Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1

Clin Genet. 2017 Apr;91(4):507-519. doi: 10.1111/cge.12904. Epub 2017 Jan 10.


Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals.

Keywords: acute myeloid leukaemia; café-au-lait spot; childhood cancer; constitutional mismatch repair deficiency; germline mutation; high-grade glioma; mismatch repair gene; neurofibromatosis type 1; rhabdomyosarcoma.

Publication types

  • Review

MeSH terms

  • Brain Neoplasms / diagnosis*
  • Brain Neoplasms / epidemiology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cafe-au-Lait Spots / diagnosis*
  • Cafe-au-Lait Spots / genetics
  • Cafe-au-Lait Spots / physiopathology
  • Child, Preschool
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • DNA Mismatch Repair / genetics
  • Diagnosis, Differential*
  • Germ-Line Mutation
  • Glioma / diagnosis
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • Leukemia, Myeloid, Acute / diagnosis
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Neoplastic Syndromes, Hereditary / diagnosis*
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics
  • Neoplastic Syndromes, Hereditary / pathology
  • Neurofibromatosis 1 / diagnosis*
  • Neurofibromatosis 1 / epidemiology
  • Neurofibromatosis 1 / genetics
  • Neurofibromatosis 1 / pathology
  • Phenotype
  • Rhabdomyosarcoma / diagnosis
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma / pathology

Supplementary concepts

  • Turcot syndrome