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Multiple endocrine neoplastic syndrome type I
Last reviewed: 04.07.2025
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Multiple endocrine neoplastic syndrome, or MEN type I (multiple endocrine adenomatosis type I, Wermer syndrome), is a hereditary disease characterized by tumors in the parathyroid glands, pancreas, and pituitary gland. Clinical manifestations are expressed by hyperparasitism and asymptomatic hypercalcemia. To determine carriers of the disease, it is necessary to study the patient's genome.
Causes of MEN syndrome type I
MEN I is most likely caused by mutations in a tumor suppressor gene. This gene codes for the protein menin, which regulates cell proliferation.
About 40% of MEN I cases involve tumors of three glands - the parathyroid, pancreas, and pituitary gland. Almost all combinations of tumors and symptoms described below are possible. A patient with a MEN I gene mutation and a patient with a MEN I tumor are at risk of developing a tumor in the future. The age of onset of the disease varies from 4 to 81 years, but the peak is in women in their 20s and men in their 30s. Women are affected twice as often as men.
Symptoms of MEN syndrome type I
The clinical picture of the disease depends on the affected glandular elements.
Forms
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Parathyroid
Hyperparathyroidism is present in 90% of cases. The most common manifestation is asymptomatic hypercalcemia: about 25% of patients suffer from nephrolithiasis or tubulomedullary lithiasis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenomas are more common than solitary adenomas.
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Pancreas
Tumors in the pancreatic islets are observed in 30-74% of cases of this syndrome. Tumors are usually multicentric, diffuse hyperplasia or multiple adenomas are common. In 30% of cases, tumors in the pancreatic islets are malignant with a tendency to metastasize. Malignant tumors in the pancreatic islets caused by MEN type I are more often benign than incidental malignant tumors in the pancreatic islets.
About 40% of tumors in pancreatic islets originate from P cells and are insulin-secreting tumors characterized by persistent hypoglycemia. Cellular tumors are more common in patients under 40 years of age. The remaining 60% are extracellular elements and occur in people over 40 years of age. Extracellular tumors are more likely to be malignant.
Most pancreatic islet tumors secrete pancreatic polypeptide, the clinical significance of which is unknown. Gastrin is secreted extracellularly by tumors (increased gastrin secretion in MEN I originates from the duodenum). Increased gastrin secretion increases gastric acidity, which can inactivate pancreatic lipase, causing diarrhea and steatorrhea. Increased gastrin secretion also leads to peptic ulcers in more than 50% of patients with MEN I syndrome. Ulcers are usually multiple and atypical in location, with significant bleeding and ulcer perforation common. Peptic ulcer may be incurable and complicated). Among patients with Zollinger-Ellison syndrome, 20-60% have MEN I syndrome.
Severe secretory diarrhea may develop and cause fluid and electrolyte depletion in extracellular tumors. This complex, termed the watery stool, hypokalemia, and achlorhydria syndrome (watery stool, hypokalemia, and achlorhydria syndrome; pancreatic cholera), has been attributed to vasoactive intestinal polypeptide, although other hormones or secretagogues (including prostaglandins) may be involved. Increased secretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH (causing Cushing's syndrome), and hypersecretion of growth hormone-releasing hormone (causing acromegaly) are occasionally seen in extracellular tumors.
Pituitary
Pituitary tumors occur in 15% to 42% of patients with MEN I syndrome. Twenty-five to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Patients have acromegaly, the clinical picture of which is indistinguishable from that of sporadic acromegaly. About 3% of tumors secrete ACTH, causing Cushing's syndrome. The remainder are nonfunctional. Local tumor extension may result in visual disturbances, headache, and hypopituitarism.
Other symptoms
Adenomas and adenomatous hyperplasia of the thyroid and adrenal glands are occasionally seen in patients with MEN I syndrome. As a result, hormone secretion is rarely impaired, and the importance of such abnormalities is uncertain. Carcinoid tumors, especially those arising in the embryologic foregut, are rare. Multiple subcutaneous and visceral lipomas may also occur.
Diagnostics of MEN syndrome type I
To diagnose the disease, blood tests for hormones and various types of examinations are used.
Patients with parathyroid, pancreatic, and pituitary tumors, especially those with a family history of endocrinopathy, should undergo clinical evaluation for other MEN I tumors. Such evaluation includes questions regarding symptoms of peptic ulcer disease, diarrhea, nephrolithiasis, hypoglycemia, and hypopituitarism; checking for defects, galactorrhea in women, and signs of acromegaly and subcutaneous lipomas; and measurement of serum Ca, uncomplicated parathyroid hormone (PTH), gastrin, and prolactin.
Additional laboratory or radiological studies should be performed if the results of screening tests suggest endocrine abnormalities associated with MEN I syndrome. Insulin secretion from pancreatic tumor cells is diagnosed by detecting fasting hypoglycemia with elevated plasma insulin levels.
Extracellular gastrin-secreting tumors of the pancreas and duodenum are diagnosed by elevated basal plasma gastrin levels, elevated gastrin levels in response to Ca infusion, and paradoxical increases in gastrin levels after secretin infusion. Elevated basal pancreatic polypeptide or gastrin levels or an exaggerated response of these hormones to standard meals may be an early sign of pancreatic involvement. CT or MRI may be helpful in localizing the tumor. Because these tumors are often small and difficult to localize, other imaging studies (eg, somatostatin scintigraphy, endoscopic ultrasound, intraoperative ultrasound) should be used.
Acromegaly is diagnosed by elevated levels of growth hormone that are not suppressed by glucose administration and elevated levels of plasma insulin-like growth factor 1.
In patients with 2 or more endocrine disorders associated with MEN I syndrome who are not related (index cases), direct DNA sequencing of the MEN I syndrome gene identifies the characteristic mutation in 80% to 90% of cases. If the index case is detected, first-degree relatives are recommended to undergo genetic or clinical testing. Annual clinical testing is necessary for first-degree relatives who have positive clinical testing results. Individuals with minimal symptoms who have not undergone genetic testing or in whom index case testing does not reveal the characteristic mutation should undergo annual testing.
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Treatment of MEN syndrome type I
Treatment of parathyroid and pituitary lesions is primarily surgical. Tumors in the pancreatic islets are more difficult to treat because the lesions are often small and difficult to localize, and the lesion often has many foci. If a single tumor cannot be found, total pancreatectomy may be necessary to adequately control insulin shock. Diazoxide may be a useful adjunct in the treatment of hypoglycemia; streptozocin and other cytotoxic drugs may improve tumor symptoms by reducing the tumor burden.
Treatment of gastrin-secreting extracellular tumors is complex. Attempts must be made to localize and remove the tumor. If localization is not possible, a proton pump inhibitor often alleviates the course of the ulcer. With the availability of these drugs, the need for gastrectomy is extremely rare.
Octreotide, a somatostatin analogue, can block hormone secretion from non-gastrin-secreting pancreatic tumors and is well tolerated, especially when given as a long-acting preparation every 4 weeks. Palliative treatment of metastatic pancreatic tumors includes hepatic artery embolization and interferon a (in combination with octreotide).