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Sexual Precocity in a 16-Month-Old C: Z, \% N( e2 A7 K7 c4 I" \
Boy Induced by Indirect Topical
9 g/ F/ }. f" }8 c2 ^; ?7 nExposure to Testosterone) f8 F A( u8 I+ V3 ~
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2; ?: W# E$ E. |! N4 h0 F3 V7 Q* r
and Kenneth R. Rettig, MD1% w$ b2 J( V) T$ j) Q O
Clinical Pediatrics
' }# Z5 d" [, [' i* FVolume 46 Number 6
- c) b3 u, h- @/ |: e/ ?July 2007 540-543
3 u# w' _9 L9 T© 2007 Sage Publications- B% N Y2 J6 d; a
10.1177/0009922806296651' m$ h8 ?, g& r. H
http://clp.sagepub.com% K3 T9 b# H1 d
hosted at3 J4 j/ d l& I9 \2 ?) C% o) I
http://online.sagepub.com
% E' r2 I6 c& G3 [1 _ B# ~Precocious puberty in boys, central or peripheral,6 P: v7 s2 Z( ^2 Y% o! E" G
is a significant concern for physicians. Central
k. t4 v+ ~5 u5 W, Z v; Dprecocious puberty (CPP), which is mediated
+ q1 ]: u5 d/ `% a0 q0 Wthrough the hypothalamic pituitary gonadal axis, has
& ^/ M% E; q, S, m4 ja higher incidence of organic central nervous system j9 P6 u( V k, G& g: O4 a5 |
lesions in boys.1,2 Virilization in boys, as manifested2 f% t4 |* F3 R9 Q. V. G, A
by enlargement of the penis, development of pubic; X$ S4 w2 Q* K
hair, and facial acne without enlargement of testi-3 M5 H6 l4 \. M' U% y3 \
cles, suggests peripheral or pseudopuberty.1-3 We
' p( L% n H r' greport a 16-month-old boy who presented with the7 ~& E6 Y" e4 ?5 N5 }# X$ |8 L
enlargement of the phallus and pubic hair develop-; `! H' [% r/ s' n7 b( v" E
ment without testicular enlargement, which was due
# ~0 \9 C" Y' ?2 rto the unintentional exposure to androgen gel used by
8 J% l3 V1 w) W/ @. i) Gthe father. The family initially concealed this infor-: t0 ]" X7 a; O8 y% ~" T
mation, resulting in an extensive work-up for this
' K! z8 \4 O7 M, r6 [) uchild. Given the widespread and easy availability of
/ w+ F8 T" i- e3 l0 Wtestosterone gel and cream, we believe this is proba-
1 r* m7 N3 ?, L$ }bly more common than the rare case report in the/ v; v6 k( H2 A7 L+ S9 }3 ?
literature.4
Z7 W$ y( u3 f$ ^/ K; e0 ~Patient Report" S3 ^: [+ \6 q9 o" k0 G4 W' M& o
A 16-month-old white child was referred to the( t5 U2 ]. c; c( ?& i8 ?
endocrine clinic by his pediatrician with the concern+ `! H# d1 L& O g, P8 o0 X
of early sexual development. His mother noticed
+ y1 o% ~* B# j! \light colored pubic hair development when he was
1 h/ Y0 }8 Q6 L7 q- Z4 pFrom the 1Division of Pediatric Endocrinology, 2University of
8 G3 y v; f6 v3 }* pSouth Alabama Medical Center, Mobile, Alabama.
/ [8 L. n, P: V# \# M) ^9 \Address correspondence to: Samar K. Bhowmick, MD, FACE,1 A C. R3 p3 l& S2 e$ Z2 Y& y- D
Professor of Pediatrics, University of South Alabama, College of8 l0 E' ]3 Q! h* W& N
Medicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;3 C' r" z: _' s
e-mail: [email protected].
# C* C, s; l* N2 Q- P Aabout 6 to 7 months old, which progressively became
1 M2 g; @. }# V- ?/ g; W- Ddarker. She was also concerned about the enlarge-
# u' ]8 f) v; `! ]3 |3 {ment of his penis and frequent erections. The child
7 m2 x% ?. l8 P; Rwas the product of a full-term normal delivery, with3 B% Q. k1 m+ \! l1 p
a birth weight of 7 lb 14 oz, and birth length of% R C" t8 Q9 Y- r N
20 inches. He was breast-fed throughout the first year8 c7 E/ S6 B9 f2 K! N F
of life and was still receiving breast milk along with& N. _9 }: R# I; X8 {/ ^ m9 Z
solid food. He had no hospitalizations or surgery,
2 G$ z3 ?: K0 M Z5 N- `8 o; h+ Rand his psychosocial and psychomotor development( i. a+ {( x7 K9 B' G4 h, J) u/ q& @
was age appropriate.
. {! C/ t. b) [/ [The family history was remarkable for the father,
/ V: e# q! \' _who was diagnosed with hypothyroidism at age 16,2 S b# Q* p2 k0 u4 D0 }3 G
which was treated with thyroxine. The father’s
; L$ }( A7 M9 W' p5 ?" ~6 }5 Jheight was 6 feet, and he went through a somewhat
. L$ K! R7 c' b( iearly puberty and had stopped growing by age 14.
) u& g$ w' O, G# f9 o. G- iThe father denied taking any other medication. The/ c6 u' {, l9 S1 I1 m1 J
child’s mother was in good health. Her menarche) P3 _' m6 y" ?9 A
was at 11 years of age, and her height was at 5 feet
1 K( O& _/ K$ i% Y5 @5 inches. There was no other family history of pre-
" {6 F" c# o2 l; l+ ]cocious sexual development in the first-degree rela-. J5 C) L8 m2 u1 E7 \
tives. There were no siblings.
$ |2 _: I8 h/ b1 f; E7 P7 T" APhysical Examination
W o% q6 D0 v- }( U: D# WThe physical examination revealed a very active,
\* Y& ?- C" J" P$ _playful, and healthy boy. The vital signs documented% V2 c: L3 Y* m% s
a blood pressure of 85/50 mm Hg, his length was- ~* n6 H+ @ d8 J: Y6 S" j; S# ?2 P" T
90 cm (>97th percentile), and his weight was 14.4 kg* ^% R- M" M% R* I
(also >97th percentile). The observed yearly growth
" _9 l. U j& s4 Gvelocity was 30 cm (12 inches). The examination of
2 j) y: @2 z& k9 I$ H% q* S8 f. J: Cthe neck revealed no thyroid enlargement.
: w+ H+ H) F" b& K8 _The genitourinary examination was remarkable for+ D# D Y( G1 t! K0 Q
enlargement of the penis, with a stretched length of
& s: }9 G7 ?6 O8 cm and a width of 2 cm. The glans penis was very well) O' `1 `8 K: l; T* H
developed. The pubic hair was Tanner II, mostly around0 Y/ j9 |9 h4 O6 n o, F
5400 @; @) F" F' V* D+ {
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the base of the phallus and was dark and curled. The6 B! w: y$ F% C
testicular volume was prepubertal at 2 mL each.& [6 f. K6 c+ z* b* m
The skin was moist and smooth and somewhat5 q- ]& }4 K9 h7 G) p
oily. No axillary hair was noted. There were no
, J/ _+ b: ^/ G; B% u' zabnormal skin pigmentations or café-au-lait spots.$ F, \' X9 L8 m0 M' t9 u$ m
Neurologic evaluation showed deep tendon reflex 2+
) @) {% t3 g! p* q0 Tbilateral and symmetrical. There was no suggestion
8 F6 h+ i2 C7 V+ b L1 yof papilledema.) a+ U9 d& o- d0 m
Laboratory Evaluation
0 _9 B8 u8 C: o- W5 j/ F0 B4 eThe bone age was consistent with 28 months by
. p+ Z2 `1 _7 R" ], n9 l6 fusing the standard of Greulich and Pyle at a chrono-
6 j/ A7 ^. `4 S& l2 rlogic age of 16 months (advanced).5 Chromosomal
# A( r+ R' C1 p. mkaryotype was 46XY. The thyroid function test
% t- T9 F: H' F9 u C! {% {0 Pshowed a free T4 of 1.69 ng/dL, and thyroid stimu-3 W# Z: u$ t& [ C
lating hormone level was 1.3 µIU/mL (both normal).
" Z: K% p7 J4 t rThe concentrations of serum electrolytes, blood1 _/ ?, I3 \) `7 W1 P, B
urea nitrogen, creatinine, and calcium all were& n% T" u; `2 V: e4 l; Z
within normal range for his age. The concentration
6 H; _/ H% M; e8 ?of serum 17-hydroxyprogesterone was 16 ng/dL
# i! S* ~/ o$ y(normal, 3 to 90 ng/dL), androstenedione was 20" ~- t/ J' Y0 T F, V
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
7 f1 V7 F- r! I* l% m( p I* Kterone was 38 ng/dL (normal, 50 to 760 ng/dL),
- K- y0 l* t3 xdesoxycorticosterone was 4.3 ng/dL (normal, 7 to
1 X* H+ x n/ H2 m- t49ng/dL), 11-desoxycortisol (specific compound S)7 ?% i @) y. Y [
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-. ~4 J" A( a- \' [( G5 m/ {
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total+ T6 ~: }- [( G9 v' c1 V
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),
6 K0 N) a; c4 K4 z B0 {and β-human chorionic gonadotropin was less than; Y* w2 X- g4 i# o& B2 V
5 mIU/mL (normal <5 mIU/mL). Serum follicular# J% b' {+ A# m/ a9 ?! a
stimulating hormone and leuteinizing hormone
! K3 E2 X. A$ Bconcentrations were less than 0.05 mIU/mL
. _) Y( ~# o+ {$ A% U6 m7 E7 U2 F" o(prepubertal).% ^4 v5 e! j T7 l# d, R4 v
The parents were notified about the laboratory
5 a- x+ q8 ?5 eresults and were informed that all of the tests were
( J( h) m" e5 u5 u K2 Cnormal except the testosterone level was high. The
. j3 W; C8 H3 s5 \- n- f6 Mfollow-up visit was arranged within a few weeks to
5 v9 }! J% A0 {8 g( I) T `obtain testicular and abdominal sonograms; how-
! g6 n8 `! `# C$ p+ L! a" ^ever, the family did not return for 4 months.
- v' c+ n& ^$ A/ R) w: cPhysical examination at this time revealed that the1 h1 w2 u. b' ^- D, N
child had grown 2.5 cm in 4 months and had gained
( {& l' {; N! v+ j5 I2 kg of weight. Physical examination remained/ }- J4 Q' C2 ]' t! ^% l$ `& Z
unchanged. Surprisingly, the pubic hair almost com-
1 F% _ [4 r* Kpletely disappeared except for a few vellous hairs at$ e& i8 H7 q4 X& L
the base of the phallus. Testicular volume was still 2& [: \9 F$ b3 s X5 a+ \
mL, and the size of the penis remained unchanged.+ L/ b6 u' v( i% J4 [+ L( f
The mother also said that the boy was no longer hav-
8 N* U% |- X/ @; A( R5 wing frequent erections.* ?, e2 y' |1 d( O- d! h& b
Both parents were again questioned about use of/ g( o( ?. f% i [+ Y" b
any ointment/creams that they may have applied to! p* ~) i, a) f6 |/ l" X
the child’s skin. This time the father admitted the
. J! r) Q- Y+ ~$ e) z7 ITopical Testosterone Exposure / Bhowmick et al 541
0 `: A! d8 C0 N0 T0 puse of testosterone gel twice daily that he was apply-
1 V) Y8 N2 U' e- W w7 k' P& d' x* oing over his own shoulders, chest, and back area for, L4 o. ?6 G6 s% O& X1 }! c
a year. The father also revealed he was embarrassed
) Y% V- A+ z9 q3 dto disclose that he was using a testosterone gel pre-: I& ~2 B3 F$ A( a0 x% v
scribed by his family physician for decreased libido
/ {4 c1 R) j* W. Hsecondary to depression.
" K7 n5 {' w& @1 U: B5 O1 {1 ZThe child slept in the same bed with parents.
9 l1 a4 a8 j7 N" g3 GThe father would hug the baby and hold him on his$ t6 E" }, x3 z0 O" {) i
chest for a considerable period of time, causing sig-& {& n0 ^; h* G. W' d4 a- {* {
nificant bare skin contact between baby and father.
- p2 q4 H. S9 ^5 S" i1 y. xThe father also admitted that after the phone call,+ E1 k( |3 j0 m% b$ o0 P+ `
when he learned the testosterone level in the baby
+ ^( Y. C p. B! Y& e( ~1 L/ o1 bwas high, he then read the product information
, ]$ a# p! i: E+ Dpacket and concluded that it was most likely the rea-1 `! I% g/ j' E1 \+ L
son for the child’s virilization. At that time, they* X5 _% u' d8 M6 E5 L0 d
decided to put the baby in a separate bed, and the
/ j5 D9 g+ {( ~7 ~. m4 Ufather was not hugging him with bare skin and had
0 [9 N. C# e' X- Xbeen using protective clothing. A repeat testosterone
& d) Z q) l# I- r# ctest was ordered, but the family did not go to the! d* c) I% _0 ?1 P. p
laboratory to obtain the test.7 ~" V% B* b/ S1 C
Discussion: S4 d; E) u* [3 e% q
Precocious puberty in boys is defined as secondary
: @! j& j* m/ e# ^" G6 |sexual development before 9 years of age.1,4
' Y: q9 p) a4 gPrecocious puberty is termed as central (true) when' G' C! {: ~- X" k3 O) r- T0 k
it is caused by the premature activation of hypo-
# e8 x& D0 u" v- {3 `! K5 zthalamic pituitary gonadal axis. CPP is more com-5 X, U) A9 `4 U
mon in girls than in boys.1,3 Most boys with CPP) I# k8 w: b2 r1 n
may have a central nervous system lesion that is
" `# v' l5 X7 G4 b' Sresponsible for the early activation of the hypothal-+ L( b" J7 P' W0 T: O# L1 B
amic pituitary gonadal axis.1-3 Thus, greater empha-3 y2 m3 t8 k$ b( L5 ~2 `
sis has been given to neuroradiologic imaging in
3 G& Q# ^+ o- L0 Tboys with precocious puberty. In addition to viril-7 z. M( p& c' R, `# ^( _
ization, the clinical hallmark of CPP is the symmet-8 q$ n, m; N) Y( K* o9 u! E: @
rical testicular growth secondary to stimulation by
" z8 [( o, E2 ^% r9 igonadotropins.1,3
1 K9 z* |4 ?8 B! E) u) `Gonadotropin-independent peripheral preco-
1 i7 v$ d5 j. P0 w4 Mcious puberty in boys also results from inappropriate
$ c, B: U: u) w3 @- O9 \androgenic stimulation from either endogenous or
. S v9 K% e7 {. l! F0 Dexogenous sources, nonpituitary gonadotropin stim-, i+ L8 E, M+ I% m
ulation, and rare activating mutations.3 Virilizing
& R+ {" o9 `7 H1 Jcongenital adrenal hyperplasia producing excessive& k: B9 F4 q9 _0 W) `. D
adrenal androgens is a common cause of precocious3 G9 t* r$ |8 y
puberty in boys.3,4
6 n. k n. E' [$ E+ G6 g/ RThe most common form of congenital adrenal4 O9 M b0 r) P: v
hyperplasia is the 21-hydroxylase enzyme deficiency.1 X7 J1 k0 o( l) ^
The 11-β hydroxylase deficiency may also result in. A) G4 S, P% a, e) v
excessive adrenal androgen production, and rarely,- n, O$ _% j( S+ c
an adrenal tumor may also cause adrenal androgen; F0 t, W0 d5 ?; i# w3 k S9 Q5 ~
excess.1,35 w4 b' ]) ] U
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from0 w, N8 V) q2 C2 L
542 Clinical Pediatrics / Vol. 46, No. 6, July 2007
! `6 F U8 @" U$ J4 o2 `4 rA unique entity of male-limited gonadotropin-
# f! z0 |1 f- A2 B1 Nindependent precocious puberty, which is also known
) ~; ~9 I' l0 ?9 K5 z4 Das testotoxicosis, may cause precocious puberty at a
9 k, e' [$ Z, a! Q5 Cvery young age. The physical findings in these boys! g$ u4 \) V/ S
with this disorder are full pubertal development,
6 ` B% ]) F' k1 R2 S9 I* qincluding bilateral testicular growth, similar to boys
. w; E0 T3 L$ p# p1 l9 vwith CPP. The gonadotropin levels in this disorder
6 P5 h6 e- {8 G9 g* fare suppressed to prepubertal levels and do not show
( R, Q7 o! C4 C C0 l) kpubertal response of gonadotropin after gonadotropin-
, a; _3 u' H0 Ureleasing hormone stimulation. This is a sex-linked- o3 i& `, O& A
autosomal dominant disorder that affects only
( R' M* Y- Q( }& d( _( qmales; therefore, other male members of the family
* ? W8 w0 _9 u) K9 \3 emay have similar precocious puberty.3# T5 U, h% l! D' T
In our patient, physical examination was incon- d! t, J/ q5 h" P% f A, P9 z
sistent with true precocious puberty since his testi-
. w" j7 M! H3 I) \cles were prepubertal in size. However, testotoxicosis
4 f" ?4 p( e0 rwas in the differential diagnosis because his father) |& Z1 _& |8 F, ?; n0 T, }$ d
started puberty somewhat early, and occasionally,
+ v+ G0 q( j! M$ h4 X9 Vtesticular enlargement is not that evident in the
& H2 _: R/ B" I- p/ Dbeginning of this process.1 In the absence of a neg-
, Z" G8 X/ M6 dative initial history of androgen exposure, our
0 T1 {/ \$ R: Y* g# g/ Ybiggest concern was virilizing adrenal hyperplasia,! @" X- G3 W5 ~ W$ r' I
either 21-hydroxylase deficiency or 11-β hydroxylase
' d% w: C5 ]$ {- c/ G+ ideficiency. Those diagnoses were excluded by find-
1 i# \* e# _0 r6 u. G% N( u' Zing the normal level of adrenal steroids." S l$ v/ n p$ s4 j* k
The diagnosis of exogenous androgens was strongly$ A: R/ n% {0 [% t/ ?9 ~
suspected in a follow-up visit after 4 months because+ S$ ?0 t. S) X, C
the physical examination revealed the complete disap-
0 K4 x9 v$ {( B% _0 ppearance of pubic hair, normal growth velocity, and
. g+ m' c: N S/ W) J- `decreased erections. The father admitted using a testos-
2 ?( x/ ^1 e% V5 x; V' Xterone gel, which he concealed at first visit. He was( D2 N$ C4 i( @ |% W0 ^
using it rather frequently, twice a day. The Physicians’) ]; g$ Q8 ~5 U8 a* f$ z
Desk Reference, or package insert of this product, gel or
8 o$ ], |9 m- c# y3 _cream, cautions about dermal testosterone transfer to
- M5 X9 u- E, F( z' Zunprotected females through direct skin exposure.1 {7 G# k0 H0 b7 ^3 j5 d, m: ]
Serum testosterone level was found to be 2 times the
+ ^$ ^7 i& m. F* ]& \8 Abaseline value in those females who were exposed to) u0 G2 i; y0 ?) ^( b. j: k7 p
even 15 minutes of direct skin contact with their male/ t$ a6 [, i1 n+ X
partners.6 However, when a shirt covered the applica-, M1 F/ B3 }$ l6 i; v; i
tion site, this testosterone transfer was prevented.
# ?8 p1 ^, s% o7 W* bOur patient’s testosterone level was 60 ng/mL,9 \2 N* F* [9 J9 x" E; Q: I* w
which was clearly high. Some studies suggest that
+ b/ j- X+ W" \# S- Zdermal conversion of testosterone to dihydrotestos-
" K4 K4 ?. I+ l, @6 ?8 ^terone, which is a more potent metabolite, is more& q; Y2 U2 v* N, E1 m9 J
active in young children exposed to testosterone3 w/ G) b6 f: s9 j" {: S6 U( ?( a
exogenously7; however, we did not measure a dihy-
* n! e; \: Z! e, M6 Q/ @! idrotestosterone level in our patient. In addition to. N$ ?; {2 n! ]& L# e% q
virilization, exposure to exogenous testosterone in6 o6 Q1 {$ V4 l. i# k1 ?/ c
children results in an increase in growth velocity and* m5 R$ I/ Y" G. H. H. S
advanced bone age, as seen in our patient.
; c; j3 f& I# xThe long-term effect of androgen exposure during! }( J2 z% T, {3 @! v5 @; ~
early childhood on pubertal development and final2 \. G, q; J7 B6 |$ j4 L; Y1 U
adult height are not fully known and always remain# V/ B* i8 v& h- o. A
a concern. Children treated with short-term testos-. i# D) B& o( w1 v3 I$ Q1 Y
terone injection or topical androgen may exhibit some
" ^2 I' B5 Q2 o3 y9 ?8 Y- o+ w5 `acceleration of the skeletal maturation; however, after2 b1 y" C' S& \! P q! v. `
cessation of treatment, the rate of bone maturation% c4 \: S" v: e, K! j
decelerates and gradually returns to normal.8,9
7 L9 P' F8 p1 _$ A7 b' MThere are conflicting reports and controversy( _2 N3 B {7 w
over the effect of early androgen exposure on adult$ u+ x1 u; }6 r5 i9 I
penile length.10,11 Some reports suggest subnormal- j, _4 J6 l4 U8 r" B
adult penile length, apparently because of downreg-
3 N) K7 q/ U5 ~8 q, S0 Eulation of androgen receptor number.10,12 However,! ~* D5 ~4 w3 q4 ^! L( t5 `5 V' a
Sutherland et al13 did not find a correlation between
$ c5 `6 y" t1 _+ V- a& Z& Tchildhood testosterone exposure and reduced adult
. m6 l1 A4 ]; N/ R, Hpenile length in clinical studies.2 G& o0 r' S# ?! z; Z$ u3 T4 h( \! F# l
Nonetheless, we do not believe our patient is
+ A$ J2 w& f) s$ y W$ Mgoing to experience any of the untoward effects from
: F2 N0 I8 {; p) h9 r) `/ [testosterone exposure as mentioned earlier because) {% Q/ E( X! U2 y/ Z, ?2 @1 o
the exposure was not for a prolonged period of time.8 v* ~% r: A( Y) |
Although the bone age was advanced at the time of
( D1 B; y7 D- @' Wdiagnosis, the child had a normal growth velocity at* j3 Y. j/ m9 ]+ m) T5 e/ u X
the follow-up visit. It is hoped that his final adult. i; r7 W* S" z( n
height will not be affected., h7 @/ d' `' p. \. A
Although rarely reported, the widespread avail-( C2 d$ Y" k. o9 p
ability of androgen products in our society may
/ q4 P% U* Z2 V1 pindeed cause more virilization in male or female
5 I# ]) T8 _( g6 V" E* r( wchildren than one would realize. Exposure to andro-
2 `! K$ z. N1 z& F; e6 s* mgen products must be considered and specific ques-
3 W! c( F! F7 x' T1 C$ ~! {tioning about the use of a testosterone product or5 J8 {; ]7 V) \3 x( h+ |% {
gel should be asked of the family members during. ^; v% ]# o; E8 _9 b- s
the evaluation of any children who present with vir-: M7 `. z7 c% x
ilization or peripheral precocious puberty. The diag-
5 K1 w+ j p' S: |nosis can be established by just a few tests and by
1 c' k# j1 ~# _! P9 @appropriate history. The inability to obtain such a
: A" H, L. ~: u6 p6 Q- Dhistory, or failure to ask the specific questions, may
9 K5 a' b" r( yresult in extensive, unnecessary, and expensive
9 [9 v* z& u( O5 s0 rinvestigation. The primary care physician should be) A- |" P# ]- M+ C0 H: ]
aware of this fact, because most of these children
+ S7 H5 i; z( a" {may initially present in their practice. The Physicians’+ \" E' n+ I9 L8 ~
Desk Reference and package insert should also put a1 y3 H: _ t5 k9 a
warning about the virilizing effect on a male or0 C! G0 q/ o3 T; f: Q
female child who might come in contact with some-( l5 I. V" ~: y
one using any of these products.# v( [, ^! }1 s0 ~' n# p
References
' K0 C2 Y% `! P b# k% _* g1. Styne DM. The testes: disorder of sexual differentiation
Q8 i; ^4 ~1 I/ }and puberty in the male. In: Sperling MA, ed. Pediatric3 @+ ~; F3 @9 A: Y' \
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;% s% y; {, G. ~5 `* O6 V
2002: 565-628./ G' o9 D3 N6 P) a$ K4 q! S
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious% g) A: A4 R# x n+ V& C
puberty in children with tumours of the suprasellar pineal |
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