Background/Purpose: Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of rare autoinflammatory diseases caused by gain-of-function mutations inthe NLRP3 gene. These mutations cause inflammasome hyperactivity and subsequent uncontrolled release of Interleukin-1β (IL-1β). CAPS patients may develop progressive sensorineural hearing loss (SNHL) due to cochlear autoinflammation, initially affecting the high-ultrahigh frequency ranges. In rare instances this may be the sole presenting symptom. A Jewish Ashkenazi family presented with autosomal dominant SNHL, a novel missense variant of unknown significance in the NLRP3 gene 001079821:c.1790G >A p.Ser597Asn, however they did not fulfill CAPS classification criteria. In order to establish the suspected diagnosis of atypical CAPS causing SNHL, and enable initiation of Anti-IL1 therapy, we performed functional studies of the inflammasome to evaluate whether the variant leads to inflammasome hyperactivity.

Methods: Our prospective study included 15 family members (10 known carriers, 5 age-group matched non-carriers who served as controls). We conducted clinical and hearing assessments along with ex-vivo functional studies of inflammasome activity. Secreted levels of IL-1β from peripheral-blood mononuclear cells (PBMCs) in carriers versus controls, were measured under 3 main conditions: basal state, in response to priming signal alone (LPS- lipopolysaccharide or LPS+CaCl₂), and in response to priming signal along with specific inflammasome inhibitor (MCC950).

Results: Of the 10 known carriers spanning 3 generations, 7 suffered from SNHL. Although most presented progressive deterioration classically associated with CAPS, some suffered from sudden episodes of unilateral SNHL as well. The severity of hearing impairment ranged from moderate, involving the high-ultrahigh frequency, to severe hearing loss requiring cochlear implant. Functional assessment of the inflammasome in carriers vs. non carriers (controls) revealed that although basal levels of secreted IL-1β were not significantly different, PBMCs isolated from NLRP3 variant carriers primed with either LPS or LPS+CaCl2 showed significantly higher secretion of IL-1β than healthy subjects. Inflammasome inhibition with MCC950 prior to addition of LPS+CaCl2 resulted in relative suppression of IL-1β secretion (Fig. 1). This evidence of NLRP3 inflammasome hyperactivity confirmed the suspected diagnosis of atypical CAPS. Indeed, administration of Anakinra therapy resulted in substantial clinical improvement, particularly among pediatric patients who exhibited near resolution of hearing impairment within 1-3 months of treatment (Fig. 2).

Conclusion: Our study revealed a novel pathogenic variant in NLRP3, causing atypical CAPS with a primary presentation of SNHL- responsive to Anti IL1 therapy. These findings highlight the crucial role of early diagnosis and subsequent treatment in reversing cochlear damage. Auditory assessment of the high and ultrahigh frequency range is important and can detect early subclinical SNHL. Incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Ex Vivo NLRP3 Inflammasome Functional Assessment

Pure-tone audiometry Pre and Post Anakinra Treatment

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/from-bedside-to-bench-and-back-discovery-of-a-novel-missense-variant-in-nlrp3-causing-atypical-cryopyrin-associated-periodic-syndromes-with-hearing-loss-as-the-primary-presentation-responsive-to-ant/