MEN Syndromes: Type 1, 2a And

Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant genetic disorders characterized by the development of tumors in two or more endocrine glands, classified into three distinct types based on their causative gene mutations and tumor spectrum. MEN1 (Wermer syndrome) is caused by inactivating mutations in the MEN1 tumor suppressor gene on chromosome 11q13, which encodes menin — a nuclear protein involved in transcriptional regulation, DNA repair, and cell cycle control. Loss of menin function leads to uncontrolled proliferation of affected endocrine tissues, producing the classic triad: primary hyperparathyroidism (95% penetrance, typically the earliest manifestation), pancreatic neuroendocrine tumors (40%, including gastrinomas causing Zollinger-Ellison syndrome and insulinomas), and pituitary adenomas (30%, most commonly prolactinomas). MEN2A (Sipple syndrome) and MEN2B are caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10q11.2, which encodes a receptor tyrosine kinase critical for neural crest cell development. Specific RET codon mutations produce distinct phenotypes with strong genotype-phenotype correlation that determines clinical aggressiveness and prophylactic thyroidectomy timing. MEN2A features medullary thyroid carcinoma (MTC, 95% penetrance — arising from parafollicular C cells that produce calcitonin), pheochromocytoma (50%), and...