Multiple Endocrine Neoplasia (MEN) refers to a collection of rare, inherited medical conditions that cause tumors to form in the body’s endocrine glands. These glands produce and release hormones that regulate various bodily functions. MEN Type 2 is a specific subgroup, further categorized into distinct subtypes: MEN2A and MEN2B.
The Genetic Cause of MEN Type 2 Syndromes
Both MEN2A and MEN2B arise from changes within a single gene known as the RET proto-oncogene. A proto-oncogene is a normal gene regulating cell growth and division. When a mutation occurs in the RET proto-oncogene, it can transform into an oncogene, promoting uncontrolled cell proliferation. This unregulated growth can lead to the formation of tumors in endocrine tissues.
These conditions are inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of the mutated RET gene from a parent to develop the syndrome. If one parent carries the mutated gene, there is a 50% chance each child will inherit the gene and thus the condition. The specific location and type of mutation within the RET gene largely determine whether an individual develops MEN2A or MEN2B.
Defining Multiple Endocrine Neoplasia Type 2A
Multiple Endocrine Neoplasia Type 2A is characterized by the presence of three primary conditions affecting different endocrine glands. The most consistent feature is medullary thyroid carcinoma (MTC), a cancer originating from the parafollicular C cells of the thyroid gland. These cells produce calcitonin, a hormone involved in calcium regulation. The tumor can lead to elevated calcitonin levels.
Individuals with MEN2A also frequently develop pheochromocytomas, tumors of the adrenal glands. The adrenal glands, located above the kidneys, produce hormones like adrenaline and noradrenaline. Pheochromocytomas can cause symptoms such as high blood pressure, headaches, and palpitations due to excessive hormone release. These tumors can be benign or, less commonly, malignant.
The third component of MEN2A is primary hyperparathyroidism. This condition involves the parathyroid glands, four small glands located near or within the thyroid. Hyperparathyroidism results from overactivity of these glands, leading to an excess production of parathyroid hormone. This excess hormone causes elevated calcium levels in the blood, which can lead to symptoms like kidney stones, bone pain, and fatigue.
Defining Multiple Endocrine Neoplasia Type 2B
Multiple Endocrine Neoplasia Type 2B shares some features with MEN2A but presents with distinct additional characteristics. Like MEN2A, individuals with MEN2B develop medullary thyroid carcinoma (MTC) and pheochromocytomas. The MTC in MEN2B, however, often appears much earlier in life, sometimes in infancy, and tends to be more aggressive.
A distinguishing feature of MEN2B is mucosal neuromas. These are benign, fleshy growths on the lips, tongue, and inside the mouth, often with a bumpy appearance. Similar neuromas can also be found lining the eyelids and throughout the gastrointestinal tract, potentially causing issues like constipation or diarrhea. These growths are noticeable in childhood.
Individuals with MEN2B exhibit a Marfanoid habitus. This involves a tall, slender build with long, thin limbs and fingers, sometimes accompanied by joint laxity. Unlike MEN2A, primary hyperparathyroidism is not a feature of MEN2B, which helps differentiate the two syndromes.
Diagnostic and Surveillance Strategies
Diagnosing MEN Type 2 syndromes primarily relies on genetic testing for mutations in the RET gene. A blood sample is sufficient for this test, identifying the specific mutation responsible for the condition. This genetic confirmation allows for early identification of affected individuals, even before symptoms develop.
Once a genetic diagnosis is made, biochemical screening methods are used to monitor for associated tumors. Blood tests for calcitonin levels are routinely performed to detect medullary thyroid carcinoma, as elevated calcitonin indicates this cancer. Plasma or urine metanephrines are measured to screen for pheochromocytomas to detect excess adrenal hormone production.
For individuals with MEN2A, regular monitoring of blood calcium levels is conducted to detect primary hyperparathyroidism. Management of MEN Type 2 syndromes centers on lifelong surveillance and proactive intervention. For individuals with the MEN2B mutation, prophylactic thyroidectomy, or the early surgical removal of the thyroid gland, is recommended in infancy or early childhood to prevent the aggressive MTC associated with this subtype. Regular follow-up appointments, including imaging studies and continued biochemical screening, are performed to monitor for other tumor developments.