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. 2025 Aug;89(2):416-428.
doi: 10.1007/s12020-025-04244-5. Epub 2025 May 18.

Comprehensive clinical and molecular characterization with long-term outcomes in 40 patients with congenital hyperinsulinism

Zehra Yavas Abali  1   2 , Firdevs Bas  3 , Jayne A L Houghton  4 , Saygin Abali  3   5 , Esin Karakilic Ozturan  3 , Cagrı Gulec  6 , Ayca Dilruba Aslanger  6 , Tugce Kandemir  3 , Durmus Durmaz  6 , Mehmet Akif Yucesoy  6 , Sarah E Flanagan  7 , Sukran Poyrazoglu  3 , Ruveyde Bundak  3   8 , Feyza Darendeliler  3
Affiliations

Comprehensive clinical and molecular characterization with long-term outcomes in 40 patients with congenital hyperinsulinism

Zehra Yavas Abali et al. Endocrine. 2025 Aug.

Abstract

Purpose: Congenital hyperinsulinism (CHI) represents the most frequent cause of recurrent hypoglycemia in neonates and infants, stemming from defects in the regulatory pathways of insulin secretion from pancreatic beta cells. This study aims to assess the clinical and genetic characteristics of a CHI cohort and to discuss the complexities involved in managing this heterogeneous disorder.

Methods: Forty patients (23 girls) with CHI were included in the study. Data on the diagnosis and treatment of CHI were obtained from the medical records.

Results: The median age at diagnosis was 1.4 months (range 0.1-30 months). The mean gestational age was 37.8 ± 2.4 weeks, and the birth weight was 1.1 ± 2.0 SDS. The consanguinity ratio was 35.0%. Median glucose, insulin, and C-peptide concentrations at diagnosis were 34.0 mg/dl (IQR 25.2-41.7), 12.4µU/ml (IQR 4.4-27.1), and 1.5 ng/ml (IQR 0.7-3.8), respectively. Molecular genetic diagnosis could be established in 62.5% (n = 25). Pathogenic variants were predominantly identified in the KATP channel genes (17/25, 68%), with the ABCC8 being the most frequent (n = 15; biallelic: 8, monoallelic: 7). KCNJ11 variants were identified in two (5.0%), GLUD1 variants in three (7.5%), and HADH variants in five patients (12.5%). Pancreatectomy was performed in 10 patients, with a mean age at the time of surgery of 3.9 ± 3.2 months. The genetic etiology was identified in all patients who underwent pancreatectomy, all of whom had defects in the KATP channel. ABCC8 variants were detected in nine (biallelic: 5, monoallelic: 4), while a biallelic variant in the KCNJ11 was identified in one case.

Conclusion: A molecular genetic diagnosis was identified in approximately two-thirds of our cohort, underscoring the significance of genetic testing in the management of CHI. Ongoing advances in genetic technologies are anticipated to enhance our understanding of the etiopathogenesis of CHI and support the development of more personalized therapeutic strategies. Although the genotype-phenotype correlation remains only partially elucidated, specific genetic variants may provide predictive insights into treatment resistance, thereby informing more targeted treatment approaches.

Keywords: ABCC8; GLUD1; HADH; KCNJ11; Congenital hyperinsulinism.

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Conflict of interest statement

Compliance with ethical standards. Informed consent: Written informed consent was obtained from the parents, including molecular genetic studies. Statement of ethics: Ethical approval was obtained for the study from the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (2023/567). The patients/their parents gave general consent approving anonymous data use for academic purposes, and written informed consent was obtained for participation in this study. Written informed consent was obtained from the parents for the publication of this study. Conflict of interest: The authors declare no competing interests.

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