Multiple Endocrine Neoplasia type 2 (MEN2) syndrome is a rare, inherited condition affecting the body’s endocrine system. It involves the development of tumors in several glands, which can be benign or malignant. Early detection and appropriate management strategies are important for this condition.
What is MEN2 Syndrome?
The acronym MEN in MEN2 syndrome stands for Multiple Endocrine Neoplasia, reflecting the involvement of multiple hormone-producing glands. These glands, such as the thyroid, parathyroid, and adrenal glands, can develop tumors that may lead to an overproduction of hormones, causing various health problems like high blood pressure or kidney stones.
MEN2 syndrome is categorized into three main subtypes: MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma (FMTC). Each subtype has a distinct set of associated health issues, influenced by specific genetic changes that determine the types of tumors and their typical age of onset.
Associated Health Conditions
All subtypes of MEN2 syndrome are highly associated with Medullary Thyroid Carcinoma (MTC). MTC is a rare form of thyroid cancer that originates from the parafollicular C-cells of the thyroid gland. It is often the initial sign of MEN2 syndrome and can appear as a lump in the neck, though many individuals may not experience symptoms until later stages.
Pheochromocytoma is another tumor associated with MEN2A and MEN2B. These tumors develop in the adrenal glands and produce excessive amounts of stress hormones like adrenaline. Symptoms of pheochromocytoma can include high blood pressure, severe headaches, increased sweating, and heart palpitations. Approximately 50% of individuals with MEN2A develop pheochromocytoma, and these tumors are bilateral in 60-80% of cases.
Primary Hyperparathyroidism (PHPT) is a condition primarily associated with MEN2A, occurring in about 20-30% of individuals. This condition involves the overactivity of the parathyroid glands. Overactivity leads to elevated levels of parathyroid hormone, resulting in high calcium levels in the blood. Symptoms of PHPT can include fatigue, increased urination, kidney stones, and bone pain.
MEN2B presents with additional distinct features beyond the endocrine tumors. Individuals with MEN2B often exhibit a “marfanoid habitus,” characterized by a tall, slender build with long limbs. Mucosal neuromas commonly appear as small, glistening bumps on the lips, tongue, and inside the mouth. Eyelid neuromas can cause thickened or everted eyelids, and infants may have difficulty producing tears. Ganglioneuromas in the intestines can lead to gastrointestinal issues such as chronic constipation or diarrhea.
The Genetic Link
MEN2 syndrome arises from specific changes, known as mutations, in the RET proto-oncogene. This gene is located on chromosome 10 and plays a role in cell growth, differentiation, and survival by encoding a receptor tyrosine kinase protein. The mutations in the RET gene are “gain-of-function,” meaning they lead to an overactive RET protein, which promotes uncontrolled cell growth and tumor formation.
The inheritance pattern of MEN2 syndrome is autosomal dominant. This means only one copy of the mutated RET gene is sufficient for an individual to develop the syndrome. Each child of an affected parent has a 50% chance of inheriting the altered gene. While most MEN2A cases are inherited, approximately 50% of MEN2B cases can result from new, spontaneous mutations, known as de novo mutations, occurring in individuals with no family history.
Diagnosis and Management
Diagnosis of MEN2 syndrome primarily relies on genetic testing for mutations in the RET gene. A blood test can identify these specific gene changes, confirming the diagnosis even before symptoms or tumors appear. When a RET mutation is identified, family members at risk are also screened for early intervention.
Beyond genetic testing, clinical screening for associated conditions is an ongoing part of diagnosis and monitoring. This includes blood tests to measure levels of calcitonin (a marker for MTC), and plasma or 24-hour urine tests for metanephrines to detect pheochromocytoma. Blood calcium and parathyroid hormone levels are also monitored for hyperparathyroidism. Imaging studies, such as neck ultrasounds, CT scans, or MRI of the abdomen, are used to locate and assess tumors.
Management of MEN2 syndrome involves a proactive and multidisciplinary approach. For individuals with a confirmed RET gene mutation, prophylactic thyroidectomy, the surgical removal of the thyroid gland, is recommended to prevent MTC. The timing of this surgery depends on the specific RET mutation; more aggressive mutations, particularly those associated with MEN2B, warrant surgery in infancy. For MEN2A, thyroidectomy may be recommended as early as 3 years of age or before age 5 for high-risk mutations.
Ongoing surveillance is also a key part of management, even after thyroidectomy. Individuals with MEN2 require lifelong monitoring for pheochromocytoma and hyperparathyroidism through annual blood and urine tests. If a pheochromocytoma is detected, surgical removal of the affected adrenal gland or glands is recommended, often after blood pressure is controlled with medication. For hyperparathyroidism, surgical removal of the affected parathyroid glands is the treatment. For advanced MTC that has spread beyond the thyroid, treatment strategies may include additional surgery, radiation therapy, or targeted therapies such as kinase inhibitors.