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Sexual Precocity in a 16-Month-Old
/ D# f1 v; a T# O/ e$ `Boy Induced by Indirect Topical& j* f: S: y" {- I/ b5 A2 ~% |
Exposure to Testosterone
* N6 j, ^6 H" N: W1 GSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
. q, R' w7 M; i1 n8 `& H& q$ j8 J2 fand Kenneth R. Rettig, MD1
. j) Z" t/ e3 EClinical Pediatrics1 ~: D1 `8 j. g2 I) J" @
Volume 46 Number 6+ t' m1 g: M1 M2 |3 c
July 2007 540-5437 L+ D2 E4 S/ Y- ~
© 2007 Sage Publications
* r+ C1 s8 c) q" V* ~10.1177/0009922806296651
: m5 p" @- m" O( Xhttp://clp.sagepub.com, _4 A6 D1 W- x" j* i) ^+ }
hosted at' `6 Q7 v5 {" T
http://online.sagepub.com- o1 h% P3 `. i" R
Precocious puberty in boys, central or peripheral,+ [8 q! \& m- i
is a significant concern for physicians. Central; D f3 F n2 S0 |- m
precocious puberty (CPP), which is mediated& n' L# ~" F9 m4 o/ W
through the hypothalamic pituitary gonadal axis, has
) P [5 ?, [$ s# l* Q+ h' Ca higher incidence of organic central nervous system$ f: U5 k1 X3 s7 |0 b: ~5 |2 u
lesions in boys.1,2 Virilization in boys, as manifested
' X" v; X# @3 _6 t+ k( hby enlargement of the penis, development of pubic0 w, a t8 E" c7 N9 `
hair, and facial acne without enlargement of testi-0 Y( e1 p( V1 J# b
cles, suggests peripheral or pseudopuberty.1-3 We
: c2 ^2 {) j5 Z; G# v- b( }' greport a 16-month-old boy who presented with the
* R2 x, z# M; Lenlargement of the phallus and pubic hair develop-1 \3 Q3 V# L$ V5 t: A4 e8 G& w2 T, {
ment without testicular enlargement, which was due
% j, p4 M% N5 i8 O# Q w hto the unintentional exposure to androgen gel used by
1 k* q4 t- }9 h# O6 F5 x# _$ k; f$ n! f( Fthe father. The family initially concealed this infor- i; H' D s5 T( e
mation, resulting in an extensive work-up for this9 g: q5 e. M: T7 ?! {+ f2 g
child. Given the widespread and easy availability of
: [7 i. ^/ ?) c& s" o9 i- otestosterone gel and cream, we believe this is proba-
( V) V p. \! R0 ubly more common than the rare case report in the
3 N! a1 K& `1 T4 |literature.4' f! t0 v k T9 w
Patient Report( B" G$ P% e$ e; q8 l
A 16-month-old white child was referred to the
" c( O6 m( K1 L9 B9 K4 d" rendocrine clinic by his pediatrician with the concern
9 T/ u( R% s1 q9 f0 \, Kof early sexual development. His mother noticed
0 H5 Q9 C% I$ Ylight colored pubic hair development when he was
C x1 P& J0 \; T$ M2 h& D9 JFrom the 1Division of Pediatric Endocrinology, 2University of
( t+ c3 R* j* P. oSouth Alabama Medical Center, Mobile, Alabama./ m& u* Y2 h- H3 n4 C( O
Address correspondence to: Samar K. Bhowmick, MD, FACE,! }- x' c: I4 G
Professor of Pediatrics, University of South Alabama, College of
1 W7 d3 |) Z# NMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;0 k6 ~' p$ S: m$ w+ N C& o
e-mail: [email protected].8 |; V; _$ d" b7 n/ c* C* d9 ?& G
about 6 to 7 months old, which progressively became% V; _# W0 {& a) A7 b
darker. She was also concerned about the enlarge-
# v- b2 a' i$ A. r, Cment of his penis and frequent erections. The child9 Q [* N. k4 Q
was the product of a full-term normal delivery, with
/ g6 l8 {) \* A% V* za birth weight of 7 lb 14 oz, and birth length of
/ \" B' w9 n) G9 W4 G20 inches. He was breast-fed throughout the first year; y7 T* M. ?3 g6 }# k
of life and was still receiving breast milk along with A8 R1 H$ ~, C- o/ U0 F
solid food. He had no hospitalizations or surgery,
5 U2 Q, {4 E( U/ Eand his psychosocial and psychomotor development
) p/ r; J0 p- k$ p% nwas age appropriate.5 s, n4 m3 X+ ~) `" j# \5 U
The family history was remarkable for the father,
( |( I0 C: E3 \: L2 Z A0 ^4 Hwho was diagnosed with hypothyroidism at age 16,% C% e* Q$ u1 X! j4 p
which was treated with thyroxine. The father’s* i/ N* X8 X" @9 i
height was 6 feet, and he went through a somewhat, b6 E8 I \1 X/ j
early puberty and had stopped growing by age 14.4 O& O$ I4 b' v& B7 P
The father denied taking any other medication. The
7 X( u( E) t! e2 G. schild’s mother was in good health. Her menarche
* |$ \- g: N% s. s- {was at 11 years of age, and her height was at 5 feet
- x4 \; l! ?( R5 inches. There was no other family history of pre-! D0 Y7 z$ v* M O; {
cocious sexual development in the first-degree rela-
' C6 B% F( @9 U, K1 J0 C: btives. There were no siblings.
7 D) ^" H* o/ B. p/ A2 j( V" ZPhysical Examination
- k' V1 R* K" uThe physical examination revealed a very active,9 i' t" S6 X) @: {$ J8 P( S
playful, and healthy boy. The vital signs documented: m9 f/ W6 u" F, L) b/ W/ u: Y
a blood pressure of 85/50 mm Hg, his length was' V) H6 C! |$ t, C
90 cm (>97th percentile), and his weight was 14.4 kg7 l3 p, s7 D) d: y5 ]
(also >97th percentile). The observed yearly growth8 S* e* q0 k" R( R5 i
velocity was 30 cm (12 inches). The examination of
/ C! w/ |- L4 S3 A! Gthe neck revealed no thyroid enlargement.1 o' ?* E6 ~/ Z
The genitourinary examination was remarkable for
! f0 w. h8 j4 f3 |5 ]$ j& Q Jenlargement of the penis, with a stretched length of
3 P2 j1 i' f! H$ N% V4 C8 cm and a width of 2 cm. The glans penis was very well
4 i' I$ ^9 v/ Q$ M+ H: C- u9 Udeveloped. The pubic hair was Tanner II, mostly around
- e b0 b+ {4 Y3 I540
6 _! U- {- J0 y! X8 r; Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- S Y3 x; X7 c9 a! V* p" g
the base of the phallus and was dark and curled. The) F' i+ j( S6 z: A3 k# k
testicular volume was prepubertal at 2 mL each.* |- D A% @+ o& W0 P- t7 X t+ R
The skin was moist and smooth and somewhat
: [5 b1 t1 k poily. No axillary hair was noted. There were no
$ ]# k) F$ `0 H+ |* y( Wabnormal skin pigmentations or café-au-lait spots.5 k+ R2 `1 y) Y* W
Neurologic evaluation showed deep tendon reflex 2+
, ~+ F' ^; e% D l- I# Bbilateral and symmetrical. There was no suggestion
2 s2 Q) ?, o. t! z9 Aof papilledema.
9 U! b4 ?" c) N2 dLaboratory Evaluation; V6 J- N/ E% `. a, k- M
The bone age was consistent with 28 months by
. r0 T: M- x/ v# N+ {/ Z8 zusing the standard of Greulich and Pyle at a chrono-/ _, }4 ^7 S' @0 f* B
logic age of 16 months (advanced).5 Chromosomal5 _% N r/ P! s! D1 M5 o! [
karyotype was 46XY. The thyroid function test
( r+ z- W- {2 p2 qshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
. O5 O! P- g5 b$ x) ^" r8 ~lating hormone level was 1.3 µIU/mL (both normal)." h- y! `( D) c) D4 B/ {# {
The concentrations of serum electrolytes, blood) }; H; H$ r* S. L
urea nitrogen, creatinine, and calcium all were+ m; w$ s+ i7 E6 L/ P1 N% V% Z
within normal range for his age. The concentration' Z7 ?5 O$ j; n+ ~
of serum 17-hydroxyprogesterone was 16 ng/dL" M0 v$ B+ A! t, l9 K- ~2 Z
(normal, 3 to 90 ng/dL), androstenedione was 20# O' [# _, }# g2 ` z
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-% l8 r* z2 m7 S G9 w, y
terone was 38 ng/dL (normal, 50 to 760 ng/dL),) C' G+ Q0 Q, E$ E- i9 s/ l
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
' P: y6 t* H2 f' l/ a) K# @49ng/dL), 11-desoxycortisol (specific compound S)3 G% i. X! K7 S) M1 E
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
! C! }6 C6 i6 C6 N+ a% vtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total& S3 i( A. Y6 L: D( ^
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
) O' ]( c+ W0 U2 U/ `; `( u& aand β-human chorionic gonadotropin was less than
1 y1 n; J7 Q" g- |; x5 mIU/mL (normal <5 mIU/mL). Serum follicular
3 [* |/ `1 ^* A0 ^( U, u7 N0 vstimulating hormone and leuteinizing hormone
# p$ {% h2 P/ T% `concentrations were less than 0.05 mIU/mL# j$ \1 O) Z4 m- ?' @* _
(prepubertal).
: c) \8 W- o& ~5 t: i( tThe parents were notified about the laboratory2 }7 `* D3 O7 Y+ t; g6 _3 o
results and were informed that all of the tests were
% E1 A* z' ~1 ~7 Q$ Qnormal except the testosterone level was high. The2 ^5 a5 _: ]0 W* J- f+ `# Y
follow-up visit was arranged within a few weeks to9 J; K0 w* H! e# M+ Q8 ]: h5 `
obtain testicular and abdominal sonograms; how-3 W( f. e4 b! O5 d. U+ Y8 g1 r
ever, the family did not return for 4 months.& ]2 m: H( A$ [& y+ Z2 j' G
Physical examination at this time revealed that the; k0 ?% Z8 ]+ }) ]: R$ d
child had grown 2.5 cm in 4 months and had gained
. P7 D6 F1 F4 O! h s# e4 b2 kg of weight. Physical examination remained5 ^; A* @3 ^; u( r' @
unchanged. Surprisingly, the pubic hair almost com-6 {5 _9 I. z/ L. k: c5 a
pletely disappeared except for a few vellous hairs at
4 L; J, Y5 H' C B3 w" G1 dthe base of the phallus. Testicular volume was still 26 q, x" B/ k: U' [, D
mL, and the size of the penis remained unchanged.
" c1 v) ~: d( M; t& d4 q! u; VThe mother also said that the boy was no longer hav-
' A" q& D& O1 ping frequent erections.0 _) a e: }" g0 p
Both parents were again questioned about use of
/ R6 Y5 Y3 Z! E: z5 K) [any ointment/creams that they may have applied to
- x b5 y/ K# f7 g2 c9 }/ Tthe child’s skin. This time the father admitted the+ g: R$ G& {7 {- q: R& k
Topical Testosterone Exposure / Bhowmick et al 541) Y: H4 q2 p) O6 s/ C
use of testosterone gel twice daily that he was apply-
( Q* U! p" y3 Z5 }" C6 W' Hing over his own shoulders, chest, and back area for0 ?! e Y- ?8 p( [6 ~; |: R- p% B
a year. The father also revealed he was embarrassed1 \& l# P' c" p* Z7 d
to disclose that he was using a testosterone gel pre-0 L0 _" t) c+ v' v
scribed by his family physician for decreased libido$ l/ [# e3 V0 e9 f) Y" E/ \4 J
secondary to depression.
9 I& I3 L0 t/ {' E2 }: x$ B4 LThe child slept in the same bed with parents./ k' K3 x5 b( U0 N
The father would hug the baby and hold him on his
5 F; W' r0 ~8 i4 I( bchest for a considerable period of time, causing sig-$ B f% ]0 g- _
nificant bare skin contact between baby and father.& M/ R& F* d' E
The father also admitted that after the phone call,
, p% s! t2 d% e- Ywhen he learned the testosterone level in the baby0 R3 [. x* |; x: k5 ~
was high, he then read the product information: t# E% L G) G
packet and concluded that it was most likely the rea-
2 L5 `# {4 n1 J6 e. {4 `son for the child’s virilization. At that time, they
4 k1 A# M. k' gdecided to put the baby in a separate bed, and the* j. X, U9 q: w% d. h7 [# ]( e6 k9 M: D
father was not hugging him with bare skin and had
# t7 n$ H* w5 q! q. a% ~% N0 a, @been using protective clothing. A repeat testosterone3 B' z- Z. M2 Z; [% H8 K
test was ordered, but the family did not go to the
% R. A) Y+ {! c, R4 F4 X4 G5 G. ~laboratory to obtain the test.: g: B# k; D5 k
Discussion) b% t3 G% ?( k) r) c- J
Precocious puberty in boys is defined as secondary3 G9 c& t5 G- X! ]" x5 b' Q
sexual development before 9 years of age.1,4# C3 D2 u! s1 p
Precocious puberty is termed as central (true) when
( b4 P0 F+ |) l) x' git is caused by the premature activation of hypo-
6 K1 u" ~5 q. |6 F9 f6 tthalamic pituitary gonadal axis. CPP is more com-
1 W8 B: C3 E; ?+ j) }mon in girls than in boys.1,3 Most boys with CPP
: `, S* R/ q5 `! l2 G: O) mmay have a central nervous system lesion that is6 C7 t$ m0 e f* D) m
responsible for the early activation of the hypothal-
$ j. `( i5 p+ U6 S+ V, |amic pituitary gonadal axis.1-3 Thus, greater empha-
& V' c2 `' r/ ]* g3 o! c$ i# }sis has been given to neuroradiologic imaging in
/ p8 H. d4 t) @ e3 Y7 X$ [boys with precocious puberty. In addition to viril-+ \. x- s. I# \' h9 m; `
ization, the clinical hallmark of CPP is the symmet-3 `6 @" N s, I' D! S# R% M
rical testicular growth secondary to stimulation by
" x$ t0 j8 s/ kgonadotropins.1,3
& R1 Z) G0 q# {, cGonadotropin-independent peripheral preco-6 W! `; E* f9 B% U$ b% b
cious puberty in boys also results from inappropriate/ r( e6 L( s6 O0 c) v* N
androgenic stimulation from either endogenous or& i& A& C, i' O. P* \6 E; C1 @
exogenous sources, nonpituitary gonadotropin stim-1 ]8 i. ]" O# W4 s: g1 g
ulation, and rare activating mutations.3 Virilizing
& _/ y$ m7 t0 s+ j( c2 P7 Lcongenital adrenal hyperplasia producing excessive5 u$ ~+ W! g$ H
adrenal androgens is a common cause of precocious0 r; d4 c9 U8 @1 D: e$ M' z
puberty in boys.3,40 [; n9 J6 g: R
The most common form of congenital adrenal4 x7 L, k' M4 c4 S6 g
hyperplasia is the 21-hydroxylase enzyme deficiency.
0 n. ^8 z( H5 {The 11-β hydroxylase deficiency may also result in
6 c& \8 d' g9 u5 x! J% Aexcessive adrenal androgen production, and rarely,) a1 u: [- h, s9 z$ O
an adrenal tumor may also cause adrenal androgen6 u9 K3 i4 b3 J1 G+ h! L/ a; y* G# W- u
excess.1,35 q0 q9 T2 ?2 e; e+ {4 A/ c4 A8 o5 v: D
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from% t1 c J+ G2 J
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007" ~% I# }: y6 F
A unique entity of male-limited gonadotropin-
0 K# P6 ~5 Q" t$ Windependent precocious puberty, which is also known
0 l% ?* s& @1 k3 jas testotoxicosis, may cause precocious puberty at a8 o& f+ C, h8 B! H) b H$ Q" o
very young age. The physical findings in these boys# s/ K- c- C) Q( I j; O8 Q! C* \. w
with this disorder are full pubertal development,- l T/ n( a& g# M) e) v7 Q
including bilateral testicular growth, similar to boys
0 h( s8 A/ F0 ?, | e; }1 Iwith CPP. The gonadotropin levels in this disorder. f! ?" G' [* h2 d9 j
are suppressed to prepubertal levels and do not show
B3 v, Y+ p ^% [1 Z. i3 p, O/ lpubertal response of gonadotropin after gonadotropin-- {5 f9 h9 {( E* ]2 q' y; s1 V
releasing hormone stimulation. This is a sex-linked) p8 |! s8 K7 U% }3 k* ^$ _- l6 B
autosomal dominant disorder that affects only
/ `7 N" B3 ]+ W) ]males; therefore, other male members of the family; ]2 O, b1 a' S$ s
may have similar precocious puberty.3
' P3 l! b3 U9 n8 O2 U0 g5 Q; \In our patient, physical examination was incon-
5 G, l$ N: V9 E- t9 I, |! C& Nsistent with true precocious puberty since his testi-0 N+ P3 G/ I' S! J8 e
cles were prepubertal in size. However, testotoxicosis4 J- _: e9 u9 g; W9 a4 n
was in the differential diagnosis because his father
7 I+ J5 Q* v9 `2 S* ]( g/ ^6 [7 Ostarted puberty somewhat early, and occasionally,! a, r8 I9 }) C* I
testicular enlargement is not that evident in the
5 I6 t. U" Y6 Wbeginning of this process.1 In the absence of a neg-1 S) j, H7 ^- c# O1 `, T9 N2 q$ W& ^; b
ative initial history of androgen exposure, our; i9 h" d, [. a0 A, w7 i1 _
biggest concern was virilizing adrenal hyperplasia,
! L% {+ G4 w% l& F* K1 O+ ieither 21-hydroxylase deficiency or 11-β hydroxylase
& M, @* x, ~7 a' ?deficiency. Those diagnoses were excluded by find-
& `% M+ I- t) y s5 j4 O! u( Iing the normal level of adrenal steroids.4 u6 v* F8 h$ S# }2 l
The diagnosis of exogenous androgens was strongly
2 ^ e# q. \) G$ V* Rsuspected in a follow-up visit after 4 months because
8 |1 V6 S0 n0 T6 z- V: j: vthe physical examination revealed the complete disap-" T* T& y( S& W, A
pearance of pubic hair, normal growth velocity, and( K5 R1 b Q6 H+ }4 g
decreased erections. The father admitted using a testos-
% m2 w+ r( g3 [terone gel, which he concealed at first visit. He was- a# L2 K! B% c. P' x+ c% p/ {
using it rather frequently, twice a day. The Physicians’
. k$ G: Y3 Z* L. N, h4 k1 iDesk Reference, or package insert of this product, gel or% r: E5 |$ m& @
cream, cautions about dermal testosterone transfer to
: U$ d0 }1 V7 c) Z* m) _unprotected females through direct skin exposure.: w4 u j( i4 z9 x( G# z3 G- {
Serum testosterone level was found to be 2 times the
5 j+ [ p* _2 S5 g3 _baseline value in those females who were exposed to
# S" b5 W; m0 }2 A9 Z; N! N; Beven 15 minutes of direct skin contact with their male9 V* H% d/ W6 H
partners.6 However, when a shirt covered the applica-
+ }4 h7 y5 X, ^, S1 B5 b# ?tion site, this testosterone transfer was prevented.
3 R% i+ _7 k. Y% T! }" BOur patient’s testosterone level was 60 ng/mL,# |! |1 e5 r3 _( V( C; f; h
which was clearly high. Some studies suggest that
2 t2 D* y( o& J6 t& \" _dermal conversion of testosterone to dihydrotestos-7 ~& k' f' @: k2 [
terone, which is a more potent metabolite, is more
* z* T1 s% f3 J W V; r8 P6 Q" ~active in young children exposed to testosterone5 y4 H! s3 B0 n) g2 z0 S/ O6 W, _5 u
exogenously7; however, we did not measure a dihy-2 g- T- A" z. Z' B# U
drotestosterone level in our patient. In addition to! D- i# t( @5 z7 {: k9 \1 i
virilization, exposure to exogenous testosterone in
$ }( {$ r7 i% |children results in an increase in growth velocity and
1 T0 D( d s/ p. ]advanced bone age, as seen in our patient.
* R8 }; d2 Z5 |) l" C4 L* I0 WThe long-term effect of androgen exposure during
. T }' I0 U4 zearly childhood on pubertal development and final
$ p1 h8 {" n& iadult height are not fully known and always remain T" J4 G) j# t
a concern. Children treated with short-term testos-
1 `5 z! W! ], xterone injection or topical androgen may exhibit some: Q0 q7 ^9 ]% z/ T7 l8 ]1 |
acceleration of the skeletal maturation; however, after
b, o4 j6 i& `cessation of treatment, the rate of bone maturation
# B3 M6 f# L/ s' z# X+ b; s6 M, idecelerates and gradually returns to normal.8,95 u& E' ~. G# f D! |
There are conflicting reports and controversy
7 q. \( j7 s( x7 W+ Bover the effect of early androgen exposure on adult
3 w& C; G+ e- O% k, Xpenile length.10,11 Some reports suggest subnormal
0 d/ s) G+ _2 N) O Z, A$ l# }adult penile length, apparently because of downreg-
$ |6 U, \1 h/ ? n8 v8 n4 P" |" Lulation of androgen receptor number.10,12 However,
! W# p' [ Q5 ^+ d- a1 b: jSutherland et al13 did not find a correlation between1 q! o* Y, m5 Y5 c) k
childhood testosterone exposure and reduced adult8 H) ?! R) @; }: _& K$ t3 u
penile length in clinical studies.) E0 _8 f5 t8 `0 y6 |/ @) p
Nonetheless, we do not believe our patient is
7 [4 N0 A5 A9 ~- k9 wgoing to experience any of the untoward effects from" F% V2 R- [$ H3 S: P3 s( t
testosterone exposure as mentioned earlier because
. n3 X1 Y5 q0 s# _the exposure was not for a prolonged period of time.
# v0 P9 Z" _8 O3 u X' HAlthough the bone age was advanced at the time of+ U- z& ?) c2 ]0 v: g) ~
diagnosis, the child had a normal growth velocity at
7 o K% T* M. Z9 d1 h/ ?( v F, Dthe follow-up visit. It is hoped that his final adult
5 J+ K) ~7 M1 j; x9 Jheight will not be affected.
: ~' I: G; i |! f5 D( E2 yAlthough rarely reported, the widespread avail-% |7 A; q9 a7 R0 u. C. O. g7 n% l f
ability of androgen products in our society may
0 Z( m$ R0 x4 Hindeed cause more virilization in male or female
2 u0 U# }0 j' |4 ]children than one would realize. Exposure to andro-* d5 i; p G2 v( z
gen products must be considered and specific ques-8 L# Q0 a1 F2 \* S; w
tioning about the use of a testosterone product or8 M/ L K* v( }$ H) ^, @5 R9 t
gel should be asked of the family members during/ C f5 G0 _$ o
the evaluation of any children who present with vir-
/ I6 N5 G1 l) x, I( L6 Jilization or peripheral precocious puberty. The diag-2 v5 K& o+ k4 U
nosis can be established by just a few tests and by& l# Q V# u( o; A
appropriate history. The inability to obtain such a
$ y0 n o) f$ d- B' nhistory, or failure to ask the specific questions, may1 l" z; q1 ^! w ]$ r
result in extensive, unnecessary, and expensive5 `% V# \1 V X) P/ R
investigation. The primary care physician should be4 s0 M$ g& ^' F0 E2 @3 l# w9 W
aware of this fact, because most of these children4 Y, l) P" u/ ^$ n
may initially present in their practice. The Physicians’
9 o2 X; \% j; h! ~. o+ L4 uDesk Reference and package insert should also put a
& s! u$ o$ J$ o7 X* r' ewarning about the virilizing effect on a male or
+ ?* Y8 @& \4 nfemale child who might come in contact with some-- U8 n0 v: C1 @& }% a4 ^. J
one using any of these products.
3 a" w' O* r" b- {9 C7 j+ c$ j% i: aReferences* g# c F" T3 H- w0 {( ]
1. Styne DM. The testes: disorder of sexual differentiation
2 x% Y4 Q- x# o% X. R3 band puberty in the male. In: Sperling MA, ed. Pediatric
% A6 n! G5 G1 PEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
1 m' S+ G; t6 V" J- V2002: 565-628.
2 r" t5 Y, a4 I0 C; l* K; v, P( Q2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious9 c) L% G5 t& {/ y
puberty in children with tumours of the suprasellar pineal |
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