Multiple Endocrine Neoplasia (MEN) type 2 A and B are rare autosomal dominant inherited cancer syndromes characterized by tumors of the C cells of the thyroid, of the adrenal medulla, and parathyroid glands. MEN2 is caused by a genetic defect in the REarranged during Transfection (RET) proto-oncogene on chromosome 10 (10q11-2), leading to a ligand-independent activation of the transmembrane RET receptor tyrosine kinase and consequently its intra-cellular pathways. Different mutations lead to different levels of activation and MEN2 is therefore characterized by a strong genotype-phenotype correlation. Nearly all patients with MEN2A have either C-cell hyperplasia (CCH) or medullary thyroid cancer (MTC), 50% have pheochromocytoma (PHEO), and 20-30% hyperparathyroidism (pHPT) but incidence of these manifestations is depending on the underlying RET mutation. Patients with MEN2B have a 100% incidence of CCH or MTC, PHEO in 30-50%, mucosal neuromas, and rarely pHPT. Endocrine tumors in MEN2 are often multifocal and bilateral. Nowadays, the diagnosis of MEN2 is made by genetic testing. After diagnosis, annual screening for associated manifestations and prophylactic thyroidectomy for preventing metastasized MTC are advised. Optimal age for preventive surgery or when to start screening for each manifestation is based upon the underlying RET mutation. In patients with MTC present at diagnosis, adequate staging is needed before surgical resection, since surgery is the only curative treatment. The most important biomarker for MTC is calcitonin. Fractionated metanephrines are used for early diagnosing PHEO and calcium and PTH for hyperparathyroidism. For PHEO, a minimal invasive surgical resection is recommended. In pHPT the surgical approach should be tailored to the amount and location of the enlarged glands visualized with imaging. Recurrent MTC requires physical examination, neck ultrasound, and measurement of serum calcitonin and carcinoembryonic antigen (CEA) levels every 6 months. For metastasized MTC, treatment can be successful with multikinase inhibitors (vandetanib, cabozantinib) and selective RET inhibitors (pralsetinib, selpercatinib). For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text,
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