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NLRP3 E311K mutation in a large family with Muckle-Wells syndrome - description of a heterogeneous phenotype and response to treatment

Jasmin B Kuemmerle-Deschner1*, Peter Lohse2, Ina Koetter3, Guenther E Dannecker4, Fabian Reess4, Katharina Ummenhofer1, Silvia Koch3, Nikolay Tzaribachev5, Anja Bialkowski1 and Susanne M Benseler6

Author Affiliations

1 Division of Pediatric Rheumatology, Dept. of Pediatrics, University Hospital Tübingen, Hoppe-Seyler-Straße 1, 72076 Tuebingen, Germany

2 Institut für Laboratoriumsmedizin, Prof. Blessing, Dr. Blessing und Kollegen, Bereich Molekulargenetik, Virchowstraße 10c, 78224 Singen, Germany

3 Division of Rheumatology, Dept. of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany

4 Department of Pediatrics and Pediatric Rheumatology, Olgahospital, Bismarckstraße 8, 70176 Stuttgart, Stuttgart, Germany

5 Center for Rheumatic Diseases, Dept. of Pediatric Rheumatology, Oskar-Alexander-Straße 26, 24576 Bad Bramstedt, Germany

6 Dept. of Pediatric Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

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Arthritis Research & Therapy 2011, 13:R196  doi:10.1186/ar3526

Published: 6 December 2011



Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment.


A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab.


All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab.


The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.