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Sexual Precocity in a 16-Month-Old
: m* E8 ]9 _' l& [ TBoy Induced by Indirect Topical
- E1 P% T8 D X$ ?Exposure to Testosterone5 s4 J, Z- v9 ^+ f% @ [
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2" ^' F8 y& Q% I* d
and Kenneth R. Rettig, MD1# D6 l5 x" a' h" Q+ Y
Clinical Pediatrics
: y- `0 R, x# y2 V: wVolume 46 Number 6
; d, v' N* D" X- CJuly 2007 540-543
: v2 L- V7 \- |. v' B0 C© 2007 Sage Publications
, z4 G) J7 `) j: g10.1177/0009922806296651, n9 N6 t: H( X; Y
http://clp.sagepub.com1 @2 V0 F% `: s
hosted at1 F4 g7 A( Y# M7 \+ f
http://online.sagepub.com0 E% D i+ C) L+ ?/ v8 ^; d- t
Precocious puberty in boys, central or peripheral,! e, ?9 K* S- z: _
is a significant concern for physicians. Central
- i, {/ R" w* G/ O- I$ j. p8 Q4 X4 y- oprecocious puberty (CPP), which is mediated
9 x+ \0 C- B* f4 athrough the hypothalamic pituitary gonadal axis, has
. O2 w3 z( ?9 q# M, S1 h( ^a higher incidence of organic central nervous system
# ^' S7 I( b* J ]lesions in boys.1,2 Virilization in boys, as manifested
/ b2 F9 \ K6 K+ d* }by enlargement of the penis, development of pubic2 X1 X8 r( f8 r
hair, and facial acne without enlargement of testi-
- s8 c: o* w: }: Gcles, suggests peripheral or pseudopuberty.1-3 We
$ o: O' _& r5 O3 E Breport a 16-month-old boy who presented with the
# `1 ?# N0 D: p c3 Z% |enlargement of the phallus and pubic hair develop-: k' C+ J X1 Q6 Y- T
ment without testicular enlargement, which was due1 l- o3 r3 ? A3 ]
to the unintentional exposure to androgen gel used by& A1 ?' ]3 L2 X& J% x
the father. The family initially concealed this infor-
0 z2 U: ]% R8 ^! Q2 xmation, resulting in an extensive work-up for this
( ]2 V7 o$ m, e W& \child. Given the widespread and easy availability of/ a, r; e7 G: ?6 Q
testosterone gel and cream, we believe this is proba-. b8 X# Z( P2 a5 x3 C4 ~' w
bly more common than the rare case report in the
# [2 g @5 B: l8 E2 v, S! Vliterature.4+ r# o3 F$ S/ f+ ^& w. g4 n' i
Patient Report0 F3 ~" z; P: }" i" M3 r) N
A 16-month-old white child was referred to the& i+ A1 {4 O g$ X
endocrine clinic by his pediatrician with the concern
4 ]. T- |, \' }7 t, j1 B% cof early sexual development. His mother noticed
; W8 G. C4 w, Qlight colored pubic hair development when he was: `1 L+ d: L. i) r
From the 1Division of Pediatric Endocrinology, 2University of
8 N+ Y3 R$ P; u4 {South Alabama Medical Center, Mobile, Alabama.
; e' X' w$ r; w e: Y6 oAddress correspondence to: Samar K. Bhowmick, MD, FACE,8 {8 V4 i: L# b6 ? o
Professor of Pediatrics, University of South Alabama, College of+ w9 I8 U1 P2 C2 ]! C. c6 `, }( ~& U
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
/ f: }4 U7 ^- L3 \- He-mail: [email protected].
H ?# k. [6 K# t/ D# F6 zabout 6 to 7 months old, which progressively became4 ]6 b; _: p* B$ ~4 K$ m) K
darker. She was also concerned about the enlarge-# l3 E; @9 ~3 Y4 l
ment of his penis and frequent erections. The child, r/ N6 i" k, Y3 N) d: k! f& H
was the product of a full-term normal delivery, with& `' t, b+ `$ Z0 A. A3 S; [
a birth weight of 7 lb 14 oz, and birth length of/ x, x5 G" j0 f( A, d$ q5 }" |
20 inches. He was breast-fed throughout the first year. G7 l, d' t1 U0 R$ L' _
of life and was still receiving breast milk along with
3 Q0 o2 D: K% o) w! _& @, Jsolid food. He had no hospitalizations or surgery,
7 c g+ | r) j( G9 v6 }5 A* ?/ Vand his psychosocial and psychomotor development! Z* Z8 B) x4 c* ?
was age appropriate.
) @5 f* a1 }1 D# z sThe family history was remarkable for the father,
$ O' ?, L7 N/ [who was diagnosed with hypothyroidism at age 16," g0 Z# F, H/ ?7 [6 X- H" @, ]
which was treated with thyroxine. The father’s* Z+ d0 m! d: H0 V% C2 @
height was 6 feet, and he went through a somewhat
7 P! l! h( d8 s4 k7 Rearly puberty and had stopped growing by age 14.
_' Z/ z5 j( ~; tThe father denied taking any other medication. The$ [& r8 k, x9 |8 y. A
child’s mother was in good health. Her menarche: o _5 B& F* z. }: E
was at 11 years of age, and her height was at 5 feet
B N7 M4 ?, X5 inches. There was no other family history of pre-
+ {* a. E9 o- ^. y1 ?4 Jcocious sexual development in the first-degree rela-
% T9 t; u- j( [- p/ n% Utives. There were no siblings.
) d/ s/ z# v8 e7 W. b# n# h/ LPhysical Examination9 b2 R. O9 @, B1 {2 [# l
The physical examination revealed a very active,: p3 W9 z: I# z" K
playful, and healthy boy. The vital signs documented
% ^( M: Y, f" u* _. x xa blood pressure of 85/50 mm Hg, his length was
# N" k, X! n" x% O' X1 c( z/ u90 cm (>97th percentile), and his weight was 14.4 kg
$ W+ T/ t: O* b' F(also >97th percentile). The observed yearly growth# s& S6 I r7 m3 n( K+ W. P0 ^+ g
velocity was 30 cm (12 inches). The examination of
/ w; a9 Q. l2 V2 Nthe neck revealed no thyroid enlargement.
8 c0 B8 H! u) I$ Y" TThe genitourinary examination was remarkable for
- t, L5 l, q: \$ G% _0 ?9 x9 lenlargement of the penis, with a stretched length of: I9 i) a! ~! `7 [ U
8 cm and a width of 2 cm. The glans penis was very well8 E5 g1 J$ P# v
developed. The pubic hair was Tanner II, mostly around+ B' n. Z) w2 w% v, y# I# [3 z* E
540) P; i" p Q& r/ J
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the base of the phallus and was dark and curled. The: f' G D6 ~1 r- g$ i# A& n
testicular volume was prepubertal at 2 mL each.
0 L+ _) W6 [1 J: j ~The skin was moist and smooth and somewhat0 Z# |" m8 w& ~3 t
oily. No axillary hair was noted. There were no
; {; _# m0 a; c0 Z+ ^abnormal skin pigmentations or café-au-lait spots.) n/ L; A" S0 }$ @9 \0 X. g
Neurologic evaluation showed deep tendon reflex 2+0 C6 @6 h& m# x% T# c O( e
bilateral and symmetrical. There was no suggestion7 X) S$ ~ z* C: a) ?
of papilledema.' J- }$ T$ v/ ~% j; q
Laboratory Evaluation
3 v2 {9 s1 O J8 X& C/ \0 xThe bone age was consistent with 28 months by; z ] f1 E; F* H/ G5 }
using the standard of Greulich and Pyle at a chrono-; \$ j* |+ h) l1 N8 N# n
logic age of 16 months (advanced).5 Chromosomal
% b5 E+ w7 S6 }* z- n/ Xkaryotype was 46XY. The thyroid function test
3 I* b6 O) F% @1 Ushowed a free T4 of 1.69 ng/dL, and thyroid stimu-
$ f( S/ `( K7 J2 ^lating hormone level was 1.3 µIU/mL (both normal).
/ u( z: Z V: n) O& SThe concentrations of serum electrolytes, blood5 c& p( X' |( Z* v7 C
urea nitrogen, creatinine, and calcium all were0 K6 k6 P7 M- c5 e6 @9 h
within normal range for his age. The concentration
4 C! V. G" M7 A6 F( b0 }of serum 17-hydroxyprogesterone was 16 ng/dL
% |& M4 Z; { p: q8 V5 u8 b4 F8 J5 I(normal, 3 to 90 ng/dL), androstenedione was 20
* u! p" |: X* m u9 e! z1 C- Gng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-* F" S/ N7 p n' ^" G
terone was 38 ng/dL (normal, 50 to 760 ng/dL),4 x/ e: Y3 H" U2 H. P( U, T
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
' _0 z* W/ j' h0 _9 d( u0 R: _49ng/dL), 11-desoxycortisol (specific compound S)5 ~ Q! n' B3 J) f2 a9 p# t
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-2 c& O" x; } {" x
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
[) b) C# ]" jtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
% m6 p- y) X2 z7 q7 [and β-human chorionic gonadotropin was less than
* i3 V, `; Y0 T8 B5 mIU/mL (normal <5 mIU/mL). Serum follicular" D" n7 v0 t1 l& S* h$ }% F
stimulating hormone and leuteinizing hormone
% l) y) E, a9 ~4 ]5 f: U% Y; cconcentrations were less than 0.05 mIU/mL9 o9 W) Y. N8 ^# T7 S2 K
(prepubertal).4 D* Y3 {. b# Z" j4 S' O L
The parents were notified about the laboratory
0 V; z$ D8 F5 u% D5 c( vresults and were informed that all of the tests were
; w6 p. }# B/ C5 b1 O" j3 W# t- w Unormal except the testosterone level was high. The
2 H) ~+ m0 E! H2 ^4 h7 Y Hfollow-up visit was arranged within a few weeks to
7 l' h, Z( ^% W8 s0 L- E- h' nobtain testicular and abdominal sonograms; how-
) v( h) H& H9 x! e# j) ^ever, the family did not return for 4 months.6 C g3 [6 K! j0 C% B& U% M1 t- ^
Physical examination at this time revealed that the7 `% ~( ], O& B# `& Y) l; }5 }
child had grown 2.5 cm in 4 months and had gained
3 u* x) a; M( ?9 B; V2 kg of weight. Physical examination remained5 s! M" |' T7 S# B2 [& j0 }
unchanged. Surprisingly, the pubic hair almost com-
; P2 G( T; x+ C0 A7 f9 ypletely disappeared except for a few vellous hairs at7 }' o+ ?2 f& @( w; {
the base of the phallus. Testicular volume was still 2( P. w1 m9 x' K# m6 E X! C- o
mL, and the size of the penis remained unchanged.4 |& ]) I9 V L+ ]4 l. V! I
The mother also said that the boy was no longer hav-
2 L5 b3 a1 M, xing frequent erections.
' e; Z, Y: E M( q; S, {Both parents were again questioned about use of: b4 z0 F; j2 n* _
any ointment/creams that they may have applied to0 _" o1 u1 t: A) y, J2 C
the child’s skin. This time the father admitted the/ g# k7 Y0 e- I
Topical Testosterone Exposure / Bhowmick et al 541
2 M! @- I; ]5 G+ ~$ Huse of testosterone gel twice daily that he was apply-/ T: E& g3 Y+ y' ]" x3 H9 T
ing over his own shoulders, chest, and back area for
# a) w1 K0 ~; z: da year. The father also revealed he was embarrassed
s6 r7 t0 b* r; ato disclose that he was using a testosterone gel pre-& Q! ?# ^2 ?3 v0 W
scribed by his family physician for decreased libido
! z6 q$ c, D. @9 _7 s1 J6 asecondary to depression.9 |3 F5 {+ k2 Z0 b
The child slept in the same bed with parents.
0 S: u0 j. B5 _The father would hug the baby and hold him on his4 E$ Y7 v* ~/ |8 j7 {2 x
chest for a considerable period of time, causing sig-! G* J% B; ?; O! R8 F$ W
nificant bare skin contact between baby and father.
1 F- ]# Y7 Q. K5 ]& |+ ~/ _The father also admitted that after the phone call,% Y/ h5 N0 ~4 \( k0 f
when he learned the testosterone level in the baby
8 G; W, v- T! ~, wwas high, he then read the product information
' `8 D2 u- r1 F* \5 w6 q4 d9 L% U5 w: p2 xpacket and concluded that it was most likely the rea-! W3 O5 b8 H/ B# t4 h4 i* W" c
son for the child’s virilization. At that time, they1 ^9 Q' e3 o. r0 z k0 l {1 w! k
decided to put the baby in a separate bed, and the. J* B; D7 _% Z
father was not hugging him with bare skin and had- Z8 x0 c2 d, N; i
been using protective clothing. A repeat testosterone
' @" p: s2 f0 S6 htest was ordered, but the family did not go to the- f& v. J$ Q7 Z% j8 ?( b
laboratory to obtain the test.' I" B3 S2 v4 Z# ~, ]- F* o6 m
Discussion
; x+ _% H; f2 v& }" v KPrecocious puberty in boys is defined as secondary
* l5 M8 _* o$ K4 j: c2 \sexual development before 9 years of age.1,4
+ {, S0 I; s) M& u7 @Precocious puberty is termed as central (true) when
" C( G; m+ d2 `' {# b8 _0 T# bit is caused by the premature activation of hypo-
$ H% B( ^& @' d: P Ethalamic pituitary gonadal axis. CPP is more com-; W4 _( u5 t A% d; ~
mon in girls than in boys.1,3 Most boys with CPP8 T" }& F# n9 G/ O7 ~' C
may have a central nervous system lesion that is3 k, _% L F9 r2 D7 z H
responsible for the early activation of the hypothal-
# p/ X1 O) M8 q5 y; ~) Lamic pituitary gonadal axis.1-3 Thus, greater empha-
. |7 x: {9 }: B8 a$ Wsis has been given to neuroradiologic imaging in
- k' G' w8 a9 g" N& C* hboys with precocious puberty. In addition to viril-5 G2 f. D: F8 ?* |" X
ization, the clinical hallmark of CPP is the symmet-
) p& [, B* ^, [rical testicular growth secondary to stimulation by* K2 x; @3 ~, S
gonadotropins.1,3
! `7 k7 U9 W1 n. U- a9 h+ jGonadotropin-independent peripheral preco-
( ~) ]7 y; }, L& W2 m/ W; \2 Icious puberty in boys also results from inappropriate
+ S! w5 }. n$ B& y4 \androgenic stimulation from either endogenous or4 s2 U P( H3 b) ~, I3 Q
exogenous sources, nonpituitary gonadotropin stim-
4 e! W1 y+ A* F8 D4 b1 y6 i/ uulation, and rare activating mutations.3 Virilizing
. R! G+ y7 a2 ?+ ]congenital adrenal hyperplasia producing excessive* H- z3 m9 P6 [& ?! y- Z/ d
adrenal androgens is a common cause of precocious
& d2 C: c5 {/ ^+ G( opuberty in boys.3,4
. B$ L7 a @% }, q; l% i. D" \The most common form of congenital adrenal
/ ^$ I# D9 b" s- {9 }8 Mhyperplasia is the 21-hydroxylase enzyme deficiency.3 w& V* z( J8 e
The 11-β hydroxylase deficiency may also result in
8 }" @$ t. u6 \excessive adrenal androgen production, and rarely,; ?* C) F! q; x1 A3 L0 q5 _# w
an adrenal tumor may also cause adrenal androgen$ V+ Q; J, M. _: t3 E
excess.1,3) i% }! H0 f3 C- D: A
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 X9 M4 x! {# o8 G2 W
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007% T7 N" H0 M! q/ h2 s6 M
A unique entity of male-limited gonadotropin-0 n$ s, f2 L- C$ {: J( g
independent precocious puberty, which is also known0 O" X# [% T/ G" X$ ?/ f
as testotoxicosis, may cause precocious puberty at a/ h, z! |6 J1 c7 g! f- H
very young age. The physical findings in these boys' V" `6 J( c @
with this disorder are full pubertal development,3 B4 S9 Q) I4 `; U, g0 x
including bilateral testicular growth, similar to boys
; g. Z; A" D6 p- T- ~" Zwith CPP. The gonadotropin levels in this disorder; Y) W- \& e8 T) e3 t
are suppressed to prepubertal levels and do not show! D7 E) E6 }7 \( V$ c
pubertal response of gonadotropin after gonadotropin-
C: U5 W- V4 ]7 Oreleasing hormone stimulation. This is a sex-linked
, M/ |% ]" b' l( G+ ]4 x% W+ s6 Rautosomal dominant disorder that affects only
. B& U# ~& T- r3 G: U Emales; therefore, other male members of the family
" ~8 O& ?+ y% [may have similar precocious puberty.3
8 Z" |( l4 v2 J; \: ~. P5 ?7 |- vIn our patient, physical examination was incon-
2 h; m6 [+ V, w1 ^ T2 Lsistent with true precocious puberty since his testi-
$ D) }. {3 ]! C2 S4 n7 Dcles were prepubertal in size. However, testotoxicosis( ` q; A3 x. J8 T! j D/ N% M+ U
was in the differential diagnosis because his father; Q# y' l1 e. E
started puberty somewhat early, and occasionally,! u% \, G; i/ q8 x
testicular enlargement is not that evident in the
- f! j, Z" R& D$ ebeginning of this process.1 In the absence of a neg-/ D! r. g% A' ]2 B, v/ x7 Z O( x
ative initial history of androgen exposure, our
; `6 b% b2 a, z7 g: Z( M: c2 }biggest concern was virilizing adrenal hyperplasia,
3 k) e% n, T( Aeither 21-hydroxylase deficiency or 11-β hydroxylase% ^3 }; o1 Q6 c. W6 C- i Y0 [9 M6 P
deficiency. Those diagnoses were excluded by find-
; D* \5 r) I9 X2 Ring the normal level of adrenal steroids.- g5 z8 o1 J( ` K8 ?1 J- v+ g+ E: T
The diagnosis of exogenous androgens was strongly5 G# W; \& X0 Q" K, X% M* j+ l0 c8 Y
suspected in a follow-up visit after 4 months because6 j) F+ a! O: P; ~: H) z2 _( o
the physical examination revealed the complete disap-6 n3 n! e, g6 ~9 X# X# ^) C* }
pearance of pubic hair, normal growth velocity, and& F# ~! z* c$ c- j% c
decreased erections. The father admitted using a testos-
" X% C, L6 a4 T' _( @6 j2 I3 v$ Tterone gel, which he concealed at first visit. He was* s n* S7 n( Q0 {! Q7 Q0 J
using it rather frequently, twice a day. The Physicians’
4 @) n* q$ \4 R4 h5 nDesk Reference, or package insert of this product, gel or0 W) L! @2 m# p3 e7 g! ^
cream, cautions about dermal testosterone transfer to
. w- @6 @: _" g( t5 N P3 punprotected females through direct skin exposure.7 w; z- Y; c+ @7 q2 `. [) S9 m5 {
Serum testosterone level was found to be 2 times the
3 s- d. n- K8 ?baseline value in those females who were exposed to
* m3 |1 v* U( feven 15 minutes of direct skin contact with their male" F J! y; w& `# m4 v8 }2 H
partners.6 However, when a shirt covered the applica-- K8 m* C0 ?$ ^. b/ s$ u1 G
tion site, this testosterone transfer was prevented.
0 C# _, ? E; p( P( [" M7 [Our patient’s testosterone level was 60 ng/mL,
$ P7 C9 V5 J4 R+ W# Q! Q+ Z/ uwhich was clearly high. Some studies suggest that
, Q3 r% x2 E) ^0 m5 a4 Ldermal conversion of testosterone to dihydrotestos- a. |2 v+ j- E5 R1 B0 K W
terone, which is a more potent metabolite, is more3 r/ T; I1 f5 O
active in young children exposed to testosterone
; _& S# w+ H* b: wexogenously7; however, we did not measure a dihy-2 j0 F9 _3 a! P1 Y$ }
drotestosterone level in our patient. In addition to& ~8 h Y Z& _2 S* e
virilization, exposure to exogenous testosterone in9 J7 D3 J3 c+ O
children results in an increase in growth velocity and
$ v" S% _! o% Wadvanced bone age, as seen in our patient.) W g1 Q& @; Z; V1 H( A3 S
The long-term effect of androgen exposure during1 {' f4 b$ ^+ b
early childhood on pubertal development and final
+ [* j6 O( ]5 W2 p9 {; ^adult height are not fully known and always remain/ n) B5 n" g7 b8 Q/ F0 e! F
a concern. Children treated with short-term testos-8 z: f% z; Q+ }- \/ ^2 D- O! X* {
terone injection or topical androgen may exhibit some
+ O) a+ F7 O* r0 Y; Iacceleration of the skeletal maturation; however, after
, F. x0 D% W/ `4 Z1 ycessation of treatment, the rate of bone maturation! s5 [: d: a4 B+ X; u
decelerates and gradually returns to normal.8,9
) z5 ^' ]9 g2 T1 p! A- J: MThere are conflicting reports and controversy
% H1 P, O$ {% r; `6 y/ ^7 r8 eover the effect of early androgen exposure on adult
- D: J8 ~5 Z, V/ P% zpenile length.10,11 Some reports suggest subnormal
8 T9 P1 H: h" y! Hadult penile length, apparently because of downreg-8 Y6 O/ j4 B, Q& x4 u) Z
ulation of androgen receptor number.10,12 However,, u8 K2 K# t" G5 H2 U2 z
Sutherland et al13 did not find a correlation between2 ?- R5 h# ~7 H$ S* u
childhood testosterone exposure and reduced adult$ O% ~' A8 `6 I4 L, N$ _
penile length in clinical studies.' A3 e! r: h, J9 [% _7 h! G; g
Nonetheless, we do not believe our patient is
6 s& l$ j- |4 k# \" Cgoing to experience any of the untoward effects from
, a2 @% N$ p$ x9 E5 u; \9 D6 ntestosterone exposure as mentioned earlier because
: n0 u1 I0 J" g4 F+ s. xthe exposure was not for a prolonged period of time.. J( Q* i% L& w! \3 h, n R
Although the bone age was advanced at the time of- j) p" ~" R5 u; H+ H
diagnosis, the child had a normal growth velocity at% n( M0 A! J. I
the follow-up visit. It is hoped that his final adult: K/ l/ [& C' _
height will not be affected.
, w' S- b' y9 w5 P: r) h. wAlthough rarely reported, the widespread avail-; v: a8 |0 y2 y, ]
ability of androgen products in our society may$ c2 S# H& i3 }0 s5 q, T" m7 U
indeed cause more virilization in male or female
c: {6 q ~! p9 i7 h) n8 U: Echildren than one would realize. Exposure to andro-; W" _: B* d( {5 l, Y
gen products must be considered and specific ques-
$ k' T3 X6 B/ C. z1 ]3 W, ]tioning about the use of a testosterone product or
3 ~$ t* u( n1 qgel should be asked of the family members during a6 P9 R' K& c4 J
the evaluation of any children who present with vir-: o& l$ w- W3 [' f" v6 a: G
ilization or peripheral precocious puberty. The diag-9 w5 T5 M) A! P! f
nosis can be established by just a few tests and by
2 _9 g' ^( `! Happropriate history. The inability to obtain such a* I+ Z) }1 n5 g0 _
history, or failure to ask the specific questions, may( O6 I6 o4 M0 ^* J. b! v+ Q/ d
result in extensive, unnecessary, and expensive
* V# \4 [+ G0 finvestigation. The primary care physician should be T3 b) d: {+ S' [9 i
aware of this fact, because most of these children6 Y8 }0 E9 y3 `
may initially present in their practice. The Physicians’
7 G6 U5 i% }& q; \Desk Reference and package insert should also put a9 N/ I2 @( }! ~( Y9 }5 B( d- ?
warning about the virilizing effect on a male or
' K' e4 Q5 N6 P% Q+ X7 Wfemale child who might come in contact with some-
5 Y- F( `3 c: l. R9 _1 Bone using any of these products., \( ^& v- |7 E
References% n L" j+ f* _, D+ w% }& J* z5 n
1. Styne DM. The testes: disorder of sexual differentiation, o% k0 T8 g+ \& i& I& C3 p
and puberty in the male. In: Sperling MA, ed. Pediatric
9 U6 s M9 [0 g3 B' ^, LEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;. ^5 `- ?; k% Q
2002: 565-628.
2 E: {+ s8 C. B" t/ z, g8 _& u8 E2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
f" Q: W" i' q0 H2 zpuberty in children with tumours of the suprasellar pineal |
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