Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis

Abstract

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10^-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Keywords: Behçet’s disease; PFAPA; aphthous ulcers; periodic fever; tonsillitis.

Fig. 1.

Expression of IL-12p70 subunits during PFAPA flares and comparison of IL-12p70 production according to IL12A risk allele. During PFAPA flares, a higher percentage of patient CD14⁺ monocytes express both subunits of IL-12p70, p35 and p40, compared with nonflare periods and with healthy controls; ex vivo FACS analysis of PBMCs (A). Peripheral blood CD14⁺ monocytes from adults homozygous and heterozygous for the risk allele near IL12A (rs17753641) secrete more IL-12p70 following priming with IFN-γ and stimulation with LPS than monocytes from individuals without the risk allele; ELISA on supernatant of in vitro-stimulated cells (B). Each dot represents an individual. Mean and SD are plotted. *P < 0.05, **P < 0.005.

Fig. 2.

The BSDs include recurrent aphthous stomatitis, PFAPA, and Behçet’s disease. Recurrent aphthous ulcers are on the mild end of the spectrum with relatively weak HLA associations, while Behçet's disease has the most severe disease manifestations and strongest HLA associations, and PFAPA is between the two.