Endocrine Abstracts (2017) 50 P249 | DOI: 10.1530/endoabs.50.P249

Multiple endocrine neoplasia type 1 (MEN1) phenocopy due to a P.Leu380Phe cell division cycle 23 (CDC73) mutation

Kate E Lines1, Lisa B Nachtigall2, Laura E Dichtel2, Treena Cranston1, Shafaq Khairi2, Hannah Boon1, Babak Torabi Sagvand2, Xun Zhang2, Mark Stevenson1, Anne Klibanski2 & Rajesh V Thakker1

1University of Oxford, Oxford, UK; 2Neuroendocrine Unit, Massachusetts General Hospital/Harvard Medical School, Boston, UK.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid tumours, and neuroendocrine tumours (NETs) of the pituitary and pancreas. MEN1 is caused by mutations of the tumour suppressor gene MEN1, and MEN1 germline mutations are found in >75% of MEN1 patients. The remaining 25% of patients may have mutations involving as yet unidentified genes, or may represent phenocopies with mutations in other genes, such as for cell cycle division 73 (CDC73), calcium sensing receptor (CASR) and cyclin dependent kinase inhibitor 1B (CDKN1B). Here, we report a heterozygous c.1138C>T (P.Leu380Phe) CDC73 mutation in a patient with clinically diagnosed MEN1 on the basis of the combined occurrence of primary hyperparathyroidism, acromegaly, and a pancreatic NET, which showed immuno-staining for glucagon and chromogranin A, but not insulin. Informed consent for genetic testing was obtained from the patient. DNA sequence analysis, using leukocyte DNA, of the MEN1 gene did not reveal any germline abnormalities, and investigations for germline mutations in 6 other genes (CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C and aryl-hydrocarbon receptor-interacting protein (AIP)) implicated in the aetiology of parathyroid and pituitary tumours was undertaken. This revealed the presence of a heterozygous P.Leu380Phe missense mutation of CDC73, mutations of which are associated with the hyperparathyroidism-jaw tumour syndrome (HPT-JT), an autosomal dominant disorder characterised by occurrence of parathyroid tumours, ossifying fibromas of the jaw, renal tumours and uterine tumours. Our findings are consistent with a previous report of a CDC73 mutation (c.1239delA) in association with MEN1 phenocopy in a patient with primary hyperparathyroidism and a prolactinoma. Thus, our results, which expanded the spectrum of tumours associated with CDC73 mutations to include somatotrophinomas and pancreatic NETs, further demonstrate that CDC73 mutations can result in a phenocopy of MEN1.