A NOVEL MUTATION IN THE TNFRSF1A GENE IDENTIFIED IN A 3 MONTH OLD MALE WITH PERIODIC FEVER HETEROZYGOUS FOR THE E148Q VARIANT OF THE MEFV GENE

Background: Autoinflammatory syndromes manifest with spontaneously recurring attacks of systemic inflammation. Examples include the tumor necrosis factor associated periodic fever syndrome (TRAPS) and Familial Mediterranean Fever (FMF), the former with autosomal dominant inheritance through mutations in the TNFRSF1A gene, the latter being an autosomal recessive disorder with mutations in the MEFV gene (1). Objectives: We report the case of a male infant of Albanian heritage with TRAPS, carrying both a novel mutation in the TNFRSF1A gene (C55F) and the E148Q variant of the MEFV gene. Methods: Mutational screening via the GeneDx periodic fever syndromes sequencing array. Results: The patient presented at 3 months of age with attacks of high fevers, raised acute phase reactants, and migratory skin eruptions of approximately 10 days duration. There was no family history of periodic fever. Sequencing array revealed the patient to be both heterozygous for a previously undescribed TNFRSF1A gene mutation (C55F) and the E148Q variant of the MEFV gene. Conclusions: This case is consistent with the diagnosis of TRAPS. The novel C55F mutation found in our patient leads to a substitution of the polar cysteine residue with a non polar phenylalanine residue possibly resulting in a change in protein structure. TNFRSF1A mutations affecting cysteine residues are associated with higher risk for amyloidosis (2). The E148Q variant in MEFV is thought to either be a benign polymorphism or a disease-causing mutation with low penetrance (3). However, it has been also argued that it may serve as a susceptibility factor for amyloidosis (4). Combinations of mutations in TNFRSF1A and the E148Q variant have been reported, and may influence the clinical presentation (5, 6). Symptoms in our patient thus far have been well controlled with NSAIDs. However, the patient's young age, concurrent presence of a MEFV mutation and the novel TNFRSF1 mutation in a cysteine residue mandates close surveillance for development of amyloidosis. This case highlights the challenges of the disease, particularly in the infant population where early commencement of immune modulating therapy might avert the later development of amyloidosis but clinical experience is sparse. References: 1. D. L. Kastner, I. Aksentijevich, R. Goldbach-Mansky, Cell 140, 784 (2010). 2. I. Aksentijevich et al., Am J Hum Genet 69, 301 (2001). 3. D. R. Booth, H. J. Lachmann, J. D. Gillmore, S. E. Booth, P. N. Hawkins, Qjm 94, 527 (2001). 4. E. Aganna et al., Genes Immun 5, 289 (2004). 5. C. Dode et al., Arthritis Rheum 46, 2181 (2002). 6. S. Stojanov et al., Rheumatology (Oxford) 43, 526 (2004). Disclosure of Interest: None DeclaredCitation: Annals of the Rheumatic Diseases, volume 70, supplement 3, year 2011, page 577Session: Other orphan diseases (Poster Presentations )