Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan.
OBJECTIVE
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.
Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan, kkkimnet@yahoo.co.jp.
Kazuo
K
Kubota
Hidenori
H
Ohnishi
Takahide
T
Teramoto
Norio
N
Kawamoto
Kimiko
K
Kasahara
Osamu
O
Ohara
Naomi
N
Kondo
D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005334:Fever / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020382:Interleukin-18 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood*; D007564:Japan; D008199:Lymphadenitis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010507:Periodicity; D010612:Pharyngitis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology; D013281:Stomatitis, Aphthous / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013577:Syndrome; D014068:Tonsillectomy; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000589760:IL18 protein, human; D020382:Interleukin-18; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha