LRBA基因突变2例病例报告

目的探讨LRBA基因突变患儿的临床特征、免疫表型、基因诊断及治疗,提高对该病的认识。方法回顾性总结2例LRBA缺陷患儿的临床表现、实验室检查、免疫球蛋白和淋巴细胞亚群等评估以及治疗。采用流式细胞术分析外周血淋巴细胞亚群精细分型。采用全外显子组测序进行基因分析,对检测到的点突变和缺失突变分别采用Sanger测序和荧光定量PCR验证。结果例1,男,13岁,主要表现为反复PLT、Hb下降6年余,反复真菌感染,持续EBV血症,生长发育迟缓和肝脾肿大;例2,男,3个月2 d,主要表现为出生后反复PLT下降。2例确诊年龄分别为13岁和4个月。2例患儿淋巴细胞亚群精细分型提示初始B细胞比例明显增高,记忆性B细胞比例降低。其他免疫表型包括:例1,免疫球蛋白Ig G、Ig A、Ig M水平下降,CD3^+T和CD8^+T淋巴细胞增多,CD4^+T、B和NK淋巴细胞减少,初始CD4^+和CD8^+T细胞比例下降,中央记忆性CD4+T和CD8+T细胞比例明显增高;例2,免疫球蛋白Ig G水平升高。2例均为LRBA基因复合杂合突变,例1为c. 1933C>T(p.R645X)杂合突变和Exon 29缺失杂合突变,分别来自于母亲和父亲;例2为c.3778G>C(p.A1260P)和c.1570G>A(p.G524S)复合杂合突变,分别来自于母亲和父亲。例2已行造血干细胞移植,临床好转中;例1未移植,对症治疗中。结论 LRBA缺陷的临床表现复杂多样,主要包括低丙种球蛋白血症、自身免疫性疾病、易感EBV等。静脉注射丙种球蛋白有助于减轻感染,阿巴西普靶向治疗和造血干细胞移植治疗是当前可选择的治疗方案。

A report of two cases with LRBA gene mutation

Objective We aimed to report the clinical manifestations, immunological features, genetic diagnosis and treatments of two cases with LRBA (LPS-responsive beige-like anchor protein) gene mutation. Methods Two male cases with LRBA gene mutations were enrolled in our study. The clinical features, immunological features and treatments of the two patients were retrospectively summarized. The lymphocyte subsets were detected by Flow Cytometry. WES was adapted for genetic analysis and the LRBA gene mutations were confirmed by Sanger sequencing，while the deletion of a gene was confirmed by fluorescence quantitative PCR. Results Patient 1 (P1) presented with recurrent throbocytopenia and hematocytopenia for six years. He also had recurrent fungal infection, persistent EBV viraemia, growth retardation and apparent hepatosplenomegaly. Patient 2 (P2) presented with recurrent thrombocytopenia after birth. They were diagnosed at the age of 13 years and 4 months respectively. Both of them presented with increased naive B cells and decreased memory B cells. P1 presented with decreased levels of immunoglobulin(Ig) M, IgG and IgA. Decreased naive CD4+ T and CD8+ T cells, expanded central memory CD4+ T and CD8+ T cells, reduced CD4+ T lymphocytes, B lymphocytes and NK cells, and increased CD8+ T cells were also observed in P1. P2 presented with increased IgG level. Sequencing results revealed that P1 had c.1933C>T (p.R645X) mutation and exon 29 deletion in LRBA gene. P2 had compound heterozygous mutations in LRBA gene (c.3778G>C, p.A1260P and c.1570G>A, p.G524S). Finally, P2 underwent hematopoietic stem cell transplantation (HSCT) and was currently in remission. Meanwhile P1 was under symptomatic treatment. Conclusion LRBA deficiency has a wide spectrum of phenotypes, characterized by hypogammaglobulinemia, recurrent infections, autoimmune diseases and susceptibility to EBV infection. Intravenous immune globulin could help relieve infection. Abatacept targeted therapy and HSCT might be the availabe therapeutic options for patients with LRBA deficiency.