Muir-Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge.

A "cancer predisposing syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes.

Muir-Torre syndrome-is it really a new syndrome?

E.G. Muir and D. Torre independently described widespread cutaneous changes associated with internal malignancy, which are presently known as the Muir-Torre syndrome. This syndrome is defined as the coexistence of sebaceous adenomas, sebaceus carcinomas, keratoacanthomas, and pedunculated tumors, some with lobulated structure. The cutaneous involvement (sebaceous gland tumor) is associated with at least a single internal malignancy; mostly colonorectal or genitourinary malignancies. The syndrome is believed to be very rare, but some cases seem to have been unrecognized or misdiagnosed. It is inherited as an autosomal dominant trait with a variable degree of penetrance. Although Muir and Torre described this syndrome in 1967/1968, we found a report on a very similar case as described by C. Hilton Fagge from Guy Hospital in London, which was published 100 years earlier. In this case, there were very abundant small tumors, some pedunculated, and some deeper ones, with a finely lobulated structure, containing "a hair follicle or the external dermal coat of the follicle." The lobulated structures developed from the sebaceous glands, which were larger than normal, and surrounded by abundant fibrous tissue. For this reason, these changes were described under the misleading name of Molluscum Fibrosum. The clinical description of this case, however, is excellent and enables the recognition of the Muir-Torre syndrome.