Frontiers in Immunology (May 2022)

Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease

  • Dominika Oziębło,
  • Marcin L. Leja,
  • Marcin L. Leja,
  • Aldona Jeznach,
  • Magdalena Orzechowska,
  • Tomasz Skirecki,
  • Ewa Więsik-Szewczyk,
  • Mariusz Furmanek,
  • Natalia Bałdyga,
  • Henryk Skarżyński,
  • Monika Ołdak

DOI
https://doi.org/10.3389/fimmu.2022.904632
Journal volume & issue
Vol. 13

Abstract

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The NLRP3 gene mutations are the cause of autosomal dominant autoinflammatory disorders (NLRP3-AID). Recently, hearing loss (HL) has been found to be the sole or major manifestation of NLRP3-AID. Here, we tested 110 autosomal dominant HL families with a custom panel of 237 HL genes and found one family carrying the NLRP3 c.1872C>G, p.Ser624Arg mutation. Functional studies revealed that this novel variant is a gain of function mutation, leading to increased activity of caspase-1 and subsequent oversecretion of proinflammatory interleukin-1β. Clinical reanalysis of the affected individuals, together with serological evidence of inflammation and pathological cochlear enhancement on FLAIR-MRI images, guided our diagnosis to atypical NLRP3-AID. The study highlights the role of genetic analysis in patients with progressive postlingual HL. This can help to identify individuals with hereditary HL as a consequence of NLRP3-AID and allow timely and effective treatment with interleukin-1-receptor antagonist.

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