Multiple Endocrine Neoplasia Type 1 (MEN1): What patients should know about

What are the MEN Syndromes?

Multiple Endocrine Neoplasia (MEN) syndromes are a group of rare inherited disorders characterized by the development of tumors in multiple endocrine glands. These syndromes are classified into several types, each associated with specific genetic mutations and clinical manifestations.

• MEN Type 1 (Wermer Syndrome)
• MEN Type 2 – MEN Type 2 is further subdivided into three subtypes:
  • MEN Type 2A (Sipple Syndrome)
  • MEN Type 2B (Multiple Mucosal Neuroma Syndrome)
  • Familial Medullary Thyroid Carcinoma (FMTC)
• MEN Type 4

This image is taken from “VeryWell Health”

Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome

Multiple Endocrine Neoplasia Type 1 (MEN1), also known as Wermer’s syndrome, is a rare genetic disorder characterized by the development of tumors in multiple endocrine glands.

Epidemiology

The epidemiology of Multiple Endocrine Neoplasia Type 1 (MEN1) provides insights into its prevalence, age of onset, and distribution among populations.

• Prevalence: MEN1 is estimated to occur in approximately 1 in 10,000 to 1 in 30,000 individuals globally. This variation in estimates reflects differences in diagnostic criteria and the methods used to identify cases in different studies.
• Incidence: Random postmortem studies have reported an incidence of Multiple Endocrine Neoplasia Type 1 (MEN1) as high as 0.25%, indicating that the syndrome may be underdiagnosed during life.
• Age of Onset: Although MEN1 can affect individuals at any age, symptoms often begin to manifest in early adulthood, with most diagnoses occurring by the age of 40.
• Gender: There is no apparent gender predilection for Multiple Endocrine Neoplasia Type 1, affecting males and females equally
• Ethnicity: Multiple Endocrine Neoplasia Type 1 (MEN1) occurs across various ethnic groups and has no specific racial predilection.

Causes and Risk Factors

Multiple Endocrine Neoplasia Type 1 (MEN1) is primarily caused by mutations in the MEN1 gene, which is responsible for producing a protein called menin. This protein plays a crucial role in suppressing tumor growth by regulating cell division and promoting cell death when necessary. When the MEN1 gene is mutated, its ability to produce functional menin is compromised, leading to increased risk of tumor development in various endocrine glands.

Genetic Causes

• MEN1 Gene Mutation: The direct cause of Multiple Endocrine Neoplasia Type 1 (MEN1) is a mutation in the MEN1 gene. This mutation can be inherited from a parent or can occur as a new mutation in an individual.
• Autosomal Dominant Inheritance: Multiple Endocrine Neoplasia Type 1 follows an autosomal dominant pattern of inheritance. This means that having just one mutated copy of the MEN1 gene is sufficient to increase the risk of developing the syndrome. Each child of an affected parent has a 50% chance of inheriting the mutation.

Risk Factors

• Family History: The most significant risk factor for Multiple Endocrine Neoplasia Type 1 (MEN1) is having a family member with the condition. This is due to the autosomal dominant pattern of inheritance associated with the MEN1 gene mutation.
• Genetic Mutation: Individuals who have the MEN1 gene mutation are at a heightened risk of developing the syndrome. This includes those who inherit the mutation as well as those with de novo (new) mutations

Symptoms

Multiple Endocrine Neoplasia Type 1 (MEN1) is characterized by a variety of symptoms that arise due to tumors in different endocrine glands. These symptoms vary widely depending on the glands affected and the hormones they produce.

This image is taken from National Cancer Institute – cancer.gov

Parathyroid Tumors

• • Kidney stones
  • Muscle weakness
  • Fatigue
  • Increased thirst and urination
  • Bone pain and fractures
  • Digestive problems
  • Depression

Pancreatic Tumors

• Tumors in the pancreas can lead to the overproduction of various hormones, causing symptoms such as
  • Stomach ulcers
  • Acid reflux
  • Abdominal pain
  • Frequent diarrhea
  • Low blood glucose levels

Pituitary Tumors

• Pituitary tumors can also produce excess hormones, leading to a range of symptoms

• • Prolactinomas, which may cause abnormal milk production, lack of menstruation in women, and decreased testosterone in men
  • Growth hormone-secreting tumors, which can cause enlarged hands and feet, and facial features (acromegaly)

Other Symptoms and Tumors

• Multiple Endocrine Neoplasia Type 1 (MEN1) can also cause tumors in other endocrine glands and parts of the body, leading to additional symptoms

• • Carcinoid tumors, which are slow-growing and can be found in the stomach, thymus, and lungs
  • Skin tumors such as angiofibromas and collagenomas
  • Neuroendocrine tumors, which may be benign or malignant and can affect various organs

General Symptoms

• General symptoms due to hormone imbalances or tumor presence include
  • Weight gain
  • Changes in facial appearance
  • Low mood or depression
  • Non-specific aches and pains

Diagnosis

The diagnosis of Multiple Endocrine Neoplasia Type 1 (MEN1) involves a combination of clinical, familial, and genetic criteria. Here are the key aspects and methods used in diagnosing MEN1:

Clinical and Familial Criteria

According to the most recent clinical practice guidelines, a diagnosis of Multiple Endocrine Neoplasia Type 1 (MEN1) can be established if any one of the following conditions is met:

1. Occurrence of at least two primary Multiple Endocrine Neoplasia Type 1 (MEN1)-associated endocrine tumors: These include parathyroid adenoma, enteropancreatic tumor, and pituitary adenoma.
2. Development of one MEN1-associated tumor in a first-degree relative of a patient with a clinical diagnosis of MEN1.
3. Identification of a germline MEN1 mutation: This can be in an individual who may be asymptomatic without biochemical or radiological evidence of MEN1.

Genetic Testing

Genetic testing plays a crucial role in the diagnosis of Multiple Endocrine Neoplasia Type 1 (MEN1), especially for asymptomatic individuals and family members of diagnosed patients. Testing for mutations in the MEN1 gene can confirm the diagnosis and help in the early detection and management of the condition. Genetic evaluation in family members of patients with Multiple Endocrine Neoplasia Type 1 has been shown to result in the diagnosis of Multiple Endocrine Neoplasia Type 1 (MEN1) approximately 10 years earlier than clinical or biochemical diagnosis alone.

Hormonal and Imaging Tests

Diagnosis is also supported by hormonal and imaging tests to detect elevated hormone levels and locate tumors. Common tests include:

• Blood tests: These can detect elevated levels of hormones such as parathyroid hormone (PTH), prolactin, insulin-like growth factor 1 (IGF-1), fasting glucose, insulin, and proinsulin.
• Imaging tests: CT scans, MRI scans, and functional imaging like (68)Gallium-DOTATATE PET/CT are used to visualize tumors in the parathyroid glands, pancreas, pituitary gland, and other areas.

In summary, the diagnosis of MEN1 is multifaceted, involving a combination of genetic testing, clinical criteria, and detailed hormonal and imaging studies. Early identification and regular monitoring are key components of managing this complex condition

Childhood Multiple Endocrine Neoplasia Type 1 (MEN1)

It is important for parents and healthcare providers to recognize the signs and symptoms early, as well as understand the diagnostic and treatment options available for managing this condition in children.

Symptoms of Childhood MEN1

Children with MEN1 may exhibit a variety of symptoms based on the affected glands:

• Parathyroid Glands: Hyperparathyroidism is common and can lead to elevated calcium levels, resulting in weakness, fatigue, bone pain, constipation, and kidney stones.
• Pancreatic Islet Cells: Tumors here may cause abdominal pain, stomach ulcers, vomiting, diarrhea, and weight changes due to fluctuating blood sugar levels.
• Pituitary Gland: Tumors can cause headaches, weight changes, visual disturbances, fertility problems, or discharge of fluid from the nipples.

Diagnosis of Childhood MEN1

Diagnosis typically involves a combination of family history, clinical evaluation, and genetic testing. If there is a known family history of MEN1, children may be screened early for the disease. Diagnostic tests may include:

• Genetic Testing: To identify mutations in the MEN1 gene.
• Blood and Urine Tests: To check hormone levels that indicate tumor activity.
• Imaging Studies: Such as MRI or CT scans to locate tumors.

Treatment Options

Treatment for MEN1 in children is tailored to the type of tumors and their effects:

• Surgical Removal: Often necessary for tumors that cause severe symptoms or are at risk of becoming cancerous.
• Medication: To manage symptoms caused by hormone overproduction, such as proton pump inhibitors for ulcers caused by gastrinomas.
• Regular Monitoring: Essential to manage the condition proactively, involving regular blood tests and imaging studies to monitor tumor growth and hormone levels.

Special Considerations in Childhood

Managing Multiple Endocrine Neoplasia Type 1 (MEN1) in children also involves considerations of growth and development. Treatment plans must balance the need to control the disease with the potential impacts on a child’s development. Genetic counseling is recommended for families, which can provide information on the risk of MEN1 in future offspring.

In summary, Childhood Multiple Endocrine Neoplasia Type 1 (MEN1) requires careful and proactive management to address the various endocrine tumors that may develop. Early intervention and regular monitoring are key to managing the health and development of children with this complex genetic disorder.

Treatment of Multiple Endocrine Neoplasia Type 1 (MEN1)

The treatment of Multiple Endocrine Neoplasia Type 1 (MEN1) involves a combination of surgical interventions, medication management, and regular monitoring to manage the various tumors associated with the syndrome.

1. Surgical Treatment

Parathyroid Tumors

• Parathyroidectomy: This is the definitive treatment for hyperparathyroidism in Multiple Endocrine Neoplasia Type 1 (MEN1) patients. Subtotal parathyroidectomy or total parathyroidectomy with forearm autotransplantation is commonly performed to control hypercalcemia.

Pancreatic and Duodenal Neuroendocrine Tumors

• Surgical Resection: Depending on the size and location of the tumors, different surgical approaches such as distal pancreatectomy or enucleation of tumors are used. Surgery aims to remove tumors while preserving as much pancreatic function as possible.
• Liver Surgery and Radiofrequency Ablation: For metastatic disease, particularly in the liver, surgical resection or radiofrequency ablation may be used to manage symptoms and control disease progression.

Pituitary Tumors

• Transsphenoidal Surgery: This is often required for macroadenomas or tumors resistant to medical therapy. It aims to remove the tumor and alleviate symptoms caused by excess hormone production.

Adrenal and Carcinoid Tumors

• Surgical Removal: If these tumors are hormone-producing or suspected to be malignant, surgical removal is recommended.

2. Medication Management

• Somatostatin Analogues: Drugs like octreotide and lanreotide are used to control hormone secretion in neuroendocrine tumors and can relieve symptoms from hormone overproduction.
• Proton Pump Inhibitors: These are essential for managing gastrinomas by reducing gastric acid secretion, thus preventing peptic ulcers.
• Dopamine Agonists: Used primarily for treating prolactinomas, these medications can reduce prolactin levels and tumor size.

3. Regular Monitoring and Supportive Care

• Periodical Clinical Monitoring: Regular blood tests and imaging studies are crucial for early detection of new or growing tumors. This includes MRI, CT scans, and endoscopic ultrasounds.
• Genetic Counseling and Testing: Recommended for patients and their family members to identify carriers of the Multiple Endocrine Neoplasia Type 1 mutation and guide clinical management.

4. Special Considerations

• Quality of Life and Psychological Support: Due to the chronic nature of Multiple Endocrine Neoplasia Type 1 (MEN1) and the impact of multiple surgeries and lifelong monitoring, psychological support and counseling are important aspects of comprehensive care.

Survivorship and Prognosis

The prognosis and survivorship for individuals with Multiple Endocrine Neoplasia Type 1 (MEN1) vary based on several factors, including the type and severity of tumors present, the effectiveness of the management strategies, and the age at diagnosis. Here are key points regarding the prognosis and survivorship of Multiple Endocrine Neoplasia Type 1 (MEN1):

Decreased Life Expectancy

• General Prognosis: Patients with MEN1 generally have a decreased life expectancy compared to the general population. This reduction in life expectancy is primarily due to complications from malignant neuroendocrine tumors.
• Survival rates: A study noted that the overall survival for patients with an identified mutation in the MEN1 gene was estimated at 73 years, compared to 87 years in mutation-negative patients diagnosed based on clinical manifestations.

Watch this video about Emma’s story from “The Association for Multiple Endocrine Neoplasia Disorders (AMEND)”

In summary, while Multiple Endocrine Neoplasia Type 1 (MEN1) is associated with a complex set of challenges and a decreased life expectancy, early diagnosis, effective management, and regular monitoring can significantly influence the prognosis and quality of life for affected individuals.

Watch this video about Steph’s story from “The Association for Multiple Endocrine Neoplasia Disorders (AMEND)”

Resources

1. American Society of Clinical Oncology (ASCO) – Cancer.net 
2. National Cancer Institute – cancer.gov
3. American Cancer Society – cancer.org
4. National Library of Medicine – clinicaltrials.gov
5. Journal of Clinical Oncology (ASCO) Publications – ascopubs.org
6. Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives – PubMed
7. Memorial Sloan Kettering Cancer Center – mskcc.org
8. Multiple Endocrine Neoplasia Type 1 – PubMed
9. Diagnosis and Management of Multiple Endocrine Neoplasia Type 1 (MEN1) – PubMed
10. Oncodaily.com – Online platform where you can find anything related to cancer such as everyday news, blogs, videos, podcasts, etc.
11. Saint John’s Cancer Institute and Health Center – saintjohnscancer.org