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Hyperinsulinemic Hypoglycemia in Beckwith-Wiedemann Syndrome due to Defects in the Function of Pancreatic ß-Cell Adenosine Triphosphate-Sensitive Potassium Channels

London Centre for Paediatric Endocrinology and Metabolism (K.H., V.V.S., M.D.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom, and The Institute of Child Health, London WC1N 1EH, United Kingdom; Faculty of Life Sciences (K.E.C., R.M.S., M.J.D.), University of Manchester, Manchester M13 9PT, United Kingdom; West Midlands Regional Genetics Service (A.L., E.A.M.), Birmingham Women’s Health Care Trust, Birmingham, B15 2TG, United Kingdom, and Section of Medical and Molecular Genetics, University of Birmingham, Birmingham B15 2TT, United Kingdom; Endocrinology and Metabolism Service (S.K., B.G.), Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel; and Department of Child Health (J.W.G.), University of Wales, Cardiff CF14 4XN, United Kingdom; Department of Biomedical Sciences (A.S.), Leeds University, Leeds LS2 9JT, United Kingdom; Department of Pediatrics/Genetics (H.T.C., B.B.J., K.B.), Odense University Hospital, 5000 Odense, Denmark; and Section of Medical and Molecular Genetics (E.A.M.), University of Birmingham, Birmingham B15 2TT, United Kingdom

Address all correspondence and requests for reprints to: Dr. K. Hussain, Unit of Biochemistry, Endocrinology, and Metabolism, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: k.hussain{at}ich.ucl.ac.uk.

Background: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear.

Patients and Methods: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K⁺ (K_ATP) channels in pancreatic ß-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia.

Results: Persistent hyperinsulinism was found to be caused by abnormalities in K_ATP channels of the pancreatic ß-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K_ATP channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy.

Conclusions: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K_ATP channels of the pancreatic ß-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K_ATP channel remains to be elucidated.

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				K. Hussain, O. Blankenstein, P. De Lonlay, and H. T Christesen Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management Arch. Dis. Child., July 1, 2007; 92(7): 568 - 570. [Full Text] [PDF]