A possible means of countering the underdiagnosis of Klinefelter Syndrome.

Klinefelter syndrome (KS) is a frequent male genetic disorder (incidence 1:1000 ~ 2:1000) provoked by a supernumerary X-chromosome and thus a 47,XXY karyotype. Although many efforts have been put into obtaining an experimental and clinical understanding of the syndrome, it remains frustratingly underdiagnosed with a remarkable portion of cases being unidentified, that is only 10% of prepubertal Klinefelter boys being diagnosed as such. This is particularly important as the disease can be associated with several adverse features such as hypergonadotropic hypogonadism and infertility but also metabolic and cognitive alterations, which are causative of significantly increased mortality and morbidity rates in those affected.1 Therefore, there is a need for novel methods enabling a fast and reliable routine diagnosis of patients. In the paper, ‘Novel Methylation Specific Real Time PCR Test for the Diagnosis of Klinefelter Syndrome’ published on Asian Journal of Andrology, Mehta et al.2 reported a molecular assay for KS diagnosis based on the detection of supernumerary X-chromosomes using primers for unmethylated and methylated copies of the X-ch inactive-specific transcript gene (XIST). The XIST transcript is only expressed in somatic cells when more than one X-chromosome is present. In Klinefelter patients, it has been shown that the supernumerary X-chromosome is inactivated in a similar manner as in women thus it has been suggested that the XIST expression can be used as a means to diagnose KS patients.3 The recognition of differences in XIST methylation has the potential of providing a very elegant sensitive and fast means of screening and diagnosing KS, even in the setting of low grade 47,XXY/46,XY mosaicism.

Other novel techniques are also available that can provide fast and reliable diagnosis of KS, for example, array based multiplex ligation-dependent probe amplification (MLPA)4 for the rapid screening of chromosomal aneuploidies or the equally elegant assessment of the copy number of the androgen receptor by quantitative polymerase chain reaction (qPCR).5 These techniques should also be considered in further development of diagnostic tools for the detection of KS.

Finally, the general goal of these efforts is to counter the dramatic failure in the timely diagnosis of these patients as such the present well-conducted study represents a worthy contribution along the route to provide this large cohort of patients with improved medical care. Therefore, the work reported in this paper2 is of high relevance to the field for two reasons: firstly, it could result in a new diagnostic tool, but secondly and perhaps more importantly, it might stimulate others to put effort into the early detection of the condition, which would be an important step towards an improved treatment of the many co-morbidities of the syndrome by setting up clinical care in these boys and men earlier.

COMPETING INTERESTS

All authors declare no competing interests.