Genotype-Treatment Correlations in Iranian Children with Congenital Hyperinsulinism: A Single-Center Cohort Study

Congenital hyperinsulinism (CHI) is a rare but severe genetic disorder characterized by inappropriate insulin secretion, leading to recurrent and persistent hypoglycemia in neonates and children. If not promptly diagnosed and adequately treated, CHI may result in irreversible neurological damage. The disease shows marked clinical heterogeneity, largely driven by underlying genetic mutations, which also influence response to medical therapy and the need for surgical intervention. Data on genotype-treatment correlations remain limited, particularly in Middle Eastern populations.

This observational cohort study was conducted at a tertiary pediatric referral center between September 2023 and September 2024. Thirty-five neonates and children (aged 1 week to 18 years) with biochemically confirmed CHI underwent genetic testing using next-generation sequencing. Two patients without pathogenic or likely pathogenic variants were excluded, and 33 genetically confirmed patients were included in the final analysis. Treatment response was assessed based on glycemic stability achieved with diazoxide alone, combination medical therapy, or the requirement for pancreatectomy. Associations between genotype groups and treatment response categories were analyzed using chi-square tests or Fisher's exact test where appropriate, with a p value <0.05 considered statistically significant.

The median age at diagnosis was 11 months (IQR: 5-42). Pathogenic or likely pathogenic variants were most frequently identified in the ABCC8 and HK1 genes. Diazoxide monotherapy was effective in 60.6% (20/33) of patients, while 18.2% (6/33) required combination therapy with diazoxide and octreotide. Approximately, 21.2% (7/33) of patients were refractory to medical treatment and required surgical intervention. A statistically significant association was observed between genotype and treatment response (p = 0.026). KATP-channel gene mutations (ABCC8 and KCNJ11) were significantly associated with poor response to diazoxide and increased likelihood of pancreatectomy, whereas HK1 mutations were predominantly associated with diazoxide responsiveness.

Our findings demonstrate a significant correlation between genetic etiology and treatment response in children with CHI. Early genetic diagnosis may play a critical role in predicting therapeutic outcomes, guiding individualized treatment strategies, and avoiding unnecessary delays in definitive management. These results should be interpreted with caution given the small sample size and the rarity of certain genotypes.