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Sexual Precocity in a 16-Month-Old$ |" \! M2 x/ ]- H3 ~
Boy Induced by Indirect Topical/ R. X, w% J& `! ~$ @
Exposure to Testosterone9 F ^7 n9 z$ S* a+ f5 B$ ^
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2# _0 _+ o/ X4 [" ? @, n9 R9 E
and Kenneth R. Rettig, MD1( B% f8 q/ q( n2 e
Clinical Pediatrics# @. t/ T) t i7 V" A+ r
Volume 46 Number 6
# H* T! ?, I8 W6 P. F+ D! {, [July 2007 540-543/ {# U) b& H# x& t+ P6 \
© 2007 Sage Publications$ L/ U" C" j% U$ _: r
10.1177/0009922806296651
% i& q6 z3 W6 `# Q6 jhttp://clp.sagepub.com
4 J. W; Q' g2 w: x5 m/ {: W, Mhosted at' E' z" t* h/ y( v
http://online.sagepub.com
; X' C! {+ W- B+ H( TPrecocious puberty in boys, central or peripheral,, @; a, K5 S8 t: Y, s; I
is a significant concern for physicians. Central
& H( E/ b( X7 R2 H J- I& Oprecocious puberty (CPP), which is mediated5 |4 a t4 }3 U$ p; H1 Z. H) Z* I& I# S- B
through the hypothalamic pituitary gonadal axis, has' d1 }8 ]( b4 B
a higher incidence of organic central nervous system4 G5 C$ `6 m0 P: S+ t
lesions in boys.1,2 Virilization in boys, as manifested
$ d: h x0 ^* d, q8 }& L: j9 Oby enlargement of the penis, development of pubic
8 C8 o8 J6 S4 H2 h1 `. \1 ]hair, and facial acne without enlargement of testi-! N2 k+ p: y: Q2 _- b$ u" X `8 w+ U
cles, suggests peripheral or pseudopuberty.1-3 We# ~' V0 ^6 y8 }) i' m/ K
report a 16-month-old boy who presented with the
& c3 T1 W$ `9 Q" h( y& Renlargement of the phallus and pubic hair develop-
# m" A9 l. ?7 M; Q/ f3 jment without testicular enlargement, which was due: B ~2 Y/ {' _2 X( Z5 y ~
to the unintentional exposure to androgen gel used by
* N2 u; J7 A$ B9 E, }4 qthe father. The family initially concealed this infor-, g! u/ V* H, @3 a9 X
mation, resulting in an extensive work-up for this
+ K9 F; t& H( b( Kchild. Given the widespread and easy availability of- U0 d+ s8 d2 f B4 }7 ~: P. B
testosterone gel and cream, we believe this is proba-. a$ L; J* J. b( F. m
bly more common than the rare case report in the
6 `* r% F4 X3 O- eliterature.45 X* R3 A8 u& G4 k) |
Patient Report- M+ n! e- u, `6 j' i( t
A 16-month-old white child was referred to the
% X# v s0 z" ~endocrine clinic by his pediatrician with the concern
% W2 m; A, g0 C7 |6 bof early sexual development. His mother noticed+ ?" `' Q: c$ L6 m7 N' j' V
light colored pubic hair development when he was- y! j8 U/ }: o9 Z3 x
From the 1Division of Pediatric Endocrinology, 2University of5 W/ V: [2 |' C% V+ F9 d: f! g. m
South Alabama Medical Center, Mobile, Alabama.
; b# `1 e: E- W% t P2 h! RAddress correspondence to: Samar K. Bhowmick, MD, FACE,
" h \! h3 i% p' MProfessor of Pediatrics, University of South Alabama, College of
+ v s- Z* m+ L, |" d- ^8 n2 LMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
! Y+ g4 G- O$ [e-mail: [email protected].2 l$ W) J- F; }
about 6 to 7 months old, which progressively became$ h, X; W- p# v" @8 Q. v0 X
darker. She was also concerned about the enlarge-
) D& J/ P6 ]8 c. H; m& l* b. b& e4 Lment of his penis and frequent erections. The child! r6 s* G* L# n
was the product of a full-term normal delivery, with
6 d$ _: @* A8 P3 ba birth weight of 7 lb 14 oz, and birth length of+ u* N ?1 a( _7 Z) B$ `/ `% Y+ O
20 inches. He was breast-fed throughout the first year& p* p {- M' r/ p! p9 L
of life and was still receiving breast milk along with; R+ |# {* r1 p$ L% y3 R7 _
solid food. He had no hospitalizations or surgery,
9 v% X: U0 e; @: vand his psychosocial and psychomotor development
. a* Z6 J* U1 l3 Iwas age appropriate.
0 s3 @1 ^% U: N- ~7 z8 s4 @; ~* W4 b( RThe family history was remarkable for the father,6 F- Q/ k* U( k: B( k7 `- F
who was diagnosed with hypothyroidism at age 16,
5 T8 ^- ]9 J# @8 S; [which was treated with thyroxine. The father’s
, Y: s# h. D4 X3 Y8 o- Nheight was 6 feet, and he went through a somewhat7 V! R' I% L$ p7 T. R
early puberty and had stopped growing by age 14.( s8 i& G# I& Z0 I3 p& i
The father denied taking any other medication. The
, \! _/ l# m3 Z/ D o9 Tchild’s mother was in good health. Her menarche
( K" e0 B) ^/ U1 K; L. M gwas at 11 years of age, and her height was at 5 feet
j! p. h9 d' @8 {# f1 Z; q% w Y2 n5 inches. There was no other family history of pre-
0 v0 ]! |8 b! ^/ D: ^+ E6 W; ~* icocious sexual development in the first-degree rela-
d2 n- ?4 h k7 utives. There were no siblings.
) o' H8 j$ Y1 D4 q' x( D, DPhysical Examination) J' C* _9 Y k; h- X+ x" i
The physical examination revealed a very active,
5 D/ B5 Y' R. V3 o' B5 wplayful, and healthy boy. The vital signs documented" H& m$ t4 C' k9 e9 o- x
a blood pressure of 85/50 mm Hg, his length was; B H% y7 J- D. G: k0 |( P" ^
90 cm (>97th percentile), and his weight was 14.4 kg! |: ]4 w* `3 Y6 s! Q
(also >97th percentile). The observed yearly growth
7 p6 s1 n- w" K0 k3 A! {: q* [velocity was 30 cm (12 inches). The examination of
; H7 @1 F& ?% ]) z9 M" B8 C4 Mthe neck revealed no thyroid enlargement.
0 p' ?$ K5 B! j% `+ hThe genitourinary examination was remarkable for# _% t% _/ \3 ?8 @
enlargement of the penis, with a stretched length of l& |. l0 C2 E/ h m3 J5 @& a2 E
8 cm and a width of 2 cm. The glans penis was very well& |* I% Q0 R' u6 z. k
developed. The pubic hair was Tanner II, mostly around/ {; a- N8 x! J
540
1 H6 S7 S( z% M6 c6 i4 z5 a: W+ Tat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from- j/ p% x# d! E! s
the base of the phallus and was dark and curled. The
. y1 R: ]; D0 P* s( s* P6 u/ N" N5 Etesticular volume was prepubertal at 2 mL each.
+ F) a' p' x, k! f. p! uThe skin was moist and smooth and somewhat2 @" e0 b! A5 {" `9 U0 S
oily. No axillary hair was noted. There were no
5 B" x X- |# Pabnormal skin pigmentations or café-au-lait spots.
0 `4 i9 `" b" `9 `4 d# M9 u# }8 xNeurologic evaluation showed deep tendon reflex 2+1 \" J Y( i* c1 n
bilateral and symmetrical. There was no suggestion) Z% m; A6 e1 L; c# X/ @
of papilledema.
6 f: X* q( I" K8 fLaboratory Evaluation1 m+ F: j7 p5 i! Y+ ~
The bone age was consistent with 28 months by9 N/ K6 W' @, X. a
using the standard of Greulich and Pyle at a chrono-+ @; E. }" y1 T" e
logic age of 16 months (advanced).5 Chromosomal" \2 r- `* J v) T+ d# a6 o; A
karyotype was 46XY. The thyroid function test
1 a* C7 g& t6 Q& V' V/ Pshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
1 _8 n/ n' X8 D! V* Xlating hormone level was 1.3 µIU/mL (both normal).
& P @: {& l; r7 g7 @ k z( c/ YThe concentrations of serum electrolytes, blood
8 d: U7 j7 T; t7 l. ?1 qurea nitrogen, creatinine, and calcium all were
( }4 l) q; K$ iwithin normal range for his age. The concentration
" q( f5 H1 h ]: C; `8 xof serum 17-hydroxyprogesterone was 16 ng/dL
1 G, q2 X F# L- T6 m! G(normal, 3 to 90 ng/dL), androstenedione was 20
2 O1 s$ D" |" e# f/ kng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-& J- n' ]& R. _" ~/ v
terone was 38 ng/dL (normal, 50 to 760 ng/dL),1 r/ L1 Z- ~% ?% S0 v4 A+ a
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
* y$ I9 o8 j5 i9 V w, g49ng/dL), 11-desoxycortisol (specific compound S)
- ]6 Q4 h/ y; b+ e: `" @+ c7 [was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
4 b0 `0 Q. A6 m$ l8 `3 htisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
9 s4 \9 s# l8 [testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
5 D& V+ j; q4 N! S; nand β-human chorionic gonadotropin was less than
$ P2 |& l( f9 B" h+ y* z5 mIU/mL (normal <5 mIU/mL). Serum follicular- h2 o8 m3 `3 q/ P' l( i+ E* k7 H, y
stimulating hormone and leuteinizing hormone) }8 j/ R! R7 k4 K% [
concentrations were less than 0.05 mIU/mL
5 ~& S, g, @3 _6 [( V2 ]) i6 V(prepubertal).4 A) J7 m6 @! E5 K o
The parents were notified about the laboratory
+ V+ Z3 q+ [3 a ~4 l6 mresults and were informed that all of the tests were) ^2 O" X: A, p
normal except the testosterone level was high. The% F2 R4 K' o# P# y' w
follow-up visit was arranged within a few weeks to
& X( [3 j3 g6 l% nobtain testicular and abdominal sonograms; how-
9 o/ T8 c* _1 Y2 L) r% pever, the family did not return for 4 months.
8 S, D2 c3 A. M3 j7 tPhysical examination at this time revealed that the9 K# C4 N6 V' ]7 S. ?
child had grown 2.5 cm in 4 months and had gained- V% v0 d) p: P% v- a! z9 {4 D
2 kg of weight. Physical examination remained
5 f2 |' Y2 X" D( j. c Zunchanged. Surprisingly, the pubic hair almost com-
6 I4 n e( j0 i/ B( apletely disappeared except for a few vellous hairs at
9 O9 V m+ W: e! ~3 f/ c/ r+ \the base of the phallus. Testicular volume was still 2
, ~; D5 ]. q) [( bmL, and the size of the penis remained unchanged.. i. u8 E' f+ a
The mother also said that the boy was no longer hav-) U2 i) T) v5 Z& _" s s, T
ing frequent erections.
! z$ [/ b& F! S+ y1 l% g, tBoth parents were again questioned about use of9 I3 P, y. M3 Z! Q5 r" M
any ointment/creams that they may have applied to
+ G4 x) Q; u- H5 }$ J) athe child’s skin. This time the father admitted the
; M# J6 _+ g9 lTopical Testosterone Exposure / Bhowmick et al 541
( N" c1 Y7 g0 yuse of testosterone gel twice daily that he was apply-( e$ M e* c# K5 W( u& g- ]8 [
ing over his own shoulders, chest, and back area for9 @4 ^7 T+ d. Y; U4 p' [ L, R
a year. The father also revealed he was embarrassed
; Q) {, R. p) Z: yto disclose that he was using a testosterone gel pre-
. }- w, a. k5 T" yscribed by his family physician for decreased libido8 Q5 K F3 Y" b
secondary to depression.* l0 g9 Q% X2 o& Y) ^7 ?: J. ?6 q
The child slept in the same bed with parents.
4 C6 `% {8 c3 VThe father would hug the baby and hold him on his+ e) O) x \' z$ S
chest for a considerable period of time, causing sig-& v% r6 _5 m) p9 ?& e5 v/ Z; g
nificant bare skin contact between baby and father.; U& A& a# S3 Z Z5 D7 d
The father also admitted that after the phone call,/ W d6 ]! A5 W& w8 a
when he learned the testosterone level in the baby
) m; i$ H3 }6 @4 Awas high, he then read the product information, t8 [) [6 g! a1 N) F7 _
packet and concluded that it was most likely the rea-( D- m/ ?9 w! G \
son for the child’s virilization. At that time, they% m% w% _7 \1 [' H" C( E
decided to put the baby in a separate bed, and the+ I; P+ e1 K& j% L4 e0 m3 K
father was not hugging him with bare skin and had2 j! R( ~, e+ {( E
been using protective clothing. A repeat testosterone1 f+ A A: u6 v( K0 s7 ]& _) N
test was ordered, but the family did not go to the
5 I+ y# l# m$ m/ y, Ylaboratory to obtain the test.3 B+ s! C- \4 n$ x v% c0 b
Discussion
, K% W# t# C& ^! K3 z' l2 WPrecocious puberty in boys is defined as secondary
& e9 T) D1 j) ?+ Q( H) t' esexual development before 9 years of age.1,4
, [& P4 D, `9 k+ z$ ZPrecocious puberty is termed as central (true) when2 J9 ^/ ~. Z0 [" p
it is caused by the premature activation of hypo-
& K& j& d2 A* x4 }( T( ythalamic pituitary gonadal axis. CPP is more com-! R: @! b. ]' Q: {8 p
mon in girls than in boys.1,3 Most boys with CPP
; ~4 Z; y N+ ?may have a central nervous system lesion that is5 |4 b# Y' L; E& r
responsible for the early activation of the hypothal-
8 K7 ~7 {2 M) r0 Z" [3 k: d9 v- |6 Camic pituitary gonadal axis.1-3 Thus, greater empha-7 u( C( f* L/ A+ L8 F
sis has been given to neuroradiologic imaging in( n' M* P) B4 s5 r% t. i2 g3 C
boys with precocious puberty. In addition to viril-
" k5 f! Z) T* A# \ization, the clinical hallmark of CPP is the symmet-1 s$ u8 w Z; {; K: U+ a
rical testicular growth secondary to stimulation by1 l0 p: i0 ~: ~" m
gonadotropins.1,3) o/ J' v4 h" R- Y4 a, w- x
Gonadotropin-independent peripheral preco-- \/ {. X8 S; I* t1 D# f
cious puberty in boys also results from inappropriate
6 }$ t# o/ u% A E" `androgenic stimulation from either endogenous or) l& w. T9 \( {* T! @6 K
exogenous sources, nonpituitary gonadotropin stim-4 L6 ^; }" u+ R4 B5 c
ulation, and rare activating mutations.3 Virilizing+ y/ m% P2 C5 _
congenital adrenal hyperplasia producing excessive
8 J+ b0 P+ h, S* v6 \3 padrenal androgens is a common cause of precocious
% q) @& r9 V4 I# O! vpuberty in boys.3,42 T W" c4 a2 Z$ ~
The most common form of congenital adrenal; E+ h- q! @, u
hyperplasia is the 21-hydroxylase enzyme deficiency.
( b; e" z# a) bThe 11-β hydroxylase deficiency may also result in2 G$ I: T3 o# l
excessive adrenal androgen production, and rarely,: N: }! S0 I. n8 C" h* i) R
an adrenal tumor may also cause adrenal androgen/ k. ]0 R+ s7 o0 o: n
excess.1,3! y0 m$ R9 x ]$ j' C# r
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from5 R/ W3 Q, S5 O0 b$ N. d
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
- d; V: i4 m& r% w% x, T& KA unique entity of male-limited gonadotropin-
% B. _8 R, d1 Z2 }$ N8 L$ Xindependent precocious puberty, which is also known
4 O) |# t2 @+ Pas testotoxicosis, may cause precocious puberty at a& T7 o- x+ \5 h- Z6 M0 e$ |# F. L
very young age. The physical findings in these boys' O/ E. X: m3 g. n
with this disorder are full pubertal development,
( J9 G2 \; Q! m5 X/ Gincluding bilateral testicular growth, similar to boys
! s0 \) X' @* F2 owith CPP. The gonadotropin levels in this disorder" o& j' o" T; q
are suppressed to prepubertal levels and do not show0 i7 c$ ^% s: D5 }; k) M' y
pubertal response of gonadotropin after gonadotropin-
! ?9 N" J% @$ lreleasing hormone stimulation. This is a sex-linked0 T+ ~' K- y, y
autosomal dominant disorder that affects only
8 w( ~# i) k" N9 [% [ T& Lmales; therefore, other male members of the family
% P4 ]% Y' `+ r5 M# }4 v" o' pmay have similar precocious puberty.3
% Y f6 o1 g) _In our patient, physical examination was incon-% ?6 G8 D( }5 z9 C
sistent with true precocious puberty since his testi-9 j8 q. t& X7 ? x
cles were prepubertal in size. However, testotoxicosis
6 ^( n- r$ o# {$ Xwas in the differential diagnosis because his father+ _9 E- ]- W2 N9 A$ |+ B( X5 A
started puberty somewhat early, and occasionally,
: n2 J/ w; r f- l" n0 ctesticular enlargement is not that evident in the( A, X1 ?' w4 u" L+ t0 D, _' k2 Y
beginning of this process.1 In the absence of a neg-4 c4 w: x* |: m5 h
ative initial history of androgen exposure, our6 G# W* ?% C! Q( f7 ?+ j0 b4 b4 o8 E
biggest concern was virilizing adrenal hyperplasia,$ D: N# o6 Z! F9 q. ]# D: d
either 21-hydroxylase deficiency or 11-β hydroxylase. p: L* E! o/ K# Y( Y
deficiency. Those diagnoses were excluded by find-
0 M! [: `/ u E- k4 v5 Ying the normal level of adrenal steroids.
1 p n* w9 V# W% UThe diagnosis of exogenous androgens was strongly
- D7 H2 [& C9 V* l: [5 ]. m. f( Gsuspected in a follow-up visit after 4 months because
J% ?' M+ g" k5 ethe physical examination revealed the complete disap-3 J/ |4 d* Q. e, `8 g. g
pearance of pubic hair, normal growth velocity, and; N9 \1 }' N o7 {3 z
decreased erections. The father admitted using a testos-
. y6 t! Q' W7 {/ a0 Hterone gel, which he concealed at first visit. He was
F% W" V! ~" susing it rather frequently, twice a day. The Physicians’& c7 p4 t& p3 j6 M6 E- d1 m
Desk Reference, or package insert of this product, gel or
' l2 I5 {$ F; mcream, cautions about dermal testosterone transfer to
8 G8 G' u! P3 h9 f, k) g# w5 Q: Kunprotected females through direct skin exposure.
$ j3 S V. A9 H X0 QSerum testosterone level was found to be 2 times the
" B9 B. m/ z) u- P8 Wbaseline value in those females who were exposed to
; g1 j* V3 `, h- A7 a/ Eeven 15 minutes of direct skin contact with their male
7 \8 c6 w, u5 p1 ^; |partners.6 However, when a shirt covered the applica-3 m* o; C1 Z) `
tion site, this testosterone transfer was prevented.
9 Z: @3 p, T3 H4 G0 POur patient’s testosterone level was 60 ng/mL,1 Y# }$ A: n$ ^. x) q* a) Z
which was clearly high. Some studies suggest that) `, m: s; X5 e( M# V1 L# U
dermal conversion of testosterone to dihydrotestos-7 L2 Q! R) g( J: X, A! x6 a" Q
terone, which is a more potent metabolite, is more
( s+ b/ }- Y7 Z: Z! Pactive in young children exposed to testosterone) R7 e9 A. ~8 P& F5 d
exogenously7; however, we did not measure a dihy-4 j7 @% I: @, u! U0 t7 e
drotestosterone level in our patient. In addition to
- ?/ ?' X3 z. H$ t! A; }+ ivirilization, exposure to exogenous testosterone in
+ H5 j* R! @$ W, dchildren results in an increase in growth velocity and
& r* p- j' |! t. padvanced bone age, as seen in our patient.% C3 @; O4 F7 {. g. |3 g% V" R( y
The long-term effect of androgen exposure during
! F7 X0 A+ h1 |& b; Dearly childhood on pubertal development and final: G0 [0 y) W: a, K! J; i
adult height are not fully known and always remain' W1 I$ b6 F( G: L7 f3 Y( f
a concern. Children treated with short-term testos-
. ~5 X! ~9 t' W( G, [terone injection or topical androgen may exhibit some. H9 _+ l* r' s
acceleration of the skeletal maturation; however, after% _# |# V, j/ J5 i
cessation of treatment, the rate of bone maturation
) @/ R/ [' j" n! E% ndecelerates and gradually returns to normal.8,9
9 s" v$ Y4 Q+ \7 @$ B! j0 kThere are conflicting reports and controversy
0 s" w9 z, t+ @! D8 `over the effect of early androgen exposure on adult
% ^; u8 U5 \& l w- X: Spenile length.10,11 Some reports suggest subnormal
, j* R3 M- ^6 x4 C% T, b3 Y4 Y0 v! }adult penile length, apparently because of downreg-
1 Q% z* V& s5 h/ u, Uulation of androgen receptor number.10,12 However,: [4 q; O) f6 `) h# m
Sutherland et al13 did not find a correlation between6 [+ k3 p- D' j% u
childhood testosterone exposure and reduced adult
! q; `' ^4 r1 d, ~, u8 l* qpenile length in clinical studies.
- j0 T1 @- h; S) t Y" L0 `5 y" ^Nonetheless, we do not believe our patient is
5 ~/ a1 M* K9 o" U% Z, _, Wgoing to experience any of the untoward effects from( L* a {, N. G3 v4 v" E% Q7 w& ~
testosterone exposure as mentioned earlier because; w) Z" _" k' x% f7 `- J
the exposure was not for a prolonged period of time.
2 ~; M$ B# K. M' K1 z0 }Although the bone age was advanced at the time of
& }9 C) s4 q1 Q4 z+ s. qdiagnosis, the child had a normal growth velocity at
' S6 G7 M; j$ Y& ?: `the follow-up visit. It is hoped that his final adult
8 r- E8 [' _1 _+ Oheight will not be affected.
# O; W& n5 q: z$ ^Although rarely reported, the widespread avail-( |0 h: x, {% j# o
ability of androgen products in our society may- }7 D: ?, f% B; S7 c& Q
indeed cause more virilization in male or female: T; i6 }7 p; p9 P/ }
children than one would realize. Exposure to andro-; u! j# ?) q, B& T* K( x: k
gen products must be considered and specific ques-/ K+ Y6 y( F, Y+ W' ?- f
tioning about the use of a testosterone product or
) r* w5 x1 K H/ E* A) k, m. c, K. Ogel should be asked of the family members during
' U3 U* _2 m! O- Ythe evaluation of any children who present with vir-4 @; D1 K: _' a$ | ^1 H1 e
ilization or peripheral precocious puberty. The diag-
1 E- l! E- l- }0 ]" ]8 [/ p! Bnosis can be established by just a few tests and by
% Z9 x3 C1 n+ F+ |appropriate history. The inability to obtain such a
/ u. N( s5 r8 ~. c( t' [: ~ zhistory, or failure to ask the specific questions, may
: v) M) q: ^' eresult in extensive, unnecessary, and expensive% {3 F. Z" m% I4 h8 ~/ g
investigation. The primary care physician should be+ v3 n" C8 L: G% b" R, k$ ~
aware of this fact, because most of these children
8 ~+ j8 R# |, O/ g" H, m2 wmay initially present in their practice. The Physicians’
5 E2 F! v- ^! w3 {. v1 h% n, fDesk Reference and package insert should also put a, J# Q* d; p. g- d
warning about the virilizing effect on a male or% u4 Y0 d+ n8 w
female child who might come in contact with some-2 O9 T; e- ^( ~! V) t( F7 X
one using any of these products.
( [9 l7 C `) F9 FReferences: y9 }3 r* v3 J/ A
1. Styne DM. The testes: disorder of sexual differentiation, u8 D; z9 q( f- s0 o3 G
and puberty in the male. In: Sperling MA, ed. Pediatric: r% O: ^( n3 w6 p3 C
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
! J x; t5 x% j* v2 T( d2002: 565-628.
+ N5 D! J* O+ \# Z# k2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious& b1 Z/ c' O4 L, q! C( U! @
puberty in children with tumours of the suprasellar pineal |
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