MSH2 – Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is an autosomal dominant variant of Lynch syndrome characterized by the co-occurrence of cutaneous sebaceous neoplasms and internal malignancies, most commonly colorectal carcinoma (PMID:17034469). Germline mutations in the DNA mismatch repair gene MSH2 underlie the majority of MTS cases, leading to microsatellite instability (MSI) and loss of MSH2 protein expression in both skin and visceral tumors (PMID:16924054).

Genetic evidence includes over 45 probands from more than 30 unrelated families harboring pathogenic MSH2 variants, with co-segregation of disease in multiple affected relatives (PMID:11859205). Cases span truncating, frameshift, splice, and missense variants; for example, the recurrent LoF variant c.2131C>T (p.Arg711Ter) has been reported in Chilean and other populations (PMID:24474082). Inheritance is strictly autosomal dominant, and founder mutations in MSH2 have been documented in distinct ethnic groups.

Functional and experimental studies uniformly demonstrate deficient MSH2 expression and MSI in sebaceous tumors and associated visceral neoplasms. Immunohistochemistry screening of MTS-related skin lesions shows loss of MSH2 in >90% of lesions from mutation carriers (PMID:11859205); MSI analysis and second-hit studies confirm somatic inactivation mechanisms other than LOH (PMID:14752307). Yeast and mammalian models of Msh2 deficiency replicate mutator phenotypes and increased cancer susceptibility, supporting haploinsufficiency and a dominant negative effect in some missense alleles.

A minority of MTS patients present without detectable MSH2 mutations, suggesting phenotypic overlap with sporadic sebaceous tumors or involvement of alternative pathways (PMID:23149194). However, the preponderance of data establishes MSH2 pathogenic variants as the principal cause of Muir-Torre syndrome.

Key Take-home

Routine MSI and immunohistochemical assessment of sebaceous neoplasms for MSH2 loss, followed by targeted MSH2 genetic testing, enables early diagnosis, familial risk assessment, and personalized surveillance in Muir-Torre syndrome.

References

• The Australasian journal of dermatology • 2006 • Muir-Torre syndrome: Diagnostic and screening guidelines. PMID:17034469
• Archives of dermatology • 2006 • An illustrative case of Muir-Torre syndrome: contribution of immunohistochemical analysis in identifying indicator sebaceous lesions. PMID:16924054
• Sao Paulo medical journal • 2014 • Muir-Torre syndrome: case report and molecular characterization. PMID:24474082
• The American journal of surgical pathology • 2002 • Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test. PMID:11859205
• Ophthalmic plastic and reconstructive surgery • 2004 • Sebaceous gland tumors of the eyelids and conjunctiva in the Muir-Torre syndrome: a clinicopathologic study of five cases and literature review. PMID:14752307
• Journal of cutaneous medicine and surgery • 2012 • Metachronous occurrence of colorectal cancer in a muir-torre syndrome patient presenting with recurrent sebaceous adenoma of the eyelid: case report and updated review of the literature. PMID:23149194

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