Keratoconus 5

Description

Keratoconus is a noninflammatory progressive corneal thinning disorder resulting in mixed myopia and irregular astigmatism. Characteristic features include stromal thinning, Vogt striae, Fleisher ring, and scissoring of the retinoscopic reflex with a fully dilated pupil. Symptoms usually develop in the second decade and are likely to progress in the third decade, whereas progression slows after age 30 years. The progression of keratoconus may result in severe visual impairment and some affected individuals require cornea transplantation. The prevalence of keratoconus is about 1 in 2,000 in Caucasian populations, and is a leading cause for cornea transplantation in developed countries (summary by Tang et al., 2005).

For a discussion of genetic heterogeneity of keratoconus, see KTCN1 (148300).

Clinical Features

Rabinowitz et al. (1992) studied a family segregating autosomal dominant keratoconus over 3 generations. Of 8 affected individuals, 2 had undergone penetrating keratoplasty; the histopathologic findings were consistent with keratoconus, including fragmentation of the Bowman membrane, stromal thinning, subepithelial fibrosis, and an iron line when stained with Prussian blue. In 4 of the 6 remaining patients, biomicroscopy revealed a cone and a Fleisher ring, and topographic maps generated using high-resolution computer-assisted videophotokeratoscopy demonstrated central steepening consistent with a nipple-type cone in all 6, including 2 family members who had normal slit-lamp findings and no change detected on corneoscopy.

Mapping

Tang et al. (2005) performed a 2-stage genomewide scan involving 27 members over 4 generations from the family with keratoconus originally reported by Rabinowitz et al. (1992). The initial scan excluded previously reported keratoconus loci and yielded suggestive linkage on chromosome 5q14.1-q21.3 with a maximum lod score of 3.48 (penetrance = 0.5). Fine mapping narrowed the region to an interval with a lod score of 3.53, and haplotype analysis further narrowed the interval to a 6-cM (8.2-Mb) region between markers D5S2499 and D5S495.

Exclusion Studies

In a 3-generation family segregating autosomal dominant keratoconus, Rabinowitz et al. (1992) selected COL6A1 (120220) as a candidate gene and by linkage analysis excluded this specific gene as well as the most telomeric region of chromosome 21 as the site of the mutation.