Heterogeneity among patients with tumor necrosis factor receptor–associated periodic syndrome phenotypes
Ebun Aganna
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorLinda Hammond
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorShane A. McKee
Belfast City Hospital, Belfast, Northern Ireland
Search for more papers by this authorHans Kristian Ploos van Amstel
University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorClaudia Mischung
Humboldt University of Berlin, Charité, and HELIOS Klinikum Buch II, Klinik für Kinderheilkunde und Jugendmedizin, Berlin, Germany
Search for more papers by this authorFrank T. Saulsbury
University of Virginia Health System, Charlottesville
Search for more papers by this authorKevin P. High
Wake Forest University School of Medicine, Winston-Salem, North Carolina
Search for more papers by this authorMichael G. Molloy
National University of Ireland, Cork, Ireland
Search for more papers by this authorNicholas Baker
Nelson Marlborough District Health Board, Nelson Hospital, Nelson, New Zealand
Search for more papers by this authorMargo L. Whiteford
Duncan Guthrie Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK
Search for more papers by this authorP. L. Janssens-Korpola
University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorPatricia Woo
Windeyer Institute of Medical Sciences, University College, London, UK
Search for more papers by this authorKirsten Minden
Humboldt University of Berlin, Charité, and HELIOS Klinikum Buch II, Klinik für Kinderheilkunde und Jugendmedizin, Berlin, Germany
Search for more papers by this authorJoost Frenkel
Wilhelmina Children's Hospital and University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorRita M. Mirakian
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorGraham A. Hitman
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorCorresponding Author
Michael F. McDermott
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
5th Floor, Alexandra Wing, The Royal London Hospital, Whitechapel, London E1 1BB, UKSearch for more papers by this authorEbun Aganna
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorLinda Hammond
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorShane A. McKee
Belfast City Hospital, Belfast, Northern Ireland
Search for more papers by this authorHans Kristian Ploos van Amstel
University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorClaudia Mischung
Humboldt University of Berlin, Charité, and HELIOS Klinikum Buch II, Klinik für Kinderheilkunde und Jugendmedizin, Berlin, Germany
Search for more papers by this authorFrank T. Saulsbury
University of Virginia Health System, Charlottesville
Search for more papers by this authorKevin P. High
Wake Forest University School of Medicine, Winston-Salem, North Carolina
Search for more papers by this authorMichael G. Molloy
National University of Ireland, Cork, Ireland
Search for more papers by this authorNicholas Baker
Nelson Marlborough District Health Board, Nelson Hospital, Nelson, New Zealand
Search for more papers by this authorMargo L. Whiteford
Duncan Guthrie Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK
Search for more papers by this authorP. L. Janssens-Korpola
University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorPatricia Woo
Windeyer Institute of Medical Sciences, University College, London, UK
Search for more papers by this authorKirsten Minden
Humboldt University of Berlin, Charité, and HELIOS Klinikum Buch II, Klinik für Kinderheilkunde und Jugendmedizin, Berlin, Germany
Search for more papers by this authorJoost Frenkel
Wilhelmina Children's Hospital and University Medical Center, Utrecht, The Netherlands
Search for more papers by this authorRita M. Mirakian
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorGraham A. Hitman
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
Search for more papers by this authorCorresponding Author
Michael F. McDermott
Barts and London, Queen Mary's School of Medicine and Dentistry, London, UK
5th Floor, Alexandra Wing, The Royal London Hospital, Whitechapel, London E1 1BB, UKSearch for more papers by this authorAbstract
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 (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.
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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