Context: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors.
Objective: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with 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, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia.
Outcome: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry.
Results: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*).
Conclusions: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 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.
Keywords: CDKN1B germline mutation; MEN4; atypical carcinoid tumor; multiple endocrine neoplasia type 4; pancreatic neuroendocrine tumor; pituitary adenoma; primary hyperparathyroidism.
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.