Cancer Types

May 31, 2024, 06:40

Multiple Endocrine Neoplasia Type 2B (MEN2B): 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 Type 2B (MEN2B) Syndrome

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a rare, autosomal dominant genetic disorder characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, and a distinctive marfanoid habitus. Understanding Multiple Endocrine Neoplasia Type 2B (MEN2B) is crucial for patients and their families due to its serious implications and the need for early diagnosis and management.

Epidemiology

MEN2B is extremely rare, with prevalence estimates varying significantly. One source estimates the prevalence of MEN2B to be between 1 in 600,000 to 1 in 4 million people. The annual incidence of MEN2B has been estimated at 4 per 100 million per year.

Causes and Risk Factors

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a rare genetic disorder characterized by the development of medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, and distinctive marfanoid habitus. Understanding the causes and risk factors associated with Multiple Endocrine Neoplasia Type 2B (MEN2B) is crucial for diagnosis, management, and genetic counseling.

Genetic Causes

The primary cause of Multiple Endocrine Neoplasia Type 2B (MEN2B) is mutations in the RET proto-oncogene. Specifically, about 95% of Multiple Endocrine Neoplasia Type 2B (MEN2B) cases are associated with a mutation in the tyrosine kinase domain of the RET protein at codon 918 (M918T mutation). This mutation leads to the constitutive activation of the RET protein, which promotes cellular growth and survival pathways that contribute to tumor development.

Risk Factors

1. Genetic Inheritance:

MEN2B follows an autosomal dominant inheritance pattern, meaning that having just one mutated copy of the RET gene is sufficient to cause the disorder. If a parent has Multiple Endocrine Neoplasia Type 2B (MEN2B), there is a 50% chance that the mutation will be passed on to each child.

2. De Novo Mutations:

Approximately 50% of MEN2B cases arise from de novo mutations, where the mutation occurs spontaneously in the individual without being inherited from a parent. These spontaneous mutations are often of paternal origin, particularly from older fathers, which may contribute to the risk of developing Multiple Endocrine Neoplasia Type 2B (MEN2B).

3. Age and Early Onset:

MEN2B typically manifests early in life, often in infancy or childhood, which is earlier than many other genetic disorders. The early onset of symptoms, particularly medullary thyroid carcinoma, is a critical factor in the prognosis and management of the disease.

Symptoms

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a rare genetic disorder characterized by a variety of symptoms, primarily due to the development of tumors in various endocrine glands and other tissues. The symptoms of Multiple Endocrine Neoplasia Type 2B (MEN2B) can vary based on the specific tumors present and their locations. Here are the key symptoms associated with MEN2B as detailed in the provided sources:

1. Medullary Thyroid Cancer (MTC)

A tumor of the thyroid gland, may be detected during a physical exam or thyroid ultrasound.
A lump in the front of the neck.
Difficulty speaking normally, swallowing, and breathing.
Large lymph nodes, throat, and neck pain.

2. Pheochromocytoma

A benign tumor of the adrenal glands, which can cause:
High blood pressure.
Rapid heart rate.
Anxiety, headaches, and sweating.
Intermittent symptoms such as headaches, sweating, pallor (pale skin) or flushing, heart palpitations, nausea, lower chest or upper abdominal pain, weakness, anxiety, weight loss, and tremors.

3. Mucosal Neuromas

Noncancerous tumors on the lips, tongue, and digestive tract
Bumps on the tongue, lips, and eyes
May lead to lips getting a swollen appearance or irregularities around the tongue.

4. Other Symptoms

Marfanoid body habitus, including being tall and thin with long arms and legs
Distinctive facial features such as enlarged lips and a “marfanoid” appearance
Skeletal anomalies like narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints, and slipped capital femoral epiphysis
Ophthalmologic abnormalities include alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves.
Gastrointestinal issues such as chronic constipation, abdominal distension, diarrhea, or megacolon at birth, are often due to generalized ganglioneuromatosis throughout the aerodigestive tract.

Multiple Endocrine Neoplasia Type 2B (MEN2B): What patients should know about

This image is taken from “Researchgate”, which shows the characteristic facial physiognomy of patients with MEN2B.

5. Hyperparathyroidism (Rare in MEN2B)

Overactive parathyroid glands may lead to symptoms such as weakness or fatigue, depression, confusion or forgetfulness, an increase in thirst and urination, nausea, lack of appetite, abdominal pain, constipation, bone and joint pain, osteoporosis (fragile bones), and an increased risk of developing kidney stones.

It’s important for individuals with MEN2B or those at risk of developing the condition to be aware of these symptoms and seek medical advice for appropriate diagnosis and management. Genetic testing can confirm the presence of mutations associated with MEN2B, and early intervention can significantly improve outcomes.

Multiple Endocrine Neoplasia Type 2B (MEN2B): What patients should know about

This image is taken from “Amboss”, which shows the main symptoms and affected organs in MEN syndromes.

Diagnosis of Multiple Endocrine Neoplasia Type 2B (MEN2B)

Multiple Endocrine Neoplasia Type 2B (MEN2B) requires a comprehensive diagnostic approach due to its complex presentation involving multiple endocrine and non-endocrine manifestations.

1. Family History and Clinical Symptoms

Multiple Endocrine Neoplasia Type 2B (MEN2B) is suspected in patients with a family history of Multiple Endocrine Neoplasia Type 2B (MEN2B), medullary thyroid carcinoma (MTC), pheochromocytoma, or multiple mucosal neuromas.
Clinical symptoms such as mucosal neuromas, marfanoid habitus, and gastrointestinal issues can prompt further investigation.

2. RET Proto-Oncogene Mutation Analysis

Genetic testing for mutations in the RET proto-oncogene is the definitive diagnostic tool for MEN2B. The most common mutation associated with Multiple Endocrine Neoplasia Type 2B (MEN2B) is the M918T mutation.
Genetic testing is recommended for individuals with a family history of MEN2B and for first-degree relatives of affected individuals.

3. Hormonal and Biochemical Markers

Medullary Thyroid Carcinoma (MTC): Serum calcitonin levels are measured to detect MTC, as elevated levels are indicative of the presence of this cancer.
Pheochromocytoma: Plasma free metanephrines and urinary catecholamines are measured to diagnose pheochromocytoma. Elevated levels of these markers suggest the presence of adrenal tumors

4. Imaging Studies

Neck Imaging: MRI or CT scans of the neck are used to identify and assess the extent of medullary thyroid carcinoma
Adrenal Imaging: MRI or CT scans of the abdomen are performed to locate pheochromocytoma

5. Pathological Examination

Thyroid Tissue: Pathological examination of thyroid tissue obtained during thyroidectomy can confirm the presence of MTC or C-cell hyperplasia.
Rectal Biopsy: In cases where gastrointestinal symptoms are present, a rectal biopsy may be performed to identify ganglioneuromatosis, a characteristic feature of MEN2B.

6. Comprehensive Diagnostic Criteria

Diagnosis of Multiple Endocrine Neoplasia Type 2B (MEN2B) is confirmed by the presence of characteristic clinical features, biochemical markers, and genetic testing results. The combination of these diagnostic tools ensures accurate identification of the syndrome.

Prophylactic thyroidectomy is recommended before the age of 1 year to prevent the development of MTC. Regular screening and monitoring for pheochromocytomas and other associated tumors are essential for managing the condition and improving patient outcomes.

Multiple Endocrine Neoplasia Type 2B (MEN2B) in Childhood

Multiple Endocrine Neoplasia Type 2B (MEN2B) often presents early in childhood. Special considerations for managing MEN2B in pediatric patients are crucial due to the aggressive nature of the associated medullary thyroid carcinoma (MTC) and the potential for other endocrine and non-endocrine manifestations.

Children with Multiple Endocrine Neoplasia Type 2B (MEN2B) often present with a combination of endocrine and non-endocrine symptoms, including mucosal neuromas, marfanoid habitus, gastrointestinal issues, and skeletal abnormalities.
Common early symptoms include failure to thrive, feeding difficulties, persistent constipation or diarrhea, and unexplained musculoskeletal symptoms.
Children with MEN2B and their families may require psychological and social support to cope with the diagnosis and the implications of lifelong monitoring and treatment.
Genetic counseling is important for family planning and understanding the inheritance patterns of MEN2B.

Watch this patient’s story with MEN2B from “The Association for Multiple Endocrine Neoplasia Disorders (AMEND)”

Treatment

Multiple Endocrine Neoplasia Type 2B (MEN2B) requires a comprehensive and multidisciplinary approach to treatment, particularly medullary thyroid carcinoma (MTC).

1. Prophylactic Thyroidectomy

Prophylactic thyroidectomy is recommended as early as possible, ideally within the first year of life, to prevent the development of MTC, which is highly aggressive in Multiple Endocrine Neoplasia Type 2B (MEN2B) patients.
The procedure typically involves total thyroidectomy and may include central neck dissection if there is evidence of lymph node involvement.
Postoperative Monitoring: After thyroidectomy, patients require lifelong monitoring of serum calcitonin levels to detect any residual or recurrent MTC.
Regular follow-up with imaging studies such as neck ultrasound, CT, or MRI may be necessary to monitor for recurrence.

2. Management of Pheochromocytoma

The primary treatment for pheochromocytoma is surgical removal of the tumor. Adrenal-sparing surgery may be considered to preserve adrenal function and reduce the risk of adrenal insufficiency.
Preoperative management includes the use of alpha-adrenergic blockers to control blood pressure and prevent hypertensive crises during surgery.

3. Management of Mucosal Neuromas and Gastrointestinal Issues

Mucosal neuromas, which are benign tumors on the lips, tongue, and digestive tract, may require surgical removal if they cause significant symptoms or functional impairment.
Gastrointestinal manifestations such as chronic constipation, abdominal distension, and megacolon are managed symptomatically. Surgical intervention may be necessary in severe cases.

4. Targeted Therapies

Tyrosine Kinase Inhibitors: For patients with advanced or metastatic MTC, targeted therapies such as tyrosine kinase inhibitors (e.g., vandetanib, selpercatinib) may be used to control tumor growth and progression.
These therapies work by blocking the signals that promote tumor growth and are typically used when surgery is not an option or in cases of recurrent disease.

Prognosis and Survivorship

The prognosis and survivorship of patients with Multiple Endocrine Neoplasia Type 2B (MEN2B) are influenced by several factors, including the timing of diagnosis, the stage of tumors at diagnosis, and the effectiveness of treatment strategies.

Prognosis

1. Medullary Thyroid Carcinoma (MTC):

MTC is the primary cause of mortality in Multiple Endocrine Neoplasia Type 2B (MEN2B) patients due to its aggressive nature and early onset. The prognosis of MTC in MEN2B is generally poorer compared to other forms of thyroid cancer because it often presents at an advanced stage.
Early diagnosis and prophylactic thyroidectomy significantly improve the prognosis. Patients who undergo thyroidectomy before the age of 1 year have a better chance of preventing the development of MTC or catching it at an early stage.

2. Pheochromocytomas:

Pheochromocytomas, which occur in about 50% of Multiple Endocrine Neoplasia Type 2B (MEN2B) patients, can cause severe cardiovascular complications if not managed properly. Regular screening and timely surgical removal of these tumors are crucial for improving outcomes.

3. Other Factors:

The presence of mucosal neuromas and gastrointestinal issues can affect the quality of life but are generally not life-threatening. However, they can contribute to the overall morbidity associated with MEN2B.

Watch this patient’s story with MEN2B from “The Association for Multiple Endocrine Neoplasia Disorders (AMEND)”

In summary, the prognosis and survivorship of MEN2B patients have improved over the years, particularly with early diagnosis and intervention. Prophylactic thyroidectomy, regular screening for pheochromocytomas, and comprehensive management of symptoms are key to improving outcomes. Continuous follow-up, psychological support, and genetic counseling are also crucial for enhancing the quality of life and long-term survivorship of MEN2B patients.