Constitutional Mismatch Repair Deficiency: Scoping Review of a Cancer-Predisposition Syndrome With Distinctive...

Constitutional mismatch repair deficiency (CMMRD) is a rare but severe hereditary cancer predisposition syndrome caused by biallelic pathogenic variants in one of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). The condition mainly presents in childhood, with cancers primarily affecting the hematological, brain, and gastrointestinal systems, along with cutaneous features typical of neurofibromatosis type 1. This scoping review aims to explore the clinical characteristics of CMMRD. A systematic search of medical databases resulted in the inclusion of 127 articles. PMS2 is the most affected gene, followed by MSH6, MLH1, and MSH2. Blood and brain malignancies occur in early childhood for all genetic variants, with the age of onset progressively decreasing from PMS2 to MSH6, to MLH1 and MSH2. Gastrointestinal tumors typically present in late adolescence in individuals with PMS2 variants, at slightly younger ages in those with MSH6 variants, and are rarely reported in MLH1 and MSH2 cases. Patients with CMMRD present with café-au-lait macules that are fewer in number and larger than in patients with neurofibromatosis type 1. Additional dermatological findings include hypopigmented patches and intertriginous freckling. PMS2 and MSH6 pathogenic variants are linked to the broadest spectrum of cutaneous manifestations, including vascular tumors, various nevi, and pilomatricomas. Despite its rarity and diverse clinical manifestations, advancements in diagnostic criteria, genetic testing, and surveillance protocols have significantly improved survival rates and cancer management in CMMRD patients.