Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2), also known as MEN 2 or Sipple syndrome (for the MEN2A subtype), is a group of inherited cancer syndromes caused by activating mutations in the RET proto-oncogene on chromosome 10q11.2. MEN2 is characterized by the development of tumors in multiple endocrine glands, most notably medullary thyroid carcinoma (MTC), which occurs in virtually all affected individuals. The condition is subdivided into three clinical variants: MEN2A (the most common, accounting for approximately 70–80% of cases), MEN2B (the most aggressive form), and familial medullary thyroid carcinoma (FMTC). MEN2A typically presents with MTC, pheochromocytoma (adrenal gland tumors occurring in about 50% of patients), and primary hyperparathyroidism (in 20–30%). MEN2B features MTC and pheochromocytoma along with distinctive physical features including mucosal neuromas of the lips and tongue, a marfanoid body habitus, and intestinal ganglioneuromatosis, but hyperparathyroidism is rare. The disease affects the endocrine system primarily, including the thyroid gland (C-cells), adrenal medulla, and parathyroid glands. MTC in MEN2B tends to develop earlier and behave more aggressively than in MEN2A, often appearing in infancy or early childhood. Pheochromocytomas can cause episodic hypertension, headaches, sweating, and palpitations and may be bilateral. Hyperparathyroidism can lead to hypercalcemia with symptoms such as kidney stones, bone loss, fatigue, and gastrointestinal complaints. Genetic testing for RET mutations is the cornerstone of diagnosis and guides clinical management, including the timing of prophylactic thyroidectomy. Current treatment involves risk-stratified prophylactic total thyroidectomy, which is recommended in early childhood or even infancy depending on the specific RET mutation and its associated risk level. Pheochromocytomas are managed surgically, ideally with adrenal-sparing approaches when feasible. For advanced or metastatic MTC, targeted therapies including the tyrosine kinase inhibitors vandetanib and cabozantinib, as well as the more selective RET inhibitors selpercatinib and pralsetinib, have been approved and represent significant advances in treatment. Lifelong surveillance for tumor recurrence and screening for associated endocrine tumors is essential for all affected individuals and at-risk family members.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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