Cornea Plana 2, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive cornea plana-2 (CNA2) is caused by homozygous or compound heterozygous mutation in the KERA gene (603288) on chromosome 12q21.

Description

Cornea plana is clinically characterized by reduced corneal curvature leading in most cases to hyperopia, hazy corneal limbus, and arcus lipoides at an early age. CNA2 is a severe form of the disorder, which is frequently associated with additional ocular manifestations (summary by Tahvanainen et al., 1996).

For discussion of genetic heterogeneity of CNA, see CNA1 (121400).

Clinical Features

Eriksson et al. (1973) pointed out that the autosomal recessive form of CNA has more severe manifestations than the dominant form (CNA1; 121400) in terms of reduced visual activity, extreme hyperopia (usually +10 diopters (D) or more), hazy corneal limbus, opacities in the corneal parenchyma, and marked arcus senilis (often detected at an early age).

Tahvanainen et al. (1996) noted that a round and opaque thickening, approximately 5 mm wide and located centrally, occurs in most cases of the recessive form but never in the dominant form. Additional anomalies such as malformations of the iris, a slit-like pupil, and adhesions between the iris and cornea are more prevalent in the recessive form.

Tahvanainen et al. (1996) compared dominant and recessive forms of cornea plana in the Finnish population by measuring horizontal corneal refraction values in diopters. A control population of 473 individuals had a mean value of 43.4 (SD = 1.5 D) for men and 43.7 (SD = 1.6 D) for women, whereas in 51 subjects affected with CNA2, the mean value was 29.9 (SD = 5.1 D), and in 5 subjects affected with CNA1, the mean value was 37.8 (SD = 1.6 D).

Al Hazimi and Khan (2015) noted that flat keratometry contributes to the hyperopia and associated refractive accommodative esotropia in recessive CNA. They compared the axial length of the right eye of 8 children, aged 10 to 12 years, from 7 families with CNA2 with the axial length of 50 control right eyes from children aged 4 to 12 years. Axial lengths were longer in the affected eyes despite greater hyperopia, providing evidence that axial length is not shortened by the disease.

Inheritance

Felix (1925) described 2 brothers with CNA from an uncle-niece mating. Forsius (1961) reported a study in Finland in which 19 cases were found in 9 families in patterns consistent with autosomal recessive inheritance.

Population Genetics

Cornea plana has a high prevalence in Finland. An extensive pedigree with 27 affected persons in 13 sibships was presented by Forsius et al. (1980).

Mapping

Tahvanainen et al. (1995) mapped the CNA2 locus to chromosome 12 by linkage to an interval of approximately 10 cM between markers D12S82 and D12S327. They tentatively assigned the locus to 12q21. Tahvanainen et al. (1995) extended the mapping studies by exploiting the haplotype and linkage disequilibrium information that could be derived from the Finnish population. By testing 32 independent families with 10 polymorphic markers in the CNA2 interval, they demonstrated strong allelic association between CNA2 and a set of markers with a peak at marker D12S351. The critical region for CNA2 could be narrowed to 0.04-0.3 cM from marker D12S351, thus defining a critical interval of 0.08-0.60 cM.

Although the 12q region was excluded as the site of the mutation in 2 Finnish families with autosomal dominant cornea plana (CNA1) by Tahvanainen et al. (1996), Tahvanainen et al. (1996) described a Cuban pedigree in which dominantly inherited cornea plana was linked to the same region of 12q in which the recessive form is located.

Molecular Genetics

Pellegata et al. (2000) cloned the human KERA gene as a candidate gene for CNA2 and identified mutations in 47 CNA2 patients. Forty-six Finnish patients were homozygous for a founder missense mutation leading to the substitution of a highly conserved amino acid (603288.0001), and 1 Chinese American patient was homozygous for a mutation leading to a premature stop codon that truncates the KERA protein (603288.0002).

In a consanguineous pedigree in which corneal plana cosegregated with microphthalmia, Lehmann et al. (2001) identified a homozygous thr215-to-lys substitution (603288.0003) at the start of a highly conserved leucine-rich repeat motif in keratocan. Structural modeling predicted that this mutation altered the length and position of 1 of these motifs on the beta-sheet array of keratocan. The authors concluded that normal corneal function is dependent on the regular spacing of collagen fibrils, and the predicted alteration of the tertiary structure of KERA is the probable mechanism of the cornea plana phenotype.

Khan et al. (2004) described the ophthalmic phenotype of a family with autosomal recessive cornea plana due to a novel KERA mutation. Five of 6 sibs were affected and had small, flat corneas with arcus juvenilis and variable degrees of corneal clouding, variable anterior chamber depth, and severe hyperopia due to decreased axial length. Genetic testing revealed a novel homozygous nonsense mutation in exon 3 (603288.0004) of the keratocan gene in affected individuals. The clinically unaffected parents were confirmed as carriers; the clinically unaffected sib had no KERA mutation. The authors stated that this novel point mutation in the KERA gene was the fourth described to that time.