Multiple Endocrine Neoplasia Type 1

CLINICAL CHARACTERISTICS

Multiple endocrine neoplasia type 1 (MEN1) includes varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors become evident either by overproduction of hormones by the tumor or by growth of the tumor itself. are the most common MEN1-associated endocrinopathy; onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years; hypercalcemia causes lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis, dehydration, hypercalciuria, kidney stones, increased bone resorption/fracture risk, hypertension, and shortened QT interval. include prolactinoma (the most common), which manifests as oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males. can manifest as Zollinger-Ellison syndrome (gastrinoma); hypoglycemia (insulinoma); hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting tumor). are non-hormone-secreting and can manifest as a large mass after age 50 years. can be associated with primary hypercortisolism or hyperaldosteronism. Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.

DIAGNOSIS/TESTING: The clinical diagnosis of MEN1 can be established in a proband with: Two or more endocrine tumors including parathyroid, anterior pituitary, and/or GEP tract tumors or one endocrine tumor (parathyroid, anterior pituitary, or GEP tract tumor); and A first-degree relative with MEN1. The molecular diagnosis can be established by identification of a heterozygous pathogenic variant in on molecular genetic testing.

MANAGEMENT

Hyperparathyroidism is treated with subtotal parathyroidectomy and cryopreservation of parathyroid tissue or total parathyroidectomy and autotransplantation of parathyroid tissue; measure parathyroid hormone (PTH) and/or serum calcium to assess for hypoparathyroidism following subtotal or total parathyroidectomy; calcimimetics are used to treat primary hyperparathyroidism in those for whom surgery is contraindicated or has failed; prior to surgery, bone antiresorptive agents are used to reduce hypercalcemia and limit bone resorption. Prolactinomas are treated with dopamine agonists (cabergoline being the drug of choice). Growth hormone-secreting tumors causing acromegaly are treated by transsphenoidal surgery; medical therapy for growth hormone-secreting tumors includes somatostatin analogs, octreotide, and lanreotide. Adrenocorticotrophic hormone-secreting pituitary tumors associated with Cushing disease are surgically removed; nonsecreting pituitary adenomas are treated by transsphenoidal surgery. Proton pump inhibitors or H-receptor blockers reduce gastric acid output caused by gastrinomas. Surgery is indicated for insulinoma and most other pancreatic tumors. Long-acting somatostatin analogs can control the secretory hyperfunction associated with carcinoid syndrome. Surgery is suggested for adrenal tumors greater than 4 cm in diameter, for tumors 1-4 cm in diameter with atypical or suspicious radiologic features, or for tumors that show significant measurable growth over a six-month interval. Measure urinary catecholamines prior to surgery to diagnose and treat a pheochromocytoma to avoid blood pressure peaks during surgery. Skin lesions in individuals with MEN1 are treated the same way as for the general population. Thymectomy may prevent thymic carcinoid in males, particularly in smokers. Annual fasting serum calcium, and consider fasting serum intact PTH from age five years; annual serum prolactin, IGF-1, fasting glucose, and insulin from age five years; head MRI every three to five years from age five years; annual chromogranin-A, pancreatic polypeptide, glucagon, and vasoactive intestinal peptide for other pancreatic neuroendocrine tumors from age eight years; annual fasting serum gastrin from age 20 years; consider abdominal CT, MRI, or endoscopic ultrasound every three to five years from age 20 years; consider chest CT, MRI, or somatostatin receptor scintigraphy octreotide scan annually from age 15 years; consider annual skin exam. Smoking increases the risk of carcinoid tumors. Because early detection affects management, molecular genetic testing is offered to at-risk members of a family in which a germline pathogenic variant has been identified. Women with primary hyperparathyroidism from any cause are at increased risk of developing preeclampsia; infants born to women with primary hyperparathyroidism should be monitored for postnatal hypocalcemia.

GENETIC COUNSELING

MEN1 is inherited in an autosomal dominant manner. Approximately 90% of individuals diagnosed with MEN1 have an affected parent; approximately 10% of individuals diagnosed with MEN1 have the disorder as the result of a pathogenic variant that occurred in early embryogenesis. Each child (regardless of sex) of an individual with MEN1 has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MEN1 are possible.