Original Paper

HORMONE Horm Res 2007;68:150–155 Received: August 8, 2006

RESEARCH DOI: 10.1159/000106375 Accepted: October 30, 2006
Published online: July 19, 2007

Genital Anomalies in Klinefelter’s

Syndrome
Yung Seng Lee a, b Anna Wai Fun Cheng c Syed Faisal Ahmed d Nick J. Shaw e
Ieuan A. Hughes b
a
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; b University of
Cambridge School of Clinical Medicine, Cambridge, UK; c Department of Paediatrics and Adolescent Medicine,
Princess Margaret Hospital, Kwai Chung, Hong Kong, SAR; d Royal Hospital For Sick Children, Glasgow, and
e
Birmingham Children’s Hospital, Birmingham, UK

Key Words ever, it is important to acknowledge the association, and rec-

Klinefelter ! Genitalia ognize Klinefelter’s syndrome as one of the causes of abnor-
mal genitalia at birth. Copyright © 2007 S. Karger AG, Basel

Abstract
Background/Aims: Klinefelter’s syndrome is characterized
by progressive testicular failure causing aspermatogenesis
and androgen deficiency. Klinefelter patients classically have
complete male sex differentiation, and genital anomalies are
generally not recognized as associated features of the syn-
drome. Methods: We reviewed the cases of Klinefelter’s syn-
drome with genitalia abnormalities from the Cambridge Dis-
orders of Sex Development Database, and also reviewed
previous case reports of genital anomalies associated with
Klinefelter’s syndrome and its variants. Results: We present
seven Klinefelter patients with abnormalities of the genita-
lia, ranging from mild anomalies (chordee) to moderate un-
dervirilisation (bifid scrotum and perineal hypospadias).
Two cases were true hermaphrodites with karyotypes 47,XXY
and 47,XXY/46,XX respectively. Though androgen insensitiv-
ity has been postulated previously as a possible pathogenic
mechanism, we demonstrated normal androgen binding in
3 cases in which this was studied. Review of other case re-
ports revealed a range of mild-to-severe abnormalities as
well as cases reported as sex reversal, testicular feminization,
and true hermaphroditism. Conclusion: Genital anomalies
are not commonly observed in Klinefelter’s syndrome. How-
Klinefelter’s syndrome is a common sex chromosome
aneuploidy with a reported incidence of one in 600–1,000
live male births [1, 2]. The classical syndrome and its vari-
ants have in common an abnormal karyotype of a Y chro-
mosome and at least two X chromosomes [3]. The syn-
drome is characterized by progressive testicular failure,
causing azoospermia, gynaecomastia and other signs of
androgen deficiency [4, 5]. Other features include unde-
scended testes, neurocognitive difficulties, tall stature
with disproportionately long legs, and increased risk of
glucose intolerance, breast cancer and osteoporosis. It is
generally acknowledged that affected individuals have
male genitalia without ambiguity, although there may be
an associated micropenis. Testis determination and lack
of ovarian development in individuals with 47,XXY and,
more strikingly, in those with 49,XXXXY complements,
indicate that a single Y chromosome and the expression
of the testis-determining gene (SRY) are sufficient to
bring about testis organogenesis and male sex differen-
tiation despite the loss of the sex chromosome hemizy-
gous state.

© 2007 S. Karger AG, Basel Prof. Ieuan Hughes

0301–0163/07/0683–0150$23.50/0 Department of Paediatrics, University of Cambridge
Fax +41 61 306 12 34 Box 116, Level 8, Addenbrooke’s Hospital
E-Mail karger@karger.ch Accessible online at: Hills Road, Cambridge CB2 2QQ (UK)
www.karger.com www.karger.com/hre Tel. +44 1223 336 885, Fax +44 1223 336 996, E-Mail iah1000@cam.ac.uk
 Cases of Klinefelter’s syndrome with abnormalities
of the genitalia have been described previously, and an-
drogen insensitivity has been postulated as the possible
pathogenic mechanism [6–8]. This paper reports 7 cas-
es of Klinefelter’s syndrome referred for investigation
via the Cambridge Disorders of Sex Development Da-
tabase because of genital anomalies. Analysis of andro-
gen binding in fibroblasts established from genital skin
biopsies collected at the time of surgery in 3 cases
showed no evidence of a dysfunctional androgen recep-
tor. The spectrum of genital anomalies reported in
Klinefelter’s syndrome is reviewed. Consent for these
studies was obtained from the local ethics committee
as part of a research programme on disorders of sex de-
velopment.
Case Reports
Case 1
Ambiguous genitalia were noted at birth, comprising a bifid
scrotum, perineal hypospadias, and micropenis with severe chor-
dee. Both gonads were in the scrotum, and vasa deferentia and
epididymes were present. Associated anomalies included a sagit-
tal craniosynostosis, dysplastic ears and crossed-fused renal ec-
topia. Karyotype was 47,XXY. A basal testosterone level was
2.2 nmol/l at 4 weeks, which failed to rise following stimulation
with human chorionic gonadotropin (hCG) (2,000 U daily for 3
days).
Androgen-binding studies were performed on cultured geni-
tal skin fibroblasts as reported previously [9]. The receptor con-
centration as measured by the binding capacity (Bmax) and recep-
tor binding affinity (Kd) were normal (Bmax 778 ! 1018 mol/!g
DNA; Kd 0.96 ! 1010 M). For our laboratory, the normal Bmax is
greater than 300 ! 10 –18/!g DNA with a Kd range of 0.8–1.7 !
10 –10.
Case 2
This patient had a bifid scrotum, penile hypospadias and bi-
lateral undescended testes. The penis was a normal size. Biopsy of
the right gonad showed a dysplastic testis. He also had elbow dys-
plasia, and radio-ulnar synostosis. Karyotype was 48,XXYY. Se-
rum testosterone concentration increased from 18 to 26 nmol/l
following a 3-day hCG stimulation performed at 13 years of age.
Case 3
This patient presented in the neonatal period with micropenis,
severe chordee, and a left undescended testis located in the ingui-
nal canal. Karyotype was 48,XXXY. The results of an hCG stimu-
lation test were as follows: testosterone 0.6 to 13.5 nmol/l; DHT
! 0.2 to 1.3 nmol/l; androstenedione !1 to 2.1 nmol/l.
Case 4
This infant was the first twin born preterm at 31 weeks’ gesta-
tion, and had a bifid scrotum, perineal hypospadias, and micro-
penis. The gonads were intra-abdominal. At surgery, the vas def-
erens, epididymis and a shallow vagina were identified, but there
Genital Anomalies in Klinefelter’s
was no uterus or Fallopian tubes. No endocrine investigation had
been undertaken prior to gonadectomy. Histology showed imma-
ture testicular tissue. Karyotype was 47,XXY.
The second twin also had ambiguous genitalia and the karyo-
type was 47,XXY. The infant died without further investiga-
tions.
Case 5
This newborn had penoscrotal transposition and perineal hy-
pospadias, but no micropenis. Both gonads were palpable in the
scrotum. Karyotype was 47,XXY. Serum testosterone increased
from 3.9 to 10.2 nmol/l, and dihydrotestosterone (DHT) from 0.6
to 2.5 nmol/l, following an hCG stimulation test at 10 days of
age.
Case 6
Presented at birth with a bifid scrotum, perineal hypospadias
and severe chordee. There was no micropenis. A gonad was lo-
cated in the left inguinal region; biopsy showed ovarian tissue
containing prominent primordial follicles. No Müllerian struc-
tures or vagina was found at surgery. The right gonad was located
in the scrotum associated with a vas deferens. Karyotype was
47,XXY in peripheral blood and fibroblasts. Serum testosterone
was undetectable before and after hCG stimulation at 5 years of
age. Serum estradiol was also undetectable. However, at 13 years
of age, repeat hCG test showed testosterone response from 1.5 to
5.8 nmol/l, and a raised oestradiol of 226 nmol/l associated with
some breast development.
An androgen binding assay gave the following normal results:
Bmax 408 ! 1018 mol/!g DNA, Kd 2.1 ! 1010 M.
Case 7
This patient was evaluated at birth for bifid scrotum, perineal
hypospadias and micropenis. The right gonad was located in the
scrotum, whereas the left gonad was intra-abdominal. Karyotype
was 47,XXY/46,XX in peripheral blood, bone marrow and fibro-
blasts. There was a small rudimentary uterus with fallopian tubes.
Histology showed both gonads were ovotestes.
At day 3, serum testosterone increased from 1.7 to 8.9 nmol/l
following a 3-day hCG stimulation test. An androgen receptor
binding assay gave the following normal results: Bmax 450 ! 10 –18
mol/!g DNA and Kd 1.2 ! 1010 M.
Table 1 provides a summary of the phenotypic findings in this
series of 7 cases of Klinefelter’s syndrome.
Previous Case Reports
A review of previous cases reported with genital anom-
alies is summarised in table 2 and subdivided into cate-
gories of complete sex reversal, true hermaphroditism
(ovotesticular disorder of sex development (DSD) [10]),
testicular feminization (complete androgen insensitivity
syndrome), undervirilisation, and mild genital anoma-
lies.
Of interest is the occurrence of sex reversal, true her-
maphroditism and androgen insensitivity in some of
Horm Res 2007;68:150–155 151
Table 1. Summary of genitourinary
anomalies identified in 7 cases Abnormalities of genitourinary system Patients Associated karyotypes

Bifid scrotum, perineal hypospadias, micropenis 3 47,XXY, 47,XXY/46XX

Bifid scrotum, perineal hypospadias 2 47,XXY, 48,XXYY
Penoscrotal transposition, perineal hypospadias 1 47,XXY
Micropenis with chordee 1 48,XXXY
Undescended testes 5 47,XXY, 48,XXYY,
48,XXXY
Presence of vagina 1 47,XXY
Presence of uterus & fallopian tubes 1 46,XX/47,XXY
Presence of ovarian tissue 2 47,XXY, 46,XX/47,XXY
Crossed fused renal ectopia 1 47,XXY

these reports associated with ambiguous or female exter-
nal genitalia. The report of a case of complete sex reversal
was associated with deletion of the SRY gene. In the 3 case
reports of androgen insensitivity, 1 had a strong family
history of the syndrome, and it is likely that the other 2
cases were also due to abnormalities of the X-linked an-
drogen receptor gene, with maternal non-disjunction of
both X chromosomes occurring during stage II meiosis.
Though the clinical definition of Klinefelter’s syndrome
or its variants is an abnormal male phenotype with extra
X chromosome, the cases of sex reversal and androgen
insensitivity with female phenotype were included to
highlight the spectrum of genital abnormalities which
can occur.
Case reports of true hermaphroditism were confined
not only to those with mosaicism, but also with a 47,XXY
karyotype, as in case 6 in this present report. However,
low-grade or gonadal mosaicism cannot be excluded. It is
noteworthy that ovarian tissue was identified in cases 6
and 7. Case 7 was a true hermaphrodite with ovotestes,
and mosaic with 47,XXY/46,XX female cell lines. Evalu-
ation of case 6 is incomplete, but it is deduced that the
right gonad comprised of testicular tissue, based on an
adjacent Wolffian duct and testosterone response to hCG
stimulation.
Discussion
Genital anomalies associated with Klinefelter’s syn-
drome have been reported sporadically, but this is not
mentioned as a feature of the condition in the standard
textbooks [5, 25]. We report seven cases from the Cam-
bridge Disorders of Sex Development Database, together
with a summary of previous case reports in order to high-
light the fact that small testes and micropenis are not the
only abnormalities of the reproductive tract in Klinefel-
ter’s syndrome.
Among a number of theories proposed to explain the
mechanism of disordered genital development is andro-
gen insensitivity [6, 7]. Cases of androgen insensitivity
and a 47,XXY karyotype have also been reported in
which there are female or ambiguous male genitalia and
clinical features consistent with the 47,XXY karyotype
[8]. In the present study, normal androgen binding char-
acteristics were demonstrated in three patients with am-
biguous genitalia in whom this was studied. It is there-
fore unlikely that the genital anomalies are related to
dysfunction of the androgen receptor (AR) secondary to
a deleterious mutation affecting androgen binding or re-
ceptor expression. Nevertheless, in a recent study of 46
Klinefelter patients heterozygous for the CAGn trinucle-
otide repeat polymorphism of the AR gene, the allele
with shorter CAGn trinucleotide repeats in the androgen
receptor was preferentially inactivated, and a longer
CAGn was positively correlated with features of hypogo-
nadism, such as gynaecomastia, smaller testis, height
and lower bone density [26]. Another study which exam-
ined genetic factors that may influence the variable phe-
notype in Klinefelter’s syndrome reported an inverse
correlation between the repeat length of the highly poly-
morphic CAGn trinucleotide repeat and penile length, a
biological indicator of early androgen action [27]. These
observations were supported by another study which re-
ported that the length of polyglutamine tract encoded by
CAGn trinucleotide repeats is inversely correlated with
the activity of the androgen receptor as a transcription
factor as measured in vitro [28]. While it is plausible that
this may influence fetal androgen production and/or ac-
tion during male sex differentiation, Leydig cells in
Klinefelter’s syndrome generally only become impaired
around puberty. Testosterone production measured fol-

152 Horm Res 2007;68:150–155 Lee /Cheng /Ahmed /Shaw /Hughes

Table 2. Summary of case reports of
Klinefelter’s syndrome with genital
anomalies
Genital Anomalies in Klinefelter’s
Phenotype Karyotype Ref.
Complete sex reversal
– Mother and daughter with normal female 47,XXY with SRY deletion 10
phenotype and fertility
True hermaphroditism (ovotesticular DSD)
– Hypospadias with bilateral ovotestes in 46,XX/47,XXY 12
scrotum, both Wolffian and Müllerian
duct-derived structures
– Hypospadias, right undescended testis, left 46,XX/47,XXY/48,XXYY 13
ovary, uterus
– Prader III ambiguous genitalia, with right testes 47,XXY
and vas deferens, left ovary with fallopian tube, SRY present
hemi-uterus
– Prader IV ambiguous genitalia, right testes with 46,XX/47,XXY
14
vas deferens, left ovotestes with fallopian tube, no SRY present
uterus
– Male genitalia (Prader V), with testes on left, 46,XX/47,XXY
ovary and fallopian tube on the right, hemi-uterus SRY present
Testicular feminization (complete androgen insensitivity syndrome)
– Testicular feminization in monozygotic twins, 47,XXY 15
with female external genitalia (vagina present),
inguinal testes; no uterus
– Testicular feminization with female external 47,XXY 16
genitalia, short vagina with blind end, left gonad
at inguinal region, right side not palpable; four
family members had Morris syndrome
– Testicular feminization with female external 47,XXY 17
genitalia, clitoromegaly, vagina, absent uterus and (both X from maternal non-
ovaries disjunction at meiosis II)
Ambiguous genitalia/undervirilisation
– Bifid scrotum with descended testes, penile 47,XXY 18
hypospadias, severe chordee
– Micropenis, marked chordee, urethral opening 47,XXY 19
at base of phallus, inguinal testes
– Penoscrotal hypospadias 47,XXY
– Scrotal hypospadias unknown 6
– Epispadias 47,XXY
– Penoscrotal hypospadias, bilateral cryptorchi- 47,XXY 20
dism
– Penoscrotal transposition, penile hypospadias; 47,XXY (80.6%)/48,XXY,+21 21
no uterus, vagina or ovary
– Female external genitalia, clitoromegaly, testes 47,XXY 22
in labia majora, urogenital sinus separating into
vagina and ureter; remnants of the ductus meso-
nephricus and uterus present
Mild abnormalities
– Identical twins with micropenis and chordee 47,XXY 23
– Chordee with unilateral cryptorchidism 47,XXY 24
– Two cases with prepenile scrotum 47,XXY 7
Horm Res 2007;68:150–155 153
lowing hCG stimulation during the neonatal period in
our cases in which this test was performed showed nor-
mal androgen production. Indeed, basal serum concen-
trations of FSH and LH, and the responses to LHRH and
hCG stimulation are within the normal range for age be-
fore puberty [4, 5, 29]. Testicular histology and androgen
production become abnormal peripubertally, leading to
the typical profile of elevated serum gonadotrophin and
low testosterone concentrations [30]. However, amniotic
fluid concentrations of testosterone and its precursors
may be subnormal in fetuses with Klinefelter’s syndrome
during the time critical for sexual differentiation. A
study reported that testosterone levels in a fetus with
Klinefelter’s syndrome measured from the 12th week of
pregnancy were comparable only to testosterone values
in female fetuses [31]; however, another study did not
detect subnormal androgen levels in two fetuses with
Klinefelter’s syndrome [32]. As masculinisation of the
external genitalia is largely completed prior to the 12th
week of gestation, these data may not be directly relevant,
but nonetheless may still reflect the events during the
first 12 weeks of gestation, and supports our hypothesis
that variability in androgen production within the criti-
cal window period in utero, CAGn polymorphisms, and
skewed X chromosome inactivation interact to deter-
mine the variable phenotype of the external genitalia
amongst cases of Klinefelter’s syndrome.
Another possibility to explain effects of disordered
genital development in Klinefelter’s syndrome may relate
to the dosage-sensitive sex reversal (DSS) or DAX-1 gene
locus on the X chromosome [33]. The presence of two
DAX-1 genes can have an anti-testis effect by suppressing
the testis determining SRY gene in utero. In Klinefelter’s
syndrome the extra X chromosome (and DAX-1) is gener-
ally inactivated. However, incomplete X-inactivation is a
possible mechanism that may explain why genital anom-
alies are not a universal finding in this syndrome. Skewed
X-inactivation has been reported in Klinefelter patients
which, together with differential expression of paternal
versus maternal alleles by imprinting, may also be a caus-
ative factor [26, 34].
Although genital abnormalities are not commonly ob-
served in Klinefelter patients, it is important to acknowl-
edge the association, and recognize Klinefelter’s syn-
drome as one of the causes of genital abnormality or am-
biguity.
It appears that the observation of an association of
genital anomalies with Klinefelter’s syndrome warrant its
inclusion in the list of phenotypic features of this com-
mon syndrome.
Acknowledgements
The authors would like to acknowledge the contribution of Dr.
Chizo Agwu and Mr. Peter Gornall who provided important in-
formation for this paper.

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