胎儿期发病的家族性噬血淋巴组织细胞增生症一例并文献复习

Fetal familial hemophagocytic lymphohistiocytosis:a case report and literature review

目的探讨胎儿期发病的家族性噬血淋巴组织细胞增生症(familial hemophagocytic lymphohistiocytosis,FHL)的临床特点及基因诊断。方法回顾性分析首都儿研所附属儿童医院2019年9月收治的1例胎儿期发病的FHL新生儿的临床资料。以“fetus”“neonate”“familial hemophagocytic lymphohistiocytosis”为关键词检索Pubmed数据库,以“家族性噬血细胞综合征”为关键词检索中国知网及万方数据库,检索时间均为建库至2021年1月3日。总结国内外胎儿期发病的FHL的病例特点。结果(1)本例患儿,胎龄39周+3宫内发现脾肿大、腹腔内游离液及脑室增大,生后出现发热、呼吸急促、肝脾肿大、皮肤淤斑淤点、淋巴结肿大,伴三系下降、肝功能异常、铁蛋白及甘油三酯升高、纤维蛋白原减低。CD107a激发试验示自然杀伤细胞的脱颗粒功能降低(ΔCD107a<5%)。骨髓穿刺涂片见噬血细胞。患儿UNC13D基因存在复合杂合突变:c.118-308C>T和c.3002T>C,患儿确诊为FHL3型。入院后予地塞米松及环孢素化疗、对症治疗,未予造血干细胞移植,生后52 d死亡。(2)共检索纳入15篇胎儿期发病的FHL的相关文献,共20例患儿,并和本例患儿进行汇总分析,发现FHL患儿胎儿期以胎儿水肿、肝脾肿大为主要表现,可伴胎儿窘迫、羊水增多等,生后可出现发热、呼吸困难、皮疹及中枢神经系统受累等。实验室及影像学检查结果符合噬血淋巴组织细胞增生症的诊断标准。目前报道的胎儿期发病的FHL基因突变类型为PRF1基因突变(FHL2型)和UNC13D基因突变(FHL3型),可分别检测到穿孔素和颗粒酶表达减低。目前以地塞米松、环孢素、依托泊苷等化疗及对症治疗为主,也有孕晚期对胎儿行宫内化疗及生后造血干细胞移植等治疗的报告。4例患儿宫内死亡,后期随访13例患儿于生后不同时间死亡,4例患儿存活。存活的患儿中最大随访至12岁。结论胎儿期发病的FHL早期表现不典型,病死率极高,诊治难度大。临床发现胎儿水肿或肝脾肿大,且鉴别诊断困难时,除考虑溶血、感染、自身免疫和遗传代谢性疾病外,还应注意与FHL鉴别。可借助免疫学技术和基因测序的方法以早期诊断、早治疗,从而改善预后。

Objective To discuss the clinical characteristics and genetic diagnosis of fetal familial hemophagocytic lymphohistiocytosis(FHL).Methods Clinical data of a case of fetal FHL from Children's Hospital,Capital Institute of Pediatrics was analyzed,and related FHL cases at home and abroad were retrieved from PubMed,CNKI,and Wanfang databases using terms including"fetus","neonate",and"familial hemophagocytic lymphohistiocytosis",from the establishment of the database to January 3,2021,to summarize the characteristics of this disease.Results This index case was found with fetal splenomegaly,free fluid in the abdominal cavity,and enlargement of the ventricle at 39+3 weeks of gestation,and presented with fever,tachypnea,hepatosplenomegaly,skin ecchymosis and petechia,and lymphadenectasis after birth.Laboratory examination revealed pancytopenia,abnormal liver function,elevated ferritin and triglyceride,and decreased fibrinogen levels.CD107a excitation experiment showed decreased degranulation function of NK cell(ΔCD107a<5%).Hemophagocytosis was observed in the bone marrow smear.Genomic DNA sequence analysis demonstrated compound heterozygous mutations of c.118-308C>T and c.3002T>C in the UNC13D gene.All the above findings led to the diagnosis of FHL3.Despite chemotherapy with dexamethasone and cyclosporin,and symptomatic treatment after admission without hematopoietic stem cell transplantation,the baby died on day 52.A total of 15 papers related to fetal FHL,including 20 infants,were retrieved.Among these 21 cases(including the index case),the main clinical symptoms were fetal edema and hepatosplenomegaly,which may be accompanied by fetal distress and increased amniotic fluid volume,and postnatal fever,dyspnea,rash,and central nervous system involvement.Laboratory and imaging examination results were consistent with the diagnostic criteria for hemophagocytic hyperplasia.As far as we know,the reported fetal FHL gene mutations were PRF1(FHL2)and UNC13D gene mutation(FHL3),in which reduced expression of perforin and granzyme can be detected,respectively.Dexamethasone,cyclosporin,etoposide,and other chemotherapy and symptomatic treatment are the primary treatments currently,and alternative therapies include intrauterine chemotherapy in the third trimester and postnatal hematopoietic stem cell transplantation.Among the 21 cases,including the index case,intrauterine death occurred in four cases,13 children died at different times after birth,and only four children survived,among which the eldest one was 12 years old.Conclusions FHL is a condition with atypical early signs,high mortality rate and treatment difficulties.Fetal FHL should be considered in differential diagnosis in fetuses with edema or hepatosplenomegaly besides hemolysis,infection,autoimmune diseases,and hereditary problems.Therefore,with immunotechnology and gene sequencing,early diagnosis and treatment can be prompted to improve the prognosis of this group of population.