The Need for a Global Registry for Charting the Natural History of Klinefelter Syndrome.

Abstract

Background: Although Klinefelter Syndrome (KS) represents the most common sex chromosome aneuploidy, several gaps in knowledge persist regarding optimal management of individuals with this condition. Individuals with KS can have a diverse phenotype including endocrine, neurodevelopmental, and cardiovascular manifestations.

Objectives: To describe the existing KS cohort within SDMregistries and the development and potential role of the dedicated I-KS module.

Methods: Retrospective review of current cases of KS on the SDMregistries.

Results: In January 2026, the SDMregistries platform that consists of dedicated registries for a wide range of rare conditions affecting sex development and maturation included a total of 10, 658 individuals and of these, 777 (7%) individuals from 17 countries had karyotypes consistent with 47, XXY or mosaic forms containing an XXY cell line. Considering those with a 47, XXY alone, the median year of birth was 1994 (range 1939, 2025) resulting in a median current age of 32 (1, 87) years. This therefore represents the largest contemporary international cohort of individuals with KS of varying ages across the lifespan currently available worldwide.

Discussion: The SDMregistries platform offers a unique opportunity to undertake natural history studies as well as evaluations of treatments in KS through the development of a KS specific registry. Such a registry would support evidence-based, personalized care by identifying which interventions work best for specific subgroups and by informing standardized clinical guidelines. This would also assist with care quality improvement, with benchmarking of care and the possibility to accelerate clinical trials by improving patient identification, recruitment, and selection of meaningful outcome measures. Finally, registry data can strengthen advocacy and policy efforts, supporting improved screening, funding, and access to multidisciplinary care.

Conclusion: Continued evaluation of existing data and identification of research priorities remain essential to improving long-term outcomes and quality of life for individuals with KS, with the likelihood of increased ease with the launch of the new I-KS module.