title: Muir-Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge.
abstract: 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.
authors.affiliation: Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Italy. Electronic address: giovanni.ponti@unimore.it.
authors.forename: G
authors.initials: G
authors.lastname: Ponti
authors.affiliation: Department of Dermatology, University of Modena and Reggio Emilia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Manfredini
authors.affiliation: Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tomasi
authors.affiliation: Department of Dermatology, University of Modena and Reggio Emilia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pellacani
mesh_terms: D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000266:history* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000266:history* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics / Q000266:history* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D015870:Gene Expression; D018095:Germ-Line Mutation; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics; D055653:Muir-Torre Syndrome / Q000175:diagnosis / Q000235:genetics / Q000266:history* / Q000473:pathology; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics / Q000266:history* / Q000473:pathology; D010375:Pedigree; D012627:Sebaceous Glands / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: Keratoacanthomas; Lynch Syndrome; MLH1; MMR founder mutations; MSH2; Muir–Torre Syndrome; Sebaceous tumors; Turcot Syndrome