Multiple endocrine neoplasia type 1 (MEN1) phenocopy due to a cell cycle division 73 (CDC73) variant

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, pituitary adenomas, and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline MEN1 mutations in > 75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (CDC73), the calcium sensing receptor (CASR), and cyclin-dependent kinase inhibitor 1B (CDKN1B), which are associated with the hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia type 1, and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) CDC73 germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly, and a PNEN. Characterization of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in CDC73 expression in the PNEN. Previously, CDC73 mutations have been reported to be associated with tumors of the parathyroids, kidneys, uterus, and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a CDC73 variant, provides further evidence that CDC73 variants may result in a MEN1 phenocopy

The Importance of Transnational Education and International Engagement for Future Collaborations

Many universities and higher educational institutes throughout the world have had a long and distinguished history with the involvement of international students, and international collaboration efforts and partnerships. International student recruitment for UK based institutes has now become, and continues to be, somewhat very competitive, as these students pay considerably more for their chosen programmes of study, when compared to their institute’s native population. Therefore, international student recruitment is factored into the business models of many UK based Higher Education (HE) institutions. Due to the competitive nature of student recruitment and the need to diversify income generation of universities from relying on native student populations, one should also consider more extensive recruiting of international students, and in doing so, establishing more international collaborations. This chapter will highlight the efforts adopted by De Montfort University (DMU) as its case study, in expanding its outreach into emerging and developing Asian markets, due to its recent (2018) Gold award in the Government’s Teaching Excellence Framework (TEF). From this engagement, several opportunities have arisen in conjunction with Asia Pacific University (APU). The author’s own experience in dealing with this particular tour of Malaysia is commented on, as too are the benefits of such engagements to that of Transnational Education (TNE) with regards to computing related subjects

Multiple endocrine neoplasia type 1 (MEN1) 5′UTR deletion, in MEN1 family, decreases menin expression

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the occurrence of parathyroid, pancreatic and pituitary tumours, and is due to mutations in the coding-region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumours. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesised that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from 5 family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides -1087 and -492 upstream of the translation start site, located within the MEN1 5' untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5'UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumour BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p<0.0001) and 16-fold (p<0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5'UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p<0.05) and 88% (p<0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5'UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations. This article is protected by copyright. All rights reserved

Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized. Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age. Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6–18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (70% had nonfunctioning tumors, >35% had insulinomas, and 55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel. Conclusion: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas