Muir-Torre syndrome

INTRODUCTION — Muir-Torre syndrome (MIM #158320) is a rare, hereditary condition characterized by the association of at least one, but often multiple, sebaceous cutaneous neoplasms and at least one, but sometimes multiple, often low-grade, synchronous or metachronous, visceral malignancies [1,2]. Muir-Torre syndrome is caused by germline variants in the deoxyribonucleic acid (DNA) mismatch repair (MMR) genes and is considered a phenotypic variant of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma syndrome [HNPCC]). However, approximately one-third of cases of Muir-Torre syndrome are caused by MUTYH variants and may represent a clinical phenotype of MUTYH-associated polyposis, an autosomal recessive polyposis syndrome caused by biallelic pathogenic variants in the base excision repair gene MUTYH.

This topic will discuss the pathogenesis, clinical features, diagnosis, and management of Muir-Torre syndrome. Lynch syndrome and MUTYH-associated polyposis are discussed separately. Sebaceous carcinoma is also discussed separately.

●(See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

●(See "MUTYH-associated polyposis".)

●(See "Sebaceous carcinoma".)

EPIDEMIOLOGY — Muir-Torre syndrome is a variant of Lynch syndrome, which accounts for approximately 3 percent of newly diagnosed cases of colorectal and endometrial cancers. Among individuals with Lynch syndrome, approximately 9 percent have Muir-Torre syndrome [3,4]. It is estimated that in the general population, 1 in 279 individuals carry variants in any DNA mismatch repair (MMR) genes associated with Lynch syndrome [5]. Approximately one-third of Muir-Torre syndrome cases represent a clinical phenotype of MUTYH-associated polyposis. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "MUTYH-associated polyposis".)

Muir-Torre syndrome is more frequent in males (male-to-female ratio 3:2), with a median age of onset of cutaneous malignancies of 53 years (range 23 to 89 years) [6]. Muir-Torre syndrome has been rarely reported in solid organ transplant recipients who developed sebaceous carcinomas and other visceral malignancies [7,8].

PATHOGENESIS

Mismatch repair gene variants — In approximately two-thirds of cases, Muir-Torre syndrome is caused by dominant germline inactivating variants of DNA mismatch repair (MMR) genes. The human DNA MMR system includes the Escherichia coli homolog genes MSH2, MSH3, MSH6, and MLH1 and the yeast homologue gene PMS2. The products of these genes are responsible for maintaining the genomic integrity by correcting base substitution mismatches and small insertion-deletion mismatches generated by errors in base pairing during DNA replication.

In contrast with Lynch syndrome, in which germline variants are almost equally distributed across all MMR genes, approximately 90 percent of patients with Muir-Torre syndrome harbor germline variants in MSH2, with less than 10 percent harboring MLH1 variants [9]. Rare cases of Muir-Torre syndrome are associated with isolated germline variants in MSH6 or PMS2 [10].

Microsatellite instability — Microsatellite instability (MSI) is the hallmark of MMR gene deficiency. Microsatellites are short, repetitive DNA sequences, typically mononucleotide or dinucleotide tandem repeats, that are susceptible to mutations during DNA replication. The loss of DNA MMR function in tumor tissue due to germline and/or somatic inactivating mutations of MMR genes leads to the accumulation of mutations across the genome and, mainly, in the microsatellite repetitive sequences, creating a molecular phenotype known as MSI [10]. Mutations in MLH1 and MSH2 have the most severe effect, producing a high microsatellite instability phenotype (MSI-H). An MSI-H phenotype can be demonstrated in nearly all cutaneous and visceral tumors from patients with Muir-Torre syndrome [11,12]. (See "Molecular genetics of colorectal cancer", section on 'Mismatch repair genes'.)

MUTYH gene — Approximately one-third of patients with Muir-Torre syndrome do not display pathogenic variants in MLH1, MSH2, MSH6, or MSI. They comprise a subtype of Muir-Torre syndrome, called Muir-Torre syndrome type 2, which is due to germline biallelic inactivation of the base excision repair gene mutY homolog (MUTYH) on chromosome 1p and inherited in an autosomal recessive manner with low to moderate penetrance [2,13-15]. Coexisting germline MSH2 and MUTYH mutations were described in one patient with Muir-Torre syndrome [16]. Sebaceous tumors in Muir-Torre syndrome type 2 do not show MSI.

MUTYH variants are associated with an attenuated form of familial adenomatous polyposis, frequently referred to as MUTYH-associated polyposis, characterized by recessive inheritance, older age of onset, and fewer colorectal adenomas. Cases of sebaceous adenomas in patients with MUTYH-associated polyposis have been reported [14,17,18]. (See "MUTYH-associated polyposis" and "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Attenuated FAP'.)

Immunosuppression — Rare cases of confirmed Muir-Torre syndrome have been reported in solid organ transplant recipients who developed single or multiple sebaceous tumors showing loss of MMR proteins on immunohistochemistry (IHC) or MSI analysis, with or without concurrent visceral cancers at the time of sebaceous tumor diagnosis [7,8,19]. Immunosuppression may have unmasked a latent Muir-Torre syndrome in these patients.

Of note, MSI has been detected in sebaceous tumors occurring in organ transplant recipients in the absence of germline mutations in MMR genes [20]. The loss of MMR proteins in these tumors may be due to de novo somatic mutations in MMR genes or CDKN2A gene promoter hypermethylation induced by immunosuppressive agents, particularly tacrolimus [8,21].

CLINICAL MANIFESTATIONS — Muir-Torre syndrome is characterized by the association of at least one sebaceous skin tumor and/or keratoacanthoma (picture 1) and at least one synchronous or metachronous, visceral malignancy.

Sebaceous tumors — Sebaceous adenomas and sebaceous carcinomas are the most typical tumors in patients with Muir-Torre syndrome [1]. Sebaceous adenoma is most common and considered the most specific marker of Muir-Torre syndrome [9,22]. Sebaceous adenoma and sebaceous carcinoma present as yellowish or skin-colored papules, usually <0.5 cm in diameter (picture 2A-B). They show a predilection for the head and neck region and, particularly, the periocular area in sporadic cases, whereas in patients with Muir-Torre syndrome, these tumors are predominantly found on the trunk [23]. Because sebaceous tumors precede the development of internal malignancies in over one-half of patients, molecular testing of the skin tumor for mismatch repair (MMR) defects in select patients is critical to early diagnosis [24]. (See 'Indications for tumor testing' below.)

Other tumors that can be seen in patients with Muir-Torre syndrome include:

●Basal cell carcinoma with sebaceous differentiation (sebaceous epithelioma)

●Histologically typical keratoacanthoma

●Keratoacanthoma with sebaceous differentiation

●Cystic sebaceous neoplasms

●True sebaceous cysts

These tumors tend to occur at an earlier age than the sporadic counterparts and can precede, occur concurrently, or follow the diagnosis of internal malignancy [25]. They can be solitary or number up to hundreds, ranging in size from a few millimeters to several centimeters [26].

The presence of Fordyce spots (ectopic sebaceous glands) on the vestibular oral mucosa has been suggested as an additional clinical feature of Muir-Torre syndrome (picture 3) (see "Oral lesions", section on 'Fordyce granules'). In a study including 13 patients with Muir-Torre syndrome and confirmed germline MMR mutations and 140 healthy individuals, Fordyce spots were found in all patients with Muir-Torre syndrome but only in 9 (6.4 percent) of the controls [27].

Visceral cancers — Internal malignancies most frequently associated with Muir-Torre syndrome include colorectal cancer and genitourinary cancer, including endometrial, ovarian, urothelial, and prostate cancer [2,9,28,29]. Breast, pancreatic, hepatobiliary, gastric, lung, brain, and hematologic cancers have also been reported in association with Muir-Torre syndrome [30-35].

Colorectal cancer is the most common visceral neoplasm associated with Muir-Torre syndrome. Compared with sporadic colorectal cancers, lesions are more often located in the proximal colon than in the distal colon and develop 15 to 20 years earlier, with a median age of onset of 50 years [1].

Colonic polyps may also be found in patients with the autosomal recessive subtype of Muir-Torre syndrome (Muir-Torre syndrome type 2) due to MUTYH variants [16]. (See "MUTYH-associated polyposis".)

DIAGNOSIS

Diagnostic approach — Muir-Torre syndrome is suspected in patients presenting with one or multiple sebaceous tumors, especially if occurring at an early age and located in extraocular or non-head and neck areas. The diagnostic approach involves the following steps (algorithm 1):

●Evaluation of the patient's risk of having Muir-Torre syndrome using the clinical criteria included in the Mayo score (age ≤60 years, number of sebaceous tumors, personal and family history of malignancy) (see 'Clinical criteria (the Mayo Muir-Torre syndrome risk score)' below)

●Testing of sebaceous tumors for mismatch repair (MMR) deficiency with immunohistochemistry (IHC) (see 'Tumor testing' below)

●Microsatellite analysis of sebaceous tumors (see 'Microsatellite instability analysis' below)

●Genetic testing for germline variants in the MLH1, MSH2, MSH6, and PMS2 genes (see 'Genetic testing' below)

Clinical criteria (the Mayo Muir-Torre syndrome risk score) — The Mayo Muir-Torre syndrome score was developed to identify patients with the highest risk of having Muir-Torre syndrome [36]. It is highly accurate in discriminating patients with and without Muir-Torre syndrome (area under the receiving operator characteristics [ROC] curve 0.96 [95% CI 0.93-1.00]) [36].

The Mayo Muir-Torre syndrome score is based on the following clinical criteria:

●Age <60 years at first presentation of sebaceous tumors, including sebaceous adenomas, sebaceous epitheliomas, and sebaceous carcinomas (score = 1)

●Two or more sebaceous tumors (score = 2)

●Personal history of any Lynch-related cancers (score = 1)

●Family history of any Lynch-related cancers (score = 1)

Patients with a Mayo Muir-Torre syndrome score ≥2 are very likely to have Muir-Torre syndrome and should undergo further evaluation with genetic testing for germline variants of MMR genes (algorithm 1) [36]. (See 'Genetic testing' below.)

It is reasonable that young patients with extraocular or periocular sebaceous tumors who do not meet the Mayo Muir-Torre syndrome criteria have their tumor tested with IHC for loss of expression of MMR proteins [37,38]. (See 'Immunohistochemistry' below.)

Tumor testing — Tumor testing for lack of MMR protein expression with IHC or microsatellite instability (MSI) analysis can be used as an initial screening test for Muir-Torre syndrome, particularly in patients who lack the clinical criteria included in the Mayo score (algorithm 1) [22,39]. (See 'Immunohistochemistry' below and 'Microsatellite instability analysis' below.)

Indications for tumor testing — Because cutaneous sebaceous neoplasms are rare in the general population and are associated with Muir-Torre syndrome in a high proportion of cases, some experts advocated universal testing for all sebaceous neoplasms, based on the relatively high rates of MMR IHC positivity detected in unselected sebaceous tumors (approximately 50 percent) as well as relatively high rates of germline variants detected in IHC-positive tumors (approximately 20 to 30 percent) [40-43].

However, others suggest a targeted use of IHC, based on consideration of the patient's age, clinical presentation, and personal history of Lynch-related tumors [44]. An expert panel suggested the following criteria as appropriate for testing sebaceous tumors with a four-antibody IHC panel (algorithm 1) [44]:

●One sebaceous tumor in a non-head and neck location (only in patients ≤60 years)

●Multiple sebaceous tumors

●Tumors most typically associated with Muir-Torre syndrome (sebaceous adenoma, sebaceous epithelioma, sebaceous carcinoma)

●Keratoacanthoma with sebaceous differentiation

●Cystic sebaceous neoplasms, including true sebaceous cysts

●History of Lynch syndrome-related, visceral malignancy (eg, colorectal carcinoma, endometrial carcinoma, urothelial carcinoma)

Of note, tumor testing is generally not recommended for periocular sebaceous tumors, including sebaceous carcinoma, based on evidence that periocular tumors are in most cases sporadic and not associated with increased risk of internal cancers [45,46]. However, the decision to test periocular sebaceous tumors, especially in younger patients, must be considered on a case-by-case basis [38].

Immunohistochemistry — Immunohistochemistry (IHC) testing of sebaceous tumors for MMR proteins (MSH2, MLH1, MSH6, and PMS2) is a relatively simple method that can be performed on formalin-fixed, paraffin-embedded sections as the initial screening test for individuals with suspected Muir-Torre syndrome [22,39]. In a large series of 282 sebaceous neoplasms, loss of MSH2 and MSH6 protein expression was the most frequent pattern observed [47]. (See 'Indications for tumor testing' above.)

The positive predictive value for Muir-Torre syndrome has been estimated to be 55 percent in unselected sebaceous tumors demonstrating loss of both MSH2 and MSH6, 100 percent for tumors with loss of both MLH1 and MSH6, and 100 percent for tumors demonstrating loss of all three MMR proteins [22].

For patients with lesions showing loss of MMR proteins, MSI analysis of tumor tissue and/or germline mutational analysis is warranted to confirm or rule out the diagnosis of Muir-Torre syndrome. (See 'Microsatellite instability analysis' below and 'Genetic testing' below.)

MSI analysis of tumor tissue is also indicated in cases in which MLH1 or MSH2 are expressed on IHC but the clinical suspicion of Muir-Torre syndrome persists. (See 'Microsatellite instability analysis' below.)

Microsatellite instability analysis — Microsatellite instability (MSI) is the hallmark of MMR gene deficiency and is found in approximately two-thirds of sebaceous tumors associated with Muir-Torre syndrome [24,48,49]. MSI analysis can be performed on paraffin-embedded tissue and typically uses five markers (the Bethesda panel including three dinucleotide [D2S123, D5S346, and D17S250] and two mononucleotide [BAT25, BAT26] repeats) [10]. Detection of MSI in any two of the five markers is considered a positive result.

Because of its greater complexity, cost, and limited availability, MSI analysis should be considered a second-line test in cases in which the IHC results are inconclusive, especially in patients with a family history supporting the suspicion of Muir-Torre syndrome or Lynch syndrome. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)

Genetic testing — Based on expert recommendations, genetic testing for germline variants in the MLH1, MSH2, MSH6, and PMS2 genes should be offered in the following situations (algorithm 1) [36,40,45]:

●Patients with a Mayo Muir-Torre syndrome risk score ≥2.

●Patients with extraocular sebaceous carcinoma and a Mayo Muir-Torre syndrome risk score ≥2. Genetic testing is generally not recommended for periocular sebaceous carcinoma [45].

●Young patients (<50 years) with their first sebaceous carcinoma, with loss of MMR protein expression on IHC and not otherwise meeting the Mayo risk score threshold [45].

●Patients with any sebaceous tumors that screened positive for loss of MMR protein expression on IHC or MSI.

Testing for variants in MUTYH should be considered for patients in whom a pathogenic variant in MMR genes is not detected. Germline biallelic inactivation of the base excision repair gene mutY homolog (MUTYH) on chromosome 1p causes a variant of Muir-Torre syndrome, called Muir-Torre syndrome type 2, which is inherited in an autosomal recessive manner [2,14]. (See 'MUTYH gene' above and "MUTYH-associated polyposis".)

The absence of a detectable germline variant in MMR genes and MUTYH in patients with tumors showing MMR deficiency warrants further tumor analysis for biallelic somatic MMR mutations or hypermethylation of the promoter region of MLH1 [42,50].

CANCER SCREENING AND MANAGEMENT — Cutaneous neoplasms and synchronous, visceral neoplasms associated with Muir-Torre syndrome should be managed in the individual patient according to available options discussed in separate topic reviews. The management of sebaceous carcinoma is also discussed separately. (See "Sebaceous carcinoma", section on 'Management'.)

The estimated lifetime risk of colorectal cancer is 40 to 70 percent, stomach cancer 6 to 13 percent, endometrial cancer 15 percent, ovary cancer 4 to 12 percent, and urinary cancers 5 to 21 percent [51,52]. Thus, patients diagnosed with Muir-Torre syndrome and at-risk family members (first-degree relatives) should undergo a preventive cancer screening program similar to that indicated for patients with Lynch syndrome (see "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management"), which involves:

●Annual skin examination for lesions suspicious for sebaceous carcinoma or keratoacanthoma.

●Colonoscopy every one to two years, beginning at age 20 to 25 years, or two to five years before the youngest age of diagnosis of colorectal cancer in the family, if diagnosed before age 25 years; annual colonoscopy in carriers of MLH1 and MSH2 mutations; consider colonoscopy starting at age 30 years in MSH6 mutation carriers and 35 years in PMS2 mutation carriers, unless an early-onset cancer exists in a given family.

●Annual screening for endometrial and ovarian cancer with pelvic examination, endometrial biopsy, and transvaginal ultrasound beginning at age 30 to 35 years.

●Upper endoscopy with biopsy of the gastric antrum starting at 30 to 35 years and subsequent surveillance every two to three years can be considered based on patient risk factors.

●Annual urinalysis and cytologic examination beginning at age 30 to 35 years.

Nearly one-half of patients with Muir-Torre syndrome have two or more internal malignancies in different locations [53,54]. A baseline and annual positron emission tomography/computerized tomography (PET/CT) scan may be a useful whole-body search for primary malignancies and disease spread [55]. However, its utility compared with the above screening tests has not been determined.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sebaceous carcinoma and Muir-Torre syndrome".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Muir-Torre syndrome is a rare, autosomal dominant condition caused by germline inactivating variants in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In approximately one-third of patients, Muir-Torre syndrome type 2 is associated with germline biallelic inactivation of the base excision repair gene MUTYH and inherited in an autosomal recessive manner. (See 'Pathogenesis' above and 'MUTYH gene' above.)

●Clinical presentation – Muir-Torre syndrome is characterized by the association of at least one sebaceous skin tumor and at least one visceral malignancy and is considered a phenotypic variant of hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC; Lynch syndrome). Sebaceous adenomas (picture 2A), sebaceous epitheliomas, sebaceous carcinomas (picture 2B), and keratoacanthomas (picture 1) are the most typical cutaneous tumors associated with Muir-Torre syndrome. Visceral neoplasms include colorectal, endometrial, ovarian, and urothelial cancers. (See 'Clinical manifestations' above and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

●Diagnosis – The diagnosis of Muir-Torre syndrome is based upon the combination of clinical criteria, tumor testing for deficiency of MMR protein or microsatellite instability (MSI), and genetic testing for germline variants in MMR genes (algorithm 1). (See 'Diagnostic approach' above and 'Clinical criteria (the Mayo Muir-Torre syndrome risk score)' above and 'Tumor testing' above.)

●Cancer screening and management – Patients diagnosed with Muir-Torre syndrome and at-risk family members (first-degree relatives) should undergo a preventive cancer screening program for colorectal cancers starting at age 20 to 25 years (or earlier if colorectal cancer was diagnosed in the family before age 25 years) and stomach and urogenital cancers starting at the age of 30 to 35 years. (See 'Cancer screening and management' above.)