Cardiac infiltration in early-on setsarcoi dosis associated with a novel heterozygous mutation
Cardiac infiltration in early-on setsarcoi dosis associated with a novel heterozygous mutation
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与新型杂合突变相关的早期 setsarcoi 剂量的心脏浸润
DOI：
10.1093/rheumatology/kep061
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Y. & Kobayashi M
中科院分区：
文献类型：
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作者：
Okada;S.;Konishi;N.;Tsumura;M.;Shirao;K.;Yasunaga;S.;Sakai;H.;Nishikomori;R.;Takihara;Y. & Kobayashi M
SIR、早发性结节病（EOS）和Blau综合征（BS）是罕见的多器官肉芽肿性炎症性疾病，临床特征为皮肤、关节和眼部病变的独特三联征，无任何明显的心肺受累[1]。CARD 15（NM_022162）中的功能获得性突变导致EOS和/或BS（EOS/BS）[2-4]，但不会导致成人型结节病[5，6]。我们在一例EOS患者的CARD 15中发现了一种新的杂合性功能获得性突变G481 D，该患者患有充血性心力衰竭的反复发作。心脏浸润是成人型结节病常见的临床表现，但在EOS/BS中是罕见和不典型的。值得注意的是，该患者的心脏表现与成人结节病非常相似。这是第一份报告，证明了心脏结节病浸润的患者与CARD 15突变的确切表现。患者为18岁女性。在3个月大时，她出现了粟粒样皮疹。其后，她出现各种表现，如葡萄膜炎、关节受累、肝脾肿大、动脉高压和充血性心力衰竭。淋巴结活检显示新鲜的多发性肉芽肿，表明EOS的诊断。给予糖皮质激素改善了她的症状。然而，由于充血性心力衰竭反复发作并伴有自身炎症反应激活，因此需要延长治疗。超声心动图显示室间隔厚度[图1A（a，B）]。右心室内膜的组织病理学检查显示炎性细胞浸润、心肌气球样变和轻度纤维化（图1B）。组织病理学表现与成人心脏结节病相似。其他免疫抑制治疗，如NSAID、MTX、AZA和/或CSA，未充分改善其症状。TNF抑制剂英夫利西单抗与MTX联合给药可有效抑制自身炎症，从而改善室间隔厚度[图1A（c，d）]。在广岛大学伦理委员会/内部审查委员会的批准和患者知情同意下，我们分析了CARD 15的核苷酸序列，并在外显子4中发现了一个新的杂合单碱基对替换，1442 G> A（G481 D）。该突变位于核苷酸结合结构域内。NF-B报告基因分析显示，CARD 15中G481 D、C495 Y和H496 L突变体中的MDP非依赖性NF-B反式激活水平显著高于野生型（WT）（图1C），因此表明G481 D突变是一种功能获得性突变[3]。只有一份报告显示CARD 15突变患者的心脏浸润[4]。该患者患有严重的多器官受累、动脉高血压和心肌肥厚，并被鉴定为杂合子C495 Y突变。C495 Y突变显示出最高水平的MDP非依赖性NF-B活化（图1C），并且值得注意的是，G481 D突变也显示出相对较高水平的活性。虽然在先前的研究中没有证明EOS/BS的基因型-表型相关性，但心脏浸润可能因此与较高水平的MDP非依赖性NF-B活化相关[3]。
SIR, Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are rare multi-organ granulomatous inflammatory disorders clinically characterized by the distinct triad of skin, joint and eye lesions without any apparent cardio-pulmonary involvement [1]. Gain-of-function mutations in CARD15 (NM_022162) cause EOS and/or BS (EOS/BS)[2–4], but not the development of adult-type sarcoidosis [5, 6]. We identified a novel heterozygous gainof-function mutation, G481D, in CARD15 from a patient with EOS, who was suffering from recurrent episodes of congestive heart failure. Cardiac infiltration is a common clinical manifestation in adult-type sarcoidosis, but is rare and atypical in EOS/BS. Notably, the cardiac manifestations of this patient are quite similar to those in adult sarcoidosis. This is the first report demonstrating the precise manifestations of cardiac infiltration of sarcoidosis in a patient with a CARD15 mutation. The patient was an 18-year-old female. At 3 months of age she developed a miliaria-like skin rash. Thereafter, she presented various manifestations, such as uveitis, joint involvement, hepatosplenomegaly, arterial hypertension and congestive heart failure. A lymph node biopsy showed fresh-looking multiple granulomas, indicating a diagnosis of EOS. The administration of glucocorticoids improved her symptoms. However, extended treatments were required because of recurrent episodes of congestive heart failure accompanied with the activation of an autoinflammatory reaction. Echocardiography showed intraventricular septum thickness [Fig. 1A (a, b)]. A histopathological examination of the right ventricle endocardium revealed inflammatory cell infiltration, ballooning of myocardium and mild fibrosis (Fig. 1B). The histopathological findings were similar to those of cardiac sarcoidosis in adults. Other immunosuppressive treatments, eg NSAIDs, MTX, AZA and/or CSA, did not sufficiently improve her symptoms. The administration of TNF-inhibitor, infliximab, in combination with MTX effectively inhibited the autoinflammation, thus resulting in an improvement of the intraventricular septum thickness [Fig. 1A (c, d)]. Under approval by the Ethics Committee/Internal Review Board of Hiroshima University and informed patient consent, we analysed the nucleotide sequence of CARD15, and found a novel heterozygous single base-pair substitution, 1442G> A (G481D), in exon 4. This mutation was located within the nucleotide-binding domain. NF-B reporter assay revealed that MDP-independent NF-B transactivation in the G481D, C495Y and H496L mutants in CARD15 showed significantly higher levels than that in wildtype (WT)(Fig. 1C), thus suggesting the G481D mutation to be a gain-of-function mutation [3].Cardiac infiltration is a rare and atypical manifestation among the patients with EOS/BS. Only one report has shown cardiac infiltration among the patients with CARD15 mutations [4]. The patient suffered from severe multi-organ involvement, arterial hypertension and myocardial hypertrophy, and was identified as being a heterozygous C495Y mutation. The C495Y mutation displayed the highest level of MDP-independent NF-B activation (Fig. 1C), and notably the G481D mutation also demonstrated a relatively higher level of activity. Although no genotype–phenotype correlation in EOS/BS could be proven in the previous study, cardiac infiltration may therefore be associated with higher levels of MDP-independent NF-B activation [3].