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Clin Exp Rheumatol. 2014 Jan-Feb;32(1):123-5. Epub 2013 Oct 11.

A novel mutation in the CIAS1/NLRP3 gene associated with an unexpected phenotype of cryopyrin-associated periodic syndromes.

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  • 1Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. insalaco@opbg.net.



Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations.


We describe a 13-year-old female who presented, in the initial phase of the disease, recurrent episodes of high fever, pericarditis, arthralgia, arthritis of the knees, abdominal pain and marked increase in inflammatory markers. In the subsequent months she developed recurrent episodes of chest pain, skin rash and swelling of the subcutaneous tissue, without fever, and with spontaneous resolution.


Molecular analysis of the CIAS1 gene revealed the presence of the Q703K variant and also a c.1105C>A mutation in the heterozygous state, that predicts a L369M amino acid substitution. The latter variant has never been reported. The L369M mutation was predicted to significantly affect protein structure (scoring as 'dangerous' and 'deleterious') by the Variant Effect Predictor tool. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours.


The rapid response to IL-1 inhibition suggests that the disease of this patient is driven by IL-1 and supports the conclusion that this novel mutation is pathogenic and may be associated with a new CAPS phenotype. The role played by the concomitant presence of the mutation Q703K remains to be clarified.

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