11例先天性中性粒细胞减少症临床分析

发布时间：2018-03-30 11:30

本文选题：先天性中性粒细胞减少症　切入点：感染　出处：《广西医科大学》2017年硕士论文

【摘要】：目的回顾性分析11例先天性中性粒细胞减少症患者及其家属的临床表现、基因检测结果、治疗等情况,总结诊疗经验,提高临床医生对该病的认识。方法(1)收集患者及其家庭成员的临床及实验室资料。(2)应用外显子目标基因捕获及二代测序技术对先证者行先天性中性粒细胞减少症相关致病基因如ELANE、HAX1、GFI1、CSF3R、WAS、G6PC3、SLC37A4、LYST、AK2、SBDS等500多个基因检测,筛查出突变位点基因序列后,进行致病性分析,并对病人及其家庭成员进行Sanger测序验证。(3)追踪随访评估患者使用重组人粒细胞集落刺激因子治疗后的疗效、不良反应。(4)采用SPSS20.0版统计软件及Microsoft Office Excel 2010进行数据分析和处理。结果(1)本组共收集11例先天性中性粒细胞减少症病例(男4例,女7例),发病年龄0.5月~6月,平均发病年龄4.23±2.0月。诊断年龄3.5月~77月,平均诊断年龄22.36±20.89月,平均诊断年龄较平均发病年龄滞后18.13月。(2)所有患者诊治前每月至少感染1次,主要的临床表现包括呼吸道感染、皮肤黏膜软组织感染、消化系统感染、中耳炎。其中平均1周、2周、3周、4周发生1次感染的比例分别为54.5%、18.2%、9.1%、18.2%;绝大部分患者诊治前均有多次住院治疗病史,平均1月、2月、3月住院治疗1次以上的比例分别为63.6%、18.2%、9.1%,无住院经历者的比例为9.1%。(3)每周至少2次,持续1个月监测血常规,结果示:所有患者ANC至少3次以上低于0.5×109/L;6例ANC持续低于0.5×109/L,故临床诊断为重型先天性中性粒细胞减少症;另5例ANC呈规律性波动,波动周期为16~29天,即anc可从中性粒细胞缺乏状态自然增长至正常并持续1周左右后,缓慢降低至粒细胞缺乏状态并持续一段时间,又可自然增长至正常,故临床诊断为周期性中性粒细胞减少症;所有病例的淋巴细胞、血红蛋白、血小板无明显异常;所有患者父母及兄弟姐妹随机血常规无明显异常。(4)骨髓细胞形态学检查(均在anc低于0.5×109/l时行骨髓检查)结果示:骨髓中性粒细胞成熟障碍,大量中性粒细胞停滞在早、中、晚幼粒细胞阶段,杆状核与分叶核粒细胞比值降低,红巨二系未见异常。(5)基因测序结果:8例行先天性中性粒细胞减少症相关致病基因检测,2例异常------病例1:slc37a4纯合突变,其父母均为该致病基因的携带者;病例8:携带fancb基因,半合子,父亲无变异,母亲为杂合子。另6例未检测出致病基因突变。(6)治疗与随访:本组治疗方案如下:(1)当scn患者在anc低于0.5×109/l时、cyn患者在中性粒细胞最低值时、所有患者有明显感染伴anc低于1.0×109/l时,使用rhg-csf治疗。起始治疗剂量均为5ug/kg.d,根据使用rhg-csf治疗后24小时的anc调节rhg-csf治疗量,使anc维持在1×109/l水平以上,必要时联合使用抗生素;(2)健康管理教育。10例病例诊断明确后按上述方案使用rhg-csf治疗,随访(随访时间2.7月~49.5月,平均18.1±15.7月)结果如下:只有1例病例有一过性轻度纳差,其余患者无不良反应;随访期间住院率为0%;感染频次较治疗前明显下降:平均1周、2周、3周、4周、4周感染1次的百分比分别为0%、0%、20%、20%、60%;1例使用rhg-csf治疗2次(剂量分别为5ug/kg.次,10ug/kg.次),anc均呈无应答状态,父母因经济原因放弃使用rhg-csf治疗,电话随访时被告知患儿于11月大时因严重感染死亡。结论(1)先天性中性粒细胞减少症的临床表现无特异性,对该病认识不足,导致了诊断时间延迟。对出生后不久即出现反复感染并伴中性粒细胞绝对值持续减少者,应考虑先天性中性粒细胞减少症的可能性,血常规和骨髓细胞形态学检查可协助临床诊断。(2)对中性粒细胞绝对值持续的监测,可将病人分为周期性中性粒细胞减少症和重型先天性中性粒细胞减少症,有利于指导重组人粒细胞集落刺激因子的使用。(3)通过外显子目标基因捕获及二代测序技术对8例先天性中性粒细胞减少症进行基因诊断,2例发现异常,阳性率仅25%,计划行全基因组测序、MLPA等技术协助诊断。(4)大多数患者对重组人粒细胞集落刺激因子反应好,不良反应少,可以明显降低感染和住院频次,提高生活质量。但若不坚持应用或对重组人粒细胞集落刺激因子治疗无反应的CN患者,会导致严重感染甚至死亡。
[Abstract]:Objective To retrospectively analyze 11 cases of congenital neutropenia in patients with clinical manifestations and their families, the results of genetic testing, treatment and so on, summarize the experience of diagnosis and treatment, in order to improve the understanding of this disease. Methods (1) were collected from the patients and their family members and clinical laboratory data. (2) using exon target gene trapping and two generation sequencing technology on the proband for congenital neutropenia related genes such as ELANE, HAX1, GFI1, CSF3R, WAS, G6PC3, SLC37A4, LYST, AK2, SBDS detection of more than 500 genes, screened mutation gene sequence, pathogenicity analysis, and Sanger sequencing of patients and their family members. (3) follow-up evaluation of patients using recombinant human granulocyte colony stimulating factor after treatment the curative effect, adverse reaction. (4) using SPSS20.0 statistical software and Microsoft Office Excel 2010 data points Analysis and treatment. Results (1) the group collected 11 cases of congenital neutropenia patients (male 4 cases, female 7 cases), the age of onset of 0.5 months ~6 months, the average age of 4.23 + 2 months. Age at diagnosis was 3.5 ~77 months, the average age at diagnosis was 22.36 + 20.89 months, the average diagnosis compared with the average age of onset age delay 18.13 months. (2) all patients per month at least 1 times before the diagnosis and treatment of infection, the main clinical manifestations included respiratory tract infection, skin and mucosa soft tissue infection, digestive system infection, otitis media. The average of 1 weeks, 2 weeks, 3 weeks, 4 weeks 1 infection percentage for 54.5%, 18.2%, 9.1%, 18.2%; most of the patients were hospitalized several times before the diagnosis and treatment of history, the average in January, February, March hospitalized more than 1 times the proportion were 63.6%, 18.2%, 9.1%, no hospitalization experience of the ratio of 9.1%. (3) at least 2 times a week, for 1 months to monitor blood routine the results showed that: all of the patients to ANC Little more than 3 times lower than 0.5 * 109/L; 6 cases of ANC remain below 0.5 * 109/L, the clinical diagnosis of severe congenital neutropenia; another 5 cases of ANC were fluctuated, the fluctuation period of 16~29 days, ANC can be from lack of neutrophils to the normal state of natural growth and lasts about 1 weeks after slowly lowered to agranulocytosis and continue for a period of time, but also the natural growth to normal, the diagnosis for periodic neutropenia; in all cases, lymphocyte, hemoglobin, platelet no obvious abnormality; all parents and siblings were not significantly abnormal. Blood (4) bone marrow cell morphology check (both in ANC is less than 0.5 * 109/l by bone marrow examination) results showed: bone marrow neutrophils dysmaturity, neutrophils, stagnation in the early metamyelocyte stage, rod-shaped nucleus and lobocyte ratio decreased, red No abnormal giant two. (5) gene sequencing results: 8 cases of congenital neutropenia associated with reduced virulence gene detection, 2 cases of abnormal cases, 1:slc37a4 homozygous mutation, whose parents were carriers of the disease gene; 8: patients carrying FANCB gene, hemizygote, no father mother was heterozygous mutation. The other 6 cases did not detect the pathogenic gene mutation. (6) treatment and follow-up of this group are as follows: (1) when the treatment plan: SCN patients in ANC is less than 0.5 * 109/l, CYN in patients with neutrophil minimum value, all patients had obvious infection with ANC less than 1 * 109/l, rhG-CSF treatment. Initial treatment dose was 5ug/kg.d, according to the use of rhG-CSF for 24 hours ANC adjust rhG-CSF amount of treatment, the ANC was maintained at more than 1 * 109/l level, combined with the use of antibiotics when necessary; (2) health management education.10 cases diagnosed according to the scheme of treatment with rhG-CSF Treatment, follow-up (follow-up time of 2.7 months ~49.5 months, an average of 18.1 + 15.7 months) results are as follows: only 1 cases had mild anorexia, no adverse reactions to the rest of the patients during the follow-up period; the hospitalization rate was 0%; the infection frequency was significantly lower than that before treatment: an average of 1 weeks, 2 weeks, 3 weeks, 4 weeks 4 weeks, 1 times the percentage of infection were 0%, 0%, 20%, 20%, 60%; 1 cases were treated with rhG-CSF 2 times (the doses were 5ug/kg., 10ug/kg., ANC) showed no response to the state, parents for economic reasons to abandon the use of rhG-CSF treatment, telephone follow-up was informed in November when children died from severe infection. Conclusion (1) of congenital neutropenia with no specific clinical manifestations, lack of awareness of the disease, resulting in the time delay of diagnosis. Shortly after repeated infections and continued to decrease with neutrophil absolute value, should be considered in congenital neutropenia the possibility of, Blood and bone marrow examination can assist clinical diagnosis. (2) on neutrophil absolute value of continuous monitoring, the patients were divided into periodic neutropenia and severe congenital neutropenia, used to guide the recombinant human granulocyte colony-stimulating factor (3) through. The target gene exon trapping and two generation sequencing technology on 8 cases of congenital neutropenia for gene diagnosis, 2 patients were abnormal, the positive rate of only 25%, the plan for whole genome sequencing, MLPA technology to assist the diagnosis. Most of the patients (4) of recombinant human granulocyte colony-stimulating factor was good less adverse reaction, can significantly reduce the frequency of infection and hospitalization, improve the quality of life. But if you do not adhere to the application or colony stimulating factor did not respond to treatment with CN on recombinant human granulocyte, can lead to serious infection and even death.

【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.5

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