Epidemiology of an Underdiagnosed Syndrome

Abstract

The first description of Klinefelter syndrome (KS) dates back to 1942, when Harry F. Klinefelter et al. (J Clin Endocrinol 2(11):615–627, 1942) reported the occurrence of a ‘not uncommon’ syndrome characterized by small testes, tall stature, gynaecomastia and azoospermia. In 1959, Patricia A. Jacobs et al. (Nature 183(4657):302–303, 1959) identified the causal role in 47,XXY chromosomal aneuploidy, allowing its diagnosis by karyotyping.

The real prevalence of KS in the whole population is still unknown. This is related to poor medical awareness of the condition, to the wide heterogeneity of the clinical presentation, and to the lack of a universal agreement on screening programmes. This leads to a delay or to an unclear diagnosis in the majority of KS men (Herlihy et al., Med J Aust 194:24–28, 2011; Swerdlow et al., J Clin Endocrinol Metab 90(12):6516–6522, 2005; Nieschlag, Dtsch Arztebl Int 110:347–353, 2013), with the potentially harmful consequence of a higher prevalence of comorbidities and increased cardiovascular mortality.

Most men suffering from KS do not receive a diagnosis throughout their life. Moreover, it is reported that almost half of the diagnoses are performed in adulthood, perhaps after the beneficial time for proper educational and medical interventions (Herlihy and McLachlan, Curr Opin Endocrinol Diabetes Obes 22(3):224–229, 2015; Simpson et al., Genet Med 5(6):460–468, 2003). KS patients may suffer from endocrinological, haematological, neurocognitive, behavioural and social disorders in a larger proportion than the rest of the population. This could be a consequence of a different expression of several genes throughout the genome due to the presence of a supernumerary X chromosome (Taylor and Moores, J Med Genet 4(4):258–259, 1967). Whether demographic differences in KS prevalence exist is currently not known. It is essential to understand the prevalence of the syndrome and how widespread are late and even failed diagnoses.