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
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.
Primary hyperparathyroidism (PHPT) is the most common clinical expression of MEN1, occurring in 95% of patients, and is the first manifestation in approximately 90% of patients. Patients present with symptoms that are similar to those of sporadic PHPT, including nephrolithiasis, abdominal pain, lethargy, psychiatric disturbances, and (if profound) osteoporosis, among others. In contrast to PHPT, which presents most often in the fifth decade of life, MEN1 patients present with hypercalcemia and related symptoms at an earlier age in the second or third decade of life and rarely as early as age 4 years.1 The parathyroid tumors result from the chance occurrence of “two hits” in the MEN1 tumor suppressor gene in a parathyroid cell, with subsequent clonal expansion of the tumor. Therefore, from a strict genetic standpoint, they are actually multiple adenomas rather than hyperplasia (polyclonal).6
Clinically manifested in nearly 40% of individuals with MEN1, pancreatic and duodenal neuroendocrine tumors are the second most frequent manifestations of MEN1. These tumors have a malignant potential, and along with the malignant intrathoracic tumors (thymic, bronchial carcinoid), they account for most of the disease-related morbidity and mortality. Diffuse, preneoplastic islet cell hyperplasia develops throughout the pancreas with subsequent development of multifocal functional and nonfunctional neuroendocrine tumors.
The two most common functional tumors are gastrinomas and insulinomas.2 Patients with gastrinomas present with classic signs and symptoms of Zollinger-Ellison syndrome (i.e., abdominal pain, reflux, secretory diarrhea, and weight loss). Patients with insulinomas present clinically with Whipple’s triad, which includes symptoms of neuroglycopenia (confusion, anxiety, tremor, and diaphoresis), fasting hypoglycemia, and reversal of the symptoms after glucose administration.
Nonfunctional tumors become symptomatic only as a result of their location or growth and mass effect on surrounding structures. They are, however, most often discovered incidentally. A recent study of the combined functional and nonfunctional neuroendocrine tumors that develop in patients with MEN1 was unable to demonstrate a correlation between maximum size of the largest tumor and regional or distant metastases.7
Anterior pituitary tumors have been reported in 30% of MEN1 patients. Clinical manifestations may be caused by mass effect or hormonal production. Local mass effects include visual field defects, blurred vision, and headaches. The most common pituitary adenoma is a prolactinoma, which may cause galactorrhea, amenorrhea, and infertility in women and hypogonadism in men.2 Additionally, anterior pituitary tumors may also produce growth hormone, causing acromegaly or adrenocorticotropic hormone, resulting in Cushing’s syndrome.8,9
Because no correlation has been found between specific mutations in the MEN1 gene and the phenotype of the affected patients, the use of genetic testing for prediction of malignant potential and prognosis is not possible at this time.8,9 Additionally, widespread genetic screening is currently impractical; however, there are a few clear indications for testing for mutations in the MEN1 gene. When an initial case is diagnosed clinically, DNA evaluation of that patient and his or her presymptomatic first-degree relatives should be completed. Presymptomatic individuals who test positive for a MEN1 mutation should then undergo more frequent and more intensive biochemical testing with special emphasis on the potentially malignant pancreaticoduodenal and intrathoracic tumors. Close observation and frequent surveillance of patients with MEN1 mutations allows for much earlier detection of biochemical abnormalities associated with neoplasia.3,5,10
Conversely, a negative genetic screening result in a family in which the previous mutation is known obviates further lifelong screening or testing with the associated costs and psychological impact.11 Because MEN1 mutations are identified in only 85% to 90% of MEN1 families with standard genetic screening methods, failure to identify a disease-associated mutation in members at direct genetic risk from a new MEN1 family with a previously unknown specific genetic change does not exclude affected status.
The diagnosis of PHPT is based on an elevated serum calcium level in the presence of an elevated level of parathyroid hormone (PTH). Some have recommended that screening for these abnormalities should begin as early as age 8 years in MEN1 mutation carriers,3,12 but the peak incidence of clinically apparent hyperparathyroidism is in the late second or early third decade of life.
Biochemical evidence of gastrinoma consists of an elevated fasting serum gastrin level (>100 pg/mL) and gastric acid hypersecretion (>15 mEq/hr with no previous gastric surgery or >5 mEq/hr with previous gastric surgery). Alternatively, a secretin stimulation test may be performed. Secretin is administered intravenously (2 U/kg); a subsequent increase in gastrin of more than 200 pg/mL is diagnostic of a gastrinoma.
Diagnosis of an insulinoma requires a closely monitored inpatient fast to eliminate the possibility of factitious hypoglycemia or exogenous insulin administration. During the inpatient fast, frequent blood samples are taken to measure levels of blood glucose and insulin. At the conclusion of the fast and before glucose administration, C-peptide, sulfonylureas, and anti-insulin antibodies should be measured. The diagnosis of an insulinoma is supported by neuroglycopenic symptoms associated with inappropriate hyperinsulinemia concomitant with profound hypoglycemia (blood glucose <40 mg/dL). C-peptide levels are also elevated in the presence of an insulinoma because this component of the insulin molecule is not present in the exogenously administered form of insulin.1
Other less common functional neuroendocrine tumors of the pancreas, such as glucagonomas, vasoactive intestinal peptide (VIP)-omas, and somatostatinomas, result in characteristic constellations of symptoms secondary to the specific hormone produced. Current recommendations indicate that annual biochemical testing, including pancreatic polypeptide, gastrin, glucagon, and chromogranin A, should begin at approximately age 15 to 20 years in presymptomatic affected individuals.3,5,10,12
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