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Sexual Precocity in a 16-Month-Old6 y# Y) `' k% v; A) V# b
Boy Induced by Indirect Topical0 A/ \, P; U" P: Y$ ?" r7 W
Exposure to Testosterone
* F3 s" K. ^% zSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2. X; y, d8 c; u
and Kenneth R. Rettig, MD1, I& P4 n3 x7 r% `8 K3 b& e
Clinical Pediatrics7 K1 q) [, f8 L
Volume 46 Number 6% B+ V2 {" n/ s1 D
July 2007 540-543
$ {) p- E2 J0 T© 2007 Sage Publications5 b& S' _0 ~0 \8 k. h
10.1177/00099228062966518 H, I Q6 O: Z* z6 R
http://clp.sagepub.com
; B0 q! L- R1 [3 M! C$ H5 ohosted at3 b; j* e& _9 W
http://online.sagepub.com
0 Y9 ?7 B5 ~9 P2 K9 T0 G1 ^4 w& VPrecocious puberty in boys, central or peripheral,# }! `8 A% G& `" p: P8 g* ~4 i
is a significant concern for physicians. Central
8 S. B. I( `! W2 hprecocious puberty (CPP), which is mediated6 o& U" B: f- S+ T1 f3 o2 ?& @' q
through the hypothalamic pituitary gonadal axis, has
$ P1 f* U8 z* M) o9 v2 j( qa higher incidence of organic central nervous system. G; `6 U, |, o( f# l' c8 [* K9 o) \) o
lesions in boys.1,2 Virilization in boys, as manifested* I, v4 X+ a% d# |
by enlargement of the penis, development of pubic
$ I: h" v: Y, U$ C( a0 e- jhair, and facial acne without enlargement of testi-! \& S" t3 O" r6 l$ t
cles, suggests peripheral or pseudopuberty.1-3 We0 k7 M' ?3 j/ o& B. K- Y
report a 16-month-old boy who presented with the4 Q1 M. }- J$ h
enlargement of the phallus and pubic hair develop-, [7 X% U' w4 z8 J7 U6 C: w
ment without testicular enlargement, which was due+ ~6 `$ h' @/ ], g
to the unintentional exposure to androgen gel used by
# q4 R: m6 S; s, {( ?the father. The family initially concealed this infor-+ r8 z8 Q' k: b: Z. s I
mation, resulting in an extensive work-up for this7 o7 d- @+ H$ k& ~, ]! S7 ~
child. Given the widespread and easy availability of
c# a8 V3 R# X9 `$ Htestosterone gel and cream, we believe this is proba-* q- y# Y9 C3 q- l& J* {& W B
bly more common than the rare case report in the
7 U) P ]$ {4 j: l( M! W6 ]0 W' Yliterature.4
8 K. {* i. q6 T. VPatient Report
! ? \0 \& T5 ~) ^0 NA 16-month-old white child was referred to the" w- t$ R, X* E0 p9 O/ v
endocrine clinic by his pediatrician with the concern! |! ^% m7 ]2 n; k9 N2 m% Q
of early sexual development. His mother noticed
4 D% U3 S7 X3 F/ u7 U9 g# Z; blight colored pubic hair development when he was
# S3 [# e3 l2 Z, q9 \; u0 a) qFrom the 1Division of Pediatric Endocrinology, 2University of- y0 L. k3 a7 v) s
South Alabama Medical Center, Mobile, Alabama.8 o8 T7 j; T& {* y; c: E2 q
Address correspondence to: Samar K. Bhowmick, MD, FACE, ?) m# F5 N9 v0 |; E
Professor of Pediatrics, University of South Alabama, College of' r- I0 {: H2 V5 `" s
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 R! g. c* i& e7 Y( v3 y; |) E
e-mail: [email protected].
; g- `- Y5 p3 o; kabout 6 to 7 months old, which progressively became" `8 C$ T, q: L F+ K- I' R8 }0 C
darker. She was also concerned about the enlarge-7 J' s8 F- C. T' @8 o5 ]
ment of his penis and frequent erections. The child* a3 E: X, c2 m. a
was the product of a full-term normal delivery, with7 d$ x. B# Y U+ |; h# b
a birth weight of 7 lb 14 oz, and birth length of0 m' T; W. x2 x. d7 E
20 inches. He was breast-fed throughout the first year
/ F1 B+ t3 j# Q7 s2 {2 Fof life and was still receiving breast milk along with
- ]* I: O% }9 ksolid food. He had no hospitalizations or surgery,! X1 m: z' @% _4 F! M- k& t
and his psychosocial and psychomotor development
9 V* x4 z; }! L* ]5 `was age appropriate.0 S, R I g& Y" a
The family history was remarkable for the father,. J$ D& u+ o3 I! W' I* z
who was diagnosed with hypothyroidism at age 16,1 N6 a6 o: a% h
which was treated with thyroxine. The father’s
' u% @4 R3 P3 c2 T* `; _ f3 z7 z" Sheight was 6 feet, and he went through a somewhat
& T5 R0 m y7 z( g* qearly puberty and had stopped growing by age 14. v' ~9 @8 |( E' H0 H/ A# |" @: B
The father denied taking any other medication. The6 O, u8 O3 [( B. E
child’s mother was in good health. Her menarche; n6 ?9 |3 k" e5 ]4 @
was at 11 years of age, and her height was at 5 feet' A( I6 v4 U) N' C S9 R
5 inches. There was no other family history of pre-
3 V" _% s& K) Y2 m( j' ~cocious sexual development in the first-degree rela-; S# l2 |1 |9 g0 M9 _
tives. There were no siblings.( Y6 j E+ q, b* j0 V' W! X
Physical Examination
5 [6 M2 P$ D, `0 O' w' C( lThe physical examination revealed a very active,
, ~" F! Y7 G4 j1 Oplayful, and healthy boy. The vital signs documented
0 I; X; |4 h* z* m0 sa blood pressure of 85/50 mm Hg, his length was
2 S5 Z) Q1 {" N; O0 Z/ ?90 cm (>97th percentile), and his weight was 14.4 kg( x+ r- p1 B5 J! L9 A, N) a
(also >97th percentile). The observed yearly growth
1 B6 Z8 q( x( U" l& @* A2 vvelocity was 30 cm (12 inches). The examination of
+ J3 N' _) g) p1 athe neck revealed no thyroid enlargement.# @' h5 R% W& C" \- y- W) K
The genitourinary examination was remarkable for& u1 b1 s+ J6 h7 ]' o
enlargement of the penis, with a stretched length of& T+ d+ \- I1 b- _# Y/ `" c6 l
8 cm and a width of 2 cm. The glans penis was very well
+ I" w0 i2 l0 L* \developed. The pubic hair was Tanner II, mostly around7 H5 H# _1 `$ H, j; n! m
540
/ B# i2 O; v% B. j7 Bat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from' N B" a( j+ [8 j' G
the base of the phallus and was dark and curled. The* J2 m! h6 W( X* v
testicular volume was prepubertal at 2 mL each.1 I2 T/ l ]: D8 Z
The skin was moist and smooth and somewhat
/ {9 s& ~. G( D$ _) F4 ooily. No axillary hair was noted. There were no$ c s+ a- n- P& f9 C& L3 l
abnormal skin pigmentations or café-au-lait spots.
/ {' L0 N- o; T) R) Y; d) r4 pNeurologic evaluation showed deep tendon reflex 2+5 J$ d* l. |# V5 x
bilateral and symmetrical. There was no suggestion( _4 s. X$ p$ E0 p
of papilledema.- v; l5 F- j! T$ F2 X
Laboratory Evaluation
# I! a O' D$ H: `: r& }* w# SThe bone age was consistent with 28 months by" C& i3 B& Y1 G6 s- |4 D
using the standard of Greulich and Pyle at a chrono-
$ s2 g' r$ m. ^+ W6 j1 v+ \" dlogic age of 16 months (advanced).5 Chromosomal: x: i! I, Y& ?' ?. ^
karyotype was 46XY. The thyroid function test# g5 z' B( n# _+ m& q
showed a free T4 of 1.69 ng/dL, and thyroid stimu-' X$ \- Q6 `/ `0 S2 y* n) o! I* d/ O
lating hormone level was 1.3 µIU/mL (both normal).% v/ E+ {" y8 {9 J
The concentrations of serum electrolytes, blood
! p0 Q5 Z! R. kurea nitrogen, creatinine, and calcium all were
- f( u* w/ d2 J! n$ G) m9 owithin normal range for his age. The concentration
& Q) @$ z8 L4 \of serum 17-hydroxyprogesterone was 16 ng/dL
w/ W" ~5 y8 F! N$ R5 _+ Y5 Z7 w(normal, 3 to 90 ng/dL), androstenedione was 20
) f$ h8 G% V" q* h. r" l$ z0 rng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-5 ^- T. O0 ]( _* l5 o
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
Q- ]9 y9 z. bdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
7 f7 m9 c: M+ q2 s w& n1 J49ng/dL), 11-desoxycortisol (specific compound S)
a8 m% I7 ~4 ]$ gwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-3 J# h0 P" r) ]1 r8 c2 U$ v: P4 l4 y4 J
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total" I) `5 O Y3 W) G3 G1 }+ j' O% M' g6 M
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
1 ]% c5 }% f4 S1 I) i* Y4 e% P; Rand β-human chorionic gonadotropin was less than& U* d6 N9 I% }
5 mIU/mL (normal <5 mIU/mL). Serum follicular
j+ a5 T, @# X! W9 I1 @, _stimulating hormone and leuteinizing hormone
3 B7 R i) p) t: S1 S; N/ Pconcentrations were less than 0.05 mIU/mL
( c! `3 J; Y4 J$ b/ H$ X(prepubertal).
- F1 T9 _6 w1 A5 G( TThe parents were notified about the laboratory
8 m8 ]# C1 l7 i& F6 Yresults and were informed that all of the tests were3 [' ?; j. K0 n. j M& ]) B
normal except the testosterone level was high. The
- U% T5 i6 ~8 H5 J) ifollow-up visit was arranged within a few weeks to) V, H/ S' s) D
obtain testicular and abdominal sonograms; how-
2 ~- r3 E+ \2 e6 aever, the family did not return for 4 months., U% |5 d; M+ E
Physical examination at this time revealed that the& o* D* w: ]1 V/ R! j# I: @/ h
child had grown 2.5 cm in 4 months and had gained
' P- D. V0 m. {2 kg of weight. Physical examination remained: p& X a/ |) R0 t" N( e# g
unchanged. Surprisingly, the pubic hair almost com-- z4 e a9 T4 }5 G6 E0 {
pletely disappeared except for a few vellous hairs at2 b/ S0 b% v8 i; P/ b
the base of the phallus. Testicular volume was still 2 i) e s+ D8 h* {) M
mL, and the size of the penis remained unchanged.
0 k7 V1 s6 l$ E, u- h3 @& P6 n, rThe mother also said that the boy was no longer hav-
8 v: O ^- _0 Wing frequent erections.
5 T5 I* U0 m% p! U' H1 @Both parents were again questioned about use of
8 @1 w9 v2 A5 v/ R! O L) Bany ointment/creams that they may have applied to
( ]+ f; F; h+ k$ V9 Bthe child’s skin. This time the father admitted the" z$ {- W. u* J5 Q1 v
Topical Testosterone Exposure / Bhowmick et al 541- Z2 x s1 [5 I' Q( h5 D
use of testosterone gel twice daily that he was apply-
: k' e6 z, e* n; X; Ving over his own shoulders, chest, and back area for
: E1 n- O7 M0 b& X9 ]a year. The father also revealed he was embarrassed
5 F- v' K( } j _% X. b( Z3 rto disclose that he was using a testosterone gel pre-
, t/ G x2 z Q; V# }% T# Nscribed by his family physician for decreased libido
! q2 D! U/ H8 X" Y1 dsecondary to depression.# w! Z0 B' j2 ^
The child slept in the same bed with parents.& T6 O4 E" s' n/ f3 D! y" P
The father would hug the baby and hold him on his
/ `) R; A& ^8 @$ R/ qchest for a considerable period of time, causing sig-2 z! E- p# {# P( D& {% ?
nificant bare skin contact between baby and father.
. a6 T+ O. D: ?$ A% e, YThe father also admitted that after the phone call,
8 v5 \5 [6 |% ]( q2 P, D3 M9 ~% nwhen he learned the testosterone level in the baby
9 a9 W3 |2 Y! |- `) ?was high, he then read the product information
( ~2 {6 M6 R1 E% ~/ Tpacket and concluded that it was most likely the rea-4 p" c+ w8 i6 K% i9 |% C2 ^3 Y
son for the child’s virilization. At that time, they
# H' E8 R4 H" `8 E [decided to put the baby in a separate bed, and the- x( T. ~6 u( I) l
father was not hugging him with bare skin and had
0 e* \ m: s9 Q8 G2 zbeen using protective clothing. A repeat testosterone- F6 R% T1 S* ] @- y
test was ordered, but the family did not go to the
0 m' x9 A( f5 j0 l Flaboratory to obtain the test., }6 \ d7 F2 I& q& t: D: S' G% y
Discussion
( _6 ~/ h$ z' K3 L( fPrecocious puberty in boys is defined as secondary
! L5 m6 D% [6 D; @* s6 o4 \sexual development before 9 years of age.1,4
9 s: }( @$ j# {" W) Y1 X6 GPrecocious puberty is termed as central (true) when
% W: d+ Z3 F( u3 c zit is caused by the premature activation of hypo-9 V% K! f7 e5 c$ R n, {6 G
thalamic pituitary gonadal axis. CPP is more com-
1 C/ m" C. x6 ]# T Q2 K! xmon in girls than in boys.1,3 Most boys with CPP
- s J/ j, m$ [& o8 }8 Kmay have a central nervous system lesion that is i( X0 O U1 Q# H
responsible for the early activation of the hypothal-
w7 i) q1 n9 Eamic pituitary gonadal axis.1-3 Thus, greater empha-
t- H, z# Q6 A( y1 v' jsis has been given to neuroradiologic imaging in/ Q+ Y/ G f* ]9 \7 M
boys with precocious puberty. In addition to viril-: k3 k$ N# M9 Z6 K- |* x3 ]
ization, the clinical hallmark of CPP is the symmet-
% J) s5 ]8 t" q2 u& Irical testicular growth secondary to stimulation by/ t9 e2 n* g' M& e3 O( V
gonadotropins.1,3
' \, M9 {; P8 v S1 f* hGonadotropin-independent peripheral preco-1 {; K! ^% N. }
cious puberty in boys also results from inappropriate
& x+ ^3 Y% l6 c% Q4 A4 {androgenic stimulation from either endogenous or. Q- o. O% m+ r, g% b
exogenous sources, nonpituitary gonadotropin stim-2 _8 Y5 T+ h7 ~3 L3 E* A# D" X
ulation, and rare activating mutations.3 Virilizing
. u9 A- |0 m- H( M0 scongenital adrenal hyperplasia producing excessive
) q1 L1 R; S- C5 w/ q9 H+ a( Yadrenal androgens is a common cause of precocious4 O1 f$ x" R% S& f% G' {1 T: ~& Z
puberty in boys.3,4$ S! P4 M& \6 c& @) m
The most common form of congenital adrenal2 ^' j/ K: q5 J0 a+ v
hyperplasia is the 21-hydroxylase enzyme deficiency.
3 X% O9 d1 W( x% w0 j0 o u( aThe 11-β hydroxylase deficiency may also result in4 [8 z9 P- B" Z) [% @
excessive adrenal androgen production, and rarely,4 K: }) O) ~# v! j
an adrenal tumor may also cause adrenal androgen
% [, p @- l, B5 `& Wexcess.1,3
, v$ Y) c1 ]7 X6 [- Q" O' xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from; n8 N: v+ h& U3 [. m% f
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
( j$ F) R, ]3 j. d) Z @; ], YA unique entity of male-limited gonadotropin-
H4 q3 D4 x1 K* z8 bindependent precocious puberty, which is also known
; {! O) }& I5 K" N. O0 @0 gas testotoxicosis, may cause precocious puberty at a* T E" h# I5 a
very young age. The physical findings in these boys z8 D8 i0 \2 l
with this disorder are full pubertal development,
9 B! e9 \# P1 e) zincluding bilateral testicular growth, similar to boys2 Y4 Q4 F# |- m5 B& w. D( T. r
with CPP. The gonadotropin levels in this disorder
) R8 j- y! D2 [3 R& t& i+ fare suppressed to prepubertal levels and do not show& D+ g+ U9 R# ^8 y" Y
pubertal response of gonadotropin after gonadotropin-
8 R! j1 p \8 O) V( k% f! ^0 wreleasing hormone stimulation. This is a sex-linked
7 I6 [9 K" W8 f- N9 f2 `autosomal dominant disorder that affects only
7 i7 S3 {; a" \* y2 @7 r" }- l; p- Zmales; therefore, other male members of the family8 K- z. N7 D! N9 _6 m4 w1 p2 ]
may have similar precocious puberty.3
1 m1 l% c# U+ D! f7 e2 ]( OIn our patient, physical examination was incon-* `, n5 g, O8 q
sistent with true precocious puberty since his testi- I/ x$ B: I4 I. S) u
cles were prepubertal in size. However, testotoxicosis
$ g i( v% j; ^was in the differential diagnosis because his father! D6 ~% j& F8 Y0 l' n. c" E
started puberty somewhat early, and occasionally,
& ~& J* Y& ?6 b; a8 F- A4 Y) atesticular enlargement is not that evident in the
# T. x N! v. tbeginning of this process.1 In the absence of a neg-
. G9 O1 D$ _. }+ Dative initial history of androgen exposure, our3 a7 B; j2 r: P$ m/ R5 [9 {! {4 P' z
biggest concern was virilizing adrenal hyperplasia,4 O) b1 |1 {! K2 G6 h
either 21-hydroxylase deficiency or 11-β hydroxylase
0 d! O+ |0 u% Mdeficiency. Those diagnoses were excluded by find-
& r9 H7 M/ A) Sing the normal level of adrenal steroids.& e e. F' K4 ]2 ^1 P! |: \
The diagnosis of exogenous androgens was strongly9 R3 O" [# I! ^1 ?; W e& U
suspected in a follow-up visit after 4 months because
' b- X/ y5 W5 Bthe physical examination revealed the complete disap-
O9 a- r& ^: O, y# Bpearance of pubic hair, normal growth velocity, and
1 ~4 \5 `2 X3 C! @) V& f7 i7 p2 j7 ndecreased erections. The father admitted using a testos-/ M+ [+ Q1 x& P C# E2 `6 f
terone gel, which he concealed at first visit. He was
4 n( S7 g. v' H, Y& h ?% R& rusing it rather frequently, twice a day. The Physicians’
* d: t8 j( Z K+ \) d2 k6 W% \Desk Reference, or package insert of this product, gel or
3 x- q+ e; N9 r+ p: |& `/ Tcream, cautions about dermal testosterone transfer to6 ^) B/ H2 r. ]" D7 e$ V2 f
unprotected females through direct skin exposure.
1 M7 ~$ n- b' d( ^3 Q% CSerum testosterone level was found to be 2 times the
9 e& q& q h* U1 l; Obaseline value in those females who were exposed to
+ f9 t, J2 ~- H) Q$ V. K, @; ~8 keven 15 minutes of direct skin contact with their male
, {9 b8 q& G" W+ n0 cpartners.6 However, when a shirt covered the applica-( n" x, v2 Y6 r: ~" o* \' _
tion site, this testosterone transfer was prevented.
8 B) p: k5 \( F/ @4 YOur patient’s testosterone level was 60 ng/mL,
0 _% o3 [! _" m' t |which was clearly high. Some studies suggest that6 i$ Y1 F F: N: p5 Q6 U* \9 _ J: }8 l" b
dermal conversion of testosterone to dihydrotestos-) x L$ ]4 K9 [9 h$ z1 I; w
terone, which is a more potent metabolite, is more5 V0 U+ k) t- t+ ?9 c- ^
active in young children exposed to testosterone
! g8 r1 N: b# \2 Q4 x' rexogenously7; however, we did not measure a dihy-
( m4 t' E- k6 k7 |( ?drotestosterone level in our patient. In addition to/ r# a |& l9 d: e' ~
virilization, exposure to exogenous testosterone in4 H8 j$ q- g# g$ k' H( c
children results in an increase in growth velocity and0 O% z! [# s0 {% Q+ ` |
advanced bone age, as seen in our patient." ~. N& _& t1 s% C) T8 {, [
The long-term effect of androgen exposure during9 n, B# M1 k: n& a" ~& N
early childhood on pubertal development and final' F5 a9 V+ ?- F
adult height are not fully known and always remain9 ]& Y, } v+ s- ~& k
a concern. Children treated with short-term testos-* v. D6 l3 N% h& ^% W
terone injection or topical androgen may exhibit some
9 f8 A. k7 t5 r% [+ Cacceleration of the skeletal maturation; however, after
7 u( Q9 V; v: S, o2 l8 bcessation of treatment, the rate of bone maturation
x. u" ?& f1 S+ }) p- tdecelerates and gradually returns to normal.8,9: q* Z1 s( U7 S/ w
There are conflicting reports and controversy
& K" ?5 m$ m% Cover the effect of early androgen exposure on adult: h+ |. K) x" V% u
penile length.10,11 Some reports suggest subnormal
b( u3 ^* p) f0 L Uadult penile length, apparently because of downreg-
( T& k( m2 a" {2 iulation of androgen receptor number.10,12 However,
3 J+ V$ N6 i+ |2 n3 hSutherland et al13 did not find a correlation between
7 W/ N& O; `' u$ S8 Cchildhood testosterone exposure and reduced adult* Z: D9 S6 Y4 x! R
penile length in clinical studies.8 T! r/ |) \4 ]
Nonetheless, we do not believe our patient is8 y: G2 ^2 K5 j9 I$ ? j' I5 i( J
going to experience any of the untoward effects from
, _' |0 R2 \+ X6 |/ ]+ Q) ~9 Htestosterone exposure as mentioned earlier because, ] E Z* }% A G) U: W
the exposure was not for a prolonged period of time.2 `/ |' ^* T1 i" n- o( `7 w* j6 v
Although the bone age was advanced at the time of
& I: A* x: Y8 W, I* [/ zdiagnosis, the child had a normal growth velocity at
; _# A3 L9 \6 K. n! K; W3 G/ n* U# {the follow-up visit. It is hoped that his final adult9 z: }! P# k* c3 j
height will not be affected.
" u8 c8 j" H2 xAlthough rarely reported, the widespread avail-
& ~7 Q3 n" ]3 Y5 l* E yability of androgen products in our society may+ I; U7 I, z* b
indeed cause more virilization in male or female6 j; s8 S& b- ^- O0 g& N0 E5 E
children than one would realize. Exposure to andro-
; `# P/ o8 x, `' _+ Egen products must be considered and specific ques-: ]' \6 B4 n# B l, [+ Z7 Y e
tioning about the use of a testosterone product or) o/ s9 @" U* q
gel should be asked of the family members during3 n* P% w, H* L$ D: C
the evaluation of any children who present with vir-/ C/ X$ K3 r3 I9 P
ilization or peripheral precocious puberty. The diag-' w. D7 @/ j# C4 c* G, T) X
nosis can be established by just a few tests and by6 ]: |0 q5 y4 f* `
appropriate history. The inability to obtain such a
6 z/ p! }3 c$ |, v6 e9 Ehistory, or failure to ask the specific questions, may
6 Y6 A: U' Q/ z) M/ hresult in extensive, unnecessary, and expensive
7 e5 g- l6 L$ }& zinvestigation. The primary care physician should be
% z8 s" r- h; n- ]1 }1 Raware of this fact, because most of these children( D) k" N' r- r% j& J
may initially present in their practice. The Physicians’
( |: d: H% y( i6 d+ l% NDesk Reference and package insert should also put a
% {6 n2 B* b2 Kwarning about the virilizing effect on a male or
7 a4 h+ R+ x1 [female child who might come in contact with some-
0 {7 v; ?2 D4 W( _- r! V$ {one using any of these products.
) u6 B. d8 X3 H; `5 bReferences
5 E0 D% M4 w1 [9 R1 @1. Styne DM. The testes: disorder of sexual differentiation" X% `5 L* I& j/ u, V) A
and puberty in the male. In: Sperling MA, ed. Pediatric) q$ \' e2 e; w+ Q
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;( j0 w$ P6 c* F0 F
2002: 565-628.3 f r+ k% H; M" c/ p5 f" ?& ~
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
; M/ q! g5 w Z0 h# ^) i2 t. fpuberty in children with tumours of the suprasellar pineal |
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