MLH1 – Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the coincidence of sebaceous skin neoplasms and at least one visceral malignancy. Germline mutations in DNA mismatch repair (MMR) genes underlie MTS, most commonly in MSH2 and, less frequently, MLH1. Loss of MLH1 function leads to microsatellite instability (MSI) and failure of repair of replication errors, predisposing carriers to both cutaneous and internal tumors in the context of Muir-Torre syndrome.

Multiple independent truncating and deletion variants in MLH1 have been reported in unrelated MTS probands. A novel nonsense mutation c.2194A>T (p.Lys732Ter) was identified in a 52-year-old woman with metachronous colon, endometrial, gastric and sebaceous carcinomas (PMID:25197397). Exonic deletion of MLH1 exon 5 via Alu-mediated homologous recombination was described in a 77-year-old man with sebaceous tumors and colon cancer (PMID:28120777). A rare MLH1 deletion was also reported in a 55-year-old woman with multiple cutaneous and visceral malignancies (PMID:26962393). These three probands exemplify the truncating and copy-number variant spectrum of MLH1 in MTS.

Immunohistochemical (IHC) and MSI analyses provide functional concordance with the genetic findings. In an IHC study of 28 skin lesions from 17 MTS patients carrying MLH1 or MSH2 mutations, both MLH1-mutant tumors showed complete loss of MLH1 staining (PMID:11859205). In a screening series of 120 patients with sebaceous neoplasms, two MTS families harbored MLH1 mutations that correlated with absent MLH1 expression and high MSI in both skin and visceral tumors (PMID:15662714).

Mechanistically, MLH1 haploinsufficiency disrupts MutLα endonuclease activity, leading to ineffective post-replication repair. The resulting MSI drives oncogenesis in sebaceous glands and a spectrum of visceral tissues, overlapping with Lynch syndrome phenotypes but distinguished by cutaneous markers. No studies have refuted the MLH1–MTS link, and the high penetrance of truncating variants underscores clinical validity.

These data establish MLH1 as a definitive MTS gene. Genetic testing for MLH1 truncating or exon-deletion variants, coupled with IHC and MSI screening of sebaceous tumors, enables timely diagnosis and targeted surveillance for extracutaneous cancers. Key Take-home: MLH1 mutation analysis and tumor IHC are essential for diagnosing and managing Muir-Torre syndrome.

References

• 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
• Cancer • 2005 • Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry. PMID:15662714
• International journal of clinical and experimental pathology • 2014 • Synchronous gastric and sebaceous cancers, a rare manifestation of MLH1-related Muir-Torre syndrome. PMID:25197397
• The Journal of clinical and aesthetic dermatology • 2016 • Muir-Torre Syndrome: A Case Associated with an Infrequent Gene Mutation. PMID:26962393
• European journal of dermatology : EJD • 2017 • Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination. PMID:28120777

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