Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Ann Rheum Dis. 2022 Oct;81(10):1453-1464. doi: 10.1136/annrheumdis-2022-222629. Epub 2022 Jul 22.
To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in , is an autoinflammatory disease.
This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of mutations on protein function and immune signalling.
The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow.
ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in and some features of disease are amenable to immunomodulatory therapy.
验证 ROSAH（视网膜营养不良、视神经水肿、脾肿大、无汗和头痛）综合征是一种由 基因突变引起的自身炎症性疾病的假说。
本队列研究系统评估了 27 例 ROSAH 综合征患者的炎症特征，并研究了 突变对免疫信号的影响。进行了临床、免疫和影像学检查，10 例患者接受了经验性的细胞因子治疗，并进行了监测。使用外显子组测序鉴定新的致病性变异。使用细胞因子谱分析、转录组学、免疫印迹和敲入小鼠评估 突变对蛋白功能和免疫信号的影响。
该队列的大多数患者携带 p.Thr237Met 突变，但我们还发现了一种新的 ROSAH 相关突变，即 p.Tyr254Cys。几乎所有患者都至少表现出一种与炎症一致的特征，包括反复发热、伴有脑膜增强的头痛和 MRI 上基底节/脑干过早矿化、变形性关节炎和 AA 淀粉样变性。然而，即使在家族内也存在显著的表型变异，一些成年人也没有明显的视力缺陷。虽然抗 TNF 和抗 IL-1 治疗抑制了全身炎症并提高了生活质量，但只有抗 IL-6（托珠单抗）治疗能改善眼内炎症（2 例患者中的 2 例）。患者的原代样本和带有突变 ALPK1 构建体的体外检测显示免疫激活，NF-κB 信号、STAT1 磷酸化和干扰素基因表达谱增加。带有 T237M 突变的 knock-in 小鼠表现出亚临床炎症。该队列中也常见一些传统上与炎症无关的临床特征，包括短牙根、牙釉质缺陷和唾液流量减少。
ROSAH 综合征是一种由 基因突变引起的自身炎症性疾病，一些疾病特征可通过免疫调节治疗。
