Actual trends in diagnostics and treatment of congenital hyperinsulinism

Authors: Juraj Staník 1,2;  Martina Škopková 1;  Monika Rosoľanková 3;  Iwar Klimeš 1;  Daniela Gašperíková 1
Authors‘ workplace: DIABGENE & Laboratórium diabetu a porúch metabolizmu, Ústav experimentálnej endokrinológie, Biomedicínske centrum SAV, Bratislava, Slovenská republika 1;  I. detská klinika LF UK a DFNsP, Bratislava, Slovenská republika 2;  Neonatologická klinika intenzívnej medicíny LF UK a DFNsP Bratislava, Slovenská republika 3
Published in: Vnitř Lék 2016; 62(Suppl 4): 103-112
Category: Reviews


Congenital hyperinsulinism (CHI) is the most common cause of severe persistent hypoglycemia in neonates and infants. Early diagnosis and effective treatment (based on the principles of pharmacogenetics) play the key role for the prognosis. The DNA anlysis, which can identify mutation in one of the 11 genes causing MODY, is crutial in the diagnostics. Moreover, The genotype determines also the optimal therapy approach (medicaments, diet or rarely surgery). There was a large progress of novel medicaments treating particularly most severe (diazoxide-resistant) forms of CHI.

Key words:
congenital hyperinsulinism – diazoxid – DNA analysis – hypoglycemia – somatostatine analogues


1. Stanik J, Huckova M, Stanikova D et al. Genetics of monogenic forms of diabetes. Vnitř Lék 2011; 57(11): 937–945.

2. Lang TF, Hussain K. Pediatric hypoglycemia. Adv Clin Chem 2014; 63: 211–245.

3. Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem 2008; 54(2): 256–263.

4. Mathew PM, Young JM, Abu-Osba YK et al. Persistent neonatal hyperinsulinism. Clin Pediatr (Phila) 1988; 27(3): 148–151.

5. Glaser B, Blech I, Krakinovsky Y et al. ABCC8 mutation allele frequency in the Ashkenazi Jewish population and risk of focal hyperinsulinemic hypoglycemia. Genet Med 2011; 13(10): 891–894. Dostupné z DOI: <>.

6. Flanagan SE, Kapoor RR, Hussain K. Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg 2011; 20(1): 13–17. Dostupné z DOI: <>-

7. Senniappan S, Shanti B, James C et al. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis 2012; 35: 589–601.

8. Dunne MJ, Cosgrove KE, Shepherd RM et al. Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 2004; 84(1): 239–275.

9. Arnoux JB, Verkarre V, Saint-Martin C et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis 2011; 6: 63. Dostupné z DOI: <–1172–6-63>

10. Arnoux JB, de Lonlay P, Ribeiro MJ et al. Congenital hyperinsulinism. Early Hum Dev 2010; 86(5): 287–294. Dostupné z DOI: <>.

11. Akcay T, Taskin N, Ulucan K et al. Congenital hyperinsulinism and cardiomyopathy. Fetal Pediatr Pathol 2012; 31(3): 190. Dostupné z DOI: <>.

12. Bulbul A, Bolat F, Comert S et al. Persistent hyperinsulinemic hypoglycemia with left ventricular hypertrophy and dysrhythmia: a case report. Fetal Pediatr Pathol 2010; 29(3): 165–171. Dostupné z DOI: <>.

13. Aynsley-Green A, Hussain K, Hall J et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82(2): F98-F107.

14. Barthlen W, Blankenstein O, Mau H et al. Evaluation of [18F]fluoro-L-DOPA positron emission tomography-computed tomography for surgery in focal congenital hyperinsulinism. J Clin Endocrinol Metab 2008; 93(3): 869–875.

15. Barthlen W. Surgery in congenital hyperinsulinism-tips and tricks not only for surgeons. A practical guide. Semin Pediatr Surg 2011; 20(1): 56–59. Dostupné z DOI: <>.

16. Banerjee I, Skae M, Flanagan SE et al. The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. Eur J Endocrinol 2011; 164(5): 733–740. Dostupné z DOI: <–1136>.

17. Sperling MA. New insights and new conundrums in neonatal hypoglycemia: enigmas wrapped in mystery. Diabetes 2013; 62(5): 1373–1375. Dostupné z DOI: <–1839>.

18. Shanti B, Silink M, Bhattacharya K et al. Congenital disorder of glycosylation type Ia: Heterogeneity in the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency. J Inherit Metab Dis 2009; 32(Suppl 1): S241-S251. Dostupné z DOI: <–009–1180–2>.

19. Bohles H, Sewell AA, Gebhardt B et al. Hyperinsulinaemic hypoglycaemia – leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis 2001; 24(8): 858–862.

20. Sun L, Eklund EA, Chung WK et al. Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab 2005; 90(7): 4371–4375.

21. Baumann U, Preece MA, Green A et al. Hyperinsulinism in tyrosinaemia type I. J Inherit Metab Dis 2005; 28(2): 131–135.

22. Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemann syndrome. Arch Dis Child Fetal Neonatal Ed 2001; 84(1): F67-F69.

23. Wangler MF, An P, Feinberg AP et al. Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband. Am J Med Genet A 2005; 137(1): 16–21.

24. Fukuzawa R, Umezawa A, Morikawa Y et al. Nesidioblastosis and mixed hamartoma of the liver in Beckwith-Wiedemann syndrome: case study including analysis of H19 methylation and insulin-like growth factor 2 genotyping and imprinting. Pediatr Dev Pathol 2001; 4(4): 381–390.

25. Kapoor RR, James C, Hussain K. Hyperinsulinism in developmental syndromes. Endocr Dev 2009; 14: 95–113. Dostupné z DOI: <>.

26. Alexander S, Ramadan D, Alkhayyat H et al. Costello syndrome and hyperinsulinemic hypoglycemia. Am J Med Genet A 2005; 139(3): 227–230.

27. Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ et al. ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. J Med Genet 2010; 47(11): 752–759. Dostupné z DOI: <>.

28. Bas VN, Ozkan M, Zenciroglu A et al. Seizure due to somatostatin analog discontinuation in a case diagnosed as congenital hyperinsulinism novel mutation. J Pediatr Endocrinol Metab 2012; 25(5–6): 553–555.

29. Abdel Khalek M, Kandil E. Is octreotide safe for the management of persistent hyperinsulinemic hypoglycemia of infancy? Eur J Pediatr Surg 2011; 21(3): 188–189.

30. Demirbilek H, Shah P, Arya VB et al. Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy. J Clin Endocrinol Metab 2014; 99(10): 3660–3667. Dostupné z DOI: <–1866>.

31. Laje P, Halaby L, Adzick NS et al. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatr Diabetes 2010; 11(2): 142–147. Dostupné z DOI: <–5448.2009.00547.x>.

32. Le Quan Sang KH, Arnoux JB, Mamoune A et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012; 166(2): 333–339. Dostupné z DOI: <–0874>.

33. Kuhnen P, Marquard J, Ernert A et al. Long-term lanreotide treatment in six patients with congenital hyperinsulinism. Horm Res Paediatr 2012; 78(2): 106–112.

34. Unal S, Gonulal D, Ucakturk A et al. A novel homozygous mutation in the KCNJ11 hgene p. F315I of a neonate with congenital hyperinsulinism and succesful management by sirolimus. J Clin Res Pediatr Endocrinol 2016. Dostupné z DOI: <>.

35. Senniappan S, Alexandrescu S, Tatevian N et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014; 370(12): 1131–1137. Dostupné z DOI: <>.

36. Shah P, Arya VB, Flanagan SE et al. Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation. J Pediatr Endocrinol Metab 2015; 28(5–6): 695–699. Dostupné z DOI: <–0371>.

37. Al-Shanafey S, Alkhudhur H. Food aversion among patients with persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2012; 47(5): 895–897. Dostupné z DOI: <>.

38. Maiorana A, Manganozzi L, Barbetti F et al. Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage. Orphanet J Rare Dis 2015; 10: 120. Dostupné z DOI: <–015–0342–6>.

39. Adzick NS, Thornton PS, Stanley CA et al. A multidisciplinary approach to the focal form of congenital hyperinsulinism leads to successful treatment by partial pancreatectomy. J Pediatr Surg 2004; 39(3): 270–275.

40. Al-Shanafey S. Laparoscopic vs open pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2009; 44(5): 957–961. Dostupné z DOI: <>.

41. Bax KN, van der Zee DC. The laparoscopic approach toward hyperinsulinism in children. Semin Pediatr Surg 2007; 16(4): 245–251.

42. Barthlen W, Mohnike W, Mohnike K. Techniques in pediatric surgery: congenital hyperinsulinism. Horm Res Paediatr 2010; 74(6): 438–443. Dostupné z DOI: <>.

43. Al-Nassar S, Sakati N, Al-Ashwal A et al. Persistent hyperinsulinaemic hypoglycaemia of infancy in 43 children: long-term clinical and surgical follow-up. Asian J Surg 2006; 29(3): 207–211.

44. Beltrand J, Caquard M, Arnoux JB et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012; 35(2): 198–203. Dostupné z DOI: <–1296>.

45. Barthlen W, Mohnike W, Mohnike K. Techniques in pediatric surgery: congenital hyperinsulinism. Horm Res Paediatr 2011; 75(4): 304–310. <>.

46. Stanley CA. Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab 2016; 101(3): 815–826. Dostupné z DOI: <–3651>.

47. Rozenkova K, Malikova J, Nessa A et al. High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism. J Clin Endocrinol Metab 2015; 100(12): E1540-E1549. Dostupné z DOI: <–2763>.

48. Bryan J, Munoz A, Zhang X et al. ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch 2007; 453(5): 703–718.

49. Flanagan S, Damhuis A, Banerjee I et al. Partial ABCC8 gene deletion mutations causing diazoxide-unresponsive hyperinsulinaemic hypoglycaemia. Pediatr Diabetes 2012; 13: 285–289.

50. Stanik J, Lethby M, Flanagan SE et al. Coincidence of a novel KCNJ11 missense variant R365H with a paternally inherited 6q24 duplication in a patient with transient neonatal diabetes. Diabetes Care 2008; 31(9): 1736–1737. Dostupné z DOI: <–0549>.

51. Fernandez-Marmiesse A, Salas A, Vega A et al. Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI). Hum Mutat 2006; 27(2): 214.

52. Ocal G, Flanagan SE, Hacihamdioglu B et al. Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic beta cell. J Pediatr Endocrinol Metab 2011; 24(11–12): 1019–1023.

53. Darendeliler F, Bas F. Hyperinsulinism in infancy – genetic aspects. Pediatr Endocrinol Rev 2006; 3(Suppl 3): S521-S526.

54. de Lonlay P, Touati G, Robert JJ et al. Persistent hyperinsulinaemic hypoglycaemia. Semin Neonatol 2002; 7(1): 95–100.

55. Delonlay P, Simon A, Galmiche-Rolland L et al. Neonatal hyperinsulinism: clinicopathologic correlation. Hum Pathol 2007; 38(3): 387–399.

56. Ismail D, Smith VV, de Lonlay P et al. Familial focal congenital hyperinsulinism. J Clin Endocrinol Metab 2011; 96(1): 24–28. Dostupné z DOI: <–1524>.

57. Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord 2010; 11(3): 171–178. Dostupné z DOI: <–010–9146–0>.

58. Kibbey RG, Choi CS, Lee HY et al. Mitochondrial GTP insensitivity contributes to hypoglycemia in hyperinsulinemia hyperammonemia by inhibiting glucagon release. Diabetes 2014; 63(12): 4218–4229. Dostupné z DOI: <–0783>.

59. Hsu BY, Kelly A, Thornton PS et al. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr 2001; 138(3): 383–389.

60. Balasubramaniam S, Kapoor R, Yeow JH et al. Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome. J Pediatr Endocrinol Metab 2011; 24(7-): 573–577.

61. Aso K, Okano Y, Takeda T et al. Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome. Osaka City Med J 2011; 57(1): 1–9.

62. de las Heras J, Garin I, de Nanclares GP et al. Familial hyperinsulinism-hyperammonemia syndrome in a family with seizures: case report. J Pediatr Endocrinol Metab 2010; 23(8): 827–830.

63. Flanagan SE, Patch AM, Locke JM 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(3): E498-E502. Dostupné z DOI: <–1906>.

64. Di Candia S, Gessi A, Pepe 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): 1019–1023. Dostupné z DOI: <–0945>.

65. Christesen HB, Tribble ND, Molven A et al. Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Eur J Endocrinol 2008; 159(1): 27–34. Dostupné z DOI: <–0203>.

66. Cuesta-Munoz AL, Huopio H, Otonkoski T et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 2004; 53(8): 2164–2168.

67. Sayed S, Langdon DR, Odili S et al. Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations. Diabetes 2009; 58(6): 1419–1427. Dostupné z DOI: <–1792>.

68. Pinney SE, Ganapathy K, Bradfield J et al. Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 2013; 80(1): 18–27. Dostupné z DOI: <>.

69. Tegtmeyer LC, Rust S, van Scherpenzeel M et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 2014; 370(6): 533–542. Dostupné z DOI: <>.

70. Meissner T, Friedmann B, Okun JG et al. Massive insulin secretion in response to anaerobic exercise in exercise-induced hyperinsulinism. Horm Metab Res 2005; 37(11): 690–694.

71. Otonkoski T, Jiao H, Kaminen-Ahola N et al. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 2007; 81(3): 467–474.

72. Zhang CY, Baffy G, Perret P 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(6): 745–755.

73. Gonzalez-Barroso MM, Giurgea I, Bouillaud Fet al. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS One 2008; 3(12): e3850. Dostupné z DOI: <>.

74. Gupta RK, Vatamaniuk MZ, Lee CS et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 2005; 115(4): 1006–1015.

75. Pearson ER, Boj SF, Steele AM et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007; 4(4): e118. Dostupné z DOI: <>.

76. Kapoor RR, Heslegrave A, Hussain K. Congenital hyperinsulinism due to mutations in HNF4A and HADH. Rev Endocr Metab Disord 2010; 11(3): 185–191. Dostupné z DOI: <–010–9148-y>.

77. Kapoor RR, Locke J, Colclough K et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 2008; 57(6): 1659–1663. Dostupné z DOI: <–1657>.

78. Conn JJ, Simm PJ, Oats JJ et al. Neonatal hyperinsulinaemic hypoglycaemia and monogenic diabetes due to a heterozygous mutation of the HNF4A gene. Aust N Z J Obstet Gynaecol 2009; 49(3): 328–330. Dostupné z DOI: <–828X.2009.01009.x>.

79. Stanescu DE, Hughes N, Kaplan B et al. Novel Presentations of Congenital Hyperinsulinism due to Mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab 2012; 97(10): E2026-E2030. Dostupné z DOI: <–1356>.

80. Flanagan SE, Kapoor RR, Mali G et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol 2010; 162(5): 987–992. Dostupné z DOI: <–0861>.

81. James C, Kapoor RR, Ismail D et al. The genetic basis of congenital hyperinsulinism. J Med Genet 2009; 46(5): 289–299. Dostupné z DOI: <>.

82. Staník J, Gašperíková D, Klimeš I. Monogénové poruchy sekrécie a účinku inzulínu. Bratislava. Univerzita Komenského, 2015. ISBN 978–80–223–3803–5.

83. Staník J, Rosoľanková M, Hučková M et al. Klinický manažment a DNA diagnostika detí s kongenitálnym hyperinzulinizmom. Diabetes a obezita 2012; 12(24): 42–60.

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