorder- \9 A" |8 z' n
are suppressed to prepubertal levels and do not show
1 r" a" M9 y( {% l% H: r# ypubertal response of gonadotropin after gonadotropin-
/ o1 n" M. N6 ?. N* sreleasing hormone stimulation. This is a sex-linked8 N1 C% \3 k4 p2 h% X! f" u+ {" y: j
autosomal dominant disorder that affects only
# R7 F5 X( k2 y' {3 _/ K4 Zmales; therefore, other male members of the family
1 c: ?1 K3 s, }) X8 l7 qmay have similar precocious puberty.3
0 c( U4 W1 K; R' Y2 V7 HIn our patient, physical examination was incon-
! j8 ~& n% [ Psistent with true precocious puberty since his testi-: {) U: v$ s- E$ \1 A
cles were prepubertal in size. However, testotoxicosis
) N* P$ U. t' ~" p& Cwas in the differential diagnosis because his father( }8 S/ |. G# L( h( |
started puberty somewhat early, and occasionally,; e/ \4 R! G4 ]& ~8 U7 M3 E. p4 f
testicular enlargement is not that evident in the( n4 U9 R/ [) h8 Y- S8 h1 y b
beginning of this process.1 In the absence of a neg-) r; q9 e b7 \
ative initial history of androgen exposure, our
a" b3 k! j L2 K) gbiggest concern was virilizing adrenal hyperplasia,4 y/ g. w$ e! [( B
either 21-hydroxylase deficiency or 11-β hydroxylase
" d8 }4 a9 P) ^$ m, Pdeficiency. Those diagnoses were excluded by find-
0 D- {0 v$ d" J/ [ing the normal level of adrenal steroids.
6 r7 g4 N/ u2 |. cThe diagnosis of exogenous androgens was strongly
9 g! h2 s; W0 A' ]2 `suspected in a follow-up visit after 4 months because3 s8 t% X* ?/ Q& ?# v2 Y% t
the physical examination revealed the complete disap-
: m; h/ K; _2 Z6 f; t' Ypearance of pubic hair, normal growth velocity, and8 O5 h( R4 G, Q
decreased erections. The father admitted using a testos-4 [8 ^) R/ ^7 m# b6 J7 d' `4 z# w5 o
terone gel, which he concealed at first visit. He was
+ W9 m" m: L6 u! t Uusing it rather frequently, twice a day. The Physicians’( W7 \' o" B6 E7 v r- g
Desk Reference, or package insert of this product, gel or, T# r! W' o, {- ~/ h7 z( Q1 g4 u
cream, cautions about dermal testosterone transfer to6 A' D1 O+ k( _- r g' e+ M; T
unprotected females through direct skin exposure.
4 W! b! _8 o7 ?+ B+ eSerum testosterone level was found to be 2 times the
2 S$ H# o) R& A1 u9 ~baseline value in those females who were exposed to( ~# `7 ?# _2 H9 n; O9 K' Q
even 15 minutes of direct skin contact with their male
$ S- k! I. k {3 Dpartners.6 However, when a shirt covered the applica-
; Q3 B' v* T& C0 p& `2 ^4 E( etion site, this testosterone transfer was prevented.% ~) K) \0 [+ w1 ] ^
Our patient’s testosterone level was 60 ng/mL,7 o% C7 n# F& ?4 o
which was clearly high. Some studies suggest that
% A6 d: K4 m3 ]6 Ydermal conversion of testosterone to dihydrotestos-
V& @/ a0 [, E3 w/ ~terone, which is a more potent metabolite, is more
8 P, Z0 p9 f/ F( w* R) E3 G$ _active in young children exposed to testosterone
9 D- S. C" f8 Vexogenously7; however, we did not measure a dihy-& J- T4 T. U* N0 _* V
drotestosterone level in our patient. In addition to) u( m6 f! v/ a% J' l
virilization, exposure to exogenous testosterone in6 V$ `6 O3 q6 [; P* D
children results in an increase in growth velocity and
. D- z$ n* B: z; C, x' yadvanced bone age, as seen in our patient.* T9 v$ u; L! L r- u& R
The long-term effect of androgen exposure during
! S) s; B6 t2 v( k! zearly childhood on pubertal development and final' H2 Y" X- Q5 ` I6 i
adult height are not fully known and always remain
0 g! z& ]; u, i6 Ea concern. Children treated with short-term testos-
+ m; _) C u, n1 C1 d6 Kterone injection or topical androgen may exhibit some
9 v) b* o( x9 ~- s" Aacceleration of the skeletal maturation; however, after
! W$ t& b: l9 ]! o/ Fcessation of treatment, the rate of bone maturation
" d0 _( @' d) Ydecelerates and gradually returns to normal.8,9
6 J& b, Z8 R& H$ }There are conflicting reports and controversy
, ^/ _ n& O3 \5 n6 C; y# q; O- }; kover the effect of early androgen exposure on adult1 L' f$ x" u x8 q7 d
penile length.10,11 Some reports suggest subnormal
" w- ?; r P7 O3 K* h6 m- aadult penile length, apparently because of downreg-8 l {/ X4 ]2 f& _. X) u+ I
ulation of androgen receptor number.10,12 However,
+ Y r9 M) d% V9 B% HSutherland et al13 did not find a correlation between
: I/ u& E' Q# Y) p6 Xchildhood testosterone exposure and reduced adult- E+ x& c7 h2 D
penile length in clinical studies.+ L& H1 q+ f9 C: Z' O+ x' j
Nonetheless, we do not believe our patient is
; Y0 w0 r6 Y) w$ cgoing to experience any of the untoward effects from
1 ^9 ^# ^4 n; ktestosterone exposure as mentioned earlier because
+ E1 `" T0 J: x0 l, u& zthe exposure was not for a prolonged period of time.
% X2 L1 O3 v( q' V% ], qAlthough the bone age was advanced at the time of$ a( d& e+ L! U/ l- ]
diagnosis, the child had a normal growth velocity at; D3 T% x9 }8 y/ D- {( w
the follow-up visit. It is hoped that his final adult
' j# C" k4 t) dheight will not be affected.8 p* ^7 A! O9 J" J: _+ l6 k G/ r
Although rarely reported, the widespread avail-
& Q) S& V3 G y, j2 y( e6 F% w9 xability of androgen products in our society may B! |6 B7 Z# S
indeed cause more virilization in male or female
: x x8 Y, r! ?$ [3 fchildren than one would realize. Exposure to andro-
8 `; ?+ M: k6 N* pgen products must be considered and specific ques-- r5 {" Z2 B2 ]3 r! W
tioning about the use of a testosterone product or
9 b1 V; P3 P( |+ X6 P& Jgel should be asked of the family members during; t# b" h: Q$ t* u+ j
the evaluation of any children who present with vir-
6 x/ N! ^5 m$ z+ Zilization or peripheral precocious puberty. The diag-
- H$ G4 G+ G2 ~ t R% m; y) H+ @nosis can be established by just a few tests and by+ A/ E1 o. I3 V) c
appropriate history. The inability to obtain such a' [! w/ ~" f6 |: ^* j% \
history, or failure to ask the specific questions, may
( U q1 c; J/ d0 {0 W) Tresult in extensive, unnecessary, and expensive
6 r, [; D' w1 @0 K) m7 Jinvestigation. The primary care physician should be
- B4 X! Y& F0 b7 _/ e6 S' O; K& ?aware of this fact, because most of these children# _0 R4 i( _4 m! m; J' X
may initially present in their practice. The Physicians’
9 s& D3 q( }5 L4 ?7 t8 V. |: w8 jDesk Reference and package insert should also put a! Y/ @7 N8 T, K8 _, e
warning about the virilizing effect on a male or7 t# G. E3 I6 k$ ^
female child who might come in contact with some-
$ S+ ]$ t1 S5 B& b$ V- Q5 t: Wone using any of these products.
* Y1 y+ _( k% o' uReferences
3 Q0 J1 V% H _$ |; u1. Styne DM. The testes: disorder of sexual differentiation
; n9 o6 z# U4 s. I' P, Mand puberty in the male. In: Sperling MA, ed. Pediatric8 Y1 t: c% R4 {6 B
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;8 t7 }$ Q! V! A4 N
2002: 565-628.
% q$ t- q/ T. [+ P7 c0 m2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
) M% b: p6 f5 S1 R, J, Lpuberty in children with tumours of the suprasellar pineal |
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