Diazoxide-Responsive Forms of Congenital Hyperinsulinism

  • Daphne Yau
  • Charles A. StanleyEmail author
Part of the Contemporary Endocrinology book series (COE)


Diazoxide responsiveness is typically the starting point for distinguishing congenital hyperinsulinism phenotypes since those who do not respond will often require surgery. Operationally, diazoxide responsiveness is defined as being able to appropriately develop a hyperketonemic response to fasting (beta-hydroxybutyrate >2 mmol/L) prior to developing hypoglycemia (<2.8–3.3 mmol/L, <50–60 mg/dL), in addition to preventing any food-induced hypoglycemia. Of note, only 35% of diazoxide-responsive patients have an identifiable mutation in one of the currently known hyperinsulinism genes. Perinatal stress-induced hyperinsulinism is a transient but often prolonged form of hyperinsulinism associated with risk factors such as birth asphyxia and intrauterine growth restriction. Screening for hypoglycemia is crucial when these risk factors are present, as is starting diuretic treatment before diazoxide to avoid fluid overload and pulmonary hypertension. Genetic forms of diazoxide-responsive hyperinsulinism include a distinctive form caused by dominant activating mutations in glutamate dehydrogenase (GDH). Leucine-induced and fasting hypoglycemia, mild hyperammonemia, and neurologic abnormalities, most commonly atypical absence epilepsy, are key features. Recessive inactivating mutations in short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an inhibitor of GDH and a fatty acid oxidation enzyme, also cause leucine-sensitive hypoglycemia, but without hyperammonemia. Heterozygous mutations in the transcription factors, hepatocyte nuclear factors 4A and 1A, cause hyperinsulinism and evolve into young adult-onset diabetes (HNF4A-MODY and HNF1A-MODY, respectively). Finally, mutations in the mitochondrial transport protein, uncoupling protein 2 (UCP2), and the plasma membrane protein, monocarboxylate transporter 1 (MCT1), cause rare forms of hyperinsulinism with the unique features of post-glucose load and exercise-induced hypoglycemia, respectively.


Diazoxide Hyperinsulinism Transient hyperinsulinism GLUD1 HADH Hepatocyte nuclear factor UCP2 MCT1 


  1. 1.
    Drash A, Wolff F. Drug therapy in leucine-sensitive hypoglycemia. Metabolism. 1964;13(6):487–92.PubMedCrossRefGoogle Scholar
  2. 2.
    Snider KE, Becker S, Boyajian L, Shyng S-L, Macmullen C, Hughes N, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endcrinol Metab. 2013;98(2):E355–63.CrossRefGoogle Scholar
  3. 3.
    van Veen MR, van Hasselt PM, de Sain-van der Velden MGM, Verhoeven N, Hofstede FC, de Koning TJ, et al. Metabolic profiles in children during fasting. Pediatrics. 2011;127(4):e1021–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Cornblath M, Levin EY, Hopkins J. Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy. J Pediatr. 1959;55(5):545–62.PubMedCrossRefGoogle Scholar
  5. 5.
    Harris D, Weston P, Harding J. Incidence of neonatal hypoglycemia in babies identified as at risk. J Pediatr. 2012;161(5):787–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Reynolds CL, Truong L, Rodriguez L, Nedrelow J, Thornton P. Risk factors for perinatal stress-induced hyperinsulinism. In: International meeting of pediatric endocrinology. 2017. p. FC90.Google Scholar
  7. 7.
    Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006;148(2):207–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Le Dune MA. Response to glucagon in small-for-dates hypoglycaemic and non-hypoglycaemic newborn infants. Arch Dis Child. 1972;47(255):754–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Collins JE, Leonard JV. Hyperinsulinism in asphyxiated and small-for-dates infants with hypoglycemia. Lancet. 1984;2(8398):311–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Stanley CA, Rozance PJ, Thornton PS, De Leon DD, Harris D, Haymond MW, et al. Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management. J Pediatr. 2015;166(6):1520–1525.e1.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bhushan Arya V, Flanagan SE, Kumaran A, Shield JP, Ellard S, Hussain K, et al. Clinical and molecular characterisation of hyperinsulinaemic hypoglycaemia in infants born small-for-gestational age. Arch Dis Child Fetal Neonatal Ed. 2013;98:F356–8.CrossRefGoogle Scholar
  12. 12.
    Yap F, Holer W, Vora A, Halliday R, Ambler G. Severe transient hyperinsulinaemic hypoglycaemia: two neonates without predisposing factors and a review of the literature. Eur J Pediatr. 2003;163:38–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Avatapalle HB, Banerjee I, Shah S, Pryce M, Nicholson J, Rigby L, et al. Abnormal neurodevelopmental outcomes are common in children with transient congenital hyperinsulinism. Front Endocrinol (Lausanne). 2013;4:60.CrossRefGoogle Scholar
  14. 14.
    Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al. Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr. 2015;167(2):238–45.PubMedCrossRefGoogle Scholar
  15. 15.
    Mizumoto H, Iki Y, Yamashita S, Kawai M, Katayama T, Hata D. Fetal erythroblastosis may be an Indicator of neonatal transient hyperinsulinism. Neonatology. 2015;108:88–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Welters A, Lerch C, Kummer S, Marquard J, Salgin B, Mayatepek E, et al. Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. Orphanet J Rare Dis. 2015;10:150.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Hu S, Xu Z, Yan J, Liu M, Sun B, Li W, et al. The treatment effect of diazoxide on 44 patients with congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2012;25:11–2.CrossRefGoogle Scholar
  18. 18.
    Diazoxide. Lexicomp online, pediatric & neonatal. Lexi-Drugs, Hudson. Ohio: Lexi-Comp.Google Scholar
  19. 19.
    Li M, LI C, Allen A, Stanley CA, Smith TJ. Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis. Neurochem Res. 2014;39:433–45.PubMedCrossRefGoogle Scholar
  20. 20.
    Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, et al. Mechanism of hyperinsulinism in short-chain 3-Hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem. 2010;285(41):31806–18.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338(19):1352–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Macmullen C, Fang J, Hsu BYL, Kelly A, De Lonlay-Debeney P, Saudubray J-M, et al. Hyperinsulinism/Hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001;86:1782–7.PubMedGoogle Scholar
  23. 23.
    Fang J, Hsu BYL, Macmullen CM, Poncz M, Smith TJ, Stanley CA. Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. Biochem J. 2002;363:81–7.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kibbey RG, Pongratz RL, Romanelli AJ, Wollheim CB, Cline GW, Shulman GI. Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab. 2007;5(4):253–64.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Li C, Matter A, Kelly A, Petty TJ, Najafi H, Macmullen C, et al. Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice. J Biol Chem. 2006;281(22):15064–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Kelly A, Ng D, Ferry RJ, Grimberg A, Koo-Mccoy S, Thornton PS, et al. Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab. 2001;86(8):3724–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT. Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism/hyperammonemia syndrome. Am J Physiol – Endocrinol Metab. 2010;298(6):E1219–25.PubMedCrossRefGoogle Scholar
  28. 28.
    Weinzimer SA, Stanley CA, Berry GT, Yudkoff M, Tuchman M, Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr Weinzimer al. 1997;130(4):661–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Bahi-Buisson N, Roze E, Dionisi C, Escande F, Valayannopoulos V, Feillet F, et al. Neurological aspects of hyperinsulinism-hyperammonaemia syndrome. Dev Med Child Neurol. 2008;50(12):945–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Zammarchi E, Filippi L, Novembre E, Donati MA. Biochemical evaluation of a patient with a familial form of leucine-sensitive hypoglycemia and concomitant hyperammonemia. Metabolism. 1996;45(8):957–60.PubMedCrossRefGoogle Scholar
  31. 31.
    Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr. 2001;138(3):383–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Raizen DM, Brooks-Kayal A, Steinkrauss L, Tennekoon GI, Stanley CA, Kelly A. Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr. 2005;146(3):388–94.PubMedCrossRefGoogle Scholar
  33. 33.
    Stanley CA, Fang J, Kutyna K, Hsu BYL, Ming JE, Glaser B, et al. Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. Diabetes. 2000;49:667–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. 0760–0769.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Odom D, Zizlsperger N, Gordon D, Bell G, Rinaldi N, Murray H, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303(5662):1378–81.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Mcdonald TJ, Ellard S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem. 2013;50(5):403–15.PubMedCrossRefGoogle Scholar
  37. 37.
    Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, et al. The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. J Clin Invest. 2005;115(4):1006–15.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, et al. Hepatocyte nuclear factor-4 is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem. 2005;281(8):5246–57.PubMedCrossRefGoogle Scholar
  39. 39.
    Grimberg A, Ferry RJ, Kelly A, Koo-Mccoy S, Polonsky K, Glaser B, et al. Dysregulation of insuin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes. 2001;50:322–8.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Li C, Ackermann AM, Boodhansingh KE, Bhatti TR, Liu C, Schug J, et al. Functional and metabolomic consequences of K ATP channel inactivation in human islets. Diabetes. 2017;66:1901–13.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Fajans SS, Bell GI. Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4α (HNF4A). Diabetologia. 2007;50:2600–1.PubMedCrossRefGoogle Scholar
  42. 42.
    Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rozenkova K, Malikova J, Nessa A, Dusatkova L, Bjørkhaug L, Obermannova B, et al. High incidence of heterozygous ABCC8 and HNF1A mutations in Czech patients with congenital hyperinsulinism. J Clin Endocrinol Metab. 2015;100(12):E1540–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Hamilton AJ, Bingham C, Mcdonald TJ, Cook PR, Caswell RC, Weedon MN, et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. J Med Genet. 2014;51:165–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Numakura C, Hashimoto Y, Daitsu T, Hayasaka K, Mitsui T, Yorifuji T. Two patients with HNF4A-related congenital hyperinsulinism and renal tubular dysfunction: a clinical variation which includes transient hepatic dysfunction. Diabetes Res Clin Pract. 2015;108:e53–5.PubMedCrossRefGoogle Scholar
  46. 46.
    Improda N, Shah P, Güemes M, Gilbert C, Morgan K, Sebire N, et al. Hepatocyte nuclear factor-4 alfa mutation associated with hyperinsulinaemic hypoglycaemia and atypical renal Fanconi syndrome: expanding the clinical phenotype. Horm Res Paediatr. 2016;86(5):337–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB. Hepatocyte nuclear factor 4 regulates the expression of pancreatic B-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem. 2000;275(46):35953–9. A.PubMedCrossRefGoogle Scholar
  48. 48.
    Kapoor RR, James CT, Hussain K. HNF4A and hyperinsulinemic hypoglycemia. In: Monogenic hyperinsulinemic hypoglycemia disorders. 2012. p. 182–90.Google Scholar
  49. 49.
    McGlacken-Byrne SM, Hawkes CP, Flanagan SE, Ellard S, McDonnell CM, Murphy NP. The evolving course of HNF4A hyperinsulinaemic hypoglycaemia-a case series. Diabet Med. 2014;31(1):e1–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Stanescu DE, Hughes N, Kaplan B, Stanley CA, De Leó DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012;97(10):E2026–30.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Flanagan SE, Kapoor RR, Mali G, Cody D, Murphy N, Schwahn B, et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol. 2010;162(5):987–92.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Heslegrave AJ, Hussain K. Novel insights into fatty acid oxidation, amino acid metabolism, and insulin secretion from studying patients with loss of function mutations in 3-Hydroxyacyl-CoA dehydrogenase. J Clin Endocrinol Metab. 2013;98(2):496–501.PubMedCrossRefGoogle Scholar
  53. 53.
    Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of b-oxidation in insulin secretion. J Clin Invest. 2001;108(3):457–65.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Heslegrave AJ, Kapoor RR, Eaton S, Chadefaux B, Akcay T, Simsek E, et al. Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA dehydrogenase. Orphanet J Rare Dis. 2012;7:25.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. 2004;53(1):221–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Hussain K, Clayton PT, Krywawych S, Ginbey DW, Geboers AJJM, Berger R, et al. Hyperinsulinism of infancy associated with a novel splice site mutation in the Schad gene. J Pediatr. 2005;146:706–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K. 3-Hydroxyacyl-coenzyme a dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. J Clin Endocrinol Metab. 2009;94(7):2221–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Martins E, Luis Cardoso M, Rodrigues E, Barbot C, Ramos A, Bennett MJ, et al. Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: the clinical relevance of an early diagnosis and report of four new cases. J Inherit Metab Dis. 2011;34:835–42.PubMedCrossRefGoogle Scholar
  59. 59.
    Di Candia S, Gessi A, Pepe G, Sogno Valin P, Mangano E, Chiumello G, et al. 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(6):1019–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Çamtosun E, Flanagan SE, Ellard S, Şıklar Z, Hussain K, Kocaay P, et al. A deep intronic HADH splicing mutation (c.636+471G>T) in a congenital hyperinsulinemic hypoglycemia case: long term clinical course. J Clin Res Pediatr Endocrinol. 2015;7(2):144–7.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Flanagan SE, Patch A-M, Locke JM, Akcay T, Simsek E, Alaei M, et al. Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. J Clin Endocrinol Metab. 2011;96:E498–502.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Babiker O, Flanagan SE, Ellard S, Al GH, Hussain K, Senniappan S. Protein-induced hyperinsulinaemic hypoglycaemia due to a homozygous HADH mutation in three siblings of a Saudi family. J Pediatr Endocrinol Metab. 2015;28(910):1073–7.PubMedGoogle Scholar
  63. 63.
    Vozza A, Parisi G, De Leonardis F, Lasorsa FM, Castegna A, Amorese D, et al. UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc Natl Acad Sci. 2014;111(3):960–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Chan CB, De Leo D, Joseph JW, Mcquaid TS, Ha XF, Xu F, et al. Increased uncoupling protein-2 levels in B-cells are associated with impaired glucose-stimulated insulin secretion mechanism of action. Diabetes. 2001;50:1302–10.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang C-Y, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta-cell dysfunction, and type 2 diabetes. Cell. 2001;105:745–55.PubMedCrossRefGoogle Scholar
  66. 66.
    González-Barroso MM, Giurgea I, Bouillaud F, Anedda A, Bellanné-Chantelot C, Hubert L, et al. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLOsOne. 2008;3(12):e3850.CrossRefGoogle Scholar
  67. 67.
    Laver TW, Weedon MN, Caswell R, Hussain K, Ellard S, Flanagan SE. Analysis of large-scale sequencing cohorts does not support the role of variants in UCP2 as a cause of hyperinsulinaemic hypoglycaemia. Hum Mutat. 2017;38(10):1442–4.PubMedCrossRefGoogle Scholar
  68. 68.
    Ferrara CT, Boodhansingh KE, Paradies E, Giuseppe F, Steinkrauss LJ, Swartz Topor L, et al. Novel hypoglycemia phenotype in congenital hyperinsulinism due to dominant mutations of uncoupling protein 2. J Clin Endocrinol Metab. 2017;102:942–9.PubMedGoogle Scholar
  69. 69.
    Meissner T, Otonkoski T, Feneberg R, Beinbrech B, Apostolidou S, Sipilä I, et al. Exercise induced hypoglycaemic hyperinsulinism. Arch Dis Child. 2001;84(3):254–7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Otonkoski T, Kaminen N, Ustinov J, Lapatto R, Meissner T, Mayatepek E, et al. Physical exercise–induced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes. 2003;52:199–204.PubMedCrossRefGoogle Scholar
  71. 71.
    Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, et al. Physical exercise–induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic b cells. Am J Hum Genet. 2007;81:467–74.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Pinney S, Ganapathy K, Bradfield J, Stokes D, Sasson A, Mackiewicz K, et al. Dominant of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr. 2013;80:18–27.PubMedCrossRefGoogle Scholar
  73. 73.
    Gao N, White P, Doliba N, Golson ML, Matschinsky FM, Kaestner K. Cell Metab. 2007;6:267–79.PubMedCrossRefGoogle Scholar
  74. 74.
    Giri D, Vignola ML, Gualtieri A, Scagliotti V, McNamara P, Peak M, et al. Hum Mol Genet. 2017;26(22):4315–26.PubMedCrossRefGoogle Scholar
  75. 75.
    Vajravelu M, Chai J, Krock B, Baker S, Landon D, Alter C, et al. Congenital hyperinsulinism and hypopituitarism attributable to a novel mutation in FOXA2. J Clin Endocrinol Metab. 2018;103:1042–7. (Online ahead of print).PubMedCrossRefGoogle Scholar
  76. 76.
    Flanagan SE, Vairo F, Johnson MB, Caswell R, Laver TW, Lango Allen H, et al. Pediatr Diabetes. 2017;18:320–3.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Scholl UI, Goh G, Stolting G, de Oliviera RC, Choi M, Overton JD, et al. Nat Genet. 2013;45(9):1050–4.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Tegtmeyer LC, Rust S, van Scherpenszeel M, Ng BG, Losfeld ME, Timal S, et al. N Engl J Med. 2014;370(6):533–42.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Otonkoski T, Meissner T. A Failure of Monocarboxylate Transporter 1 Expression Silencing. In: Stanley CA, De Leon DD, editors. Monogenic Hyperinsulinemic Hypoglycemia Disorders. Basel: Karger; 2012. p. 172–81.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Paediatric Endocrinology, Royal Manchester Children’s HospitalManchesterUK
  2. 2.Division of Endocrinology and Diabetes, Department of PediatricsPerelman School of Medicine at the University of Pennsylvania and The Children’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations