Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders
Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders
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DOI：
10.1210/jc.2015-3651
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发表时间：
2016-03-01
影响因子：
5.8
通讯作者：
Stanley, Charles A.
中科院分区：
文献类型：
--
作者：
Stanley, Charles A.
背景：先天性高胰岛素血症（HI）是儿童低血糖的最常见原因。由于诊断延误和治疗不充分，HI婴儿永久性脑损伤的风险仍然高达25-50%。自JCEM诞生以来，先天性HI被描述为各种术语，包括“婴儿期特发性低血糖”、“亮氨酸敏感性低血糖”或“胰岛母细胞增多症”。“取证：在过去的20年里，很明显HI是由调节胰腺β细胞胰岛素分泌的途径中的遗传缺陷引起的。证据合成：现在有11个基因与单基因形式的HI相关（ABCC 8、KCNJ 11、GLUD 1、GCK、HADH 1、UCP 2、MCT 1、HNF 4A、HNF 1A、HK 1、PGM 1），以及几种综合征遗传形式的HI（例如Beckwith-Wiedemann、Kabuki和Turner综合征）。HI也是过渡性新生儿低血糖和各种高危新生儿（如出生窒息、小于胎龄儿体重、糖尿病母亲的婴儿）持续性低血糖的原因。HI的管理是儿科内分泌学家面临的最困难的问题之一，并且经常需要困难的选择，例如近全胰腺切除术和/或持续管饲的高度重症监护。50年来，KATP通道激动剂二氮嗪一直是HI婴儿的主要药物;然而，它在大多数ABCC 8或KCNJ 11突变的病例中无效，而ABCC 8或KCNJ 11突变构成了大多数单基因HI婴儿。基因突变检测已成为HI婴儿的标准护理，并已被证明不仅在预测预后和家庭咨询方面有用，而且还用于诊断具有可手术治愈的局灶性HI病变的婴儿。已经发现F-18-氟-L-二羟基苯丙氨酸（F-18-DOPA）PET扫描对于术前定位这种局灶性病变是高度准确的。正在研究的新药为改善HI儿童的预后带来了希望。
Context: Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25-50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including "idiopathic hypoglycemia of infancy," "leucine-sensitive hypoglycemia," or "nesidioblastosis."Evidence Acquisition: In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic beta-cell insulin secretion.Evidence Synthesis: There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother). Management of HI is one of the most difficult problems faced by pediatric endocrinologists and frequently requires difficult choices, such as near-total pancreatectomy and/or highly intensive care with continuous tube feedings. For 50 years, diazoxide, a KATP channel agonist, has been the primary drug for infants with HI; however, it is ineffective in most cases with mutations of ABCC8 or KCNJ11, which constitute the majority of infants with monogenic HI.Conclusions: Genetic mutation testing has become standard of care for infants with HI and has proven to be useful not only in projecting prognosis and family counseling, but also in diagnosing infants with surgically curable focal HI lesions. F-18-fluoro-L-dihydroxyphenylalanine (F-18-DOPA) PET scans have been found to be highly accurate for localizing such focal lesions preoper atively. New drugs under investigation provide hope for improving the outcomes of children with HI.