FRI0012\u2005THE CLINICAL SPECTRUM AND PEDIGREE ANALYSIS OF TRAPS IN GREECE, INCLUDING A NOVEL MUTATION-RESULTS FORM A NATIONAL REFERRAL CENTRE

Abstract

Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) stems from autosomal dominantly inherited mutations in the TNFRSF1A (accession number: NM_001065) gene, encoding for the receptor of tumor necrosis factor α (TNFR1). Objectives: The aim of the study was to report a novel TNFRSF1A mutation and to describe the clinical phenotypes in families carrying different TNFRSF1A mutations. Methods: Four Greek patients with TRAPS-like clinical features were evaluated for TNFRSF1A gene mutations. Direct sequencing of exons 2, 3 and 4 of the gene was performed. Following positive testing of the index cases, samples from other family members were collected and screened. Results: A total of eighteen members deriving from four unrelated Greek families were investigated. In the first family, a novel (heterozygous) mutation in cysteine residue in exon 3 of the TNFRSF1A gene C73Y (c.305G>A) was identified in three members. Interestingly, in the same family a patient carrying the low penetrance TNFRSF1A R92Q mutation, as well as a patient with concomitant R92Q and C73Y mutations were identified. In the second family, the TNFRSF1A C73W (c.306C>G) heterozygous mutation was identified in seven members. In the third family, the TNFRSF1A T50M mutation was detected in two members while in the fourth family six members carried the TNFRSF1A R92Q mutation in heterozygous state. Clinical manifestations amongst members of the affected families were diverse with the most serious being present in patients carrying the TNFRSF1A C73Y, C73W and T50M mutations. Cardinal features included disease onset in childhood (66.7% for C73Y, 85.7% for C73W and 100% for T50M), arthritis (67% for C73Y, 100% for C73W and 100% for T50M), persistent pyrexia (67% for C73Y, 100% for C73W and 100% for T50M), abdominal pain (66.7% for C73Y, 100% for C73W and 100% for T50M), recurrent adhesive ileus (33.3% for C73Y, 14.3% for C73W and 100% for T50M) anterior uveitis (33.3% for C73Y), and diffuse maculopapular rash (14.3% for C73W and 50% for T50M). The clinical presentation was more severe in the patient with concomitant R92Q and C73Y, suggesting an additive effect. On the contrary, (as expected) the disease spectrum associated with R92Q mutation found in six members encompassed a mild phenotype, extending from asymptomatic state (four members) to adult-onset disease associated with intermittent low-grade fever, arthritis and elevated inflammation markers (two members). Conclusion: This was the first pedigree analysis of TRAPS in Greece, depicting four families with unique mutations, along with analysis of the clinical manifestation. The site of mutation might explain the diversity of clinical phenotypes in TRAPS patients that extends from mild to severe disease. In our patients, it appeared that mutations in the cysteine residues as well as in T50M were associated with more severe clinical manifestations. Among these was a novel mutation described for the first time in the literature. Disclosure of Interests: Adrianos Nezos: None declared, Ourania Argyropoulou: None declared, Eleni Klinaki: None declared, Nikolaos Marketos: None declared, KARAGIANNI PANAGIOTA: None declared, Despoina Maritsi: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared, Athanasios Tzioufas Grant/research support from: ABBVIE, PFIZER, AMGEN, NOVARTIS, GSK