MeN2

MEN2, or multiple endocrine neoplasia type 2, is a hereditary syndrome caused by germline mutations in the RET proto-oncogene on chromosome 10. It is inherited in an autosomal dominant pattern with high penetrance and is characterized by a predisposition to medullary thyroid carcinoma (MTC) and pheochromocytoma, with additional features depending on the subtype.

There are three main forms: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) as a milder spectrum. MEN2A (Sipple syndrome) typically includes MTC, pheochromocytoma, and sometimes primary hyperparathyroidism. MEN2B features MTC and pheochromocytoma as well, but also mucosal neuromas, intestinal ganglioneuromatosis, and a marfanoid habitus, with often earlier disease onset. FMTC presents primarily with MTC and lacks the full MEN2A/B constellation.

RET mutations determine risk and guide management. Mutations such as codon 634 (exon 11) are associated with MEN2A and a high risk of MTC; codon 918 (exon 16) is linked to MEN2B and carries a particularly high risk and aggressive course. Other mutations (e.g., in codons 611, 618, 620) confer varying, generally lower, risks. Some RET mutations arise de novo, especially in MEN2B.

Diagnosis relies on genetic testing of at-risk individuals and biochemical screening. Surveillance includes measuring calcitonin levels to detect MTC and plasma or urinary metanephrines to screen for pheochromocytoma, with imaging as needed. Management centers on prophylactic thyroidectomy timed to the specific RET mutation, often performed before cancer develops, and treatment of pheochromocytoma prior to thyroid surgery. Lifelong follow-up is essential for surveillance of associated conditions.

Prognosis improves with early detection and appropriate surgical intervention.