Random Dermatology MCQ - Muir-Torree syndrome

A 65-year-old man with a history of colon cancer treated 5 years ago presents with a new, rapidly growing, nodular lesion on his nose. The lesion has a central dell and a pearly, telangiectatic border. Concurrently, he has multiple, yellow, papulo-nodular lesions on his trunk that clinically resemble sebaceous adenomas. A biopsy of the nasal lesion confirms a sebaceous carcinoma. What is the most likely underlying genetic defect and the most important next step in management?

A. A mutation in the PTCH1 gene (Gorlin syndrome); order a panoramic radiograph to screen for jaw cysts.
B. A mutation in a DNA mismatch repair gene (MSH2, MLH1); initiate enhanced surveillance for internal malignancies, including repeat colonoscopy and upper endoscopy.
C. A mutation in the CYLD gene (Brooke-Spiegler syndrome); perform MRI of the parotid glands to screen for cylindromas.
D. A mutation in the TSC1/TSC2 genes (Tuberous Sclerosis Complex); obtain a renal ultrasound and brain MRI.
E. A germline mutation in the BRCA2 gene; refer for breast and ovarian cancer screening in family members.

Correct Answer: B. A mutation in a DNA mismatch repair gene (MSH2, MLH1); initiate enhanced surveillance for internal malignancies, including repeat colonoscopy and upper endoscopy.

Answer and Explanation

The correct answer is B. This question describes the hallmark of Muir-Torre syndrome (MTS). The key clues are the personal history of visceral malignancy (colon cancer), the presence of sebaceous neoplasms (sebaceous adenoma on the trunk and the aggressive sebaceous carcinoma on the nose), and the patient's age. MTS is a variant of Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer - HNPCC). It is caused by germline mutations in DNA mismatch repair (MMR) genes, most commonly MSH2, followed by MLH1. The diagnosis of a sebaceous neoplasm, especially multiple or an aggressive carcinoma, should trigger a workup for MTS and, if confirmed, mandate rigorous, lifelong surveillance for internal malignancies.

Why the Other Options are Incorrect:

• A. A mutation in the PTCH1 gene (Gorlin syndrome): Gorlin syndrome presents with multiple basal cell carcinomas, jaw keratocysts, and palmar pits. Sebaceous neoplasms are not a feature.

• C. A mutation in the CYLD gene (Brooke-Spiegler syndrome): This syndrome features multiple cylindromas ("turban tumors"), trichoepitheliomas, and spiradenomas. Sebaceous neoplasms are not typical.

• D. A mutation in the TSC1/TSC2 genes (Tuberous Sclerosis Complex): TSC is characterized by facial angiofibromas, hypomelanotic macules, and hamartomas in multiple organs. Sebaceous adenomas are not a feature; the facial lesions are angiofibromas.

• E. A germline mutation in the BRCA2 gene: BRCA mutations are associated with breast, ovarian, pancreatic, and prostate cancer. They are not associated with sebaceous neoplasms or a Lynch/MTS phenotype.

Additional High-Yield Information for Exams:

• Definition: Muir-Torre syndrome is defined by the occurrence of at least one sebaceous neoplasm (adenoma, epithelioma/sebaceoma, or carcinoma) and at least one visceral malignancy in the absence of other known causes.

• Sebaceous Neoplasms: These are the sentinel skin signs. Sebaceous adenoma is the most characteristic, but sebaceous carcinoma is highly suggestive, especially when occurring outside the periocular region (where most sporadic sebaceous carcinomas occur).

• Associated Internal Malignancies: The spectrum is that of Lynch syndrome. The most common are:

  • Colorectal carcinoma (often proximal/right-sided).

  • Genitourinary cancers (endometrial, ovarian, urothelial).

  • Upper GI cancers (gastric, small intestinal).

  • Tumors often have an earlier onset and may be multiple/metachronous.

• Diagnostic Workup:

  • Immunohistochemistry (IHC): The first diagnostic step is to perform IHC for MMR proteins (MSH2, MSH6, MLH1, PMS2) on the sebaceous neoplasm. Loss of expression suggests MTS and guides germline genetic testing.

  • Microsatellite Instability (MSI) Testing: The tumor may show high MSI.

  • Germline Genetic Testing: For mutations in MSH2, MLH1, MSH6, PMS2.

• Prognosis: The internal cancers in MTS/Lynch syndrome can be aggressive, but they also tend to have a better prognosis than their sporadic counterparts, possibly due to high immunogenicity (related to MSI).

• Management & Rationale:

  • Rationale: The goal is early detection and prevention of visceral cancers in the patient and at-risk relatives.

  • First-line/Obligatory Actions:

    1. Enhanced Cancer Surveillance: For the patient, this includes colonoscopy every 1-2 years starting at age 20-25 (or 5 years before the youngest diagnosis in the family), annual urinalysis/cytology, and consideration of endometrial biopsy/transvaginal ultrasound for women.

    2. Genetic Counseling & Testing: For the patient and first-degree relatives.

    3. Risk-Reducing Surgery: Prophylactic colectomy or hysterectomy/oophorectomy may be considered in certain high-risk scenarios.

  • Skin: Complete excision of sebaceous neoplasms is recommended, with close follow-up for new lesions.