A large duplication including exons 3 to 7 of the mismatch repair gene MSH 2 is associated with the Muir-Torre syndrome
Muir-Torre syndrome (MTS; OMIM 158320) is a highly variable rare autosomal dominant cancer predisposing syndrome, first described in 1967 by E.G. Muir. It is characterised by genodermatosis and multiple internal malignancies. Features of the affected skin include sebaceous hyperplasia, adenoma and carcinoma, with keratoacanthoma and basal cell carcinoma. The internal neoplasias are variable including tumours of colon, stomach, oesophagus, breast, uterus, ovaries, bladder, larynx and squamous cell carcinomas of the mucous membranes. MTS and HNPCC appears to be allelic (Lynch, 1985) as germ line mutations within mismatch repair genes such as MLH1 and MSH2 has been detected with both diseases. In MTS at least 90% of mutations affect the MSH2 gene but without any apparent mutational hot-spot as in HNPCC. In addition to missense, nonsense and frameshift mutations about 10% of MSH2 mutations are due to large genomic deletions. Duplications of MSH2 have not been reported so far. We describe a 3-generation family with 7 individuals, males and females, affected by MTS due to a duplication spanning exons 3-7 of MSH 2. The age of manifestation of the first malignant disease is extremely variable in that family ranging from 24 to 68 years. Five family members, i.e. grandmother, 2 of her sons and 2 of her daughters are affected by cutaneous lesions characteristic of MTS. Both of her sons developed colon cancer and one of her daughters a Non Hodgkin lymphoma and a tumour of the uterus. Her second affected daughter and even their daughter developed an urinary tract carcinoma. A third grandmaternal daughter had 5 breast operations due to calcaneous deposits. Screening for cancer in relatives of individuals with this disorder is of utmost importance and should follow that outlined for HNPCC with extracolonic manifestation, particularily of the skin.