胎儿晚期发病的家族性噬血细胞综合征——一例报告  

Familial Haemophagocytic Lymphohistiocytosis Occurs in A Fetus at His Third Trimester——A Case Report

作　　者：黄俊彬[1] 王健[1] 江莉[1] 吴晓君 陈纯[2] 徐宏贵[1] 薛红漫[2] 

机构地区：[1]中山大学孙逸仙纪念医院儿科,广东广州510120 [2]中山大学附属第七医院儿科,广东深圳518107

出　　处：《中国实验血液学杂志》2017年第6期1825-1828,共4页Journal of Experimental Hematology

基　　金：广东省科技计划项目(2017A020215126)

摘　　要：目的:报道1例胎儿晚期发病的家族性噬血细胞综合征(familial haemophagocytic lymphohistiocytosis,FHL)。方法:采用目标区序列捕获第二代高通量测序技术对1例胎儿晚期发病的噬血细胞综合征患儿及其父母进行基因检测,采用Sanger法测序验证。结果:患儿男,于孕36周B超发现"胎儿右侧胸腔积液、肝脾肿大",孕38周行剖宫产出生。患儿出生后发热、气促、黄疸,右下肺呼吸音减低,肝脾肿大等逐渐加剧。WBC 9.88×10~9/L,Hb91 g/L,Plt 13×10~9/L。TBIL 207.2μmol/L,DBIL 183.5μmol/L,甘油三酯3.05 mmol/L,纤维蛋白原0.88 g/L,血清铁蛋白3 120 ng/ml,s IL-2R 57 420 U/ml,外周血中CD3^-CD16^+CD56^+NK细胞3.6%。骨髓细胞学检查示:"偶见异常淋巴细胞、噬血细胞"。CD10~7a刺激实验显示,NK细胞脱颗粒功能严重受损。基因组DNA测序表明,该患儿为UNC13D突变双重杂合子(c.2448-13 G>A和c.1055+1 G>A),其母亲和父亲分别为UNC13D突变携带者(母:c.2448-13 G>A;父:c.1055+1 G>A)。结论:胎儿晚期发病的双重杂合子FHL3罕见。对于发热及多器官系统受累新生儿,应重视FHL的诊断,明确基因突变位点,对孕育健康下一胎意义重大。Objective： To analyze the clinical features and pathogenetic gene mutation in a fetus at his third trimester with familial haemophagocytic lymphohistiocytosis（ FHL）. Methods： Target region sequencing and high-throughput sequencing were used to detect pathogenetic gene mutations for familial haemophagocytic lymphohistiocytosis in a late onset HLH fetus. Pathogenetic gene mutations of the patient and his parents were verified by Sanger dideoxy sequencing.Results： A male neonate,who had right pleural effusion,hepatomegaly and splenomegaly previously revealed by fetus ultrasound,was delivered at full-term by cesarean section. His clinical presentation showed recurrent fever,tachypenea,decreased breath sounds on right side,hepatosplenomegaly etc.,which were gradually aggravating Lab. tests results were as follows： WBC 9. 88 × 10^9/L,Hb 91 g/L,Plt 13 × 10^9/L,ALT 18 U/L,AST 69 U/L,TBIL 207. 2 μmol/L,DBIL 183. 5μmol/L,TG 3. 05 mmol/L,Fib 0. 88 g/L,Serum ferritin 3 120 ng/ml and sIL-2R 57 420 U/ml. FCM showed that CD3^-CD16^＋CD56^＋cells reached to 3. 60% in the pripheral blood. Haemophagocytes were occasionally found in the bone marrow. NK/NKT stimulation test showed a severe damage of degranulation of NK cells. Sequence analysis of genomic DNA from his peripheral blood demonstrated the compound heterozygous mutations of UNC13D gene： c. 2448-13 G A in exon26 and c. 1055 ＋ 1 G A in exon12,both were pathogenetic mutations. In detailed family survey,it was confirmed that the mutation c. 2448-13 G A in exon26 was inherited from his mother and c. 1055 ＋ 1 G A in exon12 from his father. Conclusion： A rare case of familial haemophagocytic lymphohistiocytosis type 3（ FHL3） with late fetus onset who carried pathogenetic compound heterozygous mutations of UNC13D gene. Those neonates with recurrent fever,serous effusions and multiple organ failure should be screened for FHL. Identifying the pathogenic gene mutations laid the foundation of conceiving disease-free newborns.

关 键 词：胎儿 家族性噬血细胞综合征 双重杂合子 UNC13D 

分 类 号：R557.4[医药卫生—血液循环系统疾病]