Abstract
Mahvash disease is a novel pancreatic neuroendocrine tumor syndrome caused by inactivating glucagon receptor mutations. Its discovery was triggered by comparison of a patient with pancreatic neuroendocrine tumors, pancreatic α cell hyperplasia, extreme hyperglucagonemia but without glucagonoma syndrome, and occasional hypoglycemia, with the glucagon receptor knockout mice which exhibit similar phenotype and ultimately prove to be a model of Mahvash disease. So far 6 cases have been reported. The inheritance, prevalence, pathogenesis, natural history, diagnosis, treatment, and long-term follow-up of Mahvash disease are discussed in this article. Although rare, Mahvash disease provides important insights into the pathogenesis of pancreatic neuroendocrine tumors, pancreatic α cell fate regulation by glucagon signaling, and safety of glucagon signaling inhibition for diabetes treatment.
Highlights
Human tumor syndromes are usually caused by inherited or de novo mutations in tumor suppressor genes or oncogenes within the cells that give rise to the tumors [1,2]
We here review a novel pancreatic neuroendocrine tumor syndrome arising in a background of pancreatic α cell hyperplasia caused by inactivating glucagon receptor mutation
Based on the temporal sequence of hyperplasia, dysplasia, and pancreatic neuroendocrine tumors (PNETs) in the Gcgr–/– mice and the pathogenesis of sporadic PNETs and PNETs in (MEN1) [17,18,19,25,26,27], we posit that the pancreatic α cell hyperplasia is a direct result of glucagon receptor gene (GCGR) inactivation while PNET tumorigenesis from the hyperplastic background may be secondary and due to additional, stochastic mutations
Summary
Human tumor syndromes are usually caused by inherited or de novo mutations in tumor suppressor genes or oncogenes within the cells that give rise to the tumors [1,2]. The cells that give rise to tumors do not have intrinsic abnormalities in cell differentiation or proliferation but are forced into a hyperplastic state secondarily by neural or humoral factors. The latter phenomenon is especially relevant to certain endocrine tumors that arise in a hyperplastic background. We here review a novel pancreatic neuroendocrine tumor syndrome arising in a background of pancreatic α cell hyperplasia caused by inactivating glucagon receptor mutation
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