Relationship Between NF1 and Constitutive Mismatch Repair Deficiency

Abstract

Neurofibromatosis type 1 (NF1) is associated with an increased risk of developing a variety of benign and malignant tumors. NF1 children may develop malignant peripheral nerve sheath tumors and juvenile myelomonocytic leukemia. Other malignancies that have been found at increased frequency in NF1 children include rhabdomyosarcoma and glioblastoma. The latter malignancies also belong to the spectrum of tumors found in patients affected by an autosomal recessively inherited childhood cancer syndrome caused by a constitutive mismatch repair deficiency (CMMR-D) due to biallelic inactivating mutations in one of four mismatch repair genes. Importantly, the overlap between NF1 and CMMR-D arises not only from the partly overlapping tumor spectrum but also from the fact that most of the CMMR-D patients have multiple cafe-au-lait macules and a number of them also show other features of NF1. The tumor spectrum of CMMR-D is very broad. Therefore, CMMR-D has to be taken into consideration as a differential diagnosis in any child or adolescent presenting with features of NF1 and a malignancy other than a clearly NF1-associated one. The recognition of CMMR-D in childhood, adolescent, and young adult cancer patients has important implications for counseling, surveillance, and treatment not only of the patient but also of the wider family. Since this childhood cancer syndrome has only recently been recognized, several CMMR-D patients may have been previously misdiagnosed as NF1 patients. Therefore, awareness of this syndrome is also appropriate when interpreting retrospective clinical data and reports from the literature.