Multiple endocrine neoplastic syndrome type I

Multiple endocrine neoplastic syndrome, or Type I MEN (multiple type I endocrine adenomatosis, Vermeer's syndrome), is a hereditary disease characterized by tumors in the parathyroid glands, in the pancreas and in the pituitary gland. Clinical manifestations are expressed by hyperparasitism and asymptomatic hypercalcemia. To determine the carriers of the disease, it is necessary to study the genome of the patient. 

[1], [2], [3], [4], [5], [6]

Causes of the type I MEN syndrome

Most likely, the cause of type I MEN is the mutations of the tumor suppression gene. This gene encodes a protein called manin, which regulates cell proliferation.

About 40% of cases of ME type I diseases include tumors of three glands - parathyroid, pancreatic and pituitary. Almost all combinations of tumors and symptoms are possible, described below. A patient with a mutation of the Type I MEN gene and a patient with an I-type I-type tumor are at risk of developing a tumor in the future. The age of manifestation of the disease varies from 4 to 81 years, but the peak falls on women of 20 years of age and men of 30 years. Women get sick twice as often as men.

[7], [8]

Symptoms of the type I MEN syndrome

The clinical picture of the disease depends on the affected glandular elements.

Forms

[9], [10], [11], [12], [13]

Epithelial body

Hyperparathyroidism is present in 90% of cases. The most common manifestation is asymptomatic hypercalcemia: about 25% of patients suffer from nephrolithiasis or tubulomedullary lythiasis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenoma occur more often than single adenomas.

[14], [15], [16], [17]

Pancreas

Tumors in pancreatic islets are noted in 30-74% of cases of this syndrome. Usually tumors are multicenter, often diffuse hyperplasia or multiple adenomas. In 30% of cases, tumors in the pancreatic islets are malignant with a tendency to metastasize. Malignant tumors in pancreatic islets caused by type I MEN are more likely to have a benign course than random malignant tumors in pancreatic islets.

About 40% of tumors in pancreatic islets originate from P cells and fall on tumors secreting insulin and characterized by persistent hypoglycemia. Cellular tumors are more common in patients younger than 40 years. The remaining 60% falls outside of the cellular elements and occurs in people over 40 years of age. Extracellular tumors are most likely malignant.

Most tumors in pancreatic islets produce a pancreatic polypeptide, the clinical importance of which is not established. Gastrin is secreted outside the cell tumors (increased secretion of gastrin in the MEN type I arises from the duodenum). Increased secretion of gastrin increases the acidity of gastric juice, which can inactivate pancreatic lipase, causing diarrhea and steatorrhea. Increased secretion of gastrin also leads to peptic ulcers in more than 50% of patients with type I MEN syndrome. Usually, ulcers are plural and atypical in location, with frequent bleeding and perforation of ulcers. Peptic ulcer can be incurable and complicated). Among patients with Zollinger-Ellison syndrome, 20-60% suffer from Type I MEN syndrome.

Strong secretory diarrhea can develop and cause a decrease in the amount of fluid and electrolytes from outside the cell tumors. This complex, called watery stool syndrome, hypokalemia and achlorhydria (watery stools syndrome, hypokalemia and achlorhydria, pancreatic cholera), has been attributed to the vasoactive intestinal polypeptide, although other hormones or secretagogues (including prostaglandins) may affect process. 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 sometimes found in out-cell tumors.

Pituitary

Tumors of the pituitary gland are found in 15-42% of patients with type I MEN syndrome. 25-90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Patients have  acromegaly, the clinical picture of which does not differ from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing's syndrome. The rest are non-functional. Local expansion of the tumor can lead to visual disturbance, headache and hypopituitarism.

Other symptoms

Adenomas and adenomatous hyperplasia of the thyroid gland and adrenal gland sometimes occurs in patients with type I MEN syndrome. As a result, the secretion of hormones is rarely disturbed, and the importance of such disorders is uncertain. Carcinoid tumors, especially those that developed in the embryological anterior gut, occur in isolated cases. There may also be multiple subcutaneous and visceral lipomas.

Diagnostics of the type I MEN syndrome

To diagnose the disease, blood tests for hormones and various types of examinations are used.

Patients with tumors of the parathyroid glands, pancreas and pituitary gland, especially with a family history of endocrinopathy, should undergo clinical tests for other tumors of ME type I. Such examination includes questions concerning symptoms of peptic ulcer, diarrhea, kidney stone disease, hypoglycemia and hypopituitarism; check for defects, galactorrhea in women and signs of acromegaly and subcutaneous adipose; measurement of serum Ca, uncomplicated parathyroid hormone (PTH), gastrin and prolactin levels.

Additional laboratory or radiological studies should be performed if the results of screening tests suggest the presence of endocrine abnormalities associated with type I MEN syndrome. Pancreatic tumor cell insulin secretion is diagnosed by detecting fasting hypoglycaemia with an elevated insulin level in the plasma.

Gastrin secretion outside the cell tumor of the pancreas and duodenum is diagnosed with an elevated basal level of plasma gastrin, an increase in the level of gastrin for Ca infusion, and a paradoxical increase in the level of gastrin after the infusion of secretin. An increased basal level of the pancreatic polypeptide or gastrin or an exaggerated response of these hormones to standard foods may be an early indication of pancreatic injury. CT or MRI assists in the localization of the tumor. Since these tumors are often small and difficult to locate, other imaging studies should be used (for example, somatostatin scintigraphy, endoscopic ultrasound, ultrasound intraoperative research).

Acromegaly is diagnosed by an elevated level of growth hormone, which is not suppressed by the introduction of glucose and an elevated level of insulin-like growth factor 1 of the plasma.

In patients with 2 or more endocrine disorders associated with type I MEN syndrome that are not related (case index), direct detection of the DNA sequence of the gene for type I MEN syndrome indicates a characteristic mutation in 80-90% of cases. If a case index is found, relatives in the first generation are recommended to undergo a genetic or clinical examination. An annual clinical examination is necessary for first-generation relatives whose clinical testing results are positive. Individuals with minimal symptoms of the disease who have not undergone genetic testing, or who have not been diagnosed with a characteristic mutation, undergo an annual examination.

[18], [19], [20], [21], [22]

Treatment of the type I MEN syndrome

Treatment of parathyroid glands and lesions of the pituitary gland is mainly surgical. Tumors in the pancreatic islets are more difficult to treat, since lesions are often small and difficult to localize, the lesion often has many foci. If one tumor can not be found, general pancreatic resection may be required to properly control the insulin shock. Diazoxide may be a useful adjunct in the treatment of hypoglycemia; streptozocin and other cytotoxic drugs can improve the symptoms of the tumor, reducing the load.

Treatment of gastrin secreting outside the tumor cells is a complex process. It is necessary to make attempts to localize and remove the tumor. If localization is not possible, the proton pump inhibitor often alleviates peptic ulcer disease. With these drugs, the need for gastrectomy is extremely rare.

Octreotide, an analogue of somatostatin, can block the secretion of the hormone from the non-gastrin secretagogues of pancreatic tumors and is well tolerated, especially if used as a long-acting drug every 4 weeks. Palliative treatment of metastases of pancreatic tumors involves embolization of the hepatic artery and interferon a (in combination with octreotide).