Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

J Med Genet. 2019 Feb;56(2):53-62. doi: 10.1136/jmedgenet-2018-105664. Epub 2018 Nov 10.

Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

Keywords: clinical genetics; genetic screening/counselling; paediatric oncology.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Brain Neoplasms / diagnosis*
  • Brain Neoplasms / epidemiology
  • Brain Neoplasms / genetics*
  • Colorectal Neoplasms / diagnosis*
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • Diagnosis, Differential
  • Genetic Counseling
  • Genetic Testing
  • Humans
  • Incidence
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / genetics
  • Mutation
  • Neoplastic Syndromes, Hereditary / diagnosis*
  • Neoplastic Syndromes, Hereditary / epidemiology
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neurofibromatosis 1 / diagnosis*
  • Neurofibromatosis 1 / genetics
  • Parents
  • Patient Selection
  • Practice Guidelines as Topic

Substances

  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • SPRED1 protein, human
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1

Supplementary concepts

  • Turcot syndrome