MEN-1 syndrome is caused by germ line mutations in the MEN1 tumor suppressor gene, which encodes a protein called Menin. Menin is a component of several different transcription factor complexes, and loss of Menin function leads to deregulation of the corresponding binding partners, promoting endocrine neoplasia. Organs most commonly involved are the parathyroid, the pancreas, and the pituitary—the “3 Ps.”
Parathyroid. Primary hyperparathyroidism is the most common manifestation of MEN-1 (80%–95% of patients) and is the initial manifestation of the disorder in most patients, appearing in almost all by 40 to 50 years of age. Parathyroid abnormalities include hyperplasia and adenomas.
Pancreas. Endocrine tumors of the pancreas are the leading cause of death in MEN-1. These tumors usually are aggressive and present with metastatic disease. Pancreatic endocrine tumors often are functional (i.e., secrete hormones). Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, associated with insulinomas, are common endocrine manifestations.
Pituitary. The most frequent pituitary tumor in patients with MEN-1 syndrome is a prolactin-secreting macroadenoma. In some cases, acromegaly develops in association with somatotropin-secreting tumors.
MEN-2 syndrome actually comprises two distinct groups of disorders that are unified by the occurrence of activating (i.e., gain-of-function) mutations of the RET proto-oncogene at chromosomal locus 10q11.2. A strong genotype-phenotype correlation has been recognized for the MEN-2 syndromes, and differences in mutation patterns account for the variable features in the two subtypes. MEN-2 is inherited in an autosomal dominant pattern.
Organs commonly involved in MEN-2A include the following:
Thyroid: Medullary carcinoma of the thyroid develops in virtually all untreated cases, and the tumors usually occur in the first 2 decades of life. The tumors commonly are multifocal, and foci of C cell hyperplasia can be found in the adjacent thyroid. Familial medullary thyroid cancer is seen in a variant of MEN-2A, without the other characteristic manifestations listed here. In comparison with MEN-2, familial medullary carcinoma typically occurs at an older age and follows a more indolent course.
Adrenal medulla: Adrenal pheochromocytomas develop in 50% of the patients; fortunately, no more than 10% of these tumors are malignant.
Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidism.
A single amino acid change in RET, distinct from the mutations that are seen in MEN-2A, seems to be responsible for virtually all cases of MEN-2B. Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas. MEN-2B has the following distinctive features:
Primary hyperparathyroidism does not develop in patients with MEN-2B.
Extraendocrine manifestations are characteristic in patients with MEN-2B. These include ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and a marfanoid habitus, in which overly long bones of the axial skeleton give an appearance resembling that in Marfan syndrome (Chapter 7).
Before the advent of genetic testing, relatives of patients with the MEN-2 syndrome were screened with annual biochemical tests, which often lacked sensitivity. Now, routine genetic testing identifies RET mutation carriers earlier and more reliably in MEN-2 kindreds. All individuals carrying germ line RET mutations are advised to have prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomas.