本文選題：先天性中性粒細(xì)胞減少癥　切入點(diǎn)：感染　出處：《廣西醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的回顧性分析11例先天性中性粒細(xì)胞減少癥患者及其家屬的臨床表現(xiàn)、基因檢測(cè)結(jié)果、治療等情況,總結(jié)診療經(jīng)驗(yàn),提高臨床醫(yī)生對(duì)該病的認(rèn)識(shí)。方法(1)收集患者及其家庭成員的臨床及實(shí)驗(yàn)室資料。(2)應(yīng)用外顯子目標(biāo)基因捕獲及二代測(cè)序技術(shù)對(duì)先證者行先天性中性粒細(xì)胞減少癥相關(guān)致病基因如ELANE、HAX1、GFI1、CSF3R、WAS、G6PC3、SLC37A4、LYST、AK2、SBDS等500多個(gè)基因檢測(cè),篩查出突變位點(diǎn)基因序列后,進(jìn)行致病性分析,并對(duì)病人及其家庭成員進(jìn)行Sanger測(cè)序驗(yàn)證。(3)追蹤隨訪評(píng)估患者使用重組人粒細(xì)胞集落刺激因子治療后的療效、不良反應(yīng)。(4)采用SPSS20.0版統(tǒng)計(jì)軟件及Microsoft Office Excel 2010進(jìn)行數(shù)據(jù)分析和處理。結(jié)果(1)本組共收集11例先天性中性粒細(xì)胞減少癥病例(男4例,女7例),發(fā)病年齡0.5月~6月,平均發(fā)病年齡4.23±2.0月。診斷年齡3.5月~77月,平均診斷年齡22.36±20.89月,平均診斷年齡較平均發(fā)病年齡滯后18.13月。(2)所有患者診治前每月至少感染1次,主要的臨床表現(xiàn)包括呼吸道感染、皮膚黏膜軟組織感染、消化系統(tǒng)感染、中耳炎。其中平均1周、2周、3周、4周發(fā)生1次感染的比例分別為54.5%、18.2%、9.1%、18.2%;絕大部分患者診治前均有多次住院治療病史,平均1月、2月、3月住院治療1次以上的比例分別為63.6%、18.2%、9.1%,無(wú)住院經(jīng)歷者的比例為9.1%。(3)每周至少2次,持續(xù)1個(gè)月監(jiān)測(cè)血常規(guī),結(jié)果示:所有患者ANC至少3次以上低于0.5×109/L;6例ANC持續(xù)低于0.5×109/L,故臨床診斷為重型先天性中性粒細(xì)胞減少癥;另5例ANC呈規(guī)律性波動(dòng),波動(dòng)周期為16~29天,即anc可從中性粒細(xì)胞缺乏狀態(tài)自然增長(zhǎng)至正常并持續(xù)1周左右后,緩慢降低至粒細(xì)胞缺乏狀態(tài)并持續(xù)一段時(shí)間,又可自然增長(zhǎng)至正常,故臨床診斷為周期性中性粒細(xì)胞減少癥;所有病例的淋巴細(xì)胞、血紅蛋白、血小板無(wú)明顯異常;所有患者父母及兄弟姐妹隨機(jī)血常規(guī)無(wú)明顯異常。(4)骨髓細(xì)胞形態(tài)學(xué)檢查(均在anc低于0.5×109/l時(shí)行骨髓檢查)結(jié)果示:骨髓中性粒細(xì)胞成熟障礙,大量中性粒細(xì)胞停滯在早、中、晚幼粒細(xì)胞階段,桿狀核與分葉核粒細(xì)胞比值降低,紅巨二系未見(jiàn)異常。(5)基因測(cè)序結(jié)果:8例行先天性中性粒細(xì)胞減少癥相關(guān)致病基因檢測(cè),2例異常------病例1:slc37a4純合突變,其父母均為該致病基因的攜帶者;病例8:攜帶fancb基因,半合子,父親無(wú)變異,母親為雜合子。另6例未檢測(cè)出致病基因突變。(6)治療與隨訪:本組治療方案如下:(1)當(dāng)scn患者在anc低于0.5×109/l時(shí)、cyn患者在中性粒細(xì)胞最低值時(shí)、所有患者有明顯感染伴anc低于1.0×109/l時(shí),使用rhg-csf治療。起始治療劑量均為5ug/kg.d,根據(jù)使用rhg-csf治療后24小時(shí)的anc調(diào)節(jié)rhg-csf治療量,使anc維持在1×109/l水平以上,必要時(shí)聯(lián)合使用抗生素;(2)健康管理教育。10例病例診斷明確后按上述方案使用rhg-csf治療,隨訪(隨訪時(shí)間2.7月~49.5月,平均18.1±15.7月)結(jié)果如下:只有1例病例有一過(guò)性輕度納差,其余患者無(wú)不良反應(yīng);隨訪期間住院率為0%;感染頻次較治療前明顯下降:平均1周、2周、3周、4周、4周感染1次的百分比分別為0%、0%、20%、20%、60%;1例使用rhg-csf治療2次(劑量分別為5ug/kg.次,10ug/kg.次),anc均呈無(wú)應(yīng)答狀態(tài),父母因經(jīng)濟(jì)原因放棄使用rhg-csf治療,電話隨訪時(shí)被告知患兒于11月大時(shí)因嚴(yán)重感染死亡。結(jié)論(1)先天性中性粒細(xì)胞減少癥的臨床表現(xiàn)無(wú)特異性,對(duì)該病認(rèn)識(shí)不足,導(dǎo)致了診斷時(shí)間延遲。對(duì)出生后不久即出現(xiàn)反復(fù)感染并伴中性粒細(xì)胞絕對(duì)值持續(xù)減少者,應(yīng)考慮先天性中性粒細(xì)胞減少癥的可能性,血常規(guī)和骨髓細(xì)胞形態(tài)學(xué)檢查可協(xié)助臨床診斷。(2)對(duì)中性粒細(xì)胞絕對(duì)值持續(xù)的監(jiān)測(cè),可將病人分為周期性中性粒細(xì)胞減少癥和重型先天性中性粒細(xì)胞減少癥,有利于指導(dǎo)重組人粒細(xì)胞集落刺激因子的使用。(3)通過(guò)外顯子目標(biāo)基因捕獲及二代測(cè)序技術(shù)對(duì)8例先天性中性粒細(xì)胞減少癥進(jìn)行基因診斷,2例發(fā)現(xiàn)異常,陽(yáng)性率僅25%,計(jì)劃行全基因組測(cè)序、MLPA等技術(shù)協(xié)助診斷。(4)大多數(shù)患者對(duì)重組人粒細(xì)胞集落刺激因子反應(yīng)好,不良反應(yīng)少,可以明顯降低感染和住院頻次,提高生活質(zhì)量。但若不堅(jiān)持應(yīng)用或?qū)χ亟M人粒細(xì)胞集落刺激因子治療無(wú)反應(yīng)的CN患者,會(huì)導(dǎo)致嚴(yán)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.

【學(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.5

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