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BACKGROUND

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The multiple endocrine neoplasia type 1 (MEN1) syndrome was initially described in 1954 as Wermer’s syndrome. Dr Paul Wermer reported on a syndrome in which adenomatosis of the anterior pituitary, parathyroid, and pancreatic islets was observed in a family in which the father and four of nine siblings were affected.1 He postulated that this syndrome was likely inherited as an autosomal dominant disease and that these patients commonly also suffered from ulcers of the stomach and duodenum. It is now widely known that MEN1 consists of a constellation of multiglandular parathyroid disease, neuroendocrine tumors of the gastroenteropancreatic system, anterior pituitary adenomas, and other associated nonendocrine manifestations such as facial angiofibromas.

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EPIDEMIOLOGY/CLINICAL CHARACTERISTICS

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The MEN1 syndrome develops in 1/20,000 to 1/40,000 individuals2 and is inherited in an autosomal dominant fashion. Primary hyperparathyroidism is the most common and earliest manifestation in MEN1 patients, presenting in 80% to 100% by age 40. Gastrin-secreting tumors (gastrinomas) are the major cause of morbidity and mortality with the MEN1 syndrome and about 50% of MEN1 patients develop gastrinomas by age 50.3,4,5 Insulinomas are present in 10% to 35% of MEN1 patients and are often benign and solitary. Most of the anterior pituitary tumors are prolactinomas which are present in 20% to 50% of MEN1 patients, although there are also reports of growth hormone-, corticotropin-, and thyrotropin-secreting pituitary tumors.8

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GENETICS/PATHOGENESIS

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The multiple endocrine neoplasia type 1 occurs as a result of a loss of function of a tumor suppressor gene, MEN1, located on chromosome 11q13.6 The development of this disorder follows the two-hit hypothesis” whereby two genetic mutations, or “hits,” on both alleles result in loss of function. The first mutation is inherited in the germline and present in every cell; this confers susceptibility to disease. The second is a somatic mutation in a cell located in the target tissue resulting in tumor formation. The MEN1 gene contains 10 exons encoding a 610-amino acid protein called menin.6 Menin is known to play an important role in the regulation of gene transcription, cell cycle progression, apoptotic pathways, DNA processing and repair, cytoskeletal integrity, and genome stability. There have been more than 1330 diverse mutations reported in the MEN1 gene as a result of nonsense, missense, frameshift, deletions, and RNA splicing defects.7

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SCREENING/DIAGNOSTIC EVALUATION

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The multiple endocrine neoplasia type 1 is inherited as an autosomal dominant disorder, so the diagnosis of MEN1 has important implications for other family members because first-degree relatives have an approximately 50% risk of developing the disease. Studies have noted about 10% of germline MEN1 mutations arise de novo and about 30% of patients have no detectable mutations.8 MEN1 genetic testing should be performed in (1) a patient with two or more MEN1-associated endocrine tumors; (2) asymptomatic or symptomatic first-degree relatives ...

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