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Multiple Endocrine Neoplasia, Type 1 (MEN 1)

(Multiple Endocrine Adenomatosis, Type I; Wermer Syndrome)

by Patricia A. Daly, MD, Lewis Landsberg, MD

Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, and pituitary gland. Duodenal gastrinomas, carcinoid tumors of the foregut, benign adrenal adenomas, and lipomas also occur. 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 caused by an inactivating mutation of the gene that encodes the nuclear protein menin; > 500 mutations of this gene have been identified. The exact function of menin is unknown, but it appears to have tumor supressing effects.

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 to 40s. Men and women are equally affected.

Symptoms and Signs

The clinical features depend on the glandular elements affected (see Table: Conditions Associated With MEN Syndromes).

Parathyroid

Hyperparathyroidism is present in 95% of patients. Asymptomatic hypercalcemia is the most common manifestation, but about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia, which is often asymmetric, is typical.

Pancreas

Pancreatic islet cell tumors occur in 30 to 90% of patients. Tumors are usually multicentric and sometimes synthesize several hormones. 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.

The most common functional enteropancreatic tumor in MEN 1 is the gastrinoma, which can arise from the pancreas or the duodenum. Up to 80% of patients with MEN 1 have either multiple peptic ulcers due to gastrin-stimlulated increased gastric acid secretion or asymptomatic elevated gastrin levels.

Insulinomas are the second most common functional pancreatic tumor and can cause fasting hypoglycemia. The tumors are often small and multiple. Age of onset is often < 40.

Nonfunctioning enteropancreatic tumors occur in about one third of MEN 1 patients. Most islet cell tumors, including nonfunctioning tumors, secrete pancreatic polypeptide. Although the clinical significance is unknown, pancreatic polypeptide may be helpful for screening. The size of the nonfunctioning tumor correlates with risk of metastasis and death.

Less commonly, other functional enteropancreatic tumors can occur in 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, or pancreatic cholera—see 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 or corticotropin-releasing hormone (causing Cushing syndrome), and hypersecretion of growth hormone–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors.

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 Galactorrhea) in affected women, and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing disease. Most of the remainder are nonfunctional. Local tumor expansion may cause visual disturbance, headache, and hypopituitarism. Pituitary tumors in patients with MEN 1 appear to be larger and behave more aggressively and may occur at an earlier age than sporadic pituitary tumors.

Other manifestations

Carcinoid tumors, particularly those derived from the embryologic foregut (thymus, lungs, stomach), occur in 5 to 15% of MEN 1 patients. Thymic carcinoids are more common in affected males. Adrenal adenomas occur in 10 to 20% of patients and may be bilateral. Adenomatous hyperplasia of the thyroid occurs occasionally in MEN 1 patients. Hormone secretion is rarely altered as a result, and the significance of this abnormality is uncertain. Multiple subcutaneous and visceral lipomas, angiofibromas, meningiomas, ependymomas, and collagenomas may also occur.

Diagnosis

  • Genetic testing

  • Clinical evaluation for other tumors of the triad

  • Serum Ca, parathyroid hormone (PTH), gastrin, and prolactin levels

  • Tumor localization with MRI, CT, or ultrasonography

MEN 1 syndrome should be considered in patients with tumors of the parathyroids, pancreas, or pituitary, particularly those with a family history of endocrinopathy. Such individuals should undergo genetic testing with direct DNA sequencing of the MEN 1 gene and clinical screening for other tumors of MEN 1, including the following:

  • Asking about symptoms of peptic ulcer disease, diarrhea, nephrolithiasis, hypoglycemia, and hypopituitarism

  • Examining for visual field defects, galactorrhea in women, and features of acromegaly and subcutaneous lipomas

  • Measuring levels of serum Ca, intact PTH, gastrin, and prolactin

Additional laboratory or radiologic tests should be done if these screening tests suggest an endocrine abnormality related to MEN 1.

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 insulin -secretingβ-cell tumor of the pancreas is diagnosed by detecting fasting hypoglycemia with an elevated plasma insulin level. 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. Ultrasonography or CT can help localize tumors. Because these tumors are often small and difficult to localize, other imaging tests (eg, helical [spiral] CT, angiography, 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 (somatomedin C).

Screening

When an index case is identified, 1st-degree relatives should be given the option of genetic screening. However, 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. Some clinicians monitor gene carriers by doing pancreatic and pituitary imaging every 3 to 5 yr, although such screening has not been shown to improve outcomes.

Treatment

  • Surgical excision when possible

  • Drug management of hormone excess

Treatment of hyperparathyroidism is primarily surgical, with subtotal parathyroidectomy; however, the hyperparathyroidism frequently recurs. Octreotide and cinacalcet may help control recurrent or persistent postoperative hypercalcemia.

Prolactinoma is usually managed with dopamine agonists; other pituitary tumors are treated surgically.

Islet cell tumors are more difficult to manage because the lesions are often small and difficult to find, multiple lesions are common, and surgery often is not curative.

The treatment of gastrin-secreting non–β-cell tumors is complex. When possible, the tumor is located and removed, although it is unclear whether surgery decreases the likelihood of late metastatic disease. If localization is impossible, a proton pump inhibitor frequently provides long-term control of symptomatic peptic ulcer disease.

If a single tumor cannot be found in patients with insulinomas, distal subtotal pancreatectomy with enucleation of any palpable tumors in the head of the pancreas is recommended. Diazoxide or a somatostatin analogue (octreotide, lanreotide) may help treat hypoglycemia. Streptozocin and other cytotoxic drugs may relieve symptoms by reducing tumor burden.

Somatostatin analogs also can block hormone secretion from other nongastrin-secreting pancreatic tumors and are well tolerated. Palliative treatments for metastatic pancreatic tumors include hepatic debulking surgery and hepatic artery chemoembolization. Streptozocin, doxorubicin, and other cytotoxic drugs may relieve symptoms by reducing tumor burden.

Key Points

  • Consider MEN 1 in patients with tumors of the parathyroids, pancreas, or pituitary.

  • The main clinical manifestations are those of hormone excess, particularly hypercalcemia due to hyperparathyroidism.

  • Patients should have genetic testing of the MEN 1 gene and clinical evaluation for other tumors of the syndrome.

  • Tumors are excised when possible, but lesions are often multiple and/or difficult to find.

  • Sometimes hormone excess can be managed by drugs.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • MIACALCIN
  • H.P. ACTHAR GEL
  • PROGLYCEM
  • ZANOSAR
  • SENSIPAR
  • SOMATULINE DEPOT
  • SANDOSTATIN

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