Severe Neurodevelopmental Disorder due to Klinefelter Syndrome and CACNA1C Variant: A Case Report

Klinefelter syndrome (KS) is a common sex chromosome aneuploidy characterized by tall stature, hypogonadism, and learning disabilities. However, the severity of clinical presentation can vary significantly among individuals. We report a 13-year-old male patient adopted from Colombia who was diagnosed with KS at age 5.5 due to learning and behavioral difficulties. Despite the typical KS features, his clinical presentation was unusually severe, including significant developmental delay, behavioral issues, and physical abnormalities. Due to the uncommon severe presentation of KS in our patient, exome sequencing (ES) was performed, revealing a de novo heterozygous frameshift likely pathogenic variant in CACNA1C (c.2662del p.[Arg888Glyfs^∗18]). CACNA1C pathogenic variants are associated with several phenotypes, including neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures. This case emphasizes the importance of considering additional genetic investigations in KS patients with atypically severe symptoms. Such an approach can identify secondary genetic events that contribute to the phenotype, guiding a more comprehensive clinical management and allowing a more precise genetic counseling.