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Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation
  1. Tomoko Matsuda1,
  2. Naotomo Kambe1,2,
  3. Yoko Ueki1,
  4. Nobuo Kanazawa3,
  5. Kazushi Izawa4,
  6. Yoshitaka Honda4,
  7. Atsushi Kawakami5,
  8. Syuji Takei6,
  9. Kyoko Tonomura7,
  10. Masami Inoue8,
  11. Hiroko Kobayashi9,
  12. Ikuo Okafuji10,
  13. Yoshihiko Sakurai11,
  14. Naoki Kato12,
  15. Yuta Maruyama13,
  16. Yuzaburo Inoue14,
  17. Yoshikazu Otsubo15,
  18. Teruhiko Makino16,
  19. Satoshi Okada17,
  20. Ichiro Kobayashi18,
  21. Masato Yashiro19,
  22. Shusaku Ito20,
  23. Hiroshi Fujii21,
  24. Yasuhiro Kondo22,
  25. Nami Okamoto23,
  26. Shuichi Ito24,
  27. Naomi Iwata25,
  28. Utako Kaneko26,
  29. Mototsugu Doi27,
  30. Junichi Hosokawa28,
  31. Osamu Ohara28,
  32. Megumu K Saito29,
  33. Ryuta Nishikomori30
  34. PIDJ members in the JSIAD
    1. 1 Department of Dermatology, Kansai Medical University, Hirakata, Osaka, Japan
    2. 2 Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
    3. 3 Department of Dermatology, Wakayama Medical University, Wakayama, Japan
    4. 4 Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
    5. 5 Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
    6. 6 Department of Pediatrics, Kagoshima University School of Health Science, Kagoshima, Japan
    7. 7 Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
    8. 8 Department of Hematology/Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan
    9. 9 Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
    10. 10 Department of Pediatrics, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
    11. 11 Department of Pediatrics, Matsubara Tokushukai Hospital, Matsubara, Osaka, Japan
    12. 12 Department of Dermatology, Wakkanai City Hospital, Wakkanai, Hokkaido, Japan
    13. 13 Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan
    14. 14 Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Japan
    15. 15 Department of Pediatrics, Sasebo City General Hospital, Sasebo, Japan
    16. 16 Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
    17. 17 Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
    18. 18 Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Hokkaido, Japan
    19. 19 Department of Pediatrics, Okayama University Graduate Schoolf of Medicine, Okayama, Japan
    20. 20 Department of Dermatology, Hitachi General Hospital, Hitachi, Ibaraki, Japan
    21. 21 Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
    22. 22 Department of Pediatrics, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
    23. 23 Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan
    24. 24 Department of Pediatrics, Yokohama City University, Yokohama, Kanagawa, Japan
    25. 25 Department of Infection and Immunology, Aichi Children’s Health and Medical Center, Obu, Aichi, Japan
    26. 26 Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
    27. 27 Department of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, University of the Ryukyus, Nishihara, Okinawa, Japan
    28. 28 Kazusa DNA Research Institute, Kisarazu, Chiba, Japan
    29. 29 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    30. 30 Department of Pediatrics, Kurume University School of Medicine, Kurume, Fukuoka, Japan
    1. Correspondence to Dr Naotomo Kambe, Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan; nkambe{at}


    Objectives To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis.

    Methods Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians.

    Results The study population comprised 26 males and 24 females aged 0–61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment.

    Conclusions In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

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    • Handling editor Josef S Smolen

    • Correction notice This article has been corrected since it published Online First. Table 1 and Figure 3B have been updated.

    • Collaborators PIDJ (Primary Immunodeficiency and Autoinflammatory Diseases Database Project) members in the JSIAD (Japanese Society for Immunodeficiency and Autoinflammatory Diseases): Shigeaki Nonoyama, Kohsuke Imai, Katsuhiro Arai, Kazushi Izawa, Takashi Ishige, Masataka Ishimura, Hiroaki Ida, Norimitsu Inoue, Hidenori Ohnishi, Satoshi Okada, Nobuo Kanazawa, Hirokazu Kanegane, Toshinao Kawai, Naotomo Kambe, Tomohiro Koga, Yoji Sasahara, Hidetoshi Takada, Ichiro Takeuchi, Ryuta Nishikomori, Takahiko Horiuchi, Kiyoshi Migita, Tomoyuki Mizukami, Takako Miyamae Hideki Muramatsu, Kunihiko Moriya, Takahiro Yasumi, Takashi Yamazaki, Masafumi Yamada and Taizo Wada.

    • Contributors All authors have made substantial contribution to the conception or design of the work or acquisition, analysis or interpretation of data. All authors were involved in drafting the work, revising it critically and have read final approval of the version.

    • Funding This study was supported in part by a research grant from MHLW, Japan and AMED under Grant Numbers JP17ek0109100 and JP18ek0109237.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Ethics approval The study protocol was in accordance with the guidelines of the Institutional Review Board of Kansai Medical University (2018204).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement No data are available. There are no additional unpublished data.