Corneal Dystrophy, Posterior Polymorphous, 4

A number sign (#) is used with this entry because of evidence that posterior polymorphous corneal dystrophy-4 (PPCD4) is caused by heterozygous mutation in the GRHL2 gene (608576) on chromosome 8q22.

Description

PPCD4 is characterized by an irregular posterior corneal surface with occasional opacities of variable size and shape. There is inter- and intrafamilial as well as intraindividual variability. Symptoms can include blurred vision due to corneal edema, reduced visual acuity, secondary glaucoma, and corectopia; some affected individuals are asymptomatic. Rare patients have undergone enucleation for painful eye (Liskova et al., 2018).

For a discussion of genetic heterogeneity of PPCD, see 122000.

Clinical Features

Liskova et al. (2018) described 4 Czech families (C15, C23, C26, and C33) and 2 British families (B4 and B5) with PPCD and mutations in the GRLH2 gene (see MOLECULAR GENETICS), noting that both inter- and intrafamilial variability was present. Most of the 27 affected individuals in the Czech families, who all harbored the same mutation, presented typical corneal signs of PPCD, with an irregular posterior corneal surface and occasional opacities of variable size and shape, clinically described as bands or geographic or vesicular lesions. Other features included blurred vision due to corneal edema, nonprogressive reduced visual acuity, secondary glaucoma, and corectopia. Two patients underwent enucleation due to painful blind eye, and 9 affected individuals were asymptomatic. Specular microscopy and spectral domain optical coherence tomography documented reduced endothelial cell density, with both normal and abnormal morphology, as well as irregularities of the posterior corneal surface. Examination by light microscopy of a full-thickness corneal sample revealed an edematous cornea with variation in endothelial cell size and shape, and focal multilayering of the cells. In British family B5, the proband had markedly asymmetric disease, with diffuse geographic endothelial changes restricted to the left eye, which also exhibited amblyopia and decompensated exotropia, and showed markedly reduced endothelial cell density compared to her right eye. Her affected brother had low endothelial cell counts bilaterally, but no changes in cell morphology, and exhibited numerous Hassal-Henle bodies in the peripheral cornea. None of the PPCD-affected individuals reported hearing loss or other features of ectodermal dysplasia syndrome (ECTDS; 616029).

Mapping

Liskova et al. (2018) genotyped 9 affected and 7 unaffected members of a large Czech family (C15) segregating autosomal dominant PPCD, and identified a single locus on chromosome 8 (chr8:100,821,039-119,725,923; GRCh38), spanning 8q22.3-q24.12, with a maximum lod score of 4.38. Recombination events refined the PPCD4 locus to chr8:101,411,163-109,214,442.

Molecular Genetics

In a large Czech family (C15) with PPCD mapping to chromosome 8q22.3-q24.12, Liskova et al. (2018) performed whole-genome sequencing and identified heterozygosity for a mutation at a bivalent histone modification site within intron 1 of the GRHL2 gene (608576.0005) that segregated with disease. Targeted screening of the GRHL2 regulatory region in unsolved PPCD cases identified 3 more Czech families with the same mutation, 2 of which (C23 and C26) shared a haplotype with family C15, suggesting that the variant arose from a common ancestor. In the fourth family (C33), the variant was shown to have arisen de novo. Screening the GRHL2 region in 19 unsolved PPCD probands identified 2 different heterozygous 1-bp deletions in intron 1 (see, e.g., 608576.0006) in 2 unrelated British families, B4 and B5. The mutations segregated with disease and were not found in public variant databases. Functional analysis indicated that the mutants significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRLH2.

Pathogenesis

Liskova et al. (2018) stated that PPCD-associated mutations drive corneal endothelial cells to transition to epithelial-like cells via the mesenchymal-to-epithelial transition (MET) pathway, presenting as stratified and irregularly shaped cells. The authors concluded that MET is a convergent pathogenetic mechanism resulting in intermediate cell states and dysfunction of the endothelial barrier and disease in PPCD.