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.

1. Parathyroid tumors 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.

2. Pituitary tumors include prolactinoma (the most common), which manifests as oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males.

3. Well-differentiated endocrine tumors of the gastroenteropancreatic (GEP) tract 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).

4. Carcinoid tumors are non-hormone-secreting and can manifest as a large mass after age 50 years.

5. Adrenocortical tumors 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:

1. 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

2. A first-degree relative with MEN1.

The molecular diagnosis can be established by identification of a heterozygous pathogenic variant in MEN1 on molecular genetic testing.

Management: Treatment of manifestations: 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 H₂-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.

Prevention of primary manifestations: Thymectomy may prevent thymic carcinoid in males, particularly in smokers.

Surveillance: 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.

Agents/circumstances to avoid: Smoking increases the risk of carcinoid tumors.

Evaluation of relatives at risk: Because early detection affects management, molecular genetic testing is offered to at-risk members of a family in which a germline MEN1 pathogenic variant has been identified.

Pregnancy management: 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 de novo MEN1 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 MEN1 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.