遗传性球形红细胞增多症合并胆汁淤积患儿的临床和基因型分析

Clinical and genotypic analysis of hereditary spherocytosis combined with cholestasis among pediatric patients

目的了解合并胆汁淤积的遗传性球形红细胞增多症(HS)患儿的临床特征及遗传学特点。方法2013年1月至2022年12月期间湖南省儿童医院12例伴胆汁淤积的HS患儿为研究对象,收集临床资料,采用二代测序进行全外显子测序,应于Sanger测序法对疑似致病突变位点进行验证。结果患儿均因皮肤黄染入院,8例(66.67%)患儿有阳性家族史,临床表现为黄疸、脾大(12/12)、腹痛、贫血(4/12)和肝大(5/12)。所有患儿血红蛋白下降,网织红细胞比例、总胆红素和直接胆红素升高,红细胞脆性试验阳性,外周血可见球形红细胞。转氨酶升高者7例,重度转氨酶和胆红素升高者4例,胆道结石者8例,胆道扩张者2例。3例患儿肝脏病理检查提示肝细胞轻度损害(G1S1)。5例患儿共发现6种未报道突变,SPTB基因c.2431_2450del、c.4974-2A>G、c.2575G>A和22~35号外显子缺失,ANK1基因:c.2379-2380delCA和c.6dupC。经治疗后患儿胆红素仍有异常,2例患儿行脾脏切除,术后胆红素和血红蛋白恢复正常。结论HS患儿可出现胆汁淤积,治疗效果欠佳的患儿可考虑行脾脏切除术,6种新基因变异扩展了HS的基因突变谱。

Objective To understand the clinical and genetic characteristics of hereditary spherocytosis(HS)combined with cholestasis among pediatric patients.Methods 12 cases of HS children accompanied by cholestasis at Hunan Children's Hospital were selected as the research subjects between January 2013 and December 2022.Clinical data were collected.Whole-exome sequencing was performed by second-generation sequencing.Suspected pathogenic mutation sites were verified by Sanger sequencing.Results All pediatric patients were admitted to the hospital due to their yellow skin tone.Eight cases(66.67%)had a positive family history.The clinical manifestations were jaundice,splenomegaly(12/12),abdominal pain,anemia(4/12),and hepatomegaly(5/12).All pediatric patients had decreased hemoglobin,an increased reticulocyte ratio,total bilirubin and direct bilirubin,a positive erythrocyte fragility test,and remarkable spherical erythrocytes in their peripheral blood.Seven cases had elevated aminotransferase;four cases had severely elevated aminotransferase and bilirubin;eight cases had biliary calculi;and two cases had a dilated biliary tract.Liver pathological examination showed mild damage to the liver cells(G1S1)in three pediatric cases.Five children had a total of six unreported mutations:SPTB gene c.2431_2450del,c.4974-2A>G,c.2575G>A,and exon 22-35 deletion;ANK1 gene:c.2379-2380delC;and c.6dupC.Children still had abnormal bilirubin levels following treatment.Two pediatric cases underwent splenectomy.Bilirubin and hemoglobin levels returned to normal after surgery.Conclusion Children with HS may experience cholestasis,and those with poor treatment results may consider undergoing a splenectomy.Six new types of variants have expanded the HS gene mutation spectrum.