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Sexual Precocity in a 16-Month-Old8 M8 I+ I2 e8 \# w, u
Boy Induced by Indirect Topical
2 I4 Y" y/ ^ M/ M, a5 gExposure to Testosterone
. A. w$ s+ U# y: U: GSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
9 P) k2 Y; A1 a8 d9 t' Mand Kenneth R. Rettig, MD1
% z8 C" K. Q4 kClinical Pediatrics
7 P9 E7 V; Y% V; M* @1 K' ?Volume 46 Number 67 z8 J, [! ^3 V( n8 d8 i: B+ l O
July 2007 540-543) t# T j. ^8 o- f x
© 2007 Sage Publications! y! k* ~8 V0 b, S$ t4 q! C/ e
10.1177/0009922806296651" M" j: G' j3 S2 j
http://clp.sagepub.com9 G/ }! k1 N! I% F! k' o
hosted at
. @7 z7 D6 o% U% l. x! N- h) Qhttp://online.sagepub.com4 s+ b& V6 w+ ]3 u; J
Precocious puberty in boys, central or peripheral,1 {* \$ q4 w9 ?8 N+ d0 P' k
is a significant concern for physicians. Central5 F# M" u R- T3 y# T; _4 I
precocious puberty (CPP), which is mediated
; z/ r/ t8 R& c! I1 b5 x: e3 Hthrough the hypothalamic pituitary gonadal axis, has( S+ T0 `2 z' x: ?3 r2 C% b
a higher incidence of organic central nervous system
. Q _7 o6 L3 q8 y/ [lesions in boys.1,2 Virilization in boys, as manifested
. \, n4 y9 l# |7 mby enlargement of the penis, development of pubic6 ~9 H5 C: o/ ]; d _% [5 W
hair, and facial acne without enlargement of testi-# _& q+ @6 H, o* C+ w
cles, suggests peripheral or pseudopuberty.1-3 We8 Q; J( B: b5 K3 e: _, w$ V
report a 16-month-old boy who presented with the. E3 Z& \( j8 r% }" ~
enlargement of the phallus and pubic hair develop-) o* y8 Y5 C( t' A) P) G1 c
ment without testicular enlargement, which was due5 R: W9 V9 v. ]/ G! G3 }) w
to the unintentional exposure to androgen gel used by, V% r+ P# ~! T+ g! ~
the father. The family initially concealed this infor-& r8 \0 z# |6 U: }' `
mation, resulting in an extensive work-up for this
8 V! ?( l/ ]3 Kchild. Given the widespread and easy availability of
3 B4 A' ?* |# a' @: Z# Q; jtestosterone gel and cream, we believe this is proba-
8 V$ h0 l; }) q3 E$ cbly more common than the rare case report in the) k4 m8 U! _# v. d1 x
literature.4
' X, q5 {& M: `# e" K, FPatient Report
# G5 Z8 z" V2 d5 rA 16-month-old white child was referred to the6 n# t/ Y6 g) k! a8 c
endocrine clinic by his pediatrician with the concern3 v9 E; A0 ?3 O: m
of early sexual development. His mother noticed" ]- y( b1 r9 a \% `
light colored pubic hair development when he was
, O, W/ X$ O! ?; p T; l% ~7 C" KFrom the 1Division of Pediatric Endocrinology, 2University of
& i ]. E) p5 t' \; w% dSouth Alabama Medical Center, Mobile, Alabama.9 {! g+ S4 y& Q+ J$ K0 m6 x6 t
Address correspondence to: Samar K. Bhowmick, MD, FACE,1 B0 }8 ]' K# u( a, Z' t: ?
Professor of Pediatrics, University of South Alabama, College of
( P9 y; ?4 A" ~Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;4 i9 A3 Z! R1 c f% f
e-mail: [email protected].
" |$ I; A; K4 H" W& z Kabout 6 to 7 months old, which progressively became" s' ^0 ^" Y+ o: g& }' j' q
darker. She was also concerned about the enlarge-: q/ W: i/ f2 `' v& _: U
ment of his penis and frequent erections. The child
9 n1 D8 `( {, H/ T9 G+ \was the product of a full-term normal delivery, with
! V, M5 H8 G! c0 e$ T- ba birth weight of 7 lb 14 oz, and birth length of9 K5 `( ^* a4 t) ]' G
20 inches. He was breast-fed throughout the first year( w0 H; L2 v+ f: h) G
of life and was still receiving breast milk along with
3 r# |: l3 `2 \0 {0 G; Esolid food. He had no hospitalizations or surgery,' r: m$ t9 R1 A9 p) b5 `# L1 s% H
and his psychosocial and psychomotor development5 ?0 m& d; o+ u) t
was age appropriate.
) _7 i5 U6 S$ g) P) Y0 p3 NThe family history was remarkable for the father, M7 z7 P4 q8 g$ w
who was diagnosed with hypothyroidism at age 16,
) f0 m5 J- U e3 l0 [( X% Iwhich was treated with thyroxine. The father’s
. @9 Z7 ~$ E# B5 v! H1 zheight was 6 feet, and he went through a somewhat
# s" g3 m. f2 I7 E$ L8 qearly puberty and had stopped growing by age 14.
2 a& Q3 ~) m5 a4 v, t: y- ZThe father denied taking any other medication. The+ L9 L7 w8 c* F! ]( M0 [4 E
child’s mother was in good health. Her menarche# P9 c0 `9 a4 o! m: O
was at 11 years of age, and her height was at 5 feet, c2 y: Q4 u" F
5 inches. There was no other family history of pre- y' o; S" C8 j; {0 {
cocious sexual development in the first-degree rela-
% R& M5 X. R+ ]8 p0 ?* A2 ^tives. There were no siblings.3 p4 B m& ^( j
Physical Examination0 L# t3 l1 j) y1 f
The physical examination revealed a very active,. ~3 ], l: A1 Z& p
playful, and healthy boy. The vital signs documented/ e: r. R) `: E0 {: K+ m
a blood pressure of 85/50 mm Hg, his length was
: p6 B5 U# ~7 y6 }90 cm (>97th percentile), and his weight was 14.4 kg5 L$ x [9 S% M/ ~1 N( I
(also >97th percentile). The observed yearly growth3 Q& _& B, e' S6 x' ^% x
velocity was 30 cm (12 inches). The examination of
9 z3 p4 N( Y5 o# r* B) ~; Hthe neck revealed no thyroid enlargement.' b0 Z& E, d: f- |1 Q, \
The genitourinary examination was remarkable for G% _# k7 k/ m+ l) ], J
enlargement of the penis, with a stretched length of
- O v6 Q- p. K, e9 x! G8 cm and a width of 2 cm. The glans penis was very well
$ T) V; P& n# V/ J6 M+ Pdeveloped. The pubic hair was Tanner II, mostly around0 b5 O3 J& |9 c/ V: F7 f$ P( \" Z
540
# P9 Z) r3 N7 q* u+ d9 Oat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from2 m* g$ ^2 g# C, _
the base of the phallus and was dark and curled. The
' o$ N) V2 m3 I: s/ gtesticular volume was prepubertal at 2 mL each.
: l& h/ w* c8 T& i- uThe skin was moist and smooth and somewhat' w/ X) @& ^# m5 k, Y- |) E) b
oily. No axillary hair was noted. There were no
( Y0 d, {+ _6 l! |3 Mabnormal skin pigmentations or café-au-lait spots.1 n" u( y1 L& ]7 z1 j& p
Neurologic evaluation showed deep tendon reflex 2+
: O/ |0 ~4 u$ u- Dbilateral and symmetrical. There was no suggestion- k1 |- F* j% q' d/ f, N9 P2 [% k
of papilledema.
! E3 V0 V* O3 E. G+ PLaboratory Evaluation
- v/ g3 l; F3 N4 A: U' b" EThe bone age was consistent with 28 months by
" L# d) O, _# W- T; Z) t! Husing the standard of Greulich and Pyle at a chrono-
: }; \# |% f4 m9 e( P5 |logic age of 16 months (advanced).5 Chromosomal
- }: m2 t( d$ }* h& ]karyotype was 46XY. The thyroid function test. Z1 C+ e/ O1 \" m& U: {
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
, ?' f3 S0 v) Blating hormone level was 1.3 µIU/mL (both normal).1 Y1 x& i [1 d+ u, @7 A p! k
The concentrations of serum electrolytes, blood' V5 C9 g* Q% R y2 h0 s
urea nitrogen, creatinine, and calcium all were
! l6 O$ \1 P' }4 Vwithin normal range for his age. The concentration
4 [' z9 d q# W5 K# d/ Hof serum 17-hydroxyprogesterone was 16 ng/dL
7 Y+ X# N# w" d/ {2 w, ^* \(normal, 3 to 90 ng/dL), androstenedione was 20
+ n7 f9 Q' `8 w, i9 w; z- {$ Png/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
" k0 O. ^0 Q* h! {% hterone was 38 ng/dL (normal, 50 to 760 ng/dL),9 g7 R6 p" O9 F$ I3 K4 W. f
desoxycorticosterone was 4.3 ng/dL (normal, 7 to+ ~$ V& W5 J4 D: v
49ng/dL), 11-desoxycortisol (specific compound S)6 X& l7 ?) B- N/ U0 g5 a5 `
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-/ `6 i; w0 P+ s8 w. |) O9 ^! e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
$ G& C( C# n' ?8 U$ j- ytestosterone was 60 ng/dL (normal <3 to 10 ng/dL)," W d; r# W: z, d R. D0 }
and β-human chorionic gonadotropin was less than
+ L: I. u' @/ H5 mIU/mL (normal <5 mIU/mL). Serum follicular
$ `& i* v6 N7 I- v I9 pstimulating hormone and leuteinizing hormone
. U8 C. B% \6 @4 V+ c- [: g3 S# {concentrations were less than 0.05 mIU/mL' \" ^- Y1 ]5 H& Q
(prepubertal).
3 D' M: [% C1 O: q, q( y& yThe parents were notified about the laboratory$ f# A1 E2 C2 ^- z
results and were informed that all of the tests were# z7 _1 O& Y3 L% ?2 s1 D$ k
normal except the testosterone level was high. The& i+ ~' s l( R1 x) I/ Q' ?
follow-up visit was arranged within a few weeks to! m. _$ ]- n- H5 @ ]8 _
obtain testicular and abdominal sonograms; how-
6 r% ?" C- a. v N5 [+ p! {: Fever, the family did not return for 4 months.7 b2 y4 p0 G# \5 q' s, f9 r: L
Physical examination at this time revealed that the
% y+ j& D2 }8 T* f" d6 X( ~child had grown 2.5 cm in 4 months and had gained
- P4 l: d) ~9 R, [2 kg of weight. Physical examination remained" R8 l" u0 N9 E6 ]
unchanged. Surprisingly, the pubic hair almost com-
* C" J# L. L8 C. H! p" Gpletely disappeared except for a few vellous hairs at$ Z' I; B- J. \( p2 d: \
the base of the phallus. Testicular volume was still 2( C$ n9 Q! Q2 k* y# E# {( b
mL, and the size of the penis remained unchanged.
3 ?7 \$ J) j5 v9 GThe mother also said that the boy was no longer hav-/ p. N' s/ V- \0 @4 ^+ z
ing frequent erections.
! L& ?, B0 ~- e3 P0 c0 q) Z* _, [Both parents were again questioned about use of& c N' E, \; ^9 [; z# K
any ointment/creams that they may have applied to* h$ y- T) D6 b3 ?& f
the child’s skin. This time the father admitted the
9 A: N8 w1 D. Q, y8 E4 o" }Topical Testosterone Exposure / Bhowmick et al 541
6 o/ m% f" R% wuse of testosterone gel twice daily that he was apply-
0 v3 Z/ _9 v* k' Z4 y1 Sing over his own shoulders, chest, and back area for
4 s3 \) s! n e" ^& S& _a year. The father also revealed he was embarrassed% J# m# L0 _" H( C3 y0 ~& t
to disclose that he was using a testosterone gel pre-) H# }3 w: k3 p
scribed by his family physician for decreased libido
* R0 o- x/ \9 b" F Wsecondary to depression.
' V: Y$ V3 G* h# vThe child slept in the same bed with parents." E1 e6 q- \# z+ k
The father would hug the baby and hold him on his
! v4 r) \ s0 P5 v# C* ~chest for a considerable period of time, causing sig-) W8 z, C! m# g- R1 c
nificant bare skin contact between baby and father.
; Q9 A/ B5 e7 t( PThe father also admitted that after the phone call,
1 B( X5 _* p1 C1 t! V1 w! S hwhen he learned the testosterone level in the baby7 W2 K0 g5 ^: E, f' y [$ o
was high, he then read the product information2 M) n6 x( E7 }
packet and concluded that it was most likely the rea-6 R- Y. e" D5 Y- l
son for the child’s virilization. At that time, they
% S: @ P2 W5 Q W" wdecided to put the baby in a separate bed, and the
9 u; r" n2 i- N2 H& Y* wfather was not hugging him with bare skin and had
3 y) ^# A" s; R6 Cbeen using protective clothing. A repeat testosterone& ? ~# ?3 i1 H+ b% n. } r
test was ordered, but the family did not go to the& m0 B1 G% e+ y# c
laboratory to obtain the test.
/ p( N: V1 j6 }9 YDiscussion2 C6 c! {0 {, W. Z' r( {# @4 ?' _# L
Precocious puberty in boys is defined as secondary
J2 [, K, m. Fsexual development before 9 years of age.1,46 g4 L3 F) l% K) u" \
Precocious puberty is termed as central (true) when% n7 d1 Y' X8 P$ h
it is caused by the premature activation of hypo-
) n9 r5 ?0 C( S5 o- _6 xthalamic pituitary gonadal axis. CPP is more com-' l, L, ?: u- E
mon in girls than in boys.1,3 Most boys with CPP9 F- A L; o7 X4 H
may have a central nervous system lesion that is5 T$ A' ?$ M! B
responsible for the early activation of the hypothal-
$ E* E M, M; jamic pituitary gonadal axis.1-3 Thus, greater empha-3 j9 o H8 \- U9 {$ U5 c6 o
sis has been given to neuroradiologic imaging in: G. n2 ?2 |, e3 C- H
boys with precocious puberty. In addition to viril-$ h& ` L% l) l* ~ O8 y o
ization, the clinical hallmark of CPP is the symmet-
0 L# f' x/ L7 C9 n/ L a9 drical testicular growth secondary to stimulation by
1 N5 Z) c+ p; w9 @) B. v" @7 pgonadotropins.1,37 d6 E9 P h/ W/ ]( ~
Gonadotropin-independent peripheral preco-2 F% g6 X4 M4 K. a
cious puberty in boys also results from inappropriate
$ L$ X" @ H y" ?0 q+ {* Fandrogenic stimulation from either endogenous or3 S1 n% s& o3 k8 S
exogenous sources, nonpituitary gonadotropin stim-
& p; H, P/ Z1 W+ X$ `6 |; tulation, and rare activating mutations.3 Virilizing
8 L' M( S6 V0 G6 t3 b" J Scongenital adrenal hyperplasia producing excessive" X% D- m* r5 ?% _. F9 q5 a
adrenal androgens is a common cause of precocious; x/ i+ \% v- ~/ e1 ]+ J% x
puberty in boys.3,4$ h( J) x0 U: x A( j
The most common form of congenital adrenal! A9 Y3 K1 U; g5 a
hyperplasia is the 21-hydroxylase enzyme deficiency.: l, j) u+ t5 f# C1 `4 p: S+ m
The 11-β hydroxylase deficiency may also result in
, U6 x' L. a* B! b2 u# [excessive adrenal androgen production, and rarely,$ X3 O. M" |/ h" M- \/ I9 Q/ D
an adrenal tumor may also cause adrenal androgen9 D3 E3 R3 K9 M
excess.1,3
0 r+ i4 e; ~& V6 ^ P9 m2 iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
8 c, F3 D, _0 Q' E542 Clinical Pediatrics / Vol. 46, No. 6, July 20073 w7 Q- P) j4 s: h8 i
A unique entity of male-limited gonadotropin-6 X" X7 W S- o: H7 ^, J: O0 L# m
independent precocious puberty, which is also known. @: j0 I* I3 p+ J- d0 N
as testotoxicosis, may cause precocious puberty at a* ~% D5 }$ M5 [6 [9 N# U+ G
very young age. The physical findings in these boys6 |, Y. n, b7 x7 D
with this disorder are full pubertal development,
3 V t0 V& Q* M! g% v; q) |1 jincluding bilateral testicular growth, similar to boys( ~0 e8 h% O5 e" P
with CPP. The gonadotropin levels in this disorder
8 a- D: O+ G* h1 [/ W0 w4 e% Zare suppressed to prepubertal levels and do not show8 P6 A; L5 j3 ^ N, {. k: Q
pubertal response of gonadotropin after gonadotropin-
+ u- e* j9 \5 {* S4 i1 rreleasing hormone stimulation. This is a sex-linked
+ G! D% J) e: j' z: C& f$ p4 aautosomal dominant disorder that affects only
7 g1 ^ c: w0 o) M; F# N" Mmales; therefore, other male members of the family
+ _7 u- V) e/ E/ [* i) ?9 Y" {may have similar precocious puberty.30 n8 Q* p1 a9 N6 B" T8 {: e; i
In our patient, physical examination was incon-7 e$ D: X E, w) ^4 u4 P9 e
sistent with true precocious puberty since his testi-; u* F1 a0 K4 n# N4 T* e
cles were prepubertal in size. However, testotoxicosis7 M0 L' J$ O% Y; H
was in the differential diagnosis because his father& Y( ]7 f( @, c
started puberty somewhat early, and occasionally,- ^4 L& i7 _- P2 C" N: b
testicular enlargement is not that evident in the
* P {& R4 n" ] G" v! Pbeginning of this process.1 In the absence of a neg-7 O' | h* z- D! O: w
ative initial history of androgen exposure, our4 g+ ?4 n+ X, W% a
biggest concern was virilizing adrenal hyperplasia,
$ m4 l- B5 E5 ^) Jeither 21-hydroxylase deficiency or 11-β hydroxylase
6 N. h! Z2 }8 K+ U1 A# Sdeficiency. Those diagnoses were excluded by find-
" o; M; b8 ^. \3 bing the normal level of adrenal steroids.
; {2 L$ {" i5 i; aThe diagnosis of exogenous androgens was strongly
) Q( T' L! j. W$ Bsuspected in a follow-up visit after 4 months because* f6 v: E# X1 g+ @& @
the physical examination revealed the complete disap-
3 a1 U8 ? M/ ]$ i. e7 Zpearance of pubic hair, normal growth velocity, and& r: w8 U+ R- I/ j+ ^: h7 M
decreased erections. The father admitted using a testos-' f& o! _2 a& X" N9 M+ K' f* Z
terone gel, which he concealed at first visit. He was
. w' }+ ~7 _! g. E: Ausing it rather frequently, twice a day. The Physicians’
" h1 g5 W; W" k8 T" R$ M8 tDesk Reference, or package insert of this product, gel or! @, H5 G+ r4 L
cream, cautions about dermal testosterone transfer to; r c! M4 w$ b
unprotected females through direct skin exposure.7 d$ i! r4 Q9 Q" e5 w7 b2 S0 U" w8 {6 g4 L
Serum testosterone level was found to be 2 times the
9 U k" x3 n( ~% b+ a$ c7 l hbaseline value in those females who were exposed to
4 i+ z6 S" f* |even 15 minutes of direct skin contact with their male
' Q0 \+ ~, _) gpartners.6 However, when a shirt covered the applica-
9 v1 \# o) [: b+ `& e2 N! o9 H/ Mtion site, this testosterone transfer was prevented.
9 P8 r5 A) Q, D2 V3 z* T. ^Our patient’s testosterone level was 60 ng/mL,9 K7 f6 w6 x8 i/ m. y
which was clearly high. Some studies suggest that
) n% @0 |+ M9 u( }( \8 ?8 J/ Edermal conversion of testosterone to dihydrotestos-$ O, `4 ?9 t3 T6 E- s( d
terone, which is a more potent metabolite, is more0 H1 J# r" I/ [8 ~
active in young children exposed to testosterone& ^. m0 m) \2 d# @/ r' @0 j" x
exogenously7; however, we did not measure a dihy-! E& L' v% S/ E/ O2 v4 G5 q' p
drotestosterone level in our patient. In addition to
, c4 u( P7 k1 O" D- D' [virilization, exposure to exogenous testosterone in; k: k6 n- {) j
children results in an increase in growth velocity and
v( N+ H# M& C. ?- l. q! \advanced bone age, as seen in our patient.
* M2 y) l6 d3 ?The long-term effect of androgen exposure during
0 z3 N8 s2 f* Z9 i: hearly childhood on pubertal development and final
% y# d, n! c3 f0 w: hadult height are not fully known and always remain
- |# B, L2 A9 D/ N3 ~7 Na concern. Children treated with short-term testos-
6 ]; |" y' ] q. wterone injection or topical androgen may exhibit some
& G) A# w5 F1 |0 V' U. |acceleration of the skeletal maturation; however, after) V6 u3 Q( r: v
cessation of treatment, the rate of bone maturation
" e6 F: \/ F$ \% z9 t9 jdecelerates and gradually returns to normal.8,9
* R5 t" G- j' }) bThere are conflicting reports and controversy
1 }# k& T2 n* {- [# v Eover the effect of early androgen exposure on adult
- ?: M6 o: S) m/ Y( _penile length.10,11 Some reports suggest subnormal3 d; k3 s& |' u7 `
adult penile length, apparently because of downreg-$ C6 W% e" P, S e1 w* }, ]' N
ulation of androgen receptor number.10,12 However,6 R' p$ r$ [0 N# O' }, C
Sutherland et al13 did not find a correlation between" V5 P) K3 z% i; V9 c- ]) \
childhood testosterone exposure and reduced adult
7 c/ ^ D$ ^. A6 E7 Dpenile length in clinical studies.
3 A4 a5 Y/ E# Y8 B7 N; oNonetheless, we do not believe our patient is3 R9 p6 I3 ^( J8 |
going to experience any of the untoward effects from
+ B) U0 r: \& F! f( F R: Ctestosterone exposure as mentioned earlier because
" A- F3 `' l3 Xthe exposure was not for a prolonged period of time.
% b; d# Z# Z6 e: ~5 p# i9 RAlthough the bone age was advanced at the time of
& ] i+ d7 x o: T/ B$ _6 gdiagnosis, the child had a normal growth velocity at
! E" D {' K+ f; m1 G8 |4 kthe follow-up visit. It is hoped that his final adult4 c: B P- _: q' e
height will not be affected.
1 e, Z3 b( N& P5 D) jAlthough rarely reported, the widespread avail-
+ T( ^: f9 W; }) u; Lability of androgen products in our society may; X/ V2 I% Q: k* L
indeed cause more virilization in male or female' C# I: y' p/ z7 a) |
children than one would realize. Exposure to andro-" q5 k* h- b% ]6 v, _6 o' W5 U
gen products must be considered and specific ques-
% }0 c( w0 _, ntioning about the use of a testosterone product or
, w& G5 W8 Q: L- \ S) v' [gel should be asked of the family members during* q/ c1 u7 W D
the evaluation of any children who present with vir-
6 [6 B, U* s' R( @ilization or peripheral precocious puberty. The diag-/ |6 d7 \( F" Q) d1 U
nosis can be established by just a few tests and by
I& {6 ~, ]% p. jappropriate history. The inability to obtain such a/ W {7 r3 c9 x4 Q5 z; @" \
history, or failure to ask the specific questions, may
$ z# J2 y: i( I; _" H% b2 p- Lresult in extensive, unnecessary, and expensive& |7 L- T& B! }3 n# ~5 K! n
investigation. The primary care physician should be+ ?0 W/ T1 n9 ]) ]7 {* ?
aware of this fact, because most of these children0 H9 z U2 s+ b0 o+ F& T
may initially present in their practice. The Physicians’
' o4 f/ l$ |9 M7 E- U }Desk Reference and package insert should also put a) |0 W4 s \9 R) x
warning about the virilizing effect on a male or! n' c/ V% u4 u* v4 Z
female child who might come in contact with some-1 z1 x0 w. e0 P' i! T6 J4 w
one using any of these products.
5 V$ f( a" k. p" K4 B6 @& w U; fReferences; d. `( h7 A0 |0 X; t8 L+ y5 [( g5 d
1. Styne DM. The testes: disorder of sexual differentiation
* z4 F1 z6 o1 r6 e ~/ L% Gand puberty in the male. In: Sperling MA, ed. Pediatric3 p& ]% K+ L6 w- y+ n" B; V V5 s
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;) r, {7 t# f0 z& h& E, C
2002: 565-628.
0 E# h+ ^# H* f2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious6 ]2 U/ E ?7 b/ i7 b
puberty in children with tumours of the suprasellar pineal |
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