Congenital Hyperinsulinism with Paternally Inherited ABCC8 Variants
A Single Center Experience over a Decade in Singapore
DOI:
https://doi.org/10.15605/jafes.041.02.6197Keywords:
congenital hyperinsulinism, paternally inherited, ABCC8 gene, diazoxide, 18F DOPA PET CTAbstract
ABCC8 pathogenic variants have been found to cause neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI), depending on the nature of the mutation.
Few studies have reported on the carrier frequency of CHI-related ABCC8 variants. In Singapore, the carrier rate is 1 in 754. Paternally inherited ABCC8 recessive variants have been classically associated with focal lesions causing CHI. In our case series of five patients with paternally inherited ABCC8 variants, one patient had a second maternally inherited recessive variant, making him a compound heterozygous genotype presenting with severe, neonatal onset, diffuse disease that was not responsive to diazoxide. The remaining four patients had a single paternally inherited ABCC8 variant, of which three were previously reported to be recessive variants – only 1 had a focal lesion while the rest had diffuse disease. A comprehensive review of our cases suggests that patients with paternally inherited ABCC8 variants, whether autosomal recessive, heterozygous, or associated with genetic syndromes, were heterogeneous in their clinical manifestations and cannot be reliably distinguished based on their initial clinical presentation.
A deeper understanding of the genotype-phenotype correlation of ABCC8-related CHI will require further research and functional analyses. Both a genetic diagnosis and imaging using 18F-DOPA-PET should be pursued in a timely manner once diazoxide unresponsiveness has been established. Single-stage near-total pancreatectomy may be considered for patients with diffuse disease.
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References
1. Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab. 2007;9(Suppl 2):28-39. https://pubmed.ncbi.nlm.nih.gov/17919176 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611803 https://doi.org/10.1111/j.1463-1326.2007.00772.x
2. 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): 426-9. https://pubmed.ncbi.nlm.nih.gov/7716548 https://doi.org/10.1126/science.7716548
3. Butnariu LI, Bizim DA, Păduraru G, et al. Congenital hyperinsulinism caused by mutations in ABCC8 gene associated with early-onset neonatal hypoglycemia: Genetic heterogeneity correlated with phenotypic variability. Int J Mol Sci. 2024;25(10):5533. https://pubmed.ncbi.nlm.nih.gov/38791571 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11122115 https://doi.org/10.3390/ijms25105533
4. Kumar A, Pramanik S, Ghosh S, Saha B. Neonatal hypoglycaemia due to ABCC8 gene mutation. Indian J Endocrinol Metab. 2020;24(6):555-8. https://pubmed.ncbi.nlm.nih.gov/33643876 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906097 https://doi.org/10.4103/ijem.IJEM_780_20
5. Yan FF, Lin YW, MacMullen C, Ganguly A, Stanley CA, Shyng SL. Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: Identification and rescue. Diabetes. 2007;56(9):2339-48. https://pubmed.ncbi.nlm.nih.gov/17575084 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225993 https://doi.org/10.2337/db07-0150
6. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: Current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63. https://pubmed.ncbi.nlm.nih.gov/21967988 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199232 https://doi.org/10.1186/1750-1172-6-63
7. De Franco E, Saint-Martin C, Brusgaard K, et al. Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. Hum Mutat. 2020;41(5):884-905. https://pubmed.ncbi.nlm.nih.gov/32027066 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187370 https://doi.org/10.1002/humu.23995
8. Glaser B, Thornton P, Otonkoski T, Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F79-86. https://pubmed.ncbi.nlm.nih.gov/10685979 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1721059 https://doi.org/10.1136/fn.82.2.f79
9. 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):891-94. https://pubmed.ncbi.nlm.nih.gov/21716120 https://doi.org/10.1097/GIM.0b013e31821fea33
10. 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(4):557-64. https://pubmed.ncbi.nlm.nih.gov/23345197 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599069 https://doi.org/10.1530/EJE-12-0673
11. Nessa A, Aziz QH, Thomas AM, Harmer SC, Tinker A, Hussain K. Molecular mechanisms of congenital hyperinsulinism due to autosomal dominant mutations in ABCC8. Hum Mol Genet. 2015;24(18):5142-53. https://pubmed.ncbi.nlm.nih.gov/26092864 https://doi.org/10.1093/hmg/ddv233
12. Joyce CM, Houghton JA, O'Halloran DJ, O'Shea PM, O'Connell SM. Inheritance of a paternal ABCC8 variant and maternal loss of heterozygosity at 11p15 retrospectively unmasks the etiology in a case of Congenital hyperinsulinism. Clin Case Rep. 2020;8(7):1217-22. https://pubmed.ncbi.nlm.nih.gov/32695361 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364106 https://doi.org/10.1002/ccr3.2885
13. Sait H, Sharma L, Dabadghao P, Phadke SR. Congenital hyperinsulinemia of infancy: Role of molecular testing in management and genetic Counseling. Indian J Pediatr. 2022;89(4):395-8. https://pubmed.ncbi.nlm.nih.gov/35182381 https://doi.org/10.1007/s12098-021-04014-x
14. Chandran S, Peng FY, Rajadurai VS, et al. Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism. Endocrinol Diabetes Metab Case Rep. 2013;2013:130041. https://pubmed.ncbi.nlm.nih.gov/24616771 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922076 https://doi.org/10.1530/EDM-13-0041
15. Wong E, Bertin N, Hebrard M, et al. The Singapore national precision medicine strategy. Nat Genet. 2023;55(2):178-86. https://pubmed.ncbi.nlm.nih.gov/36658435 https://doi.org/10.1038/s41588-022-01274-x
16. Singapore Department of Statistics. Published in 2025. https://www.singstat.gov.sg/find-data/search-by-theme/population/births-and-fertility/latest-data
17. 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. https://pubmed.ncbi.nlm.nih.gov/30246418 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585719 https://doi.org/10.1111/dme.13823
18. Yorifuji T. Congenital hyperinsulinism: Current status and future perspectives. Ann Pediatr Endocrinol Metab. 2014;19(2):57-68. https://pubmed.ncbi.nlm.nih.gov/25077087 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114053 https://doi.org/10.6065/apem.2014.19.2.57
19. Männistö JME, Jääskeläinen J, Otonkoski T, Huopio H. Long-term outcome and treatment in persistent and transient congenital hyperinsulinism: A Finnish population-based study. J Clin Endocrinol Metab. 2021;106(4):e1542-51. https://pubmed.ncbi.nlm.nih.gov/33475139 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993590 https://doi.org/10.1210/clinem/dgab024
20. Crétolle C, Fékété CN, Jan D, et al. Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: A report of 45 cases from 1983 to 2000. J Pediatr Surg. 2002;37(2):155-8. https://pubmed.ncbi.nlm.nih.gov/11819190 https://doi.org/10.1053/jpsu.2002.30241
21. Dastamani A, Yau D, Gilbert C, et al. Variation in glycemic outcomes in focal forms of congenital hyperinsulinism - The UK perspective. J Endocr Soc. 2022;6(6):bvac033. https://pubmed.ncbi.nlm.nih.gov/35592516 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113085 https://doi.org/10.1210/jendso/bvac033
22. 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. https://pubmed.ncbi.nlm.nih.gov/24840042 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026387 https://doi.org/10.1371/journal.pone.0098054
23. 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. https://pubmed.ncbi.nlm.nih.gov/30343978 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339589 https://doi.org/10.1016/j.jpedsurg.2018.10.030
24. 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. https://pubmed.ncbi.nlm.nih.gov/22190679 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263917 https://doi.org/10.2337/dc11-1296
25. Verkarre V, Fournet JC, de Lonlay P, et al. 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(7):1286-91. https://pubmed.ncbi.nlm.nih.gov/9769320 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508975 https://doi.org/10.1172/JCI4495
26. Grange DK, Nichols CG, Singh GK, Guilliams K, Aggarwal M. Cantú syndrome. Updated January 29, 2026. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2026. Bookshelf ID: NBK246980
27. McClenaghan C, Hanson A, Sala-Rabanal M, et al. Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms. J Biol Chem. 2018;293(6):2041-52. https://pubmed.ncbi.nlm.nih.gov/29275331 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808765 https://doi.org/10.1074/jbc.RA117.000351
28. Zenker M, Mohnike K, Palm K. Syndromic forms of congenital hyperinsulinism. Front Endocrinol (Lausanne). 2023;14:1013874. https://pubmed.ncbi.nlm.nih.gov/37065762 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10098214 https://doi.org/10.3389/fendo.2023.1013874
29. Ismail D, Smith VV, de Lonlay P, et al. Familial focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2011;96(1):24-8. https://pubmed.ncbi.nlm.nih.gov/20943779 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217340 https://doi.org/10.1210/jc.2010-1524
30. Flanagan SE, Clauin S, Bellanné-Chantelot C, et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat. 2009;30(2):170-180. https://pubmed.ncbi.nlm.nih.gov/18767144 https://doi.org/10.1002/humu.20838
31. Smith RL, Stone SI. Identification of an ABCC8 variant in a kindred with transient diazoxide responsive hyperinsulinism. Endocrinol Diabetes Metab Case Rep. 2025;2025(3):e240106. https://pubmed.ncbi.nlm.nih.gov/40605820 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232995 https://doi.org/10.1530/EDM-24-0106
32. Chang G, Ying L, Zhang Q, et al. Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia. BMC Endocr Disord. 2024;24(1):8. https://pubmed.ncbi.nlm.nih.gov/38212772 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10785495 https://doi.org/10.1186/s12902-023-01527-8
33. Rosenfeld E, Mitteer L, Boodhansingh K, et al. Case report: Two distinct focal congenital hyperinsulinism lesions resulting from separate genetic events. Front Pediatr. 2021;9:699129. https://pubmed.ncbi.nlm.nih.gov/34336745 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322518 https://doi.org/10.3389/fped.2021.699129
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