Role of the NOD2 Genotype in the Clinical Phenotype of Blau Syndrome and Early-Onset Sarcoidosis
Role of the NOD2 Genotype in the Clinical Phenotype of Blau Syndrome and Early-Onset Sarcoidosis
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DOI：
10.1002/art.24134
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Nakahata, Tatsutoshi
中科院分区：
文献类型：
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作者：
Okafuji, Ikuo;Nishikomori, Ryuta;Nakahata, Tatsutoshi
客观的。 Blau 综合征及其散发性对应物早发性结节病 (EOS) 具有共同的表型，即皮疹、关节炎和葡萄膜炎三联征。这种全身性炎症肉芽肿病与 NOD2 基因突变有关。本研究的目的是描述日本患者 Blau 综合征/EOS 的临床表现，并确定 NOD2 基因型及其相关的基础 NF-κ B 活性是否可以预测 Blau 综合征/EOS 临床表型。方法。招募了 20 名患有 Blau 综合征/EOS 和 NOD2 突变的日本患者。突变的NOD2根据其基础NF-κB活性进行分类，基础NF-κB活性定义为没有NOD2配体胞壁酰二肽的NF-κB活性与有胞壁酰二肽的NF-κB活性的比率。结果。所有 9 个突变，包括 E383G（一种在 20 名 Blau 综合征/EOS 患者中发现的新突变），均在位于中心的 NOD 区域中检测到，并且与配体独立的 NF-κ B 激活相关。患者发病时的中位年龄为 14 个月，但 Blau 综合征家族的 2 名患者（分别携带 R334W 和 E383G 突变）的发病年龄为 5 岁或以上。大多数 Blau 综合征/EOS 患者有皮肤、关节和眼部症状三联征，发病顺序如下。即使在家族病例和具有相同突变的患者之间，临床表现也存在差异。由于 NOD2 突变，临床表型与基础 NF-κ B 活性之间没有明确的关系。然而，当注意力集中在两种最常见的突变R334W和R334Q时，R334W往往会导致更明显的视力障碍。结论。 NOD2 基因分型可能有助于预测 Blau 综合征/EOS 患者的疾病进展。
Objective. Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappa B activity predict the Blau syndrome/ EOS clinical phenotype.Methods. Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappa B activity, which was defined as the ratio of NF-kappa B activity without a NOD2 ligand, muramyldipeptide, to NF-kappa B activity with muramyldipeptide.Results. All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappa B activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappa B activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment.Conclusion. NOD2 genotyping may help predict disease progression in patients with Blau syndrome/ EOS.