Abstract
Background
Congenital hyperinsulinism (CHI) occurs due to an unregulated insulin secretion from the pancreatic β-cells resulting in hypoglycaemia. Causative mutations in multiple genes have been reported. Phenotypic variability exists both within and between different genetic subgroups.
Case presentation
A male infant born at 35+6 weeks’ gestation with a birth weight of 4.3 kg [+3.6 standard deviation score (SDS)] had recurrent hypoglycaemic episodes from birth. Biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and the dose was progressively increased to maintain euglycaemia. His father was slim and had been diagnosed with type 2 diabetes in his 30s. Sequence analysis identified a heterozygous hepatocyte nuclear factor 4 alpha (HNF4A) mutation (p.Arg245Pro, c.734G>C) and compound heterozygous ABCC8 mutations (p.Gly92Ser, c.274G>A and p.Ala1185Val, c.3554C>T) in the patient. The p.Ala1185Val ABCC8 mutation was inherited from his unaffected mother and the p.Arg245Pro HNF4A and p.Gly92Ser ABCC8 mutations from his father. All three mutations were predicted to be pathogenic. Identification of the HNF4A mutation in the father established a diagnosis of maturity-onset diabetes of the young (MODY), which enabled medication change resulting in improved glycaemic control.
Conclusions
We report a rare patient with CHI due to dual genetic aetiology. Although he is currently responsive to the maximum dose of diazoxide, the long-term prognosis remains unclear.
Acknowledgements
None.
Author contributions: LA and DG collected the data, wrote and revised the draft. JH, SF and MD contributed to the revision of the draft. SS supervised the study and revised the final draft.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Statement of ethics: Full parental consent was obtained for publication.
Conflicts of interest: None.
ESPE/PES Members: Senthil Senniappan and Dinesh Giri.
References
1. McGlacken-Byrne S, Hawkes C, Flanagan S, Ellard S, McDonnell C, et al. The evolving course of HNF4A hyperinsulinaemic hypoglycaemia – a case series. Diabet Med 2014;31:e1–5.10.1111/dme.12259Search in Google Scholar PubMed
2. Petraitienė I, Barauskas G, Gulbinas A, Malcius D, Hussain K, et al. Congenital hyperinsulinism. Medicina (Kaunas) 2014;50:190–5.10.1016/j.medici.2014.08.006Search in Google Scholar PubMed
3. Molnár Z, Balogh L, Kappelmayer J, Madar L, Gombos É, et al. Congenital hyperinsulinism caused by a de novo mutation in the ABCC8 gene – a case report. EJIFCC 2017;28:85–91.Search in Google Scholar
4. Alaei M, Akbaroghli D, Keramatipour M, Alaei A. A case series: congenital hyperinsulinism. Int J Endocrinol Metab 2016;14:e37311.10.5812/ijem.37311Search in Google Scholar PubMed PubMed Central
5. Nessa A, Aziz Q, Thomas A, Harmer S, Tinker A, et al. Molecular mechanisms of congenital hyperinsulinism due to autosomal dominant mutations in ABCC8. Hum Mol Genet 2015;24:5142–53.10.1093/hmg/ddv233Search in Google Scholar PubMed
6. Senniappan S, Arya VB, Hussain K. The molecular mechanisms, diagnosis and management of congenital hyperinsulinism. Indian J Endocrinol Metab 2013;17:19–30.10.4103/2230-8210.107822Search in Google Scholar PubMed PubMed Central
7. Demirbilek H, Hussain K. Congenital hyperinsulinism: diagnosis and treatment update. J Clin Res Pediatr Endocrinol 2017;9 (Suppl 2):69–87.10.4274/jcrpe.2017.S007Search in Google Scholar PubMed PubMed Central
8. Han B, Mohamed Z, Estebanez MS, Craigie RJ, Newbould M, et al. Atypical forms of congenital hyperinsulinism in infancy are associated with mosaic patterns of immature islet cells. J Clin Endocrinol Metab 2017;102:3261–7.10.1210/jc.2017-00158Search in Google Scholar PubMed PubMed Central
9. Yen CF, Huang CY, Chan CI, Hsu CH, Wang NL, et al. Successful treatment of a newborn with congenital hyperinsulinism having a novel heterozygous mutation in the. Ci Ji Yi Xue Za Zhi 2016;28:162–5.Search in Google Scholar
10. Stanley CA. Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders. J Clin Endocrinol Metab 2016;101:815–26.10.1210/jc.2015-3651Search in Google Scholar PubMed PubMed Central
11. Flanagan S, Damhuis A, Banerjee I, Rokicki D, Jefferies C, et al. Partial ABCC8 gene deletion mutations causing diazoxide-unresponsive hyperinsulinaemic hypoglycaemia. Pediatr Diabetes 2012;13:285–9.10.1111/j.1399-5448.2011.00821.xSearch in Google Scholar PubMed
12. Thomas P, Cote G, Wohllk N, Haddad B, Matthew P, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycaemia of infancy. Science 1995;268:426–9.10.1126/science.7716548Search in Google Scholar PubMed
13. 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;5:1809–12.10.1093/hmg/5.11.1809Search in Google Scholar
14. Arya V, Rahman S, Senniappan S, Flanagan S, Ellard S, et al. HNF4A mutation: switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response. Diabet Med 2014;31:e11–5.10.1111/dme.12369Search in Google Scholar
15. Kapoor RR, Heslegrave A, Hussain K. Congenital hyperinsulinism due to mutations in HNF4A and HADH. Rev Endocr Metab Disord 2010;11:185–91.10.1007/s11154-010-9148-ySearch in Google Scholar
16. Pearson E, Boj S, Steele A, Barrett T, Stals K, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:760–9.10.1371/journal.pmed.0040118Search in Google Scholar
17. Arya VB, Guemes M, Nessa A, Alam S, Shah P, et al. Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Eur J Endocrinol 2014;171:685–95.10.1530/EJE-14-0353Search in Google Scholar
18. Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 2006;55:13–8.10.2337/diabetes.55.01.06.db05-1128Search in Google Scholar
19. Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013;34:669–85.10.1002/humu.22279Search in Google Scholar
20. Kumaran A, Kapoor RR, Flanagan SE, Ellard S, Hussain K. Congenital hyperinsulinism due to a compound heterozygous ABCC8 mutation with spontaneous resolution at eight weeks. Horm Res Paediatr 2010;73:287–92.10.1159/000284394Search in Google Scholar
21. Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, et al. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 2003;361:301–7.10.1016/S0140-6736(03)12325-2Search in Google Scholar
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