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Sexual Precocity in a 16-Month-Old) y, {% Z& Y* r2 t4 _
Boy Induced by Indirect Topical
7 y. o: C$ u, h8 A9 zExposure to Testosterone" P) Z6 ^7 l B" p
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
$ M# }: U: | x6 X1 M; z t* y/ Dand Kenneth R. Rettig, MD1
; {' A; _( G9 j0 g2 dClinical Pediatrics
/ Z- g' T& z u3 jVolume 46 Number 6; M* L( l4 h! g" f8 T/ ^8 o
July 2007 540-5431 y9 u# c3 n; E1 l
© 2007 Sage Publications
, G2 P l' u3 Z0 R. S: f3 c9 _10.1177/0009922806296651
n- U/ H* X' Khttp://clp.sagepub.com
! C; g, M' t# ?) ^- C7 J7 r$ e. ?# g: Bhosted at0 ~* R2 Z' ~: E6 E5 b7 z; j5 {7 {
http://online.sagepub.com
1 r; a9 B7 d8 P; uPrecocious puberty in boys, central or peripheral,
! ^$ f: M' _* f* H6 Y" L# ais a significant concern for physicians. Central
! W; \, [& Z8 \/ T0 K: }2 m* {precocious puberty (CPP), which is mediated
% O8 E- e% E+ tthrough the hypothalamic pituitary gonadal axis, has1 _1 u$ g& W4 O$ G' J
a higher incidence of organic central nervous system
! I# ?" T$ E. [2 @. dlesions in boys.1,2 Virilization in boys, as manifested# U5 k/ g) c, n" i
by enlargement of the penis, development of pubic7 T& j3 a4 |- y( l
hair, and facial acne without enlargement of testi-0 G- h8 p. u: I" k
cles, suggests peripheral or pseudopuberty.1-3 We
" Y. _2 a+ N( Kreport a 16-month-old boy who presented with the! _0 i8 q( {" [
enlargement of the phallus and pubic hair develop-
( U: F k( K1 e0 C$ D- V5 ]ment without testicular enlargement, which was due* c6 C6 C; l# R* d9 E6 q- N9 K' `
to the unintentional exposure to androgen gel used by
; h, `* n( L" |/ i3 Gthe father. The family initially concealed this infor-
! v. S. `6 f- Z" \$ emation, resulting in an extensive work-up for this4 L! \9 z* Z: {# J8 H
child. Given the widespread and easy availability of: p6 v& [8 ~9 e& j" w7 m0 m3 n
testosterone gel and cream, we believe this is proba-4 E( r7 w ?0 @, Y, j3 g. Z! H( J
bly more common than the rare case report in the# Z2 Z) o/ B! b' s [/ w, `
literature.4
; T: l Y, [8 |# S1 K. x8 M" [4 }Patient Report, |& e2 Y8 j. C) X& W
A 16-month-old white child was referred to the
0 W% c$ y ]9 S) @' p3 E: ]endocrine clinic by his pediatrician with the concern( v* x, M" ?4 V1 i) Y
of early sexual development. His mother noticed c1 d6 \" v3 k8 l* Z0 }
light colored pubic hair development when he was
% x! m9 M3 a) o+ E* Z. TFrom the 1Division of Pediatric Endocrinology, 2University of2 Y- }7 P% U( L" Y
South Alabama Medical Center, Mobile, Alabama.
* W L! B! R1 } d0 A, {Address correspondence to: Samar K. Bhowmick, MD, FACE,( X' k6 E- b! X3 H! k4 U( u, V
Professor of Pediatrics, University of South Alabama, College of
: j" }5 H$ E+ g+ ZMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;$ C+ P& v/ M7 k& q$ u1 i/ z
e-mail: [email protected].
! M, M4 n% }/ e7 wabout 6 to 7 months old, which progressively became2 p8 ?$ L+ r# g5 q6 g
darker. She was also concerned about the enlarge-
% Y1 Q' o8 a) r! L+ t+ z$ nment of his penis and frequent erections. The child
$ P ^, {: r) b1 {, g6 @& F- owas the product of a full-term normal delivery, with
2 M* N9 M2 \- E, @' V Z! v& K! g' T* ta birth weight of 7 lb 14 oz, and birth length of) \+ I7 @% Y# }/ A0 Q4 ]2 \
20 inches. He was breast-fed throughout the first year
0 U9 o2 X3 G) [8 k' nof life and was still receiving breast milk along with' O& J& f6 `/ X
solid food. He had no hospitalizations or surgery,
/ ~3 Y! K& C5 Q* land his psychosocial and psychomotor development6 h$ D: l3 b" E9 ?1 J
was age appropriate.
2 S! @8 p& ^+ Y( LThe family history was remarkable for the father,9 s$ W ~0 E& M4 Q( M% W! d
who was diagnosed with hypothyroidism at age 16,5 D# G) K' Z) F2 i1 s. `
which was treated with thyroxine. The father’s% y) L2 ^; [. @2 }2 a2 r4 w! A
height was 6 feet, and he went through a somewhat
/ e- b, {* G B; bearly puberty and had stopped growing by age 14.
! J+ n/ D& X2 @1 }The father denied taking any other medication. The$ R8 u1 ?: h* M; p5 U
child’s mother was in good health. Her menarche
6 b' a6 H" V: \was at 11 years of age, and her height was at 5 feet, W1 K9 [3 W/ u( ^8 `( O
5 inches. There was no other family history of pre-
" L$ ]9 u: `+ L$ V& Mcocious sexual development in the first-degree rela- ]; V5 |* F( q4 j f
tives. There were no siblings.
1 d, d! |5 ?! a5 VPhysical Examination
7 Q! W+ J& A. o2 wThe physical examination revealed a very active," a, v2 |$ Z! C J5 q* P* V
playful, and healthy boy. The vital signs documented& O: l; S# Y( J' K3 ]
a blood pressure of 85/50 mm Hg, his length was, L: A' i% B7 o
90 cm (>97th percentile), and his weight was 14.4 kg# y- a6 W$ y" P2 w3 h: z, m
(also >97th percentile). The observed yearly growth
0 m/ E- c" k: Y& C) V3 N: ]( ]: Ovelocity was 30 cm (12 inches). The examination of
; x& D& C, }( zthe neck revealed no thyroid enlargement." S7 o8 C: t1 v* }; f9 |
The genitourinary examination was remarkable for
, P) z" Q- j5 [enlargement of the penis, with a stretched length of" d7 D3 w: L# i, u) L
8 cm and a width of 2 cm. The glans penis was very well
! S# _/ J2 }: a3 f% Y" \" udeveloped. The pubic hair was Tanner II, mostly around* _/ N# c, B$ ?' w
540
' O+ J" g; h% ~/ g2 g% Sat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
4 p: z/ |" f* q4 [; L b! I1 O& Dthe base of the phallus and was dark and curled. The; r/ f) o3 j- K8 [/ m2 h7 P
testicular volume was prepubertal at 2 mL each.
. ?- s; l& V; E1 D' H! qThe skin was moist and smooth and somewhat
6 }6 R& l9 R( q; Joily. No axillary hair was noted. There were no% I/ Q- I5 @9 K
abnormal skin pigmentations or café-au-lait spots.0 g; ]$ b; `& d2 c" D& U
Neurologic evaluation showed deep tendon reflex 2+
8 m; i' A4 i' | P) K' [bilateral and symmetrical. There was no suggestion
1 K _+ \9 J/ p( @' mof papilledema.% c# \9 X) |1 C8 K* C
Laboratory Evaluation
1 O+ J. ?8 H, K" a& d9 wThe bone age was consistent with 28 months by9 |5 g% i. D/ u. ^+ u2 t
using the standard of Greulich and Pyle at a chrono-
( ^" S. a0 o3 X6 T0 e9 n2 `logic age of 16 months (advanced).5 Chromosomal% u3 x2 ^- T- G5 k
karyotype was 46XY. The thyroid function test. Y4 n8 k: s# H
showed a free T4 of 1.69 ng/dL, and thyroid stimu-" N! c( g1 B+ S# {% v6 o( f4 m
lating hormone level was 1.3 µIU/mL (both normal).1 P% c- o0 j L$ {- i3 z
The concentrations of serum electrolytes, blood6 ]3 N# P: l/ K" O# F5 B9 s# b
urea nitrogen, creatinine, and calcium all were2 G& E1 l& h, c9 J- q
within normal range for his age. The concentration6 |& E, g5 [5 r9 L
of serum 17-hydroxyprogesterone was 16 ng/dL" Q# R7 ~( w U7 c2 g* p* ?6 b
(normal, 3 to 90 ng/dL), androstenedione was 20
1 [: e( u* Z5 `2 ] P" [2 g9 Z- N7 ~: cng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-; O$ N' Y# S+ ]4 a4 z4 {8 t X6 k( S
terone was 38 ng/dL (normal, 50 to 760 ng/dL),* A' J1 s+ T4 y8 O' z: z0 x
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
8 ?& z* h& g5 f6 N# x* m7 T49ng/dL), 11-desoxycortisol (specific compound S) M# L$ X. h% ^" t! [
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
; k" f+ l5 S% \; m% h7 i. D3 J% `tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
! |+ q/ s' m4 a8 _; R+ k2 x6 a" N8 [testosterone was 60 ng/dL (normal <3 to 10 ng/dL),, |, R" N6 J8 r5 e' L
and β-human chorionic gonadotropin was less than/ j& v/ D s; Z( l' Z
5 mIU/mL (normal <5 mIU/mL). Serum follicular
* a$ p p+ Q+ [stimulating hormone and leuteinizing hormone
" \4 F# _" o* ~8 I5 X3 e0 oconcentrations were less than 0.05 mIU/mL: q* I2 n( p1 x, z% T M. R1 Z* m1 H* t
(prepubertal).1 Z( A2 Z1 ]# V. z3 X3 c
The parents were notified about the laboratory6 l! k* W+ x3 H9 U& d
results and were informed that all of the tests were, s: C/ H5 D1 `; ~0 I
normal except the testosterone level was high. The. C$ U' K# J+ z4 k
follow-up visit was arranged within a few weeks to+ i ^* U( M7 P5 h6 M8 u* l; Z
obtain testicular and abdominal sonograms; how-
9 {7 I7 b3 _0 ]! `( H4 j" rever, the family did not return for 4 months.
" k4 D+ j% W) H8 y0 g6 NPhysical examination at this time revealed that the
( O. o' B" j+ Y4 F- f. e) X& O/ gchild had grown 2.5 cm in 4 months and had gained
! T- A) R4 {' W& c2 kg of weight. Physical examination remained
% }! n5 R' K# H/ h( \( f2 W( iunchanged. Surprisingly, the pubic hair almost com-
5 J0 {. G* T7 C! Q- l6 vpletely disappeared except for a few vellous hairs at
& C, m$ r, w* m' C* Q4 F" Z" lthe base of the phallus. Testicular volume was still 2
* r! W& h5 E6 @9 { Z5 O$ SmL, and the size of the penis remained unchanged.
1 S+ ^& o. U# m: B5 qThe mother also said that the boy was no longer hav-. T3 @" i t5 z- f2 U
ing frequent erections.
9 O7 {& V8 c/ f1 gBoth parents were again questioned about use of1 D6 y& v% ^: z% f- q0 [2 L W
any ointment/creams that they may have applied to `5 F' A" {4 E
the child’s skin. This time the father admitted the
# B% d7 ~+ D8 F1 t. R# _Topical Testosterone Exposure / Bhowmick et al 541
0 T: y( b; I" |! x* Y. b3 a: [1 ~, zuse of testosterone gel twice daily that he was apply-8 ]) E; M) ^7 K# D: k6 d
ing over his own shoulders, chest, and back area for
4 Q H' Y" f4 n7 P' `. xa year. The father also revealed he was embarrassed& `* ?$ i2 ~3 F# b' \ Z
to disclose that he was using a testosterone gel pre-
6 K8 n; R6 z6 q( v/ Z/ u' h4 Fscribed by his family physician for decreased libido9 X# Y- x7 @2 D- t8 Z+ \7 W
secondary to depression.4 ]5 T) Q- K! i
The child slept in the same bed with parents.
' t2 t% z/ z1 R7 TThe father would hug the baby and hold him on his# I+ q$ m3 l% z4 F
chest for a considerable period of time, causing sig-
! y, A3 f' Q- v' s5 Nnificant bare skin contact between baby and father.
0 V, Y; h @$ B3 ?2 D0 dThe father also admitted that after the phone call,# ?$ i0 k! g6 L' p: _
when he learned the testosterone level in the baby
' H/ G- B. i2 e, Xwas high, he then read the product information
& V2 g/ h6 v* _+ D7 i1 T) ~packet and concluded that it was most likely the rea-5 v6 K6 t3 L3 w( A9 N2 I& c/ @
son for the child’s virilization. At that time, they
! K. N2 k: ^% ~- Y, xdecided to put the baby in a separate bed, and the$ K3 w# \8 U0 h" \% Y6 Z
father was not hugging him with bare skin and had W& t& a) R- d2 D/ n! X+ B
been using protective clothing. A repeat testosterone7 H" q7 k& `; j3 x# j
test was ordered, but the family did not go to the
0 t4 q. ]3 x) x6 c* e, z: D: flaboratory to obtain the test.
6 _+ [9 v; z c1 W' ^5 DDiscussion
6 k1 c# Z" @: j6 ]! w: QPrecocious puberty in boys is defined as secondary
( b6 Y2 D. g, @. g# s" vsexual development before 9 years of age.1,4- t# X- U2 X, v! X+ `3 g3 U
Precocious puberty is termed as central (true) when
+ P) l8 k. U; P+ h4 M i" nit is caused by the premature activation of hypo-( b' T9 W& \8 [( J* J
thalamic pituitary gonadal axis. CPP is more com-. P, W0 l5 N) K9 G. C
mon in girls than in boys.1,3 Most boys with CPP* j) Q! B% ^( j2 V
may have a central nervous system lesion that is
c/ i! n. L* n9 hresponsible for the early activation of the hypothal-
' ?# v2 R6 Y" R, ~+ }$ uamic pituitary gonadal axis.1-3 Thus, greater empha-
0 H, N/ u' d* f4 ^sis has been given to neuroradiologic imaging in8 V; ?5 [* _3 C
boys with precocious puberty. In addition to viril-: X( C0 a' S; |- G& e- [ e: @
ization, the clinical hallmark of CPP is the symmet-
. k3 u1 A7 ?8 b( z+ prical testicular growth secondary to stimulation by l& q& N3 L$ z3 a# O2 |% ^
gonadotropins.1,3$ c$ s$ }) }- ~8 Y1 b& `* S
Gonadotropin-independent peripheral preco-0 K$ R4 `& v6 c9 F5 `
cious puberty in boys also results from inappropriate* e# L4 o, h0 ~* I( D, c
androgenic stimulation from either endogenous or8 W, j. ^! m9 V# Q
exogenous sources, nonpituitary gonadotropin stim-
8 o0 o( y! o$ | }; o( Xulation, and rare activating mutations.3 Virilizing/ q7 J, T: r* W# F8 w& O7 Q
congenital adrenal hyperplasia producing excessive/ r* q8 O" P+ O/ j' R
adrenal androgens is a common cause of precocious( }0 B% i W% y- x/ h
puberty in boys.3,4* x2 u9 {% H& O' t
The most common form of congenital adrenal: Y; U* V* { [4 X) z$ q
hyperplasia is the 21-hydroxylase enzyme deficiency.
* z) d& O* \+ F* x! P/ nThe 11-β hydroxylase deficiency may also result in
& T+ e- m$ a7 o: jexcessive adrenal androgen production, and rarely,# l+ s6 k& I: D. J
an adrenal tumor may also cause adrenal androgen
% k0 R, b8 ~& P6 ~/ Zexcess.1,3# Z: K; V* A! w; T5 t
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
/ ~7 z! b, h2 f5 q6 F% F+ z" w542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
6 a2 h; ?- e/ GA unique entity of male-limited gonadotropin-
8 B, c4 [$ G6 i: {$ V2 |+ G1 Oindependent precocious puberty, which is also known
5 r. q4 G% ^" ^& @' X9 ras testotoxicosis, may cause precocious puberty at a
' E; x, q6 T2 b. t& N. D6 Svery young age. The physical findings in these boys
5 R, K9 A% F: c0 Q$ Gwith this disorder are full pubertal development,
0 X1 v4 J. O' i% ^+ V5 qincluding bilateral testicular growth, similar to boys
0 @- ?) Q7 K/ Nwith CPP. The gonadotropin levels in this disorder) B% [) l5 {4 j u3 S* e- x
are suppressed to prepubertal levels and do not show
/ ^5 L. L1 o! z {9 v0 y( {; }pubertal response of gonadotropin after gonadotropin-! g% f6 d6 n, n- v& V, e
releasing hormone stimulation. This is a sex-linked
7 t, a9 R# I) V6 S+ _8 }autosomal dominant disorder that affects only# H# d) w4 t2 D% H5 A
males; therefore, other male members of the family
3 E. L7 l$ I x9 w5 }may have similar precocious puberty.3
; \! r: b; X% QIn our patient, physical examination was incon-
, K5 j* S; ^1 k+ Asistent with true precocious puberty since his testi-+ q( }3 `5 N2 I7 M
cles were prepubertal in size. However, testotoxicosis) Z3 b" _( j, k0 p- G6 N
was in the differential diagnosis because his father: ], X0 i& _: {7 @4 l
started puberty somewhat early, and occasionally,
$ ~5 |* f8 s' b. h0 O3 X9 jtesticular enlargement is not that evident in the# G# ^' c7 l# v" f
beginning of this process.1 In the absence of a neg-
, @) G! Y* b; V2 x, M! ^, W' Tative initial history of androgen exposure, our; u6 _* i" T4 y& Y/ o. ]$ y2 s
biggest concern was virilizing adrenal hyperplasia,2 v# y. U" V I4 c! ^* `2 @
either 21-hydroxylase deficiency or 11-β hydroxylase
8 K' q# o4 J; qdeficiency. Those diagnoses were excluded by find-
: w! N( i/ k& {1 ging the normal level of adrenal steroids.8 P! W' `- k4 R
The diagnosis of exogenous androgens was strongly
# w' D. t& i% T$ Gsuspected in a follow-up visit after 4 months because
, ~! R) O u+ N* V) Q( _the physical examination revealed the complete disap-! t! ^. m* ?' B) R8 l
pearance of pubic hair, normal growth velocity, and
/ M5 l5 p2 j" ^* A' l3 N7 W* c+ Sdecreased erections. The father admitted using a testos-! x6 ^! F7 b& j' ^8 x3 U- n2 Y: H
terone gel, which he concealed at first visit. He was( O: S: i9 @3 ]' R) v" k
using it rather frequently, twice a day. The Physicians’
8 V3 O# G* A, G1 S" iDesk Reference, or package insert of this product, gel or* l* J7 I a. G8 T
cream, cautions about dermal testosterone transfer to1 d S3 {, ~: j
unprotected females through direct skin exposure.8 X9 {; E) e U
Serum testosterone level was found to be 2 times the* u$ K8 C9 q. u
baseline value in those females who were exposed to; b. Z0 ]* P' K! P0 m7 @8 U
even 15 minutes of direct skin contact with their male$ o: M' x) Y- c l+ ]
partners.6 However, when a shirt covered the applica-
# w9 e. L# t+ Q. btion site, this testosterone transfer was prevented.! F7 z; i* } A% P0 i% @
Our patient’s testosterone level was 60 ng/mL,
9 ?$ b% J5 [ C3 ?* H! V2 awhich was clearly high. Some studies suggest that
0 X- `6 o- l1 C- a5 Mdermal conversion of testosterone to dihydrotestos-
/ V6 a/ q. z0 u4 z# B8 Oterone, which is a more potent metabolite, is more
9 i# d; e& r6 p% x# i1 ?active in young children exposed to testosterone
! r% m) Q0 w* o' J4 ], V0 |exogenously7; however, we did not measure a dihy-; O7 E9 e3 z4 x5 ?6 u$ t. v4 v
drotestosterone level in our patient. In addition to
% Y8 S, e/ x/ s8 a. [& U% C. @0 Fvirilization, exposure to exogenous testosterone in9 ^% K( ]+ @8 D) D7 f. u* J; @- x
children results in an increase in growth velocity and
( Q! J7 B! s; E4 T' D1 ladvanced bone age, as seen in our patient.. O- c9 t2 n4 x8 ~# O; q3 `! H
The long-term effect of androgen exposure during
* G0 ^' P$ ?% k- T, v4 X+ Bearly childhood on pubertal development and final
+ O% E6 L9 Q$ m/ }7 _9 Oadult height are not fully known and always remain
; j9 k" p: ?2 da concern. Children treated with short-term testos-
: z; f6 X9 G$ y1 d$ M9 _. Qterone injection or topical androgen may exhibit some6 o, b! g9 b& R. w
acceleration of the skeletal maturation; however, after( I8 U3 u( K' P3 c& t" t
cessation of treatment, the rate of bone maturation v7 V& ~/ a+ f% d, q. }
decelerates and gradually returns to normal.8,9
8 |! F2 b1 [5 |) i9 ]( x" m4 a* pThere are conflicting reports and controversy
3 K+ e" P, m1 t j, O, K; }1 D$ mover the effect of early androgen exposure on adult
' R9 ^" A8 m1 e! Q& tpenile length.10,11 Some reports suggest subnormal/ K _+ t+ f) ^' t& I
adult penile length, apparently because of downreg-1 \2 j# `' }5 S- G! j, h2 c6 r$ h
ulation of androgen receptor number.10,12 However," L& `; h/ g9 h0 K: }
Sutherland et al13 did not find a correlation between- U7 v8 Q# W# |, i1 h' ~& m$ O
childhood testosterone exposure and reduced adult, Z# q9 f8 S7 F
penile length in clinical studies.
) o( X! n/ I: R0 ONonetheless, we do not believe our patient is3 Q& r( ~$ {/ ]+ n* y" z
going to experience any of the untoward effects from2 I- T3 R, y: z, L
testosterone exposure as mentioned earlier because
7 e" w) C+ t% @$ C3 a9 vthe exposure was not for a prolonged period of time.! S# D% \' h5 {2 K2 X
Although the bone age was advanced at the time of
# v" a/ w$ q7 @" Gdiagnosis, the child had a normal growth velocity at- ?! \0 C* z/ U8 T9 j9 ~
the follow-up visit. It is hoped that his final adult
% p9 E. _( _: N& N# @7 Wheight will not be affected.
j7 n6 t$ @ @. o. hAlthough rarely reported, the widespread avail-* y% W) }& V& U4 ]
ability of androgen products in our society may
$ O1 e& L& `7 k: b" Y3 x, e# \indeed cause more virilization in male or female; }- v" y. X* q
children than one would realize. Exposure to andro-
# h/ f6 v" m5 z% E. y7 {+ o3 Sgen products must be considered and specific ques-
% \+ ?+ i; E1 q& j' \tioning about the use of a testosterone product or1 P; m& q- Z! e8 |; |
gel should be asked of the family members during$ L0 \: D/ q1 H: ] o4 g7 E
the evaluation of any children who present with vir-
5 }* i* c; K6 A6 L* O4 v, p7 lilization or peripheral precocious puberty. The diag-3 _7 ~ `% U. k
nosis can be established by just a few tests and by
: J, s( `% |3 `" b6 iappropriate history. The inability to obtain such a1 w9 _! b( o$ O% i
history, or failure to ask the specific questions, may6 \7 R/ |; B3 J, J; L' H5 \
result in extensive, unnecessary, and expensive
- ^ z6 ~$ o4 K- ginvestigation. The primary care physician should be
+ K. M+ i8 ]0 S) e8 Haware of this fact, because most of these children) a' g8 {9 Z- T# D
may initially present in their practice. The Physicians’
5 T# F5 f' y- n) ~. PDesk Reference and package insert should also put a5 U7 |9 v% X1 j( N9 t" x
warning about the virilizing effect on a male or$ q0 C, W0 Q! h
female child who might come in contact with some-
" O+ h- L7 l, i" E4 B1 y( Zone using any of these products.% ?5 V, C) H' a6 [* A
References2 Z3 ^3 ~/ d/ `- n# N
1. Styne DM. The testes: disorder of sexual differentiation
* W( M9 l$ l( x$ V7 K5 Xand puberty in the male. In: Sperling MA, ed. Pediatric
# F) `: c6 O$ ~) ^Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% k( ~7 `6 e. r
2002: 565-628.3 q' _9 |$ z; _ Q2 j- s+ _! |* k8 C
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious- J: Y6 D# [8 G
puberty in children with tumours of the suprasellar pineal |
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