Alternative titles; symbols
SNOMEDCT: 417395001; ORPHA: 293603; DO: 0060649;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Corneal endothelial dystrophy, autosomal recessive | 217700 | Autosomal recessive | 3 | SLC4A11 | 610206 |
A number sign (#) is used with this entry because of evidence that corneal endothelial dystrophy (CHED) is caused by homozygous or compound heterozygous mutation in the SLC4A11 gene (610206), which encodes a sodium borate cotransporter, on chromosome 20p13.
Autosomal recessive corneal dystrophy and perceptive deafness (CDPD; 217400) is also caused by mutation in the SLC4A11 gene, indicating that CHED and CDPD are allelic disorders.
Corneal endothelial dystrophy is characterized by thickening and opacification of the cornea, altered morphology of the endothelium, and secretion of an abnormal collagenous layer at the Descemet membrane (summary by Vithana et al., 2006).
Although there was initially thought to be an autosomal dominant form of congenital hereditary endothelial dystrophy ('CHED1'), further review of the clinical and pathologic descriptions of the 5 reported CHED1 families suggested that many and possibly all of the families had posterior polymorphous corneal dystrophy (see PPCD1, 122000). Thus, CHED1 was eliminated from edition 2 of the IC3D classification of corneal dystrophies (Weiss et al., 2015), and autosomal recessive CHED, previously designated CHED2, was renamed CHED.
Maumenee (1960) reported several cases in which family histories of corneal endothelial dystrophy suggested recessive inheritance. In each of 2 families a brother and sister were affected. In view of the degree of corneal clouding, vision is often remarkably good.
Redmond (1946) described 3 affected daughters of normal but consanguineous parents.
Judisch and Maumenee (1978) reviewed autosomal recessive and apparent autosomal dominant cases of CHED. They found that in the recessive form corneal clouding is observed at birth or within the neonatal period, nystagmus is often present, but no photophobia or epiphora is seen. In the dominant form (see NOMENCLATURE), corneal opacification is usually seen in the first or second year of life and progresses slowly, photophobia and epiphora may be the first signs of the dystrophy, and nystagmus is infrequently seen.
Kirkness et al. (1987) reviewed 23 patients with what they called congenital hereditary corneal edema of Maumenee, including 6 from a family with autosomal dominant inheritance previously reported by Pearce et al. (1969) (see NOMENCLATURE and 122000) and 17 from other families with either definite (8) or probable (9) autosomal recessive inheritance. They commented that in spite of significant corneal clouding from birth or early childhood, visual development is often little impaired. Penetrating keratoplasty carries a relatively good surgical prognosis and can produce a substantial visual gain even when carried out late in life. Their experience suggested that the recessive form has an earlier age of onset and earlier age of presentation to medical attention.
McCartney and Kirkness (1988) stated that secondary epithelial changes are seen in both autosomal dominant and autosomal recessive cases of CHED, but that spheroidal degeneration of stroma is seen more commonly in autosomal dominant cases. Changes at the level of Descemet membrane showing failure to regulate growth is seen in recessive cases, whereas dominant cases are associated with development of a fibrillary posterior collagen layer. See NOMENCLATURE.
The transmission pattern of CHED in the families reported by Vithana et al. (2006) was consistent with autosomal recessive inheritance.
In a large consanguineous Irish pedigree with autosomal recessive CHED, Callaghan et al. (1999) excluded linkage of the disorder to a region of chromosome 20 that had been identified for an autosomal dominant CHED/PPCD phenotype (122000). Hand et al. (1999) used homozygosity mapping to localize CHED in the Irish pedigree to an 8-cM interval on the short arm of chromosome 20. A maximum lod score of 9.30 at a recombination fraction of 0.0 was found for linkage with microsatellite marker D20S482. A region of homozygosity in all affected individuals was identified, narrowing the disease gene locus to an 8-cM region flanked by markers D20S113 and D20S882. The CHED locus was situated perhaps as little as 4.0 cM from the telomere. The closest centromeric flanking locus of CHED in the Irish family was about 25.0 cM from the most distal flanking marker of the previously identified locus for the CHED/PPCD phenotype. Thus the CHED locus in the Irish family was located in the cytogenetic band 20p13.
Vithana et al. (2006) identified a family with autosomal recessive CHED in Myanmar in which genetic analysis refined the CHED locus to an interval of approximately 2.2 Mb on 20p13 containing at least 30 genes.
Vithana et al. (2006) considered the SLC4A11 gene (610206), which resides within the CHED locus refined by them, a candidate for causative mutations. The SLC4A11 gene encodes a sodium-borate cotransporter essential for cell growth and proliferation in mammalian cells. Comparative SAGE analysis of gene expression profiles in normal corneas and those from patients with Fuchs corneal endothelial dystrophy (see 136800) showed that SLC4A11 is downregulated in corneas of Fuchs patients. Vithana et al. (2006) confirmed expression of SLC4A11 in corneal endothelium by RT-PCR. Furthermore, in situ hybridizations in embryonic mouse eyes showed expression in the cornea at embryonic day 18, equivalent to human gestational month 5, the time at which CHED pathology develops in humans.
Vithana et al. (2006) described 7 different mutations in the SLC4A11 gene in 10 families with CHED. Mutations cause loss of function of the protein either by blocking its membrane targeting or by nonsense-mediated decay. The report of Vithana et al. (2006) concerning CHED was the first of a human disease linked to a transporter that reportedly regulates the intracellular concentration of boron, the homeostasis of which is poorly understood in humans. Identification of loss-of-function mutations in the first gene underlying CHED could facilitate gene replacement therapy in this most accessible part of the eye.
Callaghan, M., Hand, C. K., Kennedy, S. M., FitzSimon, J. S., Collum, L. M. T., Parfrey, N. A. Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct. Brit. J. Ophthal. 83: 115-119, 1999. [PubMed: 10209448] [Full Text: https://doi.org/10.1136/bjo.83.1.115]
Hand, C. K., Harmon, D. L., Kennedy, S. M., FitzSimon, J. S., Collum, L. M. T., Parfrey, N. A. Localization of the gene for autosomal recessive congenital hereditary endothelial dystrophy (CHED2) to chromosome 20 by homozygosity mapping. Genomics 61: 1-4, 1999. [PubMed: 10512674] [Full Text: https://doi.org/10.1006/geno.1999.5920]
Judisch, G. F., Maumenee, I. H. Clinical differentiation of recessive congenital hereditary endothelial dystrophy and dominant hereditary endothelial dystrophy. Am. J. Ophthal. 85: 606-612, 1978. [PubMed: 306759] [Full Text: https://doi.org/10.1016/s0002-9394(14)77091-6]
Kirkness, C. M., McCartney, A., Rice, N. S. C., Garner, A., Steele, A. D. M. Congenital hereditary corneal oedema of Maumenee: its clinical features, management, and pathology. Brit. J. Ophthal. 71: 130-144, 1987. [PubMed: 3548808] [Full Text: https://doi.org/10.1136/bjo.71.2.130]
Maumenee, A. E. Congenital hereditary corneal dystrophy. Am. J. Ophthal. 50: 1114-1124, 1960. [PubMed: 13768390] [Full Text: https://doi.org/10.1016/0002-9394(60)90998-3]
McCartney, A. C. E., Kirkness, C. M. Comparison between posterior polymorphous dystrophy and congenital hereditary endothelial dystrophy of the cornea. Eye 2: 63-70, 1988. [PubMed: 3261696] [Full Text: https://doi.org/10.1038/eye.1988.14]
Pearce, W. G., Tripathi, R. C., Morgan, G. Congenital endothelial corneal dystrophy: clinical, pathological, and genetic study. Brit. J. Ophthal. 53: 577-591, 1969. [PubMed: 4900143] [Full Text: https://doi.org/10.1136/bjo.53.9.577]
Redmond, S. P. Three sisters showing congenital opacities in the cornea. Trans. Ophthal. Soc. U.K. 66: 367-368, 1946.
Vithana, E. N., Morgan, P., Sundaresan, P., Ebenezer, N. D., Tan, D. T. H., Mohamed, M. D., Anand, S., Khine, K. O., Venkataraman, D., Yong, V. H. K., Salto-Tellez, M., Venkatraman, A., Guo, K., Hemadevi, B., Srinivasan, M., Prajna, V., Khine, M., Casey, J. R., Inglehearn, C. F., Aung, T. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nature Genet. 38: 755-757, 2006. [PubMed: 16767101] [Full Text: https://doi.org/10.1038/ng1824]
Weiss, J. S., Moller, H. U., Aldave, A. J., Seitz, B., Bredrup, C., Kivela, T., Munier, F. L., Rapuano, C. J., Nischal, K. K., Kim, E. K., Sutphin, J., Busin, M., Labbe, A., Kenyon, K. R., Kinoshita, S., Lisch, W. IC3D classification of corneal dystrophies--edition 2. Cornea 34: 117-159, 2015. Note: Erratum: Cornea 34: e32, 2015. Erratum: Cornea 41: e23, 2022. [PubMed: 25564336] [Full Text: https://doi.org/10.1097/ICO.0000000000000307]