MEN4, the MEN1 Mimicker: A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations

Context Germline CDKN1B pathogenic variants result in Multiple Endocrine Neoplasia type 4, an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma and duodenopancreatic neuroendocrine tumors. Objective To report the phenotype of three unrelated cases each with a unique germline CDKN1B variant (of which two are novel) and compare these cases to those described in the current literature. Design/Methods Three case studies, including clinical presentation, germline and tumor genetic analysis and family history. Setting Two tertiary University Hospitals in Sydney, NSW, and one tertiary University Hospital in Canberra, ACT, Australia. Outcome Phenotype of the three cases and their kindred; molecular analysis and tumor p27 kip1 immunohistochemistry. Results Family A: the proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal non-functioning duodenopancreatic neuroendocrine tumor (DP-NET). Family B: the proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: the proband was diagnosed with a non-functioning pituitary microadenoma and ectopic Cushing’s syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, two of which are novel (c.179G>A, p.Trp60*; c.475G>A, p.Asp159Asn;) and one previously reported (c.374_375delCT, p.Ser125*). Conclusions Germline CDKN1B pathogenic variants cause the syndrome Multiple Endocrine Neoplasia type 4. The phenotype resulting from the three pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.