Keratoendotheliitis Fugax Hereditaria

A number sign (#) is used with this entry because of evidence that keratoendotheliitis fugax hereditaria (KEFH) is caused by heterozygous mutation in the NLRP3 gene (606416) on chromosome 1q44.

Description

Keratoendotheliitis fugax hereditaria is an autosomal dominant corneal disease that periodically and fleetingly affects the corneal endothelium, stroma, and vision, eventually resulting in central corneal stromal opacities in some patients. The disease is characterized by episodes of unilateral ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1 to 2 days, but vision remains blurry for several weeks. Onset occurs between ages 3 and 12 years, and may involve either eye. Episodes generally decrease in frequency and become more mild with age (summary by Turunen et al., 2018).

Clinical Features

Valle (1964) described keratitis fugax hereditaria as a 'new' entity in 10 members of 4 generations of a family. (Fugax means fleeting; fugitive and centrifugal are from the same Latin root, fugere, meaning to flee.) The disease usually begins between the ages of 4 and 12 years and is characterized by acute attacks of keratitis occurring 2 to 8 times a year. No permanent corneal opacities result. Attacks become milder and less frequent after age 50.

Ruusuvaara and Setala (1987) described a Finnish kindred in which 21 individuals in 5 generations had KEFH. Attacks lasted from a few days to several weeks. Corneal edema and endothelial guttata-like changes were seen during attacks; permanent opacities in the stroma were observed in some subjects after many attacks. The first attacks were at age 3 years in 2 and in their teens in others, but usually occurred about age 10.

Turunen et al. (2018) studied 30 patients with KEFH from 7 Finnish families, including the family originally reported by Ruusuvaara and Setala (1987), as well as 4 sporadic Finnish patients. All affected individuals reported repeated episodes of unilateral keratoendotheliitis, occurring from 1 to 6 times per year, starting at the median age of 11 years (range, 5-28 years). Episodes became milder in middle age, and their frequency decreased; there was no apparent seasonal variation. Symptoms included conjunctival injection, pain, and photophobia, and episodes were sometimes associated with a mild anterior chamber reaction. These symptoms resolved in 1 to 2 days, although blurred vision could last for several weeks. Corneal pseudoguttata, thought to correspond to patchy transient corneal endothelial edema, was observed during acute episodes, but all patients had normal endothelium by biomicroscopy between episodes. Chart review indicated that 41% of patients had at least 1 acute episode that was associated with a mild anterior chamber reaction, and occasional corneal erosions had been reported, but none were observed during the study. Best-corrected visual acuity (BCVA) transiently deteriorated during the episodes. Repeated episodes resulted in horizontally oval bilateral central stromal opacities that were faintly present in 8 patients (24%) and definitely present in 9 (26%), and these opacities were associated with decreased BCVA in the majority of patients. No consistent systemic associations were observed in affected individuals.

Inheritance

The transmission pattern of KEFH in the family reported by Ruusuvaara and Setala (1987) was consistent with autosomal dominant inheritance, with several instances of male-to-male transmission.

Molecular Genetics

In affected individuals from 7 Finnish families with KEFH, including the family originally reported by Ruusuvaara and Setala (1987), as well as 4 sporadic Finnish patients, Turunen et al. (2018) performed whole-exome sequencing and identified a heterozygous missense mutation in the NLRP3 gene (D21H; 606416.0012) that was present in all 34 patients and segregated with disease in the 3 families tested. In September 2017, the mutation was found in the SISu database at a minor allele frequency (MAF) of 0.023% and in the ExAC database at an MAF of 0.0090% in the aggregated non-Finnish European populations; it was not present in any other ExAC populations.