James C, Kapoor R R, Ismail D, Hussain K
London Centre for Paediatric Endocrinology and Metabolism, Hospital for Children NHS Trust, and The nstitute of Child Health,University College London, London, UK.
J Med Genet. 2009 May;46(5):289-99. doi: 10.1136/jmg.2008.064337. Epub 2009 Mar 1.
Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic beta-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period. Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from beta-cells. Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate sensitive potassium channels (ATP sensitive K(ATP) channels)) in beta-cells are the most common cause of CHI. The other recessive form of CHI is due to mutations in HADH (encoding for-3-hydroxyacyl-coenzyme A dehydrogenase). Dominant forms of CHI are due to inactivating mutations in ABCC8 and KCNJ11, and activating mutations in GLUD1 (encoding glutamate dehydrogenase) and GCK (encoding glucokinase). Recently dominant mutations in HNF4A (encoding hepatocyte nuclear factor 4alpha) and SLC16A1 (encoding monocarboxylate transporter 1) have been described which lead to HH. Mutations in all these genes account for about 50% of the known causes of CHI. Histologically there are three (possibly others which have not been characterised yet) major subtypes of CHI: diffuse, focal and atypical forms. The diffuse form is inherited in an autosomal recessive (or dominant manner), the focal form being sporadic in inheritance. The diffuse form of the disease may require a near total pancreatectomy whereas the focal form requires a limited pancreatectomy potentially curing the patient. Understanding the genetic basis of CHI has not only provided novel insights into beta-cell physiology but also aided in patient management and genetic counselling.
先天性高胰岛素血症（CHI）的生化特征是胰腺β细胞胰岛素分泌失调。它是新生儿和婴儿期持续性高胰岛素血症性低血糖症（HH）的主要原因。从遗传学角度来看，CHI是一种异质性疾病，已发现七个不同基因发生突变。CHI的遗传基础涉及调节β细胞胰岛素分泌的关键基因缺陷。β细胞中ABCC8和KCNJ11（编码三磷酸腺苷敏感性钾通道（ATP敏感性K（ATP）通道）的两个亚基）的隐性失活突变是CHI最常见的原因。CHI的另一种隐性形式是由于HADH（编码3-羟酰基辅酶A脱氢酶）发生突变。CHI的显性形式是由于ABCC8和KCNJ11的失活突变，以及GLUD1（编码谷氨酸脱氢酶）和GCK（编码葡萄糖激酶）的激活突变。最近，已描述了HNF4A（编码肝细胞核因子4α）和SLC16A1（编码单羧酸转运体1）的显性突变，这些突变会导致HH。所有这些基因的突变约占已知CHI病因的50%。组织学上，CHI有三种（可能还有其他尚未明确特征的）主要亚型：弥漫型、局灶型和非典型型。弥漫型以常染色体隐性（或显性方式）遗传，局灶型遗传方式为散发性。该疾病的弥漫型可能需要近乎全胰腺切除术，而局灶型则需要有限的胰腺切除术，有可能治愈患者。了解CHI的遗传基础不仅为β细胞生理学提供了新的见解，也有助于患者管理和遗传咨询。
