Constitutional mismatch repair deficiency syndrome (CMMRD) is a recently described major childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes (mainly PMS2, MSH6 and MLH1, MSH2).
Heterozygous monoallelic germline loss-of-function mutations in one of the MMR genes are responsible for Lynch Syndrome (LS), an autosomal dominant genetic disorder associated with an increased risk of colorectal cancer, endometrium carcinoma and other malignancies in the fourth and fifth decades of life. In contrast to LS, individuals carry biallelic homozygous or compound heterozygous deleterious germline mutations in MMR genes leading to the recessive constitutional mismatch repair deficiency (CMMRD) syndrome, now recognized as a distinct childhood cancer predisposition syndrome (OMIM #276300)
Due to the constitutional defect in MMR capacity,individuals with biallelic MMR gene mutations have a high risk of developing a diverse spectrum of malignancies already in childhood and adolescence. The spectrum includes mainly (i) haematological malignancies, (ii) brain/central nervous system (CNS) tumours and (iii) colorectal and other cancers that are typically seen in LS patients at a later age. A variety of other malignancies were seen only in a few or individual CMMRD patients. Many of the CMMRD patients, but not all, showed features reminiscent of NF1, particularly multiple café au lait macules (CALM).
Diagnosis of CMMRD in a paediatric or young adult cancer patient has important implications for the management not only of the patient but also of the entire family.