Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

Clin Cancer Res. 2017 Jun 1;23(11):e32-e37. doi: 10.1158/1078-0432.CCR-17-0574.


Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair-deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Publication types

  • Review

MeSH terms

  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / epidemiology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Child
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Early Detection of Cancer
  • Germ-Line Mutation / genetics*
  • Humans
  • Microsatellite Instability*
  • Mismatch Repair Endonuclease PMS2 / deficiency
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / deficiency
  • MutL Protein Homolog 1 / genetics
  • MutS Homolog 2 Protein / deficiency
  • MutS Homolog 2 Protein / genetics
  • Neoplastic Syndromes, Hereditary / diagnosis
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / pathology


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein

Supplementary concepts

  • Turcot syndrome