Genomic Confluence: When Cerebrotendinous Xanthomatosis, Klinefelter Syndrome, and a BRCA2 Variant Intersect

TL;DR

A rare case combines three genetic conditions—CTX, Klinefelter syndrome, and a BRCA2 variant—highlighting the need for comprehensive genomic and cytogenetic testing.

Contribution

This case report demonstrates the intersection of three distinct genetic disorders in a single patient, emphasizing the value of integrated diagnostic approaches.

Findings

Trio-based exome sequencing identified a homozygous CYP27A1 variant consistent with CTX.

Karyotyping confirmed Klinefelter syndrome (47,XXY) in the patient.

An incidental BRCA2 variant was detected, with implications for cancer risk.

Abstract

Multilocus pathogenic variation—when multiple genetic disorders coexist in a single individual—remains rare but is increasingly recognized in the era of genomic medicine. Reporting such cases is essential for improving diagnostic accuracy, refining clinical management, and informing genetic counseling. We describe a pediatric case with a complex phenotype resulting from the coexistence of two distinct genetic diagnoses—cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive lipid storage disorder caused by biallelic mutations in the CYP27A1 gene and Klinefelter syndrome a common sex chromosome aneuploidy occurring in approximately 1 in 600 males, characterized by hypogonadism, gynecomastia, pubertal delay, infertility, micrognathia, and neurodevelopmental challenges—and an additional incidental finding with clinical relevance. The patient was born to consanguineous parents, presented with neurological symptoms, gastrointestinal dysfunction, endocrine abnormalities, and dysmorphic features. Trio-based exome sequencing identified a homozygous pathogenic variant in CYP27A1 consistent with CTX, while conventional G-banded karyotyping revealed a 47,XXY chromosomal pattern, confirming Klinefelter syndrome. Additionally, a heterozygous pathogenic variant in BRCA2 was incidentally detected, associated with hereditary cancer predisposition. The overlapping manifestations of CTX and Klinefelter syndrome produced a non-classical presentation that delayed diagnosis. Although the BRCA2 variant did not contribute to the current phenotype, it has important implications for future cancer surveillance and family risk assessment. This case underscores the importance of combining classical cytogenetic and modern genomic methods to elucidate complex phenotypes, particularly in consanguineous populations, and highlights the need for the multidisciplinary management of patients with multilocus or incidental findings.

Figures