An Eye Genetics Group Identifies a Novel Cryopyrin-Associated Periodic Autoinflammatory Syndrome Affecting Corneas

An eye genetics group has identified a new genetic mutation that alters the function of cryopyrin and leads a to life-long periodic inflammation of the cornea, the transparent window of the human eye. Patients who carry the mutation also develop corneal opacities that compromise vision. The groundbreaking study that broadens the spectrum of cryopyrin-associated periodic syndromes was published online February 10, 2018 in the American Journal of Ophthalmology.

In 1964, Dr. Olavi Valle, a Finnish ophthalmologist, reported a family in which several members shared a problem: their eye became irritated for a few days several times a year, and they experienced blurry vision for a few weeks after each attack. The attacks begin when they are teenagers and continue through middle age. Eventually patients develop permanent corneal opacities. Dr. Valle named the disease keratitis fugax hereditaria, which is Latin for a transient inherited corneal inflammation. More than two decades later, a second Finnish family emerged, and it was found that the inflammation primarily affected the corneal endothelium, a cell layer that covers the back of the cornea, an observation that identified the disease as a keratoendotheliitis.

Dr. Turunen recruited thirty affected patients from seven families and four additional ones who appeared to have the disease but could not name any affected relative. After first sequencing the protein coding regions of all chromosomes from ten unrelated patients, he found that all shared an identical point mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) gene that codes cryopyrin.

Cryopyrin mutations were known to cause rare periodic autoinflammatory syndromes, diseases in which the white blood cells of the human body become activated without any outside stimulus. Corneal opacities have been reported in some patients with the previously known cryopyrin-associated syndromes. Thus, the team became confident that the mutation discovered indeed was disease causing. The team subsequently confirmed by direct sequencing that the same mutation was present in all other affected family members and absent from those oneswith healthy eyes.

Keratoendotheliitis fugax hereditaria is the fourth cryopyrin-associated periodic syndrome. The other three – familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, articular syndrome (also known as neonatal-onset multisystem inflammatory disease) – affect multiple organs and can be debiliating. Like keratoendotheliitis fugax hereditaria, they emerge during childhood, but their hallmarks are episodic fevers, skin rashes, and inflammation of the joints, gastrointestinal tract and the nervous system rather than ocular irritation.

So far, keratoendotheliitis fugax hereditaria has only been reported in Finland. Because the symptoms of keratoendotheliitis fugax hereditaria are short lived and unspecific, a family history is seldom volunteered by the patients and also unlikely to be queried by an ophthalmologist unaware of its existence, as almost all ophthalmologists outside Finland have been. Propably patients begin to emerge more widely now that the diagnosis can be made by genetic testing. The team was lucky to be informed early of the existence of this intriguing corneal disease, thanks to the astute observations by Dr. Valle.

At the moment, no specific treatment for keratoendotheliitis fugax hereditaria is known. The other cryopyrin-associated periodic syndromes have responded to drugs that target interleukin-1β, a downstream mediator of the cryopyrin cascade.


Original Study:
Turunen JA, Wedenoja J, Repo P, Järvinen R-S, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki A-E, Majander A, Tero T. Kivelä TT. Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene. Am J Ophthalmol 188: 41-50, 2018