WAS基因功能获得性突变致X连锁中性粒细胞减少症二例并文献复习

X-linked neutropenia caused by gain-of-function mutation in WAS gene: two cases report and literature review

目的探讨WAS基因功能获得性突变致X连锁中性粒细胞减少症的临床表型,总结突变类型与临床表型关联。方法回顾性总结深圳市儿童医院2例WAS基因功能获得性突变致X连锁中性粒细胞减少症患儿临床资料。以"中性粒细胞减少""中性粒细胞缺乏""X连锁""X-linked neutropenia""WAS mutation"为检索词,检索2000年1月至2018年12月万方、中国知网数据库,美国国立图书馆(PubMed)数据库,并进行文献复习。结果例1男,1岁,因发现粒细胞减少1年、咳嗽5 d、发热3 d于2015年7月入院。患儿入院前监测血中性粒细胞持续减少(0.1×10^9~0.3×10^9/L),住院期间中性粒细胞波动于0.4×10^9~0.5×10^9/L。先后经环丙沙星、头孢哌酮舒巴坦、万古霉素等抗感染共4周后病情好转,体温稳定出院。随访至2018年5月,监测中性粒细胞波动于0.1×10^9~0.6 ×10^9/L。经二代测序及SANGER验证发现WAS基因c.T869C(p.I290T)半合子突变,流式细胞检测淋巴细胞WAS蛋白阳性表达率为97.7%。例2男,42日龄,因发热12 d,发现粒细胞减少10 d于2016年5月入院。患儿因发热于外院行血常规检查发现中性粒细胞低下(0.5×10^9/L),经抗菌药物治疗后发热无缓解入院。入院后血中性粒细胞0.4×109/L,经阿莫西林舒巴坦、万古霉素、美罗培南、利福平、异烟肼治疗后体温稳定,出院时外周血中性细胞0.2×10^9/L。经二代测序及SANGER验证发现WAS基因c.T881C(p.I294T)突变,流式细胞检测淋巴细胞WAS蛋白阳性表达率为92%。文献检索共4篇英文文献,已报道5个家系18个病例因WAS基因功能获得性突变致X连锁中性粒细胞减少症,其突变为I290T、L270P、S272P、I294T 4种错义突变。4个家系来自西方国家,1个家系来自日本。18例患者中有15例患者表现为粒细胞减少(0.1×10^9~1.0×10^9/L),3例患者监测期间中性粒细胞数目正常。主要的临床表现为频繁的感染,包括呼吸道感染、中耳炎等。结论中性粒细胞减少为WAS基因功能获得性突变患者共同的临床表型,但疾病严重程度与中性粒细胞水平、突变位点并无确切相关性。对于先天性粒细胞减少的男性患者需要通过基因检测除外WAS基因功能获得性突变。

Objective To investigate the clinical and genotypic manifestations of X-linked neutropenia caused by gain-of-function mutation in WAS gene. Methods The clinical history of two patients with X-linked neutropenia caused by gain-of-function mutation in WAS gene in Shenzhen Children′s Hospital were analyzed."X-linked neutropenia" and "WAS mutation" were used as key words to search related literatures published from January 2000 to December 2018 in CNKI,Wanfang, and Pubmed databases. Results The first case was male,1 year old, admitted for 1 year of neutropenia combined with 5 days of cough and 3 days of fever. Persistent neutropenia (0.1×10^9-0.3×10^9/L) was reported before admission and during hospitalization (0.4×10^9-0.5×10^9/L). The patient was treated with Ciprofloxacin, cefoperazone sulbactam and Vancomycin,and relieved from fever after 4 weeks of hospitalization,yet the neutropenia (0.1×10^9-0.6×10^9/L) continued after discharge. Variant in WAS gene (c.T869C (p.I290T)) was identified, and the percentage of WAS protein on lymphocyte was 97.7%. The second case was male, 42 days old,admitted for fever and neutropenia (0.5×10^9/L). Similarly,he relieved from fever after 4 weeks of treatment with amoxicillin sulbactam,vancomysin,meropenem,rifampin and isoniacid,yet was discharged with continued neutropenia. Variant in WAS gene (c.T881C (p.I294T)) was identified and the percentage of WAS protein on lymphocyte was 92%. Published literature reported four variants,including I290T, L270P, S272P and I294T, as the pathogenic mutation of X-linked neutropenia in 18 patients from five families. Neutropenia (0.1×10^9-1.0×10^9/L) were reported in 15 patients,while normal neutrophil number was found in the rest. Recurrent infection,mainly pneumonia and otitis media,was the most common clinical manifestation. Conclusions Neutropenia is the prominent presentation in the patients with X-linked neutropenia caused by gain-of-function mutation in WAS gene, but it unnecessarily correlates with the clinical severity in terms of infection. Gene sequencing should be considered for the male patients with persistent neutropenia.