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Sexual Precocity in a 16-Month-Old6 j3 [8 D; e0 ?, C* c. D- Z
Boy Induced by Indirect Topical
: y' l, M, M- J% a Y. ^0 MExposure to Testosterone3 D; n5 }; N3 W C# W4 U
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2: i; h( I- l7 [3 l' @# {
and Kenneth R. Rettig, MD1
6 d$ \+ l: y( `3 a) yClinical Pediatrics* q4 y- x) h% P; a& Q, y' ]* o
Volume 46 Number 6" B, i Q! n' _4 ?
July 2007 540-543
$ o ]% e) {' X- m- Z# e1 o, Q: i© 2007 Sage Publications0 L1 j- O# n& M" {- b" w
10.1177/0009922806296651/ I. V0 e7 |/ }+ i; s3 V
http://clp.sagepub.com l5 x% z* r, T( n' {
hosted at' T) o4 ?9 y2 q9 ?, i; h
http://online.sagepub.com
6 O" ^+ i( j% MPrecocious puberty in boys, central or peripheral, @/ Y M: R/ }7 l
is a significant concern for physicians. Central
3 G' x1 d4 S [1 rprecocious puberty (CPP), which is mediated
: w; `; U0 J3 b2 m( `through the hypothalamic pituitary gonadal axis, has: L. C2 u; m# k! N
a higher incidence of organic central nervous system, s3 C0 E* q; o2 C R
lesions in boys.1,2 Virilization in boys, as manifested/ Y! U2 ]4 V" x; X3 `* F& Y% y
by enlargement of the penis, development of pubic. P+ p, D) C# z" q
hair, and facial acne without enlargement of testi-
4 l& k6 Q* c. I! _# fcles, suggests peripheral or pseudopuberty.1-3 We7 m# p" f! {* W) H
report a 16-month-old boy who presented with the3 r7 g% B1 W0 Q& E9 z
enlargement of the phallus and pubic hair develop-! h, y o9 N; @0 n- q
ment without testicular enlargement, which was due
) s- i* `( K, o+ K3 Y8 L$ o! ^to the unintentional exposure to androgen gel used by
2 G' y5 e6 a9 t7 T9 C) P# ?# E4 |% ~$ t6 vthe father. The family initially concealed this infor-
5 S6 p- A2 F1 mmation, resulting in an extensive work-up for this/ A/ S3 ?# i9 k" B, f+ \1 L
child. Given the widespread and easy availability of# X0 S8 q* X6 k, Z
testosterone gel and cream, we believe this is proba-
% f5 A L; i1 _+ F0 `* p& n7 gbly more common than the rare case report in the
$ |' f* \- ~/ v; d2 h; Uliterature.4
2 f& p& ?6 B7 tPatient Report$ f7 h/ _; G( q
A 16-month-old white child was referred to the
/ w, o; ^5 R6 {/ t" [/ G4 U3 Qendocrine clinic by his pediatrician with the concern
( v6 i" f( ?# k2 ?. Uof early sexual development. His mother noticed
* V% g: V h8 H7 ~light colored pubic hair development when he was8 C6 R1 k# h1 \. a t
From the 1Division of Pediatric Endocrinology, 2University of [7 L4 r+ z% Q |3 r
South Alabama Medical Center, Mobile, Alabama.
1 P8 R8 K0 v8 m+ y5 O; `, aAddress correspondence to: Samar K. Bhowmick, MD, FACE,: d& b F2 L* b, Z
Professor of Pediatrics, University of South Alabama, College of
0 A' Q. Q; M+ F( v* s; ~; }! @1 J- hMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;& P4 {. j7 _- M9 Z/ J
e-mail: [email protected].
, p. ~; N% z9 W s' v/ Qabout 6 to 7 months old, which progressively became3 S8 e, k8 e c4 {) z
darker. She was also concerned about the enlarge-( F* e' b$ I) `/ ]" v) P7 A! g
ment of his penis and frequent erections. The child# \ H3 L7 t4 r7 g
was the product of a full-term normal delivery, with0 J n4 M" ~! R* K4 O- t# y8 A
a birth weight of 7 lb 14 oz, and birth length of3 L7 ]0 h/ Q+ k3 `+ ^- H9 b; p9 l
20 inches. He was breast-fed throughout the first year# Q, q9 ], C9 S0 `# b
of life and was still receiving breast milk along with9 x& r: q1 p; X8 N+ Q O
solid food. He had no hospitalizations or surgery,# E/ p; ^; `0 n [, O1 h3 q, d
and his psychosocial and psychomotor development$ e+ g3 d* N4 F3 |/ X8 ~
was age appropriate.
$ K* U9 f6 A+ d" V/ x# _The family history was remarkable for the father,
: m: i. \7 F* T1 s' }who was diagnosed with hypothyroidism at age 16,0 X" \8 y- s5 {6 B, Z
which was treated with thyroxine. The father’s
% `# j9 {6 y6 ` Y1 D& `height was 6 feet, and he went through a somewhat4 l0 R% _5 [1 K2 ^$ M
early puberty and had stopped growing by age 14.$ e) F3 a1 ]2 Q) v, h9 s! z0 U
The father denied taking any other medication. The
$ d# f$ x3 N, j7 ]% l- qchild’s mother was in good health. Her menarche
& m. A( l/ r5 Qwas at 11 years of age, and her height was at 5 feet% s. ~5 S. K+ Q* a
5 inches. There was no other family history of pre-8 m/ W7 F/ v2 v. D9 }
cocious sexual development in the first-degree rela-
; U0 `5 y( R: r0 ktives. There were no siblings.# P- o, [# I7 d3 S
Physical Examination9 L, {# {; o9 x
The physical examination revealed a very active,! @& c$ P0 q5 J' J9 r0 t% S: F
playful, and healthy boy. The vital signs documented
. R" s: z. {9 R" ~0 Ba blood pressure of 85/50 mm Hg, his length was
/ ]; a" z& O1 L4 n! t1 k4 e90 cm (>97th percentile), and his weight was 14.4 kg
+ N5 p% g& H3 Z8 s1 X(also >97th percentile). The observed yearly growth
0 R8 x- }9 Y, F3 Z/ w$ V4 gvelocity was 30 cm (12 inches). The examination of* @$ |/ r: ]: I6 n
the neck revealed no thyroid enlargement.
3 }2 c. C$ a/ }+ ?The genitourinary examination was remarkable for
$ r7 {: a* ?1 _enlargement of the penis, with a stretched length of1 T" |! A" ]' t* i# g5 m C* V
8 cm and a width of 2 cm. The glans penis was very well2 S7 L# a! M G j
developed. The pubic hair was Tanner II, mostly around# k' M& t+ t3 Y+ C5 W
540, S" ?) q8 y5 p
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from( c/ ^) a- `. S
the base of the phallus and was dark and curled. The
1 A* W, K" E1 u4 {testicular volume was prepubertal at 2 mL each.4 u4 J. C% O3 D7 N$ ^& ~3 D
The skin was moist and smooth and somewhat& j/ E' K! e+ B9 T* X1 t0 P
oily. No axillary hair was noted. There were no4 i4 C8 C, Q$ V
abnormal skin pigmentations or café-au-lait spots.; L4 r2 f' {; Q/ J2 F- i3 ], L
Neurologic evaluation showed deep tendon reflex 2+$ F5 I. |( |4 Q$ D: {
bilateral and symmetrical. There was no suggestion
# o O6 \ _5 X+ M' C- mof papilledema.. i7 u3 m7 M' z ~. W3 ^
Laboratory Evaluation0 l- s7 h7 t& ~0 q* p$ K& G9 `) W f
The bone age was consistent with 28 months by
2 U. ?; k% A6 C; p& O/ ^using the standard of Greulich and Pyle at a chrono-
& b. Z4 d* h- Ylogic age of 16 months (advanced).5 Chromosomal$ f. m" X3 g. q3 I ?
karyotype was 46XY. The thyroid function test5 v: p- {1 U3 R% [( E
showed a free T4 of 1.69 ng/dL, and thyroid stimu-
( E0 a. d ^' {, m% D8 _lating hormone level was 1.3 µIU/mL (both normal).# }; E" I; I a; Z. F1 [& S: t
The concentrations of serum electrolytes, blood
. ^' k& ]) K4 ourea nitrogen, creatinine, and calcium all were
5 R- z' ~/ l' M* h8 Uwithin normal range for his age. The concentration
9 S" B1 P6 h4 l$ Yof serum 17-hydroxyprogesterone was 16 ng/dL5 E% h1 F, B9 p3 o7 j' S! A
(normal, 3 to 90 ng/dL), androstenedione was 208 J2 f# }9 V6 L W% A
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-
) X8 R$ |6 A& qterone was 38 ng/dL (normal, 50 to 760 ng/dL),6 \ Q8 F1 i" V |; b' g
desoxycorticosterone was 4.3 ng/dL (normal, 7 to+ s# _5 }$ _. b
49ng/dL), 11-desoxycortisol (specific compound S)/ ^# y# _3 h5 c% _
was 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-1 F: i9 i- O# L2 h5 e
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
' ^! Z5 ` Q+ N" etestosterone was 60 ng/dL (normal <3 to 10 ng/dL),7 j9 E4 n _4 |, L
and β-human chorionic gonadotropin was less than$ |. F0 O- l% }( y8 r8 d
5 mIU/mL (normal <5 mIU/mL). Serum follicular b% [" S9 U2 d, ^' M& P
stimulating hormone and leuteinizing hormone+ J' O8 O" {6 {9 f8 O' N! l, [
concentrations were less than 0.05 mIU/mL$ W$ W8 h7 |* G, L# {9 j, t
(prepubertal).
- L) Y, c5 n" v! L3 f0 a- m7 m& QThe parents were notified about the laboratory
* k5 i* H& k3 z) r, C; M. Vresults and were informed that all of the tests were
1 Z1 k0 ~& _' Z+ v8 P! jnormal except the testosterone level was high. The/ H7 e) m0 J+ ?9 S
follow-up visit was arranged within a few weeks to
. x9 d9 v2 C' f0 H" {, Vobtain testicular and abdominal sonograms; how-
9 H% _1 T; ]$ |8 u$ u+ pever, the family did not return for 4 months.
0 e$ V# K; g7 v( Y2 X: IPhysical examination at this time revealed that the9 n6 t5 r i5 w# `% Q) L0 v$ x: u
child had grown 2.5 cm in 4 months and had gained: z) b) A* j* r, a2 k! f
2 kg of weight. Physical examination remained3 V: `! H( i! M
unchanged. Surprisingly, the pubic hair almost com-
* `. T: w! K @! V2 F& B- opletely disappeared except for a few vellous hairs at8 i& B3 I2 P7 l2 l
the base of the phallus. Testicular volume was still 2( M$ l, h3 ]4 y/ L) d9 \
mL, and the size of the penis remained unchanged. O5 f$ W! e" _* ?5 w- c
The mother also said that the boy was no longer hav-
8 V6 m& A; i, ]- Z. [( J5 K. q2 ]ing frequent erections.: `, o2 I0 \$ g0 j: ~
Both parents were again questioned about use of
6 l2 D1 w1 d) A+ zany ointment/creams that they may have applied to2 r' u y" O* z/ h/ @' b @' E
the child’s skin. This time the father admitted the
) C- z6 E$ |! o g: E4 zTopical Testosterone Exposure / Bhowmick et al 541
* O9 y( b! S3 Y! o( p6 F" i6 tuse of testosterone gel twice daily that he was apply-# D& C* w8 L9 n1 n/ p$ J. ~
ing over his own shoulders, chest, and back area for
, F! w: i0 |! S$ C( ?& Z1 C% R$ xa year. The father also revealed he was embarrassed
, ~9 f. ^% r2 {1 C. u" g/ hto disclose that he was using a testosterone gel pre-
: e6 A6 i5 b+ b- |7 _6 fscribed by his family physician for decreased libido5 S |7 {# c" m0 H
secondary to depression.3 ^4 |) _! ~% U+ D; m, G
The child slept in the same bed with parents.
1 V: G r9 A1 Q* t' q) B* G5 xThe father would hug the baby and hold him on his3 d! j7 u: F4 n: l2 T6 D4 _( u, A
chest for a considerable period of time, causing sig-$ m6 X8 n0 f) L
nificant bare skin contact between baby and father.
6 ]0 T2 A: g, X" O. I' \+ \The father also admitted that after the phone call,
% q" ]0 }, X) m3 Fwhen he learned the testosterone level in the baby
# R9 T( @+ ]7 z( \: _( @was high, he then read the product information
0 Z% Q& ]+ C( A& \1 `5 Mpacket and concluded that it was most likely the rea-
- m w' `2 H; zson for the child’s virilization. At that time, they3 o8 X8 O* @" ?# x! I, F
decided to put the baby in a separate bed, and the
, {# ]$ d. F- ]& V& y+ Rfather was not hugging him with bare skin and had/ k$ T! c# G+ s7 y7 o- ?& F
been using protective clothing. A repeat testosterone
- {& }# u/ U* J* xtest was ordered, but the family did not go to the4 [$ \, E0 C' G, E: `$ ^ b% v0 Z% g
laboratory to obtain the test.3 e5 X2 T6 u6 J4 G
Discussion
, ~; m+ i O3 U. OPrecocious puberty in boys is defined as secondary$ W* }$ D! A+ b8 T5 \3 W
sexual development before 9 years of age.1,4
: e; K3 a4 I* c4 I. K- w8 s4 zPrecocious puberty is termed as central (true) when
' |# T4 g& g, vit is caused by the premature activation of hypo-9 O2 B; |+ j1 K$ |9 h, a
thalamic pituitary gonadal axis. CPP is more com-
! m a9 @8 O, Rmon in girls than in boys.1,3 Most boys with CPP
~% }) e! | b% [% b0 i) Xmay have a central nervous system lesion that is
9 n( `4 z' D& p% a+ e$ I/ Eresponsible for the early activation of the hypothal-
2 e" J! b5 K7 D R9 jamic pituitary gonadal axis.1-3 Thus, greater empha-8 ~ [0 y& m: ~" } O
sis has been given to neuroradiologic imaging in
! Z7 W% y/ i' O! W/ Y6 fboys with precocious puberty. In addition to viril-
' P0 t+ _' F i- R) ?# S( V7 uization, the clinical hallmark of CPP is the symmet-3 o; M r' p, i0 e
rical testicular growth secondary to stimulation by: V6 B5 q2 i- u, O
gonadotropins.1,3
9 e" e3 P$ u# r9 jGonadotropin-independent peripheral preco-
+ e+ c/ u( _* ^6 L7 `cious puberty in boys also results from inappropriate
: _- w: a6 n$ G& ]5 B. [androgenic stimulation from either endogenous or1 N6 y1 ]' C% ^, \7 z
exogenous sources, nonpituitary gonadotropin stim-
/ P. ?! }" T( J0 tulation, and rare activating mutations.3 Virilizing
6 G2 A* G0 {+ o0 i- U4 jcongenital adrenal hyperplasia producing excessive& i+ { b( s( Z; }! M, X
adrenal androgens is a common cause of precocious; ^9 G) P, i5 \. q. [" @" B! X8 s
puberty in boys.3,4; Q3 i8 e7 w5 S! }( S9 Y/ o
The most common form of congenital adrenal6 S# X! H2 V }5 ?% w, H
hyperplasia is the 21-hydroxylase enzyme deficiency.
$ B5 Z+ L. v% [! w( b+ tThe 11-β hydroxylase deficiency may also result in
' s! C: m |: D. iexcessive adrenal androgen production, and rarely,$ u5 U0 j: {% L6 X! c1 d' L$ _* y
an adrenal tumor may also cause adrenal androgen. e% A- E3 J5 j& s
excess.1,3. a- {2 a: ?/ t, F
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from) R2 W+ L0 h6 d5 G% D1 ^
542 Clinical Pediatrics / Vol. 46, No. 6, July 20071 E. V! [3 U& H/ r9 a9 v% P& F
A unique entity of male-limited gonadotropin-5 a* Y0 S* u9 u) }0 M V
independent precocious puberty, which is also known9 @( T5 b, v x6 P
as testotoxicosis, may cause precocious puberty at a3 u; x2 X0 R4 p" c
very young age. The physical findings in these boys1 D P; N# p" y9 b
with this disorder are full pubertal development,
. x4 {9 ^, n! r$ b& e, R* cincluding bilateral testicular growth, similar to boys( D, ^9 K, c8 ]9 ^# ]
with CPP. The gonadotropin levels in this disorder
7 S+ t! W4 a6 C4 q( \4 L, `- gare suppressed to prepubertal levels and do not show: k% I( r/ y' ]6 ]0 z
pubertal response of gonadotropin after gonadotropin-/ U* \. L( D, s3 U, g
releasing hormone stimulation. This is a sex-linked
* b6 f. o* E( ?8 h3 x$ T# sautosomal dominant disorder that affects only! ?/ \+ C$ F# c, t; ]. I- ^* J3 |# r
males; therefore, other male members of the family
) |0 c& X. o, R+ nmay have similar precocious puberty.3+ K4 [4 a) r! q- r
In our patient, physical examination was incon-+ ~2 V) a8 x( I
sistent with true precocious puberty since his testi-
8 P. e& ?: B0 }* tcles were prepubertal in size. However, testotoxicosis% u* |3 E/ O# V3 t" \5 P2 e
was in the differential diagnosis because his father
7 x4 V; q# E- L, u4 l+ \started puberty somewhat early, and occasionally,
' d+ Q! d9 ?/ b- `+ {testicular enlargement is not that evident in the8 r* n5 P q! c! C% J) P
beginning of this process.1 In the absence of a neg-
+ M! w0 p! }8 g& s' Iative initial history of androgen exposure, our
j2 x# ~0 ]2 G U( j# Vbiggest concern was virilizing adrenal hyperplasia,
# E/ k. l9 z# N' n! yeither 21-hydroxylase deficiency or 11-β hydroxylase5 w, h. m( o9 T7 j4 E: W5 q
deficiency. Those diagnoses were excluded by find-: b4 E7 Y+ W+ K2 s5 W! n% [
ing the normal level of adrenal steroids.6 q# O$ N) ?$ g
The diagnosis of exogenous androgens was strongly
. v8 v7 j5 _9 ?, u* ksuspected in a follow-up visit after 4 months because0 |8 E+ n& _7 A' c8 a
the physical examination revealed the complete disap-
, x3 F+ |, O8 f" I' B% T& xpearance of pubic hair, normal growth velocity, and6 Y# J( H& B" E2 ]* D4 u* c
decreased erections. The father admitted using a testos-
- e2 a5 z) @5 q- X7 }2 Oterone gel, which he concealed at first visit. He was7 {) g, [( @3 g1 o! I
using it rather frequently, twice a day. The Physicians’
0 `2 k- Q' o0 f. _. p4 _! B5 mDesk Reference, or package insert of this product, gel or: S9 v$ L, g9 s/ ?) ^+ `3 e
cream, cautions about dermal testosterone transfer to
" q- E2 c" ~- L1 }0 w$ R' e1 cunprotected females through direct skin exposure.! j0 W5 Z6 `; @8 o, A3 ]2 d
Serum testosterone level was found to be 2 times the
8 h$ h4 P" C$ h9 D3 Mbaseline value in those females who were exposed to
8 _4 H: V! v2 ]; ^7 Q) K# I/ aeven 15 minutes of direct skin contact with their male
% x$ [0 u. d' T& G6 ]) a( Ipartners.6 However, when a shirt covered the applica-; K* q& J) r! d3 P
tion site, this testosterone transfer was prevented.
7 B$ r* E! j3 u/ {Our patient’s testosterone level was 60 ng/mL,
# W5 A- e4 U5 Q) A! D! z6 a! Cwhich was clearly high. Some studies suggest that% t3 B6 a* m. j T
dermal conversion of testosterone to dihydrotestos-/ ^0 M: C6 x3 o0 ]$ ~1 w" {& f
terone, which is a more potent metabolite, is more
5 J: q# j! v/ X1 nactive in young children exposed to testosterone
% V# J: Z5 F7 i" h: ]exogenously7; however, we did not measure a dihy-
9 {; f( x* D% u# u% l3 Sdrotestosterone level in our patient. In addition to
) ^6 |* _ b3 @% L4 s* o* `& nvirilization, exposure to exogenous testosterone in
. G. y- m$ |3 i5 B0 ychildren results in an increase in growth velocity and' _3 z9 n; Y- l; |% N
advanced bone age, as seen in our patient.
3 b6 z& ^4 [ b2 q8 o) wThe long-term effect of androgen exposure during
9 V4 q+ c- c$ r- ?early childhood on pubertal development and final9 l/ q& c9 ^7 R) J2 v( R6 `
adult height are not fully known and always remain
8 L6 n& d+ K9 T- |- ga concern. Children treated with short-term testos-, m7 {* R- ^, U, J6 Y% Y2 H
terone injection or topical androgen may exhibit some7 C6 C& ^" o/ Z6 A- j0 T# T$ b
acceleration of the skeletal maturation; however, after" S! g. N; _. d, z2 ^" W
cessation of treatment, the rate of bone maturation
$ n2 g7 Q' M" jdecelerates and gradually returns to normal.8,9" j6 S/ ?+ o4 U- o7 F6 _ W7 {
There are conflicting reports and controversy
. O7 o+ T" v8 b- _' X; oover the effect of early androgen exposure on adult! E) T" t9 V/ t. T! J
penile length.10,11 Some reports suggest subnormal
9 O- J1 i! y& N, B# b6 }0 padult penile length, apparently because of downreg-8 W. Q/ O4 I# b5 B' H+ C) b
ulation of androgen receptor number.10,12 However,
" y8 s& v0 V) X3 WSutherland et al13 did not find a correlation between
" c' V" \' T2 ^* ~childhood testosterone exposure and reduced adult8 T! E# {6 U+ Z9 `: W" S1 `
penile length in clinical studies." T' C2 l ?5 ^- G! x
Nonetheless, we do not believe our patient is
) i" z% I* ?* \ wgoing to experience any of the untoward effects from W0 F% Y7 Q. `7 m4 m
testosterone exposure as mentioned earlier because
) _% N' `) L; p8 D; `5 r' Z' d' u: E/ Qthe exposure was not for a prolonged period of time.
; c5 V8 ]& H8 O( r' v; jAlthough the bone age was advanced at the time of
$ P8 V+ ~+ x$ _) K6 @diagnosis, the child had a normal growth velocity at l( E8 \& b3 g# G H
the follow-up visit. It is hoped that his final adult
1 n% | ~$ C5 k' a( B' Nheight will not be affected.; z4 y0 V' j: Q/ A4 {
Although rarely reported, the widespread avail-
; n4 r0 h& y+ k9 w6 ^ability of androgen products in our society may
8 p l3 n* ^) }9 R! eindeed cause more virilization in male or female( D0 x5 I5 ^0 [
children than one would realize. Exposure to andro-
& |; b" ~$ L3 L1 Vgen products must be considered and specific ques-: R, ]/ L k" I" h
tioning about the use of a testosterone product or/ W; r8 i2 O4 m" }7 G$ q
gel should be asked of the family members during s& d$ U. Q3 q# F. \# V
the evaluation of any children who present with vir-
0 [8 q) I) e* T$ a/ J* |& ]ilization or peripheral precocious puberty. The diag-
9 M; {& R6 {) v7 a' M% V# N' X6 Bnosis can be established by just a few tests and by; x, {; m7 [0 ~% }3 M1 X& K4 ^
appropriate history. The inability to obtain such a
5 k1 V+ D- s7 w2 Shistory, or failure to ask the specific questions, may5 F! Y4 o- s* X8 q) P5 b
result in extensive, unnecessary, and expensive0 D# y; o/ k! c& Z; l* D
investigation. The primary care physician should be
R0 i2 r& ]" Vaware of this fact, because most of these children! ^8 c8 M) D7 C
may initially present in their practice. The Physicians’/ W' a" U9 r; d! o
Desk Reference and package insert should also put a
- K- _' `- L4 @) Swarning about the virilizing effect on a male or
8 o0 y! K5 H8 h8 o" t& S+ a: \female child who might come in contact with some-/ Z! B" |; A8 E/ k$ B; y$ t
one using any of these products.- k6 r+ ^9 y% g2 P( Y8 ^
References; A( t0 ]. p& A+ k
1. Styne DM. The testes: disorder of sexual differentiation
3 S G5 B/ m9 a3 m" M# qand puberty in the male. In: Sperling MA, ed. Pediatric' c' ?9 ~6 a3 F) i; Z
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
% h- b! C. a7 u" V" A& v2002: 565-628. Q* Y& t# z1 T) r' [ A
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious' ?5 r/ [$ e/ y* q& _. S$ e) \
puberty in children with tumours of the suprasellar pineal |
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