X连锁慢性肉芽肿病12例临床分析

目的探讨X连锁慢性肉芽肿病(X-CGD)患儿的临床表现及实验室检查特点。方法总结12例经CYBB基因序列分析诊断为X-CGD患儿的临床资料,检测X-CGD患儿及家系成员中性粒细胞氧化功能。结果 12例患儿均为男性,平均起病年龄4.08个月,平均诊断年龄2岁。12例患儿均有反复肺炎,结核感染7例,淋巴结炎6例,反复腹泻6例,溃疡性口腔炎5例,肛周脓肿3例。均有生长发育延迟。血清IgG、IgA及IgM均升高9例。四唑氮蓝试验(NBT)和中性粒细胞氧化功能均显著下降。6例(50%)患儿死亡。大多患儿影像学检查提示有肺部、肝内肉芽肿形成;3例患儿有家族史。结论 X-CGD起病早,诊断较晚,病死率高;以肺部感染为主要表现,结核感染率高。中性粒细胞呼吸暴发试验有助于X-CGD临床诊断,CYBB基因序列分析可提高诊断准确性。     

Genetic heterogeneity in patients with X-linked recessive chronic granulomatous disease.

Genetic heterogeneity in 12 patients from 11 different families with X-linked recessive chronic granulomatous disease was studied by Southern blot analysis using cytochrome b heavy-chain cDNA as a probe. We found the abnormal restriction length fragment patterns of the cytochrome b heavy-chain gene in three families, which were not observed in healthy controls. DNA from one patient showed the abnormal patterns after digestion with several restriction enzymes. The DNA of two other patients showed the abnormality only with TaqI and PstI. Analysis of the same family members indicated that these abnormal patterns cosegregated with the disease. The other nine patients from eight families did not have any abnormalities detectable by Southern blot analysis. Although further experimentation should be done to study the molecular genetic heterogeneity in most X-linked chronic granulomatous disease families (eight of 11), we were able to demonstrate at least three different types of mutations in the cytochrome b heavy-chain gene responsible for the disease.     

X连锁慢性肉芽肿病及其基因突变

慢性肉芽肿病(CGD)是一种少见的遗传性疾病,分为X连锁CGD(X-CGD)和常染色体隐性遗传CCD。还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶的膜结合成分即细胞色素b558分为α和β亚单位。X-CGD是编码β亚单位gp91-phox的基因突变所引起。X-CGD的基因突变常为大片段碱基对的缺失、小片段碱基对的缺失或插入、错义突变和无义突变等。目前已有300多种gp91-phox的基因突变被登记收入国际X-CGD数据库。该文着重介绍关于内含子及拼接位点的突变。     

Severe X-linked chronic granulomatous disease in two unrelated females

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations of one of the subunits of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to decreased or complete absence of neutrophil oxidative burst. We report the clinical and laboratory findings in two young unrelated females 14 and 9 years of age and natives of Tahiti and Reunion Islands, respectively, with severe X-linked granulomatous disease. In both cases, the infectious pattern was unusual, with convergent symptoms suggesting underlying mycobacterial infection. Functional analysis revealed low residual NADPH oxidase activity with about 5–10% of normal neutrophil population. De novo null mutations affecting the CYBB gene that encodes the gp91 protein were found in both cases in the heterozygous state (in patient 1, p.Arg130X in exon 5, and in patient 2, a novel insertion in exon 6, c.632_633insCATC). Methylation analysis confirmed that phenotype expression was linked to skewed X inactivation and showed that the de novo mutation arose on the maternally inherited chromosome in one case and on the paternally inherited chromosome in the other case. In conclusion, X-linked CGD carriers could therefore be at risk for severe infectious diseases depending on the skewed X inactivation pattern and the infectious context.     

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目的总结分析感染洋葱伯克霍尔德菌的X连锁慢性肉芽肿病患儿的临床特点。方法回顾分析2010年1-2月于北京儿童医院住院治疗的2例感染洋葱伯克霍尔德菌的X连锁慢性肉芽肿病患儿的临床资料。结果 2例男性患儿,分别为0.5岁和1.7岁,均经CYBB基因突变分析明确诊断为X连锁慢性肉芽肿病。1例经反复血培养、1例经反复尿培养诊断为洋葱伯克霍尔德菌感染。药敏试验结果提示均为敏感菌株。结论洋葱伯克霍尔德菌是人类机会性病原,常表现为慢性肉芽肿病。常规抗生素治疗可根除感染。预防应用复方磺胺药物对此类患儿具有保护意义。     

Prenatal diagnosis and novel mutation in X-linked chronic granulomatous disease

BackgroundChronic Granulomatous Disease (CGD) is a rare primary immunodeficiency caused by the alteration of the enzyme complex NADPH oxidase, which affects the phagocytic function. CGD patients are susceptible to recurrent infections mainly caused by bacteria and/or fungi.MethodsWe studied a 6 year-old boy with suspicion of CGD. The diagnosis was confirmed based on the functional study of NADPH oxidase. Simultaneously, the second pregnancy of the mother was reported and genetic counselling was requested.ResultsWe identified a new disease-causing mutation by direct sequencing of the CYBB gene (X-linked CGD). The prenatal study resulted in the identification of the same mutation in the foetus.CommentsMolecular genetics characterisation of CGD is needed to obtain an accurate diagnosis of the disease and to offer prenatal diagnosis and genetic counselling in future pregnancies.     

Basidiomycetous fungal Inonotus tropicalis sacral osteomyelitis in X-linked chronic granulomatous disease

Osteomyelitis is a common clinical manifestation of chronic granulomatous disease, a disorder of phagocytic function. Fungal organisms account for a significant proportion of these infections. We describe the clinical presentation and subsequent destructive sacral osteomyelitis with a basidiomycetous mold, Inonotus tropicalis, in a patient with an X-linked chronic granulomatous disease.     

重症卡介苗淋巴结炎与儿童X连锁慢性肉芽肿病

慢性肉芽肿病(chronic granulomatous disease,CGD)是少见的原发性吞噬细胞免疫缺陷病.患者的多形核粒细胞不能通过烟酰胺腺嘌呤二核苷磷酸(NADPH)氧化酶产生超氧阴离子(O2-)来有效杀灭入侵的微生物.患者在儿童早期易于发生反复致命的过氧化氢酶阳性细菌和真菌感染,在慢性炎症部位形成肉芽肿[1].     

新生儿X-连锁慢性肉芽肿病4例分析暨文献复习

目的了解X-连锁慢性肉芽肿病（X-CGD）患儿的临床特点、治疗方法及基因突变类型。方法选择我科2013年4-12月经基因检测明确诊断为X-CGD的病例,总结患儿起病时间、症状、影像学表现、病原学检查、治疗及转归情况,了解基因突变类型。结果研究期间共收治4例X-CGD患儿,均为男婴,起病日龄13~17天,诊断日龄24-34天,1例有家族史。首发症状发热3例,咳嗽1例。肺CT表现为结节、不规则、球形或类圆形高密度灶。痰培养1例为烟曲霉菌和金黄色葡萄球菌,1例为白色念珠菌,2例阴性;血培养均阴性;血清半乳甘露聚糖（GM）试验阳性3例。应用抗细菌联合抗真菌治疗2-3周,4例均好转出院,随访6个月3例未复发,1例出院后未按医嘱服药生后5个月因反复严重感染死亡。CYBB基因突变分析示缺失突变1例,插入突变1例,错义突变2例,患儿母亲均为携带者。结论本病在新生儿期呼吸道症状及体征相对较轻,但影像学显示肺部病变严重,肺CT表现为多发结节或团块影,常规体液和细胞免疫功能正常的新生儿应考虑X-CGD。CYBB基因突变分布广泛,异质性明显,基因突变分析将成为产前诊断的重要工具。     

X- 连锁慢性肉芽肿病CYBB 基因突变分析及产前诊断

目的分析X连锁慢性肉芽肿病(X-CGD)的临床特征及CYBB基因突变。方法回顾分析1例X-CGD患儿的临床资料及其家系的CYBB基因检测结果。结果男性患儿,新生儿期起病,以反复严重的肺部感染为主要表现。患儿无刺激组及脂多糖(LPS)刺激组四唑氮蓝试验(NBT)均为0%,中性粒细胞氧化指数(NOI)为1.15。基因分析显示,患儿CYBB基因第6外显子出现缺失突变(579-582del ATTA),由此引起编码序列从189位异亮氨酸(I)发生移码突变,于212位氨基酸提前出现终止密码子(I 189 fs X 212)。患儿母亲及外祖母均为突变基因携带者。患儿母亲下一胎羊水细胞的CYBB基因未发现相同缺失突变。结论基因诊断1例CYBB基因突变X-CGD患者及其家系,产前基因检测可避免X-CGD患儿出生。     

Retroviral-mediated gene transfer and nonmyeloablative conditioning: studies in a murine X-linked chronic granulomatous disease model

Our laboratory has reported the correction of neutrophil NADPH oxidase function by retroviral-mediated gene transfer (RMGT) in murine X-linked chronic granulomatous disease (X-CGD). Few studies, however, have used nonmyeloablative conditioning in conjunction with RMGT. Promising methods of decreased intensity conditioning include low dose irradiation and antimetabolite conditioning. Preliminary studies using syngeneic mice transplanted with fresh marrow cells indicate that high levels of donor cell chimerism can be achieved with low-dose radiation or 5-fluorouracil-based conditioning regimens. Early data from experiments in which low-dose radiation-conditioned X-CGD recipients were transplanted with retrovirus-transduced X-CGD marrow cells show that gene-corrected neutrophils can be detected by NBT assay for NADPH oxidase activity reconstitution 4 months posttransplant, although these levels are much lower than the 50%-70% gene-corrected cell detected in lethally irradiated recipients. Transplantation of retrovirus-transduced marrow cells into 5-fluorouracil conditioned hosts is also being explored.     

Williams-Beuren综合征合并慢性肉芽肿病一例

患儿男,4岁,因"反复发热、咳嗽2周"入佛山市第一人民医院儿科,患儿有"小精灵脸"面容,存在轻度精神及生长发育迟缓,既往有反复感染病史,二羟罗丹明123试验提示中性粒细胞呼吸爆发功能低下,临床外显测序发现患儿的母源性染色体7q11.23 区域发生拷贝数缺失,实时荧光定量核酸扩增检测系统证实患儿NCF1基因的2号外显子纯合缺失,因此患儿同时患有Williams-Beuren综合征(WBS)合并慢性肉芽肿病(CGD)。在极罕见的遗传情况下,WBS微缺失片段包括NCF1基因,NCF1等位基因发生变异, 则会导致CGD。     

儿童X连锁慢性肉芽肿病临床特点和CYBB基因突变分析

目的了解X连锁慢性肉芽肿病患儿的临床特点及基因突变类型。方法观察X连锁慢性肉芽肿病(X-CGD)患儿起病方式、感染部位、病原谱和炎症并发症等临床特点,总结基因突变类型。结果 22例男童被诊断为X连锁慢性肉芽肿病,平均起病年龄为0.7岁,平均诊断年龄为2.7岁,6例有家族史。首发症状发热18例,咳嗽9例,皮肤/黏膜/淋巴结炎症6例,腹泻4例。首次诊断前3位依次为肺炎14例,败血症4例,脓疱疹及腹泻病各3例。感染前3位依次为至少1次肺部感染22例,败血症12例,肛周脓肿6例。肺组织及血培养曲霉菌2例、伤寒杆菌1例。BCG接种同侧腋下淋巴结钙化12例、肿大1例,远距离淋巴结钙化4例,播散性卡介苗病(BCG-osis)1例,高度怀疑肺结核4例,骨结核1例。CYBB基因突变分析示缺失/插入2例,拼接区突变6例,无义突变6例,错义突变8例。新发现的突变为8例。结论对于反复肺炎的患儿,尤其伴有败血症、皮肤过度疤痕/肛周脓肿者,若常规体液和细胞免疫功能正常,应考虑慢性肉芽肿病可能,曲霉菌肺炎需尤其关注。重症BCG淋巴结炎具有提示诊断的意义。CYBB基因突变分布广泛,异质性明显。基因突变分析是开展遗传咨询和产前诊断的重要工具。     

Cytochrome b positive X-linked chronic granulomatous disease: A normal cell surface expression of cytochrome b

The polymorphonuclear (PMN) cells from a patient with cytochrome b positive X-linked chronic granulomatous disease (Xb+CGD) were studied using flow cytometry. Both the cell surface expression of monoclonal antibody defined cytochrome b and the superoxide production (intracellular 2, 7-Dichlorofluorescin Diacetate oxidation) were investigated at a single cell level. Flow cytometry clearly demonstrated the complete absence of superoxide production in the patient's PMN cells, the mosaicism in his mother's PMN cells and also indicated the normal cell surface expression of cytochrome b. The results obtained by Western blot analysis and reduced-minus-oxidized spectra confirmed the presence of functional and normal amounts of cytochrome b. We concluded that this is a case of Xb+CGD with a normal cell surface expression of cytochrome b.     

二氢罗丹明流式细胞分析方法用于X-连锁慢性肉芽肿病诊断和携带者筛查

No abstract available

     

儿童慢性肉芽肿病1例临床特征及基因突变分析

目的探讨慢性肉芽肿病的致病机制以及诊断。方法回顾性分析1例慢性肉芽肿病患儿的临床特征及实验室检查;提取患儿及父母外周血基因组DNA,用Agilent Sure Select方法外显子捕获,Illumina测序平台进行高通量测序。结果患儿有反复感染史,伴肝脏肿大和肝功能异常,抗感染及对症治疗效果不佳。二代测序显示患儿CYBA基因存在c.7C??T(p.Gln3*)纯合突变,其母为该位点杂合,父亲可能存在大片段杂合缺失,其他候选基因测序分析未发现明显异常。结论确诊患儿为慢性肉芽肿病,CYBA基因突变是其致病原因。