Update on Physical, Psychological, and Quality of Life Management in Klinefelter Syndrome

Klinefelter syndrome (KS), most commonly arises from a 47,XXY karyotype. While KS affects around 1 in 450 to 600 male births, an estimated 50% to 75% of cases go undiagnosed. Individuals with KS are at increased risk of metabolic, cardiovascular, and reproductive comorbidities, increasing mortality risk, psychological burden, and significantly diminished health-related quality of life (HR-QoL) compared to healthy controls. We provide an updated review of the recent literature on the clinical management for people with KS, associated comorbidities, and the implications on HR-QoL.

A comprehensive literature search was conducted of key databases MEDLINE, CINAHL, Cochrane, Psychinfo, and EMBASE, followed by a gray search of relevant key papers in KS with medical guideline organizations being searched online and, where available, their publications and proposed guidelines being assessed. All databases were searched from their inception until December 2024, and English-language restrictions applied.

Current evidence highlights the need for early detection, the importance of appropriate medication management, and multidisciplinary care to address infertility, cancer risks, neurocognitive deficits, and adverse mental health. Lifespan-specific interventions remain underexplored, necessitating further research to optimize outcomes and refine clinical guidelines.

KS management is guided by only one endorsed guideline. International and interprofessional collaboration is needed to develop consensus documents. Existing guidelines pay minimal attention to the numerous HR-QoL challenges, overlooking the effect and diagnosis of psychological comorbidities. Enhancing HR-QoL and optimizing physical and mental well-being should be prioritized to improve HR-QoL outcomes in people with KS.