Fever syndromes, hereditary, periodic (overview) A68.9

Clinic and genetics now allow a more precise differentiation. A distinction is made according to inheritance:

• Sporadically inherited:
  • PFAPA syndrome
• Autosomal recessive inherited clinical pictures:
  • Familial Mediterranean fever (Familial Mediterranean fever/FMF)
  • Hyper-IgD syndrome (HIDS).
• Autosomal-dominantly inherited diseases:
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
  • Muckle-Wells syndrome (MWS )
  • Familial cold urticaria (FCAS)
  • Cryopyrin-associated periodic syndrome (CAPS): severe form of FCAS.
  • Chronic infantile neurological cutaneous and articular syndrome (CINCA syndrome).

Depending on the disease, the following genetic causes can be detected (diagnosis-determining):

• FMF: Mutations in the MEFV gene (Mediterranean fever gene; gene locus: 16p13.3).
• HIDS: Mutations in the MVK gene (mevalonate kinase gene; gene locus: 12q24)
• TRAPS: Mutations in the TNFRSF1A gene (TNF receptor superfamily 1A gene/gene locus: 12p13.2)
• Familial cold urticaria: mutations in the NLRP3 gene (alias CIAS1 gene/Cold-induced autoinflammatory syndrome gene/gene locus: 1q44).
• CAPS/cryopyrin-associated periodic syndrome (mutations in the NLRP3 gene/alias CIAS1 gene/Cold-induced autoinflammatory syndrome gene/gene locus: 1q44).
• Chronic infantile neurological cutaneous articular syndrome (mutations in the NLRP3 gene /alias CIAS1 gene/Cold-induced autoinflammatory syndrome gene/gene locus: 1q44)

The resulting functional changes in the proteins encoded by these genes, i.e. the pyrin in FMF, the mevalonate kinase in HIDS, the p55 TNF receptor in TRAPS, the cryopyrin in familial cold urticaria and chronic infantile neurological cutaneous articular syndrome, lead to uncontrolled activation of the inflammasomes and ultimately to unphysiologically increased cytokine release with the consecutive clinical symptoms.

The clinical dermatological symptoms of hereditary periodic fever syndromes can be summarized under the clinical term "neutrophilic urticarial dermatosis". Clinically, in the active phases of the disease, there are 2.0 cm large, also larger, less itchy (rather burning) pale red spots, urticarial, flat papules or plaques that persist for about 24 hours or longer. The skin changes are always accompanied by a disturbance of the AZ, fever, joint complaints, neutrophilic leukocytosis and an increase in acute phase proteins (see the respective clinical pictures below).

Molecular genetic detection of mutations of the MEFV gene (FMF), MVK gene (HIDS) or the TNFRSF1A gene (TRAPS).

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