PMS2 – Muir-Torre syndrome

Muir-Torre syndrome (MTS) is a rare autosomal dominant variant of Lynch syndrome, defined by the co-occurrence of sebaceous skin tumours or keratoacanthomas and internal malignancies due to germline mismatch repair (MMR) gene defects (PMID:29333623).

Genetic evidence for PMS2 involvement in MTS is currently limited to a single unrelated proband: a 57-year-old woman presenting with a sebaceous adenoma and a history of endometrial carcinoma, in whom a heterozygous frameshift PMS2 variant c.1021del (p.Arg341fs) was identified following immunohistochemical (IHC) screening of sebaceous neoplasms (PMID:29333623). No segregation data or additional affected relatives have been reported.

The spectrum of PMS2 variants in MTS remains narrow, with the sole reported variant being a truncating frameshift (c.1021del (p.Arg341fs)). There are no recognized recurrent or founder PMS2 alleles associated with the MTS phenotype.

Functional evidence supporting PMS2 pathogenicity in MTS derives from tumour-specific assays: IHC of sebaceous neoplasms demonstrated loss of PMS2 protein expression, confirming MMR deficiency in the tumour tissue of the proband (PMID:29333623).

Conflicting evidence arises from a population-based study of 50 Lynch syndrome families, in which MTS was not observed in carriers of PMS2 mutations, suggesting locus heterogeneity among MMR genes in the MTS phenotype (PMID:18270343).

Integration of genetic and functional findings indicates that while PMS2 deficiency can manifest as MTS, the current evidence base is limited to isolated case-level data. Key take-home: include PMS2 germline analysis in IHC-directed evaluation of patients with sebaceous neoplasms to ensure comprehensive MTS diagnostic workup.

References

• Clinical and Experimental Dermatology • 2018 • Evaluation of universal immunohistochemical screening of sebaceous neoplasms in a service setting. PMID:29333623
• Journal of the National Cancer Institute • 2008 • The frequency of Muir-Torre syndrome among Lynch syndrome families. PMID:18270343

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