Multiple endocrine neoplasia type 2B

Multiple endocrine neoplasia type 2B (MEN2B), also known as MEN 2B, MEN3, or mucosal neuroma syndrome, is a rare and aggressive hereditary cancer syndrome characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and distinctive physical features. It is caused by mutations in the RET proto-oncogene, most commonly the M918T missense mutation, which leads to constitutive activation of the RET tyrosine kinase receptor. MEN2B represents the most aggressive subtype of MEN2, with medullary thyroid carcinoma often developing in infancy or early childhood and frequently metastasizing at a very young age. The disease affects multiple body systems. The endocrine system is primarily involved, with medullary thyroid carcinoma occurring in virtually all affected individuals, often before age one. Pheochromocytomas (adrenal gland tumors) develop in approximately 50% of patients. Distinctive non-endocrine features include mucosal neuromas on the lips, tongue, and eyelids, a marfanoid body habitus (tall, thin build with long limbs and joint hypermobility), intestinal ganglioneuromatosis causing gastrointestinal symptoms such as constipation, diarrhea, or megacolon, and prominent corneal nerves visible on slit-lamp examination. Affected individuals may also have characteristic facial features including thickened, bumpy lips. Early recognition and treatment are critical for survival. Current guidelines recommend prophylactic total thyroidectomy within the first six months of life, ideally as early as possible, as MTC in MEN2B can metastasize very early. Pheochromocytomas are managed surgically when detected, typically through adrenalectomy. Lifelong surveillance for pheochromocytoma is essential. For advanced or metastatic MTC, targeted therapies including RET kinase inhibitors such as selpercatinib and pralsetinib have shown significant efficacy and represent important advances in treatment. Vandetanib and cabozantinib are also approved for progressive metastatic MTC. Genetic testing of the RET gene is recommended for all first-degree relatives of affected individuals, and approximately 50% of cases arise as de novo mutations.

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