Case Report
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Surg. Apr 27, 2015; 7(4): 60-66
Published online Apr 27, 2015. doi: 10.4240/wjgs.v7.i4.60
Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome
Helen C Miller, Mark Kidd, Irvin M Modlin, Patrizia Cohen, Roberto Dina, Panagiotis Drymousis, Panagiotis Vlavianos, Günter Klöppel, Andrea Frilling
Helen C Miller, Panagiotis Drymousis, Andrea Frilling, Department of Surgery and Cancer, Imperial College London, London W12 0HS, United Kingdom
Mark Kidd, Department of Surgery, Yale University, New Haven, CT 06510, United States
Irvin M Modlin, Emeritus Yale University, School of Medicine, New Haven, CT 06510, United States
Patrizia Cohen, Roberto Dina, Department of Histopathology, Imperial College London, London W12 0HS, United Kingdom
Panagiotis Vlavianos, Department of Gastroenterology, Imperial College London, London W12 0HS, United Kingdom
Günter Klöppel, Department of Pathology, Technical University of Munich, 81675 Munich, Germany
Author contributions: Miller HC wrote the paper and analysed genetic data; Kidd M and Modlin IM performed genetic studies; Drymousis P, Vlavianos P and Frilling A contributed to the clinical work up; Cohen P and Dina R conducted the histopathology, Klöppel G reviewed the histology; Frilling A designed the research, analysed data and reviewed and edited the manuscript.
Ethics approval: This study is part of our project R12025: Genetic signature, metabolic phenotyping and integrative biology of neuroendocrine tumors. Ethics approval REC number: 07/MRE09/54.
Informed consent: All study participants, or their legal guardian, provided informed written consent prior to study enrolment.
Conflict-of-interest: None of the authors have any relevant affiliations or financial involvements to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Andrea Frilling, Professor, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, United Kingdom. a.frilling@imperial.ac.uk
Telephone: +44-20-33133210 Fax: +44-20-33133963
Received: July 17, 2014
Peer-review started: July 18, 2014
First decision: December 17, 2014
Revised: January 21, 2015
Accepted: February 10, 2015
Article in press: February 12, 2015
Published online: April 27, 2015
Abstract

Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of non-specific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. OctreoScan® was negative. Serum glucagon was elevated to 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene (GCGR) sequencing revealed a heterozygous deletion, K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.

Keywords: Hyperglucagonemia, Glucagon receptor gene, Mutation, Adenomatosis, Pancreas

Core tip: We identify novel mutations in the glucagon receptor gene in a patient with hyperglucagonemia but no glucagonoma syndrome. Physicians dealing with pancreatic disorders should be aware of this unusual condition.