Alternative titles; symbols
SNOMEDCT: 29504002; ORPHA: 98975; DO: 0110855;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p11.23 | Corneal dystrophy, posterior polymorphous, 1 | 122000 | Autosomal dominant | 3 | OVOL2 | 616441 |
A number sign (#) is used with this entry because of evidence that posterior polymorphous corneal dystrophy-1 (PPCD1) is caused by heterozygous mutation in the promoter of the OVOL2 gene (616441) on chromosome 20p11.
Posterior polymorphous corneal dystrophy (PPCD) is a rare disorder involving metaplasia and overgrowth of corneal endothelial cells (Krafchak et al., 2005). In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. Symptoms can range from very aggressive to asymptomatic and nonprogressive, even within the same family. The age of diagnosis is, most often, in the second or third decade of life.
Clinically, PPCD is characterized by vesicles, bands, and polymorphous opacities at the level of the Descemet membrane and corneal endothelium. Peripheral anterior iris adhesions, iris atrophy, pupillary ectropion, and corectopia may also develop. Occasional severe visual disability results from secondary glaucoma or corneal edema. On ultrastructural examination, corneal endothelial cells show fibroblastic and epithelial-like transformation (summary by Liskova et al., 2012).
Genetic Heterogeneity of Posterior Polymorphous Corneal Dystrophy
Other forms of PPCD include PPCD2 (609140), caused by mutation in the COL8A2 gene (120252) on chromosome 1p34.3; PPCD3 (609141), caused by mutation in the ZEB1 gene (189909) on chromosome 10p; and PPCD4 (618031), caused by mutation in the GRHL2 gene (608576) on chromosome 8q22.
This condition was first described by Koeppe (1916) under the name of keratitis bullosa interna, an appropriately descriptive designation. Schlichting (1941) noted depressions, vesicles, and polymorphous opacities in the Descemet membrane, with opacities in the deepest layers of the stroma, in father and 4-year-old daughter. Theodore (1939) reported affected members in 3 generations. McGee and Falls (1953) reported a family.
Maumenee (1960) examined 6 affected members over 3 generations of a family with corneal endothelial dystrophy that had previously been reported by Walsh (1957).
Rubenstein and Silverman (1968) observed a mother and 2 affected children. The mother and 1 child had rupture of the Descemet membrane, and the mother had glaucoma.
Pearce et al. (1969) reported a 5-generation British family in which 39 persons had congenital endothelial corneal dystrophy. A distortion of segregation ratio was noted in the offspring of affected females, with an excess of affected females and a deficiency of affected males. No biologic explanation could be found and it was concluded that the distorted sex ratio was a chance happening. The clouding of the cornea developed in the postnatal period and was usually well established by early childhood. Changes in the posterior cornea, namely, markedly reduced number of endothelial cells and thickening of the Descemet membrane, were thought to be primary.
Kirkness et al. (1987) reviewed 23 patients with what they called congenital hereditary corneal edema of Maumenee, including 6 from the family reported by Pearce et al. (1969) with autosomal dominant inheritance, and 17 from other families with either definite (8) or probable (9) autosomal recessive inheritance (see CHED; 217700). 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. Kirkness et al. (1987) noted that advanced posterior polymorphous dystrophy may appear similar to CHED both clinically and histologically, and that some authorities have considered PPCD and CHED to represent parts of the spectrum of the same developmental anomaly.
Heon et al. (1995) studied a 5-generation family with posterior polymorphous dystrophy, previously described by Cibis et al. (1977) and Krachmer (1985), and identified 21 individuals with the characteristic endothelial abnormalities associated with the disorder. Seven of the affected patients had the diagnosis confirmed histopathologically following corneal transplantation. The diagnosis was made at age 4 years to 40 years (mean, 25 years). Visual acuity ranged from 20/20 to no light perception, with 26 eyes (61%) having a visual acuity of less than 20/40. Bilateral corneal transplants were required in 7 patients (33%). The 1 completely blind eye had become phthisical after 2 failed corneal transplants. Similarly, 1 of 2 eyes with light-perception vision had had a failed graft, while the other had never been operated upon but had severe stromal vascularization associated with poorly controlled glaucoma. Glaucoma was documented in 9 patients (42%), of whom 4 required surgery to control their intraocular pressures. None of the clinically unaffected family members were found to have glaucoma. Eight patients (38%) had iris abnormalities, and 1 of those had a prominent Schwalbe line with iridocorneal adhesions.
In a photo essay, Anderson et al. (2001) reviewed the clinical and histopathologic overlaps between posterior polymorphous membranous dystrophy and iridocorneal endothelial syndrome. PPCD is bilateral, usually asymptomatic, and usually nonprogressive; it occurs at all ages and shows no sex predilection. Sporadic iridocorneal endothelial syndrome is usually unilateral, symptomatic, and progressive; it presents at middle age and is more common in women. Corneal edema, glaucoma, and iris changes are more common in the iridocorneal endothelial syndrome. In PPCD, endothelial cells are more likely to display epithelial-like characteristics. The authors concluded that it is difficult to distinguish between these 2 endotheliopathies. They thought that an insult during embryogenesis might result in PPCD, whereas an insult later in corneal development might result in the iridocorneal endothelial syndrome. They also noted that the herpes simplex virus had been implicated as a cause in the iridocorneal endothelial syndrome.
Gwilliam et al. (2005) studied 2 large Czech families with PPCD, with 15 and 16 affected members, respectively. In the first family, 4 patients showed signs of secondary glaucoma, and 5 had undergone corneal transplant; in the second family, 7 had secondary glaucoma, and 4 had undergone transplantation. Changes observed on slit-lamp examination in affected members of both families included pathologic endothelium, geographic lesions, vesicles, and polymorphous opacities at the level of the Descemet membrane and the endothelium. Some family members exhibited corneal edema, band keratopathy, iridocorneal peripheral adhesions, iris atrophy, pupillary ectropion, and corectopia. Visual acuity in affected members of both families ranged from 20/20 to no light perception. Gwilliam et al. (2005) stated that PPCD in Czech patients is characterized by a high percentage of secondary glaucoma, present in 35% of patients, as well as of corneal graft surgery (29%), and noted that the French Canadian family studied by Heon et al. (1995) also showed a high percentage of secondary glaucoma and corneal grafts.
Yellore et al. (2007) examined 29 members of a large 5-generation American family with PPCD and classified 10 individuals as affected. The diagnosis was based on the presence of 1 or more characteristic corneal endothelial changes: scalloped bands, clustered vesicles with a surrounding gray halo, and/or geographic gray opacities. Four of the affected individuals had undergone corneal transplantation for visually significant corneal edema, 1 of whom also exhibited PPCD-associated corectopia and iridocorneal adhesions, with secondary angle-closure glaucoma in 1 eye and absolute glaucoma in the other. Histopathologic examination of the excised corneal button, when available, confirmed the diagnosis. The other 6 affected individuals were asymptomatic, with clinical features ranging from a few isolated endothelial vesicles to densely distributed endothelial vesicles and bands associated with mild corneal stromal edema. One family member, who had an isolated corneal endothelial opacity that was not typical of PPCD, was designated as having an indeterminate phenotype. None of the family members demonstrated any of the characteristic clinical features of keratoconus (see 148300).
Davidson et al. (2016) restudied the British kindred originally reported by Pearce et al. (1969), now comprising 36 affected individuals over 7 generations. Patients typically showed symptoms of epiphora and photophobia from birth, and corneal haze was noted by 1 year of age. Elevated intraocular pressure or iris abnormality was not present prior to corneal transplantation. Current data on 16 patients indicated that all had received at least 1 corneal graft or keratoplasty, as well as surgeries for secondary glaucoma. In addition, 3 had a keratoprosthesis, and 3 had undergone enucleation of an eye. Histologic examination of full-thickness corneas from 2 patients, aged 6 years and 11 years, revealed a thin and irregular Descemet membrane, reduced endothelial cell count, and accumulation of material posterior to the Descemet membrane, consistent with mild retrocorneal fibrosis. Davidson et al. (2016) also studied more than 100 affected individuals from 16 Czech PPCD pedigrees from the southwestern region of the Czech Republic, including 2 families originally described by Gwilliam et al. (2005) and 12 families reported by Liskova et al. (2012). Affected members of these families presented with irregularities of the otherwise smooth posterior corneal surface and often had focal opacities and geographic lesions of abnormal-appearing cells. The corneal endothelium showed occasional multilayering. Microscopic visualization of the specular reflection from the posterior corneal surface further documented abnormal endothelial cell morphology and irregularities of the posterior corneal surface. One-third of the patients had undergone keratoplasty in at least 1 eye, and approximately 30%, including some who had not undergone corneal transplantation, had secondary glaucoma. In contrast to the British kindred, none of the Czech patients had corneal edema at birth; the earliest manifestation was in two 5-year-old children, which was exceptionally early for the cohort. Of 75 genotyped Czech patients, only 6 had keratoplasty before the age of 18 years. The disease was fully penetrant with no systemic associations in the British kindred or the Czech families.
Heon et al. (1995) stated that the corneal endothelium is normally a single layer of cells that lose their mitotic potential after development is complete. In posterior polymorphous corneal dystrophy, however, the endothelium is often multilayered and has several other characteristics of an epithelium, including the presence of desmosomes, tonofilaments, and microvilli. These abnormal cells retain their ability to divide, and extend onto the trabecular meshwork to cause glaucoma in up to 40% of cases.
Jirsova et al. (2007) demonstrated that the abnormal endothelium of PPCD patients expressed a mixture of cytokeratins, with KRT7 (148059) and KRT19 (148020) predominating. In terms of KRT composition, the aberrant PPCD endothelium shared features of both simple and squamous stratified epithelium with a proliferative capacity. Jirsova et al. (2007) suggested that the wide spectrum of KRT expression was most probably not indicative of the transformation of endothelial cells to a distinct epithelial phenotype, but more likely reflected a modified differentiation of metaplastic epithelium.
Liskova et al. (2012) identified 113 affected individuals from 19 Czech families with PPCD, which they stated was the highest reported prevalence of PPCD worldwide. Correlated to the population, at least 1 in 100,000 inhabitants of the Czech Republic has PPCD. Because of the relative rarity of the disorder, a founder effect was suspected (see MAPPING).
In a large family with 21 members affected with posterior polymorphous dystrophy, previously described by Cibis et al. (1977) and Krachmer (1985), Heon et al. (1995) demonstrated linkage with short tandem repeat polymorphism (STRP) markers on 20q. The highest observed lod score was 5.54 at theta = 0.0 with marker D20S45. Analysis of recombination events in 4 affected individuals revealed that the disease gene lies within a 30-cM interval between markers D20S98 and D20S108.
In a large family with autosomal dominant congenital endothelial corneal dystrophy, previously reported by Pearce et al. (1969) and Kirkness et al. (1987) and believed to represent an autosomal dominant form of CHED (see 217700), Toma et al. (1995) found linkage with markers on chromosome 20. The highest observed lod score was 7.20 at theta = 0.026 with marker D20S114. Multipoint analysis gave a maximum lod score of 9.34 between D20S48 and D20S471. Toma et al. (1995) noted that this 2.7-cM region lies within the 30-cM region where the gene for PPCD is located. Analysis of the evidence on cytogenetic location of markers used in the mapping of autosomal dominant CHED and PPCD showed that both loci are in the pericentric region of chromosome 20, i.e., 20p11.2-q11.2. The authors suggested that PPCD and the autosomal dominant form of CHED (so-called 'CHED1'), might be allelic; see NOMENCLATURE.
Aldave et al. (2013) reviewed the genetics of the corneal endothelial dystrophies. Noting the clinical, histopathologic, and ultrastructural similarities between affected individuals from the 'CHED1' family (Pearce et al., 1969) that was mapped to chromosome 20 by Toma et al. (1995) and the findings in PPCD1 patients who map to an overlapping region of chromosome 20, Aldave et al. (2013) stated that it is most plausible that the 'CHED1' family actually has PPCD1.
The transmission pattern of PPCD in the families reported by Davidson et al. (2016) was consistent with autosomal dominant inheritance.
In a large British kindred with PPCD mapping to chromosome 20p, which was originally reported by Pearce et al. (1969), Davidson et al. (2016) performed whole-genome sequencing and identified a heterozygous duplication within the promoter of the OVOL2 gene (616441.0001) that segregated fully with disease in the family and was not found in 209 ethnically matched British control samples. In 16 Czech PPCD1 pedigrees, including 2 families originally described by Gwilliam et al. (2005) and 12 families previously studied by Liskova et al. (2012), Davidson et al. (2016) identified heterozygosity for a c.-370T-C mutation within the OVOL2 promoter (616441.0002) that also segregated fully with disease and was not found in controls. Screening of 8 additional British and Czech probands with genetically unsolved PPCD revealed 2 more mutations in the OVOL2 promoter in 2 British probands (616441.0003 and 616441.0004). Although expression of OVOL2 was not observed in human fetal or adult corneal endothelium, Davidson et al. (2016) noted that the OVOL2 promoter region has binding sites for multiple transcription factors, and that the majority of these transcription factors are expressed in human corneal endothelial cells. Functional analysis in transfected HEK293 cells demonstrated that each of the 4 mutants significantly increased promoter activity in vitro. In addition, Davidson et al. (2016) stated that OVOL2 is a known direct repressor of the PPCD3-associated ZEB1 gene, and suggested that dysregulation of the OVOL2-ZEB1 feedback loop was likely relevant to the pathogenetic mechanism in PPCD1.
Associations Pending Confirmation
See 605020.0002 for discussion of a possible association between variation in the VSX1 homeobox gene and PPCD.
Exclusion Studies
By SSCP analysis and direct sequencing in the large family with PPCD that was mapped to chromosome 20 by Heon et al. (1995), Heon et al. (2002) excluded mutation in the VSX1 gene.
In 2 Czech families with PPCD mapping to chromosome 20, Gwilliam et al. (2005) excluded the candidate gene VSX1 and suggested that VSX1 might not be a common cause of corneal endothelial dystrophies.
In 2 families with PPCD mapping to chromosome 20 in which mutation in the VSX1 gene had been excluded, 1 of which was the family originally studied by Heon et al. (1995), Hosseini et al. (2008) analyzed 3 candidate genes, RBBP9 (602908), ZNF133 (604075), and SLC24A3 (609839), but did not find any mutations.
In the probands from 2 Czech families with PPCD that was mapped to chromosome 20p11.2 by Gwilliam et al. (2005), Liskova et al. (2012) sequenced the candidate gene ZNF133 but found no pathogenic variants. In addition, dense chromosome 20 CGH analysis in 1 affected individual did not reveal any microdeletions or duplications at 20p12.1-p11.23.
Aldave, A. J., Han, J., Frausto, R. F. Genetics of the corneal endothelial dystrophies: an evidence-based review. Clin. Genet. 84: 109-119, 2013. [PubMed: 23662738] [Full Text: https://doi.org/10.1111/cge.12191]
Anderson, N. J., Badawi, D. Y., Grossniklaus, H. E., Stulting, R. D. Posterior polymorphous membranous dystrophy with overlapping features of iridocorneal endothelial syndrome. Arch. Ophthal. 119: 624-625, 2001. [PubMed: 11296040] [Full Text: https://doi.org/10.1001/archopht.119.4.624]
Bergman, G. D. Posterior polymorphous degeneration of the cornea. Am. J. Ophthal. 58: 125-128, 1964. [PubMed: 14177965] [Full Text: https://doi.org/10.1016/0002-9394(64)90601-4]
Cibis, G. W., Krachmer, J. A., Phelps, C. D., Weingeist, T. A. The clinical spectrum of posterior polymorphous dystrophy. Arch. Ophthal. 95: 1529-1537, 1977. [PubMed: 302697] [Full Text: https://doi.org/10.1001/archopht.1977.04450090051002]
Davidson, A. E., Liskova, P., Evans, C. J., Dudakova, L., Noskova, L., Pontikos, N., Hartmannova, H., Hodanova, K., Stranecky, V., Kozmik, Z., Levis, H. J., Idigo, N., and 14 others. Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2. Am. J. Hum. Genet. 98: 75-89, 2016. [PubMed: 26749309] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.018]
Feigin, R. D., Caplan, D. B. Corneal opacities in infancy and childhood. J. Pediat. 69: 383-392, 1966. [PubMed: 5946443] [Full Text: https://doi.org/10.1016/s0022-3476(66)80082-3]
Gwilliam, R., Liskova, P., Filipec, M., Kmoch, S., Jirsova, K., Huckle, E. J., Stables, C. L., Bhattacharya, S. S., Hardcastle, A. J., Deloukas, P., Ebenezer, N. D. Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene. Invest. Ophthal. Vis. Sci. 46: 4480-4484, 2005. [PubMed: 16303937] [Full Text: https://doi.org/10.1167/iovs.05-0269]
Heon, E., Greenberg, A., Kopp, K. K., Rootman, D., Vincent, A. L., Billingsley, G., Priston, M., Dorval, K. M., Chow, R. L., McInnes, R. R., Heathcote, G., Westall, C., Sutphin, J. E., Semina, E., Bremner, R., Stone, E. M. VSX1: A gene for posterior polymorphous dystrophy and keratoconus. Hum. Molec. Genet. 11: 1029-1036, 2002. [PubMed: 11978762] [Full Text: https://doi.org/10.1093/hmg/11.9.1029]
Heon, E., Mathers, W. D., Alward, W. L. M., Weisenthal, R. W., Sunden, S. L. F., Fishbaugh, J. A., Taylor, C. M., Krachmer, J. H., Sheffield, V. C., Stone, E. M. Linkage of posterior polymorphous corneal dystrophy to 20q11. Hum. Molec. Genet. 4: 485-488, 1995. [PubMed: 7795607] [Full Text: https://doi.org/10.1093/hmg/4.3.485]
Hogan, M. J., Bietti, G. Hereditary deep dystrophy of the cornea (polymorphous). Am. J. Ophthal. 68: 777-788, 1969. [PubMed: 4187513] [Full Text: https://doi.org/10.1016/0002-9394(69)94569-3]
Hosseini, S. M., Herd, S., Vincent, A. L., Heon, E. Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes. Molec. Vision 14: 71-80, 2008. [PubMed: 18253095]
Jirsova, K., Merjava, S., Martincova, R., Gwilliam, R., Ebenezer, N. D., Liskova, P., Filipec, M. Immunohistochemical characterization of cytokeratins in the abnormal corneal endothelium of posterior polymorphous corneal dystrophy patients. Exp. Eye Res. 84: 680-686, 2007. [PubMed: 17289024] [Full Text: https://doi.org/10.1016/j.exer.2006.12.006]
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]
Koeppe, L. Klinische Beobachtungen mit der Nernstspaltlampe und dem Hornhautmikroskop. Albrecht von Graefes Arch. Klin. Exp. Ophthal. 91: 363-379, 1916.
Krachmer, J. H. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans. Am. Ophthal. Soc. 83: 413-475, 1985. [PubMed: 3914130]
Krafchak, C. M., Pawar, H., Moroi, S. E., Sugar, A., Lichter, P. R., Mackey, D. A., Mian, S., Nairus, T., Elner, V., Schteingart, M. T., Downs, C. A., Kijek, T. G., and 9 others. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am. J. Hum. Genet. 77: 694-708, 2005. [PubMed: 16252232] [Full Text: https://doi.org/10.1086/497348]
Kwedar, E. W. Hereditary nonprogressive deep corneal dystrophy. Arch. Ophthal. 65: 127-129, 1961. [PubMed: 13755549] [Full Text: https://doi.org/10.1001/archopht.1961.01840020129021]
Liskova, P., Gwilliam, R., Filipec, M., Jirsova, K., Merjava, S. R., Deloukas, P., Webb, T. R., Bhattacharya, S. S., Ebenezer, N. D., Morris, A. G., Hardcastle, A. J. High prevalence of posterior polymorphous corneal dystrophy in the Czech Republic: linkage disequilibrium mapping and dating an ancestral mutation. PLoS One 7: e45495, 2012. [PubMed: 23049806] [Full Text: https://doi.org/10.1371/journal.pone.0045495]
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]
McGee, H. B., Falls, H. F. Hereditary polymorphous deep degeneration of the cornea. AMA Arch. Ophthal. 50: 462-467, 1953. [PubMed: 13091521] [Full Text: https://doi.org/10.1001/archopht.1953.00920030470006]
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]
Rodrigues, M. M., Sun, T.-T., Krachmer, J., Newsome, D. Posterior polymorphous corneal dystrophy: recent developments. Birth Defects Orig. Art. Ser. 18(6): 479-491, 1982. [PubMed: 6184085]
Rubenstein, R. A., Silverman, J. J. Hereditary deep dystrophy of the cornea: associated with glaucoma and ruptures in Descemet's membrane. Arch. Ophthal. 79: 123-126, 1968. [PubMed: 5299826] [Full Text: https://doi.org/10.1001/archopht.1968.03850040125002]
Schlichting, H. Blasen-und dellenfoermige Endotheldystrophie der Hornhaut. Klin. Monatsbl. Augenheilkd. 107: 425-435, 1941.
Theodore, F. H. Congenital type of endothelial dystrophy. Arch. Ophthal. 21: 626-638, 1939.
Toma, N. M. G., Ebenezer, N. D., Inglehearn, C. F., Plant, C., Ficker, L. A., Bhattacharya, S. S. Linkage of congenital hereditary endothelial dystrophy to chromosome 20. Hum. Molec. Genet. 4: 2395-2398, 1995. [PubMed: 8634716] [Full Text: https://doi.org/10.1093/hmg/4.12.2395]
Walsh, F. B. Clinical Neuro-Ophthalmology. Baltimore: Williams & Wilkins 1957. P. 343.
Yellore, V. S., Papp, J. C., Sobel, E., Khan, M. A., Rayner, S. A., Farber, D. B., Aldave, A. J. Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20. Genet. Med. 9: 228-234, 2007. [PubMed: 17438387] [Full Text: https://doi.org/10.1097/gim.0b013e31803c4dc2]