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Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, and pituitary gland. Clinical features most commonly include hyperparathyroidism and asymptomatic hypercalcemia. Genetic screening is used to detect carriers. Diagnosis is by hormonal and imaging tests. Tumors are surgically removed when possible.
MEN 1 is probably caused by an inactivating mutation of the tumor suppressor gene that encodes the transcription factor menin; many mutations of this gene may be responsible.
About 40% of MEN 1 cases involve tumors of all 3 affected glands—the parathyroids, pancreas, and pituitary. Almost any combination of the tumors and symptom complexes outlined below is possible. A patient with a MEN 1 gene mutation and one of the MEN 1 tumors is at risk of developing any of the other tumors later on. Age at onset ranges from 4 to 81 yr, but peak incidence occurs in the 20s in women and 30s in men. Women are affected twice as often as men.
Symptoms and Signs
The clinical features depend on the glandular elements affected (see Table 1: Multiple Endocrine Neoplasia (MEN) Syndromes: Conditions Associated With MEN Syndromes ).
Parathyroid:
Hyperparathyroidism is present in ≥ 90% of patients. Asymptomatic hypercalcemia is the most common manifestation: about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenomas are more common than solitary adenomas.
Pancreas:
Pancreatic islet cell tumors occur in 60 to 70% of patients. Tumors are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas. About 30% of tumors are malignant and have local or distant metastases. Malignant islet cell tumors due to MEN 1 syndrome often have a more benign course than do sporadically occurring malignant islet cell tumors.
About 40% of islet cell tumors originate from a β cell, secrete insulin (insulinoma), and can cause fasting hypoglycemia. β-Cell tumors are more common among patients < 40. About 60% of islet cell tumors originate from non–β-cell elements and tend to occur in patients > 40. Non–β-cell tumors are somewhat more likely to be malignant.
Most islet cell tumors secrete pancreatic polypeptide, the clinical significance of which is unknown. Gastrin is secreted by many non–β-cell tumors (increased gastrin secretion in MEN 1 also often originates from the duodenum). Increased gastrin secretion increases gastric acid, which may inactivate pancreatic lipase, leading to diarrhea and steatorrhea. Increased gastrin secretion also leads to peptic ulcers in > 50% of MEN 1 patients. Usually the ulcers are multiple or atypical in location, and often bleed, perforate, or become obstructed. Peptic ulcer disease may be intractable and complicated (Zollinger-Ellison syndrome—see Tumors of the GI Tract: Zollinger-Ellison Syndrome). Among patients presenting with Zollinger-Ellison syndrome, 20 to 60% have MEN 1.
A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–β-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia, and achlorhydria syndrome (WDHA; pancreatic cholera—see Tumors of the GI Tract: Vipoma), has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH (causing Cushing's syndrome), and hypersecretion of growth hormone–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors. All of these are rare in MEN 1.
Nonfunctioning pancreatic tumors also occur in patients with MEN 1 and may be the most common type of pancreatoduodenal tumor in MEN 1. The size of the nonfunctioning tumor correlates with risk of metastasis and death.
Pituitary:
Pituitary tumors occur in 15 to 42% of MEN 1 patients. From 25 to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea (see Pituitary Disorders: Galactorrhea), and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing's disease. Most of the remainder are nonfunctional. Local tumor expansion may cause visual disturbance, headache, and hypopituitarism. Pituitary tumors in MEN 1 patients appear to be larger and behave more aggressively than sporadic pituitary tumors.
Other manifestations:
Adenomas and adenomatous hyperplasia of the thyroid and adrenal glands occurs occasionally in MEN 1 patients. Hormone secretion is rarely altered as a result, and the significance of these abnormalities is uncertain. Carcinoid tumors, particularly those derived from the embryologic foregut, occur in isolated cases. Multiple subcutaneous and visceral lipomas, angiofibromas, and collagenomas may also occur.
Diagnosis
Patients with tumors of the parathyroids, pancreas, or pituitary, particularly those with a family history of endocrinopathy, should undergo clinical screening for other tumors of MEN 1. Such screening includes the following:
Additional laboratory or radiologic tests should be done if these screening tests suggest an endocrine abnormality related to MEN 1. An insulin-secretingβ-cell tumor of the pancreas is diagnosed by detecting fasting hypoglycemia with an elevated plasma insulin level.
A gastrin-secreting non–β-cell tumor of the pancreas or duodenum is diagnosed by elevated basal plasma gastrin levels, an exaggerated gastrin response to infused Ca, and a paradoxical rise in gastrin level after infusion of secretin. An elevated basal level of pancreatic polypeptide or gastrin or an exaggerated response of these hormones to a standard meal may be the earliest sign of pancreatic involvement. CT or MRI can help localize tumors. Because these tumors are often small and difficult to localize, other imaging tests (eg, somatostatin receptor scintigraphy, endoscopic ultrasonography, intraoperative ultrasonography) may be necessary.
Acromegaly is diagnosed by elevated growth hormone levels that are not suppressed by glucose administration and by elevated levels of serum insulin-like growth factor 1.
In patients with 2 or more endocrine abnormalities related to MEN 1 who are not from a known MEN 1 kindred (index case), direct DNA sequencing of the MEN 1 gene identifies a specific mutation in 80 to 90%. If an index case is identified, 1st-degree relatives should consider genetic screening. Early presymptomatic screening of family members of MEN 1 patients has not been shown to reduce morbidity or mortality; annual clinical and biochemical screening may thus be preferable in this group
Treatment
Treatment of parathyroid and pituitary lesions is primarily surgical, although prolactinoma is usually managed with dopamine agonists. Islet cell tumors are more difficult to manage because the lesions are often small and difficult to find and multiple lesions are common. If a single tumor cannot be found, total pancreatectomy may be required for adequate control of hyperinsulinism. Diazoxide may be a useful adjunct in treating hypoglycemia. Streptozocin and other cytotoxic drugs may ameliorate symptoms by reducing tumor burden.
The treatment of gastrin-secreting non–β-cell tumors is complex. Localization and removal of the tumor should be attempted. If localization is impossible, a proton pump inhibitor frequently produces symptomatic relief from peptic ulcer disease. With the availability of these drugs, gastrectomy is rarely required.
Octreotide, a somatostatin analog, can block hormone secretion from nongastrin-secreting pancreatic tumors and is well tolerated, particularly if given as a long-acting preparation administered every 4 wk. Palliative treatments for metastatic pancreatic tumors include hepatic artery embolization and interferon alfa (in combination with octreotide).
Last full review/revision June 2008 by Patricia A. Daly, MD; Lewis Landsberg, MD
Content last modified June 2008
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