Constitutional mismatch repair deficiency

Abstract

Inherited heterozygous mutations in the MMR genes result in Lynch syndrome (LS). Individuals with biallelic mutation of one of the MMR genes developed malignancies in childhood. This recessively inherited condition is named CMMRD for constitutional mismatch repair deficiency. The spectrum of tumours is distinct from LS. Malignant brain tumours are at least as frequent as gastrointestinal tumours, and in more than a third of cases, haematological malignancies were also reported. Patients also displayed clinical features of neurofibromatosis type 1. The most commonly involved genes in CMMRD are PMS2 and MSH6, while biallelic MLH1 and MSH2 mutations are rare. Because of variable clinical presentation, lack of unequivocal diagnostic features and phenotypical overlap with other cancer syndromes, CMMRD syndrome is frequently unrecognised by clinicians, and its incidence is almost certainly underestimated. A better knowledge of clinical criteria and diagnosis methods for CMMRD syndrome will increase the number of patients being identified at the time when they develop their first tumour. This will allow to adjust treatment modalities and to offer surveillance strategies to detect other malignancies not only to the patient but also to his/her family.