Multiple endocrine neoplasia type 4 (MEN4), previously known as MENX, is a rare type of multiple endocrine neoplasia syndrome (MENS) that causes tumours to develop in two or more endocrine glands. Endocrine glands are responsible for the production and secretion of hormones, and help to control many vital bodily functions.
Familial cancer syndromes, also known as hereditary cancer syndromes, are rare conditions that cause an increased risk of cancer as the result of inherited genetic mutations in certain cancer-related genes. They can affect both adults and children, however they generally develop in people at a younger age than normal. While familial cancer syndromes are not classified as cancer, they are equally as severe and can be life-threatening as they are associated with the development of various tumours throughout the body. Having a familial cancer syndrome does not guarantee the development of cancer, however the risk of developing cancer is higher than those who do not have a familial cancer syndrome.
Neuroendocrine cancers are a complex group of tumours that develop in the neuroendocrine system, which is responsible for regulating important bodily functions such as heart rate, blood pressure and metabolism. They most commonly develop in the gastro-intestinal tract, pancreas, and the lungs; however, they can develop anywhere in the body. These tumours develop from neuroendocrine cells, which are responsible for receiving signals from the nervous system and producing hormones and peptides (small proteins) in response.
There are four primary types of MENS, which vary based on tumour location and genetic mutations involved: MEN1, MEN2 (type 2A and type 2B (also known as MEN3)), MEN4 and MEN5. This page will focus on MEN4, which has some clinical overlap with MEN1.
MEN4 tends to be diagnosed equally among the sexes, and can have a varying age of diagnosis.
MEN4 Related Tumours
MEN4 is most commonly associated with the development of parathyroid tumours, however it has also been linked to other types of tumours. Some examples include:
- Pituitary adenomas, most commonly adrenocorticotropic hormone (ACTH) secreting pituitary adenomas.
- Pancreatic NETs, including:
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- Gastrinomas (common)
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- Non-functional pancreatic NETs (most common).
In rare cases, they may also involve the following tumours:
- Thyroid cancer, most commonly papillary thyroid cancer.
The following tumours may also have an increased incidence in people with MEN4, however more research is needed to confirm:
Treatment
When cancers are detected, they are staged and graded based on size, metastasis, and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you. However, each patient with MEN4 will present with a unique disease behaviour, with varying tumour locations and symptoms. As such, there is no one treatment method that will work for everyone, and there is no standard staging system for this disease. Instead of staging and grading, your doctor will recommend a treatment plan based on the following factors:
- Type of tumours present.
- Whether the tumours are malignant (cancerous) or benignnot cancerous, can grow but will not spread to other body parts (non-cancerous).
- Tumour location.
- Whether or not malignant tumours have metastasised.
- Your age.
- General health.
- Your treatment preferences.
Your doctor may also recommend genetic testinga procedure that analyses DNA to identify changes in genes, chromosomes and proteins, which can be used to analyse tumour DNA to help determine which treatment has the greatest chance of success, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you.
Treatment options for tumours associated with MEN4 may include:
- Surgery to remove as much of the tumour(s) as possible – this will vary based on tumour location.
- Chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells.
- Peptide receptor radionuclide therapy (PRRT)a targeted cancer treatment that uses radioactive substances (radionuclides) to deliver radiation directly to tumour cells.
- Somatostatin analogues (SSAs)medication used to inhibit excessive hormone production.
- Targeted therapymedication that targets specific molecular features of cancer cells.
- Hormone therapymedication that alters the levels of certain hormones in the body, such as oestrogen and progesterone.
- Watch and waitthe close monitoring of a cancer without giving treatment until symptoms appear or worsen.
- Radiation therapya treatment that uses controlled doses of radiation to damage or kill cancer cells (rare).
- Clinical trialsresearch studies performed to test new treatments, tests or procedures and evaluate their effectiveness on various diseases.
- Palliative carea variety of practices and exercises used to provide pain relief and improve quality of life without curing the disease.
Cancer Screening
Once a diagnosis of MEN4 has been confirmed, implementing a targeted screening plan becomes essential due to the increased risk of developing certain cancers. The content of this plan will vary from person to person based on the genetic mutation involved, your family’s history of cancer and the types of cancers that may be present. It will also outline the routine tests you should have and how regularly you should have them. Some recommendations for MEN4 may include:
- Blood teststesting done to measure the levels of certain substances in the blood to measure calcium, parathyroid hormone (PTH), vitamin D and/or gastrin every two years starting at age 25.
- Blood tests to measure insulin-like growth factor 1 (IGF-1) and prolactin hormones every 3-5 years or when symptomatic starting at age 25.
- MRI of the pituitary gland every five years starting at age 25.
- Abdominal MRI or CT scan every five years starting at 25, then every 2.5 years starting at 40.
Screening options for MEN4 may evolve as new technologies are developed and our understanding of the condition grows. It is essential to discuss your individual circumstances with your healthcare team to determine the most appropriate screening plan for you.
Risk factors
MEN4 is caused by a mutation in the cyclic-dependent kinase inhibitor 1B (CDKN1B) gene, which acts as a tumour suppressor. It is an autosomal dominant disease, which means you have a 50% chance of developing the condition if one of your parents carries the genetic mutation.
Symptoms
The symptoms of MEN4 often vary by the type(s) of tumours present. General symptoms of MEN4 may include:
- Hyperparathyroidism.
- Hormone abnormalities.
- General weakness.
- Fatigue.
- Nausea and/or vomiting.
- Unexplained weight loss/loss of appetite.
- Diarrhoea.
- Persistent abdominal, side, and/or back pain.
- Polyuriafrequent urination.
- Constipation.
- Difficulties concentrating.
- Bone pain.
- Headaches.
Symptoms related to specific tumours can be found on our knowledgebase.
Not everyone with the symptoms above will have cancer, but see your general practitioner (GP) if you are concerned.
Diagnosis
If your doctor suspects you have tumours associated with MEN4, they may order some of the following tests to confirm the diagnosis and refer you to a specialist for treatment. The tests required for diagnosis will often vary based on the symptoms present, and where the tumour(s) are suspected to be located.
- Physical examinationan examination of your current symptoms, affected area(s) and overall medical history.
- Genetic testing.
- Endocrine studies.
- Imaging tests, potentially including:
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- MRI (magnetic resonance imaging)a type of medical imaging that uses radiowaves, a strong magnet and computer technology to create detailed images of the body.
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- CT (computed tomography) scana type of medical imaging that uses x-rays and computer technology to create detailed images of the body.
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- PET (positron emission tomography) scana type of medical imaging that uses radioactive tracers to create detailed images of the body.
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- Ultrasounda type of medical imaging that uses soundwaves to create detailed images of the body .
- Exploratory procedures, such as an endoscopya procedure that involves inserting a long, flexible tube with a light and small camera (endoscope) into the body to view internal organs.
- Biopsyremoval of a section of tissue to analyse for cancer cells.