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Sexual Precocity in a 16-Month-Old
/ ~8 [/ j. G' j4 L# B _% u# RBoy Induced by Indirect Topical2 A# H" x7 H+ Z5 o, j
Exposure to Testosterone1 j- K8 A% f1 {* o/ y6 N, `
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2! p6 {( j7 m1 G- e
and Kenneth R. Rettig, MD1% [6 x) P+ N9 j4 Q: k) R. w2 D
Clinical Pediatrics
9 S; b& H* b. I. P# JVolume 46 Number 6
$ i: ?: ^) V. e, O3 ?July 2007 540-543
- s, d2 _- r" |2 ?* a5 ~( o© 2007 Sage Publications
3 S' b- g/ t; M; [1 r5 z10.1177/0009922806296651
9 F! ]7 p( H: F/ R3 \: \http://clp.sagepub.com6 _4 L5 {8 U2 T5 O4 D* c: ^
hosted at% u% g: \2 S" z! t
http://online.sagepub.com
& S$ O9 v% Z7 W) N; v- _. XPrecocious puberty in boys, central or peripheral,
% \6 z N( `& K! D" c: E( z2 D1 ?is a significant concern for physicians. Central
$ s) L4 V% }/ ?* B- e' O: {7 P- Nprecocious puberty (CPP), which is mediated
7 a2 r7 R: f% q5 ~through the hypothalamic pituitary gonadal axis, has) w% t/ r) @; z1 ^6 M
a higher incidence of organic central nervous system
n/ X3 t8 [: k2 ^6 i7 Clesions in boys.1,2 Virilization in boys, as manifested
" Y ?" e l( Z, }5 nby enlargement of the penis, development of pubic
* y9 E7 ]& P+ Q0 {% V" a5 `5 ohair, and facial acne without enlargement of testi-2 Y5 N; M% F/ e7 z
cles, suggests peripheral or pseudopuberty.1-3 We* W, U# t' z" \: j3 c7 C1 Z
report a 16-month-old boy who presented with the+ p* ?) u S. {* d8 J
enlargement of the phallus and pubic hair develop-
# m4 u) y |% o/ j( C5 l: j. Tment without testicular enlargement, which was due
! w0 |# M9 N3 F j! E; ato the unintentional exposure to androgen gel used by
" Z# x h, ?/ c' N# h$ ^the father. The family initially concealed this infor-
5 ~/ x( @) _; @. wmation, resulting in an extensive work-up for this
- j F, x; U7 h& ?: A( ~child. Given the widespread and easy availability of
, Y& x+ {+ l. I( }- M) btestosterone gel and cream, we believe this is proba-4 ]; B. D' i0 n8 I
bly more common than the rare case report in the. n F9 A9 G5 _, I
literature.4
; v( M& x1 C: Z' H9 zPatient Report4 i5 `7 `( r' X- u
A 16-month-old white child was referred to the
1 k) u7 r- F% t) l& P0 wendocrine clinic by his pediatrician with the concern
! Z7 X+ ^( t# q1 Aof early sexual development. His mother noticed4 M) j* K& ^% @8 R& B
light colored pubic hair development when he was
* E0 Z7 f/ L9 Y5 lFrom the 1Division of Pediatric Endocrinology, 2University of
8 v. ]+ \0 @% ^) RSouth Alabama Medical Center, Mobile, Alabama.
+ T' ^: X9 J( |Address correspondence to: Samar K. Bhowmick, MD, FACE,
4 T% a! X8 e0 b' aProfessor of Pediatrics, University of South Alabama, College of
: b8 u5 d! `2 G, {: B9 o: ]3 eMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
) i2 [: G4 N! d+ T8 ~e-mail: [email protected].
/ |+ D) j5 ^5 A- X3 vabout 6 to 7 months old, which progressively became
1 { N' [, C0 j) {# udarker. She was also concerned about the enlarge-. p" t+ |" O# G) s, k* F
ment of his penis and frequent erections. The child& y7 ` c3 w, A; B U1 Z8 Z
was the product of a full-term normal delivery, with; L/ o7 c2 U' C5 J3 D
a birth weight of 7 lb 14 oz, and birth length of, M: l5 w4 ~5 h+ F0 D$ d
20 inches. He was breast-fed throughout the first year
* h6 i X6 F% {; \3 a0 pof life and was still receiving breast milk along with
5 x) O/ p* k* ^ r$ asolid food. He had no hospitalizations or surgery,
+ x+ {2 i4 b2 u) {# v( f5 @and his psychosocial and psychomotor development/ E1 x& X B# L$ w; [% f5 e
was age appropriate.
6 N: }: J. y* E. D R# J# q+ BThe family history was remarkable for the father,+ E% b8 _" F) ?- {
who was diagnosed with hypothyroidism at age 16,, ?5 _) @6 M6 a( M5 S4 y
which was treated with thyroxine. The father’s
% j' |. s) y6 `, ?* Oheight was 6 feet, and he went through a somewhat
1 b1 H& L' Y- V* w* Z% I4 Cearly puberty and had stopped growing by age 14./ H; W: O6 A# [
The father denied taking any other medication. The7 f. W; f7 K- R9 X
child’s mother was in good health. Her menarche
/ e3 a F1 {4 t( J7 ^9 Bwas at 11 years of age, and her height was at 5 feet: G4 q, p9 J" Z/ A/ G6 e0 `
5 inches. There was no other family history of pre-
4 _" Y1 `. s# G& e" Hcocious sexual development in the first-degree rela-, W) L1 f) z$ h5 |
tives. There were no siblings.
, b* z* M$ l* ?4 P4 }4 i6 B* \; WPhysical Examination, X0 Y: f1 o! Y4 n/ m4 J" P) Q( a
The physical examination revealed a very active,
4 }% J- ]" V L7 ?0 Z) Aplayful, and healthy boy. The vital signs documented
5 Y/ J2 V9 q2 ?5 P+ t2 ~a blood pressure of 85/50 mm Hg, his length was
$ z6 l2 g: z k" W |& W6 C& [90 cm (>97th percentile), and his weight was 14.4 kg$ @2 N. v" V( n7 x# \7 W3 y
(also >97th percentile). The observed yearly growth
1 W( V% \2 N& t, m: `# @% o0 l& }* L. ~! _velocity was 30 cm (12 inches). The examination of
3 j6 {' P" I3 Y' a9 C) U8 V. Cthe neck revealed no thyroid enlargement.6 v }) D! A6 B( M6 b. U: D9 M
The genitourinary examination was remarkable for
# R- |) } M9 {" H+ I% c) Qenlargement of the penis, with a stretched length of
9 f8 {: ?( ]! I. ~8 U5 R9 [, E8 cm and a width of 2 cm. The glans penis was very well4 ^- o5 m0 ^" G
developed. The pubic hair was Tanner II, mostly around
; |9 u8 [# U! @$ {8 E$ q$ M7 _540
U! ^+ L, W: C% V/ E1 lat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
3 q4 y* L* e1 t$ ^the base of the phallus and was dark and curled. The2 X/ y0 C# S; K6 U% J1 ?( _
testicular volume was prepubertal at 2 mL each.: t4 U$ I7 r) Q3 S3 a
The skin was moist and smooth and somewhat! n4 C8 A* o' a0 c* b7 E( f
oily. No axillary hair was noted. There were no
3 @) U* q3 X# B5 S Wabnormal skin pigmentations or café-au-lait spots.
) h3 ^/ P" X/ t' F2 z/ NNeurologic evaluation showed deep tendon reflex 2+
8 ^; f9 j( K* d7 G% \- N3 h( T7 S; T3 ?bilateral and symmetrical. There was no suggestion
% R1 b# F, M3 C3 T5 {4 F. Q! |of papilledema.
8 I' Y* S3 c" t2 a9 _8 j/ m8 p8 b2 bLaboratory Evaluation
D# P" A% [% j1 v/ a# QThe bone age was consistent with 28 months by
' P+ W$ [: z! Q Busing the standard of Greulich and Pyle at a chrono-
) z% p# T+ K- ^) h2 l3 C9 ylogic age of 16 months (advanced).5 Chromosomal1 G0 h+ G, P$ e8 d/ ~$ \
karyotype was 46XY. The thyroid function test
# i/ c" Y# c' g2 K' B' Z# A2 Rshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
% _" w0 \$ ^, m% v$ V( d$ p6 d, alating hormone level was 1.3 µIU/mL (both normal).% q" L. ]& }$ I# \9 u, C
The concentrations of serum electrolytes, blood
. P& m: L0 P) R5 e5 p( l: U; curea nitrogen, creatinine, and calcium all were6 H$ V8 u# y! u4 L5 F
within normal range for his age. The concentration" u$ x, _) d7 F( q; ~! c6 t5 k" v
of serum 17-hydroxyprogesterone was 16 ng/dL) Q# q, L% q: S9 X) g) y
(normal, 3 to 90 ng/dL), androstenedione was 20* i* f v( l ^- O
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
U- O7 m# V9 Z- H: y- hterone was 38 ng/dL (normal, 50 to 760 ng/dL),
2 G$ ~7 ?( B3 Ndesoxycorticosterone was 4.3 ng/dL (normal, 7 to- ^5 H9 Q* }, D* i! x5 L
49ng/dL), 11-desoxycortisol (specific compound S)+ Y+ G) k. `8 I4 U1 K: c3 K& p
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
1 A) _" e/ \" E/ I/ G% ]tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total( z! t; w5 J$ c& t( f
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
$ i' f! W; i q( r5 H% `and β-human chorionic gonadotropin was less than
8 P- O0 y* n x* d* z- r: v5 mIU/mL (normal <5 mIU/mL). Serum follicular$ e Y3 n1 g6 S* X8 P' o
stimulating hormone and leuteinizing hormone2 W0 E# o# T3 O, c! |
concentrations were less than 0.05 mIU/mL
$ K6 ]. m) g! Y9 n2 @) A5 w( b(prepubertal).: P5 ~" v+ i' C c) }" N- r, X* p+ n
The parents were notified about the laboratory
# ~+ I7 a7 q, C, Tresults and were informed that all of the tests were6 q. I* r C/ ?) i
normal except the testosterone level was high. The, L$ ?5 B4 f3 a9 W9 N
follow-up visit was arranged within a few weeks to
/ S( {7 H" L1 x% x1 }& Z8 @" zobtain testicular and abdominal sonograms; how-4 s+ W8 D6 H- A- e5 I. q
ever, the family did not return for 4 months.' }: G9 ~. u9 K; I/ m
Physical examination at this time revealed that the
, ^+ l$ G, {7 nchild had grown 2.5 cm in 4 months and had gained' v F! _& x3 Q
2 kg of weight. Physical examination remained
3 ], ~! D( p- eunchanged. Surprisingly, the pubic hair almost com-1 ]* `6 a+ ~# M* @
pletely disappeared except for a few vellous hairs at0 K! h$ }, L" Y* j7 ?' {
the base of the phallus. Testicular volume was still 26 R8 C1 b: `- U" y Q
mL, and the size of the penis remained unchanged.
# I: s- y; `8 {6 v0 M9 Y2 {% kThe mother also said that the boy was no longer hav-5 N4 _' d3 T! X. `
ing frequent erections.
( v( W5 T! ~: ABoth parents were again questioned about use of, ` V" X0 n9 K" U0 d" m( k
any ointment/creams that they may have applied to6 ^3 [7 A: T1 H
the child’s skin. This time the father admitted the& r+ q- ^9 k/ i" F; Q' b+ k- O/ }
Topical Testosterone Exposure / Bhowmick et al 541
" j8 P3 ]" ~* ~( K, y$ E' ouse of testosterone gel twice daily that he was apply-
/ t7 @" k/ ^1 N" E9 x$ [7 Sing over his own shoulders, chest, and back area for
! l c: O8 ?- C4 sa year. The father also revealed he was embarrassed/ X& o1 k: y2 b$ y
to disclose that he was using a testosterone gel pre-
0 a( T: k6 Q6 Z/ d% j3 M, c2 P( xscribed by his family physician for decreased libido
, ~! g7 }! {8 G3 A% T! Dsecondary to depression.+ J' w; O' i8 [" R0 |! d2 t3 ?: w
The child slept in the same bed with parents.
3 ]8 n$ f, B5 V ZThe father would hug the baby and hold him on his
5 D2 N7 N( P: W$ Echest for a considerable period of time, causing sig-/ p$ t' }7 x0 o' G
nificant bare skin contact between baby and father.5 @! @' y* ]0 s$ M/ H- _
The father also admitted that after the phone call,
8 Q* ?* b8 N+ R0 s+ \! |! ]when he learned the testosterone level in the baby6 W, i4 M# l. L! X5 C
was high, he then read the product information3 F7 e: T% H0 h: b' L7 X
packet and concluded that it was most likely the rea-. l2 ?3 e5 [1 t9 G, I( H
son for the child’s virilization. At that time, they
7 ?) l0 k: D4 M. `) ddecided to put the baby in a separate bed, and the
) [9 D' [# ?: ]9 j! Bfather was not hugging him with bare skin and had9 G# {3 V& |2 e, a' W' |' n
been using protective clothing. A repeat testosterone" S" O9 l2 n5 I: ?4 d
test was ordered, but the family did not go to the
) e( u! c& P9 Q: ^! T$ m Hlaboratory to obtain the test., j+ d% d6 `/ [5 M! y) Z
Discussion
, h7 _. r7 I" g% u; ]Precocious puberty in boys is defined as secondary
! O. D2 c6 F, `3 usexual development before 9 years of age.1,4
3 x% C& K& r- w9 B7 }" Z6 P; DPrecocious puberty is termed as central (true) when/ o, c/ m5 y; o. c
it is caused by the premature activation of hypo-) A1 a6 u% D2 L3 u. j$ d( R
thalamic pituitary gonadal axis. CPP is more com-( f5 @# P7 Y F# c7 z5 x
mon in girls than in boys.1,3 Most boys with CPP
- k9 A& \3 A# Y8 Pmay have a central nervous system lesion that is6 s/ U. b* R2 u: U; b+ ? O
responsible for the early activation of the hypothal-
* E4 \2 W- R0 Xamic pituitary gonadal axis.1-3 Thus, greater empha-2 J& ?, k4 L) B1 @
sis has been given to neuroradiologic imaging in5 U1 W7 W0 }$ D- Y0 f' S
boys with precocious puberty. In addition to viril-# s! z6 d7 ~- d: v7 `8 S& Q, `" }; y
ization, the clinical hallmark of CPP is the symmet-0 Y2 n7 e4 w% I2 T3 h$ k
rical testicular growth secondary to stimulation by
2 T+ `8 r& e0 Y1 o$ \gonadotropins.1,3
4 o) U6 i; q5 ?# O" y2 n$ jGonadotropin-independent peripheral preco-
1 ]0 y& n; Q" H2 icious puberty in boys also results from inappropriate1 ]* C0 h w) o6 ^
androgenic stimulation from either endogenous or) Z7 F z9 I* }$ m
exogenous sources, nonpituitary gonadotropin stim-0 V( I4 W# e. e" [& T, \
ulation, and rare activating mutations.3 Virilizing; `2 q( R* ~: j
congenital adrenal hyperplasia producing excessive0 l ^ L$ i. g1 y4 u4 a
adrenal androgens is a common cause of precocious3 w# ~; Q2 F( u/ u% R, f, m, `
puberty in boys.3,4
# l' s! K0 \4 q3 E# KThe most common form of congenital adrenal4 H; ~- g+ x# M8 F4 d
hyperplasia is the 21-hydroxylase enzyme deficiency.+ k: \# O- d' ~4 O
The 11-β hydroxylase deficiency may also result in; Z7 U: C2 N* a$ J5 } ^8 U8 j9 b
excessive adrenal androgen production, and rarely,
+ K$ m9 }* r) S+ P3 Ian adrenal tumor may also cause adrenal androgen5 Y- X( k$ r* ` h& a
excess.1,3
" n: }# u; T. _& Iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 r1 r" h8 _8 L. v542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
% ]" A- B! u. j4 yA unique entity of male-limited gonadotropin-
5 k8 q- S$ ^7 R7 |& X5 |$ s+ Rindependent precocious puberty, which is also known
( ^0 P2 n2 L/ T, ]as testotoxicosis, may cause precocious puberty at a* S5 b5 L* S( W* V9 X
very young age. The physical findings in these boys
$ b4 C; a$ Y' k5 }8 f7 V) A; ywith this disorder are full pubertal development,
6 R" x+ M1 a" vincluding bilateral testicular growth, similar to boys
4 e0 O5 P" l) i kwith CPP. The gonadotropin levels in this disorder
6 n( T1 D, P7 _" \are suppressed to prepubertal levels and do not show/ T# J* U4 n% J! Y
pubertal response of gonadotropin after gonadotropin-
* O$ e0 d1 s* B' T# B) W* k4 J2 h, vreleasing hormone stimulation. This is a sex-linked6 t6 X7 O1 \% a O
autosomal dominant disorder that affects only
% T& O1 W9 D0 h. amales; therefore, other male members of the family% B, g3 f5 @! I, ^1 E: N2 ~; Z% |: v
may have similar precocious puberty.35 ]% j* L6 e% ?, ~; e5 I5 e; F2 ?$ B
In our patient, physical examination was incon-1 g' v. _, h5 G/ O
sistent with true precocious puberty since his testi-- t& k& l) Y# o" A+ C
cles were prepubertal in size. However, testotoxicosis, n+ x. U' f0 \5 K
was in the differential diagnosis because his father" c2 L& }& y l1 ?1 v& a
started puberty somewhat early, and occasionally,# ]! c2 x) b7 @3 n( G8 Q: ~
testicular enlargement is not that evident in the. v1 \+ D8 i, y% ?
beginning of this process.1 In the absence of a neg-
) i# S7 Z$ D2 l0 ? o$ qative initial history of androgen exposure, our
& ?' O* g, j9 l9 rbiggest concern was virilizing adrenal hyperplasia,* Z+ g' W: C2 W) s
either 21-hydroxylase deficiency or 11-β hydroxylase
! t8 g. F/ s7 {- x% C, Ndeficiency. Those diagnoses were excluded by find-
- P( r* P5 ^, T7 _' y* Zing the normal level of adrenal steroids., p9 C6 v: i6 F
The diagnosis of exogenous androgens was strongly
$ s. F) U, l, Psuspected in a follow-up visit after 4 months because' p% V- J" m. Y9 k2 \; C
the physical examination revealed the complete disap-6 h$ B6 b1 c# R6 a; H& h
pearance of pubic hair, normal growth velocity, and* l" ]# F. S0 f$ Z. ^1 r
decreased erections. The father admitted using a testos-
4 B- l7 f6 C) X' S4 I- f! ?terone gel, which he concealed at first visit. He was: U3 D& p9 x/ j0 K% y) \7 C" \
using it rather frequently, twice a day. The Physicians’
7 {& ~9 }9 B& K( Z3 X7 EDesk Reference, or package insert of this product, gel or( p* Q( Y, [" f& c# T# N
cream, cautions about dermal testosterone transfer to
$ _5 w; E* m/ }# Ounprotected females through direct skin exposure.! L" e6 p# D% L$ P+ O' Q
Serum testosterone level was found to be 2 times the
8 R% g# b5 N# M$ u& ]/ [baseline value in those females who were exposed to2 X; _/ g2 v8 L1 X! D b& |
even 15 minutes of direct skin contact with their male
% J( {+ Q8 y: R) Y0 ~partners.6 However, when a shirt covered the applica-
7 g% u' h/ Z- o8 G4 ltion site, this testosterone transfer was prevented.; _. F3 `. W \6 K% B: q
Our patient’s testosterone level was 60 ng/mL,6 N3 B# J: |" T# [/ {- y' l6 u) G
which was clearly high. Some studies suggest that
0 ~5 ~" n3 A1 @6 tdermal conversion of testosterone to dihydrotestos-
/ K5 x# g6 w+ Q1 tterone, which is a more potent metabolite, is more
. @4 b: r( i: E% ~" y. U+ ~% h8 d7 mactive in young children exposed to testosterone
: }5 N: ~$ C4 `# r: nexogenously7; however, we did not measure a dihy-8 u7 n0 O* W0 a- V9 ?5 u9 n, J4 b( m9 r/ z
drotestosterone level in our patient. In addition to
t1 ~' r. Y; o7 ^* M- \+ tvirilization, exposure to exogenous testosterone in
1 f# m+ A; r1 J l/ Schildren results in an increase in growth velocity and6 a% C1 ~- }( r: m% p
advanced bone age, as seen in our patient.
2 F3 L: ~9 \/ O! Z6 G5 ^7 q5 lThe long-term effect of androgen exposure during7 v9 h( t" t5 q y4 \- T" Q6 ~
early childhood on pubertal development and final/ H6 P* P6 J; _" b& h# t: J
adult height are not fully known and always remain5 J# J- X3 c& s0 n9 `( k
a concern. Children treated with short-term testos-
, s) D5 e1 x Y: mterone injection or topical androgen may exhibit some
/ \2 i- b5 |2 P( Uacceleration of the skeletal maturation; however, after. M C, Y% _2 K" l
cessation of treatment, the rate of bone maturation
& a/ R D! b# V hdecelerates and gradually returns to normal.8,9
$ |. Z* j! X- K% o' }There are conflicting reports and controversy/ v( @( {: Q' s1 K
over the effect of early androgen exposure on adult
: s( S% @9 J! ~- e* t E7 T* [penile length.10,11 Some reports suggest subnormal
- j; K0 h$ T4 Dadult penile length, apparently because of downreg-/ l( M% y7 u/ U! F! b
ulation of androgen receptor number.10,12 However,
9 r5 @' f1 j5 q. tSutherland et al13 did not find a correlation between M4 u7 ?. X5 d2 _# n" F
childhood testosterone exposure and reduced adult
4 v! `: x7 [, f$ Y# r+ x2 apenile length in clinical studies.
# S7 j! f# i/ |' H0 n: xNonetheless, we do not believe our patient is' i5 o& ]3 L; f6 `
going to experience any of the untoward effects from
1 L0 l) \9 Y4 S* O* ^* V- Ltestosterone exposure as mentioned earlier because- }6 m4 l' n3 Z/ F
the exposure was not for a prolonged period of time.
* S* _" C9 U, cAlthough the bone age was advanced at the time of) y) T6 P6 l! X8 g1 f' s
diagnosis, the child had a normal growth velocity at& A/ ]8 n3 O% m
the follow-up visit. It is hoped that his final adult$ g7 _* }) N& y& r: ]' _2 R+ p
height will not be affected.2 R' Z; w: R4 V& `) q
Although rarely reported, the widespread avail-% {9 Y* m7 t2 b# m# G
ability of androgen products in our society may/ `3 f- s/ c' r0 m
indeed cause more virilization in male or female4 C9 y+ _- U2 N+ I0 [
children than one would realize. Exposure to andro-6 q' h2 {; W# y: c
gen products must be considered and specific ques-
& k, P+ w* v! a9 B) ztioning about the use of a testosterone product or* i8 H0 C& e' u5 H1 C
gel should be asked of the family members during- l8 _+ X* j( }' I- b1 @- X
the evaluation of any children who present with vir-
* C8 }, W! `6 i/ o5 wilization or peripheral precocious puberty. The diag-: u2 C% L# z x$ E
nosis can be established by just a few tests and by
9 G" x1 {/ P" P( \ }+ {; Yappropriate history. The inability to obtain such a6 j# k: g; u; W3 w8 }
history, or failure to ask the specific questions, may- C3 ^, Y# h; r4 K% ^0 v
result in extensive, unnecessary, and expensive
, @2 U! k9 L2 S8 C8 H7 y, Dinvestigation. The primary care physician should be
7 z4 H( j/ t' _9 J+ Z! R. V( aaware of this fact, because most of these children* x5 |6 c) T' ?
may initially present in their practice. The Physicians’
) A7 z p: q8 j4 R0 HDesk Reference and package insert should also put a
) Y F# z$ `7 q) jwarning about the virilizing effect on a male or
9 b: P) _2 _$ [3 tfemale child who might come in contact with some-
& z) ] u3 s" ~7 uone using any of these products. s0 ]" X6 c9 S) Q/ s6 z# M
References
0 E4 D9 ?! C1 c5 K: B. X1. Styne DM. The testes: disorder of sexual differentiation
7 Y) i% i$ W, T3 B, m4 k& L4 N6 nand puberty in the male. In: Sperling MA, ed. Pediatric
. W/ I4 }8 N$ ^4 N% DEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; r4 F$ b7 ?4 x( f
2002: 565-628.7 k; c$ k4 r( h& O$ \0 o3 I
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
, {% y' K5 L/ T( S e5 [ z8 bpuberty in children with tumours of the suprasellar pineal |
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