Autosomal recessive cornea plana. A clinical and genetic study of 78 cases in Finland.

PURPOSE: To review the literature of autosomal recessive cornea plana (RCP) and to perform a clinical and genetic study on this disorder in Finland. The 78 Finnish RCP patients represent the majority of RCP cases worldwide; outside Finland only 35 cases have been reported. METHODS: Families with RCP, particularly in northern Finland, have been followed up by the senior author since the 1950s and extensive genealogical studies have been made. RESULTS: The most typical symptoms are greatly reduced corneal refraction, 25-35 dioptres, causing strong hyperopia, slight microcornea, an extended limbus zone, a central, deep corneal opacity and a marked arcus senilis, seen even before the age of 20. We present a pedigree comprising 33 affected persons with cornea plana. We have mapped the two genes for the dominantly and the recessively inherited type of cornea plana to the same region on the long arm of chromosome 12, (12q21). CONCLUSIONS: In northern Finland RCP has a higher frequency than elsewhere, probably as a result of a strong founder effect in the population that arrived in these regions approx. 400 years ago. The strong accumulation of this rare disease in these isolated areas and the strong genealogical connections between different families with RCP, suggest that probably all the Finnish RCP cases are caused by the same mutation.

The genetics of cornea plana congenita.

Cornea plana congenita is believed to occur in a mild autosomal dominant (CNA1) and a more severe autosomal recessive (CNA2) form. We recently assigned a CNA2 locus to a region on chromosome 12 by linkage analysis. In this study we compared these traits clinically and genetically. Using the horizontal corneal refraction value in diopters (D) as a parameter, a control population (n = 473) had a mean value of 43 center dot 4 (SD 1 center dot 5 D) for men and 43 center dot 7 (SD 1 center dot 6 D) for women, whereas in 51 subjects affected with CNA2 the mean value was 29 center dot 9 (SD 5 center dot 2 D) and in five subjects affected with CNA1 the mean value was 37 center dot 8 (SD 1 center dot 6 D). By linkage analysis in two CNA1 families the CNA2 locus could be conclusively excluded. These data suggest that at least two forms of hereditary cornea plana exist which are both clinically and genetically distinct.

Linkage disequilibrium mapping of the cornea plana congenita gene CNA2.

We recently assigned a gene for autosomal recessive cornea plana congenita (CNA2; MIM No. 217300) by linkage analysis to the approximately 3-cM interval between markers D12S82 and D12S327. Here, we extended these studies by exploiting the haplotype and linkage disequilibrium information that can be derived from the genetically isolated Finnish population and its subpopulations. By testing 32 independent families with 10 polymorphic markers in the CNA2 interval, strong allelic association between CNA2 and a set of markers with a peak at marker D12S351 was detected. Based on linkage disequilibrium analysis, the critical region for CNA2 could be narrowed to only 0.04-0.3 cM from marker D12S351, thus defining a critical interval 0.08-0.60 cM in length. These results provide a basis for highly focused positional cloning of CNA2.

Granular corneal dystrophy with late manifestation.

Ninety-two cases of granular corneal dystrophy, most of them belonging to 5 pedigrees are described. The age of manifestation in this Finnish type of granular dystrophy is first in the end of the second decade, and visual acuity is in mean normal through the whole life. An autopsy study showed no changes outside cornea elsewhere in the eyeball. In one family with granular dystrophy, another type of dystrophy, hereditary fleck dystrophy of the cornea, was accidentally found.