Clinical Practice Guidelines for Klinefelter Syndrome (47,XXY) Summit - ABSTRACT Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males, yet fewer than half of affected individuals are ever diagnosed, and those who are often receive recognition only after critical developmental and reproductive windows have passed. This underdiagnosis and the absence of comprehensive, international, lifespan clinical practice guidelines contribute to fragmented, inconsistent care and missed opportunities for timely endocrine, fertility, neurocognitive, and psychosocial interventions. Although the evidence base for KS has expanded substantially, clinical practice remains variable and inequitable across regions and resource settings. This R13 application will support the Clinical Practice Guidelines for Klinefelter Syndrome Summit, a 2.5-day in-person meeting to be held in Colorado in the Fall of 2026. The summit will finalize the first international, evidence-based, lifespan-oriented KS clinical practice guidelines. It represents the capstone of a three-year global effort involving 60 experts from over 15 countries. The conference will integrate systematic evidence reviews, structured use of the GRADE framework, transparent consensus-building, multidisciplinary representation, and patient and advocacy participation. Conference activities will synthesize evidence across genetics and diagnosis, hypogonadism, fertility, neurocognitive and psychological health, comorbidities, quality of life, and clinical care practices. Committees will assign evidence certainty, weigh benefits and harms, incorporate patient values, consider feasibility in diverse health systems, and draft final recommendations using real-time electronic voting. The meeting will also support early-stage investigators and individuals from groups underrepresented in biomedical research. Deliverables include final guideline recommendations, domain-specific companion manuscripts, open-access evidence repositories, patient-friendly summaries, clinical checklists, and CME-enabled dissemination. A standing committee will oversee future updates. The guidelines will standardize care, reduce health disparities, and improve reproductive, developmental, and long-term health outcomes for individuals with KS, directly advancing NICHD priorities.
