Muir-Torre Syndrome

Muir-Torre syndrome

Authors: Doctors Alexander C. Katoulis, Evangelia Bozi, Professor Nicholas G. Stavrianeas1 Creation date: May 2004

Scientific Editor: Professor Thierry Philip

1National University of Athens, 2nd Department of Dermatology and Venereology, "Attikon" General Hospital, Athens, Greece. mailto:[email protected]

Abstract Keywords Disease name Definition/Diagnostic criteria Epidemiology Genetics Histogenesis Clinical description Diagnostic methods Management References

Abstract Muir-Torre syndrome represents the association of multiple sebaceous tumors (i.e. hyperplasia, adenoma, epithelioma and carcinoma), or keratoacanthoma (KA) with one or more visceral carcinomas. This syndrome is very rare. Muir-Torre syndrome is dominantly inherited. It is caused by a mutation in DNA mismatch repair genes (hMLH1 at 3p21.3 or hMSH2 at 2p22-p21). Muir-Torre is therefore allelic to hereditary nonpolyposis colorectal cancer (HNPCC). Sebaceous tumors are usually multiple, with sebaceous adenomas being the commonest. KA, 3-10 in number, are usually located on the face or the trunk. Cutaneous tumors may precede or follow the first presentation of internal malignancy, which usually involves the gastrointestinal tract, the breast or the genitourinary tract. The malignancies are usually multiple, occur at an early age, but tend to be of low-grade and have a relatively low incidence of metastases. The management should be multidisciplinary including genetic counselling, regular dermatology follow-up and relevant cancer screening.

Keywords Muir-Torre syndrome, sebaceous tumors, keratoacanthoma, hereditary non polyposis colon cancer, hMLH1, hMSH2

Disease name The criteria for diagnosis are: 1. At least one Muir-Torre syndrome sebaceous tumor; 2. At least one internal

Definition/Diagnostic criteria malignancy. Every patient with multiple KA Muir-Torre syndrome represents the association should be evaluated for the presence of of multiple sebaceous tumors (i.e. hyperplasia, sebaceous neoplasms, the absence of which still adenoma, epithelioma and carcinoma), or requires consideration of this syndrome. keratoacanthoma (KA) (a common benign epithelial tumor of pilosebaceous origin) with one Epidemiology or more visceral carcinomas (Schwartz and Muir-Torre syndrome is very rare. Almost half of Torre, 1995). the patients have at least one KA.

Katoulis A, Bozi E, Stavrianeas N. Muir-Torre syndrome. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-MuirTorre.pdf 1

Genetics References Muir-Torre syndrome is dominantly inherited. It is Akhtar S, Oza KK, Khan SA, Wright J. Muir- caused by a mutation in DNA mismatch repair Torre syndrome: a case report of a patient with genes. Mutation may arise either in the hMSH2 concurrent jejunal and ureteral cancer and gene located on chromosome 2p22-p21 or in the review of the literature. J Am Acad Dermatol hMLH1 gene at 3p 21.3 (Mathiak et al, 2002). 1999; 41:681-6. Patients are heterozygous for the mutation. Barana D, Cetto G L, Oliani C, et al. Spectrum Normal allele inactivation results in an increased of genetic alterations in Muir-Torre syndrome is risk of malignancy. the same as in HNPCC. (Letter) Am J Med Molecular analysis in hereditary non polyposis Genet 2004;125A:318-9. colorectal cancer (HNPCC) demonstrated a Dore MX, Dieumegard B, Grandjouan S et al. common genetic basis, with the observation of Moir-Torre syndrome and colorectal cancer: two germline mutations in the hMSH2 gene in both families with molecular genetic analysis. Ann syndromes (Dore et al, 1999). Derm Venereol 1999; 126:582-6. Goudie DR, Yuille MAR, Leversha MA et al. Histogenesis Multiple self-healing epitheliomata mapped to The association of KA and sebaceous chromosome 9q22-q31 in families with common neoplasms may be explained by their common ancestry. Nat Genet 1993; 3:165-9. derivation from pilosebaceous glands. Kato N, Ito K, Kimura K, Shibata M. Ferguson Smith type multiple keratoacanthomas and a Clinical description keratoacanthoma centrifugum marginatum in a Sebaceous tumors are usually multiple, with woman from Japan. J Am Acad Dermatol 2003; sebaceous adenomas being the commonest. 49:741-6. KA, 0.5-1.0 cm in diameter, are usually located Mathiak M, Rutten A, Mangold E et al. Loss of on the face or the trunk. They vary from 3 to 10 DNA mismatch repair proteins in skin tumors in number. Cutaneous tumors may precede or from patients with Muir-Torre syndrome and follow the first presentation of internal MSH2 or MSH1 germline mutations: malignancy. Internal malignancies usually establishment of immunohistochemical analysis involve the gastrointestinal tract, such as as screening test. Am J Surg Pathol 2002; colorectal, gastric or esophageal cancer. Less 26:338-43. commonly, the breast or the genito-urinary tract Schwartz RA. Keratoacanthoma. J Am Acad may be involved. The malignancies are usually Dermatol 1994; 30:1-19. multiple, occur at an early age, but tend to be of Schwartz RA, Torre DP. The Muir-Torre low-grade and have a relatively low incidence of syndrome: a 25-year retrospect. J Am Acad metastases (Akhtar et al, 1999). Barana et al. Dermatol 1995; 33:99-104. (2004) reported the first family with Muir-Torre syndrome harboring a large deletion within the MSH2 gene. The family had 3 affected individuals in 2 generations. The father had 2 metachronous colon cancers starting at age 53 years, a daughter had a colon and ovarian cancer starting at age 42 years, and a son was affected by an adenoma with a focus of carcinoma at age 47 years. All 3 affected members presented with cutaneous lesions characteristic of Muir-Torre syndrome.

Diagnostic methods Histology: typical "seboacanthoma" of Muir-Torre syndrome displays architecture of KA with well- differentiated sebaceous lobules of sebaceous adenoma (Schwartz, 1994).

Management The management should be multidisciplinary including genetic counselling, regular dermatology follow-up and relevant cancer screening. For skin tumours, oral isotretinoin may be effective and might have a preventive role also for future malignancies.

Katoulis A, Bozi E, Stavrianeas N. Muir-Torre syndrome. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-MuirTorre.pdf 2