PFAPA (periodic fevers with aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is a periodic fever syndrome that typically manifests between 2 years and 5 years of age; it is characterized by febrile episodes lasting 3 to 6 days, pharyngitis, aphthous ulcers, and adenopathy. Etiology and pathophysiology are undefined. Diagnosis is clinical. Treatment can include glucocorticoids, colchicine, cimetidine, and, rarely, tonsillectomy.
PFAPA (periodic fevers with aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is the most common periodic fever syndrome among children. Genetic studies indicate a polygenic or oligogenic inheritance (with NLRP3, MEFV, and CARD8 variants implicated), but no single gene mutation is causative (1). Evidence supports a model involving primarily innate and secondarily active immune dysregulation, particularly activation of the NLRP3 inflammasome and overproduction of pro-inflammatory cytokines such as interleukin (IL)-1 beta during febrile episodes (2).
PFAPA syndrome typically starts in early childhood (between 2 years and 5 years of age) and tends to be more common among males. It has been recognized in adults as well (3).
General references
1. Theodoropoulou K, Vanoni F, Hofer M. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis. Curr Rheumatol Rep. 2016;18(4):18. doi:10.1007/s11926-016-0567-y
2. Kolly L, Busso N, von Scheven-Gete A, et al. Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol. 2013;131(6):1635-1643. doi:10.1016/j.jaci.2012.07.043
3. Anselmi F, Dusser P, Kone-Paut I. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome in Children-From Pathogenesis to Treatment Strategies: A Comprehensive Review. Paediatr Drugs. 2025;27(5):575-592. doi:10.1007/s40272-025-00699-1
Symptoms and Signs of PFAPA Syndrome
The syndrome causes fatigue, chills, and occasionally abdominal pain, arthralgia, and headache as well as fever, pharyngitis, aphthous ulcers, and lymphadenopathy.
Febrile episodes typically last 3 to 6 days and recur about every 21 to 28 days.
Patients are healthy between episodes, and growth is normal.
Diagnosis of PFAPA Syndrome
History and physical examination
The diagnosis of PFAPA syndrome is based on clinical findings, which include the following (1):
≥ 3 febrile episodes, lasting up to 5 days and occurring at regular intervals
Pharyngitis plus adenopathy or aphthous ulcers
Normal health and growth between episodes
Acute-phase reactants (eg, C-reactive protein, erythrocyte sedimentation rate) are elevated during a febrile episode but not between episodes.
Neutropenia or other symptoms (eg, diarrhea, rash, cough) are not present; their presence suggests a different disorder. Specifically, cyclic neutropenia needs to be ruled out.
Diagnosis reference
1. Cantarini L, Vitale A, Sicignano LL, et al: Diagnostic criteria for adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Front Immunol 8:1018, 2017. doi: 10.3389/fimmu.2017.01018
Treatment of PFAPA Syndrome
Sometimes glucocorticoids, colchicine, cimetidine, and/or tonsillectomy
Treatment of PFAPA syndrome is not always necessary and depends on the frequency and severity of attacks (1).
Treatment can include abortive treatment with glucocorticoids, such as a single dose of prednisone or betamethasone, which, when given at the onset of an episode, can dramatically abort fever attacks in a few hours, or prophylactic treatment with cimetidine, colchicine, and, rarely, tonsillectomy (Treatment can include abortive treatment with glucocorticoids, such as a single dose of prednisone or betamethasone, which, when given at the onset of an episode, can dramatically abort fever attacks in a few hours, or prophylactic treatment with cimetidine, colchicine, and, rarely, tonsillectomy (2, 3).
Other medications such as anakinra and canakinumab have been tried with some success in refractory cases. Other medications such as anakinra and canakinumab have been tried with some success in refractory cases.
PFAPA syndrome is a relatively benign and self-limited disease in which episodes gradually become less severe, less frequent, and shorter in duration over time. Spontaneous resolution typically occurs by age 10 but may persist into adolescence in some patients.
Treatment references
1. Anselmi F, Dusser P, Kone-Paut I. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome in Children-From Pathogenesis to Treatment Strategies: A Comprehensive Review. Paediatr Drugs. 2025;27(5):575-592. doi:10.1007/s40272-025-00699-1
2. Amarilyo G, Rothman D, Manthiram K, et al. 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. Pediatr Rheumatol Online J. 2020;18(1):31. doi:10.1186/s12969-020-00424-x
3. Batu ED, Sener S, Rodrigues M, et al. Corticosteroid use in PFAPA syndrome: clinical practice data from the JIR-CliPS Survey Study and a comprehensive literature review. Rheumatology (Oxford). 2025;64(6):3787-3796. doi:10.1093/rheumatology/keaf036
Drugs Mentioned In This Article
