Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder, also known as Wermer syndrome, with a prevalence in the general population estimated to be around (2–20) cases per 100,000. Approximately 10% of MEN1 cases involve de novo mutations, referred to as sporadic cases. MEN1 can present with various clinical manifestations, whose prevalence varies among families and even among different individuals within the same family.
Pathogenesis
The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein known as "menin." MEN1 is a tumor suppressor gene, and its defects exhibit diverse characteristics. In addition to germline mutations, a second allele of the MEN1 gene frequently exhibits somatic loss within tumor tissues in MEN1 patients. The loss of function of both alleles of the MEN1 gene leads to uncontrolled cell proliferation and tumor formation, consistent with the "two-hit hypothesis" of tumor suppressor gene inactivation. MEN1 gene mutations are also identified in approximately 20% of sporadic parathyroid adenomas and in certain cases of sporadic pancreatic neuroendocrine tumors and pulmonary carcinoid tumors. However, such mutations occur only in tumor tissues and are not found in normal cells, which explains the lack of familial clustering of these conditions.
Clinical Manifestations
Primary Hyperparathyroidism
Primary hyperparathyroidism is the most common and earliest manifestation of MEN1. Compared to sporadic parathyroid adenoma cases, MEN1-associated hyperparathyroidism has an earlier onset (often in individuals over 20 years old) and occurs equally in males and females. Pathologically, it manifests as multiglandular hyperplasia with varying gland sizes. The diagnostic criteria are similar to those for sporadic cases. Hypercalcemia caused by primary hyperparathyroidism can exacerbate the symptoms of concurrent gastrinoma and lead to higher serum gastrin levels.
Pancreatic and Duodenal Neuroendocrine Tumors
These tumors can be functional or non-functional and may include the following types:
Gastrinomas
Gastrinomas, often associated with Zollinger-Ellison syndrome, account for approximately 50%–60% of MEN1-related gastrointestinal and pancreatic tumors. These gastrinomas are typically small, multicentric, and sometimes ectopic, often located in the submucosa of the duodenum. The diagnosis involves the coexistence of hypergastrinemia and hypersecretion of gastric acid, which distinguishes them from hypochlorhydria-related hypergastrinemia. Secretin stimulation testing can be used when necessary, where gastrin levels increase in patients with gastrinoma. Due to the small size of MEN1-related gastrinomas, localization is challenging. While CT and MRI can detect liver metastases, they are often insufficient for diagnosing gastrinomas. Further localization techniques include endoscopic ultrasonography, selective intra-arterial injection of secretin followed by hepatic vein sampling for gastrin, and somatostatin receptor scintigraphy using radiolabeled octreotide.
Insulinomas
Insulinomas are present in approximately 20% of MEN1-related pancreatic neuroendocrine tumors. Other types include glucagonomas, VIPomas (vasoactive intestinal peptide-secreting tumors), and non-functional tumors. MEN1-related insulinomas are often multicentric and similarly challenging to localize. Endoscopic ultrasonography and selective calcium infusion with hepatic vein insulin sampling can aid in localization.
Pituitary Tumors
Pituitary tumors occur in approximately 25% of MEN1 patients, most commonly prolactinomas. These may or may not be associated with excessive growth hormone secretion. Other types include growth hormone-secreting tumors, non-functional tumors, and ACTH-secreting tumors associated with Cushing's syndrome. Malignant progression of pituitary tumors in MEN1 is rare, and their diagnosis and management are similar to those of sporadic pituitary tumors.
Adrenal Adenomas and Other Lesions
Cortisol-secreting adrenal adenomas can occur in MEN1, and Cushing's syndrome in MEN1 patients may arise from three potential causes:
- Adrenal adenomas.
- ACTH-secreting pituitary tumors.
- Ectopic ACTH syndrome associated with carcinoid tumors, with pituitary tumors being more common.
Thyroid adenomas and other thyroid disorders are also relatively common in MEN1. In MEN1 family members, subcutaneous lipomas, skin collagenomas, and multiple facial angiofibromas occur in approximately 30%–90% of cases. These skin manifestations are helpful indicators for identifying individuals who carry the MEN1 genetic mutation.
Treatment
In MEN1-associated primary hyperparathyroidism, treatment typically involves the removal of three parathyroid glands, followed by the partial removal of the fourth gland, leaving half of it intact. An alternative approach includes total parathyroidectomy, where all four glands are removed, with half of the gland that appears closest to normal transplanted into the muscle of the patient's non-dominant forearm. The rates of persistent or recurrent hyperparathyroidism following surgery are significantly higher in MEN1 patients compared to those with sporadic cases. Persistent hyperparathyroidism, defined as failure of both serum calcium and parathyroid hormone (PTH) levels to normalize postoperatively, occurs in 36% of cases. Recurrence, defined as normalization of serum calcium for at least three months followed by disease relapse, occurs in 16% of cases. In contrast, these rates in sporadic cases are 4% and 16%, respectively. One reason for the high rate of persistent hyperparathyroidism in MEN1 is the presence of more than four parathyroid glands or ectopic parathyroid tissue. The high recurrence rate is attributed to the continuous growth stimulation of the residual parathyroid tissue.
Screening
Comprehensive history-taking and physical examinations are necessary for family members of MEN1 patients. Serum calcium measurement is an essential laboratory test. Total serum calcium levels, along with plasma protein levels for correction, are recommended starting from the age of 15, with regular follow-ups. Additional diagnostic tests, such as prolactin, gastrin, and fasting blood glucose measurements, can also aid in detection. If feasible, MEN1 gene mutation testing may be conducted.