摘要
目的探讨原发性噬血细胞性淋巴组织细胞增生症(pHLH)患儿的临床特点及其家系的基因突变特征。方法选择2016年11月至2017年1月于郑州大学第一附属医院儿内科确诊的3例pHLH患儿为先证者,并且以先证者及其16例家系成员为研究对象。对先证者进行血常规、凝血功能、血清铁蛋白、自然杀伤(NK)细胞、可溶性CD25,以及骨髓细胞形态学检查。对先证者及家系成员进行HLH相关基因突变检查。根据HLH-94方案和HLH-2004方案对先证者进行治疗。回顾性分析3例先证者的病史和相关检查结果、诊断、治疗及转归。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》要求。结果①患儿1,女性,4个月,因"发热7 d,发现血小板减少6 d"于2016年11月4日至本院就诊,临床表现为发热,肝、脾大。血常规结果示三系明显降低。骨髓检查示镜下可见噬血细胞现象。NK细胞活性降低,血清铁蛋白值增高,可溶性CD25水平增高。头颅MRI示桥脑右后份、左侧桥小脑结合臂、双侧基底节区、左侧丘脑、双侧额顶枕叶多发异常信号,脑实质发育欠饱满,双侧额颞部蛛网膜下腔增宽。脑脊液检查结果示:总蛋白、白蛋白值均增高。HLH相关基因检测及家系分析结果示:患儿1的RAB27A基因第5外显子c.272delA(p.Asp91ValfsTer11)(杂合),第3外显子c.121delA(p.Thr41GlnfsTer44)(杂合),分别来源于其父母,为双重杂合突变。患儿1确诊为Griscelli综合征(GS)-2相关HLH合并中枢神经系统病变。按照HLH-2004方案规律治疗1+个月后,病情未缓解,经患儿监护人放弃治疗后出院。②患儿2,男性,8岁,因"发热27 d"于2016年11月14日至本院就诊。临床表现为发热,肝、脾和颈部淋巴结大。血常规结果示三系明显降低。纤维蛋白原值降低,NK细胞活性降低,血清铁蛋白值增高,可溶性CD25水平增高。EB病毒(EBV)-DNA为1.42×106 copies/mL。颈部淋巴结活检病理及免疫组化结果符合霍奇金淋巴瘤(HL)(混合细胞型)诊断。HLH相关基因突变及家系分析结果示:患儿2的PRF1基因第2外显子c.65delC(p.Pro22ArgfsX29)(杂合)和错义突变c.503G>A(p.Ser168Asn)(杂合),分别来源于其父母,为双重杂合突变。患儿2确诊为家族性pHLH(FHL)、HL(混合细胞型)、EBV感染。患儿2接受HLH-94方案治疗后,病情获得初步控制,此后采用HL方案化疗,病程2+个月时,病情加重后死亡。③患儿3,男性,13岁,因"当地医院初诊确诊HLH,间断发热4+个月"于2017年1月5日至本院就诊。临床表现为发热,肝、脾大。生化检测结果示甘油三酯水平增高,纤维蛋白原值降低。骨髓检查结果示偶见噬血细胞现象。NK细胞活性降低,血清铁蛋白值增高,CD107a脱颗粒功能降低。颈部淋巴结活检病理结果示淋巴结反应性增生。HLH相关基因突变家系分析结果示:患儿3的PRF1基因第2外显子c.503G>A(p.Ser168Asn)(杂合),来源于其父亲。患儿3确诊为FHL。患儿3于外院治疗效果不佳,于本院接受HLH-2004方案治疗27 d,病情控制后出院,建议行造血干细胞移植(HSCT)。此后,患儿未再返院复查,总病程7个月时FHL复发后死亡。结论对初诊淋巴结大伴EBV感染的pHLH患儿,应及早行淋巴结活检。对淋巴结大伴NK细胞活性和CD107a脱颗粒功能检测结果异常者,应进行HLH相关基因突变检测,以尽早确诊及治疗,提高pHLH患儿生存率。在此基础上,对pHLH患儿进行家系相关基因突变分析,可为遗传咨询提供依据。
Objective To explore the clinical characteristics of children with primary hemophagocytic lymphohistiocytosis(pHLH)and gene mutations of their families.Methods From November 2016 to January 2017,three children with pHLH from the Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University were selected as probands,and the 3 probands and their 16 family members were taken as the study objects.Complete blood count test,coagulation,serum ferritin,natural killer(NK)cell,soluble CD25,morphology of bone marrow cell of 3 probands were tested.And HLH related gene mutation screening were preformed among patients and their family members.The patients were treated with HLH-94 and HLH-2004 scheme.The medical history and related examination results,diagnosis,treatment and outcome of 3 probands were analyzed retrospectively.This study was in line with the requirements of World Medical Association of Helsinki revised in 2013.Results①Case 1,female,4 months old,was hospitalized in our hospital on November 4,2016 due to"fever for 7 d,thrombocytopenia for 6 d".Her clinical manifestations were fever,hepatosplenomegaly.Results of complete blood count test showed that all blood count were significantly reduced.The hemophagocytosis was observed by bone marrow puncture.NK cell activity decreased,serum ferritin increased and soluble CD25 levels increased.Brain MRI showed that the right posterior part of the pons,the left cerebellopontine combined arm,the bilateral basal ganglia,the left thalamus,the bilateral frontal parietal occipital lobes had multiple abnormal signals,the brain parenchyma was not fully developed,and the bilateral frontal temporal subarachnoid space was widened.The results of cerebrospinal fluid examination showed that the total protein and albumin levels were increased.The results of HLH related genes screening and pedigree analysis showed that this proband′s c.272delA(p.Asp91ValfsTer11)(heterozygous)in exon 5 and c.121delA(p.Thr41GlnfsTer44)(heterozygous)in exon 3 were found in RAB27A gene,which were double heterozygous and originated from her parents.She was diagnosed as Griscelli syndrome(GS)-2 related HLH with central nervous system disease.After more than one month′s regular treatment with HLH-2004 scheme,HLH of the probomd was not controlled.Her guardian gave up treatment and left hospital.②Case 2,male,8 years old,was hospitalized in our hospital on November 14,2016 due to"fever for 27 d".His clinical manifestations were fever,hepatosplenomegaly and neck lymphnodes.Results of complete blood count test showed that all blood count were significantly reduced.Fibrinogen level and NK cell activity decreased,serum ferritin and soluble CD25 levels increased.EB virus(EBV)-DNA was 1.42×106 copies/mL.The pathological results of cervical lymph node biopsy and immunohistochemical showed classic Hodgkin lymphoma(HL)(mixed cell type).The results of HLH related genes screening and pedigree analysis showed that c.65delC(p.Pro22ArgfsX29)(heterozygous)and c.503G>A(p.Ser168Asn)(heterozygous)were found in exon 2 of PRF1 gene,which were double heterozygous and originated from his parents.He was diagnosed as family pHLH(FHL),typical HL(mixed cell type),EBV infection.The proband was treated with HLH-94 scheme,and the disease was initially controlled.After that,the patient was treated with regimen of HL.When the disease course was more than 2 months,the proband died after aggravation.③Case 3,male,13 years old,was hospitalized in the our hospital on January 5,2017 due to"initial diagnosis of HLH in local hospital,intermittent fever for more than 4 months".His clinical manifestations were fever,hepatosplenomegaly.The results of bone marrow examination showed that hemophagocytosis was occasionally seen.NK cell activity decreased,serum ferritin increased,the degranulation function of CD107a decreased.The pathological results of cervical lymph node biopsy showed reactive hyperplasia of lymph nodes.The results of HLH related genes screening and pedigree analysis showed that c.503G>A(p.Ser168Asn)(heterozygous)was found in exon 2 of PRF1 gene,which was a heterozygous mutation and originated from his father.He was diagnosed as FHL.The treatments were not effect in local hospital,so the proband transfer to our hospital and receive treatment of HLH-2004 scheme for 27 d.Then he discharged after his condition was under control.The hematopoietic stem cell transplant(HSCT)were suggested to use.After that,the proband did not return to the hospital for reexamination,and died of FHL recurrence after 7 months later.Conclusions In order to improve the survival rate of children with pHLH,early lymph node biopsies should be carried out in HLH patients with large lymph nodes and EBV infection at the initial diagnosis.And early detection of HLH related gene mutations should be proceed in patients with abnormal NK cell activity and CD107a degranulation function.On this basis,the pedigree of analysis should be carried out to provide genetic counseling.
作者
苏淑芳
李白
魏林林
魏会霞
徐岩
柴方圆
毛舒婷
张林楠
刘玉峰
Su Shufang;Li Bai;Wei Linlin;Wei Huixia;Xu Yan;Chai Fangyuan;Mao Shuting;Zhang Linnan;Liu Yufeng(Department of Pediatrics,First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,Henan Province,China)
出处
《国际输血及血液学杂志》
CAS
2020年第3期233-240,共8页
International Journal of Blood Transfusion and Hematology
基金
河南省医学科技攻关计划普通项目(201702025)。
