Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, United Kingdom; Department of Immunology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom.
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Clin Immunol. 2020 Jun;215:108443. doi: 10.1016/j.clim.2020.108443. Epub 2020 Apr 27.
A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.
一名 29 岁男性，自幼反复发生呼吸道和皮肤感染、贫血和中性粒细胞减少症，16 岁起需接受免疫球蛋白替代治疗以纠正抗体缺陷。他一直相对健康，直到 28 岁时出现两周疲劳、咽痛、发热和咳痰。他被发现 EBV 病毒血症和脾肿大，骨髓活检后诊断为 EBV 驱动的淋巴增殖性疾病。家族史值得注意，有三个兄弟姐妹：一个健康的妹妹和两个贫血和中性粒细胞减少症的兄弟；其中一个在 5 岁时因中性粒细胞减少性肠炎继发败血症去世，另一个发展为肠血管炎和抗体缺陷，并成功进行了造血干细胞移植。先证者的 DNA 进行了与免疫缺陷相关的 279 个基因的靶向测序（GRID 面板）。最好的候选者是两个 ADA2 变体，p.Arg169Gln（R169Q）和 p.Asn370Lys（N370K）。对父母、未受影响的妹妹和所有三个受影响的兄弟进行 Sanger 测序和变体共分离，完全符合复合杂合遗传。随后对先证者进行全基因组测序，未发现其他潜在的致病变异。ADA2 活性与受影响家庭成员的 ADA2 缺乏诊断一致。这是 ADA2 缺乏症中 EBV 驱动的淋巴增殖性疾病的首次描述。ADA2 缺乏症可能导致对严重 EBV 诱导疾病的易感性，我们建议对患有这种诊断的患者监测 EBV 状态和病毒载量，并考虑对 ADA2 缺乏症与严重并发症相关的患者早期进行同种异体 SCT。
