CXCR4基因突变致WHIM综合征3例报告并文献复习

目的探讨CXCR4基因突变导致WHIM综合征的临床特征及基因变异特点。方法回顾性分析3例CXCR4基因突变致WHIM综合征患儿的临床资料和全外显子组测序（WES）结果，并行系统检索和文献复习，收集诊断明确的WHIM综合征患者，总结临床特征和基因突变信息。结果3例WHIM综合征患儿均为男性，确诊年龄分别为11岁、13月和5岁。3例均有反复感染，均无皮肤疣表现，1例发生糖尿病。3例患儿多次查血常规示淋巴细胞及中性粒细胞减少，但无周期性特征；3例患儿免疫球蛋白均减低。2例行骨髓穿刺检查，其中1例有典型无效生成性慢性粒细胞缺乏样表现。2例患儿经集落刺激因子治疗后，WBC可升至正常，但易反复。WES结果显示，3例患儿均为CXCR4基因第2外显子C端杂合突变，在该基因第2外显子剪切位点发生碱基替换突变（1000C>T），造成氨基酸R334X改变。共检索到46篇WHIM综合征文献（45篇英文，1篇中文），共报告WHIM患者74例（包括本文3例）。74例患者中，男32例，女42例，成人36例，儿童38例。出现皮肤疣的起病中位年龄为6.5岁；65例（87.8%）患者表现为反复感染；60例（81.1%）报告基因检测结果，共检测到9个突变，均为CXCR4基因突变。结论WHIM综合征为罕见的常染色体显性遗传病，可表现为粒细胞减少、低丙种球蛋白血症、疣状物、反复感染（尤其对人乳头状瘤病毒易感）及无效生成性慢性粒细胞缺乏。小年龄患儿可无皮肤疣，临床发现上述表现应考虑该病，并行基因检测以明确诊断。

Report of 3 cases of WHIM syndrome caused by CXCR4 gene mutation and literature review

ObjectiveTo investigate the clinical features and genetic variation of WHIM syndrome caused by CXCR4 gene mutation.MethodsThe clinical data and whole exome sequencing results of 3 children with WHIM syndrome caused by mutation of CXCR4 gene were retrospectively analyzed. Systematic search and literature review were conducted to collect patients with WHIM syndrome, and to summarize clinical manifestations and gene mutation information.ResultsThree children with WHIM syndrome were all males. The diagnosis age of 3 patients was 11 years, 13 months and 5 years, respectively. All cases had recurrent infection, 1 case developed diabetes, no patients had developed warts. After the treatment with G-CSF, white blood cells could rise to normal, but were prone to decline. All patients showed lymphopenia and neutropenia, but not periodically. Immunoglobulin decreased in all 3 cases. Gene results of whole exome sequencing showed all of the three patients had the same mutation: C-terminal heterozygous exon 2 of CXCR4 gene, and a base substitution mutation (1000C>T) occurred at the second exon cleavage site of CXCR4 gene. A total of 45 English articles and 1 Chinese literature were retrieved from the database. Altogether with the 3 patients in this study, 74 patients with WHIM syndrome were reported so far.ConclusionWHIM syndrome is a rare autosomal dominant genetic disease. Patients can present with warts, recurrent infection, leukopenia and myelokathexis. WHIM syndrome should be considered when young patients manifest symptoms described above except for the warts, thus gene analysis is critical for the diagnosis of the disease.