MSH6 – Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the coexistence of sebaceous skin tumors and internal malignancies, most frequently colorectal carcinoma (PMID:16924054). It is a phenotypic variant of Lynch syndrome resulting from germline mutations in DNA mismatch repair (MMR) genes.

While MSH2 and MLH1 mutations underlie the majority of MTS cases, pathogenic MSH6 variants account for less than 10% of patients. MSH6-related MTS exhibits hallmark microsatellite instability (MSI) and loss of MMR protein expression in both cutaneous and visceral tumors.

A pedigree with autosomal dominant inheritance demonstrated segregation of the missense variant c.2633T>C (p.Val878Ala) in three affected members (father and two sons) with sebaceous adenomas and colorectal neoplasia (PMID:22814321). Two additional unrelated probands carried truncating MSH6 mutations: c.1634_1637del (p.Lys545fs) in a pair of affected siblings (PMID:17323113) and c.642C>G (p.Tyr214Ter) in a multiplex MTS family (PMID:18236172).

Immunohistochemical studies of sebaceous and visceral tumors consistently show loss of MSH6 protein expression, accompanied by high-level MSI, confirming a loss-of-function mechanism. These findings align across multiple reports and support a direct role of MSH6 deficiency in MTS pathogenesis.

No conflicting evidence has been reported to dispute the contribution of MSH6 to MTS, though the lower frequency compared with MSH2 suggests incomplete penetrance and possible modifier effects.

Collectively, the available data support a moderate level of clinical validity for MSH6 in MTS. Pathogenic MSH6 variants should be included in genetic testing panels for patients presenting with sebaceous neoplasms to enable early diagnosis, tailored surveillance, and informed management.

References

• Archives of dermatology • 2006 • An illustrative case of Muir-Torre syndrome: contribution of immunohistochemical analysis in identifying indicator sebaceous lesions. PMID:16924054
• The American Journal of dermatopathology • 2012 • MSH6 mutation in a family affected by Muir-Torre syndrome. PMID:22814321
• Familial cancer • 2008 • Muir-Torre Syndrome: expanding the genotype and phenotype--a further family with a MSH6 mutation. PMID:18236172

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