Keratoconus, the most common corneal dystrophy, is a bilateral, noninflammatory progressive corneal ectasia. Clinically, the cornea becomes progressively thin and conical, resulting in myopia, irregular astigmatism, and corneal scarring. The disease usually arises in the teenage years, eventually ... Keratoconus, the most common corneal dystrophy, is a bilateral, noninflammatory progressive corneal ectasia. Clinically, the cornea becomes progressively thin and conical, resulting in myopia, irregular astigmatism, and corneal scarring. The disease usually arises in the teenage years, eventually stabilizing in the third and fourth decades. The incidence of keratoconus is 1 in 2,000 in the general population; it occurs with no ethnic or gender preponderance, and causes significant visual impairment in young adults. No specific treatment exists except to replace the corneal tissue by surgery (corneal transplantation) when visual acuity can no longer be corrected by contact lenses (summary by Dash et al., 2006). Ihalainen (1986) reviewed various conditions with which keratoconus is at times associated. Keratoconus is frequent in cases of amaurosis congenita of Leber (204000). - Genetic Heterogeneity of Keratoconus Other loci for keratoconus have been mapped to chromosomes 16q22.3-q23.1 (KTCN2; 608932), 3p14-q13 (KTCN3; 608586), 2p24 (KTCN4; 609271), 5q14.1-q21.3 (KTCN5; 614622), 9q34 (KTCN6; 614623), 13q32 (KTCN7; 614629), and 14q24.3 (KTCN8; 614628).
In a study of large number of patients with keratoconus in Finland, Ihalainen (1986) found that symptoms usually began in young adults. Pregnancy seemed to precipitate keratoconus in some instances.
Nielsen et al. (2003) used gene ... In a study of large number of patients with keratoconus in Finland, Ihalainen (1986) found that symptoms usually began in young adults. Pregnancy seemed to precipitate keratoconus in some instances. Nielsen et al. (2003) used gene microarrays to investigate differential gene expression in corneal epithelium from samples with and without keratoconus. Keratoconus epithelium appeared to be characterized by massive changes of the cytoskeleton, reduced extracellular matrix remodeling, altered transmembrane signaling, and modified cell-to-cell and cell-to-matrix interactions. Validation of gene expression with dChip analysis and real-time PCR indicated Gene Chip to be a valid technique for investigation of epithelium from single dissected corneal samples. Dogru et al. (2003) reviewed the ocular surface disease in keratoconus. Keratoconus patients showed disorders of tear quality, lowered tear film breakup time (BUT), squamous metaplasia of the corneal epithelium, and goblet cell loss, all of which seemed to relate to the extent of keratoconus progression. Li et al. (2004) examined 778 patients with keratoconus and found that 116 (14.9%) had clinically unilateral keratoconus at baseline. These 116 patients were followed for a period ranging from 6 months to 8 years. Approximately 50% of clinically normal fellow eyes progressed to keratoconus within 16 years. The greatest risk was during the first 6 years. Li et al. (2004) also described quantitative indices and qualitative patterns that might predict this progression. Individuals with keratoconus are not candidates for LASIK (laser-assisted in situ keratomileusis) for correction of their myopia and/or astigmatism. Jabbur et al. (2001) described the clinical course and histopathology of an individual with suspected keratoconus who underwent bilateral simultaneous LASIK. She required penetrating keratoplasty due to progressively worsening vision from corneal ectasia after LASIK. Classically, corneal allograft rejection was thought to be a Th1-mediated phenomenon. However, Th2-mediated allograft rejection has been reported in heart and kidney transplanted systems. Hargrave et al. (2003) reviewed the records of 84 consecutive patients who underwent penetrating keratoplasty for keratoconus. Because an association between keratoconus and atopic disease had been documented in the literature and had been considered significant since 1937, careful attention was paid to the clinical history of atopy (147050) in this study. Atopic patients have been shown to have a 'Th2 immune bias.' Of the 7 patients who rejected their corneal allografts, 4 had repeat penetrating keratoplasty. Of these 4 repeat corneal allografts, 3 showed eosinophilia when compared with rejected grafts in control (nonkeratoconic, nonatopic) patients. Atopic keratoconus patients had a mixed inflammatory cellular infiltrate in the rejected corneal tissue specimen with a significantly greater density of eosinophils compared with patients who did not have a preexisting Th2 bias. The histopathology was comparable to the authors' murine model of rejection in Th2 mice, characterized by a predominantly eosinophilic infiltrate when compared with wildtype (Th1) mice that had a predominantly mononuclear infiltrate in the rejected corneal graft bed.
Heon et al. (2002) identified mutations in the candidate gene VSX1 in patients with either keratoconus or posterior polymorphous corneal dystrophy (PPCD; 122000). One of the mutations (R166W; 605020.0001) responsible for keratoconus altered the homeodomain and impaired DNA ... Heon et al. (2002) identified mutations in the candidate gene VSX1 in patients with either keratoconus or posterior polymorphous corneal dystrophy (PPCD; 122000). One of the mutations (R166W; 605020.0001) responsible for keratoconus altered the homeodomain and impaired DNA binding. Two sequence changes (L159M, 605020.0003 and G160D, 605020.0002) were associated with keratoconus and PPCD, respectively, and involved a region adjacent to the homeodomain. Bisceglia et al. (2005) evaluated the role of the VSX1 gene in a series of 80 keratoconus-affected Italian subjects. They found 3 previously described missense changes (see, e.g., 605020.0002) and a novel mutation (605020.0005) in 7 of 80 unrelated patients (8.7%); they also found 2 previously undescribed intronic polymorphisms. The authors concluded that the VSX1 gene plays an important role in a significant proportion of patients affected by keratoconus inherited as an autosomal dominant trait with variable expressivity and incomplete penetrance. In a case-control panel of 77 sporadic keratoconus patients and 71 controls and a keratoconus family panel involving 444 individuals from 75 families, Tang et al. (2008) screened for 3 keratoconus-associated VSX1 mutations, L159M, R166W, and H244R. The R166W and H244R variants were not found in the case-control panel, and L159M was detected in heterozygosity in 1 control. In the family panel, R166W was not found; L159M was detected in 5 individuals, 3 affected and 2 unaffected, and H244R was detected in 3 individuals, 2 affected and 1 unaffected. Tang et al. (2008) concluded that their results did not support a role for variation in the VSX1 gene in the pathogenesis of keratoconus. Dash et al. (2010) analyzed the entire coding region, intron-exon junctions, and 5- and 3-prime UTR of the VSX1 gene in 66 unrelated patients with keratoconus, including 27 familial cases and 39 sporadic cases. The G160D change (605020.0002), previously detected in a family with posterior polymorphous corneal dystrophy (PPCD1; 122000) and in a family with keratoconus, was identified in 2 sporadic keratoconus patients and not found in 100 controls; however, other variants that were found did not segregate with disease and/or did not demonstrate pathogenicity. Dash et al. (2010) concluded that VSX1 plays a minor role in keratoconus pathogenesis. Stabuc-Silih et al. (2010) analyzed the coding regions and intron-exon junctions of the VSX1 gene in 113 unrelated Slovenian patients with keratoconus, but identified no disease-causing mutations; they concluded that other genetic factors are involved in the development of keratoconus. De Bonis et al. (2011) analyzed the VSX1 gene in 222 unrelated Italian probands with keratoconus and reviewed previously published results. De Bonis et al. (2011) found 1 novel and 3 previously identified VSX1 missense variants in 6 keratoconus patients (see, e.g., 605020.0002 and 605020.0005), none of which had been found in controls. They concluded that VSX1 has a possible pathogenic role in keratoconus, although in a small number of patients. - Associations Pending Confirmation In 15 unrelated probands with keratoconus, Udar et al. (2006) analyzed the candidate gene SOD1 (147450) and found a heterozygous splice site variant (IVS2+50del7) in 2 probands. The 7-bp deletion segregated with disease in 1 family, being present in an affected father and daughter and absent from 3 unaffected family members; DNA was not available from the other proband's family members. The variant was not found in 312 control chromosomes or in the ALS (see 105400) database either as a mutation or polymorphism. Analysis of the daughter's RNA showed that in addition to wildtype, 2 other SOD1 transcripts were expressed: 1 lacking all of exon 2, and 1 lacking all of exons 2 and 3. Udar et al. (2006) concluded that further studies would be required to determine whether a causal relationship existed between the splice variants and the keratoconus phenotype. Stabuc-Silih et al. (2010) analyzed the coding regions and intron-exon junctions of the SOD1, COL4A3 (120070), and COL4A4 (120131) genes in 113 unrelated Slovenian patients with keratoconus, but identified no disease-causing mutations in any of the genes. However, 1 polymorphism in COL4A3 showed significant association with keratoconus (D326Y; odds ratio, 14.703 for the 976G allele) as well as 2 polymorphisms in COL4A4, M1327V (OR, 0.3969 for 3979A) and F1644F (OR, 1.751 for 4932C). Stabuc-Silih et al. (2010) concluded that other genetic factors are involved in the development of keratoconus. De Bonis et al. (2011) analyzed the SOD1 and SPARC (182120) genes in 302 unrelated Italian probands with keratoconus, 80 of whom were previously studied by Bisceglia et al. (2005). The 7-bp deletion in intron 2, previously found in keratoconus patients by Udar et al. (2006), was identified in 2 sporadic patients and was not found in 200 controls. Six missense variants in the SPARC gene were detected in 1 familial and 5 sporadic cases, respectively; none was found in 200 controls, but the variant in the familial case did not segregate with disease in the family, and no relatives of the sporadic patients were available for study. De Bonis et al. (2011) concluded that the role played by SOD1 and SPARC in keratoconus was not definitively clarified. - Exclusion Studies De Bonis et al. (2011) analyzed the LOX (153455) and TIMP3 (188826) genes in 302 unrelated Italian probands with keratoconus, 80 of whom were previously studied by Bisceglia et al. (2005), and did not find any disease-causing variants.