Nakamura Haruhiko, Kikuchi Atsuo, Sakai Hideyuki, Kamimura Miki, Watanabe Yohei, Onuma Ryoichi, Takayama Jun, Tamiya Gen, Mashimo Yoichi, Ebata Ryota, Hamada Hiromichi, Suenaga Tomohiro, Onouchi Yoshihiro, Kumaki Satoru
Department of Pediatrics, National Hospital Organization Sendai Medical Center, Sendai, Japan.
Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
Front Pediatr. 2024 Mar 5;12:1340263. doi: 10.3389/fped.2024.1340263. eCollection 2024.
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described.
Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population.
We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.
周期性发热、阿弗他口炎、咽炎和颈淋巴结炎（PFAPA综合征）以及川崎病（KD）均被认为是先天性免疫系统疾病，先前已有文献描述炎症小体激活在这两种疾病免疫发病机制中的潜在作用。
在此，我们报告了3例出现PFAPA综合征和KD罕见组合的患者的临床病程。2例先出现KD的患者后来发展为PFAPA综合征，其中1例在初次诊断后2年复发KD。第3例患者在PFAPA综合征发病1年后发展为KD。个体患者同时存在这两种疾病，再结合炎症小体激活与PFAPA综合征和KD均有关的认识，提示存在共同的炎症调节异常背景。为阐明共同的炎症调节异常的潜在机制，我们研究了Nod样受体（NLRs）及其下游炎症小体相关基因的作用。所有患者均存在（CARD8 - FS）中的移码变异。先前一项研究表明，PFAPA综合征患者中CARD8 - FS的频率较高，其产物丧失CARD8活性并激活NLRP3炎症小体。此外，已知KD患者中NLRP3炎症小体被激活。综合这些结果表明，CARD8 - FS变异在KD发病机制中可能也至关重要。因此，我们分析了KD患者中的 变异。然而，我们发现KD患者与日本普通人群之间的变异频率并无差异。
我们报告了3例PFAPA综合征和KD罕见组合患者的临床病程。所有患者均有CARD8 - FS变异。然而，我们未发现KD患者与日本普通人群之间在变异频率上存在差异。由于在日本患者中KD的发病率远高于PFAPA，且KD的病因是多因素的，所以可能只有一小部分KD患者携带CARD8 - FS作为致病基因。
