Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes

Arthritis Rheum. 2003 Sep;48(9):2632-44. doi: 10.1002/art.11215.


Objective: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS.

Methods: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes.

Results: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants.

Conclusion: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / blood
  • Antigens, CD / genetics*
  • Familial Mediterranean Fever / genetics*
  • Family Health
  • Female
  • Flow Cytometry
  • Founder Effect
  • Gene Expression
  • Genetic Heterogeneity*
  • Haplotypes
  • Humans
  • Male
  • Microsatellite Repeats
  • Pedigree
  • Periodicity*
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Receptors, Tumor Necrosis Factor / blood
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor, Type I


  • Antigens, CD
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I