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Sexual Precocity in a 16-Month-Old
6 [. Q5 T7 W  P5 r: k0 XBoy Induced by Indirect Topical1 B( _, @. k, F( a% p, M
Exposure to Testosterone$ O  z  @( R3 _% `, y' v
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,22 h& {3 q' N* [  q. h! Q& u
and Kenneth R. Rettig, MD1) O  m- @# W  t( C- t/ P
Clinical Pediatrics
/ q# D+ D/ I& i1 PVolume 46 Number 6( t; Z$ F7 l- c$ i
July 2007 540-543
5 w2 q0 c  g( g  U4 _© 2007 Sage Publications, k9 M' ^% N/ h$ w, h+ D* v( g
10.1177/0009922806296651
; g8 q* B" e3 t4 _http://clp.sagepub.com7 d6 n1 D  c' ]2 O$ H
hosted at+ s$ Y' w% e6 w" o! B& C/ U2 o8 r
http://online.sagepub.com
. \2 G& ~* ]$ OPrecocious puberty in boys, central or peripheral,
  s, ~* L! M8 B8 jis a significant concern for physicians. Central
8 T3 ~6 ^9 @& s0 E" ]precocious puberty (CPP), which is mediated2 k/ G$ v( R; l
through the hypothalamic pituitary gonadal axis, has
  U0 t3 s8 y+ h( r; S$ va higher incidence of organic central nervous system' r+ J3 ]6 Z7 N2 s+ b6 c" }" G
lesions in boys.1,2 Virilization in boys, as manifested- Q- [8 Z+ e3 R& G* l) `
by enlargement of the penis, development of pubic
3 @3 Z1 m# b$ @2 Whair, and facial acne without enlargement of testi-
2 v, l/ h' {# Y5 \cles, suggests peripheral or pseudopuberty.1-3 We
7 b" p: Y5 D9 Y1 t% m/ Qreport a 16-month-old boy who presented with the
  @0 c  ]% y! Nenlargement of the phallus and pubic hair develop-
; {) j0 Q8 A& Y3 A9 Hment without testicular enlargement, which was due
6 F; [- N4 w3 u6 _5 ^7 \7 ~3 Pto the unintentional exposure to androgen gel used by
6 ]2 B: f$ e1 i4 E2 o% N) kthe father. The family initially concealed this infor-
2 o/ j9 B% Q1 ?. {5 Imation, resulting in an extensive work-up for this: j% e" m. y( y; }6 ]8 F! N# u
child. Given the widespread and easy availability of! @9 z( o, `. E$ b7 s7 n4 R1 b3 A& Q
testosterone gel and cream, we believe this is proba-
, r4 g" X3 b$ ^+ |: I! |bly more common than the rare case report in the/ F$ k7 g" N1 _9 |
literature.4  U" |3 v, e8 h: Z% ~5 |- W
Patient Report
& L2 q6 [) i" \2 `$ G6 ^8 xA 16-month-old white child was referred to the/ g4 V$ T! {8 o9 k2 w1 n, \( r
endocrine clinic by his pediatrician with the concern
( H* B8 Y4 ~8 c* e0 Yof early sexual development. His mother noticed
; B5 Y0 X% ^4 [6 x  }light colored pubic hair development when he was
* D( ~7 ~" L% RFrom the 1Division of Pediatric Endocrinology, 2University of
) H% A) ], m* |8 I) F/ f$ QSouth Alabama Medical Center, Mobile, Alabama.
0 I1 C- K1 l  E5 D( KAddress correspondence to: Samar K. Bhowmick, MD, FACE,0 ]6 Q( f; a1 d+ x& ]
Professor of Pediatrics, University of South Alabama, College of
' O0 |7 V8 G( a. T/ E" @, XMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;6 C6 \4 q7 a( P# B. l" L' T& x
e-mail: [email protected].) S0 T: e0 X1 U3 e7 m
about 6 to 7 months old, which progressively became
+ o! @! a/ z7 D  b8 t/ jdarker. She was also concerned about the enlarge-
0 R! o# Y- E2 i) e( Gment of his penis and frequent erections. The child
# k* ~/ P( `5 a/ Z- a  u0 u- R$ kwas the product of a full-term normal delivery, with# V6 t' K" ^: _
a birth weight of 7 lb 14 oz, and birth length of6 Z0 b8 i" q6 B1 H
20 inches. He was breast-fed throughout the first year
2 S2 W# M' N! T! ?of life and was still receiving breast milk along with3 `* [8 i+ ~' h# B. E8 X
solid food. He had no hospitalizations or surgery,
4 V, M& p( b2 i- @and his psychosocial and psychomotor development
0 v" W. G0 m2 {8 L. t9 n& W, A/ @was age appropriate.
  l% D0 n3 Y; n( l% L3 v7 |" j3 m# _  HThe family history was remarkable for the father,
- l5 v  v0 {2 nwho was diagnosed with hypothyroidism at age 16,# \' V5 E. N8 ~0 t- A
which was treated with thyroxine. The father’s
1 |; I+ D# G9 m2 ?4 Dheight was 6 feet, and he went through a somewhat
: ~5 ?7 `# p5 Uearly puberty and had stopped growing by age 14.
. l! S, q6 V( ~) y, L. i% v! cThe father denied taking any other medication. The6 u0 W$ B3 q3 y) d9 H7 W/ w1 w2 W
child’s mother was in good health. Her menarche  M' t. [3 K1 k( F
was at 11 years of age, and her height was at 5 feet) u( D) D7 I  s/ T+ w; ~5 r
5 inches. There was no other family history of pre-( R. ^1 [: L8 V' Y& z. c6 l; _
cocious sexual development in the first-degree rela-3 ?# H" s  s2 S8 j! @# ?
tives. There were no siblings.
. i* @4 r9 _" U8 C# n0 dPhysical Examination( \1 d( K& `3 o' @
The physical examination revealed a very active,  l+ N$ i, Q) i* e' ]! `$ E
playful, and healthy boy. The vital signs documented! z! V$ h. M" w8 K! [$ r' r
a blood pressure of 85/50 mm Hg, his length was1 e3 {# ~2 ]+ F# |+ ~
90 cm (>97th percentile), and his weight was 14.4 kg; e1 i: Z, \& N0 n
(also >97th percentile). The observed yearly growth& j1 [7 V# u, y7 D, j  m# m% P5 s
velocity was 30 cm (12 inches). The examination of
. U4 U' B* ], u& Gthe neck revealed no thyroid enlargement., `& n7 X; N" Y! m
The genitourinary examination was remarkable for
8 ]/ Z' |' V3 P# K* ?" Penlargement of the penis, with a stretched length of: X0 W$ Z$ T' V
8 cm and a width of 2 cm. The glans penis was very well
" i& z7 a5 W$ t0 }! hdeveloped. The pubic hair was Tanner II, mostly around
  C: m' r' z+ S) o540) A- j7 B1 U6 ^! C) A) O/ _+ Q  z
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from! }" @$ o! _: q/ H4 l
the base of the phallus and was dark and curled. The
3 ]  ]6 J9 O: D& Z; Z. a- I- i1 i# qtesticular volume was prepubertal at 2 mL each.
/ b1 z* _  R7 z0 j$ CThe skin was moist and smooth and somewhat
$ I5 [' T6 M+ l7 k1 s% Ooily. No axillary hair was noted. There were no
4 }2 g. s1 @4 a6 Wabnormal skin pigmentations or café-au-lait spots.( ~$ s8 x: v2 W' i4 F4 n: ~; g% q
Neurologic evaluation showed deep tendon reflex 2+% d  ]  f5 U1 X( B& W- V
bilateral and symmetrical. There was no suggestion
! v0 r- @% L7 ^of papilledema.' ~% V  K) B' {. l! d
Laboratory Evaluation  ~# G5 y4 H" h1 I$ o" p
The bone age was consistent with 28 months by
* P/ h, E; M6 Y9 o/ E) @. _# w- tusing the standard of Greulich and Pyle at a chrono-
2 t+ X# L  F3 R0 nlogic age of 16 months (advanced).5 Chromosomal
9 s" f( I3 D* T# vkaryotype was 46XY. The thyroid function test
- U: ^( N0 U/ |7 xshowed a free T4 of 1.69 ng/dL, and thyroid stimu-& `5 y' V6 G2 k& `& S4 c! c
lating hormone level was 1.3 µIU/mL (both normal).% U8 w& n# s# A
The concentrations of serum electrolytes, blood; d$ Z+ b" H, V( P
urea nitrogen, creatinine, and calcium all were: Z4 t8 ]$ z/ o( F* Q( f& _
within normal range for his age. The concentration( K8 z! x% C" w5 {( K! @
of serum 17-hydroxyprogesterone was 16 ng/dL
$ L- V6 K! f" b% n  \$ L(normal, 3 to 90 ng/dL), androstenedione was 204 _% d! x8 j7 y* @- I( }( j8 E3 Y8 K
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
; ^! [# `8 `) x! `8 y2 W6 |terone was 38 ng/dL (normal, 50 to 760 ng/dL),
& _  N8 {  N6 ^0 Z1 Qdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 ]" J5 o5 S/ ?. d" {/ M49ng/dL), 11-desoxycortisol (specific compound S)8 Z, J$ z- o! @' W& [
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-# l; @" Y  f4 x& y0 [" G8 j( X
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
9 c! h2 q% ?: U3 o8 _1 [, dtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),1 _1 P7 D* U7 y
and β-human chorionic gonadotropin was less than% m" d! r0 h" D/ o' O
5 mIU/mL (normal <5 mIU/mL). Serum follicular, [: K4 L9 ?/ G, }9 m
stimulating hormone and leuteinizing hormone3 y" E7 C* {0 |' i7 ^/ z
concentrations were less than 0.05 mIU/mL8 o/ v9 v6 A8 v# O6 R
(prepubertal).( Q7 x4 u" {: ?7 L6 x: S
The parents were notified about the laboratory) `4 e9 V4 Z) o8 t" J/ m8 h
results and were informed that all of the tests were
& `8 u- {0 B! N6 T! ^4 }& tnormal except the testosterone level was high. The* W. f3 {" n/ W
follow-up visit was arranged within a few weeks to
( C( w. e3 I7 C; u( hobtain testicular and abdominal sonograms; how-
% ]4 Y# G% J/ Lever, the family did not return for 4 months.
4 G0 L0 \  h6 W1 i* x; {Physical examination at this time revealed that the
) x) c$ X& O8 C1 S  F* Schild had grown 2.5 cm in 4 months and had gained
2 v* ]0 O& c8 U. K) b. q& F7 B- Z4 ~2 kg of weight. Physical examination remained
! q* F, u& m' H8 z& T$ ]unchanged. Surprisingly, the pubic hair almost com-
2 u4 y4 h9 b- `pletely disappeared except for a few vellous hairs at2 P& y4 S' Y  u* T: Y
the base of the phallus. Testicular volume was still 2
2 ]- b; K. ?( R& V8 c$ VmL, and the size of the penis remained unchanged.
& D8 _; R+ v) }) r: y! G  AThe mother also said that the boy was no longer hav-- y* R4 k5 n7 \# ^8 n3 b: ~, |
ing frequent erections.
: q+ r) D8 w4 D; X- R7 dBoth parents were again questioned about use of8 C4 P5 i- R/ A' H" t
any ointment/creams that they may have applied to9 o3 C0 j( ~: ]7 L8 N6 \
the child’s skin. This time the father admitted the1 P, x1 @( C- h2 I0 `
Topical Testosterone Exposure / Bhowmick et al 541% l; x1 Y  ]0 H: h
use of testosterone gel twice daily that he was apply-) H1 U0 E3 T: {9 ^  x
ing over his own shoulders, chest, and back area for
/ Z8 w9 P) G: \- M7 I+ Sa year. The father also revealed he was embarrassed
. M% N: W+ U/ f4 {2 ^, r2 Kto disclose that he was using a testosterone gel pre-
$ ~* K% `$ R3 R, h3 b/ n% }scribed by his family physician for decreased libido
# n  _. a6 ?6 U( [; e# `secondary to depression.
! A% H9 N0 s; ?( L7 oThe child slept in the same bed with parents.
8 ]/ F1 j+ z' Q$ xThe father would hug the baby and hold him on his0 n* r7 x$ A; K# B  R
chest for a considerable period of time, causing sig-
, t( k+ C) J* v# q1 anificant bare skin contact between baby and father.
6 v6 r) ~" P7 YThe father also admitted that after the phone call,/ X1 J) B0 S& m7 U: ^
when he learned the testosterone level in the baby8 E& j7 l. a' F' W# x! V
was high, he then read the product information* V7 o* H7 Q+ O2 n" T; a/ L8 o' J
packet and concluded that it was most likely the rea-
' X+ @% o8 b+ U, r9 Sson for the child’s virilization. At that time, they# R/ U9 E/ m" ], X6 B" v4 F& A' ]
decided to put the baby in a separate bed, and the
4 M/ n# g# z4 Q9 |4 S! qfather was not hugging him with bare skin and had
" a: A  Z: L" M+ Y/ t8 qbeen using protective clothing. A repeat testosterone
: P! q/ j1 \" i" i. u' C. atest was ordered, but the family did not go to the
9 H; c; `" y3 o0 o& W0 A- j& Plaboratory to obtain the test.
9 x* R! M9 i. E  u. T4 I" g& vDiscussion
" p9 @  U5 T2 \# r' n, [Precocious puberty in boys is defined as secondary+ g. ?. S+ _+ j- C* x2 }
sexual development before 9 years of age.1,4
9 R- x, }4 Z1 l- |1 n; \Precocious puberty is termed as central (true) when
0 @8 n. P* b2 G( l7 mit is caused by the premature activation of hypo-
* O: {4 S1 P* p9 ]thalamic pituitary gonadal axis. CPP is more com-
6 k; j$ Z7 k2 `& |* @! ?3 Kmon in girls than in boys.1,3 Most boys with CPP
* S3 s, h! g! @2 ]$ ?8 ^may have a central nervous system lesion that is2 ~; O" E% E# q
responsible for the early activation of the hypothal-& s' |8 Q: d! K) P1 o$ e
amic pituitary gonadal axis.1-3 Thus, greater empha-
9 G9 r1 }5 O3 `% [* xsis has been given to neuroradiologic imaging in1 o. j/ C: U' J
boys with precocious puberty. In addition to viril-
* V6 N* O$ h& g. Bization, the clinical hallmark of CPP is the symmet-) ?( ^( P4 [% L" \
rical testicular growth secondary to stimulation by( q" Q6 y: z3 v( T% x5 R$ h
gonadotropins.1,3
/ h4 k5 f3 `3 d' @Gonadotropin-independent peripheral preco-
& s: t2 S. w5 }4 ~# Dcious puberty in boys also results from inappropriate
7 J- `2 G- Y; r, ^androgenic stimulation from either endogenous or4 n. u4 Z5 B( T
exogenous sources, nonpituitary gonadotropin stim-
( ?  b( c5 Z1 @. `/ r! ]' ]ulation, and rare activating mutations.3 Virilizing
% b  O4 ^+ |2 a/ i0 N  W2 }; ?congenital adrenal hyperplasia producing excessive* I! a1 g4 t9 o' N+ D& [. Q
adrenal androgens is a common cause of precocious
0 P) Z8 U1 \4 m8 Vpuberty in boys.3,44 b* \: ?0 {4 T9 g
The most common form of congenital adrenal0 F$ x0 \9 E; z( ^# C
hyperplasia is the 21-hydroxylase enzyme deficiency.$ L# }" E5 u2 _3 P, s2 c7 F
The 11-β hydroxylase deficiency may also result in
/ j" r, K" h7 E8 j# @+ eexcessive adrenal androgen production, and rarely,
8 K4 L; Q: y! N1 wan adrenal tumor may also cause adrenal androgen
% B, P9 c5 O5 R1 I  |' `8 Wexcess.1,3% [" V( s; T; B5 |+ |6 d5 u. q
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
' S1 F: e& T  D. w) y8 \542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
& ~1 q& i1 b2 ^1 @- E% R) i2 N. @A unique entity of male-limited gonadotropin-% M$ U# w- f* b
independent precocious puberty, which is also known
9 w/ Z& K- U3 K! U" \* c" ^as testotoxicosis, may cause precocious puberty at a/ ?2 q4 Y1 i$ k: p8 K0 }5 C& q$ g
very young age. The physical findings in these boys: ^1 e# c8 _9 }5 t
with this disorder are full pubertal development,
- A3 x& z1 _+ Y9 F) Kincluding bilateral testicular growth, similar to boys: S* y' I. j% d8 H; p
with CPP. The gonadotropin levels in this disorder
5 ^$ G3 D# a, b$ r, k$ eare suppressed to prepubertal levels and do not show" Y8 g+ M  H5 j) o* E0 x" Y
pubertal response of gonadotropin after gonadotropin-
  O6 A* Q; U. q4 f: Hreleasing hormone stimulation. This is a sex-linked6 B4 h9 E) s& S, v7 I$ F
autosomal dominant disorder that affects only
" @* e! S. b; G4 y7 \+ Hmales; therefore, other male members of the family7 m9 |5 a8 g6 l3 v8 J7 y+ u
may have similar precocious puberty.3
& t& I% o/ S0 e+ {1 S" x0 n2 BIn our patient, physical examination was incon-
% P. f* g3 i. Msistent with true precocious puberty since his testi-' {( i6 a& m# G! Y% }, o1 l
cles were prepubertal in size. However, testotoxicosis' i% k9 T+ J/ s) e
was in the differential diagnosis because his father- a7 e$ ]; f7 j. w- y" t1 C
started puberty somewhat early, and occasionally,
- |$ F8 Y! n) g# z, T2 a3 Z$ J& Dtesticular enlargement is not that evident in the# s0 V, O) K0 U: A+ z* c' F
beginning of this process.1 In the absence of a neg-
& V6 L- y8 B$ _ative initial history of androgen exposure, our
, S; y: r" Q$ X, Qbiggest concern was virilizing adrenal hyperplasia,# G+ m: \* O+ g; @% t/ ~9 H
either 21-hydroxylase deficiency or 11-β hydroxylase
0 v  C  ~$ s+ Q) w' @& [deficiency. Those diagnoses were excluded by find-
) S, p/ [( z' a/ c; B  qing the normal level of adrenal steroids.
4 m$ z" o; Z  j/ P& F  PThe diagnosis of exogenous androgens was strongly
- k9 A3 D: v9 s# xsuspected in a follow-up visit after 4 months because  p% w* x0 E& R
the physical examination revealed the complete disap-
9 W6 v! Q& a# `  I" l: E/ gpearance of pubic hair, normal growth velocity, and
7 Q: a5 i+ i+ |. f5 Adecreased erections. The father admitted using a testos-  g$ f( F0 f3 A, z  k# U# q/ v
terone gel, which he concealed at first visit. He was1 ~. ]- T% _+ f) O; V! {2 G
using it rather frequently, twice a day. The Physicians’) K- y" f, @" ^- ^: x8 Z) T& n: Z5 V
Desk Reference, or package insert of this product, gel or, W* ?6 N% C2 p* l& ~3 h+ @
cream, cautions about dermal testosterone transfer to3 k* H* s( H" \1 Z3 n* @' ]' i
unprotected females through direct skin exposure.
3 N8 t3 w. K/ w/ VSerum testosterone level was found to be 2 times the
2 i4 v6 b- X1 e& mbaseline value in those females who were exposed to- O. {' N# ?# }
even 15 minutes of direct skin contact with their male
; e, B- N# u/ ]1 h; f, x  gpartners.6 However, when a shirt covered the applica-1 j6 i7 h3 V1 k( J: L( \: I9 a3 ~1 `
tion site, this testosterone transfer was prevented.; m9 G* G) B! ?8 H1 u; z( E
Our patient’s testosterone level was 60 ng/mL,; t0 b. C5 V" v3 `0 q. ?* q
which was clearly high. Some studies suggest that) r( q: k% a  H  y' J
dermal conversion of testosterone to dihydrotestos-
  E. P0 l2 i* I$ u) Mterone, which is a more potent metabolite, is more
3 ]. z# p( m5 wactive in young children exposed to testosterone
$ ^! V" j% M3 D% ]2 G3 \9 a9 n" E, |exogenously7; however, we did not measure a dihy-+ M' @3 L- a' p  A' ?. x' |
drotestosterone level in our patient. In addition to
/ F3 H. j7 D" n& ^2 h0 Evirilization, exposure to exogenous testosterone in
7 x/ f5 }4 g6 w+ a8 h) |* @children results in an increase in growth velocity and
1 W3 {8 ^1 N' @: [advanced bone age, as seen in our patient.  f% u2 Q0 @* q1 e' U1 `* ^
The long-term effect of androgen exposure during: l' h; G/ A- N; [: \
early childhood on pubertal development and final* L2 Y6 F! Y4 N* r& j4 }
adult height are not fully known and always remain* ?' w0 ]2 D4 S+ Z! L$ k9 f% L4 a# A
a concern. Children treated with short-term testos-: M0 a( m: P; k6 r
terone injection or topical androgen may exhibit some
/ B( \+ ]/ E6 t/ cacceleration of the skeletal maturation; however, after8 H; G- `7 ?/ Y* l4 H( Q
cessation of treatment, the rate of bone maturation  U" _7 o- s7 |) d# I2 y& Q
decelerates and gradually returns to normal.8,9; h. F: I6 G+ @5 M- x
There are conflicting reports and controversy
( g, B. m) ^' H+ }2 }over the effect of early androgen exposure on adult
. @/ O" O4 K, X6 p" m& Q" z" Openile length.10,11 Some reports suggest subnormal' Z) D, z2 o; Q2 s4 V. `3 `
adult penile length, apparently because of downreg-
! ?! g3 w4 |) t& ^0 |, M' O. rulation of androgen receptor number.10,12 However,
, w2 _' x/ y$ l; wSutherland et al13 did not find a correlation between2 d0 W% a* m8 k1 N' @! M
childhood testosterone exposure and reduced adult
2 z, G" ]/ F" Q' Zpenile length in clinical studies.
2 P& j- T3 T1 F* s( n2 L4 G) XNonetheless, we do not believe our patient is
1 z  x7 A; C% x( w( J: b, Kgoing to experience any of the untoward effects from# D* ^3 z2 ^4 M; ~4 v; f
testosterone exposure as mentioned earlier because8 q% F% G, B9 I& E% f" t# N) n
the exposure was not for a prolonged period of time.
0 b. k% ~; Y" v+ x: hAlthough the bone age was advanced at the time of
, U* {0 O( g& u* Jdiagnosis, the child had a normal growth velocity at! i% z# m8 {3 \" o; S+ H4 C
the follow-up visit. It is hoped that his final adult/ k, x2 D4 ~$ l+ L! L
height will not be affected.; j8 v' K. D( Q9 }* f+ x4 L8 A- Q
Although rarely reported, the widespread avail-/ v( x, l9 x" [. Z' `
ability of androgen products in our society may0 c. i2 V) ^, }) S/ y1 {0 ]$ ?4 I
indeed cause more virilization in male or female
' R1 _) M. f* D/ o  P* V- dchildren than one would realize. Exposure to andro-
; I& H+ R1 F  i* dgen products must be considered and specific ques-7 Z3 D- `$ \$ _" _) k# L
tioning about the use of a testosterone product or2 g4 F! E8 U8 K! v/ x* @
gel should be asked of the family members during
5 c3 M; ?2 v' Rthe evaluation of any children who present with vir-
! [7 C+ d5 r* x# f: X: \6 }  qilization or peripheral precocious puberty. The diag-% Q) |' r- _$ r" ]( l. J
nosis can be established by just a few tests and by) a, I& r. Y. \! U4 q
appropriate history. The inability to obtain such a! M2 a( w6 C$ x) d/ w
history, or failure to ask the specific questions, may5 ]( g+ S+ r9 C' \0 R0 t. X# v
result in extensive, unnecessary, and expensive8 |6 z+ m! f6 Q7 N6 `
investigation. The primary care physician should be9 ], X; {2 I( a: T4 Y7 ?/ H- @
aware of this fact, because most of these children. B) M# H; P. C6 D
may initially present in their practice. The Physicians’' H2 W" k: [& x& d2 I( r
Desk Reference and package insert should also put a- h$ ]! O8 q) H5 _5 H6 c
warning about the virilizing effect on a male or
3 C/ x% P. B) F1 ^' q0 y1 O3 Y# _female child who might come in contact with some-
2 z8 x5 }, Z& r+ d6 M; z3 a5 z5 |one using any of these products.9 u2 X2 q/ j+ h* m- R+ h& e( r+ h/ v
References3 g3 p  y, ]; C5 r) p* M5 s; a
1. Styne DM. The testes: disorder of sexual differentiation9 }6 w- t; r5 O
and puberty in the male. In: Sperling MA, ed. Pediatric6 n( ?* l8 L- m4 G- g4 z; y
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% O& i( P  c; G! J$ J
2002: 565-628.
5 m. S" t/ B; Q4 C! I2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious) w: N1 y3 g+ ^7 f2 b' D) M
puberty in children with tumours of the suprasellar pineal
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Sexual Precocity in a 16-Month-Old
! P# d) I+ t$ R7 qBoy Induced by Indirect Topical
! J( f) ]6 [# m! G4 y& iExposure to Testosterone
  x  J8 E0 e0 o5 h2 z7 n- ~Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
8 ^# e. K% z  w; t) B5 V1 I, pand Kenneth R. Rettig, MD1
& U: L! M. ^# p/ Z& f0 Z/ ~Clinical Pediatrics
' }- J, b9 m: d* B" [4 u( |; ~Volume 46 Number 62 ~" Z% L6 ~. f9 V: z
July 2007 540-543/ K, z8 J* j3 o4 e  t
© 2007 Sage Publications
  @  c( c+ d; [+ ]10.1177/0009922806296651
0 A8 e: a2 S0 j8 H) Bhttp://clp.sagepub.com% N6 p- }/ n, [" H3 n- ~% W/ n$ A6 p: ~
hosted at+ g- E+ ~" g7 p/ D* l4 l
http://online.sagepub.com/ w) N; D  f" J- T' }7 e! O$ m- A; ~
Precocious puberty in boys, central or peripheral,0 E6 [2 K" ?+ ~% \! U  y& r! ?
is a significant concern for physicians. Central
6 X& `( L; |& p, Zprecocious puberty (CPP), which is mediated, p7 W0 Q7 Q. X, y" X- q
through the hypothalamic pituitary gonadal axis, has
( l8 V- L% B9 i" _0 s/ xa higher incidence of organic central nervous system
1 d1 Q) N2 X2 q0 P( k# ilesions in boys.1,2 Virilization in boys, as manifested
# A1 V! a7 O0 gby enlargement of the penis, development of pubic; H7 {6 }2 E/ g9 q7 A, ?
hair, and facial acne without enlargement of testi-  t: Z% x( T% l: \+ A
cles, suggests peripheral or pseudopuberty.1-3 We& s6 F! _' }  A) p: e" b
report a 16-month-old boy who presented with the
9 {, E" W" O( W5 H0 z3 f$ X% senlargement of the phallus and pubic hair develop-( k% {& C6 h( O) g7 y7 G
ment without testicular enlargement, which was due
4 S* j4 H( a8 ~* }3 \to the unintentional exposure to androgen gel used by
4 x5 [# @" l' [" ]/ }! ]; J* Athe father. The family initially concealed this infor-8 y7 J" `6 _# N9 l
mation, resulting in an extensive work-up for this
: W8 y  W; x% m; q# c+ X, r7 p, V; rchild. Given the widespread and easy availability of
4 {, E% Y6 I' k, Ytestosterone gel and cream, we believe this is proba-  n2 F! m% t& H" @, r7 {
bly more common than the rare case report in the8 ~  C2 X/ E8 x# H  m. k1 c, _
literature.4
0 ^8 i0 g) Y' s3 a5 {Patient Report* W. h% }0 S% ?+ i  {; z
A 16-month-old white child was referred to the
8 C4 E) B8 Z% O+ o* Eendocrine clinic by his pediatrician with the concern
" g2 _% l9 i0 B; u4 [. t  Jof early sexual development. His mother noticed% p5 |4 R, \; w# [9 [% Q  Y
light colored pubic hair development when he was
' e, G4 G4 A7 p$ I8 d. iFrom the 1Division of Pediatric Endocrinology, 2University of
3 K8 b1 |/ K& {  lSouth Alabama Medical Center, Mobile, Alabama.7 x: _- g( G; d/ m/ x+ }, X% v$ @
Address correspondence to: Samar K. Bhowmick, MD, FACE,4 ^+ G# h8 T6 x7 ?9 E  P1 g
Professor of Pediatrics, University of South Alabama, College of1 s! D. a' H: Z3 U# a
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;  g3 y/ I% Q* R6 R6 V7 B
e-mail: [email protected].* W# W) Q5 j- d2 s
about 6 to 7 months old, which progressively became
3 d! d0 Q7 h! U  M& d% idarker. She was also concerned about the enlarge-5 y$ x4 h0 r8 E" M# F2 X
ment of his penis and frequent erections. The child
4 W/ c0 n- g$ j+ Fwas the product of a full-term normal delivery, with
1 K/ Z/ i' g' l8 za birth weight of 7 lb 14 oz, and birth length of
" y7 E" A( m; `/ [. H5 Y7 ]+ Z$ c20 inches. He was breast-fed throughout the first year
1 J% y9 H! B% I5 xof life and was still receiving breast milk along with. z- Q1 }2 k6 \
solid food. He had no hospitalizations or surgery,
, W; j" b2 J" Wand his psychosocial and psychomotor development4 `& g# m; ?1 }
was age appropriate.
8 y& \2 T4 X5 _" sThe family history was remarkable for the father,% u; ?3 Y# J8 g  Z& y5 |2 r
who was diagnosed with hypothyroidism at age 16,$ d$ v9 T) t( b' L& e6 s6 s& G
which was treated with thyroxine. The father’s
' z5 p9 m; c* {height was 6 feet, and he went through a somewhat
* X+ y; s% _3 T2 x1 O; l! Fearly puberty and had stopped growing by age 14.
) c% W3 Q7 S, w5 bThe father denied taking any other medication. The
4 |1 E4 k6 k# X% |: P* lchild’s mother was in good health. Her menarche$ {* R/ E4 }! V
was at 11 years of age, and her height was at 5 feet
' H9 B6 V( }/ Z  {/ @5 inches. There was no other family history of pre-: n9 x0 p# p& ~8 {
cocious sexual development in the first-degree rela-/ e  \# j6 I" Q( ?* @
tives. There were no siblings.7 p+ z4 d8 }1 G# B+ r( N& h5 g, |
Physical Examination- }5 a. b0 g3 G  K% s5 e9 T
The physical examination revealed a very active,) T- X# w1 ?  [" ~
playful, and healthy boy. The vital signs documented
! u: ^0 M* H- x7 [a blood pressure of 85/50 mm Hg, his length was3 Q8 W; G' a* a0 j# _# G
90 cm (>97th percentile), and his weight was 14.4 kg
5 {0 G5 a/ N  \2 l( ~. A% o7 s(also >97th percentile). The observed yearly growth1 u! G! }, M+ V# t  H! s: g
velocity was 30 cm (12 inches). The examination of
( M1 b$ n6 K& N" d' n+ Nthe neck revealed no thyroid enlargement.
% y+ L. L8 v% c$ hThe genitourinary examination was remarkable for
2 W0 T6 |0 B. S" e8 D2 h, _* Jenlargement of the penis, with a stretched length of
- w' C0 J- w" b' P8 cm and a width of 2 cm. The glans penis was very well
. _9 D; w& N2 B( ideveloped. The pubic hair was Tanner II, mostly around. s$ H0 g+ k% P
540
7 r4 \% ?0 y: N7 a& y! m0 Xat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from8 b8 P+ s7 g1 Y
the base of the phallus and was dark and curled. The( e4 s6 I+ n) u) Y7 N$ a
testicular volume was prepubertal at 2 mL each." V1 T4 J' c' `0 L/ S: v, h
The skin was moist and smooth and somewhat8 V% z5 L/ w2 G
oily. No axillary hair was noted. There were no  h9 C# W+ h. z
abnormal skin pigmentations or café-au-lait spots.
2 C5 y4 J/ n" ^4 d3 U( ]# `Neurologic evaluation showed deep tendon reflex 2+
* h. u' o! B" T! hbilateral and symmetrical. There was no suggestion( e, P' M+ y# d
of papilledema.; p! v: j. {& M
Laboratory Evaluation
8 q; ]/ |( ]. b! P, @The bone age was consistent with 28 months by
) r. w0 B1 @* yusing the standard of Greulich and Pyle at a chrono-
! Q# I. U) v" ?# E) P, Blogic age of 16 months (advanced).5 Chromosomal
! r" w" O- E! h5 z, n8 i. q1 zkaryotype was 46XY. The thyroid function test
5 |) ?; f, H' L7 Jshowed a free T4 of 1.69 ng/dL, and thyroid stimu-" B+ ~2 |4 K, W9 [
lating hormone level was 1.3 µIU/mL (both normal).4 z1 x: x% h3 y- v5 X1 z
The concentrations of serum electrolytes, blood( ]( w" o! h* S, g) U. K# [
urea nitrogen, creatinine, and calcium all were
4 B! x. r. ^) ]- D' {$ v( D8 |/ f) Twithin normal range for his age. The concentration
+ M/ {  n  [7 z8 O. Oof serum 17-hydroxyprogesterone was 16 ng/dL2 Y1 N6 |$ I& I& T; E$ h
(normal, 3 to 90 ng/dL), androstenedione was 20
5 g& E! b) r9 E  @# @' `ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
5 f' i% n; u. c6 z- e2 R7 ?' tterone was 38 ng/dL (normal, 50 to 760 ng/dL),* F4 W2 T/ W: u0 J$ E
desoxycorticosterone was 4.3 ng/dL (normal, 7 to+ `% D( g" v( P$ O1 d* y! S
49ng/dL), 11-desoxycortisol (specific compound S)0 j( b: G9 t4 o! I5 @
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-" c9 V4 E0 ~5 X5 P& ^
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
: V9 L9 f, `: |4 [* Z  P" }testosterone was 60 ng/dL (normal <3 to 10 ng/dL),. W# L) W' E# Z$ {8 w4 p1 }, v
and β-human chorionic gonadotropin was less than! j8 g5 U4 Z) T9 B9 V5 P  J
5 mIU/mL (normal <5 mIU/mL). Serum follicular
, p! m- V/ Y! h1 U( Fstimulating hormone and leuteinizing hormone, I& G( [# p  e& v6 ^* @9 c
concentrations were less than 0.05 mIU/mL
8 A; ^% }5 x6 H+ w(prepubertal).
' c$ h$ P' Q, [  ^7 C/ |* nThe parents were notified about the laboratory! X6 D! q/ L; P3 g
results and were informed that all of the tests were4 ~+ a# b; p2 Q6 S3 c* U
normal except the testosterone level was high. The
8 `1 z2 x0 @. W- D  d% l% Pfollow-up visit was arranged within a few weeks to
' `6 c5 E) k* ^* Y. \6 bobtain testicular and abdominal sonograms; how-+ @9 A; D, H8 D7 u) Z# r2 t
ever, the family did not return for 4 months.
. f) b2 d0 n8 f# a+ p$ }5 tPhysical examination at this time revealed that the
9 h6 e# `- Y+ ~6 ]3 F, I: E1 Rchild had grown 2.5 cm in 4 months and had gained# u' _, s4 S+ ~2 @
2 kg of weight. Physical examination remained
. D/ P  C5 u( F5 ~$ \* Eunchanged. Surprisingly, the pubic hair almost com-4 n6 v% R) g; P& _/ E3 l1 q- R; g
pletely disappeared except for a few vellous hairs at
. [$ e+ p" q1 Rthe base of the phallus. Testicular volume was still 2
! G3 _. Z$ i( `, o  y6 }3 U2 pmL, and the size of the penis remained unchanged.  f. `7 p- I& A* L, ]
The mother also said that the boy was no longer hav-( ^" M% e3 @; I% b
ing frequent erections.  q5 E7 D5 W" E6 t
Both parents were again questioned about use of0 D# Q; n8 q4 T: @* H
any ointment/creams that they may have applied to
: R; Q! \- i7 pthe child’s skin. This time the father admitted the
$ y5 @: X- ~- }( [$ pTopical Testosterone Exposure / Bhowmick et al 5413 Q* Z& B4 G, t, ~2 z- J5 w
use of testosterone gel twice daily that he was apply-
+ [# `& J& ^/ V/ m3 [+ l* ring over his own shoulders, chest, and back area for- S3 E' `" q: r0 I( d
a year. The father also revealed he was embarrassed
4 P& Z6 l, Q1 m/ n) H8 |to disclose that he was using a testosterone gel pre-: [3 x+ i6 f( k; v
scribed by his family physician for decreased libido: C! F: m; ]+ D# }* I
secondary to depression.
5 p1 a# [( B; t' ?( `: qThe child slept in the same bed with parents.+ r8 t1 K: D2 a8 b& a- t
The father would hug the baby and hold him on his6 c. m' Y! W2 x; {
chest for a considerable period of time, causing sig-+ U, t; L9 ]- m; H7 V4 A
nificant bare skin contact between baby and father.3 y$ X1 T7 |. w& N% _; G
The father also admitted that after the phone call,
" p/ X! O- q" q# s4 \2 L, {when he learned the testosterone level in the baby
. n( e  M- l# f: ^7 awas high, he then read the product information
2 e1 \" q! R% a, e/ Q/ n3 [* U- zpacket and concluded that it was most likely the rea-0 y8 B4 O8 u( F
son for the child’s virilization. At that time, they
" Z/ o3 Q) O" r) Z: Vdecided to put the baby in a separate bed, and the
1 w) Z. E  j+ V  Z6 Rfather was not hugging him with bare skin and had: g5 V( ^+ M8 k* k; K: @
been using protective clothing. A repeat testosterone
6 c. X0 n) q' B! Ytest was ordered, but the family did not go to the
: Y1 A: R8 w! L6 k3 L* llaboratory to obtain the test.6 a$ L  d" f1 S: i% I
Discussion
  K( A9 F5 q7 _7 kPrecocious puberty in boys is defined as secondary. {& W0 ?8 p# f& W
sexual development before 9 years of age.1,4. B3 x* r  |* ?
Precocious puberty is termed as central (true) when0 j& }, B  }7 |
it is caused by the premature activation of hypo-
  W4 O% x( U4 l( F; Cthalamic pituitary gonadal axis. CPP is more com-
8 A: X( q" w  J( `  l* emon in girls than in boys.1,3 Most boys with CPP
' Y" ]! {4 d0 U+ z1 o  M# q4 F8 w; hmay have a central nervous system lesion that is
9 I* p( w3 b- f* Tresponsible for the early activation of the hypothal-* {( E  i8 @+ Q0 S1 q+ N. {
amic pituitary gonadal axis.1-3 Thus, greater empha-0 C6 T/ G3 A4 e5 j
sis has been given to neuroradiologic imaging in' u( ^5 |6 Z4 L1 w# g2 H& R
boys with precocious puberty. In addition to viril-0 X7 Q6 @# n7 H% C# _
ization, the clinical hallmark of CPP is the symmet-/ ?& s8 C6 @$ h' c4 }
rical testicular growth secondary to stimulation by
3 B( w( p9 o5 k  K8 M5 Kgonadotropins.1,3/ W: T7 n" f, W9 L% c
Gonadotropin-independent peripheral preco-
2 O7 F' K1 ~" g( Z4 s, i+ Mcious puberty in boys also results from inappropriate
0 D3 A6 v- [' Sandrogenic stimulation from either endogenous or
' K& r1 I  u/ _- w) y6 Y7 rexogenous sources, nonpituitary gonadotropin stim-, F& h) }0 ?/ G' j$ S$ f
ulation, and rare activating mutations.3 Virilizing4 a3 w& d1 q/ O. C; v5 H* M
congenital adrenal hyperplasia producing excessive
1 I2 h" {, _, [% X9 s: Padrenal androgens is a common cause of precocious3 z3 W* d" q: Y2 Z* n; ~
puberty in boys.3,4/ N8 l/ d4 O8 p, P
The most common form of congenital adrenal
: R+ M) _% Z& I$ c# V1 Nhyperplasia is the 21-hydroxylase enzyme deficiency.
/ Y; A8 q' {1 h% u. x0 RThe 11-β hydroxylase deficiency may also result in7 n3 Q, `5 b- b% z! M+ N# N
excessive adrenal androgen production, and rarely,% t: D. Q3 Z6 T6 k0 O
an adrenal tumor may also cause adrenal androgen" H' C6 E0 U! v2 N7 F3 E
excess.1,3, Y# f  }9 s# f& {
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, G4 m, A6 S, m: L6 I9 @9 o, w+ V
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
; {) R. j: ?/ Z% F; W3 E$ FA unique entity of male-limited gonadotropin-- n4 W$ S2 n. r" D' V% R( M
independent precocious puberty, which is also known
" _, j. [; f2 b: r' z6 `6 Q4 \as testotoxicosis, may cause precocious puberty at a
; K/ }8 S  M: w5 pvery young age. The physical findings in these boys
$ f0 _! e' a( c3 z8 R" Qwith this disorder are full pubertal development,
8 B3 V( ^& ]2 m/ P4 wincluding bilateral testicular growth, similar to boys
( T# i4 n6 g9 z+ Mwith CPP. The gonadotropin levels in this disorder  _; d. p/ \' N8 K
are suppressed to prepubertal levels and do not show5 m& V$ R+ Z* A
pubertal response of gonadotropin after gonadotropin-
! X- d; K; d3 g1 r2 s0 }9 M# K) Oreleasing hormone stimulation. This is a sex-linked
& C6 d. @" T& s+ \/ R  Sautosomal dominant disorder that affects only3 M: p7 {/ O. j' N2 ^' O; E, D$ v
males; therefore, other male members of the family. S, p. ?0 Z$ B
may have similar precocious puberty.3
( z: b1 |7 i* t9 Q6 {: H3 BIn our patient, physical examination was incon-
' M) [$ _% L. |) ssistent with true precocious puberty since his testi-4 M; l2 e$ C8 |5 m, G/ `
cles were prepubertal in size. However, testotoxicosis
6 C" y+ L2 ?8 Swas in the differential diagnosis because his father
0 l4 ]* p$ p( I% mstarted puberty somewhat early, and occasionally,
# o9 \7 ^( g  n9 w& _testicular enlargement is not that evident in the
# o% G3 P! b4 A0 I" Wbeginning of this process.1 In the absence of a neg-
! W( z6 P; }/ Z. n! j7 |ative initial history of androgen exposure, our! q! o, W: _/ t) w, [. |
biggest concern was virilizing adrenal hyperplasia,
1 r2 x- O' O; k3 A: e" q! leither 21-hydroxylase deficiency or 11-β hydroxylase
' C1 ~  b1 G/ {& }( Y1 @/ ddeficiency. Those diagnoses were excluded by find-' _' T( u5 D7 G! N( y/ r% {
ing the normal level of adrenal steroids.
# T. N. u! y+ qThe diagnosis of exogenous androgens was strongly
( g7 r! e8 E& D0 zsuspected in a follow-up visit after 4 months because7 B* b6 C' w* Q9 z
the physical examination revealed the complete disap-
* {* \0 p+ Z; m$ e& k  W: H* q4 t. \6 xpearance of pubic hair, normal growth velocity, and/ U* y+ r( m; z# r: E* _
decreased erections. The father admitted using a testos-
6 R. O  ?$ b4 D$ K5 i* \terone gel, which he concealed at first visit. He was4 J0 q, C+ t' T, h# h
using it rather frequently, twice a day. The Physicians’7 S, l9 `3 c+ G9 Y2 _* P& ^
Desk Reference, or package insert of this product, gel or  {* F/ F& h$ Q9 u7 v9 C1 a/ ~! l" D
cream, cautions about dermal testosterone transfer to; z: v) y/ L$ [( ~
unprotected females through direct skin exposure.
/ a% G" u. o9 @% W6 t# G; bSerum testosterone level was found to be 2 times the  b8 r+ ~& ?% s9 a5 H
baseline value in those females who were exposed to
6 u) }' J: P. A, |- @even 15 minutes of direct skin contact with their male1 U* A5 v+ e) p& Y3 j
partners.6 However, when a shirt covered the applica-! B- q# g5 ~7 u' q, R' Z8 ~0 \5 r
tion site, this testosterone transfer was prevented.. u! x5 j  Q" N5 Q
Our patient’s testosterone level was 60 ng/mL,0 O, |! m1 A( l6 o5 E
which was clearly high. Some studies suggest that
5 I! D5 z; o: F6 ?- G; t" ]dermal conversion of testosterone to dihydrotestos-& R) \! s; G* M' q" [
terone, which is a more potent metabolite, is more) S& d  k+ T3 p" \1 |# G0 q" J
active in young children exposed to testosterone
; U( z/ Y# ?# Aexogenously7; however, we did not measure a dihy-: Y! h% a. K4 V+ |7 [
drotestosterone level in our patient. In addition to: r% ?3 c& y. R$ a* F5 J
virilization, exposure to exogenous testosterone in! a" Y$ Y0 m# s6 @+ e9 y3 }" f, o
children results in an increase in growth velocity and
: m4 |; i- C+ n" fadvanced bone age, as seen in our patient.
0 n, I/ h0 b- z0 y+ S9 t2 PThe long-term effect of androgen exposure during$ |8 D% o1 Q' u6 h5 j
early childhood on pubertal development and final7 c# I/ L* H" v4 Z5 J
adult height are not fully known and always remain9 |  J" t1 [1 M( q* z) `
a concern. Children treated with short-term testos-
" B/ p6 W3 Q! F. g( Gterone injection or topical androgen may exhibit some
9 Z3 B8 X! Y7 s& T! y% {acceleration of the skeletal maturation; however, after' W0 Z! w" X2 q! E
cessation of treatment, the rate of bone maturation
* A* n2 p. {" [' b$ ~6 X8 Pdecelerates and gradually returns to normal.8,9+ r- i, S% F% \3 w
There are conflicting reports and controversy0 Q9 T: }* e2 w$ a
over the effect of early androgen exposure on adult( P- G- A1 p1 R  L, {
penile length.10,11 Some reports suggest subnormal
# y' M# k& u) S0 O* S3 l) ~adult penile length, apparently because of downreg-
; T5 G1 }; ~. ~. Sulation of androgen receptor number.10,12 However,
! p/ j. P' P  ^* R1 }Sutherland et al13 did not find a correlation between: L1 U; a6 a/ Z9 A
childhood testosterone exposure and reduced adult
1 M' h! E; j. z/ Ypenile length in clinical studies.
6 O" j6 ^4 M- K3 s. z7 _Nonetheless, we do not believe our patient is( f% a. f  q  ]! x6 `( r5 J
going to experience any of the untoward effects from
" }. V6 h! L# d3 b* utestosterone exposure as mentioned earlier because
0 k! r" {. D0 @+ R  |$ P7 t4 Vthe exposure was not for a prolonged period of time.
+ r; S# I* ]" M& }Although the bone age was advanced at the time of
+ E( i0 R, I- g9 ~diagnosis, the child had a normal growth velocity at
; A, z! q$ i) c; i# G2 hthe follow-up visit. It is hoped that his final adult
1 P6 l& I/ m5 @: ?height will not be affected.# u; a& D( F0 v- s: Y, x/ p
Although rarely reported, the widespread avail-- h: Z! Y* w5 \' Q' p  e; Q
ability of androgen products in our society may
7 \5 `! H- Y8 {3 x" S/ }indeed cause more virilization in male or female* X8 k9 G) M( _1 j/ D$ H* |+ Q1 x
children than one would realize. Exposure to andro-2 m1 d5 V% Q1 t
gen products must be considered and specific ques-( q. m! B' ~/ i" z) v% k  I' Y' N
tioning about the use of a testosterone product or2 _% T+ U7 u* Z! L$ K. D/ |% n
gel should be asked of the family members during
9 V( h2 u- g* D! r  `the evaluation of any children who present with vir-3 r, m: C. w0 m
ilization or peripheral precocious puberty. The diag-
8 M- J" m) l* e" Bnosis can be established by just a few tests and by2 j9 }$ |8 o: w3 N9 l- ?
appropriate history. The inability to obtain such a, \; `$ p- R7 H; j' O6 |
history, or failure to ask the specific questions, may
5 C- U8 f0 Q7 oresult in extensive, unnecessary, and expensive# S3 R! T. T3 ]( `% J# D, n
investigation. The primary care physician should be7 T# n/ i5 F/ G8 v
aware of this fact, because most of these children
  U' n2 J6 Y9 b" X4 e. }; A9 ~$ R6 hmay initially present in their practice. The Physicians’$ Y/ K) d, ~( l
Desk Reference and package insert should also put a
0 U+ F6 M  _' v/ {/ kwarning about the virilizing effect on a male or5 L0 a3 H( N+ T; c9 A
female child who might come in contact with some-
6 |" i7 b4 U* M: Z$ }one using any of these products.
5 s6 e  \1 `" T1 A& C# O" ZReferences6 L' m5 W' [. k$ _+ i! ^$ e
1. Styne DM. The testes: disorder of sexual differentiation0 R# u7 b5 z: n) \) b
and puberty in the male. In: Sperling MA, ed. Pediatric& @7 {( o: `8 u* e
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;; e2 P5 m: n. `# q  c
2002: 565-628.- r# S3 s8 z7 f, B$ D
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% G! n! \+ j1 r! p2 P
puberty in children with tumours of the suprasellar pineal
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女厕偷拍辅导班主任尿尿老师的逼很嫩还有一点
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4个什么样的?
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. A1 b4 c" e& \! I. t8 i& `
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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么好吧v进化过程就回国参加发uft成就和;哦i回来就好v科技股份兄弟人的 路由公开vu个v库每年b
發表於 2025-4-8 11:10:25 | 顯示全部樓層
精妙絕倫的精品,感謝啊!期待你更多更好的創作哦!
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