Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: An Updated Review with Current Insights into Pathogenesis and Therapeutic Strategies

Abstract

Highlights What are the main findings? • PFAPA is the most common autoinflammatory syndrome in children, with evolving evidence indicating a multifactorial pathogenesis involving genetic susceptibility, innate immune dysregulation, and environmental triggers.• Recent advances have refined the understanding of PFAPA diagnosis, highlighted its overlap with monogenic autoinflammatory diseases, and expanded therapeutic options beyond corticosteroids and tonsillectomy, including biologic agents for selected patients. What are the implications of the main findings? • Improved recognition of PFAPA and differentiation from infections and hereditary autoinflammatory disorders are essential to prevent unnecessary investigations, antibiotic use, and delays in diagnosis.• Emerging insights into PFAPA pathogenesis and its relationship with the autoinflammatory disease spectrum may facilitate more personalized diagnostic and therapeutic approaches while guiding future research. Abstract Background/Objectives: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequently encountered periodic fever syndrome in pediatric populations. It is characterized by recurrent, stereotyped episodes of fever accompanied by pharyngitis, cervical lymphadenopathy, and aphthous stomatitis, sometimes with other additional nonspecific symptoms. Episodes usually last 3–7 days and recur at regular intervals of approximately 2–8 weeks. The etiopathogenesis of PFAPA remains incompletely understood. Accumulating evidence supports a central role of immune dysregulation with multiple genetic variants that contribute to disease susceptibility. Diagnosis is primarily based on clinical evaluation, although targeted genetic testing may be considered in selected cases particularly when overlapping with other monogenic autoinflammatory disorders. Management of PFAPA aims to decrease the frequency and intensity of febrile episodes. Acute flares are managed with antipyretics, corticosteroids, or, in selected cases, anti-interleukin-1 (IL-1) therapy, while preventive strategies include colchicine, cimetidine, or tonsillectomy. Adjunctive approaches such as vitamin D supplementation, probiotics, and other immunomodulatory interventions have also been investigated. This updated review summarizes current insights into the pathogenesis and therapeutic approaches of PFAPA. Methods: This narrative review was conducted using PubMed, and Scopus to identify English-language publications from 2010 to 2026 addressing PFAPA. Conclusions: Pediatricians should consider PFAPA in children with recurrent fevers and oropharyngeal symptoms, especially when standard treatments fail, to ensure proper management and avoid unnecessary antibiotic use.