Assessing a Model for a Complex Systemic Disorder—The Value of Male Mice With a Supernumerary X Chromosome for Klinefelter Syndrome Research

INTRODUCTION: Direct experimental investigation of Klinefelter syndrome (KS) in patients is limited because the syndrome manifests heterogeneously and affects multiple organ systems. Studying KS therefore requires a model that captures this complexity as accurately as possible while still permitting controlled experimental manipulation. METHODS: This review integrates findings from clinical studies and experimental research using male mice carrying a supernumerary X chromosome that replicate key features of the syndrome, with particular emphasis on their translational relevance, experimental utility, and inherent limitations. RESULTS: Over the past decades, these mouse models have demonstrated their value by enabling the successful translation of experimental findings into clinical applications. Using these models, researchers have investigated multiple aspects of KS, including neurocognitive function, social behavior, metabolism, bone health, brain structure and function, endocrine dysregulation, testicular degeneration, germ cell fate, Sertoli and Leydig cell function, vascular abnormalities, chromosomal imbalance, and X-chromosome dosage effects. CONCLUSION: Although these models have some limitations, their availability allows the investigation of developmental timing and tissue-specific mechanisms. They offer unique opportunities to dissect the genetic, hormonal, and systemic features of KS, thereby informing both basic research and clinical care. Given their demonstrated and ongoing value, we aim to encourage the scientific community to further adopt these models in future KS research.