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The prevalence of multiple endocrine neoplasia type 4 is unknown, but the syndrome is very rare. To date, 12 index cases have been reported. Prevalence is thought to be less than 1/million.

MEN4 is a recently described MEN-like syndrome similar to MEN1 (see this term). Age of onset of tumors is variable. Patients have been reported to develop parathyroid tumors from fourth decade of life and pituitary tumors from the third decade. Affected patients develop parathyroid tumor with associated primary hyperparathyroidism (81%) and anterior pituitary tumors (42%). In MEN4 patients, various types of pituitary adenoma have been reported: Cushing disease, somatotropic adenoma, prolactinoma, and non-functioning pituitary adenoma (see these terms). Cases of gastric and bronchial carcinoid tumor or Zollinger-Ellison syndrome (see this term) have also been reported. Other associated tumors include reproductive organ tumors, peripheral neuroendocrine tumor of cervix uteri (see this term), and adrenal or renal tumors.

MEN4 is caused by heterozygous inactivating mutations in the CDKN1B gene (12p13.1-p12) encoding p27, a cyclin-dependent kinase inhibitor that acts as a negative regulator of cell cycle progression. In MEN4, unlike in MEN1, CDKN1B acts as a non-conventional oncosuppressor gene and no loss of heterozygosity has been reported. The exact MEN4 tumorigenesis molecular mechanisms remain to be elucidated but it is suspected that the mutated allele could be responsible for the reduction of p27 protein localized in the nucleus and, thus, able to exert its role of negative regulator of cell cycle progression and cell growth.

Most cases are the result of autosomal dominant inheritance. Some cases of sporadic de novo occurrence are however reported. Genetic counseling should be provided to affected individuals and their families.