Muir-Torre Syndrome (MTS) is a rare genetic disease that increases an individual's risk of developing benign and cancerous tumour growth. Given its low prevalence and association with various cancer types, MTS treatment is only recently becoming standardised across the MTS patient population.

Here, we will introduce the MTS disease course, including its genetic causes, symptoms, and methods of diagnosis. Subsequently, the current standard management and treatment of MTS will be discussed, including screening recommendations, genetic counselling, and preventative treatments.

Introduction to MTS

Muir-Torre Syndrome (MTS) is a rare, genetic disease characterised by the increased risk of developing benign or cancerous tumours throughout the lifetime on the patient's skin or in their internal organs, most commonly in their gastrointestinal tract.

MTS has only over 200 cases documented. It seems to be more prevalent in Caucasian populations and more frequently diagnosed in Western countries. Notably, is more common in males than females, with a ratio of approximately 3:2.

Causes of MTS

MTS is a genetic disease caused by errors in gene sequences within individuals. The genes associated with MTS Type 1 include MLH1, MSH2, MSH6, and PMS2. These genes are responsible for correcting errors in the DNA sequence within our cells. In patients with MTS, one of these genes is faulty and unable to function properly. It results in the formation of tumours, which maybe cancerous and non-cancerous (benign).

MTS Type 2 is similar to Type1, It has a faulty gene in a MTS patient which is responsible for DNA repair. However, it does not participate in the repair process mediated by MLH1, MSH2, MSH6, and PMS2. Instead, the gene responsible for MTS Type 2 is MUTYH and is part of a separate group of DNA repair genes.

Both types of MTS exist within families and most individuals with MTS possess a family history of the condition. In MTS Type 1, an individual only needs to inherit one copy of the faulty gene as it is autosomal dominant. Therefore, a parent with MTS has a 50% probability of passing on the disease to a child. Similarly, the chance of having a sibling with MTS is 50% for a MTS patient.

MTS Type 2 is autosomal recessive. Two faulty gene copies manifest MTS. Both parents must possess one abnormal gene copy each, making MTS type 2 rarer than MTS type 1, each diagnosed in 35% and 65% of MTS cases.

Interestingly, some recent MTS cases have no family history. It means  MTS is not been inherited. These MTS cases are a result of probable immunosuppression.¹

Symptoms of MTS

The main symptom of MTS is the presence of multiple or recurrent skin lesions in an individual. While they can develop before, during and after cancer, these skin lesions flag the potential diagnosis of MTS to healthcare professionals.

There are various types of skin lesions associated with MTS. These include:

• Sebaceous adenomas are the most common skin lesions observed in MTS. These are benign and non-cancerous and occur around an individual’s sebaceous glands in hair follicles. MTS is suspected when sebaceous adenomas occur in the chest, abdomen, pelvis or back area. They appear as multiple yellow bumps.
• Sebaceous carcinomas: These appear very similar to sebaceous adenomas but are cancerous. They occur on the chest, abdomen, back, face or scalp. Sebaceous carcinomas on the eyelids are of particular concern as often metastasise. Individuals should alert a healthcare professional immediately.
• Keratoacanthomas: These can be either benign or cancerous. Likesebaceous adenomas and carcinomas, they appear in the chest, abdomen, back, face or scalp area. However, they have a distinctive appearance, as the bump has a keratin core.The surrounding area tends to have visible blood vessels. They fulminate.

The most common cancers associated with MTS are:

• Colorectal cancer: Most cases of MTS are associated with colorectal cancer, which describes tumours arising in the colon or rectal area.
• Stomach cancer: Symptoms of indigestion, stomach pain, and loss of appetite could indicate stomach cancer in patients with MTS.
• Urinary cancer: Tumour in the lining of the urinary system is also reported in MTS patients. The first signs are pain or blood when passing urine.
• Endometrial cancer: The endometrium is the lining of the uterus. Endometrial cancer is hence only found in females with MTS and symptoms include pelvic or abdominal pain, irregular discharge, or vaginal bleeding.

Diagnosis of MTS

MTS occurs in individuals with the above skin lesions that have a family history of cancer. Cancer also presents earlier than in the general population. MTS is diagnosed at approximately 50 years of age, although individuals have been diagnosed as young as 20 years of age.¹

Firstly, skin tumour samples are detected using immunohistochemistry (IHC). Through these tests, healthcare professionals can identify whether the genes implicated in MTS (MLH1, MSH2, MSH6, PMS2) are absent. It can flag a potential case of MTS. Genetic testing is necessary to confirm the diagnosis and differentiate it from other diseases  as Lynch Syndrome present similarly on IHC. Genetic testing is done by taking a blood sample from the individual.

Management of MTS

Following MTS confirmationcomprehensive and regular cancer screening is crucial for the treatment of tumours. This cancer screening normally involves:¹

• Upper and lower gastrointestinal endoscopy
• Annual testicular and prostate exams in males
• Annual breast, pelvic, vaginal, and endometrial exams in females
• Skin examinations are recommended bi-annually

Apart from screening, genetic counselling and testing should be conducted in families of individuals with MTS. It  would not only identify other individuals with the condition but also ensure they receive adequate treatment and screening if MTS is detected. Genetic counselling could also help patients reconcilewith the diagnosis and its consequences on their health and lifestyle. Family planning is also crucial in individuals with MTS or unaffected individuals who inherita causative MTS gene variant.

Treatment of MTS

If a benign lesion is identified in MTS patients, it is normally removed through standardised surgical procedures. If a cancerous tumour is identified in an individual with MTS, it is treated as other cases² The type of cancer and stage will dictate the precise treatment and these include:

• Surgical removal of the tumour
• Chemotherapy
• Radiotherapy
• Hormone therapy
• Immunotherapy

The key aspect of MTS treatment is the prevention of benign or cancerous lesions. Interferon (IFN) therapy isin MTS triggers cell death in cells that start developing cancer-like properties.³ Various clinical studies and case studies support IFN’s role in halting the growth of tumours associated with MTS.^4,5

IFN, in conjunction with isotretinoin,a retinoid treatment thatprevents abnormal growth of cells. Isotretinoin is known to target sebocyte and keratinocyte skin cells, which often exhibit abnormal growth in MTS, making it an ideal treatment for the condition.⁶ Individuals with MTS have previously been prescribed IFN therapy three times a week, alongside daily oral and topical isotretinoin treatment² The specific treatment regime differs among individuals.

This preventative treatment leads to a significant decrease in skin lesions and has not reported any serious side effects.² However, skin lesions tend to develop again after stopping treatment.

Summary

In conclusion, MTS is a rare genetic disorder that predisposes individuals to the formation of benign and cancerous tumours. Once MTS is diagnosed, an individual hasundergo thorough and frequent screening to allow rapid detection of any tumour growth. Genetic counselling  patients on their familial risk and emotional implications of MTS diagnosis. Subsequently, treatment of any detected lesion is similar to standardised cancer cases.

Recently, treatments to prevent tumour and skin lesion formation have been used to treat MTS.  IFN, paired with oral and topical isotretinoin, reduces the development of cancerous lesions in MTS patients with mild side effects. Given the small population size of MTS patients, it remains to be seen whether this preventative treatment is effective and safe across more individuals with MTS.