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Multiple Endocrine Neoplasia, Type 1 (MEN 1)

(Multiple Endocrine Adenomatosis, Type I; Wermer Syndrome)

By

Patricia A. Daly

, MD, University of Virginia;


Lewis Landsberg

, MD, Northwestern University Feinberg School of Medicine

Last full review/revision Apr 2021| Content last modified Apr 2021
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Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors), and/or pituitary gland tumors. 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.

About 40% of MEN 1 cases involve tumors of all 3 affected glands:

  • Parathyroids

  • Pancreas

  • 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 years, but peak incidence occurs in the 20s to 40s. Men and women are equally affected.

General references

  • 1. Perrier ND: From initial description by Wermer to present-day MEN1: What have we learned? World J Surg 42(4):1031–1035, 2018.

  • 2. Marx SJ: Recent topics around multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 103(4):1296–1301, 2018.

Symptoms and Signs of MEN 1

Parathyroid

Pancreas

Pancreatic islet cell tumors (also known as pancreatic neuroendocrine 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 Gastrinoma A gastrinoma is a gastrin-producing tumor usually located in the pancreas or the duodenal wall. Gastric acid hypersecretion and aggressive, refractory peptic ulceration result (Zollinger-Ellison... read more , 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-stimulated increased gastric acid secretion or asymptomatic elevated gastrin levels.

Insulinomas Insulinoma An insulinoma is a rare pancreatic beta-cell tumor that hypersecretes insulin. The main symptom is fasting hypoglycemia. Diagnosis is by a 48- or 72-hour fast with measurement of glucose and... read more 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–beta-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia, and achlorhydria syndrome (WDHA Vipoma A vipoma is a non-beta pancreatic islet cell tumor secreting vasoactive intestinal peptide (VIP), resulting in a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Diagnosis... read more , or pancreatic cholera), 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 Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more Cushing Syndrome ), and hypersecretion of growth hormone–releasing hormone (causing acromegaly Gigantism and Acromegaly Gigantism and acromegaly are syndromes of excessive secretion of growth hormone (hypersomatotropism) that are nearly always due to a pituitary adenoma. Before closure of the epiphyses, the result... read more Gigantism and Acromegaly ) sometimes occur in non–beta-cell tumors.

Pituitary

Pituitary tumors in patients with MEN 1 may be larger and behave more aggressively and may occur at an earlier age than sporadic pituitary tumors; however, a recent long-term cohort study found MEN 1–associated pituitary tumors were more indolent, similar to sporadic pituitary tumors (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Other manifestations

Carcinoid tumors Overview of Carcinoid Tumors Carcinoid tumors develop from neuroendocrine cells in the gastrointestinal tract (90%), pancreas, pulmonary bronchi, and rarely the genitourinary tract. More than 95% of all gastrointestinal... read more , 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. Carcinoid syndrome may occur.

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.

Symptoms references

Diagnosis of MEN 1

  • Genetic testing

  • Clinical evaluation for other tumors of the triad

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

  • Tumor localization with MRI, CT, ultrasonography, or 18F-FDG PET/CT

MEN 1 syndrome should be considered in patients with tumors of the parathyroids, pancreas, or pituitary, particularly those with a family history of endocrinopathy. Screening should also be considered in individuals diagnosed with hyperparathyroidism prior to age 30 (1 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). At risk 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:

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

A gastrin-secreting non–beta-cell tumor of the pancreas or duodenum is diagnosed by elevated basal plasma gastrin levels, an exaggerated gastrin response to infused calcium, and a paradoxical rise in gastrin level after infusion of secretin. An insulin-secreting beta-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 computed tomography (CT) can help localize tumors. Because these tumors are often small and difficult to localize, other imaging tests (eg, helical [spiral] CT, angiography, MRI, endoscopic ultrasonography, intraoperative ultrasonography) may be necessary. Thoracic imaging with fluorine-18 [18F]–labeled deoxyglucose (18F-FDG) positron emission tomography (PET)/CT may be useful in distinguishing bronchopulmonary neuroendocrine tumors from benign pulmonary nodules and in identifying thymic carcinoid (2 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). For pancreatic and duodenal neuroendocrine tumors, 68gallium-dotatate positron emission tomography/CT was threefold more sensitive than octreotide scanning or CT scanning in a study of multiple imaging modalities in 26 cases of MEN 1; when available this test should replace octreotide scanning for periodic imaging (3 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Acromegaly Gigantism and Acromegaly Gigantism and acromegaly are syndromes of excessive secretion of growth hormone (hypersomatotropism) that are nearly always due to a pituitary adenoma. Before closure of the epiphyses, the result... read more Gigantism and 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. Although early presymptomatic screening of family members of patients with MEN 1 has not been shown to reduce morbidity or mortality, a recent large cohort study reported a clinically relevant lag time between diagnosis of the index case and diagnosis in the rest of the family (4 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Some clinicians monitor gene carriers by doing pancreatic and pituitary imaging every 3 to 5 years, although such screening has not been shown to improve outcomes.

Diagnosis references

Treatment of MEN 1

  • 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. Small (< 2 cm) nonfunctioning pancreatic islet cell tumors may be managed by active surveillance; risk of hepatic metastases is significantly higher for tumors > 3 cm (1 Treatment references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

The treatment of gastrin-secreting non–beta-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.

Because MEN 1 tumors do not occur simultaneously, patients tend to have a high fear of disease occurrence for additional tumors in themselves or for disease beginning in their relatives. Studies indicate this leads to lower quality of life (as measured by emotional and physical well-being), suggesting that medical care should also address and treat the psychological burden of this condition (2 Treatment references Multiple endocrine neoplasia, type 1 (MEN 1) is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Treatment references

  • 1. Nell S, Verkooijen HM, Pieterman CRC, et al: Management of MEN1 related nonfunctioning pancreatic NETs: A shifting paradigm. Results from the Dutch MEN1 Study Group. Ann Surg 267(6):1155-1160, 2018.

  • 2. Leeuwaarde R Pieterman CRC, Bleiker EMA, et al: High fear of disease occurrence is associated with low quality of life in patients with multiple endocrine neoplasia type 1: Results from the Dutch MEN1 Study Group. J Clin Endocrinol Metab 103(6): 2354–2361, 2018.

Key Points

  • Consider multiple endocrine neoplasia, type 1 (MEN 1) in patients with tumors of the parathyroids, pancreas, and/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
ZANOSAR
SANDOSTATIN
SENSIPAR
SOMATULINE DEPOT
PROGLYCEM
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