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.
(See also Overview of Multiple Endocrine Neoplasias.)
MEN 1 is caused by an inactivating mutation of the MEN1 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-suppressing effects. Some mutations are thought to be associated with a higher rate of pancreatic islet cell tumor development, a higher rate of distant metastases, and more aggressive disease (1, 2).
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 Conditions Associated With Multiple Endocrine Neoplasia 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 (1). In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia, which is often asymmetric, is typical.
Pancreas
Pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors) occur in 30 to 90% of patients (1). 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, 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 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 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), and hypersecretion of growth hormone–releasing hormone (causing acromegaly) sometimes occur in non–beta islet cell tumors.
Pituitary
Pituitary tumors occur in 15 to 42% of patients with MEN 1 (1). From 25 to 90% are prolactinomas (1). About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause 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 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).
Other manifestations
Carcinoid tumors, particularly those derived from the embryologic foregut (thymus, lungs, stomach), occur in 5 to 15% of patients with MEN 1 (1). Thymic carcinoids are more common in affected males, and a subset of them may behave quite aggressively. Carcinoid syndrome may occur.
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.
Multiple subcutaneous and visceral lipomas, angiofibromas, meningiomas, ependymomas, and collagenomas may also occur (3).
In a study in Holland, the United States, Tasmania, and France, the relative risk of breast cancer in patients with MEN 1 was 2.3 to 2.8-fold higher and the age at diagnosis was somewhat younger than in participants without MEN 1 (4).
Symptoms references
1. Thakker RV, Newey PJ, Walls GV, et al: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97(9):2990–3011, 2012.
2. de Laat JM, Dekkers OM, Pieterman CR, et al: Long-term natural course of pituitary tumors in patients with MEN1: Results from the Dutch MEN1 Study Group (DMSG). J Clin Endocrinol Metab 100(9):3288–3296, 2015.
3. Waguespack SG: Beyond the "3 Ps": A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne) 2022; 13: 1029041 doi: 10./3389/fendo.2022.1029041
4. Dreijerink KM, Goudet P, Burgess JR, Valk GD, International Breast Cancer in MEN1 Study Group: Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med 371(6):583–584, 2014.
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).
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:
Symptoms of peptic ulcer disease, diarrhea, nephrolithiasis, hypoglycemia, and hypopituitarism
Visual field defects, galactorrhea, and features of acromegaly and subcutaneous lipomas
Abnormal levels of serum calcium, 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 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 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).
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).
Preimplantation genetic diagnosis on embryos conceived via assisted reproductive techniques is also available.
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.
Screening for breast cancer is recommended beginning at age 40 in women with MEN 1 (6).
Diagnosis references
1. Thakker RV, Newey PJ, Walls GV, et al: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97(9):2990–3011, 2012.
2. So A, Pointon O, Hodgson R, Burgess J: An assessment of 18 F-FDG PET/CT for thoracic screening and risk stratification of pulmonary nodules in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 88(5):683–691, 2018.
3. Sadowski SM, Millo C, Cottle-Delisle C, et al: Results of (68)Gallium-DOTATATE PET/CT scanning in patients with multiple endocrine neoplasia type 1. J Am Coll Surg 22:509–517, 2015.
4. van Leeuwaarde RS, van Nesselrooij BP, Hermus AR, et al. Impact of delay in diagnosis in outcomes in MEN1: Results from the Dutch MEN1 Study Group. J Clin Endocrinol Metab 101(3):1159–1165, 2016.
5. de Laat JM, van Leeuwaarde RS, Valk GD: The importance of an early and accurate MEN1 diagnosis. Front Endocrinol 2018; doi.org/10.3389/fendo.2018.00533
6. van Leeuwaarde RS, Dreijerink KM, Ausems MG, et al: MEN1-dependent breast cancer: indication for early screening? Results from the Dutch MEN1 Study Group. J Clin Endocrinol Metab 102:2083–2090, 2017.
Treatment of MEN 1
Surgical excision when possible
Pharmacologic management of endocrinopathies
Treatment of hyperparathyroidism
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).
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,
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
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.
