KS males present certain shared phenotypes such as small testes, tall stature, narrow shoulders, broad hips, sparse body hair, gynecomastia and decreased verbal intelligence. KS males also have increased risk of a wide range of additional disorders compared to the background population, i.e. comorbidities. Testicular dysfunction is prevalent in KS. It is estimated that KS causes 1–3% of all male infertility cases (5). In fact, 10% of all male patients with azoospermia are likely to be caused by KS. Numerous KS comorbidities are related to hypogonadism: osteoporosis, cognitive disorders, metabolic syndrome and diabetes and cardiac disease. Consequently, KS males are allocated lifelong testosterone replacement therapy from puberty. Yet, the therapy does not counteract or prevent all comorbidities. It is still unclear whether the chromosome abnormality adds an extra testosterone-independent facet to the complexity of KS comorbidities

Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity