Keratoendotheliitis fugax hereditaria

Keratoendotheliitis fugax hereditaria is an autosomal dominant disease that results in episodic, inflammatory episodes characterized by unilateral pain, corneal edema and opacities, conjunctival injection, and a decrease in visual acuity; these episodes last 2-5 days. Episodes occur 1-8 times per year, and an increased number of attacks may contribute to corneal scarring.

Classically, it is associated with individuals of Finnish descent. A recent report showed that the disease also occurs in non-Finnish European populations. The associated gene mutation was found in approximately 0.02% of the Finnish population and 0.01% of the non-Finnish European population.

The disease is associated with a guanine-cytosine mismutation (c.61G>C) in the "nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3" (NLRP3) gene and the resulting NLRP3 protein (also called cryopyrin). The resulting change in amino acids leads to a different charge of the protein and can lead to misfolding of the protein. The NLRP3 protein is one of the major players in the NLRP3 inflammasome. An inflammasome is a multiprotein complex that, when assembled and activated, causes inflammatory changes. Poor protein folding may inadvertently cause this process to become dysregulated or prematurely activated.

Risk factors for the occurrence of inflammatory episodes are not known. However, patients have anecdotally reported that mild viral illness, cooler temperatures, and relief of psychological or physical stress may be associated. Collagen-related pathology has also been reported in one affected strain, so there may be an association,

NLRP3 mutations can lead to a group of heritable autoinflammatory processes grouped under the term cryopyrin-associated periodic syndromes (CAPS), and in some of these syndromes, ocular manifestations overlap with keratoendotheliitis fugax hereditaria. Mutations in this gene affect the NLRP3 inflammasome, activation of which is associated with several autoimmune diseases. The specific mutation in keratoendotheliitis fugax hereditaria likely causes unnecessary activation of the inflammasome, leading to the clinically significant inflammatory flare. Several autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and irritable bowel disease are associated with an activated inflammasome. A review can be found in.

Inflammatory reactions are often associated with edema. In keratoendotheliitis fugax hereditaria, edema is present in the corneal stroma, and inflammatory reactions are often associated with edema. In keratoendotheliitis fugax hereditaria, edema is present in the corneal stroma, and pseudoguttata (edematous endothelial cells) have been noted on imaging, possibly due to a vasogenic process. Unlike true guttata, pseudoguttata regress after the episode.

1. Immonen AT et al (2022) Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3. Am J Ophthalmol 236:309-318.
2. Lin B et al (2022) Pathogenic insights from genetic causes of autoinflammatory inflammasomopathies and interferonopathies. J Allergy Clin Immunol 149:819-832.