Elsevier

The Lancet Oncology

Volume 6, Issue 12, December 2005, Pages 980-987
The Lancet Oncology

Review
Muir-Torre syndrome

https://doi.org/10.1016/S1470-2045(05)70465-4Get rights and content

Summary

Muir-Torre syndrome is an autosomal-dominant skin condition of genetic origin, characterised by tumours of the sebaceous gland or keratoacanthoma that are associated with visceral malignant diseases. The cutaneous characteristics of Muir-Torre syndrome are sebaceous adenoma, epithelioma, carcinoma, or multiple keratoacanthomas, whereas visceral malignant diseases include colorectal, endometrial, urological, and upper gastrointestinal tumours. Although Muir-Torre syndrome has a striking familial association and features of autosomal-dominant transmission, it can arise in individuals without a family history or any known mutations. Clinical and biomolecular evidence has suggested that there are two types of Muir-Torre syndrome. The most common is a variant of hereditary non-polyposis colorectal cancer, which is characterised by defects in mismatch repair genes and early-onset tumours. The second type does not show deficiency in mismatch repair and its pathogenesis remains undefined. Diagnosis of these rare sebaceous lesions warrants the search for associated internal malignant diseases: the peculiarity of skin lesions and their biomolecular characterisation with microsatellite instability analysis and immunohistochemistry could be used to identify familial Muir-Torre syndrome, allowing clinicians to tailor a personalised programme to screen for skin and visceral malignant diseases in high-risk individuals.

Introduction

Muir-Torre syndrome is an autosomal-dominant skin condition of genetic origin characterised by tumours in the sebaceous gland or keratoacanthoma that are associated (ie, arise simultaneously or sequentially) with one or more of various visceral malignant diseases, in particular, colorectal, endometrial, urological, and upper gastrointestinal neoplasms.1 The characteristic sebaceous tumours of Muir-Torre syndrome include sebaceous adenomas (figure 1), epitheliomas, and carcinomas.2

The first study of Muir-Torre syndrome is dated 1967, when Muir and colleagues3 described a Maltese man with many primary carcinomas in the colon, duodenum, and larynx who also had keratoacanthomata of the face. The patient was one of 22 siblings, including four pairs of twins, none of which had any history of malignant disease. In 1968, Torre4 reported on a patient with many sebaceous tumours (eg, sebaceous adenoma) who had a primary carcinoma of the ampulla of Vater that was resected at age 50 years and a second primary carcinoma at age 53 years. In 1971, Bakker and Tjon A Joe5 reported the first case of Torre's syndrome in which a family history of cancer had been well documented (the patient's father died of colon cancer). 5 years later, Reiffers and co-workers6 reported a patient with a remarkable and informative family history of Muir-Torre syndrome, providing the first description of the autosomal-dominant pattern of inheritance and the variety of clinical presentations.

Several other cases of Muir-Torre syndrome have been reported.7, 8, 9, 10 In 1981, Lynch and colleagues11 noted sebaceous neoplasms in patients from four families affected by colorectal cancer, and postulated that Muir-Torre syndrome was a clinical variant of hereditary non-polyposis colorectal cancer. They also12 described a patient with Muir-Torre syndrome who was found to be a descendant of the Warthin's family G, which is thought to be the first description of the familial cancer syndrome called Lynch syndrome.12

In 1995, Schwartz and Torre13 defined the disease as the simultaneous occurrence of some types of sebaceous neoplasm of the skin (with or without keratoacanthomas) with one or more visceral malignant diseases in the absence of a predisposition factor.13 1 year later, Kruse and co-workers14 identified germline mutations in the human MSH2 DNA mismatch repair gene in two unrelated patients with Muir-Torre syndrome, diagnosed because of their skin tumours. In the same year, Bapat and colleagues15 showed that mutations in human MLH1 could cause Muir-Torre syndrome.

Section snippets

Epidemiology

Muir-Torre syndrome is a rare disease, and consequently, there is little or no information on the main epidemiological features. Akhtar and co-workers,16 identified from the available published work, 205 cases of Muir-Torre syndrome, in whom 399 internal malignant diseases had been diagnosed. It is possible, though not documented, that Muir-Torre syndrome can escape diagnosis and clinical recognition. Most clinical reports on Muir-Torre syndrome involve white patients who live in countries in

Clinical features

The most typical skin tumours associated with Muir-Torre syndrome are sebaceous adenomas, carcinomas, keratoacanthomas, and basal-cell carcinomas with sebaceous differentiation.13 Sebaceous differentiation therefore seems to be a strong phenotypic marker of the disease.

Sebaceous adenoma is the most common lesion in Muir-Torre syndrome. It is composed of sebaceous lobules of various sizes that are incompletely differentiated, and contain basaloid cells at the periphery and mature sebaceous

Molecular biology

In 1994, molecular studies38, 39, 40 in patients with Muir-Torre syndrome showed microsatellite instability in tumours of the sebaceous gland and colorectal carcinomas. Microsatellites are repetitive mononucleotide, dinucleotide, trinucleotide, or tetranucleotide sequences, that are distributed over the whole genome. They are especially prone to replication errors because of their structure; thus, microsatellite instability became a hallmark of a deficiency in mismatch repair genes, especially

Muir-Torre syndrome and Lynch syndrome

Many families with Muir-Torre syndrome show close similarities with families with hereditary non-polyposis colorectal cancer. Consequently, Muir-Torre syndrome might be a clinical variant of hereditary non-polyposis colorectal cancer.7 Clinical diagnosis of hereditary non-polyposis colorectal cancer is based on the Amsterdam criteria, which refer exclusively to internal cancers in probands and their relatives.47 The range of internal neoplasms in Muir-Torre syndrome is similar to that of

Management and follow-up

Diagnosis and management of Muir-Torre syndrome needs a multidisciplinary approach, including primary-care physicians, geneticists, biologists, dermatologists, gastroenterologists, and surgeons. The initial approach includes a detailed clinical history of the proband and definition of an extended pedigree. Further steps involve the analysis of microsatellites (or immunohistochemistry for MSH2 and MLH1 expression) in skin and in visceral tumours of the proband or other affected family members,

Conclusion

Clinically, Muir-Torre syndrome is defined as the occurrence of at least one sebaceous-gland tumour, or keratoacanthoma, in conjunction with internal malignant diseases. This clinical disorder has a wide variety of phenotypes, which includes either apparently sporadic cases or families with a strong history of tumours.63

A similar variability exists molecularly, since about 35% of tumours do not show microsatellite instability. Thus, the clinical and biomolecular differences point to two

Search strategy and selection criteria

We searched MEDLINE for articles published between 1967 to May 31, 2005, using the keywords “Muir-Torre Syndrome”, “sebaceous skin tumours”, “keratoacanthoma”, “hereditary colorectal cancer”, “microsatellite instability (MSI)”, “mismatch repair genes (MMR)”, and “MYH gene”. We subsequently searched the reference lists of articles identified by our search strategy. We also reviewed the ICG-HNPCC mutation database (website:http://www.insight-group.org/).

References (66)

  • R Kruse et al.

    Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary non-polyposis colorectal cancer families defined by the Amsterdam criteria

    Am J Hum Genet

    (1998)
  • VJ Swale et al.

    Microsatellite instability in benign skin lesions in hereditary non-polyposis colorectal cancer syndrome

    J Invest Dermatol

    (1999)
  • CA Harwood et al.

    An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ trasplant recipients

    J Invest Dermatol

    (2001)
  • R Kruse et al.

    DNA mismatch repair and the significance of a sebaceous skin tumor for visceral cancer prevention

    Trends Mol Med

    (2004)
  • PR Cohen et al.

    Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome

    Am J Med

    (1991)
  • FS Pardo et al.

    Sebaceous carcinoma of the ocular adnexa: radiotherapeutic management

    Int J Radiat Oncol Biol Phys

    (1989)
  • SA Kuismanen et al.

    Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancer

    Am J Pathol

    (2000)
  • VA Mckusic

    Mendelian inheritance in man. Catalogs of autosomal-dominant, autosomal recessive, and X-Linked phenotypes

    (1990)
  • EG Muir et al.

    Multiple primary carcinomata of the colon, duodenum and larynx associated with keratoacanthoma of the face

    Br J Surg

    (1967)
  • D Torre

    Multiple sebaceous tumours

    Arch Dermatol

    (1968)
  • PM Bakker et al.

    Multiple sebaceous gland tumours, with multiple tumours of internal organs: a new syndrome?

    Dermatologica

    (1971)
  • J Reiffers et al.

    Hyperplasies sebacees, kerato-acanthomes, epitheliomas de visage et cancer du colon: une nouvelle entite?

    Dermatologica

    (1976)
  • G Lynne-Davies et al.

    Multiple sebaceous gland tumors associated with polyposis of the colon and bony abnormalities

    Can Med Assoc J

    (1974)
  • WM Stewart et al.

    Kerato-acanthomes multiples and carcinomes visceraux: syndrome de Torre

    Ann Dermatol Venereol

    (1977)
  • S Poleksic

    Keratoacanthoma and multiple carcinomas

    Br J Dermatol

    (1974)
  • MS Housholder et al.

    Sebaceous neoplasm associated with visceral carcinomas

    Arch Dermatol

    (1980)
  • HT Lynch et al.

    The cancer family syndrome: rare cutaneous phenotypic linkage of Torre's syndrome

    Arch Intern Med

    (1981)
  • HT Lynch et al.

    Muir-Torre syndrome in several members of a family with a variant of the cancer family syndrome

    Br J Dermatol

    (1985)
  • R Kruse et al.

    Is the mismatch repair deficiency type of Muir-Torre syndrome confined to mutations in the hMSH2 gene?

    Hum Genet

    (1996)
  • B Bapat et al.

    The genetic basis of Muir-Torre syndrome includes the hMLH1 locus

    Am J Hum Genet

    (1996)
  • MR Wick et al.

    Tumors with hair follicle and sebaceous differentiation

  • NA Rao et al.

    Sebaceous carcinomas of the ocular adnexa: a clinicopathologic study of 104 cases, with five years follow-up data

    Hum Pathol

    (1982)
  • JJ Abbott et al.

    Cystic sebaceous neoplasms in Muir-Torre syndrome

    Arch Pathol Lab Med

    (2003)
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