Corneal Dystrophy, Congenital Stromal

A number sign (#) is used with this entry because of evidence that congenital stromal corneal dystrophy (CSCD) is caused by heterozygous mutation in the gene encoding decorin (DCN; 125255) on chromosome 12q21.

Description

Congenital stromal corneal dystrophy (CSCD) is a rare autosomal dominant eye disease characterized by diffuse bilateral corneal clouding with flake-like whitish opacities throughout the stroma. These small flakes and spots are present at or shortly after birth and are thought to become more numerous with age. Some affected individuals may have strabismus or nystagmus. Normal corneal thickness, horizontal diameter, and endothelial function distinguish the condition from congenital corneal opacifications such as congenital hereditary endothelial dystrophy (see 121700), posterior polymorphous dystrophy (see 122000), and congenital glaucoma (see 137760). Most individuals undergo a penetrating keratoplasty in late adolescence or in early adulthood with good results (summary by Kim et al., 2011 and Jing et al., 2014).

Clinical Features

Odland (1968) described a Norwegian family with autosomal dominant inheritance of congenital corneal opacities that consisted of a large number of flakes and spots throughout all layers of the stroma. In 4 generations there were 11 affected members. Opacities increased with age.

Bredrup et al. (2005) restudied the family of Odland (1968) into the fifth generation. The opacities, which were equally pronounced in all areas of the cornea, prohibited detailed clinical study of the endothelium. Fluorescein staining revealed no signs of vascularization. Corneal sensitivity was normal or slightly reduced. The patients did not have other ocular symptoms, especially corneal erosions or photophobia. Four of 11 affected family members had strabismus (3 esotropia, 1 exotropia). Three eyes from 2 individuals had primary open-angle glaucoma No systemic abnormalities or malformations were recorded. Specifically, there were no recognized problems related to skin, teeth, joints, or bones.

Turpin et al. (1939) and Desvignes and Vigo (1955) studied the same French family in which 13 were affected in 3 consecutive generations with 5 instances of male-to-male transmission. Witschel et al. (1978) reported a branch of this family and another unrelated pedigree. Pouliquen et al. (1979) included the family of Turpin et al. (1939) in their report. Van Ginderdeuren et al. (2002) reported an affected mother and son. Bredrup et al. (2005) summarized the clinical findings in these and their own studies.

Kim et al. (2011) described a 29-year-old Korean woman and her 1-year-old daughter who both had bilateral diffuse corneal opacity from birth, with only slightly increased central corneal thickness and no photophobia, nystagmus, or strabismus. Electron microscopy of surgically excised stroma showed features similar to those of previous reports, with normal lamellae composed of collagen but separated by abnormal fibers randomly arranged in electron-lucent layers. The appearance of the corneal epithelium and the basement membrane was within normal limits, and normal keratocytes without inclusions were also seen.

Jing et al. (2014) studied a 3-generation Chinese family in which 5 members had CSCD. Confocal microscopy and optical coherence tomography (OCT) analysis demonstrated that corneal opacities develop throughout the stromal layers, with more opacities in the anterior stroma and scattered opacities in the posterior peripheral stroma. Electron microscopic findings were similar to those of Witschel et al. (1978), with abundant irregularly arranged, slightly thinned collagen filaments between normal-appearing collagen lamellae. In electron-lucent zones, the poorly formed collagen filaments were much thinner, with a diameter about half that of normal fibrils.

Clinical Management

Odland (1968) reported that 2 of the affected individuals had undergone keratoplasty, one lamellar and the other penetrating. Both types of grafts improved the visual acuity significantly, restoring reading vision, and were clear at the time of publication.

At the time of the report of Bredrup et al. (2005), 18 eyes had been treated with penetrating keratoplasty, with 7 individuals having been treated bilaterally and the remaining 4 unilaterally. The mean age at surgery was 20 years (range, 6-44 years). Ten of 18 transplanted corneas were clear, whereas 6 showed minimal changes; 2 patients had 1 eye with moderate to severe opacities, similar to those of the remaining host cornea. Both Odland (1968) and Bredrup et al. (2005) described the histopathology of the buttons removed during keratoplasty, noting diffuse stromal edema and disorganization of the fibrillar architecture of the corneal lamellae.

Inheritance

The transmission pattern of congenital stromal corneal dystrophy in the families reported by Odland (1968) and Turpin et al. (1939) was consistent with autosomal dominant inheritance.

Mapping

Bredrup et al. (2005) performed a genomewide screening that revealed linkage to chromosome 12q22 with a maximum lod score of 4.68 at marker D12S351. High-resolution mapping subsequently narrowed the candidate region to an 8.4-Mb region between markers D12S1719 and D12S101.

Molecular Genetics

Bredrup et al. (2005) identified a heterozygous deletion of 1 bp in exon 10 of the decorin gene (125255.0001) in all affected members of the family originally described by Odland (1968). Bredrup et al. (2005) postulated that the defective interaction of mutant decorin with collagen would disturb the regularity of corneal collagen in affected heterozygotes.

In the Belgian mother and son with CSCD originally reported by van Ginderdeuren et al. (2002), Rodahl et al. (2006) identified heterozygosity for a 1-bp deletion in the DCN gene (125255.0002), causing a frameshift predicted to result in a stop codon at the same codon as the frameshift mutation (125255.0001) in the Norwegian family studied by Bredrup et al. (2005). In contrast to affected individuals in the Norwegian family, the Belgian mother and son both had severe photophobia, and the affected corneas appeared to be of normal thickness.

In a Korean mother and daughter with CSCD, Kim et al. (2011) identified heterozygosity for a 1-bp deletion in DCN (125255.0003); the mutation was not found in the mother's unaffected son.

In 5 affected members of a 3-generation Chinese family segregating autosomal dominant CSCD, Jing et al. (2014) identified heterozygosity for a 1-bp deletion in the DCN gene (125255.0004) that was not present in unaffected family members or in 50 healthy controls. Jing et al. (2014) noted that all 4 CSCD-associated frameshift mutations that had been reported cause a premature termination codon with loss of the 33 C-terminal amino acids of the decorin proteoglycan, suggesting that exon 8 is a mutational hotspot and a functionally important region of DCN.

Animal Model

Mellgren et al. (2015) found that mice with a knock-in Dcn 952delT mutation, corresponding to the human 927delT mutation in CSCD, did not show any histologic organ pathology. Their corneas were clear, and the electron-lucent deposits observed in CSCD were not present. Whereas nearly equivalent amounts of normal and truncated decorin were present in CSCD corneas, truncated decorin was hardly detectable in the mouse corneas. By immunofluorescence analysis of the corneas from 952delT homozygous mice, decorin was found only in keratocytes. Truncated decorin was retained intracellularly in cells from mouse corneal explants, whereas truncated decorin was exported into the culture medium in cells from human CSCD corneas. Immunofluorescence analysis revealed that native mouse decorin localized within the Golgi complex, whereas the truncated decorin accumulated in the endoplasmic reticulum. Mellgren et al. (2015) concluded that export of truncated decorin appeared to be a prerequisite to produce the amorphous deposits of decorin typical of CSCD and that the Dcn 952delT knock-in mice are not a suitable model for CSCD.