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Sexual Precocity in a 16-Month-Old+ s, {5 q3 T' t5 c
Boy Induced by Indirect Topical% A2 ], ] q m0 [" j6 p
Exposure to Testosterone/ s: a7 |5 \2 P- |$ j! \1 W
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
- w) g2 a4 J' Q+ U' ^% eand Kenneth R. Rettig, MD1
/ L6 k, Q) j1 Y: Y% MClinical Pediatrics
1 X& M* _# U4 Y- P! i/ h; h7 LVolume 46 Number 63 {5 M0 N R# q0 I6 b9 m
July 2007 540-543
) ^- [. r7 P+ h- X2 E9 S5 J, p0 R© 2007 Sage Publications
) r' D' w& l2 c- \0 W: u10.1177/0009922806296651
1 v" B$ m! g8 D' Nhttp://clp.sagepub.com
^! J4 Y* h, z7 [1 mhosted at, c' y. f6 u$ y0 j9 m- D
http://online.sagepub.com8 Z' Q+ F1 Q2 I( z8 j
Precocious puberty in boys, central or peripheral,2 _' G# A, U! b
is a significant concern for physicians. Central* h" }$ u) x1 ^0 y
precocious puberty (CPP), which is mediated
+ B" C4 g R, Z0 j, Bthrough the hypothalamic pituitary gonadal axis, has% X2 S2 h6 P% s" g5 X3 t
a higher incidence of organic central nervous system
. H7 U+ X0 a4 ^$ A: O) M2 zlesions in boys.1,2 Virilization in boys, as manifested
& V7 g8 w4 T, w1 `( a7 Tby enlargement of the penis, development of pubic
# \1 [( A9 u$ b% chair, and facial acne without enlargement of testi-
& f& M( Y6 f) K2 Xcles, suggests peripheral or pseudopuberty.1-3 We- G6 i. M) M, K( U9 _
report a 16-month-old boy who presented with the+ H& k# Y Z1 `" e7 t
enlargement of the phallus and pubic hair develop-
3 E7 h7 h* t; u, f7 a) kment without testicular enlargement, which was due
3 G/ f: X1 F0 ]9 t$ sto the unintentional exposure to androgen gel used by7 H$ l$ H/ P5 p4 n+ F* q# `
the father. The family initially concealed this infor-
8 r- P, ?# F: |/ ?6 D& O8 k2 a7 Q. qmation, resulting in an extensive work-up for this- B' {/ ?: x0 ?$ @- l
child. Given the widespread and easy availability of
+ Y+ S# T8 k, `2 W* `testosterone gel and cream, we believe this is proba-3 j3 o3 B' a+ ?; d N, ~* P
bly more common than the rare case report in the
) N2 l8 _# A$ i) B2 e8 X% Iliterature.4
* _, C. \) @3 \& c! Q( ~Patient Report
( K) u; I5 z* a# O1 L# T/ bA 16-month-old white child was referred to the
2 P6 O$ p" I e5 S4 hendocrine clinic by his pediatrician with the concern( a9 ~; \% `% J4 _8 T& p/ \
of early sexual development. His mother noticed
& Z$ Y) a+ Q/ Z, G8 H+ P: ?light colored pubic hair development when he was# O- Z1 A: G- w6 F* [
From the 1Division of Pediatric Endocrinology, 2University of
; @+ J, ?! C2 C' \South Alabama Medical Center, Mobile, Alabama. } [1 j, x/ u9 F1 E
Address correspondence to: Samar K. Bhowmick, MD, FACE,) [7 n9 D: }$ y, E$ w: N7 H, M5 Z
Professor of Pediatrics, University of South Alabama, College of2 F2 Q% h9 L' a6 K$ }2 T
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;" P2 T) T; t6 i7 G e5 {
e-mail: [email protected].
* u$ B, l- W% q& d4 N Q( g& v& Xabout 6 to 7 months old, which progressively became# q( Y9 _8 u6 l) D# ?/ P8 t; i- k
darker. She was also concerned about the enlarge-
* r% H" o8 o/ qment of his penis and frequent erections. The child
' {7 d" b5 J# V& H3 H( c1 Gwas the product of a full-term normal delivery, with. Z. y7 G+ L# R
a birth weight of 7 lb 14 oz, and birth length of$ T/ M/ X) @+ @ n6 R- |4 I
20 inches. He was breast-fed throughout the first year! G. ~5 M6 ]" H- f* Y( |8 @1 M
of life and was still receiving breast milk along with: k: W3 Y) r- C( N" P1 `
solid food. He had no hospitalizations or surgery,
/ o- A# [# Y/ U7 Uand his psychosocial and psychomotor development
1 T' ^1 h: Q# n9 i! p8 E. n# lwas age appropriate. N1 ^0 K9 g& L j: T$ K& a6 x
The family history was remarkable for the father,
4 k8 N/ [" C+ l& r: \who was diagnosed with hypothyroidism at age 16,
& M- Z, Q: w: ^% W/ Qwhich was treated with thyroxine. The father’s2 W1 d5 _) ]3 Z5 V
height was 6 feet, and he went through a somewhat
% ?9 e: j2 N# T4 N5 A+ ?early puberty and had stopped growing by age 14., P- G/ x5 a: U$ S
The father denied taking any other medication. The
3 d+ i$ S4 M8 M3 i; V Xchild’s mother was in good health. Her menarche5 v2 ~& A7 M$ [6 i: c( s/ e
was at 11 years of age, and her height was at 5 feet) L% [, C1 y0 g! R9 W' o6 s$ x) `$ k
5 inches. There was no other family history of pre-( G' i2 a* z p* P8 q* A1 z
cocious sexual development in the first-degree rela-
6 X3 b2 @3 V5 c' b1 }tives. There were no siblings.2 ?6 |* u# ~0 G( J% b6 r$ |$ ]
Physical Examination1 V+ S( d9 u+ E7 v+ y" s, u
The physical examination revealed a very active,; _" |0 G+ p* j# i8 E7 q
playful, and healthy boy. The vital signs documented
$ [3 D6 [0 _* l1 }6 a; w& wa blood pressure of 85/50 mm Hg, his length was1 n* I) d' H7 V5 _% x0 o2 q
90 cm (>97th percentile), and his weight was 14.4 kg5 @" h; Y( J9 r# f8 T& y
(also >97th percentile). The observed yearly growth
* M9 C7 n7 F* S. W R4 [velocity was 30 cm (12 inches). The examination of
8 T. U% ?$ E9 G/ athe neck revealed no thyroid enlargement.
' v( F' ]% E" P; b. t, d: bThe genitourinary examination was remarkable for6 t& v; z" ?5 e, C) F/ K
enlargement of the penis, with a stretched length of$ y b4 V% y. _" t4 K" l
8 cm and a width of 2 cm. The glans penis was very well
6 E k) t5 K$ c+ T+ hdeveloped. The pubic hair was Tanner II, mostly around& a, Q& Y% a& g9 }$ q+ l* M6 \9 S1 }$ `
540
% F; x- T9 Y0 [1 `4 R wat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
+ d5 T4 {6 X+ G1 Wthe base of the phallus and was dark and curled. The
7 I, A8 k/ ^7 q+ I' v; [testicular volume was prepubertal at 2 mL each./ g4 I" Q6 Q5 \- B2 V6 s* H! Q- ~/ u
The skin was moist and smooth and somewhat2 Q1 U& {3 i6 z/ C% n
oily. No axillary hair was noted. There were no/ G7 r# r: y3 ~
abnormal skin pigmentations or café-au-lait spots.
* V3 c; x6 A& l- m6 R& oNeurologic evaluation showed deep tendon reflex 2+
5 L ?7 i! u2 M7 \8 Pbilateral and symmetrical. There was no suggestion! Y( |, e C: G/ a3 q# ?
of papilledema.
5 S' V# B3 C: \' N/ a% iLaboratory Evaluation8 q# s; f& r3 I4 D) b, c9 ]. L
The bone age was consistent with 28 months by1 [0 Q& I% o! Y2 `. U
using the standard of Greulich and Pyle at a chrono-
8 p: ?" R- [) d/ h, b/ Qlogic age of 16 months (advanced).5 Chromosomal+ ]9 ]7 F% i6 c4 B- ?; ]
karyotype was 46XY. The thyroid function test4 Z9 D2 t, a0 G/ T7 W, Y& {
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
' F& Z8 P9 Q/ Elating hormone level was 1.3 µIU/mL (both normal).6 {) {$ P6 X1 R" @- x$ `
The concentrations of serum electrolytes, blood) I4 j; I& ]1 B6 h
urea nitrogen, creatinine, and calcium all were: M. K8 @! e# U2 @
within normal range for his age. The concentration
5 A# j$ I" O5 f6 `of serum 17-hydroxyprogesterone was 16 ng/dL* i Y! b; B9 f' s/ D/ }
(normal, 3 to 90 ng/dL), androstenedione was 20
, S, V' A1 [" Ing/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
1 m) e5 i' r* I% s$ W; f# @terone was 38 ng/dL (normal, 50 to 760 ng/dL),
2 Y3 Z6 b% G( ~# Q! O2 Qdesoxycorticosterone was 4.3 ng/dL (normal, 7 to& ~' x; F6 Y) q7 I- h: r- h0 a
49ng/dL), 11-desoxycortisol (specific compound S)
+ Y; n# X! H/ X2 R+ ]& nwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-; Y$ [0 a$ K) M6 T. z
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
7 j' D6 }6 `& e; \8 N9 D; b# atestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
( D& X9 y4 _, }! m: oand β-human chorionic gonadotropin was less than
* w+ W% V T! {# A# d( W' u5 mIU/mL (normal <5 mIU/mL). Serum follicular
! i b* M2 [$ [" j3 e% z+ q5 wstimulating hormone and leuteinizing hormone
! B ~. B8 D' h6 h& V# fconcentrations were less than 0.05 mIU/mL) P- g7 X9 X: @9 {# j! V9 ]
(prepubertal).
) z+ w: _/ n+ M& K+ |& ~8 w ]% |The parents were notified about the laboratory" I+ u" N9 J- V t4 K0 A
results and were informed that all of the tests were, B! j* Y# Q# G( e$ ^' A
normal except the testosterone level was high. The
# q: Z1 ~, X4 ]- n( p( tfollow-up visit was arranged within a few weeks to
. _( c) v1 a: v7 n9 G p$ b: Hobtain testicular and abdominal sonograms; how-
. c5 h8 }* G1 K# f, dever, the family did not return for 4 months.: a, S# s5 O2 _" B; v# F: g
Physical examination at this time revealed that the
T) k( W9 W" |child had grown 2.5 cm in 4 months and had gained
" Y# a% `, P3 s0 ?* U$ @2 kg of weight. Physical examination remained
9 W2 t: U- T6 ]3 K Iunchanged. Surprisingly, the pubic hair almost com-
; t) k) `- J$ D! epletely disappeared except for a few vellous hairs at
0 c' Q8 P7 F" r1 Uthe base of the phallus. Testicular volume was still 2
7 E$ c+ B! C( F; W9 {. zmL, and the size of the penis remained unchanged.2 `4 C" b: V' J6 G$ X; [) R
The mother also said that the boy was no longer hav-# k( a! S- f* K6 s) [ i
ing frequent erections.2 Z+ b1 {8 F: |2 }- ^1 ]2 ~
Both parents were again questioned about use of) B! b0 a5 q) M* D% o
any ointment/creams that they may have applied to4 m1 o9 J8 R( s. y7 m- v. [
the child’s skin. This time the father admitted the- ~7 ]( A2 Z& d# N: B+ c6 X
Topical Testosterone Exposure / Bhowmick et al 5417 Z& {" J% _2 E0 v }
use of testosterone gel twice daily that he was apply-
2 b* d/ \. V) @% N' | Zing over his own shoulders, chest, and back area for+ L+ c4 h$ i% Q( j0 M( P! D
a year. The father also revealed he was embarrassed
: |+ x/ t% G/ W# H4 u. F$ k2 \to disclose that he was using a testosterone gel pre-/ D. W- @8 {5 S# _
scribed by his family physician for decreased libido
' ?# D& f; g* Wsecondary to depression.% S# }" T' c4 U; V
The child slept in the same bed with parents.0 g/ B" u1 M, e3 w0 y; d& s
The father would hug the baby and hold him on his
' q0 V, b( R7 p+ }% I; ^chest for a considerable period of time, causing sig-
. C5 r4 |7 s o* N# Q0 e6 i- ]nificant bare skin contact between baby and father.8 q5 t' w) e0 n6 O- q/ `. `
The father also admitted that after the phone call,& ?5 [5 E! ~6 ~7 D
when he learned the testosterone level in the baby
% E( L) n* O! S9 F: M! _was high, he then read the product information( l. ~# J' M$ @, q
packet and concluded that it was most likely the rea-* D$ t% t2 m2 J1 g7 `9 `0 \: n
son for the child’s virilization. At that time, they
) z* D# ?+ d) p9 Rdecided to put the baby in a separate bed, and the
# t* h& [; [2 ?5 @! Qfather was not hugging him with bare skin and had' s% [! L1 ~6 ?! V" ^
been using protective clothing. A repeat testosterone
# @1 m* O# ~8 \test was ordered, but the family did not go to the
e; s s5 O2 G" l: D4 Jlaboratory to obtain the test.8 i! G+ N* X7 Y
Discussion
5 C, E3 V. _% K/ z0 FPrecocious puberty in boys is defined as secondary9 S2 B$ u: c5 W' _9 J
sexual development before 9 years of age.1,4* ]* F9 a3 k$ k7 r
Precocious puberty is termed as central (true) when
( R6 V5 \' d" Hit is caused by the premature activation of hypo-
' R) r+ E6 G' _1 ^! c B4 W* athalamic pituitary gonadal axis. CPP is more com-
: [1 f. V* m5 x+ q; a3 B$ B! G/ tmon in girls than in boys.1,3 Most boys with CPP
+ i' a5 |# S/ D+ q' Wmay have a central nervous system lesion that is r D9 X6 n* s1 M, d- _/ N) d
responsible for the early activation of the hypothal-8 I8 E3 I+ u9 H4 @% S9 J5 N( k0 @
amic pituitary gonadal axis.1-3 Thus, greater empha-9 _% B% c2 L. C3 R+ r& s
sis has been given to neuroradiologic imaging in
$ d: [# |) ?" ~6 x; P qboys with precocious puberty. In addition to viril-/ U7 B; z# o; A' ]7 [+ ~; c
ization, the clinical hallmark of CPP is the symmet-
2 y ]- s: S" o: M6 @rical testicular growth secondary to stimulation by
0 F% i% @$ T) Bgonadotropins.1,3
9 X8 [8 Y. t% W. ^( b% bGonadotropin-independent peripheral preco-& z8 v8 I+ g- }0 \5 u- H( b
cious puberty in boys also results from inappropriate
( n p5 f! F/ a# }androgenic stimulation from either endogenous or
9 _9 T1 j; P' M3 `' R# ]& }9 bexogenous sources, nonpituitary gonadotropin stim-
4 g# N3 {& d% W5 @9 ]ulation, and rare activating mutations.3 Virilizing1 W( a( p* x0 a* S" V% m
congenital adrenal hyperplasia producing excessive
0 v- y- p$ L- U. }4 Qadrenal androgens is a common cause of precocious
3 Q, T' y$ @( w% ^puberty in boys.3,4
8 h- T% l& q9 Q5 i! c* |% N: EThe most common form of congenital adrenal( G) Q# j: k; I5 M
hyperplasia is the 21-hydroxylase enzyme deficiency." q' J+ h3 O$ s
The 11-β hydroxylase deficiency may also result in8 K7 K7 U4 H- K# T' \, w
excessive adrenal androgen production, and rarely,
- w, w: c: l/ N+ Oan adrenal tumor may also cause adrenal androgen$ @: }" h1 Q, t8 ^2 l: m6 W
excess.1,3! {2 X4 J# v- k- D
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
. \# c! r" u1 X$ e/ a* q542 Clinical Pediatrics / Vol. 46, No. 6, July 20077 k. p8 a) g* Y8 ~* M
A unique entity of male-limited gonadotropin-9 G+ _/ S: `% p; I) u
independent precocious puberty, which is also known
- A W6 r& Y9 g% qas testotoxicosis, may cause precocious puberty at a' ?8 u% O& v7 Q% z D3 N
very young age. The physical findings in these boys& {. C& u$ C, S9 Q9 _* F/ U! _
with this disorder are full pubertal development,
4 a' K: s* i X5 W, W7 tincluding bilateral testicular growth, similar to boys( S h$ F- `' I+ t2 G; a
with CPP. The gonadotropin levels in this disorder
: s5 ~, K0 m$ |/ }5 w9 U; Nare suppressed to prepubertal levels and do not show
- c) L: [1 z5 G7 ^. q$ c8 I: I! Spubertal response of gonadotropin after gonadotropin-* P* }5 W$ R; \3 N% l7 }
releasing hormone stimulation. This is a sex-linked
9 @+ e( Z6 _; M+ Dautosomal dominant disorder that affects only
u5 F8 G/ U, Y+ x. L" Rmales; therefore, other male members of the family
# p9 p. s6 `# Y/ a& [may have similar precocious puberty.3
- \; T) I9 T* v" M- m% K# Q6 M# sIn our patient, physical examination was incon-
; ?% X8 S2 A7 [- T& S! [sistent with true precocious puberty since his testi-, w x) ~2 F. v
cles were prepubertal in size. However, testotoxicosis
3 Q( ^' t0 F& S7 s3 d! j0 M- Wwas in the differential diagnosis because his father
, Z% l& l8 M! _ S3 @% Ustarted puberty somewhat early, and occasionally,
Y- p* u& m' l9 n) f4 x# Otesticular enlargement is not that evident in the# r6 {9 e. K p
beginning of this process.1 In the absence of a neg-
2 \& L5 m3 U' Z3 b# B( @ative initial history of androgen exposure, our3 n; o6 C$ U/ N) w. r3 M
biggest concern was virilizing adrenal hyperplasia,1 x! A: [" N E& m
either 21-hydroxylase deficiency or 11-β hydroxylase
! Z$ O0 U, E: p1 z: M% Ideficiency. Those diagnoses were excluded by find-
% d2 ~2 `, Y# J9 \" s' ming the normal level of adrenal steroids.+ z. j5 l/ ~. b: Y. f
The diagnosis of exogenous androgens was strongly
' r$ U+ x" B$ h' A( ~' p( c- zsuspected in a follow-up visit after 4 months because( P2 i3 n1 X& Q* G c
the physical examination revealed the complete disap-6 p, D! t& E( @7 U' U: B* \
pearance of pubic hair, normal growth velocity, and& p+ \8 |1 J6 R ^4 [. d
decreased erections. The father admitted using a testos-8 V, @( w0 h0 N( ~/ _
terone gel, which he concealed at first visit. He was
3 h! H- L4 [5 E1 z- i- _using it rather frequently, twice a day. The Physicians’
/ g& Z# {2 p. CDesk Reference, or package insert of this product, gel or8 e' x; C: S% X
cream, cautions about dermal testosterone transfer to: O/ _; \, H. f/ t$ X' m
unprotected females through direct skin exposure.: I8 k& v; |1 B: K W9 l
Serum testosterone level was found to be 2 times the' p$ T% f" l& I5 |% \7 G4 v: M! E! [
baseline value in those females who were exposed to# Y& _) [7 Q I% d* y1 f
even 15 minutes of direct skin contact with their male* u! R/ U) B$ I' t" O% O: C
partners.6 However, when a shirt covered the applica-& U2 f$ u7 b1 y! p
tion site, this testosterone transfer was prevented.
& C: o& z" V ?2 AOur patient’s testosterone level was 60 ng/mL,
- U* C7 u6 S3 I' e% Jwhich was clearly high. Some studies suggest that
7 I& z# `$ Y" X' u3 |, C: Udermal conversion of testosterone to dihydrotestos-
c w1 u6 Q+ ^. M5 ^2 J1 S# Oterone, which is a more potent metabolite, is more
. i( b' B# K! a( H9 a8 H7 N( Kactive in young children exposed to testosterone
# S) z- Z, Q5 \' zexogenously7; however, we did not measure a dihy-
+ P7 D( ]8 f/ S' Odrotestosterone level in our patient. In addition to
" Y. u, ]& z" d* G: \virilization, exposure to exogenous testosterone in% ^5 B& o) ?0 r, y2 m" g$ `
children results in an increase in growth velocity and
% i% M* v3 P/ R. f1 s7 Ladvanced bone age, as seen in our patient.7 p) A U' A# \: P# }6 Y! P
The long-term effect of androgen exposure during
! d5 c, A4 h' y3 Z3 t) Zearly childhood on pubertal development and final3 x# ?' W& L9 B z
adult height are not fully known and always remain2 d; O% o" n( \) N0 R* p7 b: J
a concern. Children treated with short-term testos-5 a5 b2 D! V7 T- S& c
terone injection or topical androgen may exhibit some" Z2 J: k0 s3 o7 \- b' }: A
acceleration of the skeletal maturation; however, after
! Y% c0 p9 T; V8 S4 D1 Ocessation of treatment, the rate of bone maturation
! c9 F/ W3 \+ l! j) {decelerates and gradually returns to normal.8,9
" W7 H! I1 J" I2 r" o }! Z5 nThere are conflicting reports and controversy
7 q& Y( f( | u+ ^over the effect of early androgen exposure on adult
7 U4 z) }) p3 Cpenile length.10,11 Some reports suggest subnormal
* J" w$ [5 w9 X9 R, F( tadult penile length, apparently because of downreg-
( c* y2 R! t" Z" `! U7 Xulation of androgen receptor number.10,12 However,
* U$ @4 G r& Y# i& ]Sutherland et al13 did not find a correlation between% J0 E. Y; ^& Y( x- I
childhood testosterone exposure and reduced adult# n. J5 O" P4 I- H4 F
penile length in clinical studies.
) i1 G! B0 Y8 ]7 q# ^Nonetheless, we do not believe our patient is
+ Q6 N& P$ q: n7 ^/ p* hgoing to experience any of the untoward effects from
" d2 ^6 r* f* u% p R3 C2 Etestosterone exposure as mentioned earlier because u* b: S( l4 s8 v) \
the exposure was not for a prolonged period of time.
4 p% c6 K9 k' ^! NAlthough the bone age was advanced at the time of
, s) B; P5 a; {* d7 O4 e4 Ydiagnosis, the child had a normal growth velocity at
5 j! ^5 ^2 v l, T; Y% ythe follow-up visit. It is hoped that his final adult5 p& Q0 ]5 [, l1 e8 L5 p% t
height will not be affected.
' T( [& Y2 Z' f7 N$ BAlthough rarely reported, the widespread avail-
8 Y1 T3 v0 |0 g& Q& X; d$ iability of androgen products in our society may
% p# p0 U, S2 e( E; Cindeed cause more virilization in male or female. B& E8 P' j" s7 m# D' [
children than one would realize. Exposure to andro-
- ~' d) i+ Y2 E8 P/ h/ l6 `& Ogen products must be considered and specific ques-
: Z4 P3 l/ g/ [+ _tioning about the use of a testosterone product or( ]. {$ x+ `5 H% ^$ x2 }" Z r: f
gel should be asked of the family members during% w# V3 V# }5 G: [, j# f
the evaluation of any children who present with vir-: ~; o/ p6 Q$ g
ilization or peripheral precocious puberty. The diag-
0 {2 k; P& A, p* k) y P0 `* Dnosis can be established by just a few tests and by
1 W' |( T _5 @0 Uappropriate history. The inability to obtain such a7 k# c) H5 E7 `; g5 |. W/ V
history, or failure to ask the specific questions, may
% _1 C/ i% s. D* }result in extensive, unnecessary, and expensive
+ X! Z( g4 r0 k& tinvestigation. The primary care physician should be
/ P1 W& Z( b% L2 s/ E5 iaware of this fact, because most of these children
4 B( ^8 H% R" k' r$ [may initially present in their practice. The Physicians’
3 r1 b+ E- g [$ B) l# M% j% l2 ODesk Reference and package insert should also put a
! N5 F; k; k) ^1 m1 w" ` ~, Q) |2 Kwarning about the virilizing effect on a male or! x7 b7 b0 V! U5 e
female child who might come in contact with some-6 G0 B5 B- D; S
one using any of these products.
9 j' q9 r9 b) }# k9 VReferences3 A1 K; C: H: P/ O( j
1. Styne DM. The testes: disorder of sexual differentiation
s2 w1 I; v- Z, land puberty in the male. In: Sperling MA, ed. Pediatric8 @9 z& ]: ~, G% y7 F2 Q' L, L
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;: l; Z& n1 F: p& U: z6 T
2002: 565-628.- N+ ]3 u- ?0 B. y* A, n
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
/ p' B2 v9 C2 w7 Ppuberty in children with tumours of the suprasellar pineal |
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