Periodic fevers

Recurrent stereotyped febrile episodes without an identifiable infection. The same patient gets the same syndrome of fever with the same accompanying features every few weeks or months. Inflammatory markers (CRP, ESR, serum amyloid A) rise with each episode and normalize between them. These are the inherited "innate immune fever syndromes": disorders of inflammasome assembly, cytokine signaling, or protein folding in innate immune cells.

Three discriminators do most of the work: duration of attacks (hours to days versus weeks), ancestry, and the company the fever keeps (serositis, urticaria, hearing loss, eye involvement, mouth ulcers, lymphadenopathy). Trial-of-therapy response (colchicine, IL-1 blockade) is itself diagnostic for several entries.

Short attacks, Mediterranean ancestry, serositis

• Familial Mediterranean fever: MEFV (pyrin), autosomal recessive. Sephardic Jewish, Armenian, Turkish, Arab ancestries. 1-3 day attacks of fever with serositis (peritonitis presenting as acute abdomen, pleuritis, monoarthritis), erysipelas-like erythema on the lower leg, AA amyloidosis with renal failure if untreated. Colchicine is both prophylactic and confirmatory; a clinical response within weeks supports the diagnosis.

Longer attacks, migratory rash, periorbital edema

• TRAPS (TNF receptor-associated periodic syndrome): TNFRSF1A, autosomal dominant. Attacks last 1-3 weeks, with migratory erythematous patches, periorbital edema, myalgia, conjunctivitis. Etanercept or IL-1 blockade controls.

Vaccination-triggered fevers in infancy

• HIDS (hyperimmunoglobulinemia D syndrome) / mevalonate kinase deficiency: MVK, autosomal recessive. Onset around 6 months, often after vaccination. Fever plus cervical adenopathy plus diarrhea or vomiting plus arthralgia, elevated polyclonal IgD. The severe enzymatic form, mevalonic aciduria, adds dysmorphism, cataracts, and developmental delay.

Urticaria with cold, hearing loss, or chronic CNS inflammation

• CAPS (cryopyrin-associated periodic syndromes): NLRP3, autosomal dominant, spectrum of severity.
  • FCAS (familial cold autoinflammatory syndrome): cold-induced fever and urticaria, mild.
  • MWS (Muckle-Wells syndrome): chronic urticaria, sensorineural hearing loss, AA amyloidosis.
  • CINCA/NOMID (chronic infantile neurologic cutaneous articular / neonatal-onset multisystem inflammatory disease): the severe end. Chronic urticaria from infancy, deforming arthropathy, chronic aseptic meningitis with developmental delay, sensorineural hearing loss.
  • IL-1 blockade (anakinra, canakinumab) has been transformative across the CAPS spectrum.

The common one that is not monogenic

• PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis): the single most common periodic fever syndrome in children. Sporadic, no identified gene. Strikingly regular cycles every 3 to 6 weeks. Often outgrown. A single dose of prednisone aborts the attack; tonsillectomy is curative.

Others worth knowing

• Behçet disease: recurrent oral and genital aphthae, uveitis, skin lesions. HLA-B51 associated, not strictly monogenic.
• Blau syndrome: NOD2 (the same gene whose somatic variants cause early-onset sarcoidosis-like disease). Early-onset granulomatous arthritis, uveitis, dermatitis.
• DADA2 (deficiency of adenosine deaminase 2): ADA2, autosomal recessive. Early-onset strokes, livedo racemosa, hepatosplenomegaly, immunodeficiency on top of autoinflammation. TNF blockade prevents strokes.

• Document the temporal pattern (fever calendar) and the accompanying features each attack.
• Inflammatory markers in attack and between (CRP, SAA, ferritin).
• IgD level (HIDS has elevated polyclonal IgD but it is non-specific; mevalonate urinary excretion is more specific).
• Hearing testing if any concern for MWS or CINCA.
• Ophthalmology for any uveitis suspicion.
• Targeted gene panel (autoinflammatory panel covers MEFV, TNFRSF1A, MVK, NLRP3, NLRP12, NOD2, ADA2, others).