Arya Ved Bhushan, Guemes Maria, Nessa Azizun, Alam Syeda, Shah Pratik, Gilbert Clare, Senniappan Senthil, Flanagan Sarah E, Ellard Sian, Hussain Khalid
Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK.
Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK.
Eur J Endocrinol. 2014 Dec;171(6):685-95. doi: 10.1530/EJE-14-0353. Epub 2014 Sep 8.
Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported.
The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.
A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted.
Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology.
Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
先天性高胰岛素血症（CHI）有两种主要的组织学类型：弥漫性和局灶性。父系遗传的ABCC8/KCNJ11杂合突变（取决于其是隐性还是显性作用以及体细胞母系等位基因缺失的发生情况）可导致任何一种表型。然而，在一大群因父系遗传的ABCC8/KCNJ11杂合突变而患CHI的患者中，这两种表型的相对比例尚未见报道。
本研究的目的是突出可变的临床表型，并描述一大群因父系遗传的ABCC8/KCNJ11杂合突变而患CHI的患者中弥漫性和局灶性疾病的分布情况。
对2000年至2013年因父系遗传的ABCC8/KCNJ11杂合突变而患CHI的患者进行回顾性病历审查。
在53例CHI患者中鉴定出父系遗传的ABCC8/KCNJ11杂合突变。其中，18例（34%）对二氮嗪有反应或自发缓解。18例儿童中的3例进行氟-18 l-3,4-二羟基苯丙氨酸正电子发射断层扫描计算机断层扫描（18F DOPA-PET CT）显示为弥漫性疾病。其余35例（66%）对二氮嗪无反应的儿童要么进行了胰腺静脉采血（n = 8），要么进行了18F DOPA-PET CT（n = 27）。分别在13例、1例和21例患者中鉴定出弥漫性、不确定和局灶性疾病。两名疑似弥漫性疾病的患者经组织学检查确定为局灶性疾病。
父系遗传的ABCC8/KCNJ11杂合突变可表现为广泛的CHI，具有可变的18F DOPA-PET CT/组织学表现和临床结局。在53例因父系遗传的ABCC8/KCNJ11杂合突变而患CHI的患者中，24例（45%）经组织学证实为局灶性疾病。
