Clinical practice guidelines "Congenital hyperinsulinism"

Congenital hyperinsulinism (CHI) is a rare, genetically heterogeneous disorder characterized by inappropriate hypersecre tion of insulin by pancreatic beta cells and is the most common cause of persistent hypoglycemia in young children. The in cidence of CHI in the general population ranges from 1:30,000 to 1:50,000 live births. Timely diagnosis and treatment of CHI are critical, as persistent hypoglycemia can lead to irreversible damage to the central nervous system. This review summa rizes current understanding of the etiology and pathogenesis of CHI and presents an up-to-date classification of CHI based on duration, etiology, histological form, and response to diazoxide therapy. A detailed diagnostic algorithm is provided, including provocative tests, molecular genetic testing, and imaging studies. The stages of conservative treatment and indi cations for surgical treatment are discussed. The review is based on updated clinical guidelines and is intended for practicing physicians — pediatricians, endocrinologists, and neonatologists — who care for children with hypoglycemic conditions.

1. Glaser B, Thornton P, Otonkoski T, Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F79-F86. doi: https://doi.org/10.1136/fn.82.2.f79

2. Болмасова А.В., Меликян М.А., Крылова Н.А., Ионов О.В., Рюмина И.И., Бокерия Е.Л., Пекарева Н.А., Дегтярева А.В. Транзиторные варианты врожденного гиперинсулинизма у новорожденных детей. Проблемы Эндокринологии. 2020;66(4):61-67 doi: https://doi.org/10.14341/probl12572

3. Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 2013;18(2):162-185. doi: https://doi.org/10.1016/j.cmet.2013.05.018

4. Vajravelu ME, De León DD. Genetic characteristics of patients with congenital hyperinsulinism. Curr Opin Pediatr. 2018;30(4):568-575. doi: https://doi.org/10.1097/MOP.0000000000000645

5. Меликян М.А., Карева М.А., Петряйкина Е.Е., Волков И.Э., Аверьянова Ю.В., Коломина И.Г., Гуревич Л.Е., Петеркова В.А., Brusgaard K., Christesen H, Дедов И.И. Врожденный гиперинсулинизм. Результаты молекулярно-генетических исследований в российской популяции. Проблемы Эндокринологии. 2012;58(2):3-9. doi: https://doi.org/10.14341/probl20125823-9

6. Меликян М.А., Тюльпаков А.Н., Карева М.А. Семейный случай врожденного гиперинсулинизма, ассоциированного с мутацией в гене GLUD1. Проблемы Эндокринологии. 2017;63(3):195-200. https://doi.org/10.14341/probl2017633195-200

7. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995;268(5209):426-429. doi: https://doi.org/10.1126/science.7716548

8. Saint-Martin C, Arnoux JB, de Lonlay P, Bellanné Chantelot C. KATP channel mutations in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):18-22. doi: https://doi.org/10.1053/j.sempedsurg.2010.10.012

9. Pinney SE, MacMullen C, Becker S, et al. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest. 2008;118(8):2877-2886. doi: https://doi.org/10.1172/JCI35414

10. de Lonlay P, Fournet JC, Rahier J, et al. 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(4):802-807. doi: https://doi.org/10.1172/JCI119594

11. Senniappan S, Shanti B, James C, Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis. 2012;35(4):589-601. doi: https://doi.org/10.1007/s10545-011-9441-2

12. Tung JY, Boodhansingh K, Stanley CA, De León DD. Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatr Diabetes. 2018;19(5):910-916. doi: https://doi.org/10.1111/pedi.12655

13. Ferrara CT, Boodhansingh KE, Paradies E, et al. Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2. J Clin Endocrinol Metab. 2017;102(3):942-949. doi: https://doi.org/10.1210/jc.2016-3164

14. 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. doi: https://doi.org/10.1159/000351943.

15. De Leon DD, Stanley CA. Congenital Hypoglycemia Disorders: New Aspects of Etiology, Diagnosis, Treatment and Outcomes: Highlights of the Proceedings of the Congenital Hypoglycemia Disorders Symposium, Philadelphia April 2016. Pediatr Diabetes. 2017;18(1):3-9. doi: https://doi.org/10.1111/pedi.12453

16. Cabezas OR, Flanagan SE, Stanescu H, et al. Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. J Am Soc Nephrol. 2017;28(8):2529-2539. doi: https://doi.org/10.1681/ASN.2016121312

17. Flanagan SE, Vairo F, Johnson MB, et al. A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia. Pediatr Diabetes. 2017;18(4):320-323. doi: https://doi.org/10.1111/pedi.12512

18. Giri D, Vignola ML, Gualtieri A, et al. Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm derived organ abnormalities. Hum Mol Genet. 2017;26(22):4315-4326. doi: https://doi.org/10.1093/hmg/ddx318

19. Меликян М.А. Врожденный гиперинсулинизм: молекулярная основа, клинические особенности и персонализированное лечение. Диссертация доктора медицинских наук. 2019 год.

20. Rahier J, Guiot Y, Sempoux C. Persistent Hypoglycaemia in a Turner Syndrome with Ring (X). Case Rep Pediatr. 2015; hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F108-F112. doi: https://doi.org/10.1136/fn.82.2.f108

21. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63. Published 2011 Oct 3. doi: https://doi.org/10.1186/1750-1172-6-63

22. 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. doi: https://doi.org/10.1373/clinchem.2007.098988

23. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2010;154C(3):343-354. doi: https://doi.org/10.1002/ajmg.c.30267

24. Subbarayan A, Hussain K. Hypoglycemia in Kabuki syndrome. Am J Med Genet A. 2014;164A(2):467-471. doi: https://doi.org/10.1002/ajmg.a.36256

25. Бенина А.Р., Меликян М.А. Врожденный гиперинсулинизм в составе синдрома Кабуки. Проблемы Эндокринологии. 2022;68(5):91-96. doi: https://doi.org/10.14341/probl13145

26. Nakamura Y, Takagi M, Yoshihashi H, et al. A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of Sotos syndrome. Am J Med Genet A. 2015;167A(5):1171-1174. doi: https://doi.org/10.1002/ajmg.a.36996

27. Cappella M, Graziani V, Pragliola A, et al. Hyperinsulinemic 2015:561974. doi: https://doi.org/10.1155/2015/561974

28. Kapoor RR, James C, Hussain K. Hyperinsulinism in developmental syndromes. Endocr Dev. 2009;14:95-113. doi: https://doi.org/10.1159/000207480

29. Ludwig A, Ziegenhorn K, Empting S, et al. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):45-49. doi: https://doi.org/10.1053/j.sempedsurg.2010.10.005

30. Thornton PS, Stanley CA, De Leon DD, 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):238-245. doi: https://doi.org/10.1016/j.jpeds.2015.03.057.

31. Demirbilek H, Hussain K. Congenital Hyperinsulinism: Diagnosis and Treatment Update. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):69-87. doi: https://doi.org/10.4274/jcrpe.2017.S007

32. De Leon DD, Arnoux JB, Banerjee I, et al. International Guidelines for the Diagnosis and Management of Hyperinsulinism. Horm Res Paediatr. 2024;97(3):279-298. doi: https://doi.org/10.1159/000531766

33. Banerjee I, Salomon-Estebanez M, Shah P, Nicholson J, Cosgrove KE, Dunne MJ. Therapies and outcomes of congenital hyperinsulinism induced hypoglycaemia. Diabet Med. 2019;36(1):9-21. doi: https://doi.org/10.1111/dme.13823.

34. Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child. 2009;94(6):450-457. doi: https://doi.org/10.1136/adc.2008.148171

35. Kapoor RR, James C, Hussain K. Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nat Clin Pract Endocrinol Metab. 2009;5(2):101-112. doi: https://doi.org/10.1038/ncpendmet1046

36. Mohnike K, Blankenstein O, Christesen HT, et al. Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res. 2006;66(1):40-42. doi: https://doi.org/10.1159/000093471

37. Hardy OT, Hernandez-Pampaloni M, Saffer JR, et al. Accuracy of [18F] fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2007;92(12):4706-4711. doi: https://doi.org/10.1210/jc.2007-1637

38. Meintjes M, Endozo R, Dickson J, et al. 18F-DOPA PET and enhanced CT imaging for congenital hyperinsulinism: initial UK experience from a technologist's perspective. Nucl Med Commun. 2013;34(6):601-608. doi: https://doi.org/10.1097/MNM.0b013e32836069d0

39. Губаева Д. Н. и др. Дифференциальная диагностика морфологических форм врожденного гиперинсулинизма методом ПЭТ/КТ с [18F]-фторДОФА // Проблемы Эндокринологии. 2018. Т. 64, № 5. С. 306-311. doi: https://doi.org/10.14341/probl9726

40. Christiansen CD, Petersen H, Nielsen AL, et al. 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation. Eur J Nucl Med Mol Imaging. 2018;45(2):250-261. doi: https://doi.org/10.1007/s00259-017-3867-1

41. 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(4):322-333. doi: https://doi.org/10.1007/s10024-002-0026-9

42. Rahier J, Guiot Y, Sempoux C. Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):3-12. doi: https://doi.org/10.1053/j.sempedsurg.2010.10.010

43. Suchi M, MacMullen CM, Thornton PS, et al. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol. 2006;19(1):122-129. doi: https://doi.org/10.1038/modpathol.3800497

44. Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management. Arch Dis Child. 2007;92(7):568-570. doi: https://doi.org/10.1136/adc.2006.115543

45. Kane C, Lindley KJ, Johnson PR, et al. Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin. J Clin Invest. 1997;100(7):1888-1893. doi: https://doi.org/10.1172/JCI119718

46. Touati G, Poggi-Travert F, Ogier de Baulny H, et al. Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr. 1998;157(8):628-633. doi: https://doi.org/10.1007/s004310050900

47. Herrera A, Vajravelu ME, Givler S, et al. Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. J Clin Endocrinol Metab. 2018;103(12):4365-4372. doi: https://doi.org/10.1210/jc.2018-01613

48. Yildizdas D, Erdem S, Küçükosmanoglu O, Yilmaz M, Yüksel B. Pulmonary hypertension, heart failure and neutropenia due to diazoxide therapy. Adv Ther. 2008;25(5):515-519. doi: https://doi.org/10.1007/s12325-008-0049-3

49. Timlin MR, Black AB, Delaney HM, Matos RI, Percival CS. Development of Pulmonary Hypertension During Treatment with Diazoxide: A Case Series and Literature Review. Pediatr Cardiol. 2017;38(6):1247-1250. doi: https://doi.org/10.1007/s00246-017-1652-3

50. Adachi J, Mimura M, Minami I, Kakihana K, Watanabe T. Thrombocytopenia induced by diazoxide in a patient with an insulinoma. Intern Med. 2014;53(7):759-762. doi: https://doi.org/10.2169/internalmedicine.53.1094

51. Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol. 2013;34(3):228-252. doi: https://doi.org/10.1016/j.yfrne.2013.07.005

52. Shah P, Rahman SA, McElroy S, et al. Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact. Horm Res Paediatr. 2015;84(5):355-360. doi: https://doi.org/10.1159/000439131

53. Hawkes CP, Adzick NS, Palladino AA, De León DD. Late Presentation of Fulminant Necrotizing Enterocolitis in a Child with Hyperinsulinism on Octreotide Therapy. Horm Res Paediatr. 2016;86(2):131-136. doi: https://doi.org/10.1159/000443959

54. Welters A, Lerch C, Kummer S, 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. Published 2015 Nov 25. doi: https://doi.org/10.1186/s13023-015-0367-x

55. Laje P, Halaby L, Adzick NS, Stanley CA. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatr Diabetes. 2010;11(2):142-147. doi: https://doi.org/10.1111/j.1399-5448.2009.00547.x

56. Меликян М.А., Губаева Д.Н., Карева М.А. Метод непрерывной подкожной инфузии аналогов соматостатина в терапии пациентов с врожденным гиперинсулинизмом. Проблемы Эндокринологии. 2020;66(3):81-87. doi: https://doi.org/10.14341/probl12421

57. Новокрещенных Е.Э., Губаева Д.Н., Меликян М.А. Применение аналогов соматостатина пролонгированного действия при врожденном гиперинсулинизме. Проблемы Эндокринологии. 2020;66(5):70-78. doi: https://doi.org/10.14341/probl12654

58. Pierro A, Nah SA. Surgical management of congenital hyperinsulinism of infancy. Semin Pediatr Surg. 2011;20(1):50-53. doi: https://doi.org/10.1053/j.sempedsurg.2010.10.009

59. Adzick NS, De Leon DD, States LJ, et al. Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children. J Pediatr Surg. 2019;54(1):27-32. doi: https://doi.org/10.1016/j.jpedsurg.2018.10.030

60. 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. doi: https://doi.org/10.2337/dc11-1296

61. Соколов Ю.Ю., Меликян М.А., Ефременков А.М., Губаева Д.Н., Дружинин В.Р., Османов И.М. Лапароскопические резекции поджелудочной железы у детей с врождённым гиперинсулинизмом // Детская хирургия. - 2020. - Т. 24. - №6. - C. 363-369. doi: https://doi.org/10.18821/1560-9510-2020-24-6-363-369

62. Helleskov A, Melikyan M, Globa E, et al. Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study. Front Endocrinol (Lausanne). 2017;8:156. Published 2017 Jul 10. doi: https://doi.org/10.3389/fendo.2017.00156

63. Mazor-Aronovitch K, Gillis D, Lobel D, et al. Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007;157(4):491-497. doi: https://doi.org/10.1530/EJE-07-0445

64. Arya VB, Flanagan SE, Kumaran A, et al. Clinical and molecular characterisation of hyperinsulinaemic hypoglycaemia in infants born small-for-gestational age. Arch Dis Child Fetal Neonatal Ed. 2013;98(4):F356-F358. doi: https://doi.org/10.1136/archdischild-2012-302880

65. Giouleka S, Gkiouleka M, Tsakiridis I, et al. Diagnosis and Management of Neonatal Hypoglycemia: A Comprehensive Review of Guidelines. Children (Basel). 2023;10(7):1220. Published 2023 Jul 14. doi: https://doi.org/10.3390/children10071220

66. Abramowski A, Ward R, Hamdan AH. Neonatal Hypoglycemia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 4, 2023.

67. Михалина С.Д., Янар Э.А., Макрецкая Н.А., Меликян М.А., Колодкина А.А., Безлепкина О.Б., Болмасова А.В. Результаты анализа клинико-лабораторных особенностей течения врожденного гиперинсулинизма при синдроме Беквита– Видемана // Неонатология: новости, мнения, обучение. 2025. Т. 13, № 3. С. 39 46. doi: https://doi.org/10.33029/2308-2402-2025-13-3-39-46

68. Arya VB, Senniappan S, Demirbilek H, et al. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism. PLoS One. 2014;9(5):e98054. Published 2014 May 19. doi:10.1371/journal.pone.0098054

69. Redkar R, Karkera PJ, Krishnan J, Hathiramani V. Subtotal Pancreatectomy for Congenital Hyperinsulinism: Our Experience and Review of Literature. Indian J Surg. 2015;77(Suppl 3):778-782. doi: https://doi.org/10.1007/s12262-013-0999-9