Yavas Abali Zehra, Bas Firdevs, Houghton Jayne A L, Abali Saygin, Karakilic Ozturan Esin, Gulec Cagrı, Aslanger Ayca Dilruba, Kandemir Tugce, Durmaz Durmus, Yucesoy Mehmet Akif, Flanagan Sarah E, Poyrazoglu Sukran, Bundak Ruveyde, Darendeliler Feyza
Istanbul University, Institute of Health Sciences, Department of Genetics, Istanbul, Türkiye.
Istanbul University, Istanbul Faculty of Medicine, Pediatric Endocrinology Unit, Istanbul, Türkiye.
Endocrine. 2025 May 18. doi: 10.1007/s12020-025-04244-5.
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.
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.
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.
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.
先天性高胰岛素血症（CHI）是新生儿和婴儿反复低血糖最常见的原因，源于胰腺β细胞胰岛素分泌调节途径的缺陷。本研究旨在评估CHI队列的临床和遗传特征，并探讨管理这种异质性疾病所涉及的复杂性。
40例CHI患者（23例女孩）纳入本研究。从病历中获取CHI的诊断和治疗数据。
诊断时的中位年龄为1.4个月（范围0.1 - 30个月）。平均胎龄为37.8±2.4周，出生体重为1.1±2.0 SDS。近亲结婚率为35.0%。诊断时葡萄糖、胰岛素和C肽浓度的中位数分别为34.0mg/dl（IQR 25.2 - 41.7）、12.4µU/ml（IQR 4.4 - 27.1）和1.5ng/ml（IQR 0.7 - 3.8）。分子遗传学诊断可在62.5%（n = 25）的患者中确立。致病变异主要在KATP通道基因中发现（17/25，68%），其中ABCC8最为常见（n = 15；双等位基因：8例，单等位基因：7例）。在2例（5.0%）中发现KCNJ11变异，3例（7.5%）中发现GLUD1变异，5例患者（12.5%）中发现HADH变异。10例患者接受了胰腺切除术，手术时的平均年龄为3.9±3.2个月。在所有接受胰腺切除术的患者中均确定了遗传病因，所有患者的KATP通道均有缺陷。9例检测到ABCC8变异（双等位基因：5例，单等位基因：4例），1例中发现KCNJ11的双等位基因变异。
在我们的队列中约三分之二的患者确定了分子遗传学诊断，强调了基因检测在CHI管理中的重要性。预计基因技术的不断进步将增进我们对CHI病因发病机制的理解，并支持开发更个性化的治疗策略。尽管基因型 - 表型相关性仍仅部分阐明，但特定的基因变异可能为治疗抵抗提供预测性见解，从而为更有针对性的治疗方法提供依据。
