Sipos B Sperveslage J Anlauf M Hoffmeister M Henopp T Buch S Hampe J Weber A Hammel P Couvelard A Höbling W Lieb W Boehm BO Klöppel G 2015 CONTEXT Glucagon cell adenomatosis (GCA) was recently recognized as a multifocal hyperplastic and neoplastic disease of the glucagon cells unrelated to multiple endocrine neoplasia type 1 and von-Hippel-Lindau disease. OBJECTIVE The study focused on the molecular analysis of the glucagon receptor (GCGR) gene in GCA and a description of the clinicopathological features of GCA with and without GCGR mutations. DESIGN Pancreatic tissues from patients showing multiple glucagon cell tumors were morphologically characterized and macro- or microdissected. All exons of the GCGR gene were analyzed for mutations by Sanger and next-generation sequencing. Genotyping for all detected GCGR variants was performed in 2560 healthy individuals. PATIENTS Six patients with GCA, and the parents of one patient were included in the study. MAIN OUTCOME MEASURES The main outcome measures were the correlations between the patients' GCGR mutation status and the respective clinicopathological data. RESULTS GCGR germline mutations were found in three of six patients. Patient 1 harbored a homozygous stop mutation. This patient's parents showed an identical but heterozygous GCGR mutation. Patient 2 had two different heterozygous point mutations leading each to premature stop codons. Patient 3 exhibited two homozygous missense mutations. No GCGR mutations were identified in the three other patients and in a large cohort of healthy subjects. The patients harboring GCGR mutations exhibited a greater number of tumors and larger tumors than patients with wild-type GCGR. One of the patients with wild-type GCGR showed lymph node micrometastases. CONCLUSIONS GCA with GCGR germline mutations seems to follow an autosomal-recessive trait. By interrupting the GCGR signaling pathways GCGR mutations probably cause GCA via glucagon cell hyperplasia. GCA also occurs in patients without GCGR mutations, but seems to be associated with fewer and smaller tumors. application/pdf https://sonar.ch/global/documents/287252 eng info:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2014-4405 info:eu-repo/semantics/altIdentifier/pmid/25695890 info:eu-repo/semantics/openAccess The Journal of clinical endocrinology and metabolism. - 2015 Adult Aged Female Glucagon Glucagon-Secreting Cells Humans Hyperplasia Male Middle Aged Mutation Pancreas Pancreatic Neoplasms Receptors, Glucagon Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. http://purl.org/coar/resource_type/c_6501