Autoinflammatory and Periodic Fever Syndromes
Pathophysiology
Autoinflammatory syndromes reflect dysregulated innate immunity without autoantibodies or antigen-specific T cells. They produce recurrent, stereotyped episodes of fever with serositis, rash, or lymphadenopathy, with complete wellness between attacks and normal growth when well controlled.
Specific syndromes
PFAPA causes clockwork episodes every 3–6 weeks with aphthous stomatitis, pharyngitis, and cervical adenitis in young children; attacks respond rapidly to a single corticosteroid dose, and tonsillectomy or colchicine may reduce frequency. Familial Mediterranean fever (MEFV) causes 1–3 day attacks of fever and serositis with an erysipelas-like rash; untreated disease risks AA amyloidosis, and colchicine is both treatment and prophylaxis. TRAPS (TNFRSF1A) produces longer attacks with migratory rash and periorbital edema. CAPS (NLRP3) causes urticaria-like rash, fever, conjunctivitis, and sensorineural hearing loss and responds to IL-1 blockade. Blau syndrome (NOD2) causes granulomatous dermatitis, arthritis, and uveitis; DIRA (IL1RN) causes pustulosis and osteitis.
Traps
Do not label recurrent fevers PFAPA when there is growth failure, inflammation between attacks, or a suggestive family history. Genetic variants of uncertain significance do not establish a diagnosis - phenotype and treatment response matter. Colchicine nonadherence in FMF is a route to amyloidosis.
Rule of thumb
Clockwork attacks with complete wellness and normal growth suggest PFAPA; serositis with an appropriate ethnic background suggests FMF.