Constitutional Mismatch Repair Deficiency

Constitutional mismatch repair deficiency is an autosomal recessive cancer syndrome caused by biallelic germline variants in MLH1, MSH2, MSH6 or PMS2. It causes childhood cancers of the blood, brain and bowel, often before 10 years of age, and mimics neurofibromatosis type 1 by its skin signs.

Pathophysiology. Without mismatch repair, replication errors accumulate across the genome. This produces hypermutated tumours, microsatellite instability and rapid tumour development, with tolerance of carriers (Lynch syndrome) but not of biallelic disease.

Parents are heterozygous carriers of Lynch syndrome, often with no family history, particularly for PMS2 and MSH6.

Hypermutated cancers respond poorly to alkylating agents such as temozolomide but may respond to immune checkpoint inhibitors.

• Haematological malignancy, mostly T-cell lymphoma or leukaemia, in early childhood
• Brain tumours: high grade glioma, medulloblastoma, primitive neuroectodermal tumour
• Lynch type cancers in adolescence and young adulthood: colorectal, small bowel, endometrial
• Multiple adenomatous polyps in the colon from the first decade
• Café-au-lait macules, often with hypopigmented areas
• Axillary freckling and neurofibroma like findings in a minority
• Agenesis of the corpus callosum and pilomatricomas
• Family history of Lynch syndrome cancers in parents' families

• Clinical suspicion: a child with a second malignancy, with a typical cancer plus café-au-lait macules, with a sibling with childhood cancer, or with a hypermutated tumour.
• Tumour immunohistochemistry: loss of one or more mismatch repair proteins in both the tumour and normal tissue (for example, normal brain or lymphocytes).
• Germline testing of MLH1, MSH2, MSH6 and PMS2 with deletion and duplication analysis, using methods that deal with the PMS2 pseudogene.
• Microsatellite instability testing, tumour mutational burden, and a mutation signature when available.
• Functional ex vivo repair testing of cells when variants are uncertain.
• Parental testing for Lynch syndrome, and counselling for siblings.

• Surveillance for carriers of biallelic variants:
  • Brain MRI every 6 months from 2 years of age.
  • Whole body MRI yearly from 6 years of age.
  • Abdominal ultrasound and full blood count every 6 months from 1 year of age.
  • Colonoscopy every 1 to 2 years from 6 years of age, and upper gastrointestinal endoscopy with small bowel assessment every 1 to 2 years from 8 to 10 years of age.
  • Gynaecological surveillance from the teens, and urine cytology or dipstick for haematuria from adolescence.
• Prophylactic colectomy for high polyp burden or high grade dysplasia.
• Aspirin 300 to 600 mg orally once daily has been used in Lynch syndrome carriers to reduce colorectal cancer risk. Use in biallelic disease is individual, with attention to bleeding risk and age (avoid in children with viral illness because of Reye syndrome).
• Treatment of cancers: avoid or minimise temozolomide, which is ineffective in mismatch repair deficiency and may add mutations. Immune checkpoint inhibitor therapy is used for recurrent or high grade tumours, for example nivolumab 3 mg/kg intravenously every 2 weeks (adult flat dose 240 mg every 2 weeks), in a specialist centre.
• Haematological cancers: conventional chemotherapy by tumour type, with attention to toxicity.
• Neurological and developmental care: early developmental assessment and school support.
• Genetic counselling: each sibling has a 25% chance of biallelic disease and parents are obligate carriers.

Special groups.

• Parents and heterozygous carriers: Lynch syndrome surveillance, colonoscopy every 1 to 2 years from about 25 to 35 years depending on gene.

Monitoring. Clinical review every 3 to 6 months, with brain and whole body MRI, colonoscopy and upper gastrointestinal endoscopy on a fixed surveillance schedule, kept in the same unit throughout.

Referral and escalation. Refer to clinical genetics and paediatric oncology with a childhood cancer predisposition service. Urgent for headache, vomiting, ataxia, lymphadenopathy, night sweats, rectal bleeding or abdominal mass.