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Sexual Precocity in a 16-Month-Old
/ |$ z1 ]8 j. V8 y* `Boy Induced by Indirect Topical
, M* C9 c `- s! e9 ZExposure to Testosterone
' b3 I0 E/ I6 G+ fSamar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
% Q' h" O3 s8 A: i$ Y4 ]and Kenneth R. Rettig, MD1. s- l, \: h2 J
Clinical Pediatrics
6 _' i) r8 A& D( u5 ]) H, D% S0 iVolume 46 Number 6
6 Y) _9 }) O0 q3 z( sJuly 2007 540-543
" p' W2 W8 k# P& D0 _7 m8 F' j© 2007 Sage Publications
9 u1 ~. z7 b5 C0 H* [10.1177/0009922806296651
( A X$ } W* w$ K$ P; k: ^http://clp.sagepub.com
! I' H; o( n7 e3 v: ^7 Nhosted at
; u! ?; R' f, m% S* vhttp://online.sagepub.com
5 ?% x' E1 T6 nPrecocious puberty in boys, central or peripheral,9 ^) ^, r& w" b2 z9 ?# ^5 ~
is a significant concern for physicians. Central1 ^7 Q# k8 A5 }" c' m* A
precocious puberty (CPP), which is mediated6 \2 `9 n ^) V6 s# s+ U2 N
through the hypothalamic pituitary gonadal axis, has
2 u; }0 {+ p8 X- A; r; f9 }0 ua higher incidence of organic central nervous system& G4 U r9 Y; u0 S5 M5 P6 \
lesions in boys.1,2 Virilization in boys, as manifested
; @! U0 A8 O1 q2 eby enlargement of the penis, development of pubic7 ?! Z9 x& u. E0 p
hair, and facial acne without enlargement of testi-
3 ]) w) R1 e. l7 B) c. d3 m. [$ h7 Hcles, suggests peripheral or pseudopuberty.1-3 We* E5 M. O) B* G$ u- v
report a 16-month-old boy who presented with the: L6 C! v9 n2 I, G
enlargement of the phallus and pubic hair develop-! d3 q; X/ N5 u1 U/ S7 S* c
ment without testicular enlargement, which was due( C% E- L; `" x& n3 r; x
to the unintentional exposure to androgen gel used by
# z! w; }. V5 u: m1 C) d% R8 ithe father. The family initially concealed this infor-
; n ], z& F" r! @mation, resulting in an extensive work-up for this
+ _! n3 L' m5 \+ bchild. Given the widespread and easy availability of9 R+ x; J8 C5 q9 `" G
testosterone gel and cream, we believe this is proba-
8 R6 r1 t# x& jbly more common than the rare case report in the; y& I6 P4 r' R6 G& i [
literature.4
3 F7 W3 s' K5 E7 O1 U A7 ]7 n, ^Patient Report
! D6 J t8 b. T3 {- r0 B1 XA 16-month-old white child was referred to the% N' D# \1 T6 p5 E
endocrine clinic by his pediatrician with the concern
) t8 R; ]$ Z+ q' S' uof early sexual development. His mother noticed4 f+ c4 o9 F/ \/ U& ]( ~# V: c
light colored pubic hair development when he was! D/ C0 }0 v/ Z& ~8 f- y: [) o9 g r- v
From the 1Division of Pediatric Endocrinology, 2University of9 q. P* s; j+ Y
South Alabama Medical Center, Mobile, Alabama.
: E( ~! r' b! h# g$ W; OAddress correspondence to: Samar K. Bhowmick, MD, FACE,3 m% m; B) C) T [3 E; p
Professor of Pediatrics, University of South Alabama, College of" z' [8 h* W; H1 y7 V6 \
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;) M" }) g4 Q) F% W
e-mail: [email protected].* C& u1 F9 _( z
about 6 to 7 months old, which progressively became' ^5 N) W& h ?, h- R1 m6 j
darker. She was also concerned about the enlarge-
# c) [8 ~' T$ w1 ]ment of his penis and frequent erections. The child" i$ V4 y1 b, V7 [
was the product of a full-term normal delivery, with9 p. c: a3 o3 }/ B5 P
a birth weight of 7 lb 14 oz, and birth length of
: N3 M' x- y% y. n20 inches. He was breast-fed throughout the first year; v: L6 u* j5 o- _" r0 O( ], p
of life and was still receiving breast milk along with
6 w: R* f+ D" x/ \solid food. He had no hospitalizations or surgery,& K! `4 |7 x1 E [) N: G- r) D& D
and his psychosocial and psychomotor development
/ k( i. k8 G' ]* f+ S. Vwas age appropriate.
/ R# S/ M) z+ p4 C8 ~The family history was remarkable for the father,0 ^3 u' b0 V, d. [8 v, n
who was diagnosed with hypothyroidism at age 16,& E; W/ C/ @- j& _ Q" n* h% M
which was treated with thyroxine. The father’s& ]) V% x- r0 Q: `7 ?6 D
height was 6 feet, and he went through a somewhat* x7 v0 {6 ~- P0 g' C
early puberty and had stopped growing by age 14.4 ]7 F1 d: f- d' m/ q; Q5 H
The father denied taking any other medication. The
9 H4 B( K) X0 _' cchild’s mother was in good health. Her menarche: `" K% s+ e+ b. Y$ U: r
was at 11 years of age, and her height was at 5 feet
/ F1 b/ C" @6 Z# y$ O, q' \5 inches. There was no other family history of pre-
" ?$ K1 |( t4 q% Qcocious sexual development in the first-degree rela-5 H" u+ M3 z; n
tives. There were no siblings./ C" h4 l( V0 b
Physical Examination
% n9 @3 U! M$ L9 KThe physical examination revealed a very active,. X2 Y( z0 R( N/ L' `$ [6 \6 N
playful, and healthy boy. The vital signs documented/ S& n* w9 J, ?5 m' {! p
a blood pressure of 85/50 mm Hg, his length was
* k+ n4 u; C( B0 x8 ?7 T( M: \90 cm (>97th percentile), and his weight was 14.4 kg9 u9 a6 G8 l! W' M/ A+ ^
(also >97th percentile). The observed yearly growth
' r6 P9 t b. j2 g- }velocity was 30 cm (12 inches). The examination of% {$ g% B8 ]# P/ o
the neck revealed no thyroid enlargement.
7 V( ` q' s/ Z$ F6 LThe genitourinary examination was remarkable for4 }! k0 c! S p8 c
enlargement of the penis, with a stretched length of7 n e5 a6 D1 W- W& G2 c
8 cm and a width of 2 cm. The glans penis was very well
" t) `" X! M* M( h8 Vdeveloped. The pubic hair was Tanner II, mostly around
. ^. ]+ G* m1 j7 F. i5 f7 s* k; ^540
- [1 t- ]6 o6 E) Iat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from3 B# d6 g, X" B1 s G X" _. U+ ?& I7 {
the base of the phallus and was dark and curled. The* ?! n) U3 D) W, }+ e X5 Y1 _1 |
testicular volume was prepubertal at 2 mL each.
+ F' J7 j' |$ f% }, |; q/ IThe skin was moist and smooth and somewhat
7 q- l5 A. n+ B5 e6 V- c& Goily. No axillary hair was noted. There were no! ?1 i+ S2 T1 w) n: o2 o
abnormal skin pigmentations or café-au-lait spots./ L' s- r! g* J8 P8 D( W g
Neurologic evaluation showed deep tendon reflex 2+! c+ P4 y7 X2 `) | B" E: _% D) y; u
bilateral and symmetrical. There was no suggestion
# p; x7 ]2 {$ Yof papilledema., ^6 m0 O6 [ G, U3 O6 q
Laboratory Evaluation
( E! E5 M& H fThe bone age was consistent with 28 months by6 t. K0 p; W) i u
using the standard of Greulich and Pyle at a chrono-
/ i" q% u6 O. L" F7 s$ o9 xlogic age of 16 months (advanced).5 Chromosomal! k( N. z5 ]5 j G6 T
karyotype was 46XY. The thyroid function test
) z# s! X$ ?4 N+ Hshowed a free T4 of 1.69 ng/dL, and thyroid stimu-- T. t7 E' R4 r' N, U% {
lating hormone level was 1.3 µIU/mL (both normal).
, j$ {6 r) R( ~2 e: Z% lThe concentrations of serum electrolytes, blood8 B- @! d4 _8 S' v; a- `; }. C" Y
urea nitrogen, creatinine, and calcium all were. w% s, e C; a2 t# u3 B# c: L
within normal range for his age. The concentration
& g) ?# M) s! E5 a. P/ s. u# @of serum 17-hydroxyprogesterone was 16 ng/dL
2 ~/ ~4 b2 f' `- S/ ](normal, 3 to 90 ng/dL), androstenedione was 20
7 l# l* A1 ^. ~' eng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-& x0 b x1 c% i& m% O) L7 z$ F% L2 b
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
5 k4 W/ i7 c$ ^( [" o: [desoxycorticosterone was 4.3 ng/dL (normal, 7 to
4 E: u4 [4 @& a P v8 Y49ng/dL), 11-desoxycortisol (specific compound S)
9 P6 T- |: c8 p _was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
% L- S7 i( V, } t! Mtisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total1 N4 V, T" q: \; ` j; o
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
, V5 c% J I" Z; X2 Kand β-human chorionic gonadotropin was less than$ B5 a/ z* A+ P D2 y+ b" V+ `
5 mIU/mL (normal <5 mIU/mL). Serum follicular
( ]' c0 B3 j# ~8 r' n4 }8 ostimulating hormone and leuteinizing hormone
7 p1 x2 O. Y- ^9 ]! Lconcentrations were less than 0.05 mIU/mL2 W6 F6 ]; q7 l. P
(prepubertal).
3 Z1 h2 b( B/ s/ Y# O/ dThe parents were notified about the laboratory! J( J* F' `! S% r8 N$ ?% r
results and were informed that all of the tests were
7 `; f- V p* W- e9 k1 }; Lnormal except the testosterone level was high. The
7 h4 C3 O7 K" T. x9 H6 \follow-up visit was arranged within a few weeks to4 B7 w4 O" P0 w) i& N
obtain testicular and abdominal sonograms; how-
( k4 Q. m9 `/ |! \' \ever, the family did not return for 4 months.
/ S- m6 v% \1 w- s* h, b) v" O: y" oPhysical examination at this time revealed that the ]! \9 E0 L9 T, v
child had grown 2.5 cm in 4 months and had gained
1 x/ K3 h2 E6 i7 ?9 M2 kg of weight. Physical examination remained
8 y1 ?% f3 o3 I7 @' J) N9 lunchanged. Surprisingly, the pubic hair almost com-2 X b$ b) B2 G7 I9 [
pletely disappeared except for a few vellous hairs at3 T9 K) c D7 n+ y0 m9 B; o# O
the base of the phallus. Testicular volume was still 2
1 S! A& I8 p/ M P* |" A7 K' emL, and the size of the penis remained unchanged.
9 @7 `$ m1 k) W9 `The mother also said that the boy was no longer hav-
, b* m+ I) l' u) s6 ging frequent erections.
( _$ z9 I9 U# {Both parents were again questioned about use of% \3 R5 r7 ]3 o+ j0 G, F
any ointment/creams that they may have applied to2 j) B% s# d9 v9 \
the child’s skin. This time the father admitted the+ f( O. H4 G, m6 ?
Topical Testosterone Exposure / Bhowmick et al 541
. |; A+ x; U/ @use of testosterone gel twice daily that he was apply-* U4 S) N- ~8 c2 N5 B1 p
ing over his own shoulders, chest, and back area for6 [7 w- L7 U* ~, A8 e/ o
a year. The father also revealed he was embarrassed( c" V* r. I) |5 O- Y
to disclose that he was using a testosterone gel pre-
& k& ?9 [( n/ y2 fscribed by his family physician for decreased libido
! { _; q3 m4 X! Z, M$ K% ysecondary to depression.
2 s! D m1 R% ]3 bThe child slept in the same bed with parents.6 x* j; C, \# ]9 \) p
The father would hug the baby and hold him on his
) k% Q/ J u% r$ U& z8 jchest for a considerable period of time, causing sig-
: M4 h( i4 O) t- j# `nificant bare skin contact between baby and father.
. k1 k' L8 U' _3 `2 a! X# DThe father also admitted that after the phone call,
$ ]8 I1 V, g- c# m2 p/ Kwhen he learned the testosterone level in the baby
9 V1 ]& v! l! q4 j; }% H3 twas high, he then read the product information
& I9 ]" ]9 Z( Zpacket and concluded that it was most likely the rea-/ w' W- z; }( @6 g% @1 E
son for the child’s virilization. At that time, they
' C. R6 |! U$ S. r& T) _decided to put the baby in a separate bed, and the/ y& J$ e w0 B: [
father was not hugging him with bare skin and had U' N, o; Q/ R1 l8 @1 E- A5 r
been using protective clothing. A repeat testosterone) n/ m& I- p8 X
test was ordered, but the family did not go to the! \8 x+ X4 h& `! }! E V b
laboratory to obtain the test.6 E& n5 E" `& _
Discussion
) V( k' t% @; n! e) y& MPrecocious puberty in boys is defined as secondary
. ]0 L! m6 P& l# Nsexual development before 9 years of age.1,4$ Q; b& I9 Q7 v$ x' l, D. i Y2 ^: a
Precocious puberty is termed as central (true) when
8 \7 h' E; v8 s( qit is caused by the premature activation of hypo-
( s) |- T) s% F8 Q+ r+ w7 kthalamic pituitary gonadal axis. CPP is more com-5 T' B$ G' X9 c/ h+ b5 |* K
mon in girls than in boys.1,3 Most boys with CPP
) H( C, v, f, X$ i; \+ gmay have a central nervous system lesion that is
- q6 a4 n' Y0 B% f# ^responsible for the early activation of the hypothal-
% s4 F- u( ~6 G; u# q3 oamic pituitary gonadal axis.1-3 Thus, greater empha-6 C. v. I! t- G1 D$ N
sis has been given to neuroradiologic imaging in. i9 f, m. h3 N; s7 D: E) h+ K
boys with precocious puberty. In addition to viril-
5 m/ e* ^ ~+ r* X4 dization, the clinical hallmark of CPP is the symmet-
& t& C. N Z2 i8 u. W) Y1 r Xrical testicular growth secondary to stimulation by
: C5 A# d1 {* K6 Z; agonadotropins.1,3) f6 o* ~9 }" m9 q- L
Gonadotropin-independent peripheral preco-
. O0 r9 N8 D8 {cious puberty in boys also results from inappropriate
5 n, U( _3 ? `* r0 oandrogenic stimulation from either endogenous or
% [& O% @* }3 z$ Sexogenous sources, nonpituitary gonadotropin stim-7 v. d: _; D; b/ J5 o( m
ulation, and rare activating mutations.3 Virilizing* P3 ]. Y4 H# A5 _) o% z
congenital adrenal hyperplasia producing excessive
, Y" e# ?- x& P( f) k0 Iadrenal androgens is a common cause of precocious
2 K, @$ B" x! f2 t6 N9 cpuberty in boys.3,4
7 M. I: h- S3 dThe most common form of congenital adrenal8 T) ]4 D9 B" R7 y8 l
hyperplasia is the 21-hydroxylase enzyme deficiency.5 h8 Z" y2 E9 [4 O( N
The 11-β hydroxylase deficiency may also result in
* X# m# a) P( j. w6 P& [+ D/ cexcessive adrenal androgen production, and rarely,/ O+ S( _5 G; g" K
an adrenal tumor may also cause adrenal androgen2 p3 d' Y; v+ C
excess.1,3/ ~( v0 o2 p+ ~3 T# M
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, w6 H: f7 G( C3 r
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007! U: E( I4 ?5 h( |+ Y
A unique entity of male-limited gonadotropin-
5 e P0 S, I, Z" {8 Rindependent precocious puberty, which is also known4 ]3 ?. x" f; G. z0 f1 e9 [
as testotoxicosis, may cause precocious puberty at a
2 j: k" @* S% @5 i; l8 R" ?very young age. The physical findings in these boys; N' K2 e' x% k, q
with this disorder are full pubertal development,+ @, d& R/ i4 X( R
including bilateral testicular growth, similar to boys
/ @) g0 l$ G# Y) O. Iwith CPP. The gonadotropin levels in this disorder0 a# ]* N& N& \7 Z1 {/ d+ y
are suppressed to prepubertal levels and do not show
4 a% i4 I6 [* E* H+ b7 bpubertal response of gonadotropin after gonadotropin-
3 C1 o6 ?9 Q: O2 z: L' _5 m1 Ireleasing hormone stimulation. This is a sex-linked
: M% S% K7 W& S- C/ Xautosomal dominant disorder that affects only
! d1 E3 d6 h9 e* Q: Smales; therefore, other male members of the family
0 l3 j8 Q" F; k3 b# t; g9 ]may have similar precocious puberty.3
8 S% S2 n5 K9 E4 ]In our patient, physical examination was incon-
H5 Y3 Q N0 Dsistent with true precocious puberty since his testi-$ D* I3 b5 i/ `! c' l( A, R
cles were prepubertal in size. However, testotoxicosis
0 S- W9 B* k! z) f1 Nwas in the differential diagnosis because his father/ @8 H" F' L$ z7 }# g
started puberty somewhat early, and occasionally,, g$ X. K7 P4 [# U
testicular enlargement is not that evident in the }1 ?0 r: w/ O& b4 T. X
beginning of this process.1 In the absence of a neg-
5 B) r9 }2 e/ o9 Uative initial history of androgen exposure, our: z/ ?; t% [4 H1 T7 a, q2 c
biggest concern was virilizing adrenal hyperplasia,
( ~& Q' C8 O: ^9 _. |/ ^/ z, p, p2 Peither 21-hydroxylase deficiency or 11-β hydroxylase
+ _. ], @0 z. O' ?deficiency. Those diagnoses were excluded by find-
% X3 ^* T& K$ d$ x* \ing the normal level of adrenal steroids.
9 e' o, [. R! g! o- W* n! e: e- b( ^The diagnosis of exogenous androgens was strongly u0 t# T. s7 r2 m
suspected in a follow-up visit after 4 months because
, U- i) U0 u+ f8 O, O* w. |the physical examination revealed the complete disap-; I: T5 z, e2 D5 N! C5 i4 |
pearance of pubic hair, normal growth velocity, and
+ a% K. y* C2 V# n; A/ vdecreased erections. The father admitted using a testos-
( Y6 n1 y' n" L5 u, l3 lterone gel, which he concealed at first visit. He was+ c+ I" h, z* H+ l3 v3 q
using it rather frequently, twice a day. The Physicians’* B- K! b M6 c" _2 E1 w- d5 ~3 ?
Desk Reference, or package insert of this product, gel or1 P3 D) w; B, M
cream, cautions about dermal testosterone transfer to
8 c' n! Z) M+ c7 ounprotected females through direct skin exposure.
. t0 B J) |7 zSerum testosterone level was found to be 2 times the
! [3 u+ n1 i" T1 u5 `. y1 k Gbaseline value in those females who were exposed to
) C$ b* y; P& P* }( \even 15 minutes of direct skin contact with their male% v/ R: [) r) U7 n6 K/ s
partners.6 However, when a shirt covered the applica-
) K- b, k# a0 @9 N3 ftion site, this testosterone transfer was prevented.
* s" z; s! B$ O* xOur patient’s testosterone level was 60 ng/mL,9 s8 L+ J b0 l
which was clearly high. Some studies suggest that
+ q/ m, I* l" T2 \1 Idermal conversion of testosterone to dihydrotestos-
9 i! U- Z2 {+ y+ ?terone, which is a more potent metabolite, is more
8 F# S1 e! T+ B6 @active in young children exposed to testosterone: P3 o' N- ]8 V# e' Q
exogenously7; however, we did not measure a dihy-' O' e S9 _# @7 t9 s7 N' a9 S& }9 r5 ]
drotestosterone level in our patient. In addition to6 j, x. N; ~( _( R2 F
virilization, exposure to exogenous testosterone in
- H% t7 O4 ? D4 Ychildren results in an increase in growth velocity and3 ~. x: J. S' ~$ ^
advanced bone age, as seen in our patient.( L2 n! D- I. ~+ g4 ~+ }" d3 @( k5 Y
The long-term effect of androgen exposure during
+ o8 I/ J; ?5 K- |. @9 |5 o, Q; ?early childhood on pubertal development and final* e K2 i" h; M+ g1 v- K8 l
adult height are not fully known and always remain6 N, _. c6 T/ g% Z7 s4 V1 e( G
a concern. Children treated with short-term testos-
6 F- P& y! ]7 N! U# q2 jterone injection or topical androgen may exhibit some
5 R- v2 E; A& [' _acceleration of the skeletal maturation; however, after' d- N! `' D: [- N; p: L
cessation of treatment, the rate of bone maturation
3 T7 M$ f V, o, \" N( b. a( m1 adecelerates and gradually returns to normal.8,9- A5 E! E6 z/ C8 i) x; b, s5 }, m
There are conflicting reports and controversy
+ r( V4 ^1 q8 k8 u) K" Wover the effect of early androgen exposure on adult- R9 X! o9 K% t+ ~5 d+ C7 l! i
penile length.10,11 Some reports suggest subnormal% K8 [& Q& x: S7 v
adult penile length, apparently because of downreg-% @. f0 L5 e( Y$ k" h9 r @
ulation of androgen receptor number.10,12 However,
' f$ _8 P& A! h" M' R& Y% zSutherland et al13 did not find a correlation between
4 N" L, u" b3 h) R0 m0 echildhood testosterone exposure and reduced adult
* a+ B" O8 N% Y' tpenile length in clinical studies.* J5 c/ T) @/ b P; |. C2 o
Nonetheless, we do not believe our patient is
1 z+ N! l+ J& q1 r2 S3 Z. f# D4 Fgoing to experience any of the untoward effects from
1 R v4 O" M) M4 otestosterone exposure as mentioned earlier because
5 F4 J! A$ I5 G5 Q vthe exposure was not for a prolonged period of time.
, G( [5 e& h/ o* q: eAlthough the bone age was advanced at the time of7 ]6 Q+ G" M8 A: W, U
diagnosis, the child had a normal growth velocity at$ c& J3 R# b3 Y* u5 Y/ z& [- z
the follow-up visit. It is hoped that his final adult8 }2 C9 V8 _& A# r1 W$ n
height will not be affected.4 J. n& P2 T( A* r( \. Y
Although rarely reported, the widespread avail-
1 I% N% V" L. zability of androgen products in our society may
! u# Q0 l/ W' D* a9 F) ?indeed cause more virilization in male or female
9 B8 _8 I3 b: P. x" t$ k# Uchildren than one would realize. Exposure to andro-$ Z4 W+ l5 G j* C
gen products must be considered and specific ques-
& W! H4 ^; A: p/ L9 ytioning about the use of a testosterone product or
: }- H8 ^% U! b0 y7 O2 M, K6 k. Wgel should be asked of the family members during
! O% f( |& N$ O" f/ h; w- cthe evaluation of any children who present with vir-
, W/ _; S0 e$ H8 S) s4 kilization or peripheral precocious puberty. The diag-
& L% ^* B% _7 @: u4 x# ~nosis can be established by just a few tests and by- d+ Q4 I( J( o: G: k+ w
appropriate history. The inability to obtain such a* N+ M; S) e3 h: ?7 u( i
history, or failure to ask the specific questions, may
) q9 s5 ]) z6 O) W m8 Presult in extensive, unnecessary, and expensive! A* T2 c3 f# x" p) C) M6 F
investigation. The primary care physician should be7 T$ M# P4 U+ v" K% V ]
aware of this fact, because most of these children
) ~, Y8 J5 @$ W: x e/ V5 }8 G6 p/ G) Cmay initially present in their practice. The Physicians’
+ Q" v0 Q0 J, a0 g2 P" A3 VDesk Reference and package insert should also put a& ]" D2 i# M! i% \
warning about the virilizing effect on a male or3 ~8 ~' r% W* u+ M- c" q! N
female child who might come in contact with some-+ i: e8 s4 j5 n+ ~" L5 g
one using any of these products.9 m% i J4 T8 E. B; J$ q4 a6 W$ n
References: M# r7 S/ n2 d7 j
1. Styne DM. The testes: disorder of sexual differentiation
- _% H2 [8 K0 q2 `- Band puberty in the male. In: Sperling MA, ed. Pediatric
- r F( y0 j' q' R, \6 ?2 HEndocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
. ^ j& o' ]& v: s2002: 565-628.! r7 X5 x7 t+ \
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious5 E s! C& j8 \8 V3 D
puberty in children with tumours of the suprasellar pineal |
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