Corneal Dystrophy, Meesmann

A number sign (#) is used with this entry because of evidence that Meesmann corneal dystrophy is caused by heterozygous mutation in the KRT12 gene (601687) on chromosome 17q21 or in the KRT3 gene (148043) on chromosome 12q13.

Description

Meesmann corneal dystrophy is a dominantly inherited disorder characterized by fragility of the anterior corneal epithelium and intraepithelial microcyst formation. Although the disease is generally mild and affected individuals are often asymptomatic, some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity (summary by Szaflik et al., 2008).

Clinical Features

Meesmann corneal epithelial dystrophy was originally described in Germany by Meesmann and Wilke (1939) and later documented by Stocker and Holt (1954, 1955) in descendants of German immigrants in the US. The condition usually appears in the first year or two of life, commencing with signs of irritation. The corneal changes, seen only with magnification, consist of myriads of fine punctate opacities in the epithelium and occasionally in Bowman membrane. Vision is only rarely impaired to a serious degree.

Behnke and Thiel (1965) demonstrated that all cases in Schleswig-Holstein were members of one kindred traced back to 1620. In the 4 living generations, 120 cases were demonstrated. Progression did not occur.

Alkemade and Van Balen (1966) observed 10 affected persons in 1 family. None had ocular complaints. Light microscopy shows a thickened basement membrane and electron microscopy shows a peculiar intracytoplasmic substance. Microcysts are filled with debris.

Badr et al. (1998) described the disorder in a Saudi Arabian family. The disorder was identified in 7 individuals, all but 1 of whom were 17 years of age or older. The findings were considered consistent with autosomal dominant inheritance with probable incomplete penetrance or delayed onset of phenotypic expression.

Patients with Meesmann corneal dystrophy are intolerant of contact lenses, as these devices directly traumatize the corneal epithelium (Irvine et al., 1997).

Liao et al. (2011) reported an extended, multigenerational British family with a severe form of autosomal dominant MECD. Affected persons tended to have recurrent corneal erosions with scarring leading to pain and reduced visual acuity. Slit-lamp photography revealed multiple microcysts in the anterior epithelium and also uneven corneal topography secondary to damage and scarring of the underlying basement membrane and anterior stroma. Several affected individuals in the family had been treated with corneal grafting, which is uncommon in MECD.

Chen et al. (2015) described 2 patients with Meesmann corneal dystrophy. The first patient was a 60-year-old man who had been symptomatic since age 2 years. He reported episodes of foreign body sensation, tearing, stinging, photophobia, and decreased visual acuity approximately every 6 months. Corneal epithelial debridement had brought relief of symptoms for up to 1 year. His corrected distance acuity was 20/20 in each eye and slit-lamp examination revealed bilateral, diffusely distributed, fine, clear epithelial microcysts. Fluorescein staining of the cornea showed diffuse stippling. The second patient was an 8-year-old boy who had episodes of photophobia since age 1 year. His parents reported a negative family history of MECD or corneal transplantation. The boy's uncorrected visual acuity was 20/200-1 OD (pinhole 20/80) and 20/80 OS (pinhole no improvement). Slit-lamp examination revealed diffuse, bilateral punctate gray-white epithelial opacities. In the superior and inferior corneal quadrants, the epithelial opacities appeared in parallel lines that stained with fluorescein and extended to the limbus.

Inheritance

Meesmann and Wilke (1939) studied 3 families with dominant inheritance of MECD and Stocker and Holt (1954, 1955) studied a family with affected members in possibly 8 generations (4 generations were examined).

Mapping

The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins KRT3 and KRT12. Because Meesmann corneal dystrophy causes fragility of the anterior corneal epithelium, where KRT3 and KRT12 are specifically expressed, Irvine et al. (1997) postulated that dominant-negative mutations in these keratins might be the cause of the disorder. In Meesmann's original German kindred, they obtained linkage to the KRT12 locus on 17q21 and found cosegregation with the KRT12 locus also in a pedigree in Northern Ireland. Linkage studies in a second pedigree in Northern Ireland showed cosegregation with the KRT3 locus on 12q13.

Molecular Genetics

In affected members of the original German kindred reported by Meesmann and Wilke (1939), Irvine et al. (1997) identified heterozygosity for a mutation in the KRT12 gene (601687.0001).

In affected members of pedigrees in Northern Ireland with MECD, Irvine et al. (1997) identified heterozygosity for mutations in the KRT3 (148043.0001) and KRT12 (601687.0002) genes. The mutations were not found in 100 normal unrelated chromosomes.

In all affected members of an extended, multigenerational British family with a severe form of autosomal dominant MECD, Liao et al. (2011) identified a heterozygous leu132-to-pro (L132P; 601687.0008) mutation in the KRT12 gene. The mutation was not found in 50 control individuals. Functional analyses showed that the L132P mutation was significantly more disruptive than the most common KRT12 mutation, arg135 to thr (R135T; 601687.0001), and resulted in greater keratin aggregate formation.