MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA

Rheumatol Int. 2010 Mar;30(5):633-6. doi: 10.1007/s00296-009-1037-x. Epub 2009 Jul 5.


PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn's disease and Muckel-Wells syndrome were analyzed in PFAPA patients. Patients (n = 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006-2007. Clinical information was complemented during physicians-parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 +/- 16.4 months. Boys (n = 33; 58%) were diagnosed earlier than girls (n = 21; 42%) at 26.18 +/- 13.83 and 36.41 +/- 18.32 months, respectively (P = 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.

MeSH terms

  • Adolescent
  • Carrier Proteins / genetics*
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • Cytoskeletal Proteins / genetics*
  • DNA Mutational Analysis*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Hereditary Autoinflammatory Diseases / ethnology
  • Hereditary Autoinflammatory Diseases / genetics*
  • Humans
  • Infant
  • Israel
  • Lymphadenitis / genetics
  • Male
  • Mutation*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nod2 Signaling Adaptor Protein / genetics*
  • Pharyngitis / genetics
  • Pyrin
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Risk Factors
  • Stomatitis, Aphthous / genetics
  • Syndrome


  • Carrier Proteins
  • Cytoskeletal Proteins
  • MEFV protein, human
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Pyrin
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human