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。     

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。     

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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。     

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。     

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。     

新生儿慢性肉芽肿一例报道并文献复习

目的 了解慢性肉芽肿病的临床特点及早期诊断要点.方法 回顾性分析1例新生儿期诊断的慢性肉芽肿患儿资料,并结合相关文献进行总结.结果 患儿系足月产男婴,生后18d即出现反复发热,肺部有感染灶,多种抗生素治疗无效.患儿母亲有两兄长在新生儿期夭折.对患儿及其父母行中性粒细胞呼吸爆发试验,患儿确诊为慢性肉芽肿,患儿母亲为致病基因携带者.结论 对早期反复出现感染的男性患儿,特别是母系有阳性家族史者,应警惕慢性肉芽肿病,中性粒细胞呼吸爆发试验可早期明确诊断.     

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CGD。吞噬细胞还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶中gp91-phox基因突变引起的CGD称为X-CGD,而由p22-phox,p47-phox和p67-phox基因突变引起的CGD称为常染色体隐性遗传CGD。X-CGD的基因突变常常是多样性的,大多为外显子部位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,还有少部分突变位于拼接位点或5′调节区域以及内含子部位。p22-phox基因大部分是大小片段碱基对的缺失或插入,以及碱基的替换引起的误义突变、无义突变、移码突变和拼接位点以及内含子的突变。p67-phox基因突变也是多样性的。p47-phox基因突变具有高度的同源性,为2个碱基GT的缺失(即ΔGT)。     

染色体1q21.3q44重复及Xp22.33p11.3缺失1例

1例1岁2月龄女性患儿出现反复呼吸道感染1年1个月余, 并存在喂养困难、体重增长缓慢、发育明显落后等表现, 检查发现包括外貌、心脏及肺部等多发畸形, 染色体核型为46, X, der(X), 全外显子高通量测序检测到1q21.3q44重复区域约93.94 Mb及Xp22.33p11.3缺失区域约44.37 Mb, 患儿父母均无出现上述基因缺失及重复。     

X连锁Alport综合征伴食管平滑肌瘤1例

患儿女, 13岁, 因"血尿9年余, 胃代食管术后贫血1年"就诊东部战区总医院儿科。患儿9年余前出现血尿, 通过皮肤活检诊断X连锁Alport综合征, 1年前出现进食哽咽, 于外院行食管病损切除+食管良性肿瘤切除+胃代食管术, 组织病理提示平滑肌瘤, 术后出现血红蛋白降低。患儿贫血貌, 此次入院进一步完善基因检测发现COL4A5基因外显子1杂合缺失及COL4A6基因外显子1-2杂合缺失, 变异来源于母亲。结合患儿临床表现及基因结果, 该患儿最终诊断为X连锁Alport综合征伴食管平滑肌瘤、胃代食管术后、缺铁性贫血。     

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。     

Clinical presentation of Bacillus Calmette-Guérin infections in patients with immunodeficiency syndromes

Nine children with immunodeficiency syndromes who developed persistent or disseminated Bacillus Calmette-Guérin (BCG) infections after BCG vaccination at birth were observed in Santiago, Chile, over a period of 10 years. This represents a risk for persistent or disseminated BCG infections of 3.4/1,000,000 vaccinated newborns. This may closely reflect the incidence of severe combined immunodeficiency syndromes, cellular immunodeficiency syndromes and chronic granulomatous disease in the study area. The clinical presentation and course of the infection varied considerably depending on the underlying immunodeficiency syndrome. Two patients with severe combined immunodeficiency presented with cutaneous nodules in the absence of any local reaction at the site of BCG vaccination. Both patients died of disseminated BCG infection within the first year of life. Four patients with cellular immunodeficiency syndromes presented with regional lymphadenitis resistant to treatment after the fifth month of life. Three of these patients had specific unresponsiveness to tuberculin and survived from 5 to 6 years of age. Two boys with X-linked chronic granulomatous disease presented with regional lymphadenitis in the first 3 months of life. A girl with autosomal recessive chronic granulomatous disease presented at 18 months of age with regional lymphadenitis. All three patients with chronic granulomatous disease had positive tuberculin reactions and died from infections other than BCG.     

16p11.2缺失综合征1例并文献复习

目的 提高对16p11.2缺失综合征的临床和基因特征的认识。方法 总结分析1例16p11.2缺失综合征患儿的临床发现、辅助检查、诊断和随访资料,并文献复习。结果 ①患儿,男,2月13 d,因“发热近20 d伴咳嗽、腹泻”起病。入院查体可见右手六指畸形,脊柱侧弯,外周血淋巴细胞及其亚群明显低于正常同龄儿。X线胸片示胸椎9～12部分椎体呈半椎体畸形,胸骨塑形异常。予抗感染等治疗后好转,并呈多动兴奋表现。出院后随访提示淋巴细胞数量较住院时好转,但WBC、中性粒细胞及CD4+T细胞均低于正常值。患儿5月龄时诊断癫,予抗癫药物治疗有效。应用染色体芯片检测技术,并采用高密度寡核苷酸微阵列比较基因组杂交技术证实16p11.2区域缺失,缺失片段大小约0.545 4 Mb,该区段所包含的基因有SPN、QPRT、 C16orf54、 KIF22、 MAZ、 SEZ6L2、 CDIPT、 ASPHD1、 KCTD13、TMEM219、 TAOK2、 DOC2A、TBX6等;患儿父母染色体芯片检查结果均未发现异常。确诊为16p11.2缺失综合征。②检索国内外报道的关于16p11.2缺失相关病例共1 378例,临床表型涉及到神经系统表现547例（39.7%）,内分泌系统371例（26.9%）,生长发育与骨骼异常84例（6.1%）,泌尿生殖与消化系统10例（0.7%）,心血管系统4例（0.3%）,免疫功能异常1例（0.07%）,由于缺失片段大小不一,导致临床表型具有较大的异质性。结论 多发骨骼畸形（尤其脊柱侧弯）,伴神经系统异常（如癫痫、孤独症等）,其他系统累及（如反复感染、内分泌异常等）应考虑16p11.2缺失综合征可能,通过染色体芯片检测技术以及高密度寡核苷酸微阵列比较基因组杂交技术帮助诊断。     

Infantile hyperinsulinism associated with enteropathy, deafness and renal tubulopathy: clinical manifestations of a syndrome caused by a contiguous gene deletion located on chromosome 11p

We describe the clinical features of a new syndrome causing hyperinsulinism in infancy (HI), severe enteropathy, profound sensorineural deafness, and renal tubulopathy in three children born to two pairs of consanguineous parents. This combination of clinical features is explained by a 122-kb contiguous gene deletion on the short arm of chromosome 11. It deletes 22 of the 39 exons of the gene coding for the SUR1 component of the KATP channel on the pancreatic beta-cell thereby causing severe HI. It also deletes all but two of the 28 exons of the USH1C gene, which causes Usher syndrome and is important for the normal development and function of the ear and the eye, the gastrointestinal tract, and the kidney, thereby accounting for the symptoms of deafness, vestibular dysfunction and retinal dystrophy seen in type 1 Usher syndrome, diarrhoea, malabsorption, and tubulopathy. This contiguous gene deletion provides important insights into the normal development of several body organ systems.     

应用DHPLC技术检测非缺失型DMD致病基因的新突变

目的建立检测Duchenne型肌营养不良症（Duchenne muscular dystrophy,DMD）致病基因dystrophin突变的快速、敏感的微小突变筛查系统。方法选择经多重PCR检测未发现dystrophin基因大尺度缺失的DMD患儿20例,年龄在2—10岁,以其基因组DNA为模板,通过PCR反应,分别扩增dystrophin基因外显子及侧翼序列,采用变性高效液相色谱（DHPLC）技术进行突变筛查,对DHPLC峰形变异的外显子片段行PCR产物直接测序,确定突变的具体位点和类型。结果筛查了包括2个缺失热点区dystrophin基因的68个外显子和3＇UTR部分片段,分别在4例患儿中检测出该基因的4种致病突变：c．6808_6811delTTHA,c．4959_4960insA,c．8656C〉T和c．8608C〉T。前两例引起移码突变分别导致p．ku2270Metfsx9和p．Ser1654LysfsX5,后两例为无义突变分别导致p．R2886X和p.R2870X。其中c．6808_6811delTTA,c．49594960insA和c．8656C〉T为文献未曾报道的新突变。结论DHPLC可以作为有效地筛查DMD微小突变的检测方法。     

Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease

Humoral immunodeficiencies have a recognized association with atopy. This study investigated the association of a T-cell disorder (chromosome 22q11.2 deletion) and a neutrophil disorder [chronic granulomatous disease (CGD)] with asthma, eczema, and rhinitis using a standardized survey instrument. Patients were recruited from either a national referral center (chromosome 22q11.2 deletion syndrome) or from a registry (CGD). Controls consisted of siblings of patients. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) was found to be significantly associated with both eczema and asthma but not allergic rhinitis. CGD was not found to be significantly associated with atopic diseases.     

Intragenic deletions in the dystrophin gene in 211 Pakistani Duchenne muscular dystrophy patients

Background: Deletions of single or multiple exonic regions within the dystrophin gene can be detected using current molecular methods in approximately 65% of the patients with X‐linked recessive neuromuscular disorder, Duchenne/Becker muscular dystrophy (DMD/BMD). Population‐based variations in frequency and distribution of dystrophin gene deletions have been reported in DMD/BMD patients. In the present study, the first in the Pakistani population, frequency and distribution of deletions of 18 exons clustered in two hot spots within the dystrophin gene in 211 unrelated DMD patients were analyzed. Methods: A total of 211 patients suffering from DMD were ascertained, and intragenic deletions within the dystrophin gene were detected on polymerase chain reaction amplification of the genomic DNA using 18 primer sets clustered within two major deletion hot spots. lovd v.1.1.0 software from the Leiden Muscular Dystrophy website has been used to predict in‐frame and out‐of‐frame deletions. Results: Intragenic deletions were detected in 86 patients (40.75%): 35 patients (40.69%) had deletions within the proximal hot spot, and 51 patients (59.30%) had deletions confined to the distal deletion hot spot of the dystrophin gene. The most frequently deleted exons were 50, 6, 47, 13 and 52 with deletion frequencies of 15.11%, 12.79%, 10.46%, 8.13%, and 4.65%, respectively. lovd v.1.1.0 predicted out‐of‐frame deletions in 67 DMD patients and in‐frame deletions in 19 DMD patients. Conclusions: The observed proportion of intragenic deletions in the Pakistani population is relatively low, which is comparable with most of the Asian data. Also, deletions in 67 patients (77.9%) are in agreement with the frame‐shift rule.     

Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years

IntroductionMore than 200 primary immunodeficiencies (PID) have been described and about 60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome.AimAnalysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years.Patients and methodsMedical records of all paediatric patients followed up in our unit were retrospectively reviewed. Clinical and epidemiological features, laboratory tests, therapy and outcome were analysed.ResultsOne hundred and eighty nine patients were followed up in this period of time. Antibody disorders were the most common diagnosis. In our series, clinical presentation at diagnosis were: recurrent respiratory infections in selective IgA deficiency and common variable immunodeficiency (CVID) patients, failure to thrive and opportunistic infections (mainly viral infections) in patients with severe combined immunodeficiency (SCID), skin abscesses (Staphylococcus aureus, Serratia spp.) and complicated pneumonia (Aspergillus spp., Rhodococcus equi) in chronic granulomatous disease, congenital heart disease and consistent phenotype in 22q11 deletion syndrome, skin abscesses and ecthyma gangrenosum in severe congenital neutropenia and opportunistic infections and sepsis (Pseudomonas aeruginosa) in children with X-linked agammaglobulinaemia (XLA). Lymphoproliferative disorders were common in CVID. No malignancies were observed during this period. One patient with XLA developed chronic encephalitis.All patients with CVID and XLA were receiving immunoglobulin replacement therapy (8 intravenous and 14 (since 2006) subcutaneous route) and in all but two SCID patients, stem cell transplantation was performed. Outcome was good in most of them except 8 SCID (2 prior and 6 after transplantation), 3 Wiskott-Aldrich syndrome, 1 complete DiGeorge, 1 chronic granulomatous disease and 1 ataxia-telangiectasia patients who died during follow-up.ConclusionThe vast majority of patients included in this series presented with typical clinical features; therefore, basic knowledge of these entities in primary care and collaboration with hospital referral centres should allow a large number of PID in children to be diagnosed at an early stage, leading to proper treatment and monitoring, and therefore improvement of patient prognosis.     

儿童慢性肉芽肿病的诊治进展

慢性肉芽肿病是一种因NADPH氧化酶功能障碍引起的原发性免疫缺陷病,在临床较为少见,病死率较高.典型的临床表现为儿童早期反复致命感染.慢性炎症持续存在导致局部形成肉芽肿,易引起局部梗阻.针对慢性肉芽肿病较特异的诊断方法包括:四氮唑蓝还原试验、二氢罗丹明流式细胞分析方法和基因序列分析等.目前造血干细胞移植是大多数慢性肉芽肿病治疗手段,但应选择合适的移植时机,以提高移植成功率并减少并发症.基因治疗慢性肉芽肿病长期的有效性和安全性还有待进一步深入研究.该文就近年来慢性肉芽肿病的发病机制、早期诊断技术和治疗等方面的研究进展作一综述.