NFS-04. Concurrent malignancies and vascular malformation in a patient with Constitutional Mismatch Repair Syndrome

Abstract Constitutional Mismatch Repair Disease (CMMRD) is a cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes, leading to an increased risk for development of childhood malignancies. We report the clinical course of an 11-year-old patient initially diagnosed with leukemia, who was later identified with CMMRD based on physical exam findings and found to have concurrent lesions, including a high-grade glioma and a vascular malformation in the buttock. He presented with diffuse lymphadenopathy, splenic, and renal lesions. Flow cytometry confirmed B-cell acute lymphoblastic leukemia. Physical exam revealed multiple café-au-lait macules and axillary freckling, prompting a skin biopsy which confirmed CMMRD. Initial concern for neurofibromatosis and the need to rule out associated brain lesions led to obtaining an MRI brain, which revealed multifocal lesions in the left frontal lobe. Biopsy confirmed one as a high-grade glioma and the other as a low-grade. There was an initial concern for CNS leukemia due to leukemia cells in the perivascular spaces. However, further testing revealed that these cells were an inflammatory reaction to the brain lesion. On surveillance imaging, he was also noted to have splenic and a right tibial lesion, and a left buttock mass. A biopsy of the buttock lesion revealed a vascular malformation. He continues leukemia treatment and remains in remission. After consultation with the CMMRD registry in Toronto, Canada, and the identification of somatic IDH mutations in both brain lesions, the plan is to initiate an IDH inhibitor and continue periodic imaging surveillance. This case highlights the diagnostic challenges and therapeutic considerations in CMMRD, emphasizing the importance of a thorough physical exam upon diagnosis of any malignancy and integrating genetic testing, imaging, and histopathology for tailored management. The coexistence of distinct brain lesions of varying grades underscores the complexity of CMMRD-related tumorigenesis and the need for multidisciplinary coordination.