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Sexual Precocity in a 16-Month-Old
9 M6 _! {1 S2 e$ v( xBoy Induced by Indirect Topical
1 G6 U! F3 E/ E% [Exposure to Testosterone
8 a5 p+ ], h* M* H, x. C9 Y9 V. [Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
. H: b' a& U0 I' _6 o: a$ ?6 Fand Kenneth R. Rettig, MD1
: L5 U2 z8 L2 M& KClinical Pediatrics$ s. [/ s# `" H% T
Volume 46 Number 6
9 n) U! _4 ]- W; K" DJuly 2007 540-543 t; A3 L0 T: o1 m
© 2007 Sage Publications1 U- \$ p! T; }* Y3 V0 v1 J" ?) B
10.1177/0009922806296651
6 p0 S+ g6 ?. s; q h: A! B" L/ i% C6 ehttp://clp.sagepub.com
# F: ]4 g$ A- f3 Shosted at
- `- j2 V9 S! m+ j, qhttp://online.sagepub.com
5 N; b9 d. S9 r% ?5 kPrecocious puberty in boys, central or peripheral,$ h6 ]# @8 ~& v
is a significant concern for physicians. Central" n8 s9 t& O6 n$ n& B
precocious puberty (CPP), which is mediated
- |% Y4 y Y) k9 Ethrough the hypothalamic pituitary gonadal axis, has
7 V3 M4 P; ?* |1 X+ Va higher incidence of organic central nervous system, }/ ]( q0 |/ x, ^) c' i+ s
lesions in boys.1,2 Virilization in boys, as manifested
" \% S! C6 `0 n; X: {) [by enlargement of the penis, development of pubic
5 z3 p V0 m- j8 whair, and facial acne without enlargement of testi-" K! q! s" |/ ~
cles, suggests peripheral or pseudopuberty.1-3 We, ~9 ?( U7 T; o5 J# `) w. s, l7 o
report a 16-month-old boy who presented with the
# Y' z: e6 |: R' j9 `8 Qenlargement of the phallus and pubic hair develop-
7 O7 \: p4 I2 |1 D# ]2 C/ F6 V# }+ Ament without testicular enlargement, which was due3 M, Y' ?1 H( q: c/ F
to the unintentional exposure to androgen gel used by" b; e! x5 k) f6 a
the father. The family initially concealed this infor-5 R# R6 r L' P, J
mation, resulting in an extensive work-up for this& x. s; S2 ]4 Z' @; Q
child. Given the widespread and easy availability of
$ K" J0 N7 @7 {: Z W6 P! Ptestosterone gel and cream, we believe this is proba-6 U {( X0 n; H/ t+ P6 Z9 j
bly more common than the rare case report in the1 }1 e" [% ]' }% q) h" \
literature.4
+ M9 s- d4 h5 l. bPatient Report
y$ ^3 W1 |0 y) ]4 L5 pA 16-month-old white child was referred to the
. m# N9 g a) j: |5 `* dendocrine clinic by his pediatrician with the concern
2 t9 Z5 ?' f' e% \2 Dof early sexual development. His mother noticed. e5 B7 V& N5 E; @( {1 ?: }
light colored pubic hair development when he was
. p- ~7 n- J# F0 s4 H EFrom the 1Division of Pediatric Endocrinology, 2University of
+ ?! m, ^" \2 K0 f- T6 n! ?% rSouth Alabama Medical Center, Mobile, Alabama.
& K0 Q5 d/ m4 ^: _* x. _$ IAddress correspondence to: Samar K. Bhowmick, MD, FACE,: S8 E6 n7 R2 e: [: Z
Professor of Pediatrics, University of South Alabama, College of' b' S. {3 [, d: D& g
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;. v+ q, M3 ~6 |6 V! u# }) C
e-mail: [email protected].# q/ x6 ?- x9 I. i# w0 E
about 6 to 7 months old, which progressively became
8 m! k( U4 c$ udarker. She was also concerned about the enlarge-' b/ O g/ O+ z% Q: G3 m: h
ment of his penis and frequent erections. The child% A+ B9 v1 F: [
was the product of a full-term normal delivery, with
: y! |' x* g3 C3 @6 [* ia birth weight of 7 lb 14 oz, and birth length of
5 q1 P$ C; h& w( X20 inches. He was breast-fed throughout the first year4 Y+ F4 s- R+ H
of life and was still receiving breast milk along with
+ n) T6 x( O4 |. }% {8 U& a8 Tsolid food. He had no hospitalizations or surgery,
& o$ E% j3 e6 q3 }" B8 K1 i, x3 Dand his psychosocial and psychomotor development
+ { k$ G+ B/ qwas age appropriate.1 D& a4 Z) s+ E/ ?0 }# Q2 J
The family history was remarkable for the father,, t/ C1 R2 R# `( n- M- u
who was diagnosed with hypothyroidism at age 16,
9 K' q" p2 g+ u# Ewhich was treated with thyroxine. The father’s
& @" k8 p+ l7 ^1 Bheight was 6 feet, and he went through a somewhat
& j+ P: ]% X2 s0 g) j2 Bearly puberty and had stopped growing by age 14.
2 d0 k4 A$ c2 b% N. f" p7 `0 j" iThe father denied taking any other medication. The
0 U# T- y1 t$ l/ [2 [child’s mother was in good health. Her menarche
# w: s) s% H! k2 x0 a: s0 Y$ kwas at 11 years of age, and her height was at 5 feet
/ F% V6 G+ N+ d! x$ V( j5 inches. There was no other family history of pre-$ L# U: y: P* x' ?( s
cocious sexual development in the first-degree rela-. w5 C* ?( D; E2 N! ^: u9 j
tives. There were no siblings.: @+ [ W8 g2 o; W
Physical Examination: ?1 [% Z- ^& Y% m+ ^" G3 Z8 R
The physical examination revealed a very active,/ Q& X5 a) j! H9 k4 f
playful, and healthy boy. The vital signs documented
- n1 _3 I. c+ N1 Aa blood pressure of 85/50 mm Hg, his length was2 {3 T3 v" {% f# T" F
90 cm (>97th percentile), and his weight was 14.4 kg
5 ]( _0 Q2 C. L; X& M(also >97th percentile). The observed yearly growth
) Q, W, a4 o) m0 w) T; Dvelocity was 30 cm (12 inches). The examination of% b$ c' e' B6 P3 W4 k+ r, W3 D
the neck revealed no thyroid enlargement." z5 D2 F1 j9 z) e4 E5 B7 |& f
The genitourinary examination was remarkable for
4 A% h3 L, z! \& kenlargement of the penis, with a stretched length of7 s9 d' m3 W: S) y( C8 y9 G
8 cm and a width of 2 cm. The glans penis was very well% B, ]$ F b: R1 e
developed. The pubic hair was Tanner II, mostly around
1 R9 x9 J: p6 m, {/ y540$ W! i' ^1 H( W
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
; s& D" \% V! S$ `/ Y2 ~the base of the phallus and was dark and curled. The" n/ B' L9 T0 G
testicular volume was prepubertal at 2 mL each.2 A; q1 n# G- y
The skin was moist and smooth and somewhat
2 B( e3 L1 q! Doily. No axillary hair was noted. There were no) d3 b: J+ G; I, W0 ?0 O
abnormal skin pigmentations or café-au-lait spots.
9 ]* T6 C# D1 _Neurologic evaluation showed deep tendon reflex 2+
1 e! b5 C. N4 D" C* g1 zbilateral and symmetrical. There was no suggestion
" l- m M' X' s2 `3 Dof papilledema.8 U4 q/ E! i0 t/ P7 m5 X+ v5 l( k8 b
Laboratory Evaluation! Z4 I y2 N) x0 W$ C1 [* P, D
The bone age was consistent with 28 months by
, O* b0 [* z! `5 T7 r3 Z4 uusing the standard of Greulich and Pyle at a chrono-
4 v. g0 p/ w g5 z6 F& Slogic age of 16 months (advanced).5 Chromosomal
3 D: Z3 K3 ?/ {+ Xkaryotype was 46XY. The thyroid function test
$ \& h) V$ X9 ]+ F- V" L3 Lshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
{ a/ [- \' Wlating hormone level was 1.3 µIU/mL (both normal).
9 I8 W: A: [; mThe concentrations of serum electrolytes, blood
' `; U! d% N4 A' ^urea nitrogen, creatinine, and calcium all were
" S( D, h" l) z4 e% iwithin normal range for his age. The concentration' f0 [3 M3 y$ m- \# ^& d
of serum 17-hydroxyprogesterone was 16 ng/dL. j8 Y" x* |0 W& m/ c
(normal, 3 to 90 ng/dL), androstenedione was 20
5 ~- o' ~6 Q; J$ [ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-8 c% U: K. o* x+ ^! m
terone was 38 ng/dL (normal, 50 to 760 ng/dL),& v0 n% D* P% q8 I0 w* C7 F
desoxycorticosterone was 4.3 ng/dL (normal, 7 to8 I' @' x% F5 `- @
49ng/dL), 11-desoxycortisol (specific compound S)
6 F$ u, F8 I, Jwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-$ ~$ n1 e9 a' |4 t( `( s# e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
* ?* F+ O, z& v8 Z5 l' q( ~" w# Htestosterone was 60 ng/dL (normal <3 to 10 ng/dL),: Y1 t0 w9 c5 j2 P
and β-human chorionic gonadotropin was less than3 m( U$ D _8 h4 V% p d- Z
5 mIU/mL (normal <5 mIU/mL). Serum follicular: E. E6 t9 t- f, S$ e, g
stimulating hormone and leuteinizing hormone0 y% p' K9 p! \6 L3 l: u p E; A$ B; S
concentrations were less than 0.05 mIU/mL
& T, u- y2 W$ }4 ~8 Q4 a) {(prepubertal).
2 J' T1 e w1 W' l. J$ E/ pThe parents were notified about the laboratory
/ ^1 h& Z r N: kresults and were informed that all of the tests were! m* y0 b8 x1 j+ Y
normal except the testosterone level was high. The
+ c L3 f" ~; d% V6 V/ p# Gfollow-up visit was arranged within a few weeks to( S6 ^5 Q% }' e# m
obtain testicular and abdominal sonograms; how-
j" e l8 u& b, c& K$ U; Jever, the family did not return for 4 months.4 U& x# Q4 v8 `$ H
Physical examination at this time revealed that the* e/ J3 V8 @2 k t" p# x
child had grown 2.5 cm in 4 months and had gained$ t/ n. k+ s" ]& \, N
2 kg of weight. Physical examination remained4 J/ Q, f- x8 Y4 _# u
unchanged. Surprisingly, the pubic hair almost com-$ p g: z" c1 ~" B* P
pletely disappeared except for a few vellous hairs at
; E6 ]- a$ V2 J, l0 Ithe base of the phallus. Testicular volume was still 2. f+ j6 c, n% U( O: ^
mL, and the size of the penis remained unchanged. C4 W3 `" u+ P4 K/ |# q
The mother also said that the boy was no longer hav-* S: x& {/ n; }. z# C; U
ing frequent erections.
# [; @6 V3 R6 sBoth parents were again questioned about use of' M3 J2 g p0 G7 y2 q2 h' u. U/ e
any ointment/creams that they may have applied to
/ X4 O5 k2 I+ Kthe child’s skin. This time the father admitted the
7 m) Z2 s5 w; Z" n: FTopical Testosterone Exposure / Bhowmick et al 541' D9 }4 @4 c+ l7 C2 ?6 d% L4 x' v
use of testosterone gel twice daily that he was apply-- a& o7 O' \; T6 C, x
ing over his own shoulders, chest, and back area for
* {" Z- O( L% w5 {* ba year. The father also revealed he was embarrassed3 q1 S5 h0 R: d" W8 Z
to disclose that he was using a testosterone gel pre-
( \4 X- K: B; H) M1 Mscribed by his family physician for decreased libido7 `5 R* U' L. u- O# G9 t4 T9 q
secondary to depression.
( ]" `$ E" N s) ~The child slept in the same bed with parents./ s* N- ?* B! u. Z- N( M
The father would hug the baby and hold him on his' e' K1 s) Z& [
chest for a considerable period of time, causing sig-
2 p$ W6 ~8 C3 T! W- z2 O# Nnificant bare skin contact between baby and father.7 O3 [% f6 b% J+ t. F! @& r. j* a
The father also admitted that after the phone call,) ^0 m1 T9 ^1 u; t. p2 U
when he learned the testosterone level in the baby
! {7 ?8 L2 J: q2 T9 iwas high, he then read the product information" O- J+ `% M9 i- A: F# ^
packet and concluded that it was most likely the rea-
" b! a, r/ n! V% q! vson for the child’s virilization. At that time, they
$ @, o& d$ M. P& Ddecided to put the baby in a separate bed, and the- N/ L+ r( _( P/ r7 |
father was not hugging him with bare skin and had* g$ A) H9 l C- v# A8 U- I
been using protective clothing. A repeat testosterone) M) y. {- l. r( M& G0 {3 e
test was ordered, but the family did not go to the: ]. m& ]' @2 u6 n! M# b% J
laboratory to obtain the test.
) x4 J8 ?; n9 E8 IDiscussion
8 B9 R4 r2 a0 h1 DPrecocious puberty in boys is defined as secondary
& u0 Z# k# u! T7 Y7 b, N" Hsexual development before 9 years of age.1,4
$ V9 h+ p, R; Y- M. _Precocious puberty is termed as central (true) when
9 l, G5 \) D8 V! Z: X5 _it is caused by the premature activation of hypo-. f5 @: a* B% l2 o4 x
thalamic pituitary gonadal axis. CPP is more com-
9 ^: ]) E% g( nmon in girls than in boys.1,3 Most boys with CPP0 _% @( r6 X# i; s# \4 H
may have a central nervous system lesion that is& B& Z/ `: o0 E& r
responsible for the early activation of the hypothal-, C% d) Q* W2 K1 @9 v, g3 ]
amic pituitary gonadal axis.1-3 Thus, greater empha-/ ]$ p+ }5 y, M7 D$ x) w
sis has been given to neuroradiologic imaging in
, a& H5 z2 J% g! A" nboys with precocious puberty. In addition to viril-
% ^: w, }+ L, o6 dization, the clinical hallmark of CPP is the symmet-9 z& U9 H% [1 O2 G
rical testicular growth secondary to stimulation by
$ l3 K, d# W) o% j7 E( dgonadotropins.1,3
8 T/ K! K$ t9 k3 ~9 hGonadotropin-independent peripheral preco-7 r' D7 S# j, |
cious puberty in boys also results from inappropriate/ R3 M1 m- q; o& Z; D
androgenic stimulation from either endogenous or
, ?1 e/ G) o e' nexogenous sources, nonpituitary gonadotropin stim-$ b) C, S: j( `( N" S- r" _; s7 v
ulation, and rare activating mutations.3 Virilizing! }" R% U) ?! U6 E: A
congenital adrenal hyperplasia producing excessive
% c6 {# P* i) J) vadrenal androgens is a common cause of precocious1 r% K) P. E2 l" g
puberty in boys.3,4
" c1 D7 o3 J" k0 L3 h" `The most common form of congenital adrenal" I7 v: S5 b% e: T8 l
hyperplasia is the 21-hydroxylase enzyme deficiency.0 z' M; O, f0 R: _- e( [" t7 \
The 11-β hydroxylase deficiency may also result in
/ G, q: u; [* q0 \5 K+ x8 kexcessive adrenal androgen production, and rarely,! q/ v" c: M- W* c4 r
an adrenal tumor may also cause adrenal androgen7 V1 m7 ?1 ~3 l7 S4 }6 v4 k7 V& I1 T
excess.1,3
- Y: ~/ s" q' Tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
& M3 A9 [. w% S542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 o0 ?- r8 p" Y$ Q0 h: m8 F
A unique entity of male-limited gonadotropin-
+ b) c' _8 v9 I. Jindependent precocious puberty, which is also known& C# l- g( F. d( `2 i" Q; q
as testotoxicosis, may cause precocious puberty at a" q- g3 z% t1 e$ K, R
very young age. The physical findings in these boys4 n: y$ c# F+ Q% K& h# Q2 U9 B
with this disorder are full pubertal development,
! r" `0 ?: d1 S5 Aincluding bilateral testicular growth, similar to boys$ m/ _# X8 U4 s% g6 ~& d0 C& V
with CPP. The gonadotropin levels in this disorder
& ~! ^) u$ q0 @are suppressed to prepubertal levels and do not show
- f2 {" V; H( C; D2 T: K) B) k( fpubertal response of gonadotropin after gonadotropin-/ |! j1 ^2 T/ T- j, c! [" E
releasing hormone stimulation. This is a sex-linked7 Y/ |5 d; x7 ^8 _' J
autosomal dominant disorder that affects only6 V7 Q. A- k4 e
males; therefore, other male members of the family
: L9 L" }$ | R# W1 W' A2 n3 gmay have similar precocious puberty.3
1 y& w( ~* C) u2 a5 @1 LIn our patient, physical examination was incon-
8 T! ^1 {4 s! R$ j8 K/ w; |sistent with true precocious puberty since his testi-2 y9 G% Z! M& x! @, s0 q2 ]0 ?1 @
cles were prepubertal in size. However, testotoxicosis
" D! H: }/ T0 d1 k8 N6 L: d1 A9 Jwas in the differential diagnosis because his father8 x: k w; z" o6 z, |
started puberty somewhat early, and occasionally,9 _) D8 Z: q) `- o! M( V8 ]) o
testicular enlargement is not that evident in the
& y/ _0 E5 \! V& \8 Abeginning of this process.1 In the absence of a neg-
1 ?+ v) M8 \# {. h1 Jative initial history of androgen exposure, our
9 @+ n! [- d% b O- q: nbiggest concern was virilizing adrenal hyperplasia,5 \: V9 d1 n; P) D6 O
either 21-hydroxylase deficiency or 11-β hydroxylase
# K: X9 [; |# f! w# D6 y) d5 Adeficiency. Those diagnoses were excluded by find-
1 K2 u8 w3 O R6 N9 f' ~8 [ing the normal level of adrenal steroids.
* p4 Z! f( X" r# [4 x( GThe diagnosis of exogenous androgens was strongly' ? c3 w/ W& T9 y5 D
suspected in a follow-up visit after 4 months because
, C( ^ V0 H4 v/ T7 ]4 {. Lthe physical examination revealed the complete disap-# H S$ v9 c6 b: r. w
pearance of pubic hair, normal growth velocity, and- \ l% i, ]* b3 S/ @) ^6 g) v
decreased erections. The father admitted using a testos-
( u, \9 _! f, l9 U- V8 c& I/ A f; w' Fterone gel, which he concealed at first visit. He was0 C1 |3 j2 ^2 y' L1 {
using it rather frequently, twice a day. The Physicians’# {$ G# X/ L5 F) K1 Q7 g2 V/ G# S- I
Desk Reference, or package insert of this product, gel or3 x0 s: ^: T* q1 J7 J
cream, cautions about dermal testosterone transfer to/ U3 J5 r4 S1 j' C& E; E( K
unprotected females through direct skin exposure.& i/ E& h; m4 f' D
Serum testosterone level was found to be 2 times the
0 h% g- k+ p- j/ q& H5 Qbaseline value in those females who were exposed to, ^2 J- L0 O$ r3 M8 K( H' s) k% Z
even 15 minutes of direct skin contact with their male
! y9 M2 C6 x) z* R) m# \( L9 V/ \partners.6 However, when a shirt covered the applica-7 f% k- U" l! I0 C- c( w4 S ^2 r
tion site, this testosterone transfer was prevented./ h& j2 [* e8 V
Our patient’s testosterone level was 60 ng/mL,$ ^; F# {& Z7 v, \- V0 q
which was clearly high. Some studies suggest that% {: V; T( O# o! z5 P/ A; J
dermal conversion of testosterone to dihydrotestos-
% n; G# _3 Z8 Z& B3 {+ {* ~8 Gterone, which is a more potent metabolite, is more1 X1 M! ~; d# U1 @+ O R
active in young children exposed to testosterone& {' P8 `/ `2 z) {
exogenously7; however, we did not measure a dihy-) \3 T8 f7 t1 x( F0 s# o
drotestosterone level in our patient. In addition to
: C7 \: S: i( w; b' H. m7 Hvirilization, exposure to exogenous testosterone in* ~& K& g o9 s; Z, u
children results in an increase in growth velocity and( h! H$ Y+ H2 O
advanced bone age, as seen in our patient.
$ Y8 U6 Q9 f8 H" uThe long-term effect of androgen exposure during4 n8 R( w/ o0 T" ^! p5 ~
early childhood on pubertal development and final
3 j C8 |5 Z. u! q! madult height are not fully known and always remain3 d k f9 M5 _) P) B: u1 s9 E; q, t4 d! u
a concern. Children treated with short-term testos-7 {2 g8 W4 @* [. @
terone injection or topical androgen may exhibit some
5 Y! j. U# [4 ~' x. O3 bacceleration of the skeletal maturation; however, after$ u/ X: j/ a( D+ e' X
cessation of treatment, the rate of bone maturation% L6 A- n& q& B) i0 |( j4 a" z
decelerates and gradually returns to normal.8,9" {! g- f! V( ]% C- y
There are conflicting reports and controversy
( s7 k) U/ {# a2 ^( i Wover the effect of early androgen exposure on adult
/ T b9 g5 @! i6 `penile length.10,11 Some reports suggest subnormal
, R* C! Z# K% H: p) aadult penile length, apparently because of downreg-
7 C+ h" B/ |* _; H+ |4 s2 N. Aulation of androgen receptor number.10,12 However,3 _9 x% \# l& x- q
Sutherland et al13 did not find a correlation between
6 W4 C1 O* n2 S0 o# Echildhood testosterone exposure and reduced adult4 i9 U5 b5 j( I B) n a9 u- Q
penile length in clinical studies.
' t% @! K& q# b2 lNonetheless, we do not believe our patient is3 P3 I. K/ l1 |. |" Q U
going to experience any of the untoward effects from
8 e8 S6 ^4 J* ktestosterone exposure as mentioned earlier because( _% L3 W- O7 B+ o2 h% Z
the exposure was not for a prolonged period of time.8 K" ], D: F. K# ]! W( A; F
Although the bone age was advanced at the time of2 I |. g! ~% ?: w) G0 E! m( [
diagnosis, the child had a normal growth velocity at" N( P4 k: i% {9 c8 R5 |( @
the follow-up visit. It is hoped that his final adult7 j9 d2 a& ~+ l. P+ Y; O
height will not be affected.0 Q( B/ G: Q0 _) q, e, w
Although rarely reported, the widespread avail-
1 j/ {, ?) u* vability of androgen products in our society may
+ n5 m$ a! _' N( nindeed cause more virilization in male or female1 ^; x4 P1 P) U; q7 w) E9 O/ J
children than one would realize. Exposure to andro-) T Y$ X; W( Y3 Q
gen products must be considered and specific ques-3 G& ?+ Y: r9 Z- _- R; o
tioning about the use of a testosterone product or
; E! U3 D$ C' B* Xgel should be asked of the family members during* Q- z# r. l. }0 E5 G/ {
the evaluation of any children who present with vir-
$ I4 ]) i K4 m7 cilization or peripheral precocious puberty. The diag-+ q! |" b# |; Y+ A; f
nosis can be established by just a few tests and by4 a1 Z( y2 w8 v5 q% |; ~
appropriate history. The inability to obtain such a9 G# }. F5 M, p0 A6 [' P, C
history, or failure to ask the specific questions, may; C- T ^0 l8 F# v/ |% w
result in extensive, unnecessary, and expensive, e) R9 y+ {& `. \
investigation. The primary care physician should be
' C9 _4 y% |/ B# y3 v$ yaware of this fact, because most of these children4 p3 o0 ~- e, h/ f
may initially present in their practice. The Physicians’3 E; J/ l3 W9 S, A* s/ X: F
Desk Reference and package insert should also put a, j2 J$ z, P& w+ @
warning about the virilizing effect on a male or1 H5 B. i9 k- l8 U/ b4 _& e6 ]
female child who might come in contact with some-* T4 s9 `4 y) d4 B. K( \6 Q
one using any of these products.- E/ {* U& q- \# y$ P1 D/ H7 I
References
+ ~! x* D# U# O& N8 I X" \, @1. Styne DM. The testes: disorder of sexual differentiation8 Z4 f8 M: m( j
and puberty in the male. In: Sperling MA, ed. Pediatric/ n1 F4 R" H8 Q7 z2 s
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;! ?' ]3 d! X3 Z$ I. I
2002: 565-628.
$ z u' t" I* g8 Z4 y2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious; g8 Q( }8 I! ?* Q: i9 ]
puberty in children with tumours of the suprasellar pineal |
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