University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
University of Gothenburg, Gothenburg, Sweden.
Arthritis Rheumatol. 2016 Sep;68(9):2314-22. doi: 10.1002/art.39699.
To describe the clinical features, genotype, and treatment in a series of subjects with confirmed adenosine deaminase 2 (ADA2) deficiency.
All symptomatic subjects were referred for genetic testing for suspected ADA2 deficiency; relatives of index cases were also screened. Demographic, clinical, and laboratory characteristics and treatments were recorded. Genetic analyses included whole-exome sequencing in 4 subjects and Sanger sequencing of CECR1 (the gene for cat eye syndrome chromosome region candidate 1) in all subjects. Assays for ADA2 enzyme activity and quantitative polymerase chain reaction analysis of CECR1 messenger RNA (mRNA) were also performed.
We identified 15 subjects with ADA2 deficiency, 5 of whom were asymptomatic (relatives of index cases; ages 5-42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. Phenotypic manifestations in the patients with symptomatic ADA2 deficiency included livedo racemosa (73.3%), neurologic involvement (53.3%), and immunodeficiency (46.7%). CECR1 mRNA expression in 8 subjects, including 5 who were presymptomatic, was significantly lower than in healthy controls (P = 0.0016). Subjects with ADA2 deficiency (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy pediatric controls (P < 0.0001) and patients with sporadic (nonfamilial) childhood polyarteritis nodosa (PAN) without CECR1 mutation (P = 0.0108). Anti-tumor necrosis factor therapy was required in 9 of the 10 symptomatic subjects.
The clinical manifestations of ADA2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one-third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment.
描述一系列确诊的腺苷脱氨酶 2（ADA2）缺陷患者的临床特征、基因型和治疗方法。
所有有症状的患者均因疑似 ADA2 缺陷而接受基因检测；指数病例的亲属也接受了筛查。记录了人口统计学、临床和实验室特征以及治疗方法。基因分析包括 4 例患者的全外显子组测序和所有患者的 CECR1（猫眼综合征染色体区候选 1 基因）的 Sanger 测序。还进行了 ADA2 酶活性测定和 CECR1 信使 RNA（mRNA）的定量聚合酶链反应分析。
我们共发现 15 例 ADA2 缺陷患者，其中 5 例无症状（指数病例的亲属；年龄 5-42 岁）。所有患者均发现 CECR1 纯合或复合杂合突变。有症状 ADA2 缺陷患者的表型表现包括Racemosa 紫癜（73.3%）、神经系统受累（53.3%）和免疫缺陷（46.7%）。8 例患者（包括 5 例无症状患者）的 CECR1 mRNA 表达明显低于健康对照组（P=0.0016）。与健康儿科对照组相比，ADA2 缺陷患者（有症状或无症状）的 ADA2 酶活性也较低（P<0.0001），与无 CECR1 突变的散发性（非家族性）儿童结节性多动脉炎（PAN）患者相比（P=0.0108）。10 例有症状患者中有 9 例需要接受抗肿瘤坏死因子治疗。
ADA2 缺陷的临床表现从局限性皮肤受累到严重多系统血管炎不等；我们的病例中有三分之一（15 例中有 5 例）目前无症状，需要密切监测。我们建议对指数病例的未受影响的兄弟姐妹、家族性血管炎病例和对标准治疗无效的 PAN 病例进行 CECR1 筛查。
