Background: Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate-sensitive potassium (KATP) channels in β-cells) are the most common cause of medically unresponsive congenital hyperinsulinism (CHI) which requires a near-total pancreatectomy. Methods/Results: A patient born at term with marked macrosomia (5,900 g) presented at the age of 2 h with severe hyperinsulinaemic hypoglycaemia. He failed to respond to treatment with the KATP agonist, diazoxide. An 18FDOPA-PET scan showed intense diffuse uptake of 18FDOPA (consistent with diffuse disease) and genetic analysis of the ABCC8 gene confirmed a compound heterozygote missense ABCC8 mutation (R168C/S606T). However, unexpectedly in this patient the hyperinsulinaemic hypoglycaemia started to improve spontaneously at 7 weeks of age prior to planned pancreatic surgery. Conclusions: This is the first report of a patient with clinically severe autosomal-recessive diffuse CHI due to a compound heterozygous ABCC8 mutation that has resulted in spontaneous resolution at such an early age. Compound heterozygote ABCC8 mutations result in complex interactions, and it is possible that this interaction may modify the potential disease pathogenesis. It is important that physicians are aware of this unusual outcome in order to avoid unnecessary early pancreatic surgery with potential life-long implications.

Keywords:
Glucose, Hypoglycaemia, Hyperinsulinism
1.
Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, de Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley JK: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98–F107.
2.
Menni F, de Lonlay P, Sevin C, Touati G, Peigné C, Barbier V, Nihoul-Fékété C, Saudubray JM, Robert JJ: Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476–479.
3.
Hussain K: Diagnosis and management of hyperinsulinaemic hypoglycaemia of infancy. Horm Res 2008;69:2–13.
4.
Thomas P, Ye Y, Lightner E: Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996;5:1809–1812.
5.
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;21;268:426–429.
6.
Ashcroft FM, Harrison DE, Ashcroft SJ: Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 1984;312:446–448.
7.
Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 1999;20:101–135.
8.
James C, Kapoor RR, Ismail D, Hussain K: The genetic basis of congenital hyperinsulinism. J Med Genet 2009;46:289–299.
9.
Cartier EA, Conti LR, Vandenberg CA, Shyng SL: Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci USA 2001;98:2882–2887.
10.
Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG: Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 1998;47:1145–1151.
11.
Nichols CG, Shyng SL, Nestorowicz A, Glaser B, Clement JP 4th, Gonzalez G, Aguilar-Bryan L, Permutt MA, Bryan J: Adenosine diphosphate as an intracellular regulator of insulin secretion. Science 1996;272:1785–1787.
12.
Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT: Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 2007;56:1930–1937.
13.
Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM: Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007;81:375–382.
14.
Greer RM, Shah J, Jeske YW, Brown D, Walker RM, Cowley D, Bowling FG, Liaskou D, Harris M, Thomsett MJ, Choong C, Bell JR, Jack MM, Cotterill AM: Genotype-phenotype associations in patients with severe hyperinsulinism of infancy. Pediatr Dev Pathol 2007;10:25–34.
15.
Otonkoski T, Näntö-Salonen K, Seppänen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekström K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H: Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13–18.
16.
Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, Stanley CA, Thornton PS, Clement JP IV, Bryan J, Aguilar-Bryan L, Permutt MA: Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 1996;5:1813–1822.
17.
Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED: Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol 2003;6:322–333.
18.
Dekel B, Lubin D, Modan-Moses D, Quint J, Glaser B, and Meyerovitch J: Compound heterozygosity for the common sulfonylurea receptor mutations can cause mild diazoxide-sensitive hyperinsulinism. Clin Pediatr 2002;41:183–186.
19.
Muzyamba M, Farzaneh T, Behe P, Thomas A, Christesen HB, Brusgaard K, Hussain K, Tinker A: Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies. Clin Endocrinol 2007;67:115–124.
20.
Gussinyer M, Clemente M, Cebrián R, Yeste D, Albisu M, Carrascosa A: Glucose intolerance and diabetes are observed in the long-term follow-up of nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene. Diabetes Care 2008;31:1257–1259.
21.
Bin-Abbas BS, Al-Ashwal AA: Diabetes in a nonpancreatectomized child with nesidioblastosis. Diabetes Care 2004;27:626–627.
22.
Abdulhadi-Atwan M, Bushmann J, Tornovsky-Babaey S, Perry A, Abu-Libdeh A, Glaser B, Shyng SL, Zangen DH: Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes 2008;57:1935–1940.
23.
Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M: A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 2003;361:301–307.
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2010
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