Errors and Delays in Diagnosing Keratitis Fugax Hereditaria

Abstract

Purpose

To study errors and delays in diagnosing keratitis fugax hereditaria (KFH), an autosomal-dominant periodic corneal autoinflammatory disease caused by the NLRP3 variant c.61G>C, by reviewing the medical records of genetically confirmed Finnish patients with KFH and by determining the frequency of the c.61G>C variant in selected biobank samples.

Design

A retrospective cohort and a cross-sectional biobank study.

Participants and subjects

Medical records of 96 clinically diagnosed, genetically confirmed patients with KFH, and 2010 DNA samples from patients with anterior uveitis, herpes keratitis, nonulcerative keratitis, or corneal opacity in the 2 largest Finnish biobanks.

Methods

The age, sex, ocular and other diagnoses, and laboratory results were reviewed in the retrospective cohort. The c. 61G>C variant was genotyped from the biobank samples using restriction fragment length polymorphism analysis. Sanger sequencing was used for validation. The most common causes of anterior uveitis, such as rheumatoid arthritis, or infectious keratitis were exclusion criteria.

Main outcome measures

Misdiagnoses and differential diagnoses of KFH, diagnostic delays, and the frequency of the c. 61G>C variant in biobank samples.

Results

The most common misdiagnoses in the retrospective cohort were anterior uveitis or anterior chamber cell reaction (40% of patients and 79% of misdiagnoses), conjunctivitis (14% and 27%, respectively), and recurrent corneal erosion (13% and 25%, respectively). Time from the onset of symptoms to KFH diagnosis ranged from 0 to 62 years (median, 19; interquartile range, 8-44). Of the 2010 biobank samples from patients with anterior uveitis, herpes keratitis, nonulcerative keratitis, or corneal opacity without an obvious cause, 12 (0.6%) carried the c.61G>C variant: 11 were diagnosed with anterior uveitis, 1 with unspecified keratitis, and 3 correctly with KFH.

Conclusions

KFH in Finland is most likely misdiagnosed as anterior uveitis. We suggest prospectively evaluating the addition of the NLRP3 variant c.61G>C to laboratory test packages for differential diagnosis of anterior uveitis. KFH should be considered in the differential diagnosis of anterior uveitis, especially in the Nordic countries and populations originating from them. Symptoms similar to those of KFH may also occur in other NLRP3-linked autoinflammatory syndromes.