Skrabl-Baumgartner Andrea, Plecko Barbara, Schmidt Wolfgang M, König Nadja, Hershfield Michael, Gruber-Sedlmayr Ursula, Lee-Kirsch Min Ae
Department of Pediatrics and Adolescent Medicine, Medical University Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria.
Division of Child Neurology, University Children's Hospital, University of Zurich, Zurich, Switzerland.
Pediatr Rheumatol Online J. 2017 Aug 22;15(1):67. doi: 10.1186/s12969-017-0193-x.
Loss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency.
We describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutières syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity.
Our findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications.
功能丧失性CECR1突变导致儿童期发病的结节性多动脉炎（PAN），这是一种无明显自身免疫迹象的自身炎症性疾病。在此，我们描述了腺苷脱氨酶2（ADA2）缺乏症患者同胞中具有组成型I型干扰素激活的自身免疫表型的异常表现。
我们描述了两名患有早发性复发性中风、关节炎、口腔溃疡、盘状皮疹、外周血管闭塞性疾病和高抗核抗体滴度的同胞。对血液中干扰素特征的评估显示存在组成型I型干扰素激活。怀疑为Aicardi-Goutières综合征（AGS），但未检测到已知AGS基因的突变。全外显子测序确定了CECR1基因中一个已知突变和一个新突变的复合杂合性。通过ADA2催化活性的显著降低证明了这些突变的功能后果。
我们的研究结果表明，ADA2缺乏可导致异常的自身免疫表型，扩展了PAN的表型谱。患者血液中的组成型I型干扰素激活提示I型干扰素在疾病发病机制中可能起作用，这可能具有治疗意义。
