Ling Eduard, Broides Arnon, Ling Galina, Shubinsky George, Hadad Nurit, Nahum Amit, Simon Amos J, Lev Atar, Somech Raz
Department of Pediatrics B and Pediatric Rheumatology Clinic, Soroka University Medical Center, Rager Avenue, Beer Sheva, Israel.
Soroka University Medical Center, Beer Sheva, Israel.
Immunol Res. 2021 Feb;69(1):100-106. doi: 10.1007/s12026-021-09172-w. Epub 2021 Jan 23.
Biallelic mutations in the zeta-associated protein 70 (ZAP70) gene cause combined immunodeficiency (CID). Neonatal screening for severe CID in Israel is implemented since 2015. We report on clinical, flow cytometry, and genetic data of an unusual ZAP70 deficiency patient. A 10-week-old Bedouin female presented with severe autoimmune hemolytic anemia. Cytomegalovirus (CMV) negative packed cell therapy was given without improvement; indexes of hemolysis worsened. At this time, thrombocytopenia was noted. The patient was treated with single dose of 1 g/kg intravenous immunoglobulin with rapid resolution of hemolysis. Serum immunoglobulin concentrations were normal; flow cytometry revealed severe CD8 lymphocytopenia. Lymphocyte proliferation test demonstrated reduced response to concanavalin A and phytohemagglutinin. Gated T cells were negative for intracellular ZAP70. A genetic analysis revealed a missense homozygous c.1388C > T (p.A463V) mutation, confirming the diagnosis of ZAP70 deficiency. She later on developed urinary tract infection due to ESBL producing E. coli treated with amikacin and severe CMV infection that partially responded to ganciclovir therapy and at 7 months of age, she successfully underwent allogeneic hematopoietic stem cell transplantation. Neonatal screening by T cell receptor excision circles (TRECs) for SCID was normal, yet very low TRECs were recorded at the time of CID diagnosis. Normal neonatal screening for SCID does not rule out the diagnosis of CID due to ZAP70 deficiency. This type of CID can present with autoimmunity as the sole initial manifestation of the disease.
ζ相关蛋白70（ZAP70）基因的双等位基因突变会导致联合免疫缺陷（CID）。自2015年起，以色列开始对重症CID进行新生儿筛查。我们报告了一名罕见的ZAP70缺陷患者的临床、流式细胞术和基因数据。一名10周大的贝都因女性出现严重的自身免疫性溶血性贫血。给予巨细胞病毒（CMV）阴性的红细胞治疗后病情无改善；溶血指标恶化。此时，发现有血小板减少。该患者接受了单剂量1 g/kg的静脉注射免疫球蛋白治疗，溶血迅速消退。血清免疫球蛋白浓度正常；流式细胞术显示严重的CD8淋巴细胞减少。淋巴细胞增殖试验表明对刀豆球蛋白A和植物血凝素的反应降低。门控T细胞的细胞内ZAP70呈阴性。基因分析发现一个错义纯合子c.1388C＞T（p.A463V）突变，确诊为ZAP70缺陷。她后来因产超广谱β-内酰胺酶（ESBL）的大肠杆菌感染出现尿路感染，接受丁胺卡那霉素治疗，还出现严重的CMV感染，对更昔洛韦治疗部分有效，在7个月大时，她成功接受了异基因造血干细胞移植。通过T细胞受体切除环（TREC）进行的SCID新生儿筛查结果正常，但在CID诊断时记录到TREC非常低。SCID新生儿筛查结果正常并不能排除ZAP70缺陷导致的CID诊断。这种类型的CID可能以自身免疫作为该疾病的唯一初始表现。
