Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2024 Mar 5:12:1340263.
doi: 10.3389/fped.2024.1340263. eCollection 2024.

Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease

Haruhiko Nakamura  1 , Atsuo Kikuchi  2 , Hideyuki Sakai  1 , Miki Kamimura  1 , Yohei Watanabe  1 , Ryoichi Onuma  1 , Jun Takayama  3   4   5   6 , Gen Tamiya  3   4   5   6 , Yoichi Mashimo  7 , Ryota Ebata  8 , Hiromichi Hamada  9 , Tomohiro Suenaga  10 , Yoshihiro Onouchi  7 , Satoru Kumaki  1
Affiliations
Case Reports

Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease

Haruhiko Nakamura et al. Front Pediatr. .

Abstract

Background: 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.

Case presentation: 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 (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 CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population.

Conclusions: 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.

Keywords: CARD8; Kawasaki disease; NLRP3; PFAPA syndrome; inflammasome; inflammatory dysregulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Similar articles

See all similar articles

Cited by

References

    1. Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr. (2010) 99(2):178–84. 10.1111/j.1651-2227.2009.01554.x - DOI - PubMed
    1. Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. (1987) 110(1):43–6. 10.1016/s0022-3476(87)80285-8 - DOI - PubMed
    1. Thomas KT, Feder HM, Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. (1999) 135(1):15–21. 10.1016/s0022-3476(99)70321-5 - DOI - PubMed
    1. Ashari K A, Rezaei N. PFAPA (Periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome: an overview of genetic background. Clin Rheumatol. (2021) 40(11):4437–44. 10.1007/s10067-021-05770-z - DOI - PubMed
    1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. (1967) 16(3):178–222. - PubMed

Publication types