Wermer Syndrome (MEN Type 1)

Updated: Feb 18, 2015
  • Author: Laura Williams, MD; Chief Editor: George T Griffing, MD  more...
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Overview

Background

Multiple endocrine neoplasia (MEN) syndromes consist of 2 categories, MEN type 1 (MEN1) and MEN type 2 (MEN2). MEN2 has been subcategorized into MEN2-A, MEN2-B, and medullary thyroid cancer (MTC)–only.

The combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors (see the images below) is characteristic of MEN1. Although usually inherited as an autosomal dominant disorder, MEN1 can also occur sporadically (without a family history) as a result of new mutations. It is also important to keep in mind that family members of an MEN1-affected individual may have been undiagnosed at the time of death. Patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years. [1]

Sagittal (left image) and coronal (right image), T Sagittal (left image) and coronal (right image), T1-weighted magnetic resonance images of the brain in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These images show a pituitary macroadenoma (arrows).
Indium-111 (111In) octreotide scan in a patient wi Indium-111 (111In) octreotide scan in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1). These nuclear images demonstrate abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).

In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity.

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Pathophysiology

Parathyroid tumors

Primary hyperparathyroidism, caused by hyperplasia of parathyroid glands, is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1) and occurs in approximately 90% of all patients. [2]

Clinical manifestations can include hypercalcemia, nephrolithiasis, and bone abnormalities (osteitis fibrosa cystica). Common symptoms associated with hypercalcemia include polydipsia, polyuria, constipation, and generalized malaise.

Primary hyperparathyroidism in MEN1 differs from non-MEN1 primary hyperthyroidism by earlier age at onset, involvement of multiple parathyroid glands, and high recurrence rate of hypercalcemia after parathyroidectomy (50% by 8-12 years after surgery). [3]

Pancreatic islet cell tumors (neuroendocrine tumors)

Pancreatic islet cell tumors represent the second most common manifestation of MEN1 and occur in 30-80% of patients. Islet cell tumors encompass gastrinomas, insulinomas, glucagonomas vasoactive intestinal polypeptidomas (VIPomas), and pancreatic polypeptidomas (PPomas). [1] Tumors are often multicentric and may undergo malignant transformation. These tumors can produce peptides and biogenic amines.

However, nonfunctioning pancreatic endocrine tumors are the most common enteropancreatic neuroendocrine tumor. The relatively recent availability and further increased use of sensitive radiological screening methods has allowed the diagnosis of these nonfunctional pancreatic tumors that have no clinical features and only minor elevations in pancreatic hormones. These tumors are important to diagnose, as malignant pancreatic neuroendocrine tumors are the most frequent cause of death in people with MEN1. [4, 5]

Gastrinomas, seen in the image below, are the most common functional pancreatic neuroendocrine tumors. Compared with non-MEN1 gastrinomas in Zollinger-Ellison syndrome (ZES), tumors in MEN1 are more often small, multicentric, and located in the duodenum, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and height of gastrin levels. The development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells. In MEN1 patients, ZES appears to only develop in the presence of primary hyperparathyroidism. [1] Longstanding MEN1 and ZES may lead to the development of gastric carcinoid tumors that may be aggressive. [6]

Computed tomography (CT) scan of the pancreas in a Computed tomography (CT) scan of the pancreas in a patient with multiple endocrine neoplasia syndrome type 1 (MEN1) and a gastrinoma. This image shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Note the calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.

Insulinomas (see the images below) can be multicentric and can metastasize either to regional lymph nodes or to the liver. Unlike non-MEN1 insulinomas, in MEN1 subjects, insulinomas usually occur in patients younger than 40 years and many are diagnosed in patients younger than 20 years. [1] Patients often present with hypoglycemic symptoms after a fast, with symptoms improving after glucose intake.

Endoscopic ultrasonogram in a patient with an insu Endoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.)
Computed tomography (CT) scan image with oral and Computed tomography (CT) scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (From: Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993: 272.)

Glucagonomas occur rarely (3%) in patients with MEN1 and can present silently or with hyperglycemia. Few patients show the typical skin lesions, known as necrolytic migratory erythema. Other presenting symptoms can be anemia, stomatitis, and weight loss, but these are often absent.

VIPomas occur in less than 1% of MEN1 patients. Presenting symptoms can include watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome). Tumors secreting pancreatic polypeptide (PPomas) may not be associated with clinical manifestations and may be nonsecretory.

Growth hormone–releasing hormone tumors (GHRHomas) have been reported in patients with MEN1 and most commonly arise in the lungs, followed by the pancreas and small intestine. [1]

Pituitary tumors

MEN1-associated pituitary tumors most commonly secrete prolactin (60%), followed by tumors that secrete growth hormone (25%). Less than 5% secrete corticotropin and others are nonfunctional. [1] Compared with non-MEN1 pituitary tumors, MEN1 pituitary tumors tend to be larger (macroadenomas) and more aggressive, with a higher rate of infiltration of tumor cells into normal pituitary tissue. MEN1-associated pituitary tumors are less responsive to therapy. However, there is no distinct histological difference between MEN1 and non-MEN1 pituitary tumors. [7]

Other tumors associated with MEN1

Carcinoid tumors can occur in patients with MEN1 and are located in the bronchi, gastrointestinal tract, pancreas, and thymus. In men, especially smokers, the thymus is most often affected. Thymic carcinoids [8] associated with MEN1 are often nonfunctional and aggressive. In women, bronchial carcinoids are most common. Carcinoids can actively secrete hormones such as serotonin, somatostatin, corticotropin, and growth hormone.

Cutaneous expression of MEN1 is common. Subcutaneous lipomas are found in one third of MEN1 patients. These lesions have loss of heterozygosity for band 11q12-12 and are associated with defective globular (G) protein function. Lipomas in MEN1 can also be retroperitoneal, visceral, or pleural. The presence of facial angiofibromas and collagenomas may allow presymptomatic diagnosis of MEN1 in relatives of diagnosed patients. [1]

Adrenal tumors occur and usually are nonfunctional. They are most often benign and consist of nonfunctional cortical adenomas or diffuse or nodular hyperplasia. They occur in 20-40% of patients. Adrenal cortical carcinomas are rare in MEN1 patients, but larger adrenal tumors (>1 cm) increase the likelihood of malignancy, so annual adrenal imaging in patients with known adrenal tumors is recommended. [1]

Thyroid adenomas occur in 5-30% of patients and have no specific MEN1-reported clinical significance. Meningiomas and other central nervous system tumors have been reported.

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Epidemiology

Random postmortem studies report an incidence of 0.25%. [1] However, clinical manifestations such as primary hyperparathyroidism have a reported incidence of multiple endocrine neoplasia type 1 (MEN1) in 1-18% of people with this disorder. Patients harboring a gastrinoma(s) have MEN1 16-38% of the time and 3% of patients with pituitary tumors have MEN1. [9, 10] The MEN1 gene has a high penetrance. By age 20 years, the gene is 50% penetrant and by age 40 years, 95% penetrant. Patients younger than 5 years have not been identified as manifesting the typical features associated with the MEN1 gene carrier status, and, thus, the gene is likely nonpenetrant before this age. [1, 2]

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Mortality/Morbidity

Patients with multiple endocrine neoplasia type 1 (MEN1) have a decreased life expectancy, with a 50% probability of death by age 50 years. Half the deaths result directly from a malignant process or the sequela of an endocrine disorder. Malignant pancreatic neuroendocrine tumors and thymic carcinoid tumors have been associated with a marked increase in the risk of death in MEN1 patients. [11]

Race

No racial differences have been found.

Sex

The female-to-male incidence is approximately equal.

Age

The peak incidence of symptoms in multiple endocrine neoplasia type 1 (MEN1) is during the third decade of life in women and during the fourth decade of life in men. The reported age range is 5-81 years.

Hyperparathyroidism, the most common feature in MEN1, occurs at an earlier age (20-25 years) compared with non-MEN1 patients (55 years).

MEN1-associated gastrinomas usually develop after age 30 years, and insulinomas occur in those younger than 40 years but many have appeared in patients younger than 20 years.

Pituitary tumors and neuroendocrine tumors can occur as early as age 5 years.

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