{"id":27116,"date":"2024-05-26T12:56:24","date_gmt":"2024-05-26T10:56:24","guid":{"rendered":"https:\/\/www.krebs-praedisposition.de\/?post_type=kompendium&p=27116"},"modified":"2025-08-26T10:31:27","modified_gmt":"2025-08-26T08:31:27","slug":"constitutional-mismatch-repair-deficiency","status":"publish","type":"kompendium","link":"https:\/\/www.krebs-praedisposition.de\/en\/kompendium\/constitutional-mismatch-repair-deficiency\/","title":{"rendered":"Constitutional Mismatch Repair Deficiency"},"content":{"rendered":"

Constitutional Mismatch Repair Deficiency \u2013\u00a0Definition<\/h2><\/div>
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Constitutional mismatch repair deficiency (CMMRD; OMIM #276300) results from biallelic pathogenic germline variants of mismatch repair genes and is a rare, highly aggressive cancer predisposition syndrome that leads to malignancies in childhood and predisposes to leukemias or lymphomas, brain tumors, Lynch syndrome-associated tumors and other neoplasms. In addition, germline deletions in the EPCAM<\/em> gene (upstream of the\u00a0MSH2 <\/em>gene) can also lead to hypermethylation of the MSH2 promoter and, consequently, to the absence of\u00a0MSH2<\/em>, thus triggering CMMRD.<\/p>\n<\/div>

Synonyme:<\/p>\n<\/div><\/div><\/div>

Constitutional mismatch repair deficiency<\/p>\n<\/div><\/div><\/div><\/div>

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Gene:<\/p>\n<\/div><\/div><\/div>

MSH2, MSH6, MLH1, PMS2<\/em> (mismatch repair genes, MMR <\/em>genes),<\/p>\n

TACSTD1 <\/i>(EPCAM <\/i>gene)<\/p>\n<\/div><\/div><\/div><\/div>

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Gene \u00adproducts:<\/p>\n<\/div><\/div><\/div>

MSH2, MSH6, MLH1, PMS2 (mismatch repair proteins),
\nEPCAM<\/p>\n<\/div><\/div><\/div><\/div>

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Function:<\/p>\n<\/div><\/div><\/div>

Correction of incorrectly replicated base pairs and small insertions\/deletions in the DNA<\/p>\n<\/div><\/div><\/div><\/div>

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Pattern of inheritance:<\/p>\n<\/div><\/div><\/div>

autosomal recessive<\/p>\n<\/div><\/div><\/div><\/div>

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Prevalence:<\/p>\n<\/div><\/div><\/div>

unknown, the incidence is higher in regions with a high consanguinity rate<\/p>\n<\/div><\/div><\/div><\/div>

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Genotype-phenotype correlation:<\/p>\n<\/div><\/div><\/div>

Not yet fully understood. Biallelic pathogenic germline variants of the MMR genes<\/i> often show the phenotypic picture of neurofibromatosis type 1, associated with various childhood cancers.<\/p>\n

Pathogenic variants in MSH6<\/i> and PMS2 <\/i>are significantly more frequent and lead to a different clinical picture than pathogenic variants in MLH1<\/i> and MSH2<\/i>. The latter lead more frequently to hematologic cancers and the average age at first cancer diagnosis is lower than for carriers of biallelic pathogenic variants in MSH6 <\/i>or PMS2<\/i>. Patients with pathogenic variants in MSH6 <\/i>or PMS2 <\/i>are particularly prone to Lynch syndrome (LS)-associated cancers and brain tumors and usually develop another cancer after surviving the first one.<\/p>\n

Due to the low monoallelic penetrance of PMS2<\/i> and MSH6 <\/i>, affected children often have unaffected parents, even though they are carriers of the defective gene.<\/p>\n<\/div><\/div><\/div><\/div>

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Penetrance:<\/p>\n<\/div><\/div><\/div>

Extremely high; most children do not reach adulthood.
\nLong-term observations with significantly more patients are required for more precise information.<\/p>\n<\/div><\/div><\/div><\/div><\/div><\/div>

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Overview of the Chapters on This Page:<\/h4><\/div><\/div><\/div>