Institute for Children's Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro.
Department of Pediatric Endocrinology, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", Radoja Dakica 8, Belgrade, 11070, Serbia.
Eur J Pediatr. 2021 Sep;180(9):2815-2821. doi: 10.1007/s00431-021-04051-w. Epub 2021 Mar 26.
Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: • Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). • Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: • Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. • Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.
新生儿和婴儿持续性低血糖最常见的原因是先天性高胰岛素血症（CHI）。大多数 CHI 研究报告了来自近亲结婚和非近亲结婚家庭的儿童的结果，这可能会影响表型-基因型分析。本研究的目的是分析来自塞尔维亚 21 个非近亲结婚家庭的 CHI 患者的特征。这项回顾性队列研究共纳入了过去 20 年在塞尔维亚母婴保健研究所接受治疗的 21 名 CHI 患者。我们的队列中出生时巨大儿的患病率非常低（4.8%）。中位发病年龄为 6 天，76%的患者以癫痫发作为首发症状。仅有 4 名患者（19%）对二氮嗪无反应，最终接受了胰腺切除术。对 15 名患者进行了基因检测，60%的患者基因诊断得到确认，所有患者均为检测到突变的杂合子。55.6%的患者检测到 ABCC8 基因突变，3 名患者（33.3%）存在 HIHA 综合征，1 名患者存在 HNF4A 基因突变，二氮嗪停药后出现异常延长的高血糖，持续 6 天。33%的患者存在神经发育缺陷。结论：这是塞尔维亚关于 CHI 患者的第一项研究。它表明，在近亲结婚率低的国家，大多数 CHI 患者对二氮嗪有反应。最常见的突变是杂合 ABCC8，其次是 GLUD1 和 HNF4A 突变，这表明在近亲结婚率低的地区，通过针对显性遗传模式导致 CHI 的突变，采用人群特异性基因分析方法具有潜在的益处。已知：•婴儿期和幼儿期持续性低血糖最常见的原因是先天性高胰岛素血症（CHI）。•近亲结婚是 CHI 遗传和表型的一个非常重要的因素，增加了常染色体隐性遗传疾病的风险，包括由 ABCC8 和 KCNJ11 隐性失活突变引起的严重、二氮嗪无反应的形式。新内容：•本研究包括来自 21 个非近亲结婚家庭的 CHI 患者，结果表明，在近亲结婚率低的国家，大多数 CHI 患者可以对二氮嗪有反应，最常见的突变是杂合 ABCC8，其次是 GLUD1 和 HNF4A 突变。•本研究还描述了一名 HNF4A 突变患者在接受二氮嗪治疗时出现异常延长的高血糖反应。
