Muir–Torre syndrome

Overview

Muir–Torre syndrome (MTS) is a rare, autosomal dominant genetic disorder characterized by the development of sebaceous skin tumors and an increased risk of internal malignancies, particularly colorectal and genitourinary cancers. MTS is considered a subtype of Lynch syndrome (hereditary nonpolyposis colorectal cancer, or HNPCC), and it shares a similar genetic basis involving mutations in DNA mismatch repair (MMR) genes.

The hallmark of MTS is the presence of at least one sebaceous neoplasm (such as sebaceous adenoma or carcinoma) and at least one visceral malignancy, most commonly colorectal cancer. Early identification of Muir–Torre syndrome is crucial as it allows for intensive cancer surveillance, early detection, and preventive management for affected individuals and their family members.

Causes

Muir–Torre syndrome is caused by inherited mutations in DNA mismatch repair genes that are responsible for correcting errors during DNA replication. The most commonly affected genes include:

• MSH2 (most frequently mutated in MTS)

• MLH1

• MSH6 (rarely)

These mutations lead to microsatellite instability (MSI), a condition in which repetitive sequences of DNA become unstable and prone to mutations, increasing the risk of tumor development.

Inheritance Pattern

• Autosomal dominant: A mutation in just one copy of the gene is sufficient to increase cancer risk.

• Each child of an affected parent has a 50% chance of inheriting the mutation.

Because Muir–Torre syndrome is a phenotypic variant of Lynch syndrome, families with a history of Lynch-associated cancers (colorectal, endometrial, ovarian) should be evaluated for MTS, particularly if sebaceous tumors are present.

Symptoms

Symptoms of Muir–Torre syndrome can vary but typically involve a combination of skin tumors and internal cancers. Skin lesions often precede or coincide with the diagnosis of visceral malignancy, serving as an important clinical clue.

1. Cutaneous Manifestations

• Sebaceous adenomas (benign tumors of oil glands)

• Sebaceous carcinomas (malignant and potentially aggressive)

• Sebaceomas or sebaceous epitheliomas

• Keratocanthomas (rapidly growing skin nodules with central keratin plugs)

2. Internal Malignancies

• Colorectal cancer: Most common visceral tumor in MTS

• Genitourinary cancers: Including bladder, ureter, and kidney cancers

• Endometrial and ovarian cancers: Especially in women with MTS

• Other reported cancers: Including stomach, small intestine, hepatobiliary tract, and brain tumors

Skin tumors typically appear between ages 30–60 and may be solitary or multiple. Visceral cancers can develop simultaneously or over time, necessitating lifelong surveillance.

Diagnosis

Diagnosis of Muir–Torre syndrome requires clinical evaluation, histopathological examination of tumors, and genetic testing. Suspicion arises in individuals with sebaceous tumors, especially when accompanied by personal or family history of Lynch-associated cancers.

Clinical Criteria

• At least one sebaceous gland tumor (adenoma, carcinoma, or epithelioma)

• At least one visceral malignancy (most commonly colorectal or genitourinary)

Diagnostic Workup

• Histopathology: Biopsy of skin lesions to confirm sebaceous origin

• Immunohistochemistry (IHC): Tests for loss of expression of MMR proteins (MSH2, MLH1, MSH6)

• Microsatellite instability testing: Detects instability in tumor DNA sequences

• Germline genetic testing: Confirms mutations in MMR genes (especially MSH2 or MLH1)

Diagnosis may also involve assessment using the Amsterdam criteria or revised Bethesda guidelines, which aid in identifying Lynch syndrome and its variants.

Treatment

Treatment for Muir–Torre syndrome involves a combination of surgical, dermatologic, and oncologic management, tailored to each individual’s clinical findings. As there is no cure for the genetic mutation, the goal is early detection and treatment of tumors and prevention of further malignancies.

1. Management of Skin Tumors

• Surgical excision: Preferred method for removing sebaceous tumors, especially carcinomas

• Mohs micrographic surgery for facial or recurrent lesions

• Regular dermatologic surveillance for new or recurring lesions

2. Management of Internal Cancers

• Surgical resection: For colorectal and genitourinary tumors

• Chemotherapy or radiation: As indicated based on cancer type and stage

3. Surveillance and Prevention

• Colonoscopy: Every 1–2 years starting at age 20–25 or 10 years earlier than the youngest case in the family

• Skin exams: Every 6–12 months by a dermatologist

• Annual pelvic exams and transvaginal ultrasound: For women to monitor for endometrial and ovarian cancer

• Urinalysis: Periodic screening for urinary tract cancers

4. Genetic Counseling

• Offered to all individuals with confirmed MTS

• Family members should undergo predictive genetic testing if a pathogenic mutation is identified

Education about symptoms of internal cancers and the importance of routine screening is critical for patients and families.

Prognosis

The prognosis of Muir–Torre syndrome depends largely on the early detection and management of associated malignancies. Skin tumors are often benign or low-grade, but internal cancers can significantly impact morbidity and mortality if not caught early.

Favorable Prognostic Factors

• Early diagnosis and routine cancer surveillance

• Prompt treatment of sebaceous and internal malignancies

• Genetic testing and monitoring of at-risk family members

Potential Challenges

• Delayed diagnosis in the absence of recognizable skin lesions

• Risk of recurrence or development of multiple tumors over time

• Potential for aggressive or metastatic sebaceous carcinomas if untreated

With vigilant monitoring and proactive care, individuals with Muir–Torre syndrome can often live long and healthy lives. Early involvement of a multidisciplinary team and personalized screening protocols are essential for optimal outcomes.