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Sexual Precocity in a 16-Month-Old8 F8 [1 P4 K& o/ b' P; S8 j
Boy Induced by Indirect Topical4 ]) j% ^+ h, _. `* z$ T9 z* W: l
Exposure to Testosterone! ]* [) v4 B% q+ \ J
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2( Q, n7 w- O) i8 O
and Kenneth R. Rettig, MD1
( ^! G+ Q+ E; T& ]7 `Clinical Pediatrics3 s- Z; c5 m- i( T9 `) b% T; o' D
Volume 46 Number 6
( X% @1 |* i, P: g7 I @4 s5 e& aJuly 2007 540-543# _8 K' p$ G, j0 q2 Z; m
© 2007 Sage Publications9 O( L; F$ F, s
10.1177/00099228062966513 W! g) [) P! u/ j( A
http://clp.sagepub.com
" {" `/ T% m1 w/ r! o8 w: n" Q) Qhosted at8 P% ~5 w. s( J9 R
http://online.sagepub.com/ c6 r9 T' s: ?" K, J9 u2 l8 q
Precocious puberty in boys, central or peripheral,
9 M1 `# h/ y( \is a significant concern for physicians. Central! h& H! X4 u7 f* X
precocious puberty (CPP), which is mediated
7 X7 ?. m+ M8 Mthrough the hypothalamic pituitary gonadal axis, has! S$ a3 N! u F
a higher incidence of organic central nervous system
% z2 s2 \/ z/ llesions in boys.1,2 Virilization in boys, as manifested
: Q2 r2 u3 C; pby enlargement of the penis, development of pubic
" G4 c/ ~7 J& _4 s* yhair, and facial acne without enlargement of testi-* z; i0 W- C' J! ]
cles, suggests peripheral or pseudopuberty.1-3 We* h7 Z% G* a3 t% B; `8 e8 Q
report a 16-month-old boy who presented with the+ G2 I5 ]0 D& c/ D! f
enlargement of the phallus and pubic hair develop-
7 v% I+ l. ]* ^" d" yment without testicular enlargement, which was due
+ w8 h6 b. b9 G+ m8 Uto the unintentional exposure to androgen gel used by
( Z+ M0 m1 t" W( ^! s7 J5 |the father. The family initially concealed this infor-
; _4 W Y4 D% c, `' Lmation, resulting in an extensive work-up for this: @5 S ]! C2 O2 q2 j7 H
child. Given the widespread and easy availability of" S% U; e1 C F( _+ g3 \, T. O2 i! ~) W
testosterone gel and cream, we believe this is proba-
, n+ S( V) r" n8 X- Z; h! mbly more common than the rare case report in the5 |, B2 E/ S- r2 F
literature.4
$ i( L' Z/ Z5 v: w4 F- R5 Q- XPatient Report* I; v2 j# j$ g3 T/ c7 ^1 V
A 16-month-old white child was referred to the2 M8 H( x+ f' Q6 Q. S3 w9 E/ @ a. J
endocrine clinic by his pediatrician with the concern6 R2 ^/ B$ j: h4 G+ Y. `1 U
of early sexual development. His mother noticed
" u1 h; j9 Y- i- zlight colored pubic hair development when he was
: G0 z, i+ N% \1 `/ eFrom the 1Division of Pediatric Endocrinology, 2University of' c2 g" O/ C( A# O2 E- i
South Alabama Medical Center, Mobile, Alabama.' B5 ? C5 F8 }# E1 }) g
Address correspondence to: Samar K. Bhowmick, MD, FACE,
' z# }$ [0 }' \3 I$ h( S3 O- MProfessor of Pediatrics, University of South Alabama, College of
: ?+ P! P8 I5 Q( G; o7 r: D9 ]Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;) l/ N* s; \' O; V. M0 \9 a# g
e-mail: [email protected].0 [3 N* f* N% B' `7 c
about 6 to 7 months old, which progressively became
b+ T0 H# s8 Ndarker. She was also concerned about the enlarge-
i7 K; T) ]5 O% P8 [ment of his penis and frequent erections. The child
$ |/ @% N/ `& C/ ^( E e, \ p+ Xwas the product of a full-term normal delivery, with9 m/ t2 a ?, M- e, k
a birth weight of 7 lb 14 oz, and birth length of( G/ Z3 S/ x6 k6 r* ?( Z2 d% r
20 inches. He was breast-fed throughout the first year7 D1 Y2 f1 S2 Y9 T: G
of life and was still receiving breast milk along with: s4 \( P$ L/ L/ X* [9 [
solid food. He had no hospitalizations or surgery," x" p* ~& s2 i
and his psychosocial and psychomotor development
) m0 O8 H6 _+ h5 a) _was age appropriate.7 r& X3 W6 i5 b! V8 X2 f( n
The family history was remarkable for the father,
- F$ I) i- M7 W% q+ |who was diagnosed with hypothyroidism at age 16,
9 P( _$ \2 e3 V( m: twhich was treated with thyroxine. The father’s
$ o$ M6 t6 w2 r1 f* i% hheight was 6 feet, and he went through a somewhat
# v+ v% J9 L. A) ]early puberty and had stopped growing by age 14.% v, h0 ^# X5 X' q# f; t
The father denied taking any other medication. The9 Y3 T1 o* O" n# a" `: Z
child’s mother was in good health. Her menarche
% d/ m6 h7 N6 owas at 11 years of age, and her height was at 5 feet
7 F- P& G* z3 `4 c3 X! d5 inches. There was no other family history of pre-( p1 ~9 A3 ^# ?$ r7 z
cocious sexual development in the first-degree rela-
+ w3 p, b) v, Htives. There were no siblings.
; s/ [ x8 o, @7 J) S' e8 wPhysical Examination
& G B0 M: Q1 Y/ _; d1 E2 t/ A4 FThe physical examination revealed a very active,) h7 x- b% l1 y4 K: {
playful, and healthy boy. The vital signs documented+ B* N/ ~- t& I# o7 _, B0 S
a blood pressure of 85/50 mm Hg, his length was' r P+ F1 T8 m
90 cm (>97th percentile), and his weight was 14.4 kg
1 c; y* C. e! m: l( g(also >97th percentile). The observed yearly growth
1 Y: b' [3 x( }velocity was 30 cm (12 inches). The examination of9 x: b) |% d( `' G
the neck revealed no thyroid enlargement.$ L5 ~+ t, [, F# W
The genitourinary examination was remarkable for
" H4 P! R9 o2 _2 \4 v5 H& `0 D! zenlargement of the penis, with a stretched length of
9 w7 ]$ C* u/ }- }8 cm and a width of 2 cm. The glans penis was very well- W/ V% o7 A1 f3 Y* U3 P6 k
developed. The pubic hair was Tanner II, mostly around& g' m! W+ o2 L; O1 e1 L
540# @) n8 b8 t1 D+ g5 A! s
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
* U7 I1 r# f* a- C; T5 cthe base of the phallus and was dark and curled. The
8 j8 g+ x4 N. B1 q3 rtesticular volume was prepubertal at 2 mL each.
. E4 j; g0 Q9 P* X G/ U& {+ EThe skin was moist and smooth and somewhat
. e q3 D) W& M6 Ooily. No axillary hair was noted. There were no
" G0 ?" s2 H7 t! X" F0 Babnormal skin pigmentations or café-au-lait spots.
+ e- P- \, U T, u BNeurologic evaluation showed deep tendon reflex 2+; s1 M6 s$ _' c( a& x6 X
bilateral and symmetrical. There was no suggestion0 U r* k h7 s
of papilledema.; ^) Z) a# w8 v8 w
Laboratory Evaluation
2 z; E9 _, K; u P! F7 BThe bone age was consistent with 28 months by
/ G7 ?* u& i1 X' q4 @using the standard of Greulich and Pyle at a chrono-
# R. M% N" p6 S. V! {' z" Wlogic age of 16 months (advanced).5 Chromosomal
- O& K x+ T+ e3 z/ y2 Bkaryotype was 46XY. The thyroid function test* Z: {! L5 M" ?9 T* ]2 n8 d
showed a free T4 of 1.69 ng/dL, and thyroid stimu-+ `* ~& K' k/ T. p
lating hormone level was 1.3 µIU/mL (both normal).
, F$ d8 ^% \# \& UThe concentrations of serum electrolytes, blood4 s# I$ D& p, j
urea nitrogen, creatinine, and calcium all were( I7 @8 V, L! C* w
within normal range for his age. The concentration; w1 P/ v! A. B" A5 x. N
of serum 17-hydroxyprogesterone was 16 ng/dL
: ]) A& _0 O. w(normal, 3 to 90 ng/dL), androstenedione was 20: A5 E1 i& [1 H
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
! f3 V8 \, E3 Pterone was 38 ng/dL (normal, 50 to 760 ng/dL)," n5 @6 `, g, |2 |; @4 u4 j2 E
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 k! u3 }9 H$ Z& f% m9 M49ng/dL), 11-desoxycortisol (specific compound S)
" r6 y: U5 Q" G" Dwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
3 _1 D7 w9 l) M1 w# q6 Qtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total* s# e+ Y% u* F# e3 ?
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),' ^9 {( \( `$ { {
and β-human chorionic gonadotropin was less than
6 x' p8 x) V( }7 a! ]5 mIU/mL (normal <5 mIU/mL). Serum follicular$ g# p" n* {" ^/ {; B# [- i0 e
stimulating hormone and leuteinizing hormone
2 |) d- X( Y4 Mconcentrations were less than 0.05 mIU/mL" I$ u# t1 n0 I7 n0 l+ T
(prepubertal).& |& q8 G, H% P6 h, L$ E0 Q7 g
The parents were notified about the laboratory2 ~* \8 F/ n1 e; _% e
results and were informed that all of the tests were
! F% x o8 B% u" X9 P% Rnormal except the testosterone level was high. The7 ]! A( a, I, q' a9 q
follow-up visit was arranged within a few weeks to" ]: H' c* h: z- b1 [% i, Z; A
obtain testicular and abdominal sonograms; how-
8 q0 a' m& C! [. u7 uever, the family did not return for 4 months.
1 ~, A; p, t" H8 oPhysical examination at this time revealed that the' h, u' Q4 c4 ]6 ^5 _9 Q+ p. l& e
child had grown 2.5 cm in 4 months and had gained
1 L B& H5 m" L7 Z( o6 y2 kg of weight. Physical examination remained
' s1 @ j. h" l9 h( T! o3 ]unchanged. Surprisingly, the pubic hair almost com-/ p9 o2 `5 ]2 b- [; x
pletely disappeared except for a few vellous hairs at! D0 z2 {9 x: V! H3 G
the base of the phallus. Testicular volume was still 2
: s0 i( i/ Y, E6 ~# UmL, and the size of the penis remained unchanged.
; [9 c2 p. k8 XThe mother also said that the boy was no longer hav-+ z7 K0 ~! Q+ q" x
ing frequent erections.
4 z6 |) V* g9 O5 F+ [# _5 d/ cBoth parents were again questioned about use of
6 k# ]* m2 F; z D9 Oany ointment/creams that they may have applied to
' ?& i4 R9 P. i7 U3 lthe child’s skin. This time the father admitted the
8 I. D' u0 J6 _" d0 h2 gTopical Testosterone Exposure / Bhowmick et al 541* X: U4 `5 Y8 _
use of testosterone gel twice daily that he was apply-
7 I0 ^6 ?& z7 R, _$ g( _4 Ling over his own shoulders, chest, and back area for
! u* a+ ]1 L2 \9 B$ i% [1 ?a year. The father also revealed he was embarrassed7 |9 a) ~* b/ |# |/ s# L2 Z
to disclose that he was using a testosterone gel pre-! t; }. X0 D/ d
scribed by his family physician for decreased libido5 y1 N3 k- W- Q
secondary to depression.
+ h9 W( t/ }$ G1 ^" i8 e: hThe child slept in the same bed with parents.
% r: Y+ v# S* Z. ]0 M* }8 xThe father would hug the baby and hold him on his# O c9 T- P8 Y# s5 u3 e& |
chest for a considerable period of time, causing sig-
1 P$ j& @1 w, Vnificant bare skin contact between baby and father.; E' b- s, D7 p t. ~
The father also admitted that after the phone call,/ W* ?* N' a% E$ W2 S% U5 j# S
when he learned the testosterone level in the baby) p5 T! D7 H& ?8 g# t L0 \9 m
was high, he then read the product information
# {" m% s8 A' W8 S2 apacket and concluded that it was most likely the rea-
. i4 d5 V3 k7 z7 g! Json for the child’s virilization. At that time, they" I( `+ \% X: F9 _2 a
decided to put the baby in a separate bed, and the% |4 l7 k: }. ~" F5 F, a
father was not hugging him with bare skin and had% ~. ^/ o# [7 O! i5 m, X
been using protective clothing. A repeat testosterone
- V% X( b. S# w4 ltest was ordered, but the family did not go to the( C; {' b+ f* X/ _( Z i0 L' \
laboratory to obtain the test.
5 g( Z7 v2 p& cDiscussion. A3 }) K; [7 b, l* E
Precocious puberty in boys is defined as secondary) ?+ z3 A- B/ r
sexual development before 9 years of age.1,4+ J. G8 {9 U6 H+ f& N; T% A+ t
Precocious puberty is termed as central (true) when7 R2 M6 O9 O, ~2 h9 n# P$ B0 v! c
it is caused by the premature activation of hypo-6 c1 a. |4 u0 O" S& S8 x
thalamic pituitary gonadal axis. CPP is more com-
0 C- w* }& f, k; p: S' Jmon in girls than in boys.1,3 Most boys with CPP0 L8 n8 `9 \: ]+ H( s2 D/ f* H) N
may have a central nervous system lesion that is- h9 ], r6 S5 {- d8 K- O1 }
responsible for the early activation of the hypothal-
2 ^( w( E& e: G8 `+ |amic pituitary gonadal axis.1-3 Thus, greater empha-
; D2 t7 Z+ e4 Y# W6 n& Esis has been given to neuroradiologic imaging in
% G& i0 h# l$ Dboys with precocious puberty. In addition to viril-3 m& i) F K, h" f) c% _; R
ization, the clinical hallmark of CPP is the symmet-8 k% M0 ]' Q1 |1 v4 ]* v
rical testicular growth secondary to stimulation by- u' P1 y& a& {( S* z- Z, |8 M
gonadotropins.1,3
$ a0 `& W2 {% q, p2 jGonadotropin-independent peripheral preco-
, ]0 E. V* [0 m/ `1 Xcious puberty in boys also results from inappropriate
$ a/ \" ]' \! S9 aandrogenic stimulation from either endogenous or+ [+ `9 S6 z5 {) x
exogenous sources, nonpituitary gonadotropin stim- `, n) H4 @: H" K
ulation, and rare activating mutations.3 Virilizing
- n! O9 m9 c8 ] f" w7 Zcongenital adrenal hyperplasia producing excessive
$ _6 S1 s! y Madrenal androgens is a common cause of precocious
; ~+ g( G) v2 y! a. ppuberty in boys.3,4' c u/ Z6 F$ y
The most common form of congenital adrenal$ h, D( ]# o# o- X
hyperplasia is the 21-hydroxylase enzyme deficiency.
. {3 I" W0 f2 \The 11-β hydroxylase deficiency may also result in' b7 _ V9 t8 _) O) x# q
excessive adrenal androgen production, and rarely,. h/ s$ [- a6 @8 d5 M
an adrenal tumor may also cause adrenal androgen. o* C" z1 x& }0 o5 f' }
excess.1,3
& w* }4 S9 q" p( d8 F. U2 Q- K6 Eat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from+ `( e( K6 ]2 K; x6 j% O
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
6 N2 P. F- r# fA unique entity of male-limited gonadotropin-1 S+ G% I0 l- s8 \& b
independent precocious puberty, which is also known
4 l2 R9 x5 ^$ kas testotoxicosis, may cause precocious puberty at a
, X! a/ D- f. s6 _# A/ }, L- Jvery young age. The physical findings in these boys0 c8 u5 f, V' V% p. v9 B
with this disorder are full pubertal development,+ k' I% ~5 w& u' h8 c) f0 D0 r" d5 _
including bilateral testicular growth, similar to boys% t6 a: |1 W3 o& r, t& u5 c
with CPP. The gonadotropin levels in this disorder
$ l( r7 B9 X" sare suppressed to prepubertal levels and do not show" M6 c5 G& y5 f. \$ O; K
pubertal response of gonadotropin after gonadotropin-
; `- w# @7 f) S& Rreleasing hormone stimulation. This is a sex-linked
6 [2 O: V$ H8 v1 W7 F9 A9 kautosomal dominant disorder that affects only
$ j; `' z3 u( R/ Amales; therefore, other male members of the family: U- o- w4 n7 ~# K% K3 m# X, u$ U
may have similar precocious puberty.3, a$ m7 O, B% w8 [, ~1 y
In our patient, physical examination was incon-$ g+ i5 q1 ]" \& z' o3 l7 `
sistent with true precocious puberty since his testi-( g" I Y8 R9 V
cles were prepubertal in size. However, testotoxicosis1 @& C/ y* ^8 q' q; p, D# u
was in the differential diagnosis because his father
6 A3 l6 g5 f- c- [- G% Sstarted puberty somewhat early, and occasionally,
0 _( I1 r( W8 N* k+ C6 h. ftesticular enlargement is not that evident in the. g a4 D1 Q+ M& Q& p0 E* k: o
beginning of this process.1 In the absence of a neg-
3 t W& [: q, Mative initial history of androgen exposure, our
7 P1 M: @" E( z0 e; ~6 ?biggest concern was virilizing adrenal hyperplasia,
4 H- h) p( L# O, ?, s% Geither 21-hydroxylase deficiency or 11-β hydroxylase
& W% t+ ^0 [2 K, q4 p& k6 mdeficiency. Those diagnoses were excluded by find-1 }) |7 ^/ v5 a1 G# G1 ]8 d/ r, [0 X
ing the normal level of adrenal steroids.( \2 Q, H/ Y; |9 O5 [/ L
The diagnosis of exogenous androgens was strongly% q# O3 b5 R' `8 y& C, f- e
suspected in a follow-up visit after 4 months because
/ E( |7 D& Q0 ~& B0 w$ dthe physical examination revealed the complete disap-9 r( y( m2 r0 o; e2 n% B
pearance of pubic hair, normal growth velocity, and
0 T: I; j! x1 r) o% Wdecreased erections. The father admitted using a testos-+ p0 p" P0 ~, ]( T$ B7 R
terone gel, which he concealed at first visit. He was
6 G/ D' e+ v8 G; k. b: }using it rather frequently, twice a day. The Physicians’8 D- ~& m* p! J m
Desk Reference, or package insert of this product, gel or
+ [6 \8 ^0 B" o; j' Ucream, cautions about dermal testosterone transfer to
. x/ |. T6 ~* i. j* t+ l3 ounprotected females through direct skin exposure.4 H( T" I* f8 h; O
Serum testosterone level was found to be 2 times the x4 g$ G3 s/ A U
baseline value in those females who were exposed to
3 b+ @1 v I& ieven 15 minutes of direct skin contact with their male
* i- E$ \( j G2 W( t& xpartners.6 However, when a shirt covered the applica-5 a4 c; x b1 P# Q/ G$ `- V8 L6 X
tion site, this testosterone transfer was prevented.5 M* H. p3 q; K) {3 ~8 A% r5 v. o
Our patient’s testosterone level was 60 ng/mL,, k5 t! E1 R% f/ p
which was clearly high. Some studies suggest that/ T! R a# Y2 R! P; h y2 v
dermal conversion of testosterone to dihydrotestos-* y! ~4 Z* l4 [ N
terone, which is a more potent metabolite, is more, ]) r& @6 W7 L% E2 F8 Y) h7 P6 t
active in young children exposed to testosterone1 |8 t" r5 E. s1 h
exogenously7; however, we did not measure a dihy-
7 ^7 e# A" T1 M! Adrotestosterone level in our patient. In addition to
6 C7 \7 u* t9 S; b4 `, a1 g% Bvirilization, exposure to exogenous testosterone in
7 V& H+ a8 M. ^- _- ] ~) xchildren results in an increase in growth velocity and
, }8 m) k7 j9 w2 Z/ H, X5 U- g; t" |advanced bone age, as seen in our patient.
7 p8 Z; G( w! t$ \3 ~" uThe long-term effect of androgen exposure during
9 @% M6 D6 q6 Bearly childhood on pubertal development and final9 s8 [, t7 L, J7 z) B6 R+ r
adult height are not fully known and always remain% v1 Z+ p. z' ~8 y! k) f6 x
a concern. Children treated with short-term testos-
: A8 r. h+ X' v6 n- Sterone injection or topical androgen may exhibit some
) ^) |6 w; }5 C( w* F7 jacceleration of the skeletal maturation; however, after
" f7 x! w! o/ e: Pcessation of treatment, the rate of bone maturation
+ H0 U* m {$ x/ E$ f/ Cdecelerates and gradually returns to normal.8,97 Y t9 G9 Q5 c7 j2 y; O- S. }5 T. A
There are conflicting reports and controversy
# Q! Z3 Q* R; M* bover the effect of early androgen exposure on adult" ~) ^* y8 ^1 G* ~; ]2 l y6 |
penile length.10,11 Some reports suggest subnormal: o) c8 \9 E0 p# ?$ \0 m# V
adult penile length, apparently because of downreg-( X) l! Z, K9 Q% p" f7 |9 D( l
ulation of androgen receptor number.10,12 However,8 o6 j4 t0 G# p0 P
Sutherland et al13 did not find a correlation between& C& S$ \( r' }; D$ W
childhood testosterone exposure and reduced adult& ^0 m/ ]: i) F. |
penile length in clinical studies.( E5 g+ ^. e& l& i m u+ w6 p
Nonetheless, we do not believe our patient is
D! Y0 P/ i8 h! Z( |8 e4 _" Sgoing to experience any of the untoward effects from& I5 _& H, S8 h0 v" Z
testosterone exposure as mentioned earlier because
$ I5 ~3 @4 k( D' a8 ~7 T! ^the exposure was not for a prolonged period of time.
, h, b8 S. a& x+ jAlthough the bone age was advanced at the time of* Z1 N- r) H# D
diagnosis, the child had a normal growth velocity at
" ~6 t) R, y! m4 g o, Othe follow-up visit. It is hoped that his final adult" B5 K6 q6 i' C" {6 d( z+ E
height will not be affected.
+ O& a K0 q! h: p4 y. K3 ^" uAlthough rarely reported, the widespread avail-
( b) \; r7 }2 b! p( iability of androgen products in our society may
) N+ H- r6 i$ H0 ]9 g! Tindeed cause more virilization in male or female& n8 j4 w& t. j3 E/ o# G" K4 a9 w
children than one would realize. Exposure to andro-6 t3 |; S4 N& G u
gen products must be considered and specific ques-) b/ N. K" X# L/ L4 t. V
tioning about the use of a testosterone product or( a- X- K1 y9 M7 @
gel should be asked of the family members during
6 p& X3 p( g9 u0 t0 bthe evaluation of any children who present with vir-
Z# j* x' Y$ i8 y$ H; B* ]& Milization or peripheral precocious puberty. The diag-. s. z" O6 y9 [% \- v, O7 ^
nosis can be established by just a few tests and by( t% K' K4 e9 [
appropriate history. The inability to obtain such a
( f3 h& [2 E$ y# d) xhistory, or failure to ask the specific questions, may( \+ \' y" f/ `* r9 p; ]
result in extensive, unnecessary, and expensive+ M. K+ ~ }7 G; U$ M
investigation. The primary care physician should be
O2 b: q! ?: e6 ~8 Daware of this fact, because most of these children
' q! z* Q9 Q- ?# ~may initially present in their practice. The Physicians’
% {7 U& T" f7 g+ ~Desk Reference and package insert should also put a
$ _& V: [( L# gwarning about the virilizing effect on a male or
- S0 V* _* w* c4 K( nfemale child who might come in contact with some-# ~6 U4 ~! k0 }& U4 ^/ j8 H
one using any of these products.
0 o' M; o+ ?/ O% j+ F. p D1 l4 Z4 _References1 C7 S" e& g& T) e$ O' Q
1. Styne DM. The testes: disorder of sexual differentiation
6 |8 A% t8 L, @4 ]and puberty in the male. In: Sperling MA, ed. Pediatric
/ W4 D/ j1 N8 u% T+ w0 q' B9 b: XEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
* u$ O) f- x5 G. d& _4 [9 s; J# N2002: 565-628.
8 |- L- E0 U( n* n' b# E2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
9 H9 M5 t5 Q% J+ Npuberty in children with tumours of the suprasellar pineal |
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