MEN1

MEN1 is caused by inactivating mutations in the MEN1 gene on chromosome 11q13, which encodes menin, a tumor suppressor protein involved in transcriptional regulation, genome stability, and cell division control. Inheritance follows an autosomal dominant pattern with high penetrance (>90% by age 50), and tumorigenesis follows Knudson's two-hit hypothesis (loss of both alleles). The classic clinical triad ('3 P's') includes: (1) Parathyroid tumors (most common, ~95%) causing primary hyperparathyroidism with hypercalcemia—often the first manifestation; (2) Pancreatic (and duodenal) neuroendocrine tumors (~40-70%), most commonly gastrinomas (causing Zollinger-Ellison syndrome with recurrent peptic ulcers) or insulinomas (causing hypoglycemia); and (3) Pituitary adenomas (~30-40%), most commonly prolactinomas, but also somatotroph (acromegaly) or non-functioning tumors. Additional associated findings can include adrenal adenomas, carcinoid tumors (bronchial, thymic, gastric), lipomas, angiofibromas, and collagenomas. Diagnosis is clinical (2 or more of the primary tumors) or genetic (identification of MEN1 mutation in a patient with one tumor plus a first-degree relative with MEN1). Screening of at-risk family members involves biochemical testing (calcium, PTH, gastrin, prolactin) and imaging. Management is tumor-specific: parathyroidectomy (often subtotal) for hyperparathyroidism, surgical resection or medical management (e.g., proton pump inhibitors for gastrinomas) for pancreatic tumors, and dopamine agonists (e.g., cabergoline) for prolactinomas. This differs from MEN2 (RET proto-oncogene mutations, associated with medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease) and MEN4 (CDKN1B mutations, similar phenotype to MEN1). High-yield boards association: 'Pancreas, Parathyroid, Pituitary' = 3 P's of MEN1, and remember it's a tumor SUPPRESSOR gene loss (unlike MEN2's RET proto-oncogene gain-of-function).