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Clinical and Genetic Characterization of Japanese Sporadic Cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome from a Single Medical Center in Japan

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Abstract

Purpose

To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.

Methods

Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1β levels were measured by ELISA.

Results

The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3–6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C-reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 ± 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-α and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1β, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1β production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes.

Conclusions

Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder-associated genes.

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Acknowledgement

We thank the members of the families who agreed to participate in the study. We thank Dr. Y. Uchida, Dr. A. Imamura, Dr. K. Goto and Dr. A. Sakai for patient recruitment. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Health and Labour Science Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare.

Conflict of Interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Kazuo Kubota, Hidenori Ohnishi, Takahide Teramoto, Norio Kawamoto, Kimiko Kasahara & Naomi Kondo

  2. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    Osamu Ohara

  3. Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

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  1. Kazuo Kubota
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  2. Hidenori Ohnishi
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  3. Takahide Teramoto
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  4. Norio Kawamoto
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  7. Naomi Kondo
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Correspondence to Kazuo Kubota.

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Kubota, K., Ohnishi, H., Teramoto, T. et al. Clinical and Genetic Characterization of Japanese Sporadic Cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome from a Single Medical Center in Japan. J Clin Immunol 34, 584–593 (2014). https://doi.org/10.1007/s10875-014-0043-2

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  • DOI: https://doi.org/10.1007/s10875-014-0043-2

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