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

• DOI: 10.1002/art.11215
• Publication Date: 2003-09-16T14:43:17Z
• Authors: Ebun Aganna; Linda Hammond; Philip N. Hawkins; Anna Aldea; Shane A. McKee; Hans Kristian Plo...; Claudia Mischung; Koichi Kusuhara; Frank T. Saulsbury; Helen J. Lachmann; Alison Bybee; Elizabeth M. McDe...; 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‐Ko...; Raffaele Manna; Richard J. Powell; Patricia Woo; Pilar Solis; Kirsten Minden; Joost Frenkel; Jordi Yagüe; Rita M. Mirakian; Graham A. Hitman; Michael F. McDermott
• Keywords: Family Health; Male; Periodicity; Gene Expression; Flow Cytometry; Founder Effect; Receptors, Tumor Necrosis Factor; 3. Good health; Familial Mediterranean Fever; Pedigree; Genetic Heterogeneity; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Haplotypes; Antigens, CD; Receptors, Tumor Necrosis Factor, Type I; Humans; Female; Promoter Regions, Genetic; Microsatellite Repeats

AbstractObjectiveTo investigate the prevalence of tumor necrosis factor receptor–associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS.MethodsMutational 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.ResultsEight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (ΔD42) 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.ConclusionThe 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.