June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Keratoendotheliitis fugax hereditaria: A novel NLRP3 mutation
Author Affiliations & Notes
  • Saloni Gupta
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Kavya Jatavallabhula
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Onyinye Onyia
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Doug Chung
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Dominic Williams
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Kaidi Wang
    Virginia Mason Medical Center, Seattle, Washington, United States
  • Anthony Aldave
    University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
    Jules Stein Eye Institute, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Saloni Gupta None; Kavya Jatavallabhula None; Onyinye Onyia None; Doug Chung None; Dominic Williams None; Kaidi Wang None; Anthony Aldave None
  • Footnotes
    Support  National Eye Institute P30 EY000331
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1728. doi:
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      Saloni Gupta, Kavya Jatavallabhula, Onyinye Onyia, Doug Chung, Dominic Williams, Kaidi Wang, Anthony Aldave; Keratoendotheliitis fugax hereditaria: A novel NLRP3 mutation. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1728.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Keratoendotheliitis fugax hereditaria (KFH) is an autosomal dominant episodic keratitis characterized by attacks of unilateral or bilateral ocular pain, photophobia, corneal opacification, and pseudoguttata. It has been previously reported only in individuals of Finnish descent. Genetic analyses of five Finnish families affected with KFH identified the same rare heterozygous c.61G>C (p.Asp21His) missense mutation in the NLRP3 gene, which is predicted to lead to misfolding of the cryopyrin protein and subsequent dysregulation of the NLRP3 inflammasome. Here, we report a novel NLRP3 mutation identified in the first non-Finnish individual with a diagnosis of KFH.

Methods : Ophthalmic examination was performed with slit lamp microscopy and AS-OCT on a 52 year-old Ashkenazi Jewish woman with a diagnosis of a Not Otherwise Specific (NOS) systemic autoinflammatory disease and two of her asymptomatic family members. The three individuals underwent exome sequencing of 29 genes associated with inherited corneal disorders. The symptomatic woman underwent Sanger sequencing of the NLRP3 gene and the results were compared to the published NLRP3 reference sequence (NG_011672.1). In silico analysis was performed with SIFT and Mutation Taster to predict functional consequences of identified mutations.

Results : Slit lamp examination of the symptomatic woman showed bilateral central corneal opacification with central gray-white stromal pigmentation and peripheral arcus-like degeneration. AS-OCT showed sub-epithelial anterior to mid-stromal thickened deposits and scarring. Targeted exome and Sanger sequencing revealed a novel heterozygous NLRP3 c.1712G>T (p.Gly571Val) missense mutation, which is predicted by SIFT and Mutation Taster to be damaging and pathogenic, respectively, with a scaled-CADD score of 23.5. Family members were negative for this mutation.

Conclusions : Ophthalmologists should be aware that KFH may affect individuals of non-Finnish ancestry and that molecular genetic analysis can be used to confirm the diagnosis in suspected cases that are atypical in terms of the ancestry, associated clinical features, or disease course.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1. Slit lamp microphotograph of the proband's cornea shows bilateral gray-white central corneal stromal opacification with central pigmentation and peripheral arcus-like degeneration.

Figure 1. Slit lamp microphotograph of the proband's cornea shows bilateral gray-white central corneal stromal opacification with central pigmentation and peripheral arcus-like degeneration.

 

Figure 2. Sanger sequencing chromatogram of NLRP3 exon 2 in the proband demonstrating a heterozygous c.1712G>T mutation.

Figure 2. Sanger sequencing chromatogram of NLRP3 exon 2 in the proband demonstrating a heterozygous c.1712G>T mutation.

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