Multiple Endocrine Neoplasia Syndromes

Multiple endocrine neoplasia (MEN) syndromes are inherited conditions in which a germline variant predisposes a person to tumours in several endocrine organs. The clinical consequence is not merely “multiple tumours.” It is repeated hormone excess, cancer risk, surgery across a lifetime, and risk in biologic relatives. MEN1 and MEN2 have different genetic mechanisms and therefore different tumour patterns: - MEN1 results from loss-of-function variants in the MEN1 tumour-suppressor gene. A tumour suppressor normally acts as a cellular brake; when that brake is lost, several endocrine tissues become vulnerable to tumour development. - MEN2 results from activating variants in the RET proto-oncogene. RET signalling is driven too strongly, creating a characteristic risk of medullary thyroid carcinoma (MTC), pheochromocytoma, and—in MEN2A—primary hyperparathyroidism. - MEN4 is uncommon and is associated with germline CDKN1B variants. It resembles MEN1, particularly with primary hyperparathyroidism and pituitary adenomas, but gastroenteropancreatic neuroendocrine tumours are less frequent. These syndromes are generally autosomal dominant. Each child of an affected parent has a 50% chance of inheriting the familial pathogenic variant. A family history may be absent because of a new...