Multiple Endocrine Neoplasia
Type 1 (MEN1)

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome characterized by the occurrence of often multifocal tumors in at least two of three endocrine target tissues: the parathyroid glands, the anterior pituitary, and the pancreas/duodenum. MEN1 accounts for about 2 to 4% of all primary hyperparathyroidism (HPT) and for about 25% of all gastrinomas (1). In addition, numerous other endocrine and non-endocrine tumors have been in observed in patients with MEN1. Prevalence of MEN1 has been estimated at 1:30,000 (2).

Morbidity and mortality from MEN1 result from the effects of hormone overproduction by functional endocrine tumors and from malignancy. While there is no cure for MEN1, many of the manifestations are manageable. Early diagnosis is important, since treatment for MEN1-associated tumors may differ from that for sporadic tumors (1,3). In addition, a diagnosis of MEN1 can facilitate regular biochemical screening, which can detect additional neoplasms years before they become clinically apparent (1,4). However, diagnosis based on clinical criteria alone is often significantly delayed (3,4). At the time of diagnosis, half of all MEN1-associated gastrinomas have typically already metastasized (1).

Since MEN1 has been associated with loss-of-function mutations in the tumor suppressor gene MEN1 (5,6), genetic testing can confirm a diagnosis of MEN1 and identify family members at risk for developing the disease before they become symptomatic.

Types and Causes of MEN1

MEN1 is associated with loss-of-function mutations in the gene MEN1, which functions as a tumor suppressor gene in certain tissues (5,6). The mechanism of MEN1-associated tumorigenesis is described by Knudson’s “two hit” model (7): If the MEN1 gene on one chromosome copy is disabled, the reduced “dose” of the MEN1 gene product, menin, may lead to polyclonal hyperplasia; if both MEN1 gene copies are defective, growth of the affected cell is no longer properly regulated, allowing tumorigenesis (2,8). Carriers of a germline loss-of-function mutation in MEN1 already have one copy of the MEN1 gene disabled in each cell. In these individuals, only one somatic event affecting the other MEN1 gene copy is necessary to allow growth of a neoplasm. The probability of such a single somatic event, often a large deletion encompassing the entire normal MEN1 gene copy, is much higher than the probability of two independent somatic events occurring within the same cell. Therefore, carriers of a MEN1-associated mutation have a greatly increased risk of developing tumors compared to the general population. They typically develop tumors early and in several different tissues, and their tumors tend to be multifocal. By age 30, 87% of carriers have developed a MEN1-related neoplasm, and, by age 60, virtually all carriers are symptomatic (9).

Menin

MEN1 codes for the 610-amino acid protein menin. The function of menin, which is mainly located in the nucleus, is not known and can, at present, not be inferred, because menin does not show homology to any proteins with known function. Menin has been shown to bind to JunD, a transcription factor that inhibits cell growth. It has been proposed that, by binding to JunD, menin could repress JunD-dependent cell-growth inhibition, thus promoting cell growth. Menin has also been found to interact with Smad3, a component of the TGF-beta signaling pathway, as well as with various other proteins involved in the regulation of cell growth and differentiation (10,11). A role of menin in the regulation of cell growth is supported by the observation that overexpression of menin in ras-transformed NIH3T3 cells leads to partial normalization of the transformed phenotype (12). However, there is also increasing evidence that menin may function in DNA repair or synthesis (8,11).

MEN1 typically manifests in the third or fourth decade of life (3). The initial clinical symptom of MEN1 is often primary HPT, presenting as nephrolithiasis due to hypercalcemia and/or bone pain due to osteoporosis (1,3,13,14). Primary HPT has a life-time penetrance of over 90% in MEN1 carriers. Tumors often occur in three or all four parathyroid glands, but are typically benign.

Disease due to neoplasms of the anterior pituitary is the initial symptom in about 20% of patients (1,15). Between 10 and 60% of MEN1 carriers develop pituitary adenomas that can cause hormone excess syndromes or lead to hypopituitarism through mass effects (1). The most frequent type of pituitary adenoma associated with MEN1 is a prolactinoma, which, in women, can give rise to galactorrhea-amenorrhea. MEN1-associated pituitary neoplasms are rarely malignant, although they tend to be larger and more aggressive than sporadic pituitary adenomas (15).

Pancreatic islet tumors or gastrinomas occur in 30-75% of MEN1 carriers and are often multifocal (1). Many pancreatic islet tumors are non-functional or pancreatic- polypeptide producing (14), but functional tumors such as gastrinomas, insulinomas, glucagonomas, and VIPomas also occur. Gastrinomas and insulinomas are the most common types of functional entero-pancreatic neoplasm, affecting about 40% and 10%, respectively, of MEN1 carriers. Gastrinomas, which are frequently located in the duodenal submucosa, lead to mucosal ulceration, diarrhea, and malabsorption, the hallmarks of Zollinger Ellison syndrome (ZES). In almost half of all MEN1 patients with ZES, gastrinoma-related symptoms are the initial presentation (3). Most of the MEN1-associated entero-pancreatic tumors, except for insulinoma, have a high malignancy potential.

Other endocrine neoplasms associated with MEN1 include gastric, thymic, and bronchial carcinoids, adrenal cortical lesions, and thyroid adenomas. Carcinoids, which seem to be especially common in MEN1 patients with ZES (30% vs 6% in all MEN1 carriers), have a high malignancy potential (3). Adrenal cortical lesions, which occur in about 30% of MEN1 carriers, are less frequently malignant and often non-functional (14,16). Thyroid adenomas, which occur in 5-30% of MEN1 patients, appear to have little clinical significance (14). Non-hormonal neoplastic manifestations include facial angiofibroma, lipoma, collagenoma, meningioma, and smooth muscle tumors (17).

The type and number of neoplasms associated with MEN1 generally differs within and between affected families (18). In some pedigrees, however, MEN1 seems to lead to familial idiopathic hyperparathyroidism (FIHPT), with primary HPT as the only manifestation. About 20% of FIHPT can be attributed to mutations in MEN1 (1).

While asymmetric multiglandular parathyroid disease at a young age, true recurrence of parathyroid disease, FIHPT, or ZES are indicative of MEN1, clinical diagnosis of MEN1 is typically delayed until at least two of the three characteristic endocrine neoplasms have developed. Presence of more than three angiofibromas together with any type of collagenoma has been proposed as an alternative diagnostic criterion for MEN1 (17). Genetic testing for mutations in MEN1 can confirm a diagnosis of MEN1 in about 80% of cases and is able to identify family members at risk for MEN1 at any age (8,19).

Parathyroid tumors are typically treated with parathyroidectomy. Parathyroid gland removal is often subtotal or, if total, accompanied by immediate autografting of parathyryoid tissue to guard against hypoparathyroidism (20). Recurrence or persistence of hyperparathyroidism after surgery is seen in about 50% of cases, and re-operation is frequently necessary (1).

Pituitary tumors are treated with surgergy or radiotherapy, or, in the case of prolactinomas, drug therapy with dopamine agonists (1).

Most of the symptoms caused by hormone oversecretion from entero-pancreatic lesions associated with MEN1 can be managed with drug therapy. ZES caused by gastrinomas responds well to proton pump inhibitors or H2 receptor blockers, and somatostatin analogues usually are effective in controlling hormone release from functional pancreatic islet tumors, except from insulinomas. Surgery is indicated for insulinomas and other pancreatic tumors, but controversial for gastrinomas (1). In contrast, surgery is usually recommended for non-MEN1 associated, sporadic gastrinomas.

Carriers of MEN1-associated mutations in MEN1 should be screened for parathyroid, pituitary, and entero-pancreatic disease by biochemical testing on a yearly basis, starting in childhood (1). MRI imaging to detect pituitary tumors and pancreatic imaging by CT scan or somatostatin receptor scintigraphy should also be performed regularly, although surveillance for pancreatic tumors is usually not necessary before adulthood (1,14).

MEN1 belongs to the familial cancer syndromes and is inherited in an autosomal dominant manner. Loss-of-function mutations in MEN1 are the only known cause of MEN1, and germline MEN1 mutations can be detected in about 80% of typical MEN1 families (8,19). Mutations are scattered throughout the coding region of the gene, and no genotype-phenotype correlations could be demonstrated (21), except for the association of one specific variant, known as the “Burin” variant, with a high incidence of prolactinoma and a low incidence of gastrinoma (22,23). The de novo mutation rate is estimated at 10% for MEN1 in general and at 25% for MEN1 patients with ZES (3,9).

Somatic mutations on both copies of MEN1 have been found in about 20% of certain non-hereditary, sporadic tumors, such as parathyroid adenomas, gastrinoma, insulinoma, and bronchial carcinoid (11).

The MEN1 Evaluation detects mutations in the gene MEN1 and can confirm a diagnosis of MEN1 in patients presenting with only one of the characteristic manifestations. The MEN1 Evaluation can also identify pre-symptomatic carriers of an MEN1-associated mutation among family members of patients. Individuals confirmed to suffer from MEN1 or to be predisposed to developing MEN1 can then be screened regularly for new neoplasms and endocrinopathies, facilitating timely diagnosis and treatment. Conversely, the MEN1 Evaluation can also identify members of MEN1 families who do not carry the pathogenic MEN1 mutation, eliminating the need for screening in these individuals.

How Is Genetic Testing for MEN1 Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of MEN1 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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