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Multiple Endocrine Neoplasia, Type 1 (MEN 1)

(Multiple Endocrine Adenomatosis, Type I; Wermer Syndrome)

By

Lawrence S. Kirschner

, MD, PhD, The Ohio State University;


Pamela Brock

, MS, CGC, The Ohio State University

Reviewed/Revised Jun 2023
View PATIENT EDUCATION

Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or 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. Hyperparathyroidism and asymptomatic hypercalcemia commonly occur. Family members are offered genetic screening. Diagnosis is by hormonal and imaging tests. Tumors are removed surgically if they cause symptoms or for suspected malignancy based on size criteria.

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

The clinical features depend on the glandular elements affected (see table ).

Parathyroid

Pancreas

Pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors) occur in 30 to 90% of patients (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). They are one type of gastroenteropancreatic neuroendocrine tumor (GEP-NET), which can also develop in parts of the gastrointestinal tract, usually in the stomach and duodenum. Tumors are usually multicentric and sometimes synthesize several hormones. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the duodenum rather than the pancreas. About 30% of tumors are metastatic at diagnosis. Islet cell tumors due to MEN 1 syndrome often have a less aggressive course than do sporadically occurring 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 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-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 years.

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 islet 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 syndrome, 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 islet cell tumors.

Pituitary

Pituitary tumors Pituitary Lesions Patients with hypothalamic-pituitary lesions generally present with some combination of Symptoms and signs of a mass lesion: headaches, altered appetite, thirst, visual field defects—particularly... read more occur in 15 to 42% of patients with MEN 1 (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). From 25 to 90% are prolactinomas (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea Prolactinoma Prolactinomas are noncancerous tumors made up from lactotrophs in the pituitary gland. The most common symptom of a prolactinoma is galactorrhea. Diagnosis is by measurement of prolactin levels... read more in affected women, and excess growth hormone causes 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 clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing disease 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 . Most of the remainder are nonfunctional.

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 long-term cohort study found MEN 1–associated pituitary tumors were more indolent, similar to sporadic pituitary tumors (2 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Other manifestations

Adrenal adenomas occur in up to 33% of patients and may be bilateral. There is a risk that a benign-appearing adenoma may undergo degeneration into an aggressive adrenocortical carcinoma.

Adenomatous hyperplasia of the thyroid occurs occasionally in patients with MEN 1. Hormone secretion is rarely altered as a result, and the significance of this abnormality is uncertain.

Symptoms references

Diagnosis of MEN 1

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

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

  • Genetic testing

MEN 1 syndrome should be considered in patients with tumors of the parathyroids, pancreas, or pituitary, particularly those with a family history of endocrinopathy. MEN 1 should also be considered in individuals diagnosed with hyperparathyroidism prior to age 30 years (1 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or 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 a panel of genes that may cause MEN 1 or related syndromes, including MEN 4 and other forms of familial hyperparathyroidism (eg, CDC73-related disorders, which may include the rare syndrome of hyperparathyroidism and jaw tumors).

All of these individuals should also undergo clinical screening for other tumors of MEN 1, including evaluation for 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 gastroenteropancreatic neuroendocrine (GEP-NET) 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.

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).

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) or gallium Ga 68 dotatate 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 an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). For pancreatic and duodenal neuroendocrine tumors, gallium Ga 68 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 an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Genetic screening

When an index case is identified, 1st-degree relatives should be given the option of genetic screening. Family members can also be screened biochemically by measurement of calcium and PTH, which is frequently useful because of the high penetrance of hyperparathyroidism in MEN 1.

Although early presymptomatic screening of family members of patients with MEN 1 has not been shown to reduce morbidity or mortality, a large cohort study reported a significant lag time between diagnosis of the index case and diagnosis in the rest of the family. This lag was found to be clinically relevant, because patients diagnosed after a preventable delay were found to have a higher incidence of pancreatic tumors, including metastatic lesions (4, 5 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or 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

  • Pharmacologic management of endocrinopathies

Treatment of hyperparathyroidism is primarily surgical, with subtotal parathyroidectomy; however, 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 an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

The treatment of gastrin-secreting gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is complex. When possible, the tumor is located and removed. Larger tumors have a higher incidence of metastasis, so gastrinomas should be removed when they are smaller than a threshold, typically between 2 and 3 cm. If localization and/or removal is impossible, a proton pump inhibitor frequently provides long-term control of symptomatic peptic ulcer disease.

In patients with insulinomas, if a single tumor cannot be found, 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 or other cytotoxic drugs may relieve symptoms by reducing tumor burden.

Somatostatin analogs also can block hormone secretion from other nongastrin-secreting pancreatic tumors, including carcinoid 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 that 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 an autosomal dominant syndrome characterized by hyperplasia or 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, particularly in patients with a family history of one or more of these tumors.

  • 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 medications.

Drugs Mentioned In This Article

Drug Name Select Trade
NETSPOT
Bynfezia, Mycapssa, Sandostatin, Sandostatin LAR
Sensipar
Hyperstat, Proglycem
Somatuline Depot
Zanosar
Adriamycin, Adriamycin PFS, Adriamycin RDF, Rubex
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NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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