Periodic Fever Syndromes and Autoinflammatory Disorders

Periodic fever syndromes and related autoinflammatory disorders encompass a group of conditions driven by dysregulation of the innate immune system, leading to recurrent episodes of fever and systemic inflammation in the absence of infection or conventional autoimmunity. Classic monogenic disorders such as familial Mediterranean fever, tumour necrosis factor receptor-associated periodic syndrome and hyperimmunoglobulinaemia D syndrome are defined by mutations in key regulators of inflammasome activation, resulting in excessive production of proinflammatory cytokines. In contrast, polygenic or multifactorial conditions—including the most common paediatric syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA)—likely arise from oligogenic inheritance and environmental triggers. Clinical features range from stereotyped febrile attacks with mucosal ulceration and lymphadenopathy to overlaps with adult-onset presentations. Advances in classification criteria, biomarkers and targeted anti-cytokine therapies have underscored the global significance of these disorders for paediatric and adult medicine, with practical applications in precision diagnosis and tailored management to reduce disease burden and improve quality of life.

Research from Nature Portfolio

Seminal genetic studies have interrogated the hereditary basis of PFAPA by performing linkage analysis and whole-exome sequencing in multiplex families. These investigations have demonstrated the absence of a single causative gene, instead favouring a model of oligogenic susceptibility involving multiple low-penetrance variants in inflammasome-related pathways. Detailed screening of established autoinflammatory genes failed to identify common pathogenic mutations, indicating that PFAPA is not monogenic but rather emerges from complex interactions between multiple genetic loci and non-genetic factors. Such findings have shifted the research paradigm away from single-gene causation towards integrated genomic and epigenomic approaches for understanding disease mechanisms and for the future development of precision therapeutics.

Periodic Fever Syndromes and Autoinflammatory Disorders publication trend

The graph below shows the total number of articles in periodic fever syndromes and autoinflammatory disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Autoinflammatory disorder: A condition characterised by innate immune dysregulation causing recurrent sterile inflammation without high-titre autoantibodies or antigen-specific T cells.

Inflammasome: A cytosolic multiprotein complex that activates caspase-1, leading to processing and release of interleukin-1β and interleukin-18.

Monogenic: Disease arising from mutation in a single gene; often follows Mendelian inheritance.

Oligogenic inheritance: Disease susceptibility resulting from combined effects of a few gene variants, each with low penetrance.

Interleukin-1β (IL-1β): A proinflammatory cytokine central to fever induction and recruitment of inflammatory cells during autoinflammatory flares.

PFAPA syndrome: A recurrent febrile illness in children typified by periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis with symptom-free intervals.

References

1. The use of ketotifen as long-term anti-inflammatory prophylaxis in children with PFAPA syndrome. Frontiers in Immunology (2023).
2. Tonsillectomy reduces the family impact of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and improves health-related quality of life in affected children. Orphanet Journal of Rare Diseases (2023).
3. Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Scientific Reports (2015).
4. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome and Syndrome of Unexplained Recurrent Fevers in Children and Adults. The Journal of Allergy and Clinical Immunology In Practice (2023).
5. Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): a framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatric Rheumatology (2020).