Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Central European Institute of Technology Masaryk University Brno Czech Republic

Clinical Pharmacy Section of Hospital Pharmacy University Hospital Brno Brno Czech Republic

Department of Biochemistry Faculty of Science Masaryk University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Paediatrics University of Toronto Toronto ON Canada

Department of Pathology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatric Neurology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine ERN PaedCan Center Masaryk University Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Division of Haematology Oncology The Hospital for Sick Children Toronto ON Canada

Institute of Medical Genetics and Genomics University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

The Arthur and Sonia Labatt Brain Tumour Research Centre The Hospital for Sick Children Toronto ON Canada

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