Meesmann corneal dystrophy (MECD) is an autosomal dominant corneal dystrophy characterized by numerous microcysts in the corneal epithelium. In 1938, German ophthalmologist Alois Meesmann, together with F. Wilke, first described its histopathological features. It is also called juvenile hereditary epithelial dystrophy.
The causative genes are KRT3 (12q13.13) and KRT12 (17q11-q12), which encode corneal epithelial keratins. Mutations in KRT3 cause type 1 (MECD1), and mutations in KRT12 cause type 2 (MECD2). To date, 6 mutations in KRT3 and 25 mutations in KRT12 have been identified 1).
In the IC3D classification, it is classified as an epithelial corneal dystrophy with autosomal dominant (AD) inheritance. Incomplete penetrance may occur.
Most patients are asymptomatic or have only mild symptoms, and the impact on vision is usually minimal. However, some patients may experience vision loss due to recurrent corneal erosions or subepithelial scarring. Symptoms tend to progress more in older patients.
Epithelial cysts appear from 1 to 2 years of age, but most patients remain asymptomatic until late adolescence or adulthood. Subjective symptoms include foreign body sensation, photophobia, tearing, and temporary blurred vision.
When epithelial cells containing cysts reach the outermost layer of the ocular surface, epithelial damage occurs, causing irritation symptoms. Recurrent corneal erosion may occur, and pain is particularly common upon waking.
Under slit-lamp microscopy, microcysts of various sizes are observed as fine opacities within the corneal epithelium. They appear as small punctate white opacities, and the lesions are more prominent in the central cornea compared to the periphery. Density is higher in the interpalpebral zone.
Slit-Lamp Microscopy Findings
Direct illumination: Observed as numerous small gray punctate opacities.
Indirect illumination: Depicted as a collection of fine opacities by light reflected from the iris.
Retroillumination: Intraepithelial microcysts are observed like transparent dew droplets with refractive properties. This is the most sensitive observation method.
Scleral scatter method: Allows wide-area evaluation of the distribution of corneal epithelial bullae.
Advanced Imaging Diagnostics
In vivo confocal microscopy (IVCM): Low-reflectivity round microcysts of 12–32 μm are observed within the epithelium 1).
Anterior segment optical coherence tomography (AS-OCT) epithelial thickness map: Shows epithelial thickening (52–68 μm) in the interpalpebral zone and thinning in the superior and inferior areas 1).
Changes in Bowman’s layer and tortuosity of subepithelial nerves are also observed 1).
The number of microcysts increases with growth. Cytology shows positive peripheral iris adhesion staining, confirming mucopolysaccharide deposition. The epithelium adjacent to the cysts remains clear.
MECD is caused by heterozygous mutations in the KRT3 or KRT12 genes. These genes encode keratin 3 (K3) and keratin 12 (K12), respectively. K3 and K12 are subunits of intermediate filaments specifically expressed in the corneal epithelium, associating as heteropolymers to form the structural framework of the epithelium.
Mutant keratin lacks normal strength, leading to fragility of the corneal epithelium. Aggregates of abnormal keratin protein and cellular debris accumulate within cysts, and when the cysts rupture, they cause ocular irritation symptoms.
A novel KRT3 mutation c.1527G>T (p.Glu509Asp) has been identified in a Spanish family 1). This mutation is located at the highly conserved position 509 of the helix termination motif of keratin K3, affecting the same amino acid position as a known mutation (p.E509K) reported in an Irish family 1).
In genetic counseling, it is explained that because this is an autosomal dominant disorder, there is a 50% chance of transmitting the mutation to each child of an affected individual. However, phenotypic variability is large, and the severity of symptoms may differ even within the same family 1).
Genetic testing can provide a definitive diagnosis and is useful for differentiating from other corneal dystrophies and for genetic counseling. Since April 2020, genetic testing for corneal dystrophies has been covered by insurance in Japan. Identifying the mutation is also important for the future development of gene therapy, so testing is recommended.
The diagnosis of MECD is primarily based on slit-lamp microscopy. If bilateral microcysts within the corneal epithelium are observed, the disease is strongly suspected. Taking a family history is important.
Retroillumination is the most sensitive observation method, where microcysts appear as refractive, transparent water droplets. Under direct illumination, they appear as gray punctate opacities, and under indirect illumination, as a collection of fine opacities.
IVCM (in vivo confocal microscopy) allows quantitative evaluation of low-reflective round microcysts within the epithelium. Microcyst diameter is reported to be 12–32 μm, and density 38–64 cysts/mm² 1). Highly reflective material (cellular debris), changes in Bowman’s layer, and activated keratocytes are also observed 1).
AS-OCT epithelial thickness mapping is useful as a non-invasive quantitative assessment method. Epithelial thickening is observed in the interpalpebral zone, while thinning patterns are seen in the superior and inferior areas 1).
For definitive diagnosis, mutation analysis of the KRT3/KRT12 genes is recommended.
| Differential Disease | Distinguishing Features |
|---|---|
| Epithelial basement membrane dystrophy | Map-dot-fingerprint epithelial findings |
| Reis-Bücklers dystrophy | Primarily Bowman layer changes |
| Lisch epithelial corneal dystrophy | X-linked dominant inheritance |
| Microcysts after continuous soft CL wear | History of CL wear; may be unilateral |
Treatment for MECD is mainly symptomatic. Many patients have mild symptoms and do not require active treatment.
Conservative treatment includes symptomatic therapy with corneal protective eye drops and artificial tears. For severe irritation, therapeutic contact lenses may be used. Ophthalmic ointment at bedtime is useful for epithelial protection and prevention of recurrent corneal erosion.
Recurrent corneal erosion is treated stepwise. First, continue bedtime ointment and artificial tears upon waking. If no improvement, try continuous wear of therapeutic soft contact lenses.
Surgical treatment is indicated for cases resistant to conservative therapy. PTK (phototherapeutic keratectomy) is currently the recommended first-line surgical treatment, achieving removal of superficial corneal opacities, smoothing of the corneal surface, and promotion of epithelial adhesion. However, recurrence of dystrophy is common after surgery.
In severe cases, lamellar or full-thickness corneal transplantation may be necessary, but dystrophy can recur in the graft, so it is desirable to postpone as much as possible.
Recently, autologous plasma-derived growth factor eye drops (is-ePRGF) have been reported at the case report level to promote corneal epithelial repair 1).
Currently, no curative treatment has been established. However, at the research stage, gene therapies targeting mutant keratin genes, such as siRNA (small interfering RNA) and CRISPR/Cas9, have shown promising results in vitro and in animal studies. Further research is needed for clinical application, but they are expected as future treatment options.
The essence of MECD pathology is epithelial fragility due to structural abnormalities of corneal epithelium-specific keratins (K3/K12).
K3 and K12 form intermediate filaments as heteropolymers, maintaining the structural framework of the corneal epithelium. Mutations in KRT3 or KRT12 genes produce abnormal keratins, impairing filament formation. Abnormal assembly of intermediate filaments leads to mechanical fragility of epithelial cells and formation of intracellular cysts.
Histopathologically, the corneal epithelium becomes uneven in thickness, and microcysts are distributed at various levels within the epithelium. The cysts contain degenerated epithelial cells and cellular debris, and show positive staining for periodic acid–Schiff (indicating mucopolysaccharide deposits). Electron microscopy reveals electron-dense fibrogranular material called “peculiar substance” within epithelial cells.
The epithelial basement membrane is coarsely and irregularly thickened and multilayered. In contrast, Bowman’s layer and the corneal stroma are usually not affected. However, recent IVCM findings suggest that chronic epithelial inflammation may affect deeper layers, including changes in Bowman’s layer and activation of keratocytes 1).
When epithelial cells containing cysts reach the outermost layer of the ocular surface, epithelial damage occurs, causing recurrent corneal erosions. Spontaneous rupture of cysts forms small epithelial defects on the corneal surface.
Identification of novel gene mutations for MECD is progressing worldwide. A novel pathogenic variant c.1527G>T (p.Glu509Asp) in the KRT3 gene was reported in a Spanish family, further expanding the genetic diversity of the disease 1). Identification of mutations not only enables accurate diagnosis but also provides a basis for future gene therapy strategies.
Epithelial thickness mapping using AS-OCT is attracting attention as a new tool for quantitative evaluation of epithelial changes in MECD 1). The pattern of epithelial thickening in the interpalpebral zone may be useful for monitoring disease progression and evaluating treatment efficacy.
Allele-specific siRNA that suppresses the expression of mutant K12 has shown promising results in human MECD cell lines 1). In vivo suppression of mutant K12 expression using CRISPR/Cas9 has also been experimentally successful 1). However, further validation of efficacy and safety is required for clinical application of these therapies.
- De Faria A, Charoenrook V, Larena R, et al. A novel pathogenic variant in the KRT3 gene in a family with Meesmann corneal dystrophy. J Clin Med. 2025;14:851.
