Abstract：
Maturity-Onset Diabetes of the Youth (MODY) diabetes remains commonly misdiagnosed. A monogenic form should be suspected in individuals presenting hyperinsulinemic hypoglycemia (HH) associated with, either later development of MODY (hypoglycemia-remission-diabetes sequence), or with first/second-degree family history of diabetes. Herein, we aimed to describe this individual or family monogenic association between HH and diabetes, and identify potential genotype-phenotype correlations. We conducted a systematic review of 26 studies, including a total of 67 patients with this association resulting from variants in GCK (n = 5 cases), ABCC8 (n = 29), HNF1A (n = 5), or HNF4A (n = 28). A family history of hypoglycemia and/or diabetes was present in 91% of cases (61/67). Median age at first hypoglycemia was 24 h after birth. Diazoxide was initiated in 46 children (46/67-69%); responsiveness was found in 91% (42/46). Median HH duration was three years (1 day-25 years). Twenty-three patients (23/67-34%) later developed diabetes (median age: 13 years; range: 8-48); more frequently in those untreated with diazoxide. This association was most commonly inherited in an autosomal dominant manner (43/48-90%). Some genes were associated with less severe initial hypoglycemia (HNF1A), shorter duration of HH (HNF4A), and more maternal (ABCC8) or paternal (HNF4A) transmission. This study illustrates that the same genotype can give a biphasic phenotype in the same person or a reverse phenotype in the same family. Wider awareness of this association is necessary in pediatrics to establish annual monitoring of patients who have presented HH, and during maternity to screen diabetes and optimize genetic counseling and management of pregnancy, childbirth, and the newborn.PROSPERO registration: CRD42020178265.
摘要：
青年早期糖尿病（MODY）糖尿病通常被误诊。在出现高胰岛素血症性低血糖（HH）的个体中应怀疑单基因形式，MODY（低血糖-缓解-糖尿病序列）的晚期发展，或有一/二级糖尿病家族史。在这里，我们旨在描述HH与糖尿病之间的个体或家族单基因关联，并确定潜在的基因型-表型相关性。我们对26项研究进行了系统回顾，包括总共67例GCK变异导致这种关联的患者（n=5例），ABCC8（n=29），HNF1A（n=5），或HNF4A（n=28）。91%的病例有低血糖和/或糖尿病家族史(61/67)。首次低血糖的中位年龄为出生后24小时。46名儿童（46/67-69％）开始使用二氮嗪；91％（42/46）的反应性。平均HH持续时间为3年(1天-25年)。23名患者（23/67-34％）后来发展为糖尿病（中位年龄：13岁；范围：8-48）；在未经二氮嗪治疗的患者中更常见。这种关联最常以常染色体显性遗传方式遗传（43/48-90％）。一些基因与较不严重的初始低血糖（HNF1A）相关，HH持续时间较短（HNF4A），和更多的母亲（ABCC8）或父亲（HNF4A）传播。这项研究表明，相同的基因型可以在同一个人中产生双相表型或在同一家庭中产生反向表型。在儿科中，有必要对这种关联进行更广泛的认识，以建立对出现HH的患者的年度监测，在孕产期间筛查糖尿病，优化遗传咨询和妊娠管理，分娩,和新生儿。PROSPERO注册：CRD42020178265。
