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| is a significant concern for physicians. Central6 O. \' W7 ^" ~7 i. J  R. g( F) H  } precocious puberty (CPP), which is mediated
 0 r! A6 |+ }! g/ @through the hypothalamic pituitary gonadal axis, has
 0 |# \1 `1 z+ T) F; z" F, Ka higher incidence of organic central nervous system
 , X: G. ]3 c' ^* nlesions in boys.1,2 Virilization in boys, as manifested) _+ i$ I6 R% q/ I3 V4 }& D
 by enlargement of the penis, development of pubic' S. k* n$ E* ]2 d# \  B
 hair, and facial acne without enlargement of testi-" ?# l, E( ^6 ~& t  A4 [
 cles, suggests peripheral or pseudopuberty.1-3 We
 2 ]; B+ _, j$ R) t' z  p5 g( s3 x5 B- breport a 16-month-old boy who presented with the4 V$ i8 v9 C( F. O: Q0 J( O! H
 enlargement of the phallus and pubic hair develop-
 1 F5 I( ~- P6 N# zment without testicular enlargement, which was due  c- F. N) X4 g. x. y
 to the unintentional exposure to androgen gel used by6 d& d8 H! w' t
 the father. The family initially concealed this infor-+ J  C( J. E, {/ U4 H( R
 mation, resulting in an extensive work-up for this
 ; y* Z% x; m( i; [* U- q2 A5 Wchild. Given the widespread and easy availability of) c; m$ Y2 w8 x- o" |
 testosterone gel and cream, we believe this is proba-: D3 V: F  H8 o
 bly more common than the rare case report in the
 1 m5 z5 s5 h8 S- `% W! U6 n, e& [+ ^literature.4
 $ U3 x+ v" `) u/ i" J- `/ u& VPatient Report
 ' [6 c1 j& N" W* ]+ \' X4 O. dA 16-month-old white child was referred to the5 R+ i! W0 S/ ~5 G4 \* Z) E8 V* \
 endocrine clinic by his pediatrician with the concern
 2 N1 [# U% [3 ?1 H% ^7 rof early sexual development. His mother noticed  d6 e: q( u1 N: _/ a0 i
 light colored pubic hair development when he was
 5 E' w+ G& s. E8 _0 r. BFrom the 1Division of Pediatric Endocrinology, 2University of" k0 e/ u3 z+ D0 r
 South Alabama Medical Center, Mobile, Alabama.* }& `6 Q* L* e8 g, Z
 Address correspondence to: Samar K. Bhowmick, MD, FACE,/ ^2 M+ S: Q+ v7 H, P" T
 Professor of Pediatrics, University of South Alabama, College of
 9 ~6 l# m& D: s' ~3 I. _) L) h* bMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;; J2 @" V8 R% C" h' o( w
 e-mail: [email protected].6 V6 K3 _2 D5 n
 about 6 to 7 months old, which progressively became
 9 A' r/ B3 E+ q5 f" Q8 I5 g' Cdarker. She was also concerned about the enlarge-% L0 j2 N- |8 Z0 ]- Z
 ment of his penis and frequent erections. The child# W* Q! ^% s2 S7 x0 T& i& u
 was the product of a full-term normal delivery, with7 @% `5 {9 T+ r( w8 E! W- N" g/ I
 a birth weight of 7 lb 14 oz, and birth length of! y2 z' F- D5 ?6 X
 20 inches. He was breast-fed throughout the first year% @% n/ W" h- N' c
 of life and was still receiving breast milk along with
 0 u5 e0 ]3 b- l5 m' Nsolid food. He had no hospitalizations or surgery,
 ! ~# t" G$ {. B% g$ g# @& n9 Eand his psychosocial and psychomotor development; I  F: q4 K7 ^4 ^
 was age appropriate.
 6 p; M( s+ Q! H) w1 l2 gThe family history was remarkable for the father,
 ! O$ @% g) j8 V/ Gwho was diagnosed with hypothyroidism at age 16,7 M! J+ `" ^6 B; x5 a
 which was treated with thyroxine. The father’s& G: H+ I( f0 {* m3 c. r1 z: ~
 height was 6 feet, and he went through a somewhat
 " B7 s1 z* N& E% d* ^0 Bearly puberty and had stopped growing by age 14.# b$ ~+ u1 \8 f! s$ p0 Y& j8 O
 The father denied taking any other medication. The
 $ m+ w) j: k' R3 u6 wchild’s mother was in good health. Her menarche' _7 a5 F% p; P" _' t: o
 was at 11 years of age, and her height was at 5 feet4 \9 i4 n4 ]( q" ]+ |/ c) N: d
 5 inches. There was no other family history of pre-
 1 h& U' T  X, q7 Q) [7 e3 jcocious sexual development in the first-degree rela-+ L( c' t; S* V+ {
 tives. There were no siblings., N+ C6 X- o; `, Q) [0 ^
 Physical Examination
 / T; l4 ~$ I1 @The physical examination revealed a very active,( o: `% D( [( g. P! v" n# i
 playful, and healthy boy. The vital signs documented
 " B5 p& g$ Z1 D, v; {a blood pressure of 85/50 mm Hg, his length was
 . @7 }% O6 D% ^2 H. u90 cm (>97th percentile), and his weight was 14.4 kg
 8 K) Q7 ~5 s# t4 k# ]" m* e(also >97th percentile). The observed yearly growth
 9 s! [* b- F) \6 f  \% rvelocity was 30 cm (12 inches). The examination of
 1 j+ T$ {0 T) y+ [/ e  k/ gthe neck revealed no thyroid enlargement.& l( W* U9 h3 [/ e& v
 The genitourinary examination was remarkable for
 . f$ [2 K" z- S4 i; uenlargement of the penis, with a stretched length of& ^9 m1 _; k1 d  g' {' a4 P6 j
 8 cm and a width of 2 cm. The glans penis was very well8 {- u+ g' S! h  n5 Q
 developed. The pubic hair was Tanner II, mostly around
 8 C; e+ e5 ?% `/ N3 p: C540
 ( G$ v) h7 o  A. f% K7 B& Bat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from& p) I9 h1 R" N7 J5 y
 the base of the phallus and was dark and curled. The
 0 c7 F; V! Q: a/ q, _testicular volume was prepubertal at 2 mL each.
 + S2 y: k( A% u* b; s: _. KThe skin was moist and smooth and somewhat
 6 p: R  t: r2 ~; Y2 X( ?7 a& e( ]* ^oily. No axillary hair was noted. There were no
 0 Y5 ^8 V/ V, u" S& b5 f- S+ [abnormal skin pigmentations or café-au-lait spots.
 ) E# }5 _3 A8 b. x' _Neurologic evaluation showed deep tendon reflex 2+# p5 [& e% l1 C0 q4 g4 w
 bilateral and symmetrical. There was no suggestion. Y* ^5 `: P( U' z
 of papilledema.2 {, D2 |9 }1 R1 w- }; C+ v
 Laboratory Evaluation
 ( k# Y, |- k' D! FThe bone age was consistent with 28 months by$ j. l5 `& z, h8 [: h
 using the standard of Greulich and Pyle at a chrono-4 u; U# O7 I& F. a
 logic age of 16 months (advanced).5 Chromosomal- f9 h6 P! z6 n5 B5 Z7 k3 E  h, T
 karyotype was 46XY. The thyroid function test/ k1 |+ Y" b+ \, u
 showed a free T4 of 1.69 ng/dL, and thyroid stimu-/ ~& y# C6 k1 z- [
 lating hormone level was 1.3 µIU/mL (both normal).
 & x% t$ m! f3 d9 r/ i4 GThe concentrations of serum electrolytes, blood; x3 J: X& Q( W( e4 x
 urea nitrogen, creatinine, and calcium all were
 7 S, v$ ~' Y$ ?3 r& ?within normal range for his age. The concentration3 ~  H) h7 P7 |
 of serum 17-hydroxyprogesterone was 16 ng/dL- }, @' e9 i$ e9 q) |: E0 {; h$ z
 (normal, 3 to 90 ng/dL), androstenedione was 20
 0 I) A2 K2 w2 x; l3 qng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-7 T3 ^2 U2 G- J( o/ u
 terone was 38 ng/dL (normal, 50 to 760 ng/dL),
 4 U# ^* U# L, v6 i# U( g: i3 M: kdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
 0 i0 k# A& \) q49ng/dL), 11-desoxycortisol (specific compound S)& |  R6 n8 s' d4 I5 d( m
 was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-& z% u) X3 g5 Z5 T. a( Q. O
 tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total2 r; |# X7 ~* M5 K7 f) N' @
 testosterone was 60 ng/dL (normal <3 to 10 ng/dL),6 Y1 p8 L# ^  p* _5 s1 q& S
 and β-human chorionic gonadotropin was less than( m* n% m: t' ]9 }5 F- e
 5 mIU/mL (normal <5 mIU/mL). Serum follicular
 ) K2 h5 V8 x8 O8 a( V) ustimulating hormone and leuteinizing hormone% a. }9 p, T# v4 @2 C' j7 g+ V
 concentrations were less than 0.05 mIU/mL
 7 W5 l, Q5 _/ `! Y4 X) }(prepubertal).
 6 h1 |4 s6 s: E+ u! [: f8 WThe parents were notified about the laboratory+ v7 t, U& T" x/ {, ]
 results and were informed that all of the tests were; z2 d* X) w$ t: W. C: k
 normal except the testosterone level was high. The
 9 V( \- q$ B0 b' k5 u: Tfollow-up visit was arranged within a few weeks to
 ; \- H5 D5 s6 Q0 q) T, I8 }obtain testicular and abdominal sonograms; how-2 C5 G6 O: }6 B7 b7 u
 ever, the family did not return for 4 months.* w# y+ k4 S" j7 D' g
 Physical examination at this time revealed that the
 ' W  `* C4 r# gchild had grown 2.5 cm in 4 months and had gained
 7 K0 g1 [! @' b% C2 kg of weight. Physical examination remained
 , }; K" o7 e* Q* Y2 M: I- f* q: Tunchanged. Surprisingly, the pubic hair almost com-
 6 A. \; R% f/ ?! J7 w# Gpletely disappeared except for a few vellous hairs at3 j+ ], l" q6 m
 the base of the phallus. Testicular volume was still 2  Z, M# d+ |9 i) n8 q7 l
 mL, and the size of the penis remained unchanged.6 Q  {! `/ n- z  i/ y% D
 The mother also said that the boy was no longer hav-% O" h/ Q6 w4 k
 ing frequent erections." ]5 E$ j0 }; C. b" r+ @- v6 V
 Both parents were again questioned about use of4 Z1 F) X( v8 ~! p0 {1 Q! q
 any ointment/creams that they may have applied to
 ) R) F; |  d: ^8 e* z+ }the child’s skin. This time the father admitted the2 b& a0 e) u% _
 Topical Testosterone Exposure / Bhowmick et al 541
 8 Y0 y9 w* @+ j. X8 A- Ruse of testosterone gel twice daily that he was apply-
 ' f3 o- d4 D9 L" U; fing over his own shoulders, chest, and back area for/ G# N; I; D( y5 u# G2 r, P) p. ^3 \$ G
 a year. The father also revealed he was embarrassed- s- c; t: b1 Q4 {! E
 to disclose that he was using a testosterone gel pre-
 + W) A1 |- W1 O2 ^scribed by his family physician for decreased libido
 , d/ H8 Q# ~) I' dsecondary to depression.1 h8 r& |2 z: G% s, c4 K
 The child slept in the same bed with parents.4 f+ n/ n6 b  o: s: ?/ |
 The father would hug the baby and hold him on his: O: J6 L6 w8 D9 p& r2 N
 chest for a considerable period of time, causing sig-
 - T* y% ~0 }* \0 vnificant bare skin contact between baby and father.
 # C/ @  b. J' |2 X' WThe father also admitted that after the phone call,
 ' j1 @* {2 T7 S; \- J0 Awhen he learned the testosterone level in the baby
 8 q7 Z" d) _6 b1 A: S6 dwas high, he then read the product information; t1 s" [8 Q4 e" B9 d! I+ O
 packet and concluded that it was most likely the rea-. W; O6 r. z( w4 v1 {8 o9 s
 son for the child’s virilization. At that time, they
 4 J8 \  d# F6 ]! l* |% Mdecided to put the baby in a separate bed, and the
 2 L6 t8 G( N$ P, M3 }3 lfather was not hugging him with bare skin and had  Y9 ~" O& j3 {3 Q( U0 m( d
 been using protective clothing. A repeat testosterone
 4 W  n3 R# J8 Utest was ordered, but the family did not go to the1 f( M8 w6 c3 m: u0 b* {) D( y
 laboratory to obtain the test.
 & u6 Y+ |2 P  M* tDiscussion8 I0 ^; N1 j5 k/ i6 \
 Precocious puberty in boys is defined as secondary, M' \" N( s; ]1 m" y* T8 E
 sexual development before 9 years of age.1,4
 + z, N2 z: \( u5 e. V! fPrecocious puberty is termed as central (true) when
 $ P3 ^1 i- U0 m  X" B% m) y5 nit is caused by the premature activation of hypo-
 - w, b/ }, M, V- T" vthalamic pituitary gonadal axis. CPP is more com-
 0 j. }2 s( F# c8 R" p( |) ~mon in girls than in boys.1,3 Most boys with CPP% B* @6 r6 ~* P. j6 t# k0 u
 may have a central nervous system lesion that is
 2 O  s/ j$ w) W2 `$ ]5 kresponsible for the early activation of the hypothal-
 % M* d8 F, L, ~& N1 ?% samic pituitary gonadal axis.1-3 Thus, greater empha-
 , q6 J: Y' n% @6 B; @, Q) _sis has been given to neuroradiologic imaging in8 u4 Y8 [. _1 o& a$ G* t2 n
 boys with precocious puberty. In addition to viril-
 - }  I% q% h, Y% H% O0 \ization, the clinical hallmark of CPP is the symmet-
 8 V1 X- C9 R' A; w2 K2 ~6 Trical testicular growth secondary to stimulation by
 - f/ u. X3 }( d  wgonadotropins.1,3
 ~9 y$ C( r! N. m5 G& Y* T9 s5 fGonadotropin-independent peripheral preco-
 9 W4 D; ^% E4 }; q( t: jcious puberty in boys also results from inappropriate
 $ q. ?7 S) F* \# n2 y' o7 T! f7 sandrogenic stimulation from either endogenous or( S: [/ H6 \* M. p6 c  S' \- O
 exogenous sources, nonpituitary gonadotropin stim-
 / C0 H3 Y4 v6 u& I+ m! zulation, and rare activating mutations.3 Virilizing
 4 m4 e1 j6 P$ h% P3 Ycongenital adrenal hyperplasia producing excessive
 z7 K" C8 G* a( Gadrenal androgens is a common cause of precocious
 1 P+ ]9 l, H0 @  z+ w9 r9 `puberty in boys.3,4, w) o  ]" S. u. [& Q. W
 The most common form of congenital adrenal
 & p( s) o& t/ e$ u; Fhyperplasia is the 21-hydroxylase enzyme deficiency.
 6 l3 x# f! L) }! mThe 11-β hydroxylase deficiency may also result in+ V4 c0 \8 B- s+ q/ t* k2 V$ ^. V" L
 excessive adrenal androgen production, and rarely,
 8 I; l' m5 i! ian adrenal tumor may also cause adrenal androgen: Z/ B3 i) L; R) r! M
 excess.1,3
 % W) Q3 f' r6 [  _# j: T8 ^at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
 # Y; C7 e- L  P542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
 , M' i: k+ w. r) mA unique entity of male-limited gonadotropin-8 t- ~. ?' G$ O* Z
 independent precocious puberty, which is also known
 7 i9 b0 I% l# j( v4 l4 Q0 Vas testotoxicosis, may cause precocious puberty at a% \! G3 `$ `( \; x* I2 ?
 very young age. The physical findings in these boys
 ! x% g; X# c, O& M; ?  mwith this disorder are full pubertal development,2 `: g* n% q+ q3 A- {8 G
 including bilateral testicular growth, similar to boys/ Z6 b% H) J" J! ?
 with CPP. The gonadotropin levels in this disorder
 ' m* d; h! R4 A; q' y) S5 e8 iare suppressed to prepubertal levels and do not show, P! Q& [6 p8 g" V0 _9 ~
 pubertal response of gonadotropin after gonadotropin-; m: n: i! |) @) m6 v
 releasing hormone stimulation. This is a sex-linked" |, s/ a. i! a
 autosomal dominant disorder that affects only( @" r4 b7 M  t2 e' K8 ?
 males; therefore, other male members of the family
 0 k! v/ k& c+ }; x$ umay have similar precocious puberty.3$ i- ^/ u3 k$ |) d6 E- X
 In our patient, physical examination was incon-
 / I' n; F; N8 j/ B% v0 _) i$ ssistent with true precocious puberty since his testi-
 , k/ |" U  @: ?# g2 scles were prepubertal in size. However, testotoxicosis: f/ }$ K$ w  ^1 k
 was in the differential diagnosis because his father) p2 F. ^( |  B3 J0 S8 v
 started puberty somewhat early, and occasionally,
 4 _  s1 |& g% l4 I% R- Htesticular enlargement is not that evident in the( G4 T0 M: l' g# U, h6 l4 T( x( ^
 beginning of this process.1 In the absence of a neg-" \7 k& w2 k5 W
 ative initial history of androgen exposure, our$ `$ n5 n) w0 i9 a" s0 q: X
 biggest concern was virilizing adrenal hyperplasia,: Q: X6 q1 f2 R. b- U* x
 either 21-hydroxylase deficiency or 11-β hydroxylase: [% g- W2 I$ b
 deficiency. Those diagnoses were excluded by find-% l+ n6 R2 B0 w# ~2 O
 ing the normal level of adrenal steroids.
 5 k, V  E+ w: x- @/ \5 S( mThe diagnosis of exogenous androgens was strongly
 3 e) D' k1 e! z, |6 {  G' rsuspected in a follow-up visit after 4 months because
 0 x' l1 m8 K# X' m( S" tthe physical examination revealed the complete disap-
 ) T+ J; O! m# X  @1 U! Y6 w; r# ~pearance of pubic hair, normal growth velocity, and
 1 N# B2 u: r9 O6 P% J) Q: Gdecreased erections. The father admitted using a testos-
 # z2 I4 Q, C9 }- uterone gel, which he concealed at first visit. He was
 & W3 K3 h1 ?7 b$ n7 p. N; ~using it rather frequently, twice a day. The Physicians’7 F- Y, K( R/ [3 n' o; k
 Desk Reference, or package insert of this product, gel or5 h8 k  R( ]: C9 x% W  F! v
 cream, cautions about dermal testosterone transfer to+ y; L+ J7 z! m8 K
 unprotected females through direct skin exposure.
 ' S3 ^8 F# Z, }% `/ [Serum testosterone level was found to be 2 times the
 5 f8 B6 U6 b. |* i# Y" h5 V" f. mbaseline value in those females who were exposed to
 8 ?$ f; V( r* H  }; x& Beven 15 minutes of direct skin contact with their male4 a. m" S( M, K* {8 v$ U
 partners.6 However, when a shirt covered the applica-
 / U7 K& o, f. \" h2 ^" f" e- W1 b% otion site, this testosterone transfer was prevented.
 ' L7 O/ b. i7 a' BOur patient’s testosterone level was 60 ng/mL,
 ) r% Y8 c* e2 f# e8 n. f& pwhich was clearly high. Some studies suggest that
 $ a) U' B+ x+ k6 o' V( tdermal conversion of testosterone to dihydrotestos-8 V$ s* g) Z! R. J
 terone, which is a more potent metabolite, is more& \0 e2 Z+ B6 ^. i9 H) @# M1 \. z
 active in young children exposed to testosterone
 ( r8 W& v% {, ]5 U% nexogenously7; however, we did not measure a dihy-
 ( ~% g4 x# I4 h: {6 Ldrotestosterone level in our patient. In addition to
 : r- X; t* S) ]# Nvirilization, exposure to exogenous testosterone in9 {7 Z4 h; Y. D/ i' ^! G7 X
 children results in an increase in growth velocity and
 ) W+ M/ f( J% g4 xadvanced bone age, as seen in our patient.
 2 w7 c6 z+ W, p! FThe long-term effect of androgen exposure during, H9 {( l8 A& t& p0 H' q
 early childhood on pubertal development and final, s' u. i, c7 _" a3 H
 adult height are not fully known and always remain, U* E: W' o. F/ p* w
 a concern. Children treated with short-term testos-
 5 U% f. }1 f1 n6 U# Bterone injection or topical androgen may exhibit some
 ) [2 f2 d0 m& Xacceleration of the skeletal maturation; however, after
 6 M1 i' a9 m& w' M: }2 }8 \cessation of treatment, the rate of bone maturation9 W9 C# c  d# M& r4 P
 decelerates and gradually returns to normal.8,9
 7 O! y) a9 `. @. h# tThere are conflicting reports and controversy& y1 E, x. N) f8 k; B
 over the effect of early androgen exposure on adult
 8 w4 E. e3 o9 [  Zpenile length.10,11 Some reports suggest subnormal* p5 x. W) F& Z! f! t, P/ L
 adult penile length, apparently because of downreg-
 3 w( l0 }2 A: W9 s# S  }, K% |/ tulation of androgen receptor number.10,12 However,
 1 K8 X4 z! s2 [5 l- OSutherland et al13 did not find a correlation between
 . h1 C( {: N2 b4 b( Q& ~childhood testosterone exposure and reduced adult1 o# ]) T, n) m2 S
 penile length in clinical studies.) V% Q* v. a9 @% f6 A
 Nonetheless, we do not believe our patient is( N2 Z; _. ]. V$ [: p- K
 going to experience any of the untoward effects from* x, f" K  ]8 @
 testosterone exposure as mentioned earlier because
 7 L3 ], H  n  V! cthe exposure was not for a prolonged period of time.
 # c' X, C$ J+ E! \1 t6 r6 j4 P1 l0 vAlthough the bone age was advanced at the time of
 1 e/ S) @% m, u% Z! @& @diagnosis, the child had a normal growth velocity at* Y$ P$ p0 S4 s5 @% I2 q: g1 M
 the follow-up visit. It is hoped that his final adult
 / H$ \; `; H* l# z" \/ g: Y8 vheight will not be affected.
 8 A: o5 f: R# s3 a" VAlthough rarely reported, the widespread avail-
 # w; F( F8 A# S( B3 `, Xability of androgen products in our society may0 }3 [% R& D" f3 ]( [+ R
 indeed cause more virilization in male or female4 v* q" B/ L8 j# B1 X( [8 u$ h
 children than one would realize. Exposure to andro-  j% Q( {8 e$ m. s: v
 gen products must be considered and specific ques-! q2 R1 m; x# Y, d  l8 Q) B
 tioning about the use of a testosterone product or& Y& P+ Z2 n- }; C6 Y. }5 w
 gel should be asked of the family members during5 H8 d4 v2 Z$ A8 Y0 u* A* v
 the evaluation of any children who present with vir-" n! g! x3 U8 ~# i
 ilization or peripheral precocious puberty. The diag-
 ) t# C3 @$ U/ |$ B, ^# z2 Qnosis can be established by just a few tests and by
 0 J0 C4 i) K0 ~; a$ L+ z3 }- Gappropriate history. The inability to obtain such a
 - D$ B1 _; o* C1 B- G5 X5 Dhistory, or failure to ask the specific questions, may
 ! z8 O& Q# e% C& m* |result in extensive, unnecessary, and expensive
 ; F! ?, d: A- tinvestigation. The primary care physician should be
 7 ~& H# y2 A+ [: F+ d  [9 ]aware of this fact, because most of these children
 ' u* J; K4 {5 X: u$ ~: dmay initially present in their practice. The Physicians’8 h! A1 J( \2 e0 g# H0 ~; \5 ]
 Desk Reference and package insert should also put a1 a- f/ R) p( R7 o; C
 warning about the virilizing effect on a male or
 9 k- G0 d* e/ C2 ~. N2 X( B1 C9 \female child who might come in contact with some-" [+ u( s3 ~+ C, l
 one using any of these products.1 l2 `* M% l# H8 N8 W2 S/ [6 T
 References
 0 @# d0 }+ [- V5 e  y9 l1 n7 |+ S1. Styne DM. The testes: disorder of sexual differentiation
 4 y7 t" ]! l- v+ aand puberty in the male. In: Sperling MA, ed. Pediatric
 0 O1 v& X' ]$ f5 `Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
 4 \& ~  F, {8 _; l2002: 565-628.) K5 g! n% O3 j: r2 z
 2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious+ l- X* g, T) J% H2 C3 \+ k  K
 puberty in children with tumours of the suprasellar pineal
 / z$ b3 j1 u3 J/ Sat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
 : E6 A5 G8 M6 WTopical Testosterone Exposure / Bhowmick et al 543
 5 m  j9 q8 Q4 A1 o$ `6 L0 V  k* Tareas: organic central precocious puberty. Acta Paediatr.$ y2 Y9 z# G8 G, R) m) ^9 u
 2001;90:751-756.
 ! H9 a% Z- c( S9 M9 E1 s0 J- {6 U3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.' A/ @+ U! a; |3 W# j0 D; p* l
 Pediatric Endocrinology. 4th ed. New York, NY: Marcel0 f. J5 S; m+ ~, Q2 b3 ^4 W, T
 Dekker Inc; 2003:211-238.
 " F( M, S, a' m; i8 Q4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual
 $ M+ z! E% E# `/ v" l, m2 ^development in a two-year-old boy induced by topical
 ) f9 ]4 ^$ K/ |* b7 Texposure to testosterone. Pediatrics. 1999;104:e23.; `7 E* I$ }' {
 5. Greulich WW, Pyle SI, eds. Radiographic Atlas of
 " E  z8 w0 i$ |7 k4 D: ~) x0 ASkeletal Development of the Hand and Wrist. 2nd ed.
 " \+ ], U8 v7 u/ j6 r) {Stanford, CA: Stanford University Press; 1959.
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