Uncovering a Novel Homozygous MSH6 Variant in a Child Presenting With Glioblastoma: A Case of Constitutional Mismatch Repair Deficiency.

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. We report a previously healthy seven-year-old boy who presented with a high-grade glioma and was later diagnosed with T-lymphoblastic lymphoma (TLL). Immunohistochemistry (IHC) of the brain tumor showed partial loss of MSH6 expression in both tumor and adjacent normal cells. Genetic testing identified a homozygous MSH6 variant (c.3680T>G, p.Ile1227Arg), with both parents confirmed as heterozygous carriers. This variant has not previously been reported in the homozygous state with clear clinical correlation. The combined clinical, histologic, and genetic findings strongly support a diagnosis of CMMRD and fulfill multiple American College of Medical Genetics and Genomics (ACMG) criteria, supporting reclassification of this variant as likely pathogenic. This case is notable for providing one of the few documented homozygous MSH6 mutations with a well-defined childhood CMMRD phenotype. It underscores the importance of integrating clinical, radiologic, histologic, and genetic evidence for accurate diagnosis, guiding surveillance, treatment, and family counseling.