CAJ | 학술논문

目的分析儿童遗传学骨髓衰竭(IBMFS)的分子诊断及移植结果,丰富我国此类罕见疾病资料库.方法自2009年起上海儿童医学中心建立基于下一代测序技术为基础的IBMFS分子诊断技术,常规开展临床诊断;回顾性分析2005年11月至2015年6月该中心完成的17例IBMFS患儿的分子诊断及移植结果.结果除了早年3例IBMFS患儿未行基因诊断外,14例患儿中12例经基因检查确诊.2例范科尼贫血(FA)为新突变,3个家庭据此进行产前检查,避免了后续患儿的出生.17例患儿[10例FA、5例先天性纯红细胞性再生障碍性贫血(DBA)和2例先天性角化不良(DKC)]分别接受了人类白细胞抗原(HLA)相合同胞供体(n=2)、非血缘HLA相合(n=8)及部分相合(n=7)供体的异基因造血干细胞移植(HSCT).其中干细胞来源包括外周血(n=12)和脐带血(n=5).FA、DKC患儿接受以氟达拉滨为主的减低剂量预处理,DBA患儿接受了白消安为主的清髓预处理.HSCT中位年龄36 (7 ～ 156)个月,移植过程中输注有核细胞和CD34+细胞数分别为(10.6±6.7)×108/kg和(5.9±7.0)×106/kg,粒细胞重建中位时间为13(10～19)d,外周血HSCT患儿血小板重建明显快于脐血移植[(16.3±6.0)比(30.0±17.1)d,t=-2.487,P=0.026].中位随访17(2～114)个月,除1例FA患儿因植入失败死于肺炎及心力衰竭外,其余患儿均移植成功并存活至末次随访.移植后3年无病生存率为94％.结论基于下一代测序的分子诊断技术和有效的HSCT为治疗我国儿童IBMFS提供了有力支持,并将极大丰富国内该罕见疾病的诊治资料库.
목적 분석인동유전학골수쇠갈(IBMFS)적분자진단급이식결과,봉부아국차류한견질병자료고.방법 자2009년기상해인동의학중심건립기우하일대측서기술위기출적IBMFS분자진단기술,상규개전림상진단;회고성분석2005년11월지2015년6월해중심완성적17례IBMFS환인적분자진단급이식결과.결과 제료조년3례IBMFS환인미행기인진단외,14례환인중12례경기인검사학진.2례범과니빈혈(FA)위신돌변,3개가정거차진행산전검사,피면료후속환인적출생.17례환인[10례FA、5례선천성순홍세포성재생장애성빈혈(DBA)화2례선천성각화불량(DKC)]분별접수료인류백세포항원(HLA)상합동포공체(n=2)、비혈연HLA상합(n=8)급부분상합(n=7)공체적이기인조혈간세포이식(HSCT).기중간세포래원포괄외주혈(n=12)화제대혈(n=5).FA、DKC환인접수이불체랍빈위주적감저제량예처리,DBA환인접수료백소안위주적청수예처리.HSCT중위년령36 (7 ～ 156)개월,이식과정중수주유핵세포화CD34+세포수분별위(10.6±6.7)×108/kg화(5.9±7.0)×106/kg,립세포중건중위시간위13(10～19)d,외주혈HSCT환인혈소판중건명현쾌우제혈이식[(16.3±6.0)비(30.0±17.1)d,t=-2.487,P=0.026].중위수방17(2～114)개월,제1례FA환인인식입실패사우폐염급심력쇠갈외,기여환인균이식성공병존활지말차수방.이식후3년무병생존솔위94％.결론 기우하일대측서적분자진단기술화유효적HSCT위치료아국인동IBMFS제공료유력지지,병장겁대봉부국내해한견질병적진치자료고.
Objective To enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS).Method Next-generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS.Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November.2005-June 2015).Result Three patients were diagnosed only by clinical manifestation before 2012.After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients).Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype-analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses.Seventeen IBMFS patients (10 FA, 5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n =2), matched unrelated donors (n =8) or mismatched unrelated donors (n =7).The source of stem cells for transplantation included peripheral blood (n =12) and cord blood (n =5).With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning.Median age at the time of HSCT was 36 months (7-156 months).The number of infused mononuclear cells and CD34 + cells was (10.6 ± 6.7) × 108 and (5.9 ± 7.0) × 106 per kilogram of recipient body weight, respectively.The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days).Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3±6.0) days vs.(30.0±17.1) days,t=-2.487,P=0.026).During a median follow-up of 17 months (range: 2-114 months) , except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT.The failure-free survival rate of the patients three years after HSCT was 94％.Conclusion NGS-based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited.