DESCRIPTION

• Unexplained episodes of fever with a characteristic frequency and constellation of symptoms
• Need three or more episodes of unexplained fevers in a 6-month period, occurring at least 7 days apart
• May have strict periodicity or recur with varying intervals between attacks
• Classified as autoinflammatory diseases: seemingly unprovoked exaggerated activation of the innate immune system/inflammation without significant levels of autoantibodies or antigen-specific T cells seen in autoimmune diseases
• Some conditions are caused by hereditary defects (monogenic), whereas some are multifactorial.
• Hereditary PFS include the following:
  • Familial Mediterranean fever (FMF)
    • Most common monogenic autoinflammatory disease
    • Gene defect: MEFV
    • Mode of inheritance: autosomal recessive with gain-of-function mutations
    • Most common clinical symptoms: abdominal pain/peritonitis (can vary from mild to severe, generalized or localized), pleuritis (usually unilateral), arthralgia>arthritis, myalgia, rash (erysipeloid erythematous rash on the dorsum of the foot, ankle, or lower leg)
    • Episodes last 12 to 72 hours, with interval between episodes varying from days to months, during when children are usually well.
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS); previously known as familial Hibernian fever
    • Second most common hereditary periodic fever disorder
    • Gene defect: TNFRSF1A
    • Mode of inheritance: autosomal dominant
    • Longer attacks (1 to 4 weeks) compared to other hereditary PFS
    • Main clinical symptoms are “eye and skin”
      • Rash: macular erythematous rash on torso or extremities, warm, tender, may resemble cellulitis or bruises; migratory; can have associated myalgia due to inflammation of underlying fascia
      • Ocular manifestations: periorbital edema, conjunctivitis
      • Other: abdominal pain (may resemble acute abdomen), recurrent pericarditis, arthralgia>arthritis
  • Mevalonate kinase deficiency (MKD)
    • Mode of inheritance: autosomal recessive
    • Mild phenotype, previously known as hyperimmunoglobulin D syndrome (HIDS)
      • Manifests in early childhood, often by the age of 6 months
      • Attacks last 3 to 7 days and are usually separated by 1 to 2 symptom-free months; episodes heralded by chills, headache, rising fever, abdominal pain, nausea, vomiting
      • Main symptoms: diffuse erythematous maculopapular rash; sometimes painful; can be nodular, urticarial, morbilliform; can involve palms/soles, cervical lymphadenopathy; severe headache; splenomegaly; oral and genital ulcers; symptoms may improve as children age.
    • Severe phenotype previously known as mevalonic aciduria—near complete deficiency of mevalonic kinase
      • Developmental delay of varying severity, hematologic abnormalities, dysmorphic features, hepatosplenomegaly
      • Periodic crises with fever, rash, arthralgia
  • NLRP3-associated autoinflammatory disease
    • Previously known as cryopyrin-associated periodic syndromes (CAPS)
    • Gene defect: NLRP3
    • Mode of inheritance: autosomal dominant (can also be sporadic, especially severe disease)
    • Mild phenotype: previously known as familial cold autoinflammatory syndrome (FCAS)
      • Recurrent, short, and self-limited episodes of fever, rash, and arthralgia triggered by exposure to cold/rapid drop in temperature; conjunctivitis is also common.
      • Usually presents at birth or within first 6 months of life
      • Duration of episodes usually short (<24 hours); in between episodes can have daily rash, headache, myalgia, fatigue worse in afternoon/night
    • Moderate phenotype: previously known as Muckle Wells syndrome (MWS)
      • Episodes last 2 to 3 days (sometimes can have more persistent course).
      • Not triggered by cold exposure; occur at irregular intervals
      • Age at onset is variable.
      • Main clinical manifestations: fever not always present; urticarial rash, conjunctivitis (less commonly episcleritis/iridocyclitis), sensorineural hearing loss in late childhood/adolescence (up to 70% untreated), polyarthralgia/oligoarthritis; can also have abdominal pain, headache
    • Severe phenotype: previously known as neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)
      • Symptoms occur at birth or early infancy.
      • Fever can be intermittent, mild, or absent.
      • Main clinical symptoms: urticarial rash (usually present at birth), joint involvement ranges from arthralgia to severe disease (bony overgrowth of metaphyses/epiphyses of long bones); most often involving knees, prematurity/growth restriction, neurologic manifestations (seizures, chronic aseptic meningitis, cerebral ventricular dilation, cerebral atrophy, optic disc edema, and high-frequency hearing loss), ocular manifestations (uveitis)
  • Cyclic hematopoiesis/cyclic neutropenia
    • Gene defect: ELANE
    • Mode of inheritance: autosomal dominant, can also be sporadic or acquired
    • Symptoms start within 1st year of life; each episode lasts 3 to 5 days with ~19 to 21 days in between episodes when children are generally well.
    • During episodes, absolute neutrophil count (ANC) <200/μL—during these times, patients susceptible to infection with normal flora: recurrent oral ulcers, gingivitis, fever, lymphadenopathy; severe infections may occur.
    • Other symptoms include bone pain, fatigue, malaise, diarrhea, and headache.
    • In between episodes, ANC in low normal to mild neutropenia range
• Nonhereditary/multifactorial
  • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)
    • Onset usually before the age of 5 years
    • Febrile episodes usually very regular, occurring every 28 days and lasting ~5 days
    • Can start with malaise, chills, oral lesions, and then abrupt onset of fever as high as 40°C to 41°C; fever usually resolves over 24- to 48-hour period.
    • A majority of patients have aphthous stomatitis; lesions resolve without scarring in 3 to 5 days; other common manifestations include pharyngitis and cervical adenitis. Minor manifestations include abdominal pain, arthralgia, and headaches.
    • Diarrhea, chest pain, diffuse lymphadenopathy, rash, and arthritis are NOT typically seen and should prompt reevaluation for other conditions.
• Other autoinflammatory syndromes presenting without recurrent fever as a major manifestation
  • These disorders are exceedingly rare and unlikely to be encountered in routine clinical practice.
  • Deficiency of the interleukin (IL)-1 receptor antagonist (DIRA): early-onset osteomyelitis with periostitis and pustulosis
  • PSTPIP1-associated arthritis, pyoderma gangrenosum, and acne (PAPA): early-onset destructive arthritis, aggressive ulcerative skin lesions
  • Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE): recurrent fevers, violaceous skin rashes, lipodystrophy, joint involvement
  • Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI): early-onset systemic autoinflammatory disease with rash, small-vessel vasculitis, and interstitial lung disease
  • Deficiency of adenosine deaminase 2 (DADA2): lacunar strokes and features of systemic vasculitis (may resemble polyarteritis nodosa)
  • Deficiency of IL-36 receptor antagonist (DITRA): causes generalized pustular psoriasis
  • Haploinsufficiency of A20 (HA20): Features may overlap with those of Behçet disease and inflammatory bowel disease. HA20 is a type of very early-onset inflammatory bowel disease
  • Blau syndrome (juvenile systemic granulomatosis): triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis

EPIDEMIOLOGY

• PFS have been reported in all ethnicities with certain syndromes being more commonly described in specific populations with founder mutations.
  • FMF: Sephardi and Ashkenazi Jewish, Arab, Armenian, Italian, and Turkish populations
  • MKD: Northern European ancestry (50% Dutch ancestry)
  • TRAPS: Irish-Scottish descent; formerly known as familial Hibernian fever
• Most commonly, PFS occur during infancy or childhood and rarely during adolescence or adulthood.

RISK FACTORS

PATHOPHYSIOLOGY

• Genetic and environmental factors are involved in the pathogenesis of PFS.
• In contrast to the typically recognized autoimmune conditions such as lupus where the adaptive immune system is involved, PFS represent disorders of innate immunity.
• Disease-specific mutations in genes encoding for important innate immunity components lead to a defective antigen-independent hyperactivation of the immune system with subsequent exaggerated inflammation and tissue damage.
• Potential episode triggers that have been identified in some PFS include infections, immunizations, cold exposure, menstrual periods, emotional distress, and trauma.
• Different pathogenesis themes have been described based on the affected innate immune genes and pathways (e.g., disorders of inflammasomes and related IL-1 family cytokines: FMF, MKD/HIDS, NLRP3/CAPS, PAPA, DIRA, DITRA).