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Abstract Details for Philip J Hashkes

Abstract Information : Is the CIAS1 Q705K Mutation Pathogenic? Three Case Presentations Philip J. Hashkes               Dept. of Rheumatic Diseases, Cleveland Clinic Foundation, Cleveland, OH 44195 Background: More than 50 mutations of the CIAS1 gene have been described. The clinical significance for some, including the Q705K CAG/AAG glutamine to lysine substitution, is not clear, since it is present in 5-11% of the population. I describe 3 cases that suggest this mutation may be pathogenic in some patients. Case reports: 1. A 3.5 year old Caucasian male of German ancestry who developed from the age of 1 year a rash and arthropathy, with erythematous nodules. He also has episodic fever with worsening of the rash and arthropathy with marked increases in inflammatory indices (normal between episodes). Episodes last 2-14 days. At age 15 months he developed spastic diplegia and ataxia after MMR vaccine that is gradually improving. Father has an undiagnosed arthropathy. ANA was positive; other autoantibodies were negative and an extensive work-up for other arthropathy causes and genetic conditions was negative. CIAS1 testing revealed Q705K and T221 (threonine to threonine) mutations. His arthropathy is well controlled with anakinra. 2. A 12 year-old Caucasian male of German-Italian ancestry who from age 9 years had recurrent episodes of fever, sore throat, mouth sores, abdominal pain, erythematous hive-like rash, arthralgia and myalgia with elevation of inflammatory indices during episodes. Episodes last 2-6 weeks. In an early episode he had knee swelling and was diagnosed with seronegative enthesopathy arthropathy syndrome and treated for 2 years with methotrexate. After 2 years of treatment he developed 3 episodes. Extensive work-up was negative except finding Q705K and A244G (alanine to alanine) mutations. Since his genetic diagnosis he has had no episodes and anakinra was not started. 3. A 17 year-old Caucasian female of German-Irish-Scottish ancestry developed at age 5 months a left parietal and thalamic stroke and has since had recurrent rash, canker sores and arm swelling. At 14 years she developed labyrinthitis, at 16 years she developed left retinal occlusion and at 17 years had a left TIA. ESR and CRP are persistently elevated and serum amyloid A was markedly elevated. Comprehensive inflammatory work-up was negative except finding Q705K, T221T and IVS3+59g/a-mutations. Conclusion: The Q705K CIAS1 mutation may be pathogenic in some patients, especially if accompanied by additional heterozygote mutations. The clinical manifestations are not those typically described for cryopyrin syndromes but may include neurologic manifestations. It is possible that the second mutation (although not resulting in a substitution) may have influence on the pathogenicity of the Q705K mutation.

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