Chapter 21

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant genetic predisposition to develop multiglandular parathyroid disease, benign and malignant neuroendocrine tumors (NET of the pancreas and duodenum, and adenomas of the anterior pituitary.1,2 Benign and malignant tumors of these organs may develop, with multiple target organs affected and multifocal tumors within a target organ. Less often, carcinoid tumors (bronchial, gastrointestinal, or thymic), lipomas, cutaneous angiofibromas, or ependymomas of the central nervous system may be associated with this syndrome. The clinical definition of MEN1 includes a patient with tumor development in two associated endocrine tissues (parathyroid, pancreas, pituitary) and a first-degree relative with involvement of one of the three principal endocrine tissues. Direct genetic testing can detect disease-associated germline mutations in the MEN1 gene and identify affected individuals.

MEN1 has an estimated frequency of one in 30,000 people, with no apparent geographic or race predilection.3 However, it has been noted that often the syndrome is not completely recognized, which may lead to a underestimation of the actual prevalence.2 In patients presenting with early-onset hyperparathyroidism, multiple gland parathyroid disease, or rare neuroendocrine neoplasms, the diagnosis of MEN1 should be considered and specifically sought. The peak age of incidence in men and women may differ. Women most often present with clinical symptoms in the third decade of life, and men present in the fourth decade.4 Systematic, prospective biochemical screening in presymptomatic but known genetically affected patients may reveal evidence of endocrine neoplasia 5 to 10 years before the development of clinical manifestations.5

### Genetics

The MEN1 tumor suppressor gene is located on chromosome 11 and encodes for the protein menin. Menin is primarily an intranuclear protein whose functions are not yet clearly understood. However, menin does appear to participate in many different cellular processes, including transcription regulation, cell proliferation, genomic stability, and regulation of apoptosis.3 As a tumor suppressor gene, development of MEN1 requires two genetic "hits" involving both allelic copies of the gene to result in loss of function. The first mutation is inherited in the germline and present in every cell; the second somatic mutation occurs in an individual cell of an involved target tissue and results in tumor formation. Various types of genetic alterations (frameshift, missense, or nonsense; RNA spicing defects; and large genomic deletions) of the menin gene and result in protein loss of function by subsequent truncation, absence, or point mutation and substitution of a single erroneous amino acid. More than 300 independent MEN1 gene mutations have been described, almost as many unique mutations as families. Although the MEN1 mutation has high penetrance, there is a great degree of variation in the expression of the syndrome in individual patients, specifically regarding chronology, type, course, and outcomes of the various clinical manifestations.

### Parathyroid Tumors

Primary hyperparathyroidism (PHPT) is the most common clinical expression of MEN1, occurring in 95% of patients, and ...

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