Pathophysiology
Summary
Multiple endocrine neoplasia (MEN) is an inherited disorder characterized by the development of tumors in multiple endocrine organs, often at a young age (< 35 years). All types of MEN are autosomal dominant, with a family history of endocrine tumors serving as a prominent risk factor.
MEN type 1 (MEN1) occurs due to mutations in the MEN1 gene, located on chromosome 11, and acts as a tumor suppressor gene. The primary organs affected in MEN1 are the parathyroid, pancreas, and pituitary.
In the parathyroid, tumors generally involve more than one gland and lead to primary hyperparathyroidism, which presents identically to sporadic primary hyperparathyroidism. Pancreatic tumors are the #1 cause of death in MEN1 and occur primarily as islet cell types. Gastrinomas are the most common islet cell tumor in MEN1, which often present with peptic ulcer disease and being the most prevalent. Pancreatic tumors are the #1 cause of death in MEN1. In the pituitary, prolactinomas (lactotroph adenomas) are the most frequent tumors, and present identically to sporadic prolactinomas.
MEN type 2A (MEN2A) and MEN type 2B (MEN2B) are forms of multiple endocrine neoplasia caused by gain-of-function mutations in the RET proto-oncogene on chromosome 10. The RET gene encodes a receptor tyrosine kinase that is pivotal in the development of several forms of tumors in MEN2A and MEN2B. Both are primarily associated with medullary thyroid cancer, a malignancy originating from the parafollicular C cells. Unlike sporadic forms, in MEN2A and MEN2B, this cancer is usually preceded by diffuse, bilateral C cell hyperplasia.
MEN2A and MEN2B are both linked with pheochromocytomas, which manifest similarly to their sporadic counterparts. Parathyroid hyperplasia causing primary hyperparathyroidism is specific to MEN2A, while MEN2B is unique in presenting with mucosal neuromas on the tongue, lips, and buccal mucosa. MEN2B may also manifest GI abnormalities due to intestinal ganglioneuromatosis and can present with a ‘Marfanoid’ habitus characterized by lordosis, kyphosis, and elongation of long bones.
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FAQs
Multiple endocrine neoplasia (MEN) is an inherited disorder that leads to the formation of tumors in multiple endocrine organs. The condition has three main types: MEN type 1, type 2A, and type 2B. Each type is autosomal dominant often appear at a young age, usually before 35, and have a tendency to recur even after surgical removal.
MEN type 1 is caused by mutations in the MEN1 gene, a tumor suppressor gene located on chromosome 11. This type commonly presents with tumors in the parathyroid, pancreas, and pituitary glands. These tumors usually appear before the age of 35 and are prone to recurrence after surgical intervention. Parathyroid tumors in MEN1 often involve multiple glands and lead to primary hyperparathyroidism, characterized by elevated levels of parathyroid hormone (PTH) and increased serum calcium.
In MEN type 1, the most common pancreatic tumors are islet cell tumors, with gastrinomas being the predominant subtype. Gastrinomas lead to peptic ulcer disease due to elevated levels of gastrin. Pancreatic tumors are the leading cause of death in MEN1 patients.
MEN types 2A and 2B are caused by gain-of-function mutations in the RET gene, located on chromosome 10. Both types are associated with medullary thyroid cancer, originating from parafollicular C cells. Unlike sporadic forms, medullary thyroid cancer in MEN2A and 2B is often preceded by diffuse, bilateral C cell hyperplasia. Additionally, both types are linked to pheochromocytomas, adrenal medulla tumors. MEN2A also features parathyroid hyperplasia, resulting in primary hyperparathyroidism.
MEN2B is distinct in its presentation, often manifesting as mucosal neuromas on the tongue, lips, and buccal mucosa. It may also lead to gastrointestinal abnormalities like constipation and diarrhea due to diffuse intestinal ganglioneuromatosis. Patients with MEN2B can exhibit a ‘Marfanoid' habitus, characterized by skeletal features such as lordosis, kyphosis, and elongation of long bones.
