Cancer Types

May 30, 2024, 09:16

Multiple Endocrine Neoplasia Type 2A (MEN2A): 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

Multiple endocrine neoplasia - Wikipedia

This image is taken from Wikimedia Commons

Multiple Endocrine Neoplasia Type 2A (MEN2A) Syndrome

Multiple Endocrine Neoplasia Type 2A (MEN2A) also known as Sipple syndrome, is a hereditary cancer syndrome that primarily affects the endocrine glands, leading to the development of tumors that can be either benign or malignant.

Epidemiology

Incidence: A study conducted in Denmark reported an incidence of Multiple Endocrine Neoplasia Type 2A (MEN2A) of 28.4 per million live births per year from 1971 to 2000. This figure highlights the rarity of the condition but also underscores the importance of surveillance and genetic testing in populations with known cases of MEN2A.
Prevalence: The total prevalence of all variants of Multiple Endocrine Neoplasia Type 2A (MEN2A), which includes MEN2A, is approximately 1 in 35,000. MEN2A accounts for about 95% of all MEN2 cases, making it the more common form of the syndrome.

Causes and Risk Factors

Multiple Endocrine Neoplasia Type 2A (MEN2A) is a hereditary condition characterized by a predisposition to develop multiple endocrine tumors, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas or hyperplasia. The primary cause and risk factor for Multiple Endocrine Neoplasia Type 2A (MEN2A) is a genetic mutation in the RET proto-oncogene.

Genetic Causes

Multiple Endocrine Neoplasia Type 2A (MEN2A) is caused by mutations in the RET proto-oncogene, which is located on chromosome 10. The RET gene encodes a receptor tyrosine kinase involved in cell growth and differentiation. Mutations in this gene lead to the activation of intracellular signaling pathways that promote cell proliferation and survival, contributing to tumor development

Risk Factors

Genetic Inheritance: MEN2A is inherited in an autosomal dominant pattern, meaning that having just one copy of the mutated gene can predispose an individual to the disease. This implies that if one parent has MEN2A, there is a 50% chance of passing the mutated gene to each child.
Specific RET Mutations: Different mutations in the RET gene are associated with varying levels of risk for developing medullary thyroid carcinoma and other components of MEN2A. For example, mutations in specific codons such as 634 are commonly associated with classical MEN2A, which includes MTC, pheochromocytoma, and primary hyperparathyroidism.
Age: The risk of developing MTC and other tumors in Multiple Endocrine Neoplasia Type 2A (MEN2A) can manifest at different ages, often depending on the specific RET mutation. Some mutations lead to earlier onset of disease than others.
Phenotypic Variability: Even within families sharing the same RET mutation, there can be variability in the age of onset, the types of tumors developed, and the severity of the disease. This suggests that other genetic, environmental, or lifestyle factors may also influence disease manifestation

Symptoms of Multiple Endocrine Neoplasia Type 2A (MEN2A)

Multiple Endocrine Neoplasia Type 2A (MEN2A) is characterized by a variety of symptoms that arise from the tumors affecting different endocrine glands.

Medullary Thyroid Carcinoma (MTC)

Thyroid gland tumors: Nearly all patients with Multiple Endocrine Neoplasia Type 2A (MEN2A) develop medullary thyroid carcinoma (MTC). Symptoms can include a lump in the front of the neck, difficulty speaking normally, swallowing, or breathing, and pain in the throat and neck.

Pheochromocytoma

Adrenal gland tumors: About 50% of individuals with Multiple Endocrine Neoplasia Type 2A (MEN2A) develop pheochromocytoma, which are typically benign tumors of the adrenal glands. Symptoms include high blood pressure, rapid heart rate, severe headaches, sweating, and anxiety attacks. These symptoms may occur intermittently.

Parathyroid Hyperplasia

Parathyroid gland abnormalities: Between 5% to 10% of Multiple Endocrine Neoplasia Type 2A (MEN2A) patients experience issues with their parathyroid glands, such as hyperplasia or adenomas, leading to primary hyperparathyroidism. Symptoms include muscle and joint pain, constipation, fatigue, memory problems, and kidney stones due to elevated calcium levels in the blood.

Additional Symptoms

Diarrhea: This is a common systemic symptom in Multiple Endocrine Neoplasia Type 2A (MEN2A), potentially linked to hormonal imbalances caused by the tumors.
Cutaneous lichen amyloidosis: Some patients may develop itchy skin conditions due to this variant of Multiple Endocrine Neoplasia Type 2A (MEN2A).
Hirschsprung disease: Associated with Multiple Endocrine Neoplasia Type 2A (MEN2A), this condition affects the nerves in parts of the gut, potentially leading to blockages.

Multiple Endocrine Neoplasia Type 2A (MEN2A): What patients should know about

“Cutaneous lichen amyloidosis” from PubMed

Diagnosis

The diagnosis of Multiple Endocrine Neoplasia Type 2A (MEN2A) involves a combination of clinical evaluation, genetic testing, and various diagnostic tests to confirm the presence of associated tumors and to assess the extent of the disease.

1. Genetic Testing

The cornerstone of diagnosing Multiple Endocrine Neoplasia Type 2A (MEN2A) is genetic testing for mutations in the RET proto-oncogene. Mutations in this gene are found in more than 95% of families with MEN2A. Testing is recommended for individuals with a family history of Multiple Endocrine Neoplasia Type 2A (MEN2A), as well as for anyone diagnosed with medullary thyroid cancer (MTC), as early detection significantly impacts management and outcomes.

2. Clinical Evaluation

A clinical diagnosis of MEN2A may be considered if a patient presents with two or more MEN2A-associated tumors, which typically include Medullary Thyroid Carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia or adenoma. The presence of these tumors often prompts further investigation through genetic testing.

3. Hormonal and Biochemical Tests

Hormonal and biochemical tests are crucial for detecting the secretory activity of the tumors associated with MEN2A:

Calcitonin levels are used to screen for MTC. Elevated levels can indicate the presence of MTC even before it becomes palpable.
Catecholamines and metanephrines are measured to screen for pheochromocytoma, a common tumor in MEN2A that can significantly affect cardiovascular health.
Parathyroid hormone (PTH) and calcium levels are tested to assess for hyperparathyroidism, another component of MEN2A.

4. Imaging Tests

Imaging studies are employed to locate tumors and assess their extent:

Ultrasound of the neck is commonly used to visualize thyroid abnormalities indicative of MTC.
Computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen may be used to detect pheochromocytoma. CT or MRI scans can also help in identifying parathyroid abnormalities and assessing any metastatic spread of MTC.

5. Additional Diagnostic Tests

In some cases, additional tests may be required to confirm the diagnosis:

Fine-needle aspiration (FNA) may be used to biopsy thyroid nodules to confirm MTC.
Biochemical tests for additional hormones secreted by the tumors may be conducted depending on the clinical presentation.

Treatment

The treatment of Multiple Endocrine Neoplasia Type 2A (MEN2A) involves a comprehensive approach that includes surgical interventions, genetic testing, and ongoing monitoring to manage the various tumors associated with the syndrome.

Surgical Treatment

1. Prophylactic Thyroidectomy

Medullary Thyroid Carcinoma (MTC): Prophylactic thyroidectomy is recommended for individuals with identified RET mutations, particularly in children. The timing of the surgery is crucial and is based on the specific mutation type, with some guidelines suggesting surgery before age 5 to prevent the development of MTC.
Postoperative Management: Following thyroidectomy, patients require lifelong thyroid hormone replacement therapy to maintain normal thyroid function.

2. Adrenalectomy

Pheochromocytoma: Surgical removal of the adrenal glands (adrenalectomy) is performed when pheochromocytoma is diagnosed. Cortical-sparing surgery may be considered to preserve adrenal function and avoid lifelong dependency on steroid replacement.

3. Parathyroidectomy

Hyperparathyroidism: Surgical removal of the parathyroid glands (parathyroidectomy) is indicated if hyperparathyroidism is diagnosed. The approach may vary from removing only the enlarged glands to performing a subtotal parathyroidectomy, depending on the extent of gland involvement.

Genetic Testing and Monitoring

RET Gene Mutations: Genetic testing for mutations in the RET proto-oncogene is essential for diagnosing MEN2A and determining the risk level for associated tumors. This testing guides the timing and extent of surgical interventions.
Regular Monitoring: Patients with Multiple Endocrine Neoplasia Type 2A (MEN2A) require regular monitoring for the development of pheochromocytoma and hyperparathyroidism. This includes biochemical tests for catecholamines and calcium levels, as well as imaging studies to detect new or recurrent tumors.

Additional Considerations

Psychological Support: Given the hereditary nature of Multiple Endocrine Neoplasia Type 2A (MEN2A) and the significant impact of prophylactic surgeries, psychological support and genetic counseling are recommended for patients and their families.
Lifelong Surveillance: Due to the risk of recurrent or new tumor development, lifelong surveillance is necessary. This includes regular biochemical testing and imaging, as well as physical examinations to monitor for symptoms of associated conditions.

Emerging Treatments

Targeted Therapies: Research into targeted therapies for managing advanced MTC that cannot be surgically removed or has metastasized is ongoing. These therapies aim to target specific molecular pathways involved in tumor growth.

In summary, the treatment of MEN2A is multifaceted, involving early and aggressive surgical management based on genetic findings, lifelong monitoring, and supportive care. The goal is to prevent the development of malignant tumors, manage endocrine dysfunctions, and improve the overall quality of life for affected individuals.

Multiple Endocrine Neoplasia Type 2A (MEN2A) in Childhood

Multiple Endocrine Neoplasia Type 2A (MEN2A) in childhood requires special considerations due to the early onset and aggressive nature of the associated tumors, particularly medullary thyroid carcinoma (MTC).

Early Diagnosis and Genetic Testing

Early diagnosis through genetic testing is crucial for children at risk of MEN2A. Identifying mutations in the RET proto-oncogene allows for timely interventions and better management of the disease. Children with a family history of MEN2A should undergo genetic testing ideally by age 5 or earlier if possible.

Prophylactic Surgery

Prophylactic thyroidectomy is recommended for children with identified RET mutations. The timing of this surgery is critical and should be based on the specific mutation type, with some guidelines suggesting surgery before age 5 to prevent the development of MTC. This approach has been shown to significantly reduce the incidence of MTC and improve long-term outcomes.

Monitoring for Other Tumors

Children with MEN2A should be regularly monitored for the development of other associated tumors, particularly pheochromocytoma and hyperparathyroidism:

Pheochromocytoma: Screening should begin in early childhood, even though these tumors are rare before age 10. Monitoring should include measurements of catecholamines and metanephrines.
Hyperparathyroidism: Although less common in children, monitoring for elevated calcium levels and parathyroid hormone is important

Multidisciplinary Care

Management of MEN2A in children involves a multidisciplinary team including pediatric endocrinologists, surgeons, geneticists, oncologists, and psychologists. This team approach ensures comprehensive care addressing all aspects of the syndrome.

In summary, special considerations in managing MEN2A in childhood include early genetic testing, timely prophylactic surgeries, regular monitoring for associated tumors, codon-specific risk assessments, lifelong follow-up, and a multidisciplinary care approach. These strategies are essential to improve outcomes and quality of life for affected children.

Multiple Endocrine Neoplasia Type 2A (MEN2A): What patients should know about

This image is taken from “National Cancer Institute”

The prognosis and survivorship

The prognosis and survivorship for patients with Multiple Endocrine Neoplasia Type 2A (MEN2A) largely depend on several factors, including the type of RET mutation present, the age at diagnosis, and the effectiveness of the treatment strategies employed, particularly the timing of surgical interventions.

Prognosis

Medullary Thyroid Carcinoma (MTC): The major cause of mortality in MEN2A is MTC. The aggressiveness of MTC varies according to the specific RET genotype, with certain mutations associated with a more aggressive form of the disease. Early diagnosis and treatment, especially prophylactic thyroidectomy based on genetic testing and RET mutation analysis, have significantly improved the prognosis for patients with MEN2A.
Pheochromocytoma: This tumor, while typically benign, can cause significant complications if not managed properly. Effective surgical removal of the tumor, when indicated, can lead to a good prognosis, but the condition requires careful monitoring due to the potential for recurrence or development in the contralateral adrenal gland.
Hyperparathyroidism: This component of MEN2A is generally less aggressive but can contribute to morbidity if associated complications such as kidney stones and bone disease are not managed effectively.

Survivorship

Survivorship in MEN2A patients has improved with advancements in genetic testing and targeted treatments. Early and aggressive management strategies, including prophylactic surgeries and regular monitoring for associated conditions, have enhanced long-term outcomes:

Early Intervention: Prophylactic thyroidectomy, performed based on the risk associated with specific RET mutations, can prevent the development of MTC or treat it at a very early stage, significantly improving survival rates.
Regular Monitoring: Continuous monitoring for the development of pheochromocytoma and primary hyperparathyroidism is crucial. This includes regular biochemical tests and imaging studies to detect new or recurrent tumors early.
Genetic Counseling: Ongoing genetic counseling is recommended for patients and their families to understand the hereditary nature of the disease and to manage the psychological impact of living with a chronic condition.

Long-Term Management

Managing MEN2A is a lifelong process that involves regular medical check-ups to monitor for the recurrence of tumors or the emergence of new symptoms. Patients often require care from a multidisciplinary team including endocrinologists, surgeons, geneticists, and oncologists to address the various aspects of the syndrome.

Watch this patient story from “The Association for Multiple Endocrine Neoplasia Disorders (AMEND)”

In summary, while MEN2A poses significant challenges, the prognosis can be favorable with early diagnosis, appropriate genetic counseling, and proactive management of the endocrine tumors associated with the syndrome. Survivorship has improved with advances in medical science, particularly in genetic testing and surgical techniques, allowing for tailored interventions that significantly reduce disease-related complications and mortality.