Al-Hussaini Abdulrahman, AlSaleem Badr, AlHomaidani Hamad, Asery Ali, Alruwaithi Muhanad, Alameer Mohammed, Afashah Waleed, Salman Bashir Muhammed, Almontashiri Naif
The Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Front Pediatr. 2021 Nov 10;9:741835. doi: 10.3389/fped.2021.741835. eCollection 2021.
There are only a few case reports and small case series on neonatal-onset Dubin-Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe. In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS. We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in gene. Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3-6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5-14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes ( < 0.001). The median urinary coproporphyrin I% was 88% (IQ1-IQ3 = 84.2-92.7%). We identified four homozygous variants in the gene (from 22 unrelated families), one splicing variant (c.3258+1G>A; p.?), and three were missense variants; two of which were novel missense variants [c.1594G>A (p.Glu532Lys) and c.2439G>C (p.Lys813Asn)]. The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families). Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with "founder effects." Identification of the predominant variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.
关于新生儿期发病的杜宾-约翰逊综合征（DJS），仅有少数病例报告和小型病例系列研究，特别是来自远东地区、伊朗和摩洛哥犹太人以及欧洲的相关研究。在这项来自阿拉伯人群的首次研究以及迄今为止报告的最大病例系列中，我们描述了基因确诊的新生儿期发病DJS的临床、实验室和分子特征及转归。我们回顾了2008年至2019年期间在我们中心就诊的533例新生儿胆汁淤积症患者的数据库。我们确定了基因中存在致病突变的新生儿。28例新生儿被诊断为DJS（5.3%）。这28例均为足月儿，外观良好，无肝脾肿大，自出生1周起出现胆汁淤积，肝脏合成功能正常，在3至6个月龄时症状缓解，随后在中位随访期9.25年（范围2.5至14年）内，43%的患儿出现黄疸复发，病程呈良性。26例患者（92%）的丙氨酸转氨酶水平在正常范围内，2例患者轻度升高。DJS新生儿的ALT水平显著低于其他病因导致的新生儿胆汁淤积症患者（<0.001）。尿中粪卟啉I%的中位数为88%（四分位间距1-四分位间距3 = 84.2-92.7%）。我们在基因中鉴定出4个纯合变异（来自22个无亲缘关系的家庭），1个剪接变异（c.3258+1G>A；p.?），3个为错义变异；其中2个为新的错义变异[c.1594G>A（p.Glu532Lys）和c.2439G>C（p.Lys813Asn）]。p.Gly758Val突变出现在23例患者中（来自19个无亲缘关系的家庭）。我们的研究表明，外观良好的新生儿出现正常ALT水平的胆汁淤积应引发对DJS的评估。ABCC2基因中的p.Gly758Val变异是阿拉伯人群中具有“奠基者效应”的最主要突变。确定任何人群中的主要变异可能有助于通过未来针对该特定突变进行靶向检测来实现快速分子分析。
