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Vol. 79, No. 4, 2013
Issue release date: May 2013
Horm Res Paediatr 2013;79:236-242

Genetic Analysis of Italian Patients with Congenital Hyperinsulinism of Infancy

Sogno Valin P. · Proverbio M.C. · Diceglie C. · Gessi A. · di Candia S. · Mariani B. · Zamproni I. · Mangano E. · Asselta R. · Battaglia C. · Caruso-Nicoletti M. · Mora S. · Salvatoni A.
aDepartment of Pediatrics, San Raffaele Scientific Institute, Milan, bDipartimento di Fisiopatologia e dei Trapianti (DePT), Università degli Studi di Milano, Milan, cLaboratory of Pediatric Endocrinology, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, dScuola di Dottorato di Medicina Molecolare, Università degli Studi di Milano, Milan, eInstitute of Biomedical Technology (ITB), CNR, Segrate and fDipartimento di Biotecnologie Mediche e Medicina Traslazionale (BIOMETRA), Università degli Studi di Milano, Milan, gDepartment of Clinical and Experimental Medicine, Pediatric Unit, Insubria University, Varese, and hDipartimento di Scienze Mediche e Pediatriche, Università di Catania, Catania, Italy

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Background/Aims: Congenital hyperinsulinism of infancy is a rare disease that needs prompt treatment to avoid brain damage. There are currently no data regarding the clinical and molecular features of Italian patients. Methods: Thirty-three patients with HI and their parents were included. Consanguinity was reported in six patients. Half of patients were macrosomic at birth. None had raised 3-hydroxybutyrylcarnitine or hyperammonemia. Molecular analysis of ABCC8 and KCNJ11 genes was performed in all patients, and subjects with no mutation underwent analysis of HNF4A and GCK. GLUD1 and HADH genes were analyzed in a patient with leucine sensitivity. Results: Mutations in the ABCC8 and KCNJ11 genes were found in 45% of the patients (6 novel). No mutations in HNF4A, GLUD1 and GCK genes were found. Recessive mode of inheritance was found in 21% of patients. A single heterozygous mutation was identified in 24% of probands. 72% of the patients were responsive to medical treatment, and 44% of the 17 patients with no identified mutation achieved spontaneous remission. Nine children, unresponsive to medical therapy, underwent pancreatectomy. Conclusion: This is the first report on hyperinsulinism of infancy in Italy, confirming the complexity of the clinical forms and the heterogeneity of the genetic causes of the disease.

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  1. Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fékété C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ: Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107.
  2. Arnoux JB, de Lonlay P, Ribeiro MJ, Hussain K, Blankenstein O, Mohnike K, Valayannopoulos V, Robert JJ, Rahier J, Sempoux C, Bellanné C, Verkarre V, Aigrain Y, Jaubert F, Brunelle F, Nihoul-Fékété C: Congenital hyperinsulinism. Early Hum Dev 2010;86:287-294.
  3. Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K: Hyperinsulinaemic hypoglycaemia. Arch Dis Child 2009;94:450-457.
  4. Goossens A, Gepts W, Saudubray JM, Bonnefont JP, Nihoul-Fekete, Heitz PU, Klöppel G: Diffuse and focal nesidioblastosis: a clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 1989;13:766-775.

    External Resources

  5. de Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F, Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997;100:802-807.
  6. Verkarre V, Fournet JC, de Lonlay P, Gross-Morand MS, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fékété C, Saudubray JM, Junien C: Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998;102:1286-1291.
  7. 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.
  8. James C, Kapoor RR, Ismail D, Hussain K: The genetic basis of congenital hyperinsulinism. J Med Genet 2009;46:289-299.
  9. Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD: Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab 2012;97:E2026-E2030.
  10. Dekel B, Lubin D, Modan-Moses D, Quint J, Glaser B, Meyerovitch J: Compound heterozygosity for the common sulfonylurea receptor mutations can cause mild diazoxide-sensitive hyperinsulinism. Clin Pediatr (Phila) 2002;41:183-186.
  11. Bellanné-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul- Fekete C, de Lonlay P: ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. J Med Genet 2010;47:752-759.
  12. Christesen HB, Brusgaard K, Alm J, Sjöblad S, Hussain K, Fenger C, Rasmussen L, Hovendal C, Otonkoski T, Jacobsen BB: Rapid genetic analysis in congenital hyperinsulinism. Horm Res 2007;67:184-188.
  13. Fékété CN, de Lonlay P, Jaubert F, Rahier J, Brunelle F, Saudubray JM: The surgical management of congenital hyperinsulinemic hypoglycemia in infancy. J Pediatr Surg 2004;39:267-269.
  14. Cazzaniga G, Lo Nigro L, Cifola I, Milone G, Schnittger S, Haferlach T, Mirabile E, Costantino F, Martelli MP, Mastrodicasa E, Di Raimondo F, Aversa F, Biondi A, Falini B: Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family. Leukemia 2009;23:199-203.
  15. Di Candia S, Gessi A, Pepe G, Sogno Valin P, Mangano E, Chiumello G, Gianolli L, Proverbio MC, Mora S: Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18-fluoro-L-3,4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH gene. Eur J Endocrinol 2009;160:1019-1023.
  16. Giurgea I, Sempoux C, Bellanné-Chantelot C, Ribeiro M, Hubert L, Boddaert N, Saudubray JM, Robert JJ, Brunelle F, Rahier J, Jaubert F, Nihoul-Fékété C, de Lonlay P: The Knudson's two-hit model and timing of somatic mutation may account for the phenotypic diversity of focal congenital hyperinsulinism. J Clin Endocrinol Metab 2006;91:4118-4123.
  17. Snider KE, Becker S, Boyajian L, Shyng SL, Macmullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A: Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 2013;98:E355-E363.
  18. Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, Nesher Y, Kuchinski N, Ben-Shushan E, Shatz O, Nahari E, Potikha T, Zangen D, Tenenbaum-Rakover Y, de Vries L, Argente J, Gracia R, Landau H, Eliakim A, Lindley K, Dunne MJ, Aguilar-Bryan L, Glaser B: Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. J Clin Endocrinol Metab 2004;89:6224-6234.
  19. Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 1999;20:101-135.
  20. Biagiotti L, Proverbio MC, Bosio L, Gervasi F, Rovida E, Cerioni V, Bove M, Valin PS, Albarello L, Zamproni I, Grassi S, Doglioni C, Mora S, Chiumello G, Biunno I: Identification of two novel frameshift mutations in the KCNJ11 gene in two Italian patients affected by congenital hyperinsulinism of infancy. Exp Mol Pathol 2007;83:59-64.
  21. Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA: Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet 1998;7:1119-1128.
  22. Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C, Thornton P, Ganguly A, Shyng SL, Stanley CA: Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 2008;118:2877-2886.
  23. Banerjee I, Skae M, Flanagan SE, Rigby L, Patel L, Didi M, Blair J, Ehtisham, S, Ellard S, Cosgrove KE, Dunne MJ, Clayton PE: The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. Eur J Endocrinol 2011;164:733-740.
  24. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K: Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol 2013;168:557-564.
  25. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B: Beta-Cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy diabetes 2000;49:1325-1333.
  26. Heslegrave AJ, Kapoor RR, Eaton S, Chadefaux B, Akcay T, Simsek E, Flanagan SE, Ellard S, Hussain K: Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-hydroxyacyl-CoA dehydrogenase. Orphanet J Rare Dis 2012;7:25.

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