Alternative titles; symbols
SNOMEDCT: 715908008; ORPHA: 293381; DO: 0070337;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.1 | Epithelial recurrent erosion dystrophy | 122400 | Autosomal dominant | 3 | COL17A1 | 113811 |
A number sign (#) is used with this entry because of evidence that epithelial recurrent erosion dystrophy (ERED) is caused by heterozygous mutation in the COL17A1 gene (113811) on chromosome 10q25.
Epithelial recurrent erosion dystrophy (ERED) is characterized by frequent painful recurrent corneal erosions, with onset in the first decade of life and subsequent gradual decrease in frequency, with cessation in the third or fourth decade. Small gray anterior stromal flecks associated with larger focal gray-white disc-shaped, circular, or wreath-like lesions with central clarity, in the Bowman layer and immediately subjacent anterior stroma, varying from 0.2 to 1.5 mm in diameter, appear to be clinically diagnostic of ERED (Oliver et al., 2016).
Franceschetti (1928) described a family in which 6 successive generations were affected. The disorder became manifest between 4 and 6 years of age. Recurring ulcerations are also seen in macular and lattice types of classic dystrophy. See also keratitis fugax hereditaria (148200). A follow-up in 1958 showed 40 affected members of the family (Franceschetti and Klein, 1961).
Wales (1955) described affected persons in 3 generations. Valle (1967) described a family with 6 affected persons in 3 sibships in 2 generations. The progenitor had Fuchs corneal dystrophy (see 136800).
Vincent et al. (2009) reported 6 affected individuals over 3 generations of a New Zealand family (06NZ-TRB1) with early-onset recurrent erosions associated with an unusual anterior membrane/fleck dystrophy. Affected individuals presented within the first decade of life with corneal erosions that occurred approximately every 2 to 3 months. With increasing age, the erosions became much less frequent, and the episodes appeared to cease in the third decade of life. Slit-lamp examination revealed corneal features common to all patients, including accumulation of small variable-size discrete grayish-white oval-round or annular opacities in the Bowman layer and superficial anterior stroma, typically fewer than 6 lesions per cornea; numerous prominent small gray flecks in the anterior quarter of the stroma, extending from the central cornea to the limbus; and prominent corneal nerves, with reduced corneal sensation more prevalent in the older members of the pedigree. A few older adults reported photophobia and foreign-body sensation, and continued to use topical ocular lubricants. The lesions appeared on a background of generally clear translucent cornea, with no involvement of the deeper stroma, Descemet membrane, or endothelium, and there was no neovascularization. In vivo confocal microscopy confirmed restriction of the corneal opacities to the Bowman layer and anterior stroma.
Nakamura et al. (2012) studied a 4-generation family, previously reported by Lohse et al. (1989) and Yee et al. (1997), with a corneal dystrophy (CD) of the anterior basement membrane/Bowman membrane. Nakamura et al. (2012) found evidence of variable phenotypic expression in this family, including within the same eye, within the same individual, and between 2 individuals in the same generation. In 3 patients, a classic 'honeycomb' pattern of Thiel-Behnke CD (CDTB; 602082) was seen, whereas 2 others exhibited a honeycomb pattern in 1 eye and the 'geographic' pattern typical of Reis-Bucklers CD (CDRB; 608470) in the other. In another patient, a dense corneal scar surrounded by a geographic region gradually extended into a fine reticulated network resembling a honeycomb pattern. Other distinct phenotypes that were observed included numerous white punctate opacities on the surface of the cornea in 1 patient, as well as small superficial vesicles in the 2 youngest patients. Longitudinal observations in 3 patients demonstrated an initial geographic or plaque phenotype that developed into a honeycomb pattern, suggesting an age-related phenomenon. Lohse et al. (1989) had originally diagnosed the CD in this family as CDRB; Yee et al. (1997) considered the disorder to represent CDTB.
Jonsson et al. (2015) studied 5 Swedish families, not known to be related, with a phenotype consistent with ERED. All of the families originated from West Bothnia in northern Sweden, and church record analysis identified a common ancestor, 8 generations removed from the youngest family members. Affected individuals had recurrent episodes of pain, epiphora, and photophobia, 1 to 3 times a year in childhood with a tendency to decrease in the late teens to 20s. Most patients had onset of symptoms between 6 and 7 years of age, although 3 patients reported late onset and 2 family members were asymptomatic despite characteristic corneal changes. Vision was not affected initially except during acute episodes of pain, but 95% of patients older than 40 years experienced unstable refraction and impaired vision, with feelings of dryness and photophobia. Examination revealed characteristic diffuse subepithelial opacities in the paracentral cornea, sometimes showing a net-like pattern with raised areas of Salzmann degeneration, and the opacities tended to increase with age. Two female patients developed persistent epithelial defects during the study period, 1 of whom exhibited secondary corneal neovascularization. Phototherapeutic keratectomy (PTK) was performed in 16 affected individuals and provided relief for many years, but opacities tended to recur and 2 patients required repeat PTK almost 20 years later.
Oliver et al. (2016) reported 4 families with ERED, including the New Zealand family (06NZ-TRB1) previously studied by Vincent et al. (2009), another New Zealand family (15NZ-LED1), a Tasmanian family (CDTAS1), and a family from the UK (UKOGA). Patients presented between 5 and 7 years of age, and episodes of erosions decreased in frequency over time, subsiding in the third to fourth decade. Persistent symptoms consisted of foreign-body sensation, photophobia, and variable reduction in vision. Key features on slit-lamp biomicroscopy included a small number of focal disc-shaped, circular, or wreath-like gray-white opacities, from 0.2 to 1.5 mm in diameter, involving the Bowman layer and adjacent anterior stroma, on a relatively subtle background of numerous smaller (less than 100 micrometers) gray flecks limited to the anterior 20% of the stroma. There was a tendency for stromal opacities to appear and gradually increase throughout life, but variable expression was present among family members. In vivo confocal microscopy revealed brightly hyperreflective polymorphous intraepithelial opacities, and there were areas in which disc-shaped opacities showed bowl-like epithelial thickening extending into the anterior stroma, with complete destruction of the Bowman layer and subepithelial nerve plexus. The adjacent anterior stroma showed diffuse accumulation of extracellular matrix, which was limited to focal lesions in younger patients. Patients over 60 years of age showed needle-like stromal opacities affecting the anterior more than the posterior stroma. The corneal endothelium was not affected.
The transmission pattern of ERED in the families reported by Jonsson et al. (2015) was consistent with autosomal dominant inheritance.
In a large family exhibiting a form of corneal dystrophy with variable phenotypic expression (see CLINICAL FEATURES), Sullivan et al. (1997) and Yee et al. (1997) reported linkage to chromosome 10q24. By genomewide search using a panel of microsatellite markers, Yee et al. (1997) obtained a maximum 2-point lod score of 4.0 at 0% recombination between the disease locus in this kindred and the marker D10S1239, which maps to 10q23-q24. Testing with additional microsatellite markers from 10q placed the disease locus between D10S677 and D10S1671, a distance of approximately 12.0 cM, with a maximum multipoint lod score of 5.5.
Using DNA from 5 affected members of an extended Swedish pedigree segregating autosomal dominant ERED, Jonsson et al. (2015) performed genomewide SNP analysis and identified 5 shared regions larger than 1 Mb, with the largest on chromosome 10q23.1-q24.32, between rs2245310 and rs10787781.
Oliver et al. (2016) performed genomewide analysis of haplotypes conserved between 7 affected members of New Zealand family 06NZ-TRB1, previously studied by Vincent et al. (2009), and identified a single peak on chromosome 10 with a maximum lod score of 2.7, corresponding to a 100.14-Mb region between rs1111060 and rs11195400 (chr10:12,576,562-112,763,135; GRCh37). The maximum lod score rose to 3.3 with retrospective reassignment of 2 younger family members from 'unknown' to 'unaffected' status, when they did not demonstrate erosions by age 10 years.
In an extended Swedish pedigree with ERED, negative for mutation in the TGFBI gene (601692) and for 339 known corneal dystrophy-associated mutations in 12 other genes, Jonsson et al. (2015) performed whole-exome sequencing and identified a heterozygous missense mutation in the COL17A1 gene (T939I; 113811.0015) that segregated fully with disease and was not found in 139 ethnically matched controls or in the Exome Sequencing Project database. In addition, Jonsson et al. (2015) reviewed data from a large 4-generation family, originally studied by Lohse et al. (1989), with corneal dystrophy that linked to the same region on chromosome 10q23-q24 (Yee et al., 1997) but in which mutation in COL17A1 had previously been excluded (Sullivan et al., 2003). Analysis of a synonymous variant (G1052G; 113811.0016) that segregated completely with disease in the family revealed that it creates a cryptic splice donor site, resulting in aberrant pre-RNA splicing. Jonsson et al. (2015) concluded that the COL17A1-associated phenotype in this family was consistent with the ERED-like phenotype observed in the Swedish pedigree, and stated that they were unaware of any skin disorders or other symptoms in affected individuals from either family.
In a 3-generation New Zealand family (06NZ-TRB1) with ERED mapping to chromosome 10, Oliver et al. (2016) performed whole-exome sequencing and identified heterozygosity for the same synonymous COL17A1 variant, G1052G, that had been detected in a Swedish ERED pedigree by Jonsson et al. (2015). Oliver et al. (2016) screened 3 more presumably unrelated families with ERED for the COL17A1 mutation, including 1 family from the UK (UKOGA), 1 from New Zealand (15NZ-LED1), and 1 from Tasmania (CDTAS1), and found that the COL17A1 variant segregated with disease in all 3 families. Haplotype analysis with flanking microsatellite markers showed segregation with affected individuals in all 4 families, consistent with a founder effect. Oliver et al. (2016) also detected a D112N substitution at a conserved residue in the DNAJC9 gene (611206) that segregated with disease in the first family (06NZ-TRB1); however, the variant was not present in any of the other 3 families. Noting that disease presentation in family 06NZ-TRB1 trended toward an earlier age at onset than in the other families, Oliver et al. (2016) concluded that the DNAJC9 variant was not necessary for ERED corneal disease, but could not be excluded as a modifier of disease.
Exclusion Studies
In a 3-generation New Zealand family (06NZ-TRB1) segregating autosomal dominant early-onset recurrent corneal erosions, Vincent et al. (2009) excluded mutation in the candidate genes TGFBI and ZEB1 (189909), as well as known mutations in 12 corneal dystrophy-associated genes.
In a 4-generation family with corneal dystrophy, originally studied by Lohse et al. (1989), Nakamura et al. (2012) sequenced the KRT3 (148043), KRT12 (601687), and TGFBI genes but did not detect any mutations.
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Franceschetti, A. Hereditaere rezidivierende Erosion der Hornhaut. Z. Augenheilk. 66: 309-316, 1928.
Jonsson, F., Bystrom, B., Davidson, A. E., Backman, L. J., Kellgren, T. G., Tuft, S. J., Koskela, T., Ryden, P., Sandgren, O., Danielson, P., Hardcastle, A. J., Golovleva, I. Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED). Hum. Mutat. 36: 463-473, 2015. [PubMed: 25676728] [Full Text: https://doi.org/10.1002/humu.22764]
Lohse, E., Stock, E. L., Jones, J. C. R., Braude, L. S., O'Grady, R. B., Roth, S. I. Reis-Bucklers' corneal dystrophy: immunofluorescent and electron microscopic studies. Cornea 8: 200-209, 1989. [PubMed: 2663347]
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Oliver, V. F., van Bysterveldt, K. A., Cadzow, M., Steger, B., Romano, V., Markie, D., Hewitt, A. W., Mackey, D. A., Willoughby, C. E., Sherwin, T., Crosier, P. S., McGhee, C. N., Vincent, A. L. A COL17A1 splice-altering mutation is prevalent in inherited recurrent corneal erosions. Ophthalmology 123: 709-722, 2016. [PubMed: 26786512] [Full Text: https://doi.org/10.1016/j.ophtha.2015.12.008]
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Sullivan, L. S., Zhao, X., Bowne, S. J., Xu, X., Daiger, S. P., Yee, S. B., Yee, R. W. Exclusion of the human collagen type XVII (COL17A1) gene as the cause of Thiel-Behnke corneal dystrophy (CDB2) on chromosome 10q23-q25. Curr. Eye Res. 27: 223-226, 2003. [PubMed: 14562173] [Full Text: https://doi.org/10.1076/ceyr.27.4.223.16595]
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Yee, R. W., Sullivan, L. S., Lai, H. T., Stock, E. L., Lu, Y., Khan, M. N., Blanton, S. H., Daiger, S. P. Linkage mapping of Thiel-Behnke corneal dystrophy (CDB2) to chromosome 10q23-q24. Genomics 46: 152-154, 1997. [PubMed: 9403072] [Full Text: https://doi.org/10.1006/geno.1997.5028]