From bedside to bench and back: discovery of a novel missense variant in NLRP3 causing atypical CAPS with hearing loss as the primary presentation, responsive to anti-IL-1 therapy

Cryopyrin-associated periodic syndromes (CAPS) also known as NLRP3-associated auto-inflammatory diseases, are a spectrum of rare auto-inflammatory diseases caused by gain-of-function mutations in the NLRP3 gene, resulting in inflammasome hyper-activation and dysregulated release of Interleukin-1{beta} (IL-1{beta}). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) due to cochlear auto-inflammation which, in rare cases, may be the sole manifestation. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting autosomal dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821:c.1790G>A, p.Ser597Asn). To do so, we conducted an ex vivo functional assessment of the NLRP3 inflammasome in carries (n=10) and healthy family members (n=5). The assay revealed hyper-activation of the inflammasome among carriers, supporting the hypothesis that this missense variant is a pathogenic gain-of-function mutation. Administration of anti-IL-1 therapy resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1-3 months of treatment. Our findings highlight the crucial role of early diagnosis and treatment of hearing loss due to hyperactivation of the inflammasome with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high and ultrahigh frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.