Clinical Features of Multiple Endocrine Neoplasia Type 4 - Novel pathogenic variant and review of published cases.

CONTEXT: The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment. OBJECTIVE: To expand current knowledge of the MEN4 phenotype including assessment of penetrance. DESIGN: This is a case report and a brief review of previously published MEN4 cases. PATIENTS: We report a large Danish family with multiple cases of endocrine tumors that segregated with a novel pathogenic variant in the CDKN1B gene. MAIN OUTCOME/RESULT: The medical history of the proband included primary hyperparathyroidism and Cushing's disease. Genetic analysis identified a novel pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another twelve individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcaemia due to primary hyperparathyroidism occurred in all thirteen of the available carriers of the genetic variant, and four patients also had functioning or non-functioning pituitary adenomas, while one patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity (LOH) was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and non-functioning pituitary tumors. CONCLUSION: Hypercalcaemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastro-intestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in multiple endocrine neoplasia type 1.