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is a significant concern for physicians. Central
" n( _+ Y8 Y _# C* N% q1 eprecocious puberty (CPP), which is mediated1 ?& h/ h: Z1 c$ u, p6 M
through the hypothalamic pituitary gonadal axis, has
; H2 q/ \7 {* n4 _6 Q. {a higher incidence of organic central nervous system3 ?6 Z4 _+ i8 i- q% D
lesions in boys.1,2 Virilization in boys, as manifested
' ~6 Q3 O+ g* Wby enlargement of the penis, development of pubic, E2 E( l V) M% J( p, B
hair, and facial acne without enlargement of testi-
; G8 B \' {$ _" ycles, suggests peripheral or pseudopuberty.1-3 We
) }5 u8 c5 Y7 Ereport a 16-month-old boy who presented with the
) o. W# l# w/ d7 Q' m& denlargement of the phallus and pubic hair develop-
# M, D6 `/ d6 L% G, U' ?1 oment without testicular enlargement, which was due& d! w2 ^- U. E D8 u0 z
to the unintentional exposure to androgen gel used by
+ T! S3 B' [9 _' A7 p+ \# Ythe father. The family initially concealed this infor-
g& D% _0 x7 [' k7 Q. F# H# ]9 omation, resulting in an extensive work-up for this
7 w( I6 X( m8 {& m& Dchild. Given the widespread and easy availability of
; H5 U9 B$ O1 J) l1 etestosterone gel and cream, we believe this is proba-
% N7 M) ~/ [$ h, ]) J7 s* qbly more common than the rare case report in the Y: Q. a- d' l# R( p! t
literature.4+ @9 x; g, o% F+ O W H8 {
Patient Report" h# ?7 ^+ f1 k0 V% }
A 16-month-old white child was referred to the
- \) W; m) C$ }. H0 @endocrine clinic by his pediatrician with the concern4 C4 l B6 ]. o9 R6 p
of early sexual development. His mother noticed
* o# v! M! `0 ~/ {light colored pubic hair development when he was. h' Q3 O6 {5 m8 V9 c" V, e- s
From the 1Division of Pediatric Endocrinology, 2University of
' }' P7 G" |2 XSouth Alabama Medical Center, Mobile, Alabama.
7 i9 R, C# w% u$ I5 l! K: ^3 FAddress correspondence to: Samar K. Bhowmick, MD, FACE,
" e8 R( g. O3 pProfessor of Pediatrics, University of South Alabama, College of( H/ \) m- k- l; \: q! _, x
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;7 {. ^0 M6 S e- {$ U
e-mail: [email protected].' O4 i- [9 U1 N, o3 k8 ] k+ s
about 6 to 7 months old, which progressively became
2 Q& H- P. {' m/ \; Idarker. She was also concerned about the enlarge-
3 ]; G& a1 m8 m) h nment of his penis and frequent erections. The child
) M5 k1 u) r4 w% C. V3 hwas the product of a full-term normal delivery, with. r' ` V6 x& e8 C# C
a birth weight of 7 lb 14 oz, and birth length of( w1 `$ Q, W) A: J6 u* I4 g- [* V( o
20 inches. He was breast-fed throughout the first year+ O3 D! R. T |, P9 d# w# Q2 D3 u
of life and was still receiving breast milk along with' f: E8 Q! ~2 \% U' ]* o
solid food. He had no hospitalizations or surgery,
3 B) N. e* `9 K% k4 s" o; q! M' nand his psychosocial and psychomotor development
1 a% u$ d, U Z5 y1 C9 Bwas age appropriate.5 e0 R% l/ M9 T* ~1 r; G
The family history was remarkable for the father,
! D) Z' r* Y2 Ywho was diagnosed with hypothyroidism at age 16,
& N0 L- W2 c- w, E- j6 cwhich was treated with thyroxine. The father’s
; b) Y5 \1 I( u/ Z& t3 d. M/ |height was 6 feet, and he went through a somewhat
- O2 M9 e$ q1 N4 x! r6 l- ^early puberty and had stopped growing by age 14.5 c5 g# J; A L; o4 F9 S2 ]9 V' q
The father denied taking any other medication. The! u( s1 w6 d. [3 e
child’s mother was in good health. Her menarche
' M: Y: t2 m' N ^" ?& K/ Owas at 11 years of age, and her height was at 5 feet3 w6 E1 v! k$ B o4 P
5 inches. There was no other family history of pre-
* {* {/ u9 g$ X0 [' Fcocious sexual development in the first-degree rela-! w' }' A: ^6 u% ^9 n
tives. There were no siblings.
]5 S' t4 V( [, e+ K& r' x2 F3 IPhysical Examination
$ d2 }' J- l8 QThe physical examination revealed a very active,0 z, e& M5 b! h4 i$ m
playful, and healthy boy. The vital signs documented3 P- F- m; }; T3 c$ d2 I& a) |0 v
a blood pressure of 85/50 mm Hg, his length was) Y. e' I( c" `5 e8 ? C# }
90 cm (>97th percentile), and his weight was 14.4 kg
5 @* Z+ a' m2 o! l1 ?(also >97th percentile). The observed yearly growth
0 O0 a) d, ]/ a @" Avelocity was 30 cm (12 inches). The examination of
% R* l1 c0 w* U3 S( W, Gthe neck revealed no thyroid enlargement.1 E$ d% H: ?# l% J
The genitourinary examination was remarkable for! s' R2 k$ N$ L7 j/ m3 q, `
enlargement of the penis, with a stretched length of; E/ }6 F/ P9 e/ R% ?& ]( A/ s2 z
8 cm and a width of 2 cm. The glans penis was very well6 X# h' h+ w7 V4 ^# v9 b
developed. The pubic hair was Tanner II, mostly around
1 ~7 |$ U0 r5 ]; v5400 U- T y: j8 {8 B; Y2 A
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) K, A% O. M, u }# q6 U- H
the base of the phallus and was dark and curled. The) h. D% q& N8 U( C
testicular volume was prepubertal at 2 mL each.
G4 g) _/ x" T! b( C7 M& gThe skin was moist and smooth and somewhat# F* K' z6 }4 \1 _9 x
oily. No axillary hair was noted. There were no
* s3 }9 g6 l- w% [: kabnormal skin pigmentations or café-au-lait spots.% p& |/ A- w3 Q& t
Neurologic evaluation showed deep tendon reflex 2+$ f; |0 t1 n% l# c l; U+ a, ?
bilateral and symmetrical. There was no suggestion5 ^/ r' |' c+ ?8 ?; G/ F4 ?
of papilledema.! ]+ w5 b) L% } c r- @6 a' |
Laboratory Evaluation
5 P+ \( ~9 N5 z0 {. D( u' u% y: MThe bone age was consistent with 28 months by
! \: Z) Z6 X' g* e. R% xusing the standard of Greulich and Pyle at a chrono-5 U1 L k5 J' S( W7 e
logic age of 16 months (advanced).5 Chromosomal; E- s( _: m J: b& A
karyotype was 46XY. The thyroid function test4 D. v) A( o2 [& a
showed a free T4 of 1.69 ng/dL, and thyroid stimu-: \5 J9 ?4 i8 E' H, P
lating hormone level was 1.3 µIU/mL (both normal)./ o- }! T- u" T
The concentrations of serum electrolytes, blood! e4 E+ O6 }- s5 l ?7 f
urea nitrogen, creatinine, and calcium all were9 X) w* p* ~- w. [1 Q9 V
within normal range for his age. The concentration) K( x( V: k8 C( u( w$ x( s$ U
of serum 17-hydroxyprogesterone was 16 ng/dL
: O; m% _. A& Z1 H s, I) ^(normal, 3 to 90 ng/dL), androstenedione was 20+ f. u+ _ H# b) C
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-" `6 X8 I+ G& v9 r
terone was 38 ng/dL (normal, 50 to 760 ng/dL),$ L, i- H. r' }; y; z% v
desoxycorticosterone was 4.3 ng/dL (normal, 7 to
) S7 F+ c' E; N$ P7 y49ng/dL), 11-desoxycortisol (specific compound S)1 h& B+ i8 l; I2 `: O$ a0 a* W
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-: E% K7 }2 _8 E/ U2 w% I$ N
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
- w( G& @) B5 Rtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
1 W' {3 n' U- z: N s& rand β-human chorionic gonadotropin was less than
9 ]) Y/ p& R6 v F/ t0 I5 mIU/mL (normal <5 mIU/mL). Serum follicular
# u" _+ T8 ?3 f/ Z& pstimulating hormone and leuteinizing hormone
& W: H$ h0 m* V) E6 h' b5 B" zconcentrations were less than 0.05 mIU/mL
& n! K- i! V; X: A7 M2 g(prepubertal).7 t ~, |! A# ^6 B6 O- s- n7 h
The parents were notified about the laboratory
1 ^/ y5 }0 n: N$ U6 Uresults and were informed that all of the tests were8 R& F* g( b. I1 u1 F& b5 ]0 q' c
normal except the testosterone level was high. The x7 N$ O# o3 m& m% X% A/ n7 Q9 O
follow-up visit was arranged within a few weeks to: D& y. W. r/ u
obtain testicular and abdominal sonograms; how-$ q1 O2 R% {4 F3 F5 E
ever, the family did not return for 4 months.
1 v4 J. H J. ZPhysical examination at this time revealed that the" ]% t; }$ M+ X
child had grown 2.5 cm in 4 months and had gained
1 j. ?; z4 \9 P' ?2 kg of weight. Physical examination remained
& E3 r& E& W& sunchanged. Surprisingly, the pubic hair almost com-
- G6 l5 ?; x) D8 @( M npletely disappeared except for a few vellous hairs at3 R* Y- k+ X( q: d
the base of the phallus. Testicular volume was still 23 [/ m2 J# M. o. } U9 B/ B
mL, and the size of the penis remained unchanged.8 s6 Z8 D5 P5 |
The mother also said that the boy was no longer hav-. ?/ D! y# K4 @( I8 U: T
ing frequent erections.
! N% q3 p' q6 F; E; X8 |7 zBoth parents were again questioned about use of
: W0 P7 M( F. }any ointment/creams that they may have applied to
) O& h' k: X5 w0 N% g! ]the child’s skin. This time the father admitted the
8 R3 x" \: `4 ?& ATopical Testosterone Exposure / Bhowmick et al 541" |; L: u+ U( S; V2 d+ k
use of testosterone gel twice daily that he was apply-# p( D6 o' W6 _7 {: L; A# q
ing over his own shoulders, chest, and back area for
" L$ \/ z0 O+ S% Ea year. The father also revealed he was embarrassed
3 ^% ]* g. {. }to disclose that he was using a testosterone gel pre-7 ~8 e2 p: P1 v& l0 h b( \0 a
scribed by his family physician for decreased libido" u* l0 C: u2 U
secondary to depression.$ {5 l/ j& A$ D4 g5 ]) U, q
The child slept in the same bed with parents.
( F6 H3 Q: E, b' [6 s _) hThe father would hug the baby and hold him on his
+ U1 n0 P' F5 R. Q2 z) {% Zchest for a considerable period of time, causing sig-
1 P" a2 Q7 X% I7 T' n; \. C3 unificant bare skin contact between baby and father.
0 Q' U& A3 ^; X/ G" L9 V2 p5 _The father also admitted that after the phone call,: ?) m8 G" R" `$ b; ~! G* @; B8 i
when he learned the testosterone level in the baby
9 ^, p3 i0 \, v! I4 Cwas high, he then read the product information, _- C( D1 ?( j
packet and concluded that it was most likely the rea-" v8 [ }' j( W6 H# G" ^
son for the child’s virilization. At that time, they
( N" c8 g5 s; g5 A, hdecided to put the baby in a separate bed, and the
$ H& o9 }; p Tfather was not hugging him with bare skin and had
$ W) N. a: t- t$ {6 ~- ~been using protective clothing. A repeat testosterone, V" R# L0 N, P5 n. n% s9 ?; n
test was ordered, but the family did not go to the* O7 S5 ?( }. ^4 i* \
laboratory to obtain the test.# Z; n; p) k1 J5 G* ^9 ^$ q
Discussion
/ ~2 A; t8 D) \8 NPrecocious puberty in boys is defined as secondary
0 B r% t" ^! R% }sexual development before 9 years of age.1,4% Q4 {, D) Y" W& d9 \
Precocious puberty is termed as central (true) when
- D1 d6 v. h5 t2 Y5 Q* E' @it is caused by the premature activation of hypo-
9 I$ \4 J) X I2 _thalamic pituitary gonadal axis. CPP is more com-
$ X6 A5 \8 E/ v* Imon in girls than in boys.1,3 Most boys with CPP5 {7 F ~ C- T$ F% o
may have a central nervous system lesion that is
7 o1 ?7 K$ y% n% K' \responsible for the early activation of the hypothal-1 H$ u ?" q# L6 [- U9 r& S9 J0 s
amic pituitary gonadal axis.1-3 Thus, greater empha-9 E" u9 I) l2 Y$ z9 [% ^- f2 D. x
sis has been given to neuroradiologic imaging in
. u8 I& c' I; T5 iboys with precocious puberty. In addition to viril-9 d+ L* |! y' d b( \, r
ization, the clinical hallmark of CPP is the symmet-
+ U: U* m9 f% i. Q4 U! {0 Orical testicular growth secondary to stimulation by
! X/ \( P% k, K. A% Sgonadotropins.1,3 `/ _8 P& g/ [9 K
Gonadotropin-independent peripheral preco-
% c. t4 p! y) N% Qcious puberty in boys also results from inappropriate+ d9 F' R8 \8 s$ m, r1 `5 n
androgenic stimulation from either endogenous or5 g8 x' O+ M. K6 h |
exogenous sources, nonpituitary gonadotropin stim-
3 |2 p0 L6 J4 P, Bulation, and rare activating mutations.3 Virilizing. m5 R% m7 o% K# q( D7 E, i! ?
congenital adrenal hyperplasia producing excessive
- r, u& d! ^2 L. ]. qadrenal androgens is a common cause of precocious
" g' x3 C, y" A0 u- I% G7 Xpuberty in boys.3,4! }% o+ T+ z9 L5 y
The most common form of congenital adrenal
, q5 {! z0 t( S" {7 Shyperplasia is the 21-hydroxylase enzyme deficiency.1 v2 _# a: Y# h
The 11-β hydroxylase deficiency may also result in
; V$ j h5 r: jexcessive adrenal androgen production, and rarely,& R- j0 s7 ^, v
an adrenal tumor may also cause adrenal androgen
0 ?/ L+ n8 B' b6 ~excess.1,3
- O/ d/ K; X ~& ^) X% Zat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) V5 H1 U; v4 _) Q e/ @' N H: y d
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007# V$ W: l _+ a( m6 w3 ?9 k% U) o o. F
A unique entity of male-limited gonadotropin-/ g8 p- Y0 J: e( D- L
independent precocious puberty, which is also known
! p8 [# x" Q, J U% `8 e, Jas testotoxicosis, may cause precocious puberty at a' Q5 S8 y4 P6 u7 l/ O
very young age. The physical findings in these boys4 ?# C& ^! X8 n. I4 i) F
with this disorder are full pubertal development,
5 Q' k( K* e( E4 G7 d) T2 eincluding bilateral testicular growth, similar to boys& {/ h2 Q+ ^7 W1 T6 s9 V
with CPP. The gonadotropin levels in this disorder* _ x v9 O; l! Z8 ?3 y
are suppressed to prepubertal levels and do not show
$ h+ g9 c& S; j. Gpubertal response of gonadotropin after gonadotropin-; V- D" P" d0 p3 t, m
releasing hormone stimulation. This is a sex-linked
% r% Z k6 R' M) Oautosomal dominant disorder that affects only8 Q- {6 d' Q K" g4 C+ r2 i% \8 V
males; therefore, other male members of the family
% w* K' U8 o6 X% ^ T/ ^* wmay have similar precocious puberty.3
; l! |, x) N* QIn our patient, physical examination was incon-
6 J5 J/ K1 w' E+ Asistent with true precocious puberty since his testi-
* U( H) M. ^+ z G+ jcles were prepubertal in size. However, testotoxicosis
* Y/ `3 P1 [! \: Ywas in the differential diagnosis because his father
* G/ v0 S. C6 X# H7 s6 U" d0 Sstarted puberty somewhat early, and occasionally,
. k8 K. [0 p2 ]4 X# c$ ~* S: C, C) l* Etesticular enlargement is not that evident in the
8 j; A h) ]0 L1 Q! J) [beginning of this process.1 In the absence of a neg-- K/ c/ Z1 N- C c! p. C8 Z6 C1 G# V* P
ative initial history of androgen exposure, our
" u. {* ]6 c9 z2 h8 {" P( sbiggest concern was virilizing adrenal hyperplasia,
0 d8 {6 s$ _, v' g& v! N) leither 21-hydroxylase deficiency or 11-β hydroxylase
2 w: M$ {* }( c# P! ?8 Xdeficiency. Those diagnoses were excluded by find-
& A; b% r0 t3 t" X) r6 f$ y9 Sing the normal level of adrenal steroids.1 p1 a7 X6 ?; }/ p
The diagnosis of exogenous androgens was strongly
0 h* v0 Z' v- z' r7 I9 b- h0 \5 Xsuspected in a follow-up visit after 4 months because
/ @4 P$ w& P1 V f& c) bthe physical examination revealed the complete disap-
; T0 s1 g' b( l) G# h2 jpearance of pubic hair, normal growth velocity, and8 }3 t$ S5 V! z1 p$ t
decreased erections. The father admitted using a testos-! U2 E$ }% o9 |5 {& _! X9 q+ b
terone gel, which he concealed at first visit. He was
" b* j. ?, g0 O: U0 kusing it rather frequently, twice a day. The Physicians’
- B8 K8 v, S+ l$ U- nDesk Reference, or package insert of this product, gel or
6 d0 T# g" g/ @! g8 p( D; Dcream, cautions about dermal testosterone transfer to% ~) Z; B! U. E6 }
unprotected females through direct skin exposure.) j9 U6 q4 Z* {
Serum testosterone level was found to be 2 times the0 U* `& ?0 F$ m1 h3 B3 M# t1 z! X
baseline value in those females who were exposed to
' c5 ~4 t1 s* r2 Q) X5 g Xeven 15 minutes of direct skin contact with their male
4 Q6 U3 x! n3 c9 f/ L3 Rpartners.6 However, when a shirt covered the applica-
2 r$ C3 d% u. r8 |tion site, this testosterone transfer was prevented.
- A( Z7 }. P/ O3 e/ ?Our patient’s testosterone level was 60 ng/mL,
! v7 l4 H- Z& n4 `which was clearly high. Some studies suggest that1 S! M. H; Y2 D
dermal conversion of testosterone to dihydrotestos-
/ ?; W6 `, i& x. i3 N4 Fterone, which is a more potent metabolite, is more
1 ^3 L ?6 u5 B8 J6 Eactive in young children exposed to testosterone
5 @9 a7 t5 \) `exogenously7; however, we did not measure a dihy-
" D d! k4 |$ Y. X- c2 ~7 ldrotestosterone level in our patient. In addition to6 G6 u) i4 Y5 d: z; B& s% g
virilization, exposure to exogenous testosterone in
2 {* @! N; f/ o" Q. B4 l" b; Rchildren results in an increase in growth velocity and
( I) h1 r8 P: |1 f3 Sadvanced bone age, as seen in our patient.0 K- ^! O7 v+ ~% t# N: z
The long-term effect of androgen exposure during$ x. M3 M" O7 H1 Q6 p
early childhood on pubertal development and final/ C( K5 b+ g9 k/ }
adult height are not fully known and always remain- X) @# s* l. r0 W- y e7 j; q
a concern. Children treated with short-term testos-6 g6 M/ [1 S( L% a$ U. |
terone injection or topical androgen may exhibit some
" J6 q0 V2 y, ]acceleration of the skeletal maturation; however, after
% f+ D% Y1 A% ], ^, I9 `cessation of treatment, the rate of bone maturation
/ G7 I. a9 w: Z& H9 ?4 y( y+ ]decelerates and gradually returns to normal.8,9
. c6 P0 f5 u/ SThere are conflicting reports and controversy
h1 s; s0 B, G# {, t7 M5 A0 z( e( ~6 Qover the effect of early androgen exposure on adult
" N- z0 U& |1 F8 T4 bpenile length.10,11 Some reports suggest subnormal8 G* y' r( M: ^- z- P
adult penile length, apparently because of downreg-+ g9 r$ ]' |4 R( X7 Q# }
ulation of androgen receptor number.10,12 However,
8 g+ _1 c' j0 M& t% ~Sutherland et al13 did not find a correlation between
0 O( J4 r4 _1 _- M, X3 `childhood testosterone exposure and reduced adult
% ^* B# }+ I. A. R j. x4 zpenile length in clinical studies.
! ]- G' X& T7 _Nonetheless, we do not believe our patient is
2 h$ W; r+ [ }$ O5 `7 \, x+ }going to experience any of the untoward effects from2 [1 v% I& {+ `) L
testosterone exposure as mentioned earlier because
2 b# q K0 [7 S! K8 a0 Jthe exposure was not for a prolonged period of time.2 @) F/ {; O9 ~5 `0 T5 P" G
Although the bone age was advanced at the time of
* H2 {; [# t1 c- q+ F) ]2 @+ O5 k0 y' Hdiagnosis, the child had a normal growth velocity at
+ _, h1 G; B6 [ G& G2 _' S& [, ]the follow-up visit. It is hoped that his final adult
) @: X' ~3 I& [- [height will not be affected.
0 w$ f" }( _1 W& Q5 C d; ZAlthough rarely reported, the widespread avail-
2 X9 M- A- j8 {1 d+ a7 h" \ability of androgen products in our society may6 x/ R. V+ L5 k+ K: K$ N
indeed cause more virilization in male or female
5 J+ S1 j9 Q- v" Q* E- o9 E2 G; jchildren than one would realize. Exposure to andro-, X J+ A9 r; c. N: D$ S, C0 u
gen products must be considered and specific ques-4 u# ~! `8 Y* a, W4 d
tioning about the use of a testosterone product or9 V5 n( `7 ]4 Z8 g
gel should be asked of the family members during
) e2 s$ H7 l* Y$ t2 Y" F hthe evaluation of any children who present with vir-2 ?, c5 d. c. E/ x
ilization or peripheral precocious puberty. The diag-$ c+ k! A0 g- f* e- o- B9 R/ b
nosis can be established by just a few tests and by
& M0 d: r' p/ d3 s Wappropriate history. The inability to obtain such a- C; H; {9 }- b/ K# {
history, or failure to ask the specific questions, may4 _* e8 R# N: `4 W: i/ X" i& W
result in extensive, unnecessary, and expensive
6 ], R8 U9 P# b3 Z1 D5 Finvestigation. The primary care physician should be
4 T) `3 F& Z9 W$ W1 }! o! Aaware of this fact, because most of these children7 L: R9 v; ?' l' y& A
may initially present in their practice. The Physicians’
2 h3 H9 F3 d- I. F& oDesk Reference and package insert should also put a7 Q6 I. y5 b% D, s/ \6 p" @5 s* q
warning about the virilizing effect on a male or( Q0 S% H, F: ?/ X# Y$ j, F. A, s
female child who might come in contact with some-
" D2 \, w. c+ O' D ^$ j1 Xone using any of these products.+ C" [$ |3 ^5 n) d- [! q
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Economics Company, Inc; 2004:3239-3241.
T) M7 P B5 _/ |" \' n1 [& H7. Klugo RC, Cerny JC. Response of micropenis to topical
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