Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in non-Mediterranean children, presenting with regular episodes of fever, pharyngitis, cervical adenitis, and aphthous ulcers. It is self-limiting but can persist into adulthood and affect quality of life.

Pathogenesis involves innate immune dysregulation, NLRP3 inflammasome activation, and Th1-driven inflammation, with genetic overlaps with familial Mediterranean fever (FMF) and Behçet’s disease.

Diagnosis is clinical; differential diagnoses include monogenic autoinflammatory diseases (e.g., FMF, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD)), syndrome of undifferentiated recurrent fever (SURF), cyclic neutropenia, and recurrent infections. Genetic testing and selected biochemical markers may aid in the differential diagnosis.

Treatment remains variable owing to the lack of standardized guidelines. Corticosteroids are effective for aborting flares but may shorten intervals; colchicine may help in MEFV carriers; and tonsillectomy can be curative. Management should follow a shared decision-making process or a personalized case-by-case approach.