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Open Access Research article

Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature

Dorota M Rowczenio1, Hadija Trojer1, Tonia Russell1, Anna Baginska1, Thirusha Lane1, Nicola M Stewart1, Julian D Gillmore1, Philip N Hawkins1, Patricia Woo2, Bozena Mikoluc3 and Helen J Lachmann1*

Author Affiliations

1 National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine Royal Free Campus, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK

2 Division of Infection & Immunity, UCL, Rayne Building, 5 University Street, London WC1E 6JF, UK

3 Department of Pediatrics and Developmental Disorders, Children's Teaching Hospital, Waszyngtona Street 17, Bialystok 15-224, Poland

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Arthritis Research & Therapy 2013, 15:R30  doi:10.1186/ar4171

Published: 19 February 2013

Abstract

Introduction

Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center.

Methods

DNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals.

Results

NLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members.

Conclusions

The NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.