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Sexual Precocity in a 16-Month-Old
* j6 V4 j# X% g+ W4 XBoy Induced by Indirect Topical
: }1 B R- {+ r6 i5 z9 OExposure to Testosterone
7 t9 \% ^' l# V* V+ X( }5 Y# bSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
8 R7 R7 E9 v; |and Kenneth R. Rettig, MD1) b0 |6 h4 T( g r; A6 |- }0 r
Clinical Pediatrics
' C9 I& c! D0 C- YVolume 46 Number 6
0 E1 u4 ]9 w \2 ?# P- [) m: ^July 2007 540-543
; j4 ]; E2 R3 I+ {8 L- ~© 2007 Sage Publications; L, z, b. N) |' p5 A( a
10.1177/0009922806296651
; T5 L$ {* {; H1 R) F, Q0 M! lhttp://clp.sagepub.com
6 L3 k& d4 ~* y/ X: z8 ahosted at
! j; e/ z* ~% z9 |/ Hhttp://online.sagepub.com
- Z. |9 ]! o0 ]# D. FPrecocious puberty in boys, central or peripheral,
( f9 V( ]6 t( o! y- Nis a significant concern for physicians. Central4 d6 w" A7 h s \3 q( b" B
precocious puberty (CPP), which is mediated
; q/ Y9 ]( h8 R" {/ {' V' sthrough the hypothalamic pituitary gonadal axis, has0 |0 [/ V* }, f0 l; t3 n1 i
a higher incidence of organic central nervous system
8 w( R4 [/ G) }+ `4 Ilesions in boys.1,2 Virilization in boys, as manifested* [! e1 x- L* l- E" V9 j; z
by enlargement of the penis, development of pubic1 C/ S1 p; l4 i7 z- G- s1 _8 O
hair, and facial acne without enlargement of testi-
* n# r. K3 g" ]; V9 i3 rcles, suggests peripheral or pseudopuberty.1-3 We
5 `& N: \$ z' k8 K( Y+ u) jreport a 16-month-old boy who presented with the$ A4 _! t4 i$ h2 ]
enlargement of the phallus and pubic hair develop-
* R' X5 t# v* X1 q* |9 w# T0 ument without testicular enlargement, which was due% L" _1 W; h# p6 I; f/ M4 l8 p
to the unintentional exposure to androgen gel used by. U( ]1 h' Q8 a- s
the father. The family initially concealed this infor-" b+ [5 o+ U. u7 I8 h4 t- p
mation, resulting in an extensive work-up for this
# W. @9 x. Q1 Q: h2 T& Schild. Given the widespread and easy availability of
& |2 U8 Q7 T( |: I* K. z& H, |testosterone gel and cream, we believe this is proba-- a& K' B( o2 ?1 j7 Q3 H% i
bly more common than the rare case report in the3 p) i3 t$ N, {, ~7 H6 u
literature.4
* Q% L+ n, r0 u+ Z# {( WPatient Report
! f+ d. e# P/ C$ P9 _( G' JA 16-month-old white child was referred to the4 W' k. M, x8 h- l) c; X2 p; ]
endocrine clinic by his pediatrician with the concern
; u# F1 b3 U# e5 ]of early sexual development. His mother noticed% @& C; A) [. Y; {2 Y
light colored pubic hair development when he was
4 r$ D( p' _. b M# G, Q) ~From the 1Division of Pediatric Endocrinology, 2University of
- [% O' U( r/ |7 U% LSouth Alabama Medical Center, Mobile, Alabama.9 j5 l9 Z9 A! l1 l4 J
Address correspondence to: Samar K. Bhowmick, MD, FACE,9 Y! ]4 e* Q; R) F
Professor of Pediatrics, University of South Alabama, College of3 j/ ]+ B2 \! }# n" f3 o2 K
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;$ |: b1 I0 j' K# b, f
e-mail: [email protected].& Y, s$ K( \8 v! \8 V
about 6 to 7 months old, which progressively became# v/ C( |$ g3 f8 t
darker. She was also concerned about the enlarge-" g( ]! l& I# s# j G
ment of his penis and frequent erections. The child
' v! @' l; x6 ^# v; k; V- Bwas the product of a full-term normal delivery, with
0 P% Z \. G1 d; f# Ia birth weight of 7 lb 14 oz, and birth length of( Y6 _4 V0 c6 I1 b9 K
20 inches. He was breast-fed throughout the first year
: ?1 A& C v3 Y+ f& g/ bof life and was still receiving breast milk along with
) L* q6 ^% ^' y' `1 |solid food. He had no hospitalizations or surgery,
( e9 Z, D7 k3 H" @) {! I" band his psychosocial and psychomotor development9 M( F3 v M$ l" d) T+ }) d
was age appropriate.
; s: ?, \0 `# F8 ^( P& vThe family history was remarkable for the father,9 k& |. Z4 y9 W! ^8 P; u
who was diagnosed with hypothyroidism at age 16,3 q, [3 E' H: S6 b
which was treated with thyroxine. The father’s
4 f3 j F* H' B1 Uheight was 6 feet, and he went through a somewhat9 C& n0 F+ S8 q$ r
early puberty and had stopped growing by age 14.
& O, \: [- {( {6 X) HThe father denied taking any other medication. The
) v8 B: l6 \- schild’s mother was in good health. Her menarche
! ]7 _: K; Y; O% l# g0 [; twas at 11 years of age, and her height was at 5 feet4 l: b2 S' g# x
5 inches. There was no other family history of pre-# ?/ q1 f! u. |- M
cocious sexual development in the first-degree rela-
8 Z( G# f b4 Ttives. There were no siblings.5 |* a# b& C* s& l* A8 O
Physical Examination
! L. ~6 `- ?" y2 R0 L: ~& ZThe physical examination revealed a very active,
. J, W' U* Y/ j, Q. Iplayful, and healthy boy. The vital signs documented6 ]& ^: G) h" f e% t5 I+ x- |
a blood pressure of 85/50 mm Hg, his length was! v, G/ E1 W# L5 a% Z
90 cm (>97th percentile), and his weight was 14.4 kg
) k7 ?1 L4 p7 q' Y. w(also >97th percentile). The observed yearly growth
- ~2 B4 H; Y/ p2 `4 C! I; tvelocity was 30 cm (12 inches). The examination of K* V- d' B+ f( H
the neck revealed no thyroid enlargement.$ ?' t9 Q6 J, [3 f0 ~; E
The genitourinary examination was remarkable for
. }& O2 q# x1 }enlargement of the penis, with a stretched length of3 Q7 ]3 t/ H2 ^4 F ~
8 cm and a width of 2 cm. The glans penis was very well
% q$ K* M9 U; I$ G! V4 y! Ddeveloped. The pubic hair was Tanner II, mostly around7 ]- j" y! K6 h* A7 c2 B1 e
540
- z% `2 a4 d3 x* O9 \at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
$ D/ Z K# o+ |( qthe base of the phallus and was dark and curled. The
8 u, n5 z5 B! H5 N( X# D: V) Ytesticular volume was prepubertal at 2 mL each.
# w& ]+ D$ J1 w; R9 U. JThe skin was moist and smooth and somewhat
. W" z1 C& C* _* ?oily. No axillary hair was noted. There were no
4 j; `2 `; T9 e" S5 W1 fabnormal skin pigmentations or café-au-lait spots.8 x9 t7 D0 q$ {" c* R, h0 b
Neurologic evaluation showed deep tendon reflex 2+
2 @0 _- O3 \9 Sbilateral and symmetrical. There was no suggestion
" `) r5 I0 F X6 u3 }4 [of papilledema.4 Z: S! O/ I5 ^; h, Q5 _8 @
Laboratory Evaluation
$ u) K! O1 W' UThe bone age was consistent with 28 months by
) j. l2 r) @& n/ h" |6 g6 y) Tusing the standard of Greulich and Pyle at a chrono-
. u; o( u5 M4 C% R* Z+ flogic age of 16 months (advanced).5 Chromosomal; K, m# s. |# e y+ e) m6 e8 ]
karyotype was 46XY. The thyroid function test8 w& d/ q. h, a0 U* G+ f8 t
showed a free T4 of 1.69 ng/dL, and thyroid stimu-5 Q f3 H3 _4 ~
lating hormone level was 1.3 µIU/mL (both normal).
7 { J/ m6 ~$ t& T8 @* U, CThe concentrations of serum electrolytes, blood
6 Z, i+ ?3 q6 C! s' [urea nitrogen, creatinine, and calcium all were3 e# H3 q' I! ^
within normal range for his age. The concentration
/ m$ ]0 e9 ]+ Q3 d0 W8 @* j8 N+ e. R( d7 Rof serum 17-hydroxyprogesterone was 16 ng/dL
3 X; }, r `. L! T! k. B& X/ [0 T(normal, 3 to 90 ng/dL), androstenedione was 20
# s$ q; `) \, @8 Yng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
$ O* A5 c5 `- \8 ?8 Xterone was 38 ng/dL (normal, 50 to 760 ng/dL),9 S5 G5 w* W( s% z1 X) t |
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
- _8 |0 b4 g. V' T9 V/ z) f49ng/dL), 11-desoxycortisol (specific compound S)" V$ e! Q8 z, x! g) j* T
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
: v' h$ }" w. ^6 F( x+ x% m& D0 etisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total' y) T p( I: P6 L& S' E
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
8 ^' f6 R: y3 _9 g: [/ ~: M; f4 |and β-human chorionic gonadotropin was less than e3 }6 ` y1 }+ w7 G' F) z
5 mIU/mL (normal <5 mIU/mL). Serum follicular
! s6 g b& J% @; n$ ?stimulating hormone and leuteinizing hormone& q+ q* c5 @7 q4 e
concentrations were less than 0.05 mIU/mL
" z! E0 f5 Q. S/ s, D2 V* n& z. Q(prepubertal).6 X, M4 N9 t( C, R* B+ [, P
The parents were notified about the laboratory
, l0 p n& X5 }7 i [# l: aresults and were informed that all of the tests were8 d2 `! G& H) [1 b
normal except the testosterone level was high. The I# M% [7 t( O, O
follow-up visit was arranged within a few weeks to
: R; G% c7 L1 f4 o1 u2 [obtain testicular and abdominal sonograms; how-8 K! B0 n& r/ M' Z1 a& I. l
ever, the family did not return for 4 months.
% d J7 h1 v7 dPhysical examination at this time revealed that the
3 i5 R% f0 H4 x/ Lchild had grown 2.5 cm in 4 months and had gained7 c! L) T" t3 P
2 kg of weight. Physical examination remained& O' E, n: b+ e9 T" c7 W8 m3 h! _
unchanged. Surprisingly, the pubic hair almost com-
* e) ~; Q6 _# B- `; wpletely disappeared except for a few vellous hairs at
F) v" o; }% |3 [) F4 H3 h; Dthe base of the phallus. Testicular volume was still 29 u9 d; ?# }2 k0 e5 w
mL, and the size of the penis remained unchanged.3 Q7 W) C7 H; U5 E7 s) |
The mother also said that the boy was no longer hav-9 f" d( a9 a1 D. r1 _) C# ]
ing frequent erections.
; G3 _# `! k9 y; z9 N+ nBoth parents were again questioned about use of
, X+ ?* [: \) ^) w! G8 \# Pany ointment/creams that they may have applied to% H4 h( Y6 H( r/ u, @( Q
the child’s skin. This time the father admitted the3 U5 G) X" g# A/ ]$ k- n( }5 j' G; X
Topical Testosterone Exposure / Bhowmick et al 541
8 i, p; P: D G @use of testosterone gel twice daily that he was apply-2 T8 C8 G- r% u% m4 a% S$ C
ing over his own shoulders, chest, and back area for2 W5 T+ Y& ^& K# A4 a
a year. The father also revealed he was embarrassed$ x% S2 c. I. E
to disclose that he was using a testosterone gel pre-7 Z& n) m! A8 W9 }% R, A. N$ `
scribed by his family physician for decreased libido# g N$ i2 X% d0 r1 R
secondary to depression./ k% @- `% C/ p
The child slept in the same bed with parents.
3 _8 a3 t+ [" B# {The father would hug the baby and hold him on his" j4 ]' L A1 k l) W4 Q0 I
chest for a considerable period of time, causing sig-9 I# X C5 X! G7 a# \
nificant bare skin contact between baby and father./ n2 c' k- E _! i
The father also admitted that after the phone call,! z) O* g$ x [- N/ h6 D8 a
when he learned the testosterone level in the baby
9 ~: ?5 W* G% k" D) |was high, he then read the product information
) ?/ X$ x) a; e& |: Ypacket and concluded that it was most likely the rea-4 b! `* @7 ~* p3 y; Q. M
son for the child’s virilization. At that time, they
1 D/ Q* j, p& ~- A& D' {0 Wdecided to put the baby in a separate bed, and the
" j7 A; e4 ]& S7 nfather was not hugging him with bare skin and had p) r6 I) T( \1 V# w9 G, I
been using protective clothing. A repeat testosterone
$ o2 u- M8 D! S$ s! z& f/ [test was ordered, but the family did not go to the
; E* d0 _5 g1 f$ alaboratory to obtain the test.
+ F; X- V2 S# n3 W, {Discussion
( T" ` I2 p4 p! c, jPrecocious puberty in boys is defined as secondary* Z" F: ]: O0 G8 L) ]( H
sexual development before 9 years of age.1,4
; Y( @+ T% ?$ C7 tPrecocious puberty is termed as central (true) when
% q& U" S6 U r! X/ J" U7 zit is caused by the premature activation of hypo-
) n# O* l! W( t- uthalamic pituitary gonadal axis. CPP is more com-+ C' s: S. L# X& B' m8 M
mon in girls than in boys.1,3 Most boys with CPP \; c9 k: }7 x1 q" k' N
may have a central nervous system lesion that is
8 b- j% t6 |* r( w Lresponsible for the early activation of the hypothal-
[$ g# H- K3 N; c8 Y! F3 wamic pituitary gonadal axis.1-3 Thus, greater empha-
. j; Z) P) Q& W( o' j! X" O" `, Fsis has been given to neuroradiologic imaging in8 o8 I0 Q' p, ?% P t
boys with precocious puberty. In addition to viril-
' r% F/ Z; c7 e0 `" v, ?; T* ~ization, the clinical hallmark of CPP is the symmet-3 ^& Z0 ^$ {) R2 c* ^: v: \
rical testicular growth secondary to stimulation by8 C" p" h9 H/ t8 N$ \ {/ ]
gonadotropins.1,34 j0 w& x, d/ ^" |8 o' k E
Gonadotropin-independent peripheral preco-1 D/ I. H0 r" C* ~# A2 p
cious puberty in boys also results from inappropriate/ \1 V8 {: l+ w3 \
androgenic stimulation from either endogenous or
: ?/ A) }7 a% W2 Mexogenous sources, nonpituitary gonadotropin stim-
! A& T+ l, n( t L1 Oulation, and rare activating mutations.3 Virilizing1 X/ }( v s' T# `0 x
congenital adrenal hyperplasia producing excessive* u ^" L- ^1 m' V. N" G
adrenal androgens is a common cause of precocious; L$ K7 W8 h9 t, t& G) f6 |- R
puberty in boys.3,47 V$ P# d/ k! ?2 w4 w( j
The most common form of congenital adrenal) M( G% H0 c5 R
hyperplasia is the 21-hydroxylase enzyme deficiency.; K W @* n/ ]7 Q! b* l
The 11-β hydroxylase deficiency may also result in$ u5 T; s5 T6 e5 |5 N3 b
excessive adrenal androgen production, and rarely,
; t& {' p5 c4 i, t1 J6 Ian adrenal tumor may also cause adrenal androgen
% I" U( o: \6 {3 |excess.1,33 P3 S' W0 ^4 M; o" D0 G; P
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from4 L+ H8 `) r- R+ a! R, _
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
& A* T, ]. g4 l- \) T+ \A unique entity of male-limited gonadotropin-: M: ?- ^ ^% v$ O! |. T' A
independent precocious puberty, which is also known
9 l+ X, G3 I V3 i' Eas testotoxicosis, may cause precocious puberty at a% f9 a5 W9 Q% ?3 D; [
very young age. The physical findings in these boys
5 Y- |2 L4 i; E2 d3 D( lwith this disorder are full pubertal development,' L n0 t, F0 w2 A; x+ }+ f+ F; S
including bilateral testicular growth, similar to boys% j+ [+ N; e# d% K) [( V
with CPP. The gonadotropin levels in this disorder. i7 D. q3 p7 O5 ]+ T2 f; B( j
are suppressed to prepubertal levels and do not show% E% J0 c/ T/ a( J: L1 q
pubertal response of gonadotropin after gonadotropin-
( L$ C7 h4 T. }3 ]5 o% [3 U, q1 ereleasing hormone stimulation. This is a sex-linked
' I6 A9 ~* |' E, \autosomal dominant disorder that affects only
: p. l; \& W9 s kmales; therefore, other male members of the family
+ ]1 R9 _, N# m9 S8 R! u" bmay have similar precocious puberty.3
6 V& m+ v( m) F! ^In our patient, physical examination was incon-
, e9 D1 ?6 z% Isistent with true precocious puberty since his testi-2 M9 b9 J/ }: Q5 c& s; y
cles were prepubertal in size. However, testotoxicosis
7 C- _) E4 X: e9 T' t6 |was in the differential diagnosis because his father
- K! ^4 }6 K6 H; dstarted puberty somewhat early, and occasionally,
- x( x7 M8 ~% B: A0 R! Dtesticular enlargement is not that evident in the$ p! d, `) E6 s# m$ P4 N; \$ o$ d
beginning of this process.1 In the absence of a neg-
4 U( _3 N) e2 Gative initial history of androgen exposure, our
# ^& @9 U, z& D" v- B1 b5 H, Kbiggest concern was virilizing adrenal hyperplasia,8 K6 ?0 H0 J3 J
either 21-hydroxylase deficiency or 11-β hydroxylase
" @4 E+ e) ?1 ^$ v( Z8 |6 f( {* Xdeficiency. Those diagnoses were excluded by find-+ e- _! J1 |' u5 l1 Z' o8 L, G# h& M
ing the normal level of adrenal steroids.
( p" K# T& R$ IThe diagnosis of exogenous androgens was strongly8 Q6 L9 e+ a3 b6 \- K
suspected in a follow-up visit after 4 months because
9 u+ r4 c5 G5 P2 ^/ e) n2 ^- U/ `the physical examination revealed the complete disap-
% w5 X) L& W) q% y9 Opearance of pubic hair, normal growth velocity, and0 j; k' z( I! T4 s8 G0 h
decreased erections. The father admitted using a testos-
/ z' q' I, x3 z5 R) Q2 Hterone gel, which he concealed at first visit. He was0 g9 H6 `9 P' Q# J5 D
using it rather frequently, twice a day. The Physicians’7 w" l) M q5 s
Desk Reference, or package insert of this product, gel or
, B: E: n6 r( [! J) I$ Mcream, cautions about dermal testosterone transfer to4 [% j* V, h: ^5 m: S+ {
unprotected females through direct skin exposure.: `7 w( w' s$ ?6 q' b
Serum testosterone level was found to be 2 times the
- l+ B! a9 L$ M7 n" r# l0 ~. Pbaseline value in those females who were exposed to' g% b) K, l2 F8 w" D
even 15 minutes of direct skin contact with their male
$ }0 T2 ?- E& y( v$ j) ypartners.6 However, when a shirt covered the applica-
4 O. a0 s8 m# u- Ktion site, this testosterone transfer was prevented.8 p y1 M+ D8 A& x" f
Our patient’s testosterone level was 60 ng/mL,3 N" u7 R& t4 J/ ]; f
which was clearly high. Some studies suggest that
: ^6 O0 x2 ]/ F' h# rdermal conversion of testosterone to dihydrotestos-, c5 G% `# t5 N, K8 D
terone, which is a more potent metabolite, is more
/ r- w9 W) w+ k! A) mactive in young children exposed to testosterone( l* q- A Z* K3 V' h
exogenously7; however, we did not measure a dihy-
. o$ v' d' }) q* u3 a- }8 Jdrotestosterone level in our patient. In addition to
* y/ h, L! S. L) t3 Fvirilization, exposure to exogenous testosterone in
' O9 ^, b: h5 L% ~0 Wchildren results in an increase in growth velocity and
# B" ?2 M8 B" I: Madvanced bone age, as seen in our patient.
2 v6 |# T' M! Y8 j- }The long-term effect of androgen exposure during
: d, A! B" E2 {; z3 tearly childhood on pubertal development and final( ]/ W# t& o) w$ t8 n
adult height are not fully known and always remain- S5 F. C# ]: q9 A# r
a concern. Children treated with short-term testos-+ w' l& \, H5 D
terone injection or topical androgen may exhibit some' A; e) \: @ y4 ~1 v
acceleration of the skeletal maturation; however, after z' `' T: t, [
cessation of treatment, the rate of bone maturation8 i! [, `, _1 v/ D8 t3 i6 N- [
decelerates and gradually returns to normal.8,9
: z4 \) X% E$ X, |: ^# JThere are conflicting reports and controversy9 U8 [9 y! p9 _; _- Z$ ^; D
over the effect of early androgen exposure on adult
) ]/ T2 D3 I+ E/ T; Apenile length.10,11 Some reports suggest subnormal5 m, \9 f* I) i8 `- T
adult penile length, apparently because of downreg-1 X1 m! o1 R7 S" k* I7 g; y
ulation of androgen receptor number.10,12 However,
5 ^( R4 w% k9 m* f4 q- KSutherland et al13 did not find a correlation between
0 Z# z1 y/ x4 }4 i6 ichildhood testosterone exposure and reduced adult
) ? Z0 R `# M# i+ G5 Dpenile length in clinical studies.
" t; c- s- j- gNonetheless, we do not believe our patient is( Y! P0 j5 S4 E I4 Y
going to experience any of the untoward effects from, p1 S9 u6 Z' N3 @8 u4 G
testosterone exposure as mentioned earlier because, x. y5 G* h" [7 x2 B
the exposure was not for a prolonged period of time.0 v" J+ e1 v6 V
Although the bone age was advanced at the time of
$ C( v! \' O3 c. Q3 _diagnosis, the child had a normal growth velocity at( F! T- F) w- Z* U4 \
the follow-up visit. It is hoped that his final adult! s/ l" f1 ^) {
height will not be affected.3 m) l; d1 A* N
Although rarely reported, the widespread avail-! M4 e+ p: [: k5 N/ F' `
ability of androgen products in our society may
1 V" j: E( \; I$ vindeed cause more virilization in male or female
8 ]0 j. p# r# A% g+ d* |children than one would realize. Exposure to andro-
( ?3 }( ?/ H# Y$ Bgen products must be considered and specific ques-
; i. E6 G, |5 ~( u. M" p$ Utioning about the use of a testosterone product or) l7 z, [3 z# w( Q, B U
gel should be asked of the family members during, {; L8 Q9 W' _- R9 h) \' H" g
the evaluation of any children who present with vir-. A& H( k, I4 u" ]( ?
ilization or peripheral precocious puberty. The diag-
7 i2 k- @* P# R: n6 K: b! H Enosis can be established by just a few tests and by
7 h m; g8 @3 B9 c+ `! A9 C3 p. ]appropriate history. The inability to obtain such a. {3 o3 F+ l( X- Y3 J
history, or failure to ask the specific questions, may; e# g6 Y: R$ \; D2 B
result in extensive, unnecessary, and expensive; F, [7 K& D6 Q- E" Q' x
investigation. The primary care physician should be% F+ P& C( H. e' c4 Y" l
aware of this fact, because most of these children6 L4 |5 d2 b; M! e
may initially present in their practice. The Physicians’
9 j1 h' S* {, d" _Desk Reference and package insert should also put a
' w* e0 ^# H+ p5 H2 dwarning about the virilizing effect on a male or
9 l9 x- w. ^2 Ffemale child who might come in contact with some-
7 x! I- t6 V/ Q( Y8 P! ]4 i; u1 Jone using any of these products.. y% @. H* R! P% M9 _4 q C
References! _- R2 S, }" @( L& ?7 l2 w" f/ p
1. Styne DM. The testes: disorder of sexual differentiation
4 y9 m6 ?* M) J3 i3 D4 K2 H5 |and puberty in the male. In: Sperling MA, ed. Pediatric* v. Y& j9 B. e r, N/ \: [
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;/ C6 z1 I- O3 i9 @5 ] t
2002: 565-628.4 N8 _( |% m' g& P6 X) ]9 A6 U5 k
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
; R+ H+ ^2 x% X- N# F# ?puberty in children with tumours of the suprasellar pineal |
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