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

Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14405-14411. doi: 10.1073/pnas.2002051117. Epub 2020 Jun 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Behcet Syndrome / genetics*
  • Behcet Syndrome / immunology
  • Child
  • Cohort Studies
  • Fever / genetics*
  • Fever / immunology
  • Genes, MHC Class I / genetics
  • Genes, MHC Class I / immunology
  • Genes, MHC Class II / genetics
  • Genes, MHC Class II / immunology
  • Genetic Loci / immunology
  • Genetic Predisposition to Disease*
  • Humans
  • Lymphadenitis / genetics*
  • Lymphadenitis / immunology
  • Pharyngitis / genetics*
  • Pharyngitis / immunology
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Stomatitis, Aphthous / genetics*
  • Stomatitis, Aphthous / immunology
  • Syndrome

Supplementary concepts

  • Sutton disease 2