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Sexual Precocity in a 16-Month-Old
& k; ~$ c. J3 c, G9 q* h4 ~Boy Induced by Indirect Topical2 m% K% b8 t& L3 K- z1 x4 O! `
Exposure to Testosterone2 t% {* t# p) R' R: e# j9 g
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
`5 D0 ?# U Y' ~ oand Kenneth R. Rettig, MD1
5 w' r0 a& K, @+ LClinical Pediatrics
) o( j! N9 M# hVolume 46 Number 6
& L/ N# |0 e9 h* e7 `' H* k/ RJuly 2007 540-543
, m5 O0 {0 I3 b, g, Y; F© 2007 Sage Publications
0 q: a& O( t' o' S10.1177/0009922806296651
! I. s! z9 Q9 [) k I5 e2 j1 Ohttp://clp.sagepub.com
7 e/ D. ~+ i5 {4 L7 }# xhosted at# i _4 ?% C. g+ S" Z
http://online.sagepub.com5 c4 I. s! r- i4 h7 k; L
Precocious puberty in boys, central or peripheral,' J2 D8 V. k6 g1 M; L3 z
is a significant concern for physicians. Central; Z; ?# s$ K0 }" }
precocious puberty (CPP), which is mediated& V" T: b9 x# `
through the hypothalamic pituitary gonadal axis, has' x W8 I$ B' o& y5 v; r+ q
a higher incidence of organic central nervous system
9 x f" h' p: K9 c2 d U! Blesions in boys.1,2 Virilization in boys, as manifested0 m, \& i/ j& B/ O$ O; j3 Y# O. I
by enlargement of the penis, development of pubic/ p! s* V1 X! {: q& ?( D# M: [
hair, and facial acne without enlargement of testi-0 G+ \6 _$ W* l2 q, a5 q
cles, suggests peripheral or pseudopuberty.1-3 We5 U4 H# E6 S4 l) i
report a 16-month-old boy who presented with the
/ a1 E. n4 H3 d, O8 [# D7 y/ T. Z. \enlargement of the phallus and pubic hair develop-
, {/ l9 m( V% @4 I0 @ment without testicular enlargement, which was due
3 N8 F6 f6 p5 h4 S! Gto the unintentional exposure to androgen gel used by
- }8 Y1 ]# w% z: b* }+ q( Uthe father. The family initially concealed this infor-0 x& R* W& Z c& N' j
mation, resulting in an extensive work-up for this
3 ?9 C2 X3 O, I7 _, Bchild. Given the widespread and easy availability of; N2 B' G4 h. q+ z' |
testosterone gel and cream, we believe this is proba-
6 C% `3 ~6 m% h1 E- ^" P" sbly more common than the rare case report in the0 @1 R- Z- n6 h" R) W+ K8 m' e
literature.4! i- _& a* i6 P( M' t$ S* N
Patient Report/ H/ U4 f) g1 n+ v' s( F
A 16-month-old white child was referred to the
$ [) K- l% x3 t: t+ {8 p9 Iendocrine clinic by his pediatrician with the concern! M! k: O D; G+ M& \. M) X% Q
of early sexual development. His mother noticed
0 M; [) v3 Y9 x: Q$ ]/ N4 Y4 w+ Flight colored pubic hair development when he was
$ L7 n8 t, r, U5 {From the 1Division of Pediatric Endocrinology, 2University of+ d. v5 h/ y4 x. P
South Alabama Medical Center, Mobile, Alabama.1 T1 J8 `6 H# F' u ^8 S( l
Address correspondence to: Samar K. Bhowmick, MD, FACE,
* ]- k) C7 M `3 i# l8 LProfessor of Pediatrics, University of South Alabama, College of
# u- d/ U! [( P* k) F! HMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
7 h7 r: m' r" H4 Ee-mail: [email protected].
3 [, L3 }6 L9 S/ }: r: Tabout 6 to 7 months old, which progressively became0 K- M! j1 t- n( D2 S* x8 j: H
darker. She was also concerned about the enlarge-
3 o! }: \, z$ s* E; p* cment of his penis and frequent erections. The child
4 D5 |8 K V, e3 rwas the product of a full-term normal delivery, with
; w/ a6 J( a1 R0 ia birth weight of 7 lb 14 oz, and birth length of b1 G, ^8 x7 `4 ]4 d
20 inches. He was breast-fed throughout the first year/ Z2 Y q- Y: I1 y6 P2 K
of life and was still receiving breast milk along with Q+ T& X4 `1 G/ u3 S) b
solid food. He had no hospitalizations or surgery,
6 @1 ^" a' v) X+ G( aand his psychosocial and psychomotor development
0 P3 c: E" b4 r+ ?$ zwas age appropriate.
! c6 H/ b5 Y' }4 j# h0 F3 rThe family history was remarkable for the father,9 n; O9 [ \3 K2 N# ^+ s
who was diagnosed with hypothyroidism at age 16,
9 q: u, F0 P T M) J/ S( \4 l% }which was treated with thyroxine. The father’s2 r9 C9 K, { W6 r' ^
height was 6 feet, and he went through a somewhat
7 @. ]1 N" s0 `/ V5 Y, e6 ~( V" bearly puberty and had stopped growing by age 14.# Q2 o' Z% N- z N9 N0 W' Z
The father denied taking any other medication. The/ N8 f/ o, _5 k2 [
child’s mother was in good health. Her menarche
+ @* ?! S5 n$ d$ B! |, G* vwas at 11 years of age, and her height was at 5 feet
) ^! d. i7 T& y5 inches. There was no other family history of pre-* w8 }/ j6 c. f4 U! E' ^
cocious sexual development in the first-degree rela-
s/ @+ G7 @* l; j/ A% k3 X: ? xtives. There were no siblings./ P' e9 \, }7 d; k
Physical Examination
) g3 b; a" A/ dThe physical examination revealed a very active,
- [$ J, j0 ^. v# Y/ g0 q Tplayful, and healthy boy. The vital signs documented
2 J- [# w, ^# s- U0 K( a# Qa blood pressure of 85/50 mm Hg, his length was: s" j7 f Q% @3 O( N
90 cm (>97th percentile), and his weight was 14.4 kg8 C) W, W( v+ I- j8 N* ]
(also >97th percentile). The observed yearly growth
% e" y3 u3 R( c( Lvelocity was 30 cm (12 inches). The examination of
_3 H `. ? c8 F; |the neck revealed no thyroid enlargement.8 h7 R; ]& h( e6 Z P" u
The genitourinary examination was remarkable for
) R, |" L' \3 A S; s- [enlargement of the penis, with a stretched length of" _, R- E6 ^3 V
8 cm and a width of 2 cm. The glans penis was very well& F: T% j5 g+ H2 ]
developed. The pubic hair was Tanner II, mostly around
- `6 m/ o6 d' _- H/ f2 k540
' T5 f c0 J" q$ d8 y! V: Pat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 O9 e0 V- e3 E; b
the base of the phallus and was dark and curled. The m! [- S( H K4 f) p6 P5 T
testicular volume was prepubertal at 2 mL each.: Q3 \, \1 d) ^4 O8 P* A" b9 e- h
The skin was moist and smooth and somewhat
* x c. D' s1 \; Q/ W! voily. No axillary hair was noted. There were no* j& I; U3 v6 I- B: V+ I+ g% \! ^
abnormal skin pigmentations or café-au-lait spots.
x! p8 X$ U5 X9 X3 L. j+ u4 ~Neurologic evaluation showed deep tendon reflex 2+7 B# e/ Y- h- o( U* k
bilateral and symmetrical. There was no suggestion2 Z( z. g2 X! k, ~; ?
of papilledema.3 ^! u2 {- H, w- q) w" i, G$ _
Laboratory Evaluation3 G' s2 a" T) w
The bone age was consistent with 28 months by
4 x" ], O" Z+ k* B6 n( |using the standard of Greulich and Pyle at a chrono-
5 }" k. q* {; V1 @3 C, n# F( Dlogic age of 16 months (advanced).5 Chromosomal8 J$ p! q6 e7 E" v* s8 m9 m
karyotype was 46XY. The thyroid function test7 ?+ w1 ?6 J9 [: z
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
# a8 Q$ D: U$ u" dlating hormone level was 1.3 µIU/mL (both normal).
|$ T) T4 a9 I s( a% V' n- RThe concentrations of serum electrolytes, blood" I0 ]2 `4 k4 z1 A" Y( x
urea nitrogen, creatinine, and calcium all were
5 z4 w" _/ g, y) \% swithin normal range for his age. The concentration/ G- q- ^$ ^) k- i
of serum 17-hydroxyprogesterone was 16 ng/dL- W) N# P: h% e) n f
(normal, 3 to 90 ng/dL), androstenedione was 20
% n+ v9 M8 t0 n9 w$ E" K F2 Png/dL (normal, 18 to 80 ng/dL), dehydroepiandros-; }! D+ t) v7 X( ^/ f: [* x, ?
terone was 38 ng/dL (normal, 50 to 760 ng/dL),6 X# l* X; x; e
desoxycorticosterone was 4.3 ng/dL (normal, 7 to# l# [5 w; e0 s
49ng/dL), 11-desoxycortisol (specific compound S)3 n0 J# n g4 g0 `, l% d
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-9 d- h' q& R7 B9 W! H/ n/ h
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total# j6 ^% V! K5 W9 b) |1 U6 i
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),# k S8 c) a n. I- d6 v
and β-human chorionic gonadotropin was less than
* e1 ?1 d ^: O5 e4 F5 mIU/mL (normal <5 mIU/mL). Serum follicular4 P% ]8 p1 A# g. t$ x
stimulating hormone and leuteinizing hormone
+ v. S% {" E: P$ r1 \9 F% n* yconcentrations were less than 0.05 mIU/mL
. j6 g/ m& `, U, j8 ~7 _3 J. H+ p- Q(prepubertal).) P) P2 y# Z: t% Y. O ]
The parents were notified about the laboratory7 M7 e1 k+ e/ u. t
results and were informed that all of the tests were
& B" H% N+ V3 Fnormal except the testosterone level was high. The2 Q1 t- Z e( ^" J
follow-up visit was arranged within a few weeks to
5 L4 V. i+ ~! ]4 Zobtain testicular and abdominal sonograms; how-$ Z+ L. n) ]( Z9 \8 k
ever, the family did not return for 4 months.
% S) V! M7 o! W+ S# FPhysical examination at this time revealed that the7 b, C- ~8 W S& F* v: P( B
child had grown 2.5 cm in 4 months and had gained* T4 U8 X; X* h7 _
2 kg of weight. Physical examination remained
; c0 E* y+ G9 G' s3 a% K) Eunchanged. Surprisingly, the pubic hair almost com-
$ X1 n! C5 M( [$ S9 u9 D g- q# S8 bpletely disappeared except for a few vellous hairs at8 b' r1 m+ A# ~5 ]" d$ K2 B
the base of the phallus. Testicular volume was still 29 m( D) V: E$ \, h/ k5 |
mL, and the size of the penis remained unchanged.# p" P9 x$ ~$ K' D0 f3 x% p
The mother also said that the boy was no longer hav-
- [. v( n6 M* z3 _7 d+ Xing frequent erections.
2 D7 Z! P1 x! D3 A3 c' [Both parents were again questioned about use of
" W- p7 N* k8 S/ |4 @any ointment/creams that they may have applied to
) T1 a6 W$ U0 `the child’s skin. This time the father admitted the4 D3 |9 B% ?( y* K# B% ]: m: ^
Topical Testosterone Exposure / Bhowmick et al 541
+ f8 v& t# k# |use of testosterone gel twice daily that he was apply-" ?% p# ~' H5 T! v+ i; y1 _
ing over his own shoulders, chest, and back area for
q6 Y$ e" b5 c, G! _a year. The father also revealed he was embarrassed
9 }- o1 I$ F# {0 m" Vto disclose that he was using a testosterone gel pre-
) c8 Y2 n* j! N; \: w$ ^scribed by his family physician for decreased libido. b& m6 }3 c) m% @
secondary to depression., L" U: w8 {! ~" v9 C
The child slept in the same bed with parents.
0 J# o, v# `' X* qThe father would hug the baby and hold him on his( x1 H- n* K) l# T0 @0 i1 h
chest for a considerable period of time, causing sig-+ K4 B& w0 ^% j* j
nificant bare skin contact between baby and father.1 o' i& j" K V3 w: A
The father also admitted that after the phone call,
# d" w3 J! S3 v, O5 @' y) |when he learned the testosterone level in the baby
6 T0 i9 J+ \4 qwas high, he then read the product information, l( n. G* S. C3 v2 e6 ~
packet and concluded that it was most likely the rea-, v' \; r! `/ t- \
son for the child’s virilization. At that time, they6 L! p, ^/ v4 q& k) u$ Q& m
decided to put the baby in a separate bed, and the6 c _) x( h: o9 J/ n
father was not hugging him with bare skin and had
. n9 w* x1 [" J- n: B4 Kbeen using protective clothing. A repeat testosterone" q7 A5 {# V, W) u' p+ K
test was ordered, but the family did not go to the
; R% M, M v+ P- Nlaboratory to obtain the test.: \0 T. b# ~1 o% @$ \
Discussion# p3 W* [5 o' {% V
Precocious puberty in boys is defined as secondary! Z' v! U c+ x! `% D2 b" g. }
sexual development before 9 years of age.1,46 P, n U1 v7 p/ H/ g/ q
Precocious puberty is termed as central (true) when' D6 [; i* _% K
it is caused by the premature activation of hypo-2 H5 v3 T" ?! V
thalamic pituitary gonadal axis. CPP is more com-
O. X( R8 D. ~/ a" P; W( z% Hmon in girls than in boys.1,3 Most boys with CPP
8 p& F) _* S( A }may have a central nervous system lesion that is8 o- O8 g4 C& ]) |
responsible for the early activation of the hypothal-/ F8 ] [9 H/ ~5 V ^3 R
amic pituitary gonadal axis.1-3 Thus, greater empha-
& G. y' Y3 }/ v" \+ u: psis has been given to neuroradiologic imaging in) s6 [6 I X* C2 l. M+ ]
boys with precocious puberty. In addition to viril-$ q' q, }- ?. l1 o/ i- F1 c
ization, the clinical hallmark of CPP is the symmet-
0 e5 v9 _* q8 S7 B# D) w7 drical testicular growth secondary to stimulation by
1 q. L! i+ H1 `; w- X& hgonadotropins.1,3
; R i' K: I8 C6 i4 f) A1 H" a' j2 JGonadotropin-independent peripheral preco-
1 b9 s* x! l% r- j) }: R* fcious puberty in boys also results from inappropriate9 h+ L7 Y8 D; o) J l3 B6 C
androgenic stimulation from either endogenous or2 \; S! M' {6 ~. g4 i. M
exogenous sources, nonpituitary gonadotropin stim-
4 g4 ^: N/ l) y( c1 w/ Z/ x$ vulation, and rare activating mutations.3 Virilizing. F2 ~5 T4 Z* O% q& g* p/ M% I
congenital adrenal hyperplasia producing excessive2 L: ~# h( ~3 W4 B% H; h( b3 f
adrenal androgens is a common cause of precocious8 S* H* \3 r/ b3 g0 }8 J
puberty in boys.3,4
/ e, w6 F! `4 u: x+ U" r% y1 [The most common form of congenital adrenal
$ J% Q! w) j( G! Z# V, d; rhyperplasia is the 21-hydroxylase enzyme deficiency.
& C$ i q9 c3 U2 E" SThe 11-β hydroxylase deficiency may also result in& w$ `% e7 Q/ g; g+ r
excessive adrenal androgen production, and rarely," a, Z$ c9 M4 _$ j6 t
an adrenal tumor may also cause adrenal androgen% I7 X4 W4 O, f5 V* R1 x' u0 E, t
excess.1,3
4 d1 X! N, W# y' a" yat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
Z# j6 h* @8 x$ ?+ t( m, ]4 m# i) q542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
4 @2 k! v' `: }5 aA unique entity of male-limited gonadotropin-0 y' o7 \. j" ~' ]" H" v5 O- w! U
independent precocious puberty, which is also known
" O7 Q3 [/ Z5 p) [# o6 E/ zas testotoxicosis, may cause precocious puberty at a
5 Z, t7 p( ]: o. D7 Hvery young age. The physical findings in these boys$ t3 P% _1 \3 t# E
with this disorder are full pubertal development,
8 W8 l# z- y5 k! h: H0 C' X+ a6 aincluding bilateral testicular growth, similar to boys! u: s3 t( A/ w7 z1 u
with CPP. The gonadotropin levels in this disorder
! Y* C! s9 Y+ aare suppressed to prepubertal levels and do not show
4 `5 [5 Z0 n) }* Y, F! epubertal response of gonadotropin after gonadotropin-3 _. ?& U C, w- G6 i1 R$ s- L
releasing hormone stimulation. This is a sex-linked% T( R1 |- B, c* O! N% K, d
autosomal dominant disorder that affects only; E) n# J0 a% u) B: b
males; therefore, other male members of the family
! i$ `! {3 H; wmay have similar precocious puberty.3 @$ ?5 g9 m# i" s; }
In our patient, physical examination was incon-
( d. R3 c% r+ E: r3 X' {' psistent with true precocious puberty since his testi-, D% J+ A! m: c" H# v' m
cles were prepubertal in size. However, testotoxicosis
0 T! I' o2 r) y! Fwas in the differential diagnosis because his father. ?" D( |( e' u+ |% W
started puberty somewhat early, and occasionally,
( a8 o/ x% R2 P9 ^testicular enlargement is not that evident in the
: N1 J7 X! A/ w: t; }1 Pbeginning of this process.1 In the absence of a neg-
8 t, c1 {+ K, \# e" j9 F* x! Cative initial history of androgen exposure, our; E' P! v9 ^( A4 ?
biggest concern was virilizing adrenal hyperplasia,
0 F0 E* p2 p- U, f" `either 21-hydroxylase deficiency or 11-β hydroxylase! i6 m! u$ v) F0 W
deficiency. Those diagnoses were excluded by find-& x! _, v( A/ v3 Z, f
ing the normal level of adrenal steroids.
3 w0 z; |2 f1 a( tThe diagnosis of exogenous androgens was strongly
. b/ L7 u' `3 d' [suspected in a follow-up visit after 4 months because$ C2 ?$ h) ~! T# r: T& g8 a3 o4 X& h$ k
the physical examination revealed the complete disap-# Y5 F, h- V! {! E2 e
pearance of pubic hair, normal growth velocity, and2 d1 M9 _6 M: `9 v5 ^) Z
decreased erections. The father admitted using a testos-
t' s- v) e# hterone gel, which he concealed at first visit. He was
) E0 v: j! H t0 z$ ~7 cusing it rather frequently, twice a day. The Physicians’0 c; L9 e! G3 E" W, \3 w
Desk Reference, or package insert of this product, gel or
$ l% ^: e; Z9 `2 |* ncream, cautions about dermal testosterone transfer to2 {9 w. N2 `! J: i7 C
unprotected females through direct skin exposure.( ?% W3 n# e6 z
Serum testosterone level was found to be 2 times the
D) V( e7 h& O- u( O T: jbaseline value in those females who were exposed to
$ F& d( [3 v1 S" ~$ heven 15 minutes of direct skin contact with their male
. i7 g) f, f+ ~4 ]& L" [partners.6 However, when a shirt covered the applica-
" t" g/ B8 g0 T# t* c5 l. m& ~$ q4 N% Ttion site, this testosterone transfer was prevented.
; w& ^2 i4 q& i. h* o9 nOur patient’s testosterone level was 60 ng/mL,7 b6 n0 ~4 v, w$ f/ Z, z
which was clearly high. Some studies suggest that8 b, T' I* Q5 o* @& B! I
dermal conversion of testosterone to dihydrotestos-( m) m$ L% C4 Z) K. T8 B4 @
terone, which is a more potent metabolite, is more
- K# G- m" w# iactive in young children exposed to testosterone
( R8 s, v" {8 c9 J% Fexogenously7; however, we did not measure a dihy-+ }6 m I& _ M m% B. l
drotestosterone level in our patient. In addition to3 n5 [8 G9 A( |% g8 _3 V7 a
virilization, exposure to exogenous testosterone in
& E9 O1 A8 r, j; z8 wchildren results in an increase in growth velocity and
: h. v @# C2 Tadvanced bone age, as seen in our patient.) L; u0 m* R2 d& m; M
The long-term effect of androgen exposure during, l z8 _- i0 O" t, |. n. M
early childhood on pubertal development and final: f- T8 Z/ [( r; C; j- t! }! x
adult height are not fully known and always remain# Y% L- ?4 d( i. k6 J1 s+ _
a concern. Children treated with short-term testos-
9 K* K, p2 a8 R) l& y; [terone injection or topical androgen may exhibit some
3 D% V7 E* ?3 @/ Macceleration of the skeletal maturation; however, after" l/ M, }3 t, ^$ b! l
cessation of treatment, the rate of bone maturation
; R: F- t' O& B& M( jdecelerates and gradually returns to normal.8,9
. j v; O' a9 H( ^There are conflicting reports and controversy6 a' l2 t f$ x6 K' W
over the effect of early androgen exposure on adult
* S& _8 n& A7 f4 W. y/ ]penile length.10,11 Some reports suggest subnormal
4 Z$ X$ v0 S# r: q# l; h7 B2 zadult penile length, apparently because of downreg-
" }6 q4 {( o1 d( S3 D( A; T8 }ulation of androgen receptor number.10,12 However,
7 F0 o) w9 U8 |" P4 O3 g. ?' \Sutherland et al13 did not find a correlation between+ V& t- \1 P2 W- `+ J4 u
childhood testosterone exposure and reduced adult
. F+ [$ \$ r9 N5 C3 Upenile length in clinical studies.' {/ u6 [3 M2 }$ O8 X
Nonetheless, we do not believe our patient is( p8 H \' ]( q! M( W% f/ ^2 \3 {* C
going to experience any of the untoward effects from
% @4 b E7 ?+ }testosterone exposure as mentioned earlier because$ {; O, G) j. d5 n% O4 ^: t
the exposure was not for a prolonged period of time.
* @/ O' R* e# U9 jAlthough the bone age was advanced at the time of
1 [7 v) V: _9 h: udiagnosis, the child had a normal growth velocity at
4 d$ u2 o) k) I' r, S- ]the follow-up visit. It is hoped that his final adult6 I3 P; @% _$ Z8 V: ?$ D, [
height will not be affected.
+ a8 O+ _: _* ?- ]Although rarely reported, the widespread avail-
# z! \& W! K2 L; c6 P& Eability of androgen products in our society may* R* b) B0 t/ X* _3 v
indeed cause more virilization in male or female0 `5 s- w" a1 ?6 }4 Q8 S; y$ B( E
children than one would realize. Exposure to andro-
* ^; Z. M9 Y4 M w; ?. Igen products must be considered and specific ques-/ _% v, d5 E: P
tioning about the use of a testosterone product or
5 E* J7 v2 l: Z. I. v5 r$ cgel should be asked of the family members during' A' S# K, i2 H/ s5 X7 g" @* Z# P
the evaluation of any children who present with vir-
3 o% D% `* i; g& f O* Vilization or peripheral precocious puberty. The diag-
# g, s- i# C" ~$ Fnosis can be established by just a few tests and by
, h* M* e1 R* ~appropriate history. The inability to obtain such a
, ]" f, B' x; B5 u3 Ghistory, or failure to ask the specific questions, may, b( M' N% c8 t( `8 _
result in extensive, unnecessary, and expensive, Z8 o5 w, h( y4 ]; o
investigation. The primary care physician should be& _% r5 S. x6 _' F
aware of this fact, because most of these children
3 Y+ l9 b1 p# r9 S5 w1 M! {may initially present in their practice. The Physicians’4 q, `$ t$ B4 O6 w/ _3 z0 j- t
Desk Reference and package insert should also put a
, Z- \1 Z" Q2 q2 e, K$ dwarning about the virilizing effect on a male or$ e& ~% A0 \7 h4 H5 \4 f$ e
female child who might come in contact with some-; [4 \; d) a) p
one using any of these products. \7 L' l4 P0 q& e
References
0 ` w9 @$ X( w# D3 Z3 _6 w; }) X1. Styne DM. The testes: disorder of sexual differentiation
: A4 r5 J& h& ?5 pand puberty in the male. In: Sperling MA, ed. Pediatric* z ~2 q: {- d. H$ M
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
1 P9 S2 ~8 z3 s; X; I/ O1 R2002: 565-628.
* w; H/ {6 o U7 D& @2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
9 `; y, e& T+ G* J7 ]3 Dpuberty in children with tumours of the suprasellar pineal |
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