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

Ebun Aganna, Linda Hammond, Philip N Hawkins, Anna Aldea, Shane A McKee, Hans Kristian Ploos van Amstel, Claudia Mischung, Koichi Kusuhara, Frank T Saulsbury, Helen J Lachmann, Alison Bybee, Elizabeth M McDermott, Micaela La Regina, Juan I Arostegui, Josep M Campistol, Sharron Worthington, Kevin P High, Michael G Molloy, Nicholas Baker, Jeff L Bidwell, José L Castañer, Margo L Whiteford, P L Janssens-Korpola, Raffaele Manna, Richard J Powell, Patricia Woo, Pilar Solis, Kirsten Minden, Joost Frenkel, Jordi Yagüe, Rita M Mirakian, Graham A Hitman, Michael F McDermott
Arthritis and Rheumatism 2003, 48 (9): 2632-44

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.

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