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.

中文翻译：

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ADA2 缺乏症并发 EBV 驱动的淋巴组织增生性疾病。

一名 29 岁男性，在儿童时期患有反复呼吸道和皮肤感染、贫血和中性粒细胞减少症，从 16 岁开始需要免疫球蛋白替代抗体缺乏症。直到 28 岁，他一直保持相对良好的状态，当时他出现了两周的疲劳、喉咙痛、发烧和咳痰。他被发现患有 EBV 病毒血症和脾肿大，并在骨髓环钻后诊断为 EBV 驱动的淋巴组织增生性疾病。三个兄弟姐妹的家族史值得注意：一个健康的姐妹和两个患有贫血和中性粒细胞减少症的兄弟；一位在 5 岁时死于中性粒细胞减少性小肠结肠炎继发的败血症，另一位患有肠血管炎和抗体缺乏症，并成功进行了造血干细胞移植。先证者' s DNA 对 279 个与免疫缺陷相关的基因进行了靶向测序（GRID 面板）。最佳候选者是两个 ADA2 变体，p.Arg169Gln (R169Q) 和 p.Asn370Lys (N370K)。父母、未受影响的姐妹和所有三个受影响的兄弟中变异的 Sanger 测序和共分离与复合杂合遗传完全一致。随后对先证者进行的全基因组测序未发现其他潜在的因果变异。ADA2 活性与受影响家庭成员中 ADA2 缺乏的诊断一致。这是对 ADA2 缺乏症中 EBV 驱动的淋巴组织增生性疾病的首次描述。