Constitutional mismatch repair deficiency (CMMRD)
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A child with café-au-lait macules develops a brain tumor at age 6 and colorectal cancer at age 12. Both parents are found to have Lynch syndrome.
AR; biallelic MMR gene variants (MLH1, MSH2, MSH6, PMS2)
- Parents are Lynch syndrome carriers
- Childhood cancers (brain tumors, leukemia/lymphoma, GI cancers)
- Café-au-lait macules (NF1-like)
- Adenomatous polyps in childhood
- MSI-high tumors
- Very high lifetime cancer risk
- Suspect in a child or young adult with a Lynch-spectrum or childhood cancer plus café-au-lait macules, especially with consanguinity or two parents from Lynch families
- Tumors show microsatellite instability and loss of the corresponding MMR protein on IHC; importantly, normal (non-tumor) tissue also lacks MMR protein expression, distinguishing CMMRD from sporadic/Lynch tumors
- Confirm with germline testing demonstrating biallelic (homozygous or compound heterozygous) variants in MLH1, MSH2, MSH6, or PMS2
- Intensive multi-organ surveillance protocol begun in early childhood: regular brain MRI, abdominal ultrasound, and whole-body MRI for solid tumors
- GI surveillance with upper endoscopy and colonoscopy starting in childhood, at shorter intervals than in Lynch syndrome, with polypectomy as indicated
- Hematologic monitoring (CBC, exam) for leukemia/lymphoma
- Avoid or minimize diagnostic radiation; immune checkpoint inhibitors are active in the resulting hypermutated tumors
- Genetic counseling for parents (Lynch syndrome carriers) and at-risk siblings
CMMRD = "amped up" Lynch: CMMRD results from 2 inherited (biallelic) variants in any Lynch syndrome gene. Lynch is AD (heterozygous); CMMRD is the AR (homozygous/compound heterozygous) version with childhood-onset cancers.
AR cancer gene pattern: Heterozygous (AD) MMR variants cause Lynch syndrome; biallelic (AR) variants in the same genes cause CMMRD. Similar to how heterozygous BRCA variants cause HBOC but biallelic BRCA variants cause Fanconi anemia.