Hereditary keratoendotheliitis fugax is an autosomal dominant autoinflammatory disease caused by a missense mutation (c.61G>C) in the NLRP3 gene 1). It is characterized by recurrent episodes of unilateral pain, corneal edema, conjunctival injection, and vision loss.
Turunen et al. (2018) performed genetic and clinical analysis of 34 Finnish patients and reported unilateral attacks 1–6 times per year (median 2.5), median age at onset 11 years (range 5–28), duration 1–2 days, and attenuation in middle age 1). Classically considered more common in Finnish populations, but recent reports have described cases in non-Finnish European populations and North America 2). The frequency of the associated gene mutation is approximately 0.02% in Finns and 0.01% in other Europeans 1).
Hereditary keratoendotheliitis fugax follows an autosomal dominant inheritance pattern. If one parent carries the gene mutation, the child has a 50% chance of inheriting it. In cases with a positive family history, clinical diagnosis is often possible based on typical symptoms. In sporadic cases without family history, genetic testing is useful for diagnosis.
Attacks may begin with neck stiffness or a foreign body sensation. They rapidly progress to severe eye pain and redness with visual impairment. Tearing and ipsilateral nasal congestion may also occur. After pain subsides, visual acuity gradually recovers as corneal edema and opacity resolve.
Findings During Acute Attack
Conjunctival injection: Marked redness during attacks.
Corneal edema: Corneal thickness increases by 5–14%. Edematous opacity of the corneal stroma is often observed centrally.
Pseudo-guttata: A finding due to edematous endothelial cells, which disappears after the attack subsides, distinguishing it from true guttata in Fuchs endothelial dystrophy.
Keratic precipitates (KP): May be present.
Interictal Findings
Usually asymptomatic: The eye is quiet between attacks.
Corneal scarring: In adults, residual scarring from multiple attacks may be present. Cumulative attacks can cause permanent corneal opacity and vision loss.
Specular microscopic changes: Polymorphism and intracellular dark spots may persist between attacks and can aid diagnosis.
This disease is caused by a missense mutation (c.61G>C) in the NLRP3 gene (also known as CIAS1), resulting in an amino acid substitution in the NLRP3 protein (cryopyrin), altering the protein’s charge and potentially causing misfolding.
No established risk factors trigger inflammatory attacks. Patient reports suggest that mild viral illness, cold exposure, or relief from mental or physical stress may be associated. Some families report comorbid collagen-related conditions.
With typical symptoms and positive family history, clinical diagnosis is possible and genetic testing is not mandatory. Genetic testing is useful for sporadic cases without family history or when diagnosis is unclear.
| Test | Finding |
|---|---|
| Specular microscope | Pseudo-guttata (dark non-reflective areas) |
| Confocal microscope | Abnormalities between endothelial cells |
| Corneal pachymetry | 5–14% increase (during attack) |
On specular microscopy and confocal microscopy, pseudo-guttata are observed as dark non-reflective areas among normal hexagonal endothelial cells during an attack. Polymorphism and intracellular dark spots may persist during the interictal period 3).
Differential diagnoses include anterior uveitis, infectious/autoimmune/drug-induced corneal endotheliitis, iridocorneal endothelial syndrome (ICE syndrome), Chandler syndrome, Brown-McLean syndrome, and posterior polymorphous corneal dystrophy (PPCD). If examined during the resolution phase of an acute attack, it may be misdiagnosed as anterior uveitis.
Treatment recommendations are based on case reports. Supportive therapy with topical steroid eye drops is considered most effective, but not all patients respond. No standard protocol for the frequency or dosage of steroid eye drops has been established.
Oral antihistamines have been reported to be beneficial for symptoms through their sedative effect. Topical or oral NSAIDs may be used for pain.
Treatment should be initiated immediately upon noticing signs of an attack. Early intervention is expected to reduce the attack and promote recovery.
Currently, there is no established method to reliably prevent attacks. Cold exposure and stress have been reported as possible triggers, and avoiding them may be beneficial. Starting treatment such as steroid eye drops as soon as signs of an attack are felt is expected to prevent the attack from becoming severe. In the future, drugs targeting the NLRP3 inflammasome pathway may be effective in preventing attacks.
The NLRP3 protein is a key component of the NLRP3 inflammasome. The inflammasome is a multi-protein complex that induces inflammatory changes upon assembly and activation. Mutations in this disease are thought to cause abnormalities in protein folding mechanisms, leading to inappropriate activation of the inflammasome.
Mutations in the NLRP3 gene can cause a group of autoinflammatory diseases collectively called cryopyrin-associated periodic syndromes (CAPS). CAPS includes syndromes that show ocular symptoms overlapping with this disease. Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease are also associated with inflammasome activation.
Specific NLRP3 mutations in hereditary transient corneal endothelialitis cause unnecessary activation of the inflammasome, leading to clinically significant inflammatory attacks.
Corneal edema is probably secondary to an angiogenic process. Edema occurs in the corneal stroma, and endothelial cells become edematous, observed as pseudoguttata. Unlike true guttata (e.g., Fuchs endothelial dystrophy), pseudoguttata disappear after the episode resolves.
Research on drugs targeting the NLRP3 inflammasome pathway is ongoing. Many of these drugs have shown anti-inflammatory effects in ocular cell lines and may be useful in reducing the frequency and severity of attacks and suppressing corneal scarring. However, clinical use of inflammasome-targeting drugs for this disease has not yet been reported.
This disease has been reported mainly in Finnish populations, but in recent years, reports in non-Finnish European populations have increased. With the spread of genetic testing, case detection in a wider range of populations is expected.
