Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
The Genomics Laboratory, Royal Devon University Healthcare NHS foundation Trust, Exeter EX2 5DW, UK.
J Clin Endocrinol Metab. 2023 Feb 15;108(3):680-687. doi: 10.1210/clinem/dgac604.
Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood.
We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease.
We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children.
We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy.
We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis.
先天性高胰岛素血症（HI）的特征是尽管血糖低，但胰岛素分泌仍不适当。持续性 HI 通常为单基因疾病，大多数病例在婴儿期诊断。对于在儿童期出现的疾病，单基因形式的疾病的发病机制知之甚少。
我们研究了在儿童期 HI 中发现遗传原因的可能性，并探讨了导致疾病发病年龄较晚的潜在因素。
我们在 1848 名 HI 患者中筛查了已知的致病基因，这些患者作为常规临床护理的一部分接受基因检测。患者被分为婴儿期发病（HI 诊断<12 个月）或儿童期发病（1-16 岁诊断）。我们评估了在儿童期诊断为单基因 HI 的个体的临床特征和基因型，以深入了解这些儿童 HI 诊断较晚的原因。
我们在儿童期 HI 队列中确定了单基因病因在 24%（n = 42/173）的患者中；这显著低于婴儿期 HI 病例中遗传诊断的比例（74.5%[n = 1248/1675]，P < 0.00001）。大多数（75%）经基因证实的儿童期 HI 患者在 2.7 岁之前被诊断，这表明这些病例代表了诊断年龄正态分布的末端。这一发现得到了支持，即在儿童期 HI 队列中发现的 81%的变异在婴儿期被诊断出。
我们已经表明，单基因 HI 是婴儿期以外出现的高胰岛素血症的一个重要病因。无论诊断年龄如何，对于持续性 HI 的儿童，都应考虑进行基因检测。
