新生儿慢性肉芽肿病11例临床表现及基因特征分析

Clinical and genetic characteristics of eleven neonates with chronic granulomatous disease

目的:总结新生儿慢性肉芽肿病(chronic granulomatous disease,CGD)的临床特点、诊断方法及基因变异特征。方法:回顾性分析北京儿童医院新生儿中心2013年4月至2020年8月收治、经中性粒细胞呼吸爆发试验和基因检测确诊新生儿CGD患儿的病例资料,总结其临床特点、诊断方法及基因检测结果。结果:共收治11例CGD患儿,男10例,发病日龄(14.6±5.6)d,入院日龄(20.9±4.9)d,3例有家族史。首发症状发热10例,咳嗽1例;伴随症状咳嗽6例,呼吸困难4例,皮肤脓疱疹3例,发热、腹泻各1例。肺部CT表现为团絮状阴影6例,肺内结节影3例,圆形及不规则高密度影、肺内实变各1例,合并胸腔积液1例,胸膜增厚2例,经病理诊断CGD 1例。痰培养白色念珠菌3例,烟曲霉菌2例,烟曲霉菌合并金黄色葡萄球菌1例,烟曲霉菌合并肺炎克雷伯菌、大肠埃希氏菌1例。GM试验阳性2例,阴性2例。血和脑脊液培养均阴性。白细胞计数(10.0~44.0)×109/L,C反应蛋白14~165 mg/L。筛查诊断:中性粒细胞呼吸爆发试验阳性11例。基因检测结果:CYBB基因变异9例,NCF1基因、NCF2基因变异各1例。抗细菌联合抗真菌治疗2~5周,均好转出院。8例存活,其中5例行造血干细胞移植,4例成功,1例失败后继续口服药物存活;3例长期口服磺胺甲噁唑及伏立康唑或伊曲康唑。3例自行停药后死于重症感染。结论:新生儿CGD以肺部感染多见,影像学多表现为肺内结节或团絮状阴影,少数可有实变或伴胸腔积液。可通过中性粒细胞呼吸爆发试验和基因检测诊断;基因变异以X连锁CYBB基因变异为主,少数为常染色体隐性遗传的NCF1/NCF2基因变异导致。

Objective To study the clinical characteristics,diagnostic methods and genotypes of neonatal chronic granulomatous disease(CGD).Methods From April 2013 to August 2020,neonates admitted to our hospital,diagnosed with neonatal CGD and confirmed using neutrophil respiratory burst test and genetic testing were retrospectively studied.Their clinical characteristics and diagnostic methods were summarized.Results A total of eleven neonates with CGD were enrolled,including ten males and one female.The age of onset was 3-23 d and the age of admission was 11-28 d.3 cases had family history.The initial symptoms were fever(10 cases)and coughing(1 case).The accompanying symptoms included coughing(6 cases),dyspnea(4 cases),skin pustules(3 cases),fever(1 case)and diarrhea(1 case).Lung CT showed patchy shadows(6 cases),pulmonary nodules(3 cases),round and irregular high-density shadow(1 case),pulmonary consolidation(1 case),pleural effusion(1 case)and pleural thickening(2 cases).CGD was pathologically diagnosed in one patient.Sputum culture showed Candida albicans(3 cases),Aspergillus fumigatum(2 cases),Aspergillus fumigatum combined with Klebsiella pneumoniae and Escherichia coli(1 case),Aspergillus fumigatum combined with Staphylococcus aureus(1 case).GM tests were positive in two cases and negative in other two cases.Blood and cerebrospinal fluid cultures were negative.White blood cell counts were(10.0-44.0)×109/L and C-reactive proteins were(14-165)mg/L.11 cases had positive neutrophil respiratory burst test.Genetic tests showed CYBB gene mutations(9 cases),NCF1 gene mutation(1 case)and NCF2 gene mutation(1 case).All cases received antibacterial and antifungal treatments for 2-5 weeks and were discharged with improvement.8 patients survived,5 received hematopoietic stem cell transplantation,4 succeeded and one failed and continued to survive on oral medication.3 cases took sulfamethoxazole,voriconazole or itraconazole orally for long periods.3 cases died of severe infections after withdrawal of medication.Conclusions Neonatal CGD is characterized by lung infections.Pulmonary CT shows mostly nodular or patchy shadows with occasional pulmonary consolidation or pleural effusion.It can be diagnosed by neutrophil respiratory burst test and genetic testing.X-linked CYBB gene mutations are common and autosomal recessive NCF1/NCF2 gene mutations less common.