Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations
Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations
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DOI：
10.1530/eje-09-0861
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Ellard, S.
中科院分区：
文献类型：
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作者：
Flanagan, S. E.;Kapoor, R. R.;Ellard, S.
目的：与杂合子HNF4A基因突变相关的表型最近已经扩展到包括二氮氧化合物反应性新生儿低血糖以及成熟型糖尿病（MODY）。迄今为止，突变筛查仅限于具有与MODY一致的家族史的患者。在这项研究中，我们调查了HNF4A突变在一大批二氮氧化合物反应性高胰岛素性低血糖症（HH）患者中的患病率。研究对象和方法：我们对220例对二氮氧化物有反应的HH患者的ABCC8、KCNJ11、GCK、GLUD1和/或HNF4A基因进行了测序。基因检测的顺序取决于临床表型。结果：遗传学诊断为59/220（27%）。K-ATP通道突变最为常见（15%），其次是GLUD1突变导致高胰岛素血症伴高氨血症（5.9%）和HNF4A突变（5%）。在11个携带杂合性HNF4A突变的先证中，有7个父母没有糖尿病，4个新突变被证实。这些患者在出生后第一周（中位年龄1天）被诊断为HI，并且他们的出生体重增加（中位+2.4 SDS）。二氮唑治疗的持续时间从3个月到8年不等。结论：在这个大系列中，HNF4A突变是导致二氮氧化物反应性HH的第三大常见原因。我们建议在排除KATP通道突变后，对所有出生第一周诊断为二氮氧化合物反应性HH的患者考虑HNF4A测序，无论其是否有糖尿病家族史。
Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype.Results: A genetic diagnosis was possible for 59/220 (27%) patients. K-ATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years.Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.