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Sexual Precocity in a 16-Month-Old
+ X; I7 \3 f- ^% I$ w. vBoy Induced by Indirect Topical
/ o! b0 Z& @; Y) a. RExposure to Testosterone3 Q! ~! ^3 ?' G7 t
Samar K. Bhowmick, MD, FACE,1 Tracy Ricke, MD,2
3 @. y/ C s$ S8 S3 F. Wand Kenneth R. Rettig, MD1. g+ ~( _0 v* r6 [6 H3 i
Clinical Pediatrics
! T. d& v" }/ }3 R$ B' MVolume 46 Number 6
- I! r" y' Q4 L& T# ^5 m& IJuly 2007 540-5430 X1 q) L0 e8 I3 c( s! d0 e0 l
© 2007 Sage Publications$ w0 n5 L$ T6 k1 G: h% w* o/ S: `+ p
10.1177/0009922806296651/ x+ U# B, H' y2 L
http://clp.sagepub.com
, _8 P( r( ]1 i( |1 A: z shosted at& l7 Q: Z; J! l' J+ s1 P) l
http://online.sagepub.com6 s* z: s" d- m0 k3 i
Precocious puberty in boys, central or peripheral,
* K6 `* O) ]+ g+ H3 }2 Z6 F, {is a significant concern for physicians. Central5 A: E9 f0 [! t% O
precocious puberty (CPP), which is mediated% d" f' ~7 B9 m: v; d# o% Y
through the hypothalamic pituitary gonadal axis, has& m# P* j/ |. m# P6 o
a higher incidence of organic central nervous system
- i; e! j; @# F6 O9 o6 Ulesions in boys.1,2 Virilization in boys, as manifested
# E" @$ f# A3 c% U2 x6 e2 wby enlargement of the penis, development of pubic
$ J. T5 Y8 J0 P3 O* ~hair, and facial acne without enlargement of testi-( h/ z* { Q) S$ B8 g* e5 ]
cles, suggests peripheral or pseudopuberty.1-3 We1 Q0 k8 t8 g# C
report a 16-month-old boy who presented with the: i1 O3 |9 v0 G5 E( ^
enlargement of the phallus and pubic hair develop-# ~6 x7 R4 N" `6 q/ }
ment without testicular enlargement, which was due7 k2 b/ e' e, w3 Q4 e4 P+ {
to the unintentional exposure to androgen gel used by8 u+ ^7 X# @1 h7 q0 X
the father. The family initially concealed this infor-# S3 N ]( ?- N* Z+ B2 r
mation, resulting in an extensive work-up for this
, W) t' }6 k9 w" y' F; zchild. Given the widespread and easy availability of5 r" W4 b/ Y/ R6 ^' d& C4 U
testosterone gel and cream, we believe this is proba-% U6 L3 l# Y) ]6 x
bly more common than the rare case report in the* |9 _ X& o& [ L
literature.4
7 I( F- P, P5 ^; o4 m- }8 w1 l% E3 oPatient Report
9 w1 `& \5 \9 SA 16-month-old white child was referred to the' A L+ r: u4 p1 a7 b
endocrine clinic by his pediatrician with the concern" D% }3 X& D0 Y' \8 a: ~4 m$ l
of early sexual development. His mother noticed2 a& T( V0 V4 P% _4 q- b5 M0 x
light colored pubic hair development when he was
) n' F x f8 n# |) E6 s6 DFrom the 1Division of Pediatric Endocrinology, 2University of% M! j$ L7 h* V3 }# w9 p
South Alabama Medical Center, Mobile, Alabama. p" `/ \( q) h, u2 R
Address correspondence to: Samar K. Bhowmick, MD, FACE,
! t) ]$ T- l- g. [Professor of Pediatrics, University of South Alabama, College of
6 T: F6 C- `' R) U& o4 gMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;5 t' D3 Z% F: T
e-mail: [email protected].
. k+ @8 Y+ T" Dabout 6 to 7 months old, which progressively became
. K9 b% G" N" ?+ C4 j$ Gdarker. She was also concerned about the enlarge-' S1 g+ o6 S }" a/ F; @5 I
ment of his penis and frequent erections. The child
. y, k4 p/ S7 wwas the product of a full-term normal delivery, with3 _- |) y$ }# F$ u2 G- m; c. W
a birth weight of 7 lb 14 oz, and birth length of& V: X `4 X& }4 p
20 inches. He was breast-fed throughout the first year/ W+ {# Z" \6 j$ }8 B
of life and was still receiving breast milk along with
+ g1 _0 e4 ~1 f8 V3 w% ]% wsolid food. He had no hospitalizations or surgery,
: a% _" t2 u% T% p5 q' iand his psychosocial and psychomotor development
/ t! w; k9 S* m% w. v, Y; gwas age appropriate.! U2 a" F) d" U( T; A, j. o
The family history was remarkable for the father,9 \5 x: _2 G# v. z
who was diagnosed with hypothyroidism at age 16,5 z" ?- w# ^# d( L( A
which was treated with thyroxine. The father’s/ P( d6 _+ N: k
height was 6 feet, and he went through a somewhat Y* |* S6 n" y! z3 O, s) r
early puberty and had stopped growing by age 14.0 z. B2 j4 |" g
The father denied taking any other medication. The
9 S' t5 i* j) X8 tchild’s mother was in good health. Her menarche, [/ F" q k2 L( }4 l+ R" \# g1 ]
was at 11 years of age, and her height was at 5 feet7 i; _& W0 d) W. t/ _- N. k# e
5 inches. There was no other family history of pre-
/ f! o3 x/ A2 [, Gcocious sexual development in the first-degree rela-: S/ k2 a+ G @$ M: m
tives. There were no siblings.9 P, F8 j- G' k8 u }
Physical Examination0 ], T/ [: ~- A: D; P$ N; W
The physical examination revealed a very active," ~1 T' G4 l: K; g, U; Y7 _0 C6 G
playful, and healthy boy. The vital signs documented
9 ^& N5 B0 c, H" _a blood pressure of 85/50 mm Hg, his length was" ^0 ~% L# p9 u
90 cm (>97th percentile), and his weight was 14.4 kg" a8 Q/ s4 w0 I2 e
(also >97th percentile). The observed yearly growth5 s, _. \+ W3 a! |7 ?- Z
velocity was 30 cm (12 inches). The examination of2 v( F- _2 m t) @$ b
the neck revealed no thyroid enlargement.7 p+ `% |' @4 G! H* T5 Q
The genitourinary examination was remarkable for8 e8 V2 p" l0 Q* y3 y; k! M L
enlargement of the penis, with a stretched length of5 I/ |0 A' B: W( {( w
8 cm and a width of 2 cm. The glans penis was very well
6 [; u6 F* D# y" } u( v3 [1 Udeveloped. The pubic hair was Tanner II, mostly around
1 L W8 ^+ D- g1 I) n% U0 u540- K: z, D" S. Y4 g) C( M% ]. N
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
5 Z/ V* u; q, }; ~the base of the phallus and was dark and curled. The5 V) z5 _$ L" e+ w
testicular volume was prepubertal at 2 mL each. c; s2 _( e1 C$ Q
The skin was moist and smooth and somewhat" K. p! G: a7 }+ }
oily. No axillary hair was noted. There were no' l+ I8 v4 C ^
abnormal skin pigmentations or café-au-lait spots./ H% \" z4 X% X4 b: Y3 S
Neurologic evaluation showed deep tendon reflex 2+
# F2 |3 p V( @4 Qbilateral and symmetrical. There was no suggestion
& g0 J0 K- g4 e: |9 Eof papilledema.
# E- Z4 e& O% k) Q3 aLaboratory Evaluation6 `/ a! v/ h9 C8 W9 u
The bone age was consistent with 28 months by5 S1 ]9 P! m9 U8 s+ ]
using the standard of Greulich and Pyle at a chrono-
" J; b T( C) f Flogic age of 16 months (advanced).5 Chromosomal
; u* n* O- s* `$ Z- mkaryotype was 46XY. The thyroid function test
: h2 r( [$ J8 k1 kshowed a free T4 of 1.69 ng/dL, and thyroid stimu-
% T( C8 C$ R8 b A7 }1 J! ulating hormone level was 1.3 µIU/mL (both normal).
+ s* v. j: ?3 }, F4 ZThe concentrations of serum electrolytes, blood Y( I7 t! c( T0 s' E* a1 A
urea nitrogen, creatinine, and calcium all were2 X: \/ {. v: R- |4 Y0 S
within normal range for his age. The concentration
' _+ Q; c: o# D, Pof serum 17-hydroxyprogesterone was 16 ng/dL& J" [# d, K* r V% M
(normal, 3 to 90 ng/dL), androstenedione was 20* }4 E1 K @( d6 P5 u
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-" {# N/ q: C3 q E
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
' `; `( g* l( D; [3 hdesoxycorticosterone was 4.3 ng/dL (normal, 7 to8 m& U& v2 h) m O
49ng/dL), 11-desoxycortisol (specific compound S)
, G' d0 l! y0 Vwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-* o: d! I1 N- a- [& s2 X0 U& @7 p, U
tisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total
: T% Y1 e' b# _+ d( Qtestosterone was 60 ng/dL (normal <3 to 10 ng/dL),
7 o4 E1 n* B8 w1 [4 H" t$ uand β-human chorionic gonadotropin was less than
& K$ w& s( [2 `0 {+ Z9 V5 mIU/mL (normal <5 mIU/mL). Serum follicular
& L: L& r. d. u8 zstimulating hormone and leuteinizing hormone
5 @6 _ ?) L7 F/ D. L7 b9 {4 Dconcentrations were less than 0.05 mIU/mL: N. | w% }: b; p* [) ~
(prepubertal).2 d9 M/ E$ ^! @
The parents were notified about the laboratory0 \) J& h, M. f& O- Q8 J i8 k
results and were informed that all of the tests were
2 G& V4 C0 t5 [. t, q; t4 O4 \normal except the testosterone level was high. The9 @( {. T! j( H5 }
follow-up visit was arranged within a few weeks to
0 \$ V+ v) z* ^obtain testicular and abdominal sonograms; how-
4 n$ e0 U; O6 oever, the family did not return for 4 months.$ f; r$ T& C" t H
Physical examination at this time revealed that the. O" ^# X* Y& X/ a+ u, D
child had grown 2.5 cm in 4 months and had gained
$ x9 }5 r1 a% j2 e4 b' n2 kg of weight. Physical examination remained6 i: L* M3 p- {9 q* K
unchanged. Surprisingly, the pubic hair almost com-, t8 M/ n: g4 }; g; E( b
pletely disappeared except for a few vellous hairs at
2 I' S0 z& `! D) a2 b: Z# O: Qthe base of the phallus. Testicular volume was still 2( D' T$ |% _# q: q
mL, and the size of the penis remained unchanged.# j2 Y& s5 t3 {
The mother also said that the boy was no longer hav-
: o$ {! w# p. G' B3 Y5 Ying frequent erections.
7 Q }8 L' k' n0 _Both parents were again questioned about use of3 y# }. n0 f" V7 E; ^
any ointment/creams that they may have applied to
: Z0 j* ^% ^+ l( J9 bthe child’s skin. This time the father admitted the. Q# H1 {- q' ~( ?. |. B
Topical Testosterone Exposure / Bhowmick et al 5412 @4 H2 w2 A% H, i) r; z" Q
use of testosterone gel twice daily that he was apply-4 R+ n) i% O6 w
ing over his own shoulders, chest, and back area for
9 u0 G, [" N6 i- f$ u7 va year. The father also revealed he was embarrassed
: e* D: h) e. k7 M" z4 P' hto disclose that he was using a testosterone gel pre-) i0 _" @7 I' I( V9 |5 M, m: C4 i+ W
scribed by his family physician for decreased libido
. @- `% K1 ]3 ^secondary to depression.# n; c0 J4 U6 W/ J# X# d4 ?' ^
The child slept in the same bed with parents.
/ A+ w F6 c2 c0 m/ D5 G# ^The father would hug the baby and hold him on his4 p2 [ A, o- c1 ~( }" b
chest for a considerable period of time, causing sig- T3 I6 S: @2 E8 i! U' o
nificant bare skin contact between baby and father.! y) T+ l- l5 @# O
The father also admitted that after the phone call,0 g8 e% E3 k( h! Y# h2 b. ], M
when he learned the testosterone level in the baby+ o3 w) o; K- W5 c: n1 c' \
was high, he then read the product information* j/ o4 Y* r* W3 y+ Y; M
packet and concluded that it was most likely the rea-8 z, c3 y A9 O9 q
son for the child’s virilization. At that time, they
3 f* L( R3 m, B5 D& n) ^decided to put the baby in a separate bed, and the- W% ?9 H/ w9 V$ h8 G
father was not hugging him with bare skin and had; V8 \( P5 Y" K
been using protective clothing. A repeat testosterone5 U! w9 ?# k9 r1 c6 I
test was ordered, but the family did not go to the, z1 o! _8 w; j; s
laboratory to obtain the test.
* e* z1 d; k# ?/ L9 P2 @Discussion
2 ~8 l8 D4 g% t. }3 S7 ^! HPrecocious puberty in boys is defined as secondary0 |1 f9 X1 j. f; ]9 t
sexual development before 9 years of age.1,4
0 o3 w# M, E `* y4 {. T% @Precocious puberty is termed as central (true) when
p: K6 J" t- V0 R& P4 \it is caused by the premature activation of hypo-
8 l: x& w' u$ c6 H' Bthalamic pituitary gonadal axis. CPP is more com-
! w0 F+ \/ t% h& K6 Ymon in girls than in boys.1,3 Most boys with CPP
0 U9 d- g* J rmay have a central nervous system lesion that is! F4 a' [4 |6 C$ _7 l" a
responsible for the early activation of the hypothal-) m) n6 m+ ]/ q/ x" U& h* {
amic pituitary gonadal axis.1-3 Thus, greater empha-
! l7 b* t% ?8 F" D7 Vsis has been given to neuroradiologic imaging in) W1 q0 h, v) M" d
boys with precocious puberty. In addition to viril-: d; E( |: z* _; L+ g8 a9 s8 |
ization, the clinical hallmark of CPP is the symmet-
7 O9 \7 H$ C0 X4 e' ~: |rical testicular growth secondary to stimulation by" _1 V1 D/ [. F7 ^7 t- K
gonadotropins.1,3
2 C3 U# r2 N# H) I' NGonadotropin-independent peripheral preco-8 j& T R2 C4 A( N& D9 K
cious puberty in boys also results from inappropriate
1 y. U" [7 v( z0 \androgenic stimulation from either endogenous or$ n& E$ A# O# G- c2 l9 G
exogenous sources, nonpituitary gonadotropin stim-
9 p0 ?4 k8 ?- [5 b0 s! i% eulation, and rare activating mutations.3 Virilizing
; Y, a) s5 D! p& C/ w( Jcongenital adrenal hyperplasia producing excessive; _% ]% k) j! ]/ n
adrenal androgens is a common cause of precocious
3 L( y( D/ s! b' q1 }: wpuberty in boys.3,4
0 p6 |, A5 i. ]( JThe most common form of congenital adrenal# N% l! `0 E$ j0 V4 H& m$ }
hyperplasia is the 21-hydroxylase enzyme deficiency.
3 n# S2 |) H$ O1 R. `9 XThe 11-β hydroxylase deficiency may also result in8 h& o# q/ w9 ]2 I5 r! a! c8 `
excessive adrenal androgen production, and rarely,! |& k- O% u0 `2 D+ E
an adrenal tumor may also cause adrenal androgen. c' u d7 M% A; q7 }: o& ~# y0 {
excess.1,31 i( K- }: |, G9 j. L
at University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
* h1 b0 Y M2 q% ]" p542 Clinical Pediatrics / Vol. 46, No. 6, July 2007, j+ j! `/ T. Q$ p1 l6 M5 K
A unique entity of male-limited gonadotropin-
# F. Q) d% \4 z3 ?$ Y7 rindependent precocious puberty, which is also known; y" X1 u9 L0 h% w
as testotoxicosis, may cause precocious puberty at a
9 p# Y2 z) L# D, q8 U% x( Avery young age. The physical findings in these boys
/ K6 O2 `8 s/ h. W+ o: Q" wwith this disorder are full pubertal development,
' o z' H7 z6 \6 V" w& G6 K: V" _; Vincluding bilateral testicular growth, similar to boys2 d6 i3 C" h/ K0 G. ^2 T: {2 B; p" q6 @
with CPP. The gonadotropin levels in this disorder
8 [* j+ ~+ j' ?7 `# v# O, lare suppressed to prepubertal levels and do not show
; `5 i6 |( o0 p3 w; a% p: Ypubertal response of gonadotropin after gonadotropin-+ [2 L: F/ F" m! ^! Z( x* C& A
releasing hormone stimulation. This is a sex-linked
% X1 I- P _) x$ {autosomal dominant disorder that affects only, q% {6 B0 r* ~# m4 Z' U& `
males; therefore, other male members of the family3 i j1 [7 \( X7 u) o
may have similar precocious puberty.3
) G4 J+ W. m" O5 ~4 `5 yIn our patient, physical examination was incon- Q# d& V4 l. S7 L/ ]
sistent with true precocious puberty since his testi-
0 d( N& S" c/ R3 Z* E% r" Bcles were prepubertal in size. However, testotoxicosis
7 u! g- O+ ^2 `5 awas in the differential diagnosis because his father
8 `" M8 V" ] j' {& vstarted puberty somewhat early, and occasionally,$ x5 F0 L! K7 N( A: r* K ?
testicular enlargement is not that evident in the: R5 T* q A' N! ^- I/ f
beginning of this process.1 In the absence of a neg-
2 D. r" a% _9 B$ e/ Vative initial history of androgen exposure, our, J' N' z# R$ u1 h0 m! @4 ?
biggest concern was virilizing adrenal hyperplasia,
9 L2 p$ E' _; E6 T6 d" Eeither 21-hydroxylase deficiency or 11-β hydroxylase- j3 V, ]# d) y3 ~2 v
deficiency. Those diagnoses were excluded by find-
" g( f" z! }1 i: bing the normal level of adrenal steroids.5 H) B' {' `9 O* g% n8 a
The diagnosis of exogenous androgens was strongly
/ T/ I ^8 z& F2 vsuspected in a follow-up visit after 4 months because
# `& d6 A0 b+ f) U* \9 Z7 `the physical examination revealed the complete disap-6 M: r# C( J9 F( N
pearance of pubic hair, normal growth velocity, and
n* }( @3 t- r, [/ Bdecreased erections. The father admitted using a testos-
( s2 z7 v3 `1 H3 Uterone gel, which he concealed at first visit. He was9 O) V9 Y$ `, s8 E9 E8 o' C
using it rather frequently, twice a day. The Physicians’
; o% `) p2 s' T9 gDesk Reference, or package insert of this product, gel or1 m# U7 M4 k6 I6 I
cream, cautions about dermal testosterone transfer to/ r: v/ Z( G0 y# s! k; E
unprotected females through direct skin exposure.
- C9 A* F8 z( l8 V8 F$ ^Serum testosterone level was found to be 2 times the/ a; p) R8 T% L! E, J
baseline value in those females who were exposed to
* V" u/ a! O; T1 ^# E: ]even 15 minutes of direct skin contact with their male1 Y) R i6 d* @% g4 ]7 K- _0 H) M
partners.6 However, when a shirt covered the applica-
" D! A4 j! _3 d: Y- h) P, w( Ction site, this testosterone transfer was prevented.: O7 M( z' S& J8 h9 a9 I9 w
Our patient’s testosterone level was 60 ng/mL,
! @# t' F4 m0 kwhich was clearly high. Some studies suggest that
7 ~8 i2 c- I7 [- ~dermal conversion of testosterone to dihydrotestos-
4 x# y3 F8 k: ~, O1 Q# \0 z* Vterone, which is a more potent metabolite, is more, p1 A& C6 ?3 Y8 q8 {/ h( M' E3 P' f
active in young children exposed to testosterone
5 s' r$ s. q" n ?% qexogenously7; however, we did not measure a dihy- z7 D/ f, e4 W" \# a4 P8 M
drotestosterone level in our patient. In addition to' o) B. b; n: M* ], M$ e
virilization, exposure to exogenous testosterone in) L% X& p& B0 p7 @& d# S+ K
children results in an increase in growth velocity and' w6 N+ J( `! B- M7 n
advanced bone age, as seen in our patient.! ]+ R- l2 N. M* X: r
The long-term effect of androgen exposure during
9 k: \: t* }$ d- [# j! T% searly childhood on pubertal development and final
?$ s8 f; u/ v9 Z2 q* zadult height are not fully known and always remain
3 t$ q( } V3 `- Ga concern. Children treated with short-term testos-
6 t" t% u1 @& [- ]% @/ tterone injection or topical androgen may exhibit some8 H* F$ C/ J& W k2 f* c; [
acceleration of the skeletal maturation; however, after8 I; G0 Y. `; p& v' }, r: \
cessation of treatment, the rate of bone maturation
( I0 q, f" K, v4 d9 t( Ydecelerates and gradually returns to normal.8,9
5 M- p, _7 @2 a# nThere are conflicting reports and controversy5 X1 s' S# L# Z1 S# y1 \3 }& l
over the effect of early androgen exposure on adult1 U8 Q4 f2 s4 n3 Z
penile length.10,11 Some reports suggest subnormal: O9 `4 W8 F( @" Q7 w
adult penile length, apparently because of downreg-. O3 [4 [* }- P) D- M
ulation of androgen receptor number.10,12 However,
+ b3 h O# H& C% b6 r: e* e, RSutherland et al13 did not find a correlation between2 `# C/ }0 |2 v. j
childhood testosterone exposure and reduced adult9 o6 C3 k5 l+ m. I. M j' O
penile length in clinical studies.
$ G0 I8 Z" \, z* w% ]Nonetheless, we do not believe our patient is
* X+ i7 V/ Z! q8 e; X/ u; |going to experience any of the untoward effects from
9 c l5 O9 _3 a# ~0 Itestosterone exposure as mentioned earlier because
, K0 m" ?4 ^0 Dthe exposure was not for a prolonged period of time.
( P& z, |, D. B8 AAlthough the bone age was advanced at the time of
6 U( C" S( @0 ^1 ?/ d/ i6 idiagnosis, the child had a normal growth velocity at7 e7 u0 i, F# e8 p3 \
the follow-up visit. It is hoped that his final adult
1 w- e. J* N6 V1 O$ o" \ gheight will not be affected.; l, t; o0 q& Z1 Q9 |
Although rarely reported, the widespread avail-
% W8 W0 T$ k& h l7 a4 f$ l. @ability of androgen products in our society may
u4 r( P7 |+ O- j2 `2 R- p; ?4 cindeed cause more virilization in male or female3 }! |7 U( G7 F6 F
children than one would realize. Exposure to andro-
' k/ N$ D7 W2 e O, q8 n$ \+ jgen products must be considered and specific ques-: F+ o; l; L8 M
tioning about the use of a testosterone product or
# L; U- K+ h6 e, |gel should be asked of the family members during
1 K+ p' s, H) X0 |% P2 s; ythe evaluation of any children who present with vir-
( E8 O" E. l! @" n, ailization or peripheral precocious puberty. The diag-* ]) O g, j& E
nosis can be established by just a few tests and by; y% X$ O3 K% l9 A# G* p2 n# C2 T
appropriate history. The inability to obtain such a4 w5 Q5 [, h* S
history, or failure to ask the specific questions, may3 }5 ]* W' z8 {2 p! K$ G
result in extensive, unnecessary, and expensive) e$ D* g8 z0 _7 `7 c: B$ E1 Y
investigation. The primary care physician should be
* ^* H* ^" J% e& uaware of this fact, because most of these children
4 F" I; o" H* q+ w0 Pmay initially present in their practice. The Physicians’
) l, i; T8 c4 J8 B" ] _1 `Desk Reference and package insert should also put a4 M8 D" b' S( \1 A/ v5 Q+ U+ T
warning about the virilizing effect on a male or
7 @# D, U4 H: yfemale child who might come in contact with some-
4 v6 z% f3 B" d+ z; o! R2 sone using any of these products.& `) A; b5 y* `3 S4 `
References
$ ]4 R6 M+ b: k; G( V1. Styne DM. The testes: disorder of sexual differentiation
; S" y; c/ u Z- ~- R, a: i* a" eand puberty in the male. In: Sperling MA, ed. Pediatric5 l4 A) ]$ o% P2 Q
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
7 p) e2 y5 b/ y" r6 X/ U2002: 565-628.% `- }2 V* s& `5 n2 M& y; y
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
% v. J7 Q/ _- M7 W5 vpuberty in children with tumours of the suprasellar pineal |
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