58: Multiple Endocrine Neoplasia Type 1

Key Points

• Disease summary:

  • The term multiple endocrine neoplasia 1 (MEN1) refers to a familial tumor syndrome characterized by the combination of tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland.

  • Patients may also develop adrenal cortical tumors, carcinoid tumors, facial angiofibromas, collagenomas, and lipomas.

  • Parathyroid tumors are the first manifestation of MEN1 in more than 85% of patients. In less than 15% of patients, the first manifestation may be an insulinoma or prolactinoma.

  • The frequency of MEN1 is estimated to be 1 case in 30,000 persons with a female to male ratio of 1:1.

  • The age of onset of endocrine tumors is usually in the teenaged years; however, the diagnosis is frequently delayed until the fourth decade of life.

• Hereditary basis:

  • The gene for MEN1 has been localized to chromosome band 11q13 and codes for a 610-amino acid protein, referred to as menin.

  • Loss of heterozygosity (LOH) has been found in the region associated with MEN1, suggesting that the gene has tumor suppression function consistent with Knudson’s two hit hypothesis. More than 90% of tumors from MEN1 patients have LOH.

  • MEN1 germline mutations are identified in about 80% to 90% of probands with familial MEN1 syndrome and about 65% of individuals with sporadic MEN1 syndrome (ie, a single occurrence of MEN1 syndrome in a family)

  • 5-10% of patients with MEN1 may not harbor mutations in the coding region of the MEN1 gene; these individuals may have whole gene deletions or mutations in the promoter or untranslated regions.

  • More than 10% of the MEN1 mutations arise de novo.

• Differential diagnosis:

  • MEN4 syndrome: Germline mutations in CDKN1B/p27 gene, encoding the p27kip protein, have been reported in (a) a small family presented with characteristics of MEN1: somatotropinoma, parathyroid tumors, and renal angiomyolipoma, (b) in a Dutch patient diagnosed with three lesions compatible with a diagnosis of MEN1: small-cell neuroendocrine cervical carcinoma, adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and hyperparathyroidism.

  • Sporadic primary hyperparathyroidism (PHPT)

    • It presents as a single parathyroid adenoma, mostly in the sixth decade of life.

    • Symptoms are due to hypercalcemia, in contrast to individuals with MEN1 syndrome, who are often asymptomatic and identified during evaluation for manifestations of MEN1 syndrome.

  • Familial isolated hyperparathyroidism due to mutations other than MEN1

    • CASR, the gene encoding the calcium-sensing receptor, responsible for familial benign hypercalcemia (FBH), also called familial hypocalciuric hypercalcemia (FHH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT).

    • HRPT2, the gene encoding parafibromin, which is responsible for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome

  • MEN2 syndrome, caused by mutations in RET characterized by medullary thyroid carcinoma, pheochromocytoma, and PHPT.

  • Familial isolated pituitary adenoma (FIPA)

    • Germline mutations in the AIP gene, encoding aryl hydrocarbon receptor-interacting protein, have been identified in 15% to 20% of FIPA cases.

    • The causative gene or genes in the majority (70%-80%) of FIPA families is currently unknown.

  • Zollinger-Ellison Syndrome (ZES)

    • Gastric acid hypersecretion and severe peptic ulceration due to tumor ...