A 6-year-old Caucasian boy is seen by his pediatrician for a 14-month history of fever episodes lasting up to 10 days. During these episodes, he develops a red rash, nonspecific joint pains, and abdominal pain variably accompanied by diarrhea. Between episodes he is asymptomatic. He has had serial evaluations in the primary care clinic and has been admitted to a children’s hospital for work up to rule out potential infectious, gastrointestinal, and oncologic etiologies. The work-up is only positive for nonspecific elevations in inflammatory markers and a mild leukocytosis. The pediatrician suspects a periodic fever syndrome and refers the child to a pediatric rheumatologist. During an episode of fever, the child is evaluated by the pediatric rheumatologist. The only clinical finding is a rash on the back and trunk (Figure 176-1). Work-up for a periodic fever syndrome reveals a heterozygous missense mutation in the gene encoding the cell surface receptor for tumor necrosis factor (TNF) TNFRSF1A, and the diagnosis of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is made. The boy is treated with etanercept, a soluble TNF-α receptor fusion protein, after which the frequency and severity of his episodes lessen.

Periodic fever syndromes refer to a class of auto-inflammatory (AI) disorders characterized by spells of fever with other associated symptoms, typically occurring with three or more episodes of unexplained fever in a six-month period at least seven days apart. As in the case presented, a recurrent fever syndrome diagnosis may have a monogenetic etiology; however, many cases are characterized phenotypically,¹ There is an expanding spectrum of genetic AI diseases including but not limited to: TRAPS, familial Mediterranean fever (FMF), mevalonate kinase deficiency (MVK), otherwise known as hyperimmunoglobulin D syndrome (HIDS), and cryopyrin associated periodic syndromes (CAPS), which includes three overlapping phenotypes (familial cold auto-inflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease). The disorder termed periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome (PFAPA or Marshall Syndrome), is a benign condition with regular intervals of high fever which last approximately 5 days (Table 176-1).²

Periodic fever syndrome, recurrent fever syndrome, or auto-inflammatory disorder.

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  Of the periodic fever syndromes, PFAPA is perceived to be the most prevalent.

  
  
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  TRAPS may present from infancy into adulthood, but most commonly presents in toddlers. TRAPS patients characteristically have an Irish ancestral pattern.

  
  
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  FMF is more common in those with Sephardic Jewish, Armenian, or Turkish ancestry. Clinical signs of FMF typically develop by 10 years of age.

  
  
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  The first HIDS episode typically occurs prior to 12 months. HIDS was first described in patients from the Netherlands and is believed more common in those from Western Europe.

  
  
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  In France, the prevalence of CAPS with NLRP-3 (pyrin domain) mutations has been estimated 1/360,000.³

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  Unlike classic rheumatic diseases with autoimmune pathogenesis, autoinflammatory diseases do not rely on autoreactive T lymphocytes or pathogenic autoantibodies.

  
  
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  To date, nearly all mutations linked to AI syndromes disrupt inflammatory signaling within the innate immune system. This disruption generates a pro-inflammatory state, often leading to a final common pathway ending with activation of the inflammasome, a complex of distinct proteins, which serve to convert inactive pro-IL-1β to active pro-IL-1β (Figure 176-2).

  
  
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  Stress or infection may trigger episodes by stimulating an inflammatory process through the inflammasome.

  
  
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  TRAPS is an autosomal dominantly inherited disease with incomplete penetrance.

  
  
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  CAPS’ inheritance is autosomal dominant, while FMF and HIDS inheritance is autosomal recessive.