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Abstract
Background/Aims: Klinefelter’s syndrome is characterized
by progressive testicular failure causing aspermatogenesis Klinefelter’s syndrome is a common sex chromosome
and androgen deficiency. Klinefelter patients classically have aneuploidy with a reported incidence of one in 600–1,000
complete male sex differentiation, and genital anomalies are live male births [1, 2]. The classical syndrome and its vari-
generally not recognized as associated features of the syn- ants have in common an abnormal karyotype of a Y chro-
drome. Methods: We reviewed the cases of Klinefelter’s syn- mosome and at least two X chromosomes [3]. The syn-
drome with genitalia abnormalities from the Cambridge Dis- drome is characterized by progressive testicular failure,
orders of Sex Development Database, and also reviewed causing azoospermia, gynaecomastia and other signs of
previous case reports of genital anomalies associated with androgen deficiency [4, 5]. Other features include unde-
Klinefelter’s syndrome and its variants. Results: We present scended testes, neurocognitive difficulties, tall stature
seven Klinefelter patients with abnormalities of the genita- with disproportionately long legs, and increased risk of
lia, ranging from mild anomalies (chordee) to moderate un- glucose intolerance, breast cancer and osteoporosis. It is
dervirilisation (bifid scrotum and perineal hypospadias). generally acknowledged that affected individuals have
Two cases were true hermaphrodites with karyotypes 47,XXY male genitalia without ambiguity, although there may be
and 47,XXY/46,XX respectively. Though androgen insensitiv- an associated micropenis. Testis determination and lack
ity has been postulated previously as a possible pathogenic of ovarian development in individuals with 47,XXY and,
mechanism, we demonstrated normal androgen binding in more strikingly, in those with 49,XXXXY complements,
3 cases in which this was studied. Review of other case re- indicate that a single Y chromosome and the expression
ports revealed a range of mild-to-severe abnormalities as of the testis-determining gene (SRY) are sufficient to
well as cases reported as sex reversal, testicular feminization, bring about testis organogenesis and male sex differen-
and true hermaphroditism. Conclusion: Genital anomalies tiation despite the loss of the sex chromosome hemizy-
are not commonly observed in Klinefelter’s syndrome. How- gous state.
these reports associated with ambiguous or female exter- only abnormalities of the reproductive tract in Klinefel-
nal genitalia. The report of a case of complete sex reversal ter’s syndrome.
was associated with deletion of the SRY gene. In the 3 case Among a number of theories proposed to explain the
reports of androgen insensitivity, 1 had a strong family mechanism of disordered genital development is andro-
history of the syndrome, and it is likely that the other 2 gen insensitivity [6, 7]. Cases of androgen insensitivity
cases were also due to abnormalities of the X-linked an- and a 47,XXY karyotype have also been reported in
drogen receptor gene, with maternal non-disjunction of which there are female or ambiguous male genitalia and
both X chromosomes occurring during stage II meiosis. clinical features consistent with the 47,XXY karyotype
Though the clinical definition of Klinefelter’s syndrome [8]. In the present study, normal androgen binding char-
or its variants is an abnormal male phenotype with extra acteristics were demonstrated in three patients with am-
X chromosome, the cases of sex reversal and androgen biguous genitalia in whom this was studied. It is there-
insensitivity with female phenotype were included to fore unlikely that the genital anomalies are related to
highlight the spectrum of genital abnormalities which dysfunction of the androgen receptor (AR) secondary to
can occur. a deleterious mutation affecting androgen binding or re-
Case reports of true hermaphroditism were confined ceptor expression. Nevertheless, in a recent study of 46
not only to those with mosaicism, but also with a 47,XXY Klinefelter patients heterozygous for the CAGn trinucle-
karyotype, as in case 6 in this present report. However, otide repeat polymorphism of the AR gene, the allele
low-grade or gonadal mosaicism cannot be excluded. It is with shorter CAGn trinucleotide repeats in the androgen
noteworthy that ovarian tissue was identified in cases 6 receptor was preferentially inactivated, and a longer
and 7. Case 7 was a true hermaphrodite with ovotestes, CAGn was positively correlated with features of hypogo-
and mosaic with 47,XXY/46,XX female cell lines. Evalu- nadism, such as gynaecomastia, smaller testis, height
ation of case 6 is incomplete, but it is deduced that the and lower bone density [26]. Another study which exam-
right gonad comprised of testicular tissue, based on an ined genetic factors that may influence the variable phe-
adjacent Wolffian duct and testosterone response to hCG notype in Klinefelter’s syndrome reported an inverse
stimulation. 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
Discussion observations were supported by another study which re-
ported that the length of polyglutamine tract encoded by
Genital anomalies associated with Klinefelter’s syn- CAGn trinucleotide repeats is inversely correlated with
drome have been reported sporadically, but this is not the activity of the androgen receptor as a transcription
mentioned as a feature of the condition in the standard factor as measured in vitro [28]. While it is plausible that
textbooks [5, 25]. We report seven cases from the Cam- this may influence fetal androgen production and/or ac-
bridge Disorders of Sex Development Database, together tion during male sex differentiation, Leydig cells in
with a summary of previous case reports in order to high- Klinefelter’s syndrome generally only become impaired
light the fact that small testes and micropenis are not the around puberty. Testosterone production measured fol-
References
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