Muir-Torre Syndrome

A number sign (#) is used with this entry because of evidence that Muir-Torre syndrome is part of the Lynch cancer family syndrome II (see 120435), which has been related to mutation in the MSH2 gene (609309) on chromosome 2p.

MRTES can also be caused by mutation in the MLH1 gene (120436) on chromosome 3p.

Clinical Features

Muir-Torre syndrome represents the association of sebaceous skin tumors with internal malignancy. The Gardner and Peutz-Jeghers syndromes are examples of skin-polyposis syndromes. Polyps of the stomach have been reported with the basal cell nevus syndrome (109400). Muir et al. (1967) described a Maltese male with multiple primary carcinomata of the colon, duodenum, and larynx in association with keratoacanthomata of the face. Although he was one of 22 sibs, including 4 sets of twins, no family history of malignancy was obtained. Torre (1968) emphasized the occurrence of multiple sebaceous tumors (sebaceous adenoma) in a patient who had a primary carcinoma of the ampulla of Vater resected at age 50 years and a primary carcinoma of the colon resected at age 53. Stewart et al. (1977) reported a woman who had 11 keratoacanthomata removed over a 21-year period and who also had Bowen disease of the vulva and a carcinoma of the rectum. The cancers, although multiple, are usually relatively indolent.

Reiffers et al. (1976) presented evidence for autosomal dominant inheritance including male-to-male transmission. The families have characteristics of the Lynch II cancer family syndrome. Lynch et al. (1981) observed sebaceous neoplasms in affected members of cancer families and postulated that the purportedly distinct Muir-Torre syndrome is actually one mode of manifestation of the cancer family syndrome. Lynch et al. (1981) expressed doubts that intestinal polyposis is a part of this syndrome. See also Lynch et al. (1985), who reported continuing uncertainty as to the nosologic place of the Muir-Torre syndrome.

That the Muir-Torre phenotype is an expression of the Lynch II cancer family syndrome was supported by the fact that one of the cases described by Lynch et al. (1981) was found to be a descendant of Warthin's family G which is considered to be the first description of the familial cancer syndrome now termed 'Lynch II' (Finan and Connolly, 1984).

Rothenberg et al. (1990) described 2 cases suggesting that a single sebaceous adenoma can be the sole tip-off to the presence of colon cancer in the Muir-Torre syndrome. A 68-year-old woman had a solitary, 2-mm tumor of the forehead. Both she and her mother had had colonic resections for carcinomas. A 50-year-old male physician with a solitary, 6-mm sebaceous adenoma removed from the scalp was investigated for colonic abnormalities and found to have a fungating low-grade adenocarcinoma at the splenic flexure. The man's father had had a colon carcinoma removed at the age of 29 years. Guitart et al. (1991) described a case of a 44-year-old man with a keratoacanthoma of the left nasolabial fold; his mother died of gastric carcinoma and his sister of colonic cancer. He and his brother had alpha-1-antitrypsin deficiency (613490). The keratoacanthoma developed after immunosuppressive therapy for necrotizing vasculitis. Stone et al. (1986) reported a patient with Muir-Torre syndrome in whom exacerbation of the cutaneous lesions occurred during immunosuppression after heart transplant. Cohen (1992) used the label Muir-Torre syndrome in describing a man with Hodgkin lymphoma who subsequently developed a sebaceous carcinoma of the upper eyelid. Rodenas et al. (1993) reported a family in which multiple members had the Muir-Torre syndrome and hyperlipidemia.

Approximately 15% of female patients with Muir-Torre syndrome develop endometrial cancer (Cohen et al., 1991).

Schwartz and Torre (1995) reviewed the Muir-Torre syndrome defined as the association of certain types of sebaceous neoplasms of the skin, with or without keratoacanthomas, with one or more low-grade visceral malignancies in the absence of other predisposing factors. The sebaceous tumors were relatively uncommon or rare types: sebaceous adenoma, sebaceous epithelioma, basal cell epithelioma with sebaceous differentiation, and sebaceous carcinoma. They suggested that the visceral cancers are often multiple and usually indolent, permitting prolonged survival. Even metastatic disease may respond well to aggressive surgical treatment. The sebaceous cancers in this syndrome, like the visceral malignancies, are less aggressive than their counterparts unassociated with this syndrome.

Akhtar et al. (1999) stated that only 205 cases of Muir-Torre syndrome with 399 internal malignancies had been reported. The common presentation was the presence of sebaceous tumors along with a low-grade visceral malignancy. Sebaceous tumors appeared before the internal malignancy in 45 cases (22%), concurrently in 12 (6%), and after the internal malignancy in 114 (56%). In 33 (16%) of the 205 patients, a temporal relationship of the 2 features was not reported. The total number of sebaceous gland carcinomas reported was 44; 17 of 44 were neoplasms of the meibomian gland. Keratoacanthomas were noted in 48 (23%) of 205 patients. Gastrointestinal cancers are the most common internal malignancies (61%), followed by genitourinary (22%).

Holbach et al. (2002) examined biopsy specimens of periocular sebaceous gland carcinoma from 6 patients with Muir-Torre syndrome. They found that the fragile histidine triad protein (FHIT; 601153) was detectable in just 1 sebaceous gland carcinoma from 1 patient with microsatellite instability. FHIT was undetectable in the remaining 5 sebaceous gland carcinomas, which showed no evidence of microsatellite instability. The authors concluded that inactivation of the FHIT tumor suppressor gene or inactivation of the mismatch-repair system resulting in microsatellite instability might contribute to the development of periocular sebaceous gland carcinoma in Muir-Torre syndrome.

Diagnosis

Ponti et al. (2005) concluded that the clinical, biomolecular, and immunohistochemical characteristics of sebaceous skin lesions and keratoacanthomas can be used in screening for families at risk of Muir-Torre syndrome. Through pathology records, they collected 120 patients with sebaceous skin lesions and keratoacanthomas. Seven of the 120 patients were also affected by gastrointestinal tumors, thus meeting the clinical criteria for the disorder. In the Muir-Torre syndrome families, a wide phenotypic variability was evident, both in the spectrum of visceral tumors and in the type of skin lesions. Microsatellite instability was found in 5 patients. A constitutional mutation in the MSH2 gene was found in 1 patient. Lack of expression of MSH2/MSH6 (600678) or MLH1 proteins was evident in the skin lesions and in the associated internal malignancies of 3 patients and 2 patients, respectively.

Roberts et al. (2014) developed a scoring system, based on logistic regression analysis, for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir-Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers. Patients with a score of 3 or more were more likely to have Muir-Torre syndrome (28 of 29 patients), whereas those with a score of 2 had intermediate likelihood (12 of 20 patients); no patient with a score of 0 or 1 was diagnosed with Muir-Torre syndrome. Roberts et al. (2014) concluded that the Mayo Muir-Torre syndrome risk scoring system appeared to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation. The authors pointed out that abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.

Mapping

Hall et al. (1994) reported a 5-generation family in which at least 2 persons displayed the Muir-Torre phenotype, while many other family members had tumors consistent with cancer family syndrome. Most of the tumors were gastrointestinal, gynecologic, and urologic, with several persons having multiple synchronous or metachronous primaries. The prognosis appeared to be better than might be expected. Hall et al. (1994) found that in this and a second Muir-Torre family, the disease locus mapped to 2p in the same region as the Lynch II syndrome, namely to the MSH2 locus. Haplotype analysis of the pedigree showed that the persons with colorectal or endometrial cancer (with or without sebaceous lesions of the skin) shared the same segment of 2p at this locus.

Molecular Genetics

Kruse et al. (1996) identified germline mutations in the MSH2 DNA mismatch repair gene in 2 unrelated Muir-Torre syndrome patients ascertained because of their skin tumors. They suggested that the results, together with published cases of Muir-Torre syndrome, supported the hypothesis that this disorder with its characteristic skin lesions is confined to mutations in the MSH2 gene. They tabulated 4 reported cases in addition to the 2 of their own.

Bapat et al. (1996) demonstrated that mutation in the MLH1 locus can also underlie the Muir-Torre syndrome (see 120436.0006).

About half of Muir-Torre syndrome cases, defined as the coincidence of at least 1 sebaceous skin tumor and 1 internal malignancy, are affected by colorectal cancer. In a subgroup of MRTES patients, the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). In 16 MRTES patients with sebaceous skin tumors and colorectal cancer, Kruse et al. (1998) found that all exhibited high genomic instability in at least 1 tumor from the skin or colon. A search for germline mutations in the MSH2 and MLH1 genes in 13 of the patients revealed truncating mutations in 9 (69%): 8 mutations in the MSH2 gene and 1 in the MLH1 gene. Thus, MRTES patients exhibited significantly more mutations in the MHS2 gene than in the MLH1 gene. The subpopulation of MRTES patients who were also affected by colorectal cancer, irrespective of family history and age at onset of tumors are likely to have an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.

In Muir-Torre syndrome, the vast majority of germline mutations identified have been in MSH2. Microsatellite instability in tumor tissue develops after somatic inactivation of the corresponding second mismatch repair allele ('second hit'). Kruse et al. (2001) examined whether allele loss (loss of heterozygosity; LOH) is a frequent mechanism for inactivation of the second MSH2 allele in a sample of 9 microsatellite instability-positive skin tumors from 8 unrelated Muir-Torre patients with known MSH2 germline mutations. Only 1 of the 9 skin tumors exhibited LOH at the MSH2 locus. Kruse et al. (2001) concluded that LOH most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.

Barana et al. (2004) reported the first family with Muir-Torre syndrome harboring a large deletion involving exons 1-6 of the MSH2 gene (609309.0023). 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 MRTES.

Mangold et al. (2004) screened for mutations in the MSH2 and MLH1 genes in 41 unrelated index patients diagnosed with Muir-Torre syndrome, most of whom were preselected for mismatch repair deficiency in their tumor tissue. Germline mutations were identified in 27 patients (mutation detection rate of 66%). Mangold et al. (2004) noted that 25 (93%) of the mutations were located in MSH2, in contrast to HNPCC patients without the MRTES phenotype, in whom the proportions of MLH1 and MSH2 mutations are almost equal (p less than 0.001). Mangold et al. (2004) further noted that 6 (22%) of the mutation carriers did not meet the Bethesda criteria for HNPCC and suggested that sebaceous neoplasm be added to the HNPCC-specific malignancies in the Bethesda guidelines.

Animal Model

Fong et al. (2000) found that 100% of mice heterozygous for knockout of the Fhit gene developed multiple tumors of the forestomach that were a mixture of adenomas, squamous papillomas, and invasive carcinomas, as well as tumors of sebaceous glands, within 10 weeks after treatment intragastrically with nitrosomethylbenzylamine; adenoma or papilloma of the forestomach had developed in only 25% of the homozygous wildtype (+/+) mice.