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Key Points

  • Disease summary:

    • Autoinflammatory diseases (AIDs) are illnesses of the innate immune system without high-titer autoantibodies or antigen-specific T cells in contrast to autoimmune diseases that relate to a deficit of acquired immunity. These diseases are characterized by recurrent fever and systemic inflammation, and the main complication is the risk of generalized or renal amyloidosis in untreated patients. Other sporadic, undefined, or complex disorders have been also linked to the AIDs group. This review will focus on hereditary recurrent fevers (HRFs).

  • Hereditary basis:

    • Both dominant and recessive autosomal transmission, with incomplete penetrance

  • Differential diagnosis:

    • Nonhereditary recurrent fevers, for example, PFAPA syndrome (Marshall syndrome)

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

Example: at least one of the following

  • Recurrent fever accompanied with various association of osteoarticular, cutaneous, and abdominal signs

  • Biologic marker of inflammation (enhanced C-reactive protein [CRP]) during acute episodes

  • Familial history

And the absence of

  • Infection, antibodies

Clinical Characteristics

  • Symptom-free periods, pediatric onset

Screening and Counseling


See Fig. 77-1.

Figure 77-1
Algorithm for Screening of Patient With Hereditary Recurrent Fever.


Inheritance, Penetrance

FMF and MKD are recessively inherited. TRAPS and CAPS are dominant diseases, but de novo mutations have been identified in rare cases of TRAPS and in all cases of severe forms of CAPS (also named, chronic infantile neurologic cutaneous and articular syndrome [CINCA]). Because of clinical similarities across AIDs, differential diagnosis is sometimes difficult. A decade ago, specific diagnosis has become possible after the discovery of the respective genes responsible for HRF (Table 77-1). The definitive genetic diagnosis of hereditary AIDs lies on the finding of unambiguous mutations in the causative genes, for example, M694V in the FMF gene, and C30R in the TRAPS gene. However, several variants are currently debated as to whether they are low-penetrance causing mutations or functional polymorphisms. Well-known examples are E148Q for MEFV, R121Q or P75L (old names R92Q and P46L) for TNFRSF1A, and V198M for NLRP3, respectively. A registry of mutations named infevers is available online at

Table 77-1Genetic Differential Diagnosis

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