Klinefelter syndrome beyond hypogonadism: multisystem manifestations and a framework for clinical surveillance

Klinefelter syndrome (KS) is the most common male sex chromosome aneuploidy, affecting approximately 1 in 450-600 male births. Characterised by a 47,XXY karyotype in the majority of cases, it is widely known for its association with hypergonadotropic hypogonadism, infertility, and impaired testicular function; however, the clinical consequences of the supernumerary X chromosome extend far beyond the reproductive axis. This review provides an updated and integrative overview of the multisystem involvement in KS, with particular emphasis on metabolic derangements, cardiovascular and thromboembolic risk, skeletal health, malignancy patterns, thyroid dysfunction, and neurocognitive outcomes. Emerging concepts, including the bone-testicular axis, the role of insulin-like peptide 3 (INSL3), and osteocalcin-mediated endocrine crosstalk, are critically appraised. Recent data on mortality, accelerated biological ageing, and the systemic impact of testosterone replacement therapy (TRT) are discussed in light of contemporary evidence. Given the substantial burden of comorbidities and the high rate of underdiagnosis, early recognition and implementation of a structured, multidisciplinary surveillance strategy are essential to improve long-term outcomes in individuals with KS.