临床指标结合基因突变位点分析指导儿童WAS个体化诊疗

Application of clinical parameters and genetic mutation for guiding the individualized diagnosis and treatment of children patients with Wiskott-Aldrich syndrome:analysis of 23 cases in a single-center

目的:通过应用湿疹血小板减少伴免疫缺陷综合征(WAS)评分系统回顾性评价我中心23例WAS患儿的病例资料及临床转归,为临床开展综合评价并指导个体化治疗提供依据。方法:收集我中心接收诊治23例确诊为WAS患儿的临床资料、实验室数据、基因突变位点;应用WAS评分对其逐一进行回顾性分析;并与临床预后转归进行对比分析。结果:①基本情况:23例患儿中男22例,女1例(正常X染色体失活);中位发病年龄为30 d,中位确诊年龄为6个月龄。100%存在血小板减少和不同程度的出血表现,48%(11/23例)病初血小板最低值<20×10~9/L;26%(6/23例)临床伴严重出血表现。78%(18/23例)患儿存在不同程度的感染情况,17%(4/23例)合并严重感染。39%(9/23例)患儿病初合并湿疹表现。83%(19/23例)患儿存在二联征,39%(9/23例)存在三联征。23例患儿中错义突变为48%(11/23例)。②评价结果:应用WAS评分系统进行评价,61%(14/23例)评分≥3分,考虑诊断为典型WAS;39%(9/23例)评分<3分,诊断为X连锁血小板减少症(XLT)。结合临床综合评价后错义突变中有55%(6/11例)诊断为XLT;非错义突变患儿中75%(9/12例)诊断为典型WAS(P=0.071)。③治疗转归与评价相关性:随访到20例患儿(3例失访):其中2例死亡,18例存活患儿中9例行造血干细胞移植(HSCT)治疗(8例为典型WAS),8例患儿HSCT治疗后获益。9例患儿未行HSCT治疗,其中7例为XLT,均于血小板严重减少时应用静脉注射丙种球蛋白(IVIG)治疗,伴或不伴轻度出血表现,血小板维持在(20~80)×10~9/L,不伴明显感染湿疹表现;2例为典型WAS,均存在反复感染、血小板下降及出血表现,其中1例不规律给予抗感染IVIG治疗,1例规律治疗等待行HSCT中。2例死亡患儿中,1例因合并肺出血死亡,1例因严重败血症死亡。结论:WAS作为一种免疫缺陷综合征,其临床表现具有显著异质性,需要结合临床、实验室和基因突变位点进行综合评价:对典型WAS积极开展骨髓移植治疗,对XLT长期随诊观察,可能会获得更佳预后。

Objective:To guide the clinical comprehensive evaluation and individualized treatment by retrospectively evaluating clinical parameters and disease outcome of 23 patients of children with WAS using Wiskott-Aldrich syndrome(WAS)disease severity scoring system.Method:A retrospective study was conducted in 23 children who were diagnosed with WAS.Clinical characteristic,laboratory data and gene mutation sites were collected.Result:①Twenty-two of the 23 cases were male and 1 case was female(the normal X chromosome was inactivation).Median age of onset was 30 days,and the median age of diagnosis was 6 months.All of them had thrombocytopenia and bleeding:48%(11/23)cases had the lowest platelet value<20×10~9/L at the beginning of the disease;26%(6/23)cases were associated with severe bleeding.78%(18/23)cases were infected and 17%(4/23)cases had severe infection.39%(9/23)cases had eczema at the beginning of the disease.Bigeminal signs was present in 83%(19/23)cases and trilogy was present in 39%(9/23)cases.Two cases(9%)had autoimmune disease,and no one had malignant tumor.48%(11/23)cases had missense mutation.(2)WAS disease severity scoring system was used for evaluation:61%(14/23)cases scored≥3 points,which were considered as typical WAS;39%(9/23)cases scored<3 points,which were diagnosed as X-linked thrombocytopenia(XLT).55%(6/11)cases of missense mutation were diagnosed as XLT;75%(9/12)cases of non-missense mutation were diagnosed as typical WAS(P=0.071).(3)Twenty cases were followed up(3 cases were lost to follow-up).Among them,9 cases were treated with hematopoietic stem cell transplantation(HSCT)(8 cases were typical WAS),8 cases of them were benefited after HSCT treatment.Nine children were not treated with HSCT.Seven cases of them were XLT,all of them received IVIG treatment when suffered from severe thrombocytopenia.The platelet counts were then maintained at(20-80)×10~9/L.And no obvious infection and eczema was observed.Two cases were typical WAS,all of them presented with repeated infection,thrombocytopenia.One case received antibiotics and IVIG treatment irregularly,and the other one received regular treatment and waited for HSCT.Two cases were died,with one case died of pulmonary hemorrhage and one case died of severe sepsis.Conclusion:As an immune deficiency syndrome,WAS has significant heterogeneity in its clinical manifestations,which requires comprehensive evaluation combined with clinical,laboratory and gene mutation sites.Bone marrow transplantation should be actively carried out for typical WAS,and long-term follow-up observation for XLT may lead to better prognosis.