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is a significant concern for physicians. Central: _& A$ Y8 d! h' k" q
precocious puberty (CPP), which is mediated- K+ A) W! G4 R$ B
through the hypothalamic pituitary gonadal axis, has
0 f0 J% r8 D1 Y% j2 Wa higher incidence of organic central nervous system! U; p& \ I- S; @$ W- m7 w4 C% t: j
lesions in boys.1,2 Virilization in boys, as manifested# K6 C1 O, T3 `" [3 e
by enlargement of the penis, development of pubic
/ Q4 d/ E7 h8 [) v7 n8 g+ Chair, and facial acne without enlargement of testi-4 A& {: p Y- N
cles, suggests peripheral or pseudopuberty.1-3 We
5 W/ T x" o6 x/ n; Wreport a 16-month-old boy who presented with the8 L% Y x& s, H. X
enlargement of the phallus and pubic hair develop-
* h7 n) c' o) Q% e# A1 xment without testicular enlargement, which was due" q. E/ b8 F: M6 `
to the unintentional exposure to androgen gel used by
6 V8 d3 _9 w! Cthe father. The family initially concealed this infor-
" X; C+ h; l* h8 a; \mation, resulting in an extensive work-up for this
; r& f2 r: [; F0 Nchild. Given the widespread and easy availability of
& N9 H3 h- {& w& V3 Ftestosterone gel and cream, we believe this is proba-
5 z: |5 N+ c; A, J" Q) R5 qbly more common than the rare case report in the5 ]" z+ W! M9 o! M. o/ i7 i
literature.4
" w5 F& `) h. @4 F4 I( ePatient Report
' E6 |! @& x A; c8 Q3 E: CA 16-month-old white child was referred to the7 j" N& O. z- P6 P4 d- f
endocrine clinic by his pediatrician with the concern
0 z" b {* Q3 s! Dof early sexual development. His mother noticed8 S) b8 A/ ]' ?
light colored pubic hair development when he was
8 r, p- p* m) AFrom the 1Division of Pediatric Endocrinology, 2University of
& c, [: f) \9 C$ e' k' E5 qSouth Alabama Medical Center, Mobile, Alabama.
; n5 g8 m1 ^ b" p7 i* w2 {( kAddress correspondence to: Samar K. Bhowmick, MD, FACE,
9 }* _" u0 O* u+ QProfessor of Pediatrics, University of South Alabama, College of$ K& W |9 Z i$ X# X+ T4 F
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
* g, Z3 O/ {! Y; l3 c6 Ge-mail: [email protected].
& j) a1 u0 p2 M4 ^about 6 to 7 months old, which progressively became! e5 O+ v& t! B) B) o' G( [
darker. She was also concerned about the enlarge-
$ b7 Y D# b9 Q0 l% F% b% E, ument of his penis and frequent erections. The child
5 i; R1 v7 H) B' O* |9 V& S( @was the product of a full-term normal delivery, with
8 d. q' [5 l( Ua birth weight of 7 lb 14 oz, and birth length of
2 i, d9 ^& T$ r! @1 s20 inches. He was breast-fed throughout the first year: K2 Y+ S0 ]8 R5 h
of life and was still receiving breast milk along with1 w2 Y: ?) v5 v$ c
solid food. He had no hospitalizations or surgery,
' ^3 n, T# X' L6 Oand his psychosocial and psychomotor development- R& z/ a, m) z/ F Z0 [* b* I$ ~; W
was age appropriate.: c3 D) ~% ]8 A3 c' E+ Q- y# H
The family history was remarkable for the father,
$ I4 ~8 R+ \! X2 Y: I( swho was diagnosed with hypothyroidism at age 16,
i1 C7 t6 @/ n0 F3 W- _which was treated with thyroxine. The father’s
: q: e3 T& D2 Y1 n8 ^, s) wheight was 6 feet, and he went through a somewhat4 q9 \$ a9 a( g( e8 o4 E
early puberty and had stopped growing by age 14.
$ l9 `. t5 E- J3 M7 P3 g0 w# |( O/ eThe father denied taking any other medication. The
: A+ ~. M. x3 d8 fchild’s mother was in good health. Her menarche% g- a% z* p9 P# h+ t4 z( ]" i6 K' i
was at 11 years of age, and her height was at 5 feet1 X' d$ Q" j0 m
5 inches. There was no other family history of pre-" U9 o" e, T1 A. B2 f- R- Y; h
cocious sexual development in the first-degree rela-% e% {) q. o) R# r# O3 X
tives. There were no siblings.4 I! U' c1 b4 {: w& O( {0 Q
Physical Examination
4 B2 v# b" F" e" `$ F( e6 DThe physical examination revealed a very active,
- O- M4 ?- B$ v* Z, ^$ Jplayful, and healthy boy. The vital signs documented
O6 |7 z7 G; `9 a$ ya blood pressure of 85/50 mm Hg, his length was" h" L5 t9 P4 F/ r* \/ x% ?6 ~
90 cm (>97th percentile), and his weight was 14.4 kg
+ E1 y4 B9 R2 X4 t(also >97th percentile). The observed yearly growth$ V j" c7 a$ a% k2 W
velocity was 30 cm (12 inches). The examination of7 \0 C0 u, u7 }' P- p: ?1 L( _$ j
the neck revealed no thyroid enlargement./ E9 x. A% z0 g% `# R
The genitourinary examination was remarkable for
* n) L/ q( M) z5 G2 Genlargement of the penis, with a stretched length of# u1 ~! R# M4 j, [" Q
8 cm and a width of 2 cm. The glans penis was very well! g: M7 Y' M1 |& `' t
developed. The pubic hair was Tanner II, mostly around
6 ?# a! s. A, A {) k5 M/ B ~540- ]$ h y {/ U4 ?3 D3 V
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# v& b2 H7 v. u: ?the base of the phallus and was dark and curled. The6 b* R: H3 u$ D' O, w; S7 f
testicular volume was prepubertal at 2 mL each.
* D0 J+ S w# S1 W6 _% ^The skin was moist and smooth and somewhat/ f" a* p4 ~; x0 C# U1 P
oily. No axillary hair was noted. There were no
/ K1 \5 g7 Z: w6 nabnormal skin pigmentations or café-au-lait spots.% a e& M3 y0 v8 [% m
Neurologic evaluation showed deep tendon reflex 2+6 b9 A3 a; `0 v" n. [! w8 `
bilateral and symmetrical. There was no suggestion
) Y; o* I5 l5 N- S- n- }5 Oof papilledema./ g+ q, c( @" P
Laboratory Evaluation
$ E5 W; a: v: k/ _# DThe bone age was consistent with 28 months by
# G8 ` a0 Q1 T; b) @8 _ s. wusing the standard of Greulich and Pyle at a chrono-6 p* K; E+ u6 f7 \& L
logic age of 16 months (advanced).5 Chromosomal
6 {4 f& x8 f3 N: @9 B, Y& d) ~9 ckaryotype was 46XY. The thyroid function test
- a |: i }/ h# s- N# r& Ushowed a free T4 of 1.69 ng/dL, and thyroid stimu-( J: o" Q* ^8 A
lating hormone level was 1.3 µIU/mL (both normal).: d2 E5 `6 O1 s- p/ A5 I h
The concentrations of serum electrolytes, blood8 l [9 E/ i' t1 }$ Y0 {: _# Q' P
urea nitrogen, creatinine, and calcium all were
1 C$ ?! n y/ }& U. u e# dwithin normal range for his age. The concentration, X" ?: |" _% R) H4 P3 j
of serum 17-hydroxyprogesterone was 16 ng/dL
2 f9 m% a( T( ^(normal, 3 to 90 ng/dL), androstenedione was 20
! C* ]* \' p' D% O" a4 Z$ {7 vng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
" d; _- ~1 ]/ L& G( c0 H4 G4 fterone was 38 ng/dL (normal, 50 to 760 ng/dL),0 J I% l5 T' ~; m9 s
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
) v e- ]6 e2 w9 T+ }/ C/ Y49ng/dL), 11-desoxycortisol (specific compound S)
1 _4 i$ F/ t, \8 F3 h8 n, Q" F8 jwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-0 Z1 N9 Y1 N+ q( R
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
* K: H6 V: G( U) S# _testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
& Z( Q/ U) t! S# C' Pand β-human chorionic gonadotropin was less than2 f( l5 [* C2 } U! f( t8 Q
5 mIU/mL (normal <5 mIU/mL). Serum follicular- ^ i+ J- B$ D( Y, O( H, Q
stimulating hormone and leuteinizing hormone8 V+ U# z. _$ j B
concentrations were less than 0.05 mIU/mL
: D _1 p9 U* ^1 o' |0 p(prepubertal).) W2 ?" g0 P6 h! h T5 \
The parents were notified about the laboratory
! q9 r5 q0 B4 x6 P: s6 A! }' Nresults and were informed that all of the tests were
8 ?2 F: S% O3 ^2 {: |& s4 e! D+ |normal except the testosterone level was high. The
: b# g4 z: h I. xfollow-up visit was arranged within a few weeks to
O3 L% S, E- H: fobtain testicular and abdominal sonograms; how-
( g8 l$ ?, T6 P7 I0 Aever, the family did not return for 4 months.) Y' h1 F8 |* C/ `: w* v0 b
Physical examination at this time revealed that the
2 k+ m% t: { E! ~" ]( m' Y( Z# I! wchild had grown 2.5 cm in 4 months and had gained: n- h3 o0 n5 c
2 kg of weight. Physical examination remained
: }. _* `# D: \, C1 v+ P6 U2 B% aunchanged. Surprisingly, the pubic hair almost com-
5 K r" j+ D1 b5 F3 y9 w; Rpletely disappeared except for a few vellous hairs at
5 D0 K; V9 D& r3 r& |/ mthe base of the phallus. Testicular volume was still 2
8 }- o1 c# Y6 |& UmL, and the size of the penis remained unchanged.
! w/ u% S" t9 N3 O9 GThe mother also said that the boy was no longer hav-
0 N4 ~" O! l5 R6 Ting frequent erections.- ~( s& x# ~7 \6 P, e, O( Q0 ?* s# s+ p
Both parents were again questioned about use of
( u4 \* f/ N- @3 S/ t! Hany ointment/creams that they may have applied to$ q% ^+ Y+ _) H3 K8 @. J
the child’s skin. This time the father admitted the* J- } S n0 B; Y6 C) e
Topical Testosterone Exposure / Bhowmick et al 541
, H% T k: b9 u) y1 _use of testosterone gel twice daily that he was apply-
, \% W6 J$ R2 p+ Eing over his own shoulders, chest, and back area for
) O: ]$ H) D( g3 u9 Ja year. The father also revealed he was embarrassed& Q4 S0 ]- a" P5 f
to disclose that he was using a testosterone gel pre-
$ I7 n" R% C. c4 k6 E3 u$ ~# Xscribed by his family physician for decreased libido0 ~" G8 T) m7 j
secondary to depression." ~) f* c. q, x9 H. F2 j' r
The child slept in the same bed with parents.* T* u3 r2 x7 X/ F
The father would hug the baby and hold him on his
4 O% j6 y4 I& ~/ Q7 h$ cchest for a considerable period of time, causing sig-
8 e+ t; \( G0 V- [; }1 ^' onificant bare skin contact between baby and father.8 F; w7 u. }! L& K5 G
The father also admitted that after the phone call, B" u- [! i6 _( M1 t9 S
when he learned the testosterone level in the baby
& b+ m4 u; x& Z( \1 \( I5 _5 owas high, he then read the product information- ]* E6 a8 O' G: K8 E
packet and concluded that it was most likely the rea-' i3 f$ t8 l. O- i% M/ A- d7 q0 F
son for the child’s virilization. At that time, they9 f/ ^* n; x8 x- W+ ]; ]1 L
decided to put the baby in a separate bed, and the
5 [0 E0 L- l rfather was not hugging him with bare skin and had( Z' \& E& Q" X8 o+ B0 T
been using protective clothing. A repeat testosterone
" q2 @; j8 b h5 Y+ x5 {' F. ?test was ordered, but the family did not go to the
$ N9 ^# b( K9 B6 k) y6 k+ `4 ^9 Vlaboratory to obtain the test.
( C" R U% W8 x' D% SDiscussion& d! D0 X" t. q) t4 q1 p2 O) X! A
Precocious puberty in boys is defined as secondary. Y% _) @) k9 H. L
sexual development before 9 years of age.1,4
4 E2 \5 Y: A B& T: wPrecocious puberty is termed as central (true) when
8 V1 M) G* [; O5 e+ v' jit is caused by the premature activation of hypo-
; ?8 r. j- d8 Y4 h* @1 g6 H1 [' rthalamic pituitary gonadal axis. CPP is more com-
: p" X0 W* q; g2 E9 X5 Y' s' Ymon in girls than in boys.1,3 Most boys with CPP( S, U$ B J* p1 ?
may have a central nervous system lesion that is
3 x: K# ?, F4 U% S' Qresponsible for the early activation of the hypothal-
9 N3 l* h. ~+ `amic pituitary gonadal axis.1-3 Thus, greater empha-
, ], U& x9 X$ \- q9 A$ e9 ksis has been given to neuroradiologic imaging in
# K9 F5 q U) Nboys with precocious puberty. In addition to viril-
7 j! D6 Y9 e6 w" Q) z: b) @ization, the clinical hallmark of CPP is the symmet-
$ |/ l+ w7 L5 ?' c+ y+ Orical testicular growth secondary to stimulation by
+ h, {3 Y+ z* o2 c5 W Qgonadotropins.1,3* L# G3 P! s& U+ ^
Gonadotropin-independent peripheral preco-0 ^/ D5 c$ v0 V; G2 l, M
cious puberty in boys also results from inappropriate7 z3 {; [4 |/ n) F
androgenic stimulation from either endogenous or4 t# O, f" {9 a- j
exogenous sources, nonpituitary gonadotropin stim-
, j4 d/ \6 ]& _) Julation, and rare activating mutations.3 Virilizing X6 a. ]; Q4 }- ^) R- k- p
congenital adrenal hyperplasia producing excessive
a1 V; H1 e8 Gadrenal androgens is a common cause of precocious
1 w# M! {. a/ vpuberty in boys.3,4. n* z! W4 k8 e I/ v: }
The most common form of congenital adrenal
1 g4 B. n8 t [- khyperplasia is the 21-hydroxylase enzyme deficiency.
; b4 a1 ^: V: S, SThe 11-β hydroxylase deficiency may also result in/ ~% |8 \; M2 C6 {2 R
excessive adrenal androgen production, and rarely,
7 ~" i# } ?. n" l1 ?$ P J# D. kan adrenal tumor may also cause adrenal androgen4 o5 g% M/ d; H$ z1 l7 o
excess.1,33 { }& n* v+ M$ x& o- T5 _& h& Y
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
' j t) `# U9 j5 q4 [9 @& A542 Clinical Pediatrics / Vol. 46, No. 6, July 20077 ^4 E/ W, A9 s9 U
A unique entity of male-limited gonadotropin-
5 U* G* {/ ~3 [9 _# N5 N1 Gindependent precocious puberty, which is also known' O& [9 U( G2 f5 z! K( _% y
as testotoxicosis, may cause precocious puberty at a6 a7 Y2 H& J" i9 O8 y; R6 Q
very young age. The physical findings in these boys
) J- E2 K% P5 }" ]1 [0 }3 Jwith this disorder are full pubertal development,% n, Y2 A8 |! O! ]/ ^
including bilateral testicular growth, similar to boys
2 V. Z0 _7 Y8 w; K- a4 awith CPP. The gonadotropin levels in this disorder2 a3 W- |- V8 q7 H( W$ X
are suppressed to prepubertal levels and do not show' L" Q6 e( R9 r! W2 @
pubertal response of gonadotropin after gonadotropin-$ G5 g5 r+ X z# ~
releasing hormone stimulation. This is a sex-linked# ^+ Y( n& R3 K/ ]
autosomal dominant disorder that affects only* p+ f4 k% Q% G+ s
males; therefore, other male members of the family$ R0 t6 V/ t0 x$ P ?$ i
may have similar precocious puberty.3
! R L7 y: X; D: J; P h AIn our patient, physical examination was incon-$ {/ g1 `: }) ]
sistent with true precocious puberty since his testi-
% D* ]5 ~4 L. A0 ^. K ~cles were prepubertal in size. However, testotoxicosis7 k' @+ q' ]! }" i% L! c, k
was in the differential diagnosis because his father/ y6 z; D( w2 D, s# u; |2 J" K
started puberty somewhat early, and occasionally,
. k' j( c* `# J' P. l; p btesticular enlargement is not that evident in the
6 s. ?" k$ j' n u! ebeginning of this process.1 In the absence of a neg-7 a# j4 K& @, S3 \; b v# r
ative initial history of androgen exposure, our
4 s" C0 W" y G8 w4 nbiggest concern was virilizing adrenal hyperplasia,
* X. |3 y! b7 F! K) a* leither 21-hydroxylase deficiency or 11-β hydroxylase8 X5 e0 r3 _2 r4 m- ?5 i
deficiency. Those diagnoses were excluded by find-
5 |7 R5 S5 T9 O$ Z/ ~% Fing the normal level of adrenal steroids.
# g& U! E% n+ xThe diagnosis of exogenous androgens was strongly) P! L. L" d: h- _. i+ j4 }6 H7 A
suspected in a follow-up visit after 4 months because9 c4 w: c4 O( i3 R1 Q& W
the physical examination revealed the complete disap-+ G1 t4 }0 J1 O
pearance of pubic hair, normal growth velocity, and
" {. x% |0 `% x/ ]; k# Cdecreased erections. The father admitted using a testos-
6 I. B T, A4 ]' a: [$ C4 w# bterone gel, which he concealed at first visit. He was
" {7 `/ j- o3 p/ Z2 T! kusing it rather frequently, twice a day. The Physicians’$ D# D0 D- K l* }9 c
Desk Reference, or package insert of this product, gel or
, r4 l2 U$ _9 D6 ]" hcream, cautions about dermal testosterone transfer to! s$ d1 F' l7 q$ `! [9 R* N) a
unprotected females through direct skin exposure.
3 H% h3 G1 ]' q% E. K: o' U! MSerum testosterone level was found to be 2 times the
8 m7 d4 n* l2 B9 C2 Q! Bbaseline value in those females who were exposed to6 [" |& m) p7 W/ r5 Z* h
even 15 minutes of direct skin contact with their male8 u3 b+ a5 P" m* C3 L0 A1 b" _
partners.6 However, when a shirt covered the applica-2 ^$ }8 w [, N# b2 \$ }& o# U' c
tion site, this testosterone transfer was prevented.9 T+ f+ C X; q& |
Our patient’s testosterone level was 60 ng/mL,
! M+ S4 \( [! b# a6 r5 pwhich was clearly high. Some studies suggest that
/ K: R; x4 c3 S8 a2 I9 k" j7 O/ [dermal conversion of testosterone to dihydrotestos-( z$ E7 b- a# w9 D7 x* X. V& o" I
terone, which is a more potent metabolite, is more
; N2 V; h2 W+ A& g {5 v6 Jactive in young children exposed to testosterone
2 d1 w9 Y; Y- vexogenously7; however, we did not measure a dihy-
3 ^9 H! Y3 C. qdrotestosterone level in our patient. In addition to, O$ p5 V' A/ r* [2 B# b0 G
virilization, exposure to exogenous testosterone in
$ B/ k) ~+ d0 i- [4 |# Schildren results in an increase in growth velocity and* b) G# l$ m6 J
advanced bone age, as seen in our patient.
% O+ e5 c( H @3 Q3 U( Z+ ZThe long-term effect of androgen exposure during
& g+ U0 ]* u& _4 `7 Learly childhood on pubertal development and final
2 x0 Z: L: z0 B5 y+ xadult height are not fully known and always remain+ A r6 W/ T1 r) m$ V) S4 G
a concern. Children treated with short-term testos-
2 |, y5 K+ V. Cterone injection or topical androgen may exhibit some- N* O$ f' W9 @% S9 s3 d! E% @7 H
acceleration of the skeletal maturation; however, after$ w/ Q4 U$ p$ |
cessation of treatment, the rate of bone maturation
?! a6 s. e- Zdecelerates and gradually returns to normal.8,9. }$ {) A& M P; \9 B- t! Z! E; S$ g
There are conflicting reports and controversy
7 a; |2 O* f, y* h4 v" h, j x5 Lover the effect of early androgen exposure on adult
+ q) s; Z, s' Zpenile length.10,11 Some reports suggest subnormal. t9 n0 B: u' M R
adult penile length, apparently because of downreg-
, p/ L6 }$ j) f4 P5 |: ]7 Dulation of androgen receptor number.10,12 However,
y3 Y, ]* B3 e# ]- L3 u2 w1 D( TSutherland et al13 did not find a correlation between
9 O* B- H* s% |3 Q/ vchildhood testosterone exposure and reduced adult8 \* u2 ^0 e1 V
penile length in clinical studies.
& H* [/ [# r# f# N: x5 [% f% DNonetheless, we do not believe our patient is4 c f3 Z& B$ Y, y$ G2 {3 d% E
going to experience any of the untoward effects from
[; L0 i0 I# N+ C G9 Ytestosterone exposure as mentioned earlier because; _3 e a c, H! p# X
the exposure was not for a prolonged period of time.5 l5 I: o$ P e% _6 U
Although the bone age was advanced at the time of6 T. V1 Q3 l% F: `$ s1 b
diagnosis, the child had a normal growth velocity at
3 d8 v* O6 t0 |3 U# Sthe follow-up visit. It is hoped that his final adult$ O: } Y2 h! w& e! _& U
height will not be affected.
) p' v" p. n/ z$ x6 u- m: p" S( qAlthough rarely reported, the widespread avail-
& Q8 L# p; }2 @7 Dability of androgen products in our society may' b9 }* j5 p% {6 w+ U
indeed cause more virilization in male or female( x& q D# R- C$ h. W# t
children than one would realize. Exposure to andro-
7 l+ A5 b, }( E3 W! E3 Igen products must be considered and specific ques-
, |. X1 j6 z9 E3 x7 y" h, Ztioning about the use of a testosterone product or
, K& `+ B4 D, y( Y+ X8 P, cgel should be asked of the family members during
9 O- w4 l- Q+ K, f5 K4 o$ Ethe evaluation of any children who present with vir-( n+ ?& s# I" p* d
ilization or peripheral precocious puberty. The diag-
" d! E' M$ G& _. w5 ]$ d3 Xnosis can be established by just a few tests and by/ Q5 l4 }: v' e4 s# S( l/ d( j
appropriate history. The inability to obtain such a
5 Z! f J1 p- A" j9 uhistory, or failure to ask the specific questions, may
2 \, ?: N! Z) {& |7 Q0 l7 Aresult in extensive, unnecessary, and expensive; H* \5 p$ Q) ?7 H* u
investigation. The primary care physician should be( M% N1 a D9 b( G! c" R7 h* x
aware of this fact, because most of these children1 h5 F1 o8 A' _7 T9 A
may initially present in their practice. The Physicians’
, h, t. B* P% x2 sDesk Reference and package insert should also put a
) g: N8 h, p6 W8 ^2 h+ lwarning about the virilizing effect on a male or
3 H8 T9 b" Y5 s) K: Y0 ^- F+ bfemale child who might come in contact with some-
0 l' a; N+ O) D" R/ Rone using any of these products.
3 M. l9 m7 _' d% b' F" vReferences
2 Y# X/ e- I9 z( ^! N' T; U! I1. Styne DM. The testes: disorder of sexual differentiation! C7 ^6 a0 |" v( G' y( d6 X
and puberty in the male. In: Sperling MA, ed. Pediatric2 X8 J) [( A) [) {4 S- p
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;( `/ G8 L# t- {( }% [
2002: 565-628.% p' z$ p) \7 F! b) F
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious; T1 W9 H( \# @$ Y2 C' C
puberty in children with tumours of the suprasellar pineal
' ~2 `9 ^0 {0 {7 nat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
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areas: organic central precocious puberty. Acta Paediatr.
9 Q& b2 [7 V3 R( o$ w @. P) K2001;90:751-756.! N! a! |6 q1 h! r1 q
3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.
" U. R% U0 M8 [) C9 ?Pediatric Endocrinology. 4th ed. New York, NY: Marcel
! ]/ X* b6 d& a, hDekker Inc; 2003:211-238.% V X$ V% f i4 f% ^6 \5 q
4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual+ R! T' l: e- w9 m3 [3 V
development in a two-year-old boy induced by topical
0 L x% Q; l2 A8 |exposure to testosterone. Pediatrics. 1999;104:e23.7 ^# A% n$ y/ g
5. Greulich WW, Pyle SI, eds. Radiographic Atlas of7 t2 r3 |7 X7 L
Skeletal Development of the Hand and Wrist. 2nd ed.
! u6 f/ J! w; H: L8 V) BStanford, CA: Stanford University Press; 1959.
- U+ W# q9 d2 ?( h, Q& T0 n1 a2 s5 u6. Physicians’ Desk Reference. Androgel 1% testosterone,
- \! Y0 r5 h9 Z0 q* i: ~' mUnimed Pharmaceutical Inc. Montvale, NJ: Medical
- j; T: i8 Y9 ]( c0 N, z# s) K& xEconomics Company, Inc; 2004:3239-3241.) g' w h1 l, R0 m2 w
7. Klugo RC, Cerny JC. Response of micropenis to topical
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