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is a significant concern for physicians. Central4 f, l8 g( r& @' s0 T3 }
precocious puberty (CPP), which is mediated2 Y3 X) w) s- s- |0 P l
through the hypothalamic pituitary gonadal axis, has1 Y4 B$ K1 F; H' p, p: P; V8 l3 |
a higher incidence of organic central nervous system
. B: K* e; R2 w6 q: d9 Klesions in boys.1,2 Virilization in boys, as manifested( b [$ ^5 p9 p$ W8 k
by enlargement of the penis, development of pubic
" K- ~5 Y2 i( P ghair, and facial acne without enlargement of testi-, f% Q( n7 f0 O1 G% l
cles, suggests peripheral or pseudopuberty.1-3 We# a( y4 p6 {9 s( n B2 F- S+ _
report a 16-month-old boy who presented with the; e U `& Y8 U. ^% r
enlargement of the phallus and pubic hair develop-
+ c. q5 s" _2 I9 y! s Xment without testicular enlargement, which was due# \. P; o* p S3 Z# V
to the unintentional exposure to androgen gel used by
# F- e3 N2 X1 F1 T. D: Uthe father. The family initially concealed this infor-6 h! x% q& @2 s2 Q- H/ E
mation, resulting in an extensive work-up for this
' K2 U: B! F) q4 k1 dchild. Given the widespread and easy availability of
: d% U" K1 o# H3 e( ~/ _; wtestosterone gel and cream, we believe this is proba-
) }0 _. z7 Q" |bly more common than the rare case report in the
8 c# X: F' e* T1 e6 Fliterature.48 U* K; E r& w1 V! V% _
Patient Report
1 ^# ?' \6 @4 Z7 H" T- W" cA 16-month-old white child was referred to the
- n2 C7 |! b! e8 N+ l* Uendocrine clinic by his pediatrician with the concern
+ N: R" t; |& P6 y" Iof early sexual development. His mother noticed
5 u" Z# c- x2 q1 Y8 I$ _. F3 Rlight colored pubic hair development when he was
' O* K" z1 r4 X0 f) z0 O G& Q) zFrom the 1Division of Pediatric Endocrinology, 2University of
" c- P1 w4 j* U z$ Z7 [8 TSouth Alabama Medical Center, Mobile, Alabama.! g# I4 B$ Z/ O) V2 Z$ n6 |) m. l8 o
Address correspondence to: Samar K. Bhowmick, MD, FACE,2 N# m, o! c5 H
Professor of Pediatrics, University of South Alabama, College of6 g7 D; T3 \6 v% z H
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;2 b$ f0 N" r0 G
e-mail: [email protected].0 u5 a- H# P: D9 \# ]# r
about 6 to 7 months old, which progressively became
2 v% d& h& g$ v6 m1 sdarker. She was also concerned about the enlarge-# F# V8 Z+ C- _* K7 ?5 H. E
ment of his penis and frequent erections. The child
9 }/ l% w. l# j# [! ], p, Cwas the product of a full-term normal delivery, with
% y. \) _* I0 v. G7 S7 |8 e8 Va birth weight of 7 lb 14 oz, and birth length of
@/ I1 H E. k9 }# E20 inches. He was breast-fed throughout the first year8 C! [8 f4 t$ z% a
of life and was still receiving breast milk along with
$ u$ N; x0 y' ~. M8 wsolid food. He had no hospitalizations or surgery,
5 u4 O0 [# O4 d2 dand his psychosocial and psychomotor development
/ v! U5 X; {. s. c1 a4 p# b& Rwas age appropriate.
1 {+ m/ w: _) t5 t* WThe family history was remarkable for the father,2 a2 y S/ @. T+ S
who was diagnosed with hypothyroidism at age 16,
e" l" @% C3 I D x2 v5 i/ \) I. gwhich was treated with thyroxine. The father’s
! ]1 x U0 T$ C$ P; vheight was 6 feet, and he went through a somewhat E0 p1 o! |* m0 |, R
early puberty and had stopped growing by age 14.* C) e& ^! b1 M* `: E/ W: E. [
The father denied taking any other medication. The ? M0 ?; N/ J& e/ \
child’s mother was in good health. Her menarche
4 e/ i3 |2 P( ]0 Y- v: ^8 F3 T( hwas at 11 years of age, and her height was at 5 feet
; s: b$ u3 b# }. c+ v5 inches. There was no other family history of pre-
. p4 E2 Q' y# P$ I% o+ g% K# ycocious sexual development in the first-degree rela-
9 i$ Q$ V$ r" t& A* Itives. There were no siblings.7 _4 x0 i, F1 H* x
Physical Examination
8 C9 b$ Q, ^ {$ |, {The physical examination revealed a very active,* Q5 x( P7 f% T' Y0 I) m
playful, and healthy boy. The vital signs documented
7 E- Q" |& ]6 \* e& ea blood pressure of 85/50 mm Hg, his length was
) u7 i; k5 K5 C2 L90 cm (>97th percentile), and his weight was 14.4 kg, B+ }# J, X6 C
(also >97th percentile). The observed yearly growth7 W% ~6 g% `6 `: h" Z1 @5 y8 ]7 q* r% h* K
velocity was 30 cm (12 inches). The examination of
# o: t& P. g$ r6 Rthe neck revealed no thyroid enlargement.
6 d2 C. z9 C, A4 }5 [- V8 h- WThe genitourinary examination was remarkable for8 |3 t8 m/ `9 S
enlargement of the penis, with a stretched length of
% x/ r6 n8 Q1 `% E, }$ x8 cm and a width of 2 cm. The glans penis was very well; G- G+ m6 y2 u. i4 ~
developed. The pubic hair was Tanner II, mostly around! u& ]9 ^+ S; ~" P+ q
540
7 k) Y" G& x; W: Z. vat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
( v& W) B5 T/ Hthe base of the phallus and was dark and curled. The
( H: H3 N( M9 L7 F8 C2 @testicular volume was prepubertal at 2 mL each.
% \. H$ u5 `/ ]" W4 v5 Z! z1 hThe skin was moist and smooth and somewhat' V) L- q" O# I7 O; \/ u" ~
oily. No axillary hair was noted. There were no5 X* y+ X6 K' p, W2 p
abnormal skin pigmentations or café-au-lait spots.
. G* P$ Q: K2 `& V# J# [$ A2 XNeurologic evaluation showed deep tendon reflex 2+
3 ~% {! }& o* _bilateral and symmetrical. There was no suggestion
+ ~2 H9 T5 o+ Xof papilledema.
) ?! K* B, ]( GLaboratory Evaluation
" ~4 C. b: [0 ~The bone age was consistent with 28 months by
" [& X+ k8 |- _) g* E: Xusing the standard of Greulich and Pyle at a chrono-
+ i8 w0 I6 c! S$ }- t- Y7 flogic age of 16 months (advanced).5 Chromosomal6 r3 v9 _2 P6 [+ `/ X9 B
karyotype was 46XY. The thyroid function test" ~; D$ K# @, U T$ X
showed a free T4 of 1.69 ng/dL, and thyroid stimu-/ ]7 _+ Q% c; t% k7 ^. n
lating hormone level was 1.3 µIU/mL (both normal).( Y) n, V: N" p9 X0 T0 X
The concentrations of serum electrolytes, blood9 m1 ~& C* \0 t( j/ Z. g% m ?
urea nitrogen, creatinine, and calcium all were/ X- @% O9 S: E# ]6 C; \0 m
within normal range for his age. The concentration5 v" V7 k4 V% A) G" N' W% f
of serum 17-hydroxyprogesterone was 16 ng/dL/ Z2 q! I' }, n: k& A; m4 c
(normal, 3 to 90 ng/dL), androstenedione was 20% A$ p6 V* d, B% h
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-3 p/ s/ Q z+ \1 ~
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
% {. P+ q' _2 o2 p$ Hdesoxycorticosterone was 4.3 ng/dL (normal, 7 to9 {1 i: |% M) q, Z
49ng/dL), 11-desoxycortisol (specific compound S)
& ^2 H8 D A/ Wwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
& z) @5 t7 F( [1 P2 Y, Ntisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total$ D& Q. j& h) J' }$ u. [
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),; i! I1 E: G& P/ R0 ]
and β-human chorionic gonadotropin was less than/ h) j9 x4 I& p5 U9 r& v) v4 e$ o
5 mIU/mL (normal <5 mIU/mL). Serum follicular/ S+ l& \+ e" Z4 F1 E* C U7 w4 J
stimulating hormone and leuteinizing hormone! V; ^$ `& L' o- V, ~6 S
concentrations were less than 0.05 mIU/mL
, |4 ]" U$ o9 K* P& E; ` v% t, i(prepubertal).
0 f5 ^1 F* W" cThe parents were notified about the laboratory2 i2 g( K1 ~6 s$ b' n5 O2 ?- u
results and were informed that all of the tests were( `+ h6 C# G% L/ L' R* O5 E% @
normal except the testosterone level was high. The+ V, p3 _7 L4 V3 }* j
follow-up visit was arranged within a few weeks to
: t [5 W; ]9 ^+ Lobtain testicular and abdominal sonograms; how-
; f |9 i+ b3 Aever, the family did not return for 4 months.
& w5 B9 d' S, u) g* w) lPhysical examination at this time revealed that the' e$ u6 Y- n: w% I, h
child had grown 2.5 cm in 4 months and had gained. b1 A7 o2 w3 {0 i/ F1 `# v
2 kg of weight. Physical examination remained. G, d8 r; r" I" K
unchanged. Surprisingly, the pubic hair almost com-7 Z0 S6 H' A6 H, E" R$ T
pletely disappeared except for a few vellous hairs at
% P' P; }9 F* ?# R4 Pthe base of the phallus. Testicular volume was still 29 Y% ~; ~2 f0 E, p0 ^: k. ]: }
mL, and the size of the penis remained unchanged.
+ C) R5 i( S, z0 z I# }The mother also said that the boy was no longer hav-
. Y* E* c! G/ F1 y" Z4 e3 p/ Fing frequent erections.
+ W1 J# }/ N1 X9 e. c7 ?; K4 Q! PBoth parents were again questioned about use of
( x3 A3 @" x* W- q4 Bany ointment/creams that they may have applied to
1 I3 k# P- t* }6 w6 U9 E: kthe child’s skin. This time the father admitted the
# b; m+ o9 M4 eTopical Testosterone Exposure / Bhowmick et al 541. y! \. m4 p7 _: D9 u
use of testosterone gel twice daily that he was apply-
% R; V) }1 K g6 g& D* m, X) `ing over his own shoulders, chest, and back area for- ]& ^" B) ~& M& Q
a year. The father also revealed he was embarrassed( V" h! X2 l2 c6 @7 b
to disclose that he was using a testosterone gel pre-( t, a1 b6 `( E* q
scribed by his family physician for decreased libido* y2 D6 v x# W: w7 q' W4 [" \& A
secondary to depression.. g! {* |' g0 c( P, R
The child slept in the same bed with parents." `# Q1 X2 A& s) Q# A* U2 V
The father would hug the baby and hold him on his9 A' D; l& y7 e9 r7 y
chest for a considerable period of time, causing sig-
# C' I$ E& I* ?3 ]( Snificant bare skin contact between baby and father.
2 l- b" |5 I3 eThe father also admitted that after the phone call,
# ^5 d' k3 A7 a4 a0 S) Fwhen he learned the testosterone level in the baby
0 ~5 a! i% I# I8 {$ c& e* Ywas high, he then read the product information
- S0 F( I# U/ ?8 J, d, @packet and concluded that it was most likely the rea-) k* @/ C0 r* J! @% Y: E2 t; {/ A
son for the child’s virilization. At that time, they
' j$ p5 K- t# [! Z4 U$ \8 b. s6 Idecided to put the baby in a separate bed, and the
( x5 f1 o4 Y; ?5 e/ Sfather was not hugging him with bare skin and had: |7 ?3 Y* c u: \" \( O( Y& O) E
been using protective clothing. A repeat testosterone
; w3 J8 p9 \9 ^) [9 |% \test was ordered, but the family did not go to the% u* `5 k1 o4 w) \
laboratory to obtain the test.
) f! ~9 N7 H9 ^) ]: aDiscussion! F9 |, i! ]4 u
Precocious puberty in boys is defined as secondary# K! r7 Q. W! R6 o. b: _+ ]5 d
sexual development before 9 years of age.1,4
/ Z1 O, P L' i$ o6 T+ `, CPrecocious puberty is termed as central (true) when
$ ~5 ?) i3 v; K3 J: U9 xit is caused by the premature activation of hypo-
7 U* _; v- t/ f( t$ V' s9 Zthalamic pituitary gonadal axis. CPP is more com-
" J& ^0 U; u3 y4 y4 ymon in girls than in boys.1,3 Most boys with CPP6 e( t/ k& u* p- }" _+ a" S4 D/ y
may have a central nervous system lesion that is
$ _" S. r+ n% b9 G7 presponsible for the early activation of the hypothal-5 V+ C y- z, r0 n: v8 y
amic pituitary gonadal axis.1-3 Thus, greater empha-
- z) s: @( R/ j+ a/ ssis has been given to neuroradiologic imaging in) k; f4 u% w8 `
boys with precocious puberty. In addition to viril-
G& Q3 _( }/ h3 b" I& v& f: ]ization, the clinical hallmark of CPP is the symmet-; \2 C" x- m6 C; H, n
rical testicular growth secondary to stimulation by9 ~' B8 x# J/ W7 n
gonadotropins.1,33 X/ ]" X0 o3 U8 o5 D2 k
Gonadotropin-independent peripheral preco-
: r* E0 f \& ~9 }$ T6 d fcious puberty in boys also results from inappropriate& D3 P: ~ L$ e- V, l' e
androgenic stimulation from either endogenous or
9 t8 q) \9 X/ H" {) b* jexogenous sources, nonpituitary gonadotropin stim-
( |* _/ j3 ^( n' Yulation, and rare activating mutations.3 Virilizing' q( p+ W1 U: R, [8 u8 \6 ^% Y
congenital adrenal hyperplasia producing excessive
R. j- I3 S* L3 b, aadrenal androgens is a common cause of precocious
" p2 v) `" ^" M6 O9 Jpuberty in boys.3,47 C% S% D2 {+ o- |3 `$ k- D
The most common form of congenital adrenal* h z9 i$ w" E
hyperplasia is the 21-hydroxylase enzyme deficiency.
7 `. z# q* C/ |4 \5 I/ w. iThe 11-β hydroxylase deficiency may also result in' I9 b( _. I9 q3 }
excessive adrenal androgen production, and rarely,- n, j) b( D, O t$ }
an adrenal tumor may also cause adrenal androgen4 {' ~, j0 }& b v, U, n
excess.1,3
E: O4 `7 ?* g: h: c! L2 Q- \at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
# j' j5 z9 f6 e- W542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 z: r% F0 t3 l8 v% x0 d+ G
A unique entity of male-limited gonadotropin-
- p9 I$ K6 B9 d# g3 n" a$ q: N+ i% }! Windependent precocious puberty, which is also known
b$ _/ p. r/ aas testotoxicosis, may cause precocious puberty at a
- M/ l1 S8 s) F+ S% Q5 R3 |very young age. The physical findings in these boys
' b3 B6 ?6 Z- B2 I" `4 N Kwith this disorder are full pubertal development,
1 [; ?, v7 l$ F1 Fincluding bilateral testicular growth, similar to boys1 X! ^- n$ D! c8 h s) @
with CPP. The gonadotropin levels in this disorder
6 x' u3 R3 v m$ Mare suppressed to prepubertal levels and do not show
, n2 i' |( e6 Opubertal response of gonadotropin after gonadotropin-6 J5 c H- H N! C z
releasing hormone stimulation. This is a sex-linked( Z7 V4 X/ V b8 p. R
autosomal dominant disorder that affects only
3 Y2 u( @2 R, i- D8 ^; bmales; therefore, other male members of the family m8 u2 E; a0 @* N5 h r
may have similar precocious puberty.35 K7 V8 y5 n; H- L+ u
In our patient, physical examination was incon-
: I8 U( T% @1 l# t6 t0 j3 o8 t. nsistent with true precocious puberty since his testi-
/ n0 r/ J, m& Q, I- kcles were prepubertal in size. However, testotoxicosis
. b; J, { n7 V; Gwas in the differential diagnosis because his father# b7 T, g+ J2 V3 J. D
started puberty somewhat early, and occasionally,- Y) h% _1 Q* a1 A2 C
testicular enlargement is not that evident in the
6 ^& j, d/ V" G) N# fbeginning of this process.1 In the absence of a neg-
5 l9 u6 I {3 t6 u5 T% iative initial history of androgen exposure, our- B2 C9 v% q. G. ]8 t: Z8 v5 m8 d! z
biggest concern was virilizing adrenal hyperplasia,
; a7 o* k& b9 t: }6 E5 |either 21-hydroxylase deficiency or 11-β hydroxylase# M) [& S3 w2 f0 H
deficiency. Those diagnoses were excluded by find-
5 h+ W8 `# Y' S! Y# Z7 I$ S$ T1 Xing the normal level of adrenal steroids.
8 m: y% T2 @2 b( n0 b+ [2 CThe diagnosis of exogenous androgens was strongly
4 f( c/ X1 s' {# k' Ysuspected in a follow-up visit after 4 months because$ M4 q& B% h/ S/ F
the physical examination revealed the complete disap-
+ c. B5 I; }$ I/ w, ^. G: P$ }pearance of pubic hair, normal growth velocity, and0 ?( ~9 d) M3 q: X0 W/ I
decreased erections. The father admitted using a testos-
; x9 ]* ?" @( Z& C; c' kterone gel, which he concealed at first visit. He was
- X' k7 D, `- u5 [2 K( X5 A0 Wusing it rather frequently, twice a day. The Physicians’
, }; e/ s# |6 yDesk Reference, or package insert of this product, gel or
- a, P" K% Y) r' `cream, cautions about dermal testosterone transfer to
^# [; i$ r6 g0 \4 n( Eunprotected females through direct skin exposure.& Q) Q4 R5 V. V3 H! v
Serum testosterone level was found to be 2 times the
$ m( q3 D0 N2 Q7 W0 v: Dbaseline value in those females who were exposed to
' l; G# l5 T5 ^3 q1 Ieven 15 minutes of direct skin contact with their male
w3 D8 T8 c: i, p9 ^8 m+ mpartners.6 However, when a shirt covered the applica-
5 H$ s& L. _. ntion site, this testosterone transfer was prevented.( k0 `9 v& N4 j; J2 |, {& k
Our patient’s testosterone level was 60 ng/mL,
- j% X \" }( j2 K! X8 W4 fwhich was clearly high. Some studies suggest that ^) L/ s" X" ]8 {
dermal conversion of testosterone to dihydrotestos-+ h8 B; {' U. j+ r k
terone, which is a more potent metabolite, is more
4 {) ~4 |7 t7 Z9 Y/ Nactive in young children exposed to testosterone
6 J2 b8 |6 A5 M+ v( q. gexogenously7; however, we did not measure a dihy-* J( \5 L$ P% a7 ?- c
drotestosterone level in our patient. In addition to
" ]0 C8 ?- y- X" p6 W! Lvirilization, exposure to exogenous testosterone in1 c4 G5 H! n# G- d' j% U
children results in an increase in growth velocity and
& |7 q. P" k4 o* k% U- d$ Tadvanced bone age, as seen in our patient.
4 \$ i( \2 c# n* J: {9 JThe long-term effect of androgen exposure during* l9 E0 F: g6 G2 Y
early childhood on pubertal development and final& A7 G, U, S; L2 d4 r
adult height are not fully known and always remain
! B( P1 Z5 N. Ea concern. Children treated with short-term testos-
' M' T! p" X; t: }- bterone injection or topical androgen may exhibit some
$ F. u- `9 V2 U4 j/ A, N; tacceleration of the skeletal maturation; however, after
0 i9 i( \9 c( O4 L, n) Acessation of treatment, the rate of bone maturation8 V% H6 B% o( L
decelerates and gradually returns to normal.8,9
4 N0 z2 \+ W3 \ m/ LThere are conflicting reports and controversy
|6 f. T: Q( A, |, K0 J1 gover the effect of early androgen exposure on adult; A3 n% o: U/ Y5 l" `7 A
penile length.10,11 Some reports suggest subnormal r9 [( q* D5 \
adult penile length, apparently because of downreg-
3 n& S8 g0 o3 x. }, q: Bulation of androgen receptor number.10,12 However,
# m* o' \+ c6 Z, P: c0 V6 CSutherland et al13 did not find a correlation between
! K+ C/ B. ^' k, D9 d, Rchildhood testosterone exposure and reduced adult
0 `! a/ c" y1 m5 X8 g9 u& dpenile length in clinical studies.7 _+ b. T+ t; ^/ a9 R7 N3 l
Nonetheless, we do not believe our patient is7 Z9 m9 {3 s" ?6 v
going to experience any of the untoward effects from$ r1 \1 e" \ f/ X
testosterone exposure as mentioned earlier because9 ~% @. [! H _1 J- ^
the exposure was not for a prolonged period of time.1 c( H5 |3 \2 ^7 }( z+ x
Although the bone age was advanced at the time of, |% O' z# ^; t2 O
diagnosis, the child had a normal growth velocity at: [, F7 i; O( N G, p
the follow-up visit. It is hoped that his final adult" l% B o+ ?" z8 @
height will not be affected.0 W( a2 V7 v1 D" h
Although rarely reported, the widespread avail-
+ e! |! T7 Z2 `0 b% p7 X. I- k* L) I* pability of androgen products in our society may2 c; ^* L( K4 R5 D+ H' ^
indeed cause more virilization in male or female
) J) `1 O$ m |3 m% h4 x- R uchildren than one would realize. Exposure to andro-
3 R. O* u5 w( u8 u7 xgen products must be considered and specific ques-+ E! r" d) A8 I; d
tioning about the use of a testosterone product or% \9 T3 o! K) s- `. k& x
gel should be asked of the family members during7 h8 w# i, L( Z' x
the evaluation of any children who present with vir-
5 p8 B3 ~3 t0 \6 q& Cilization or peripheral precocious puberty. The diag-
0 k3 ~8 ?6 y9 H' J$ U2 D7 bnosis can be established by just a few tests and by
3 z, C) O6 D8 r& ]) kappropriate history. The inability to obtain such a
7 T. k: ]% @9 u% fhistory, or failure to ask the specific questions, may4 U% |4 j# m& L1 g" J
result in extensive, unnecessary, and expensive
% F/ k6 ]' `; _: w0 M7 sinvestigation. The primary care physician should be
* Q0 U+ L7 Q* eaware of this fact, because most of these children/ _3 z) T4 z8 T0 H# H4 I) |* o
may initially present in their practice. The Physicians’- O0 O L* [ ]4 {2 Z) B$ u
Desk Reference and package insert should also put a/ j& G# Y* A3 n; I8 V
warning about the virilizing effect on a male or
; H/ o" z( n4 N$ m) ]female child who might come in contact with some-
+ @2 f/ P6 M+ p# \& aone using any of these products.
* V+ E5 Y) l" }; w( {0 mReferences
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( N/ D6 |3 v0 e, R2 }! c$ B3 z. D5. Greulich WW, Pyle SI, eds. Radiographic Atlas of
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7 M% o4 R% ]3 j" f6. Physicians’ Desk Reference. Androgel 1% testosterone,
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7. Klugo RC, Cerny JC. Response of micropenis to topical
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4 J9 G: Q" {5 A J8. Guthrie RD, Smith DW, Graham CB. Testosterone
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