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 heterogenous 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.
Downloads
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`````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````````
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Cherie Chua, Daniel Chan, Ai Ling Koh, Suresh Chandran, Fabian Yap
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The full license text is available at: http://creativecommons.org/licenses/by-nc/3.0/legalcode.
To request permission to translate, reproduce, download, or use articles or images for commercial reuse or business purposes from the Journal of the ASEAN Federation of Endocrine Societies (JAFES), kindly complete the Permission Request for Use of Copyrighted Material Form and email jafes@asia.com or jafes.editor@gmail.com.
A written agreement will be issued to the requester once permission has been granted.
