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Published on: July 14, 2016
Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis
Kalpana Manthiram1, Silvia Preite2,3, Fatma Dedeoglu4
1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; kalpana.manthiram@nih.gov dan.kastner@nih.gov.
Insights
Genetic variants near IL12A are strongly associated with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) syndrome. This suggests PFAPA, recurrent aphthous stomatitis, and Behçet's disease may exist on a common spectrum.
Area of Science:
- Genetics and immunology of autoinflammatory and autoimmune diseases.
- Molecular mechanisms underlying oropharyngeal ulcerative disorders.
Background:
- Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) syndrome is the most prevalent periodic fever syndrome in children.
- The genetic underpinnings and pathogenesis of PFAPA remain largely unknown, despite familial clustering.
- Oropharyngeal ulcerative disorders like Behçet's disease and recurrent aphthous stomatitis share clinical features with PFAPA.
Purpose of the Study:
- To investigate the genetic associations between PFAPA and variants common in Behçet's disease and recurrent aphthous stomatitis.
- To elucidate the immunological pathways involved in PFAPA pathogenesis.
- To explore the potential spectrum relationship between these oropharyngeal ulcerative disorders.
Main Methods:
- Meta-analysis of genetic data from three cohorts (two European-American, one Turkish) totaling 231 individuals with PFAPA.
- Genotyping for common variants previously linked to Behçet's disease and recurrent aphthous stomatitis.
- Functional assessment of monocyte-derived IL-12p70 production in individuals with specific risk alleles.
Main Results:
- A significant association was identified between PFAPA and an IL12A upstream variant (rs17753641), with an odds ratio of 2.13.
- Monocytes from individuals carrying the risk allele exhibited heightened IL-12p70 production upon stimulation, indicating altered immune cell function.
- Additional susceptibility loci near STAT4, IL10, and CCR1-CCR3 were identified, implicating antigen-presenting cell and T cell dysfunction.
- Distinct HLA class I and II associations for PFAPA were found, separate from Behçet's disease and recurrent aphthous stomatitis.
Conclusions:
- The genetic findings suggest that PFAPA pathogenesis involves dysregulated innate and adaptive immune responses at the oropharyngeal mucosa.
- Recurrent aphthous stomatitis, PFAPA, and Behçet's disease may represent a spectrum of related disorders, potentially termed 'Behçet's spectrum disorders'.
- HLA alleles likely modulate the clinical presentation along this spectrum.
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.
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