Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Prince Abdullah bin Khalid Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia.
Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
J Pediatr. 2021 Sep;236:113-123.e2. doi: 10.1016/j.jpeds.2021.04.040. Epub 2021 Apr 27.
To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations.
We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease).
Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively).
We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.
描述阿拉伯人群中经基因证实的进行性家族性肝内胆汁淤积症（PFIC）1-3 的临床、实验室、组织学和分子特征，并评估“基因型-表型”相关性。
我们回顾性分析了 2008 年至 2019 年间因胆汁淤积就诊的 65 名儿童（ATP8B1 缺陷=5，ABCB11=35，ABCB4=25）的病历。根据胆汁淤积和瘙痒对熊去氧胆酸的反应以及最终结果，将疾病的临床表型分为轻度（完全缓解）、中度（部分缓解、非进行性）和重度（进展为终末期肝病）。
共发现 27 种不同的突变（ATP8B1，n=5；ABCB11，n=11；ABCB4，n=11），包括 10 种新突变。6 名携带杂合错义突变的患者（ATP8B1，n=2；ABCB11，n=4）出现短暂性胆汁淤积。在其余 3 名 PFIC1 患者中，2 名患者出现严重表型（剪接和移码突变）。在其余 31 名 PFIC2 患者中，25 名患者出现严重疾病（15 名因移码和剪接突变）。在 25 名 PFIC3 患者中，10 名患者出现严重表型（1 名剪接和 3 名移码突变；6 名错义突变）。PFIC2 患者的生存时间明显短于 PFIC3 患者（P<.001），疾病进展速度也明显快于 PFIC3 患者。ABCB11 基因（p.Thr127Hisfs∗6）和 ABCB4 基因（p.Phe210Serfs∗5）中存在移码突变的患者的生存时间明显短于错义突变患者（P=.011；P=.0039）。
我们在 ABCB11 和 ABCB4 基因的突变中发现了基因型-表型相关性，这突显了早期基因诊断的预后价值。熊去氧胆酸治疗可显著改善 PFIC3 患者的疾病进程。
