Clinical and molecular characteristics of constitutional mismatch repair deficiency syndrome: a case series of five children and appraisal of diagnostic guidelines

DNA mismatch repair (MMR) is critical for maintaining genome integrity through correction of single-base mismatches and insertion-deletion loops arising from DNA replication. Heterozygous germline alteration of MMR genes (MSH2, MSH6, MLH1, PMS2) cause autosomal dominant Lynch syndrome (LS), most commonly manifesting as colonic or endometrial cancers, although brain, ovarian, and other organ systems may be involved. Neoplasia in LS usually arises after the age of 30 years. Constitutional mismatch repair deficiency (CMMRD) is inherited in an autosomal recessive manner due to biallelic germline alteration in one of the four MMR genes. Individuals with CMMRD typically develop cancer in the first decade of life, although some may present during the second decade. We present a series of five children who developed cancer prior to the age of 20 years (range: 2-12 years) with malignancies including colonic adenocarcinoma (N = 1), T-lymphoblastic lymphoma (N = 3), and high-grade glioma (N = 4). Two patients with MSH6 alterations developed a constellation of three primary tumors: high-grade glioma, T-lymphoblastic lymphoma, and colonic neoplasia including colonic adenocarcinoma in one patient and a tubular adenoma in the other.