Posterior Polymorphous Dystrophy Research Articles

Mutationsanalyse im VSX1-Gen bei einem Patienten mit posteriorer polymorpher Hornhautdystrophie und drei Familien mit autosomal-dominant vererbter Fuchs’scher Hornhautendotheldystrophie

Fuchs endothelial corneal dystrophy is the most common disease of the corneal endothelium. Besides some sporadic cases, an autosomal dominant inheritance is frequently described. Mutations in the VSX-1 gene are identified as the underlying gene defect for a rarer kind of endothelial dystrophy, posterior polymorphous endothelial dystrophy. We report on mutational analysis of the VSX-1 gene in affected and non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy and one male patient showing posterior polymorphous endothelial dystrophy. From one patient with posterior polymorphous endothelial dystrophy and 10 affected and 15 non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy DNA was extracted from leukocytes of the peripheral blood and mutational analysis was performed by direct sequencing of the VSX-1 gene. Screening of the VSX-1 gene did not reveal sequence variants in any affected or non-affected individuals from the three families with Fuchs endothelial corneal dystrophy or the patient with posterior polymorphous endothelial dystrophy. The absence of pathogenic mutations in the VSX-1 gene in affected family members of 3 pedigrees indicates that other genetic factors are involved in the development of familial Fuchs endothelial corneal dystrophy. In addition, VSX-1 seems unlikely to be the crucial gene in our patient with posterior polymorphous endothelial dystrophy.

Cytomegalovirus Endotheliitis in Descemet's Stripping Endothelial Keratoplasty

To report 4 cases of undiagnosed cytomegalovirus (CMV) endotheliitis in patients who underwent Descemet's stripping automated endothelial keratoplasty (DSAEK). Retrospective interventional case series. Four eyes of 4 patients diagnosed with active CMV endotheliitis after DSAEK. Retrospective review of the medical records of 4 patients with DSAEK who had an aqueous tap that was positive for CMV DNA but negative for herpes simplex virus (HSV) and varicella zoster virus. Clinical features and management. Four immunocompetent Chinese male patients with a mean age of 67 years underwent DSAEK for posterior polymorphous dystrophy (1), Fuchs' heterochromic cyclitis (1), pseudophakic bullous keratopathy (1), and herpetic keratouveitis (1). Clinical findings seen in all patients were localized corneal edema, increased intraocular pressure, pigmented keratic precipitates (KPs), and no/minimal anterior chamber (AC) activity. An unexplained sudden decrease in endothelial cell count (ECC) in the absence of rejection or significant inflammation was seen in 3 patients, whereas 1 patient also developed concomitant retinitis. CMV DNA was positive in all aqueous specimens and from the vitreous of the patient with retinitis. All patients were treated with oral valganciclovir with resolution of inflammation; 2 patients had recurrences; 1 patient developed recurrent retinitis; and 1 patient developed recurrent CMV endotheliitis and is currently receiving maintenance therapy with oral valganciclovir. CMV endotheliitis with corneal edema masqueraded as a variety of other endothelial conditions, which resulted in DSAEK surgery being performed in these patients who may have responded to antiviral treatment without the need for endothelial transplantation. A heightened awareness is required to exclude CMV endotheliitis as the cause for endothelial decompensation or unexplained, sudden reduction in ECCs post-DSAEK in the absence of other complications, and it should be differentiated from allograft rejection in view of the critical difference in treatment.

Keratoconus Associated With Other Corneal Dystrophies

To report the concomitant presentation of keratoconus and corneal dystrophies at Wills Eye Hospital for the 10-year period from January 1, 1997, to December 31, 2006. Patients with concomitant keratoconus and corneal dystrophies were identified using a computer database. Complete ophthalmologic examination, keratometry, pachymetry, and computerized videokeratography were performed in all patients. When present, cornea guttata were confirmed by clinical examination and specular microscopy. Histopathologic examination with special stains of excised corneal buttons was performed. Fifty-one patients manifested typical signs and topographic evidence of keratoconus associated with another corneal dystrophy. Fuchs dystrophy was the most common association accounting for 27 cases (52.9%), followed by anterior basement membrane dystrophy with 13 cases (25.5%) and posterior polymorphous dystrophy with 7 cases (13.8%). A bilateral combination of Fuchs dystrophy and anterior basement membrane dystrophy with keratoconus was seen in 3 cases (5.8%). Finally, there was 1 bilateral case (2%) of granular dystrophy. Histopathologic studies in cases that underwent penetrating keratoplasty confirmed the clinical diagnoses. To our knowledge, this is the largest report of such a concurrence in the English literature and could lead to further studies on the possible pathophysiologic or genetic links between these entities, although a chance association cannot be excluded.

Descemet’s Stripping Automated Endothelial Keratoplasty – A Review

Descemet’s stripping automated endothelial keratoplasty (DSAEK) has become the procedure of choice to treat corneal endothelial dysfunction. The technique involves replacing the diseased host endothelium with a graft consisting of a thin layer of posterior stroma, Descemet’s membrane and endothelium. In comparison with penetrating keratoplasty (PK), DSAEK confers quicker visual and structural recovery with absence of corneal surface incisions or sutures, and also limits astigmatism. DSAEK has been proved to successfully achieve favourable visual acuity and graft clarity in bullous keratopathy, posterior polymorphous dystrophy and failed PK grafts. This literature review discusses various DSAEK surgical techniques, short- and long-term post-surgical results, complications and comparisons with other types of keratoplasty. With the advent of Descemet’s membrane endothelial keratoplasty (DMEK), in which only Descemet’s membrane is transplanted, visual rehabilitation may be attained sooner.

Distrofia polimorfa posterior y LASIK

A 50-year-old hyperopic woman requested information about refractive surgery. Vesicle and band lesions at Descemet's membrane and endothelium were suggestive of posterior polymorphous dystrophy (PPD). Lower than normal endothelial cell densities were detected. A corneal refractive procedure was not recommended in this case. The presence of vesicles and bands at Descemet's membrane and endothelium is suggestive of PPD. Specular microscopy is mandatory in such patients, although corneal decompensation is not evident. A low endothelial cell count may be a contraindication for a hyperopic LASIK procedure in cases of PPD because of the possible risk of corneal decompensation.

Analysis of the Posterior Polymorphous Corneal Dystrophy 3 Gene,TCF8, in Late-Onset Fuchs Endothelial Corneal Dystrophy

Because the endothelial (posterior) corneal dystrophies share common pathologic features and result from primary endothelial dysfunction, it is possible that a proportion of them could be clinical manifestations of different mutations of the same gene. The aim of our study was to determine whether mutations of the TCF8 gene, recently implicated in posterior polymorphous dystrophy, may also play a role in the development of the more common Fuchs endothelial corneal dystrophy (FECD). Genomic DNA was extracted from leukocytes of peripheral blood, and the nine exons of the TCF8 gene were PCR amplified and subjected to bidirectional sequencing and analysis. Samples from 74 unrelated Chinese patients (55 women, 19 men) with a diagnosis of late-onset FECD and 93 age- and race-matched controls were studied. The affected probands ranged in age from 52 to 91 years (mean age, 65.1 years); 8 had familial FECD and 66 had sporadic FECD. The authors found two mutations in the coding region of the TCF8 gene: a novel missense mutation in one patient c.2087A>G in exon 7 (Asn696Ser) and a silent mutation in exon 2 c.192T>C (D64D). The identification of a novel missense mutation in only one of the patients implied that TCF8 does not play a significant role in the pathogenesis of FECD in this Chinese population.

Congenital Corneal Opacities: A Review with a Focus on Genetics

Congenital corneal opacities present in approximately 3/100,000 newborns. Many different disorders may result in corneal opacifications of infancy, including Peters' anomaly (PA), congenital hereditary endothelial dystrophy (CHED), congenital hereditary stromal dystrophy (CHSD) and posterior polymorphous dystrophy (PPMD). Current studies have localized defects using genetic testing in PA, CHED, CHSD and PPMD. Identifying mutations for specific disorders may lead to better understanding of the underlying pathogeneses and may help with diagnosis and prognosis. This article will review the clinical presentations, treatments and genetics of Peters' anomaly, congenital hereditary endothelial dystrophy, congenital hereditary stromal dystrophy and posterior polymorphous dystrophy.

In vivo confocal microscopy in different types of posterior polymorphous dystrophy

Posterior polymorphous dystrophy is a rare corneal dystrophy, usually detected by chance. This case series describes the morphologic features in the three different types of posterior polymorphous dystrophy using confocal microscopy.

Epithelial Metaplasia of the Corneal Endothelium in Fuchs Endothelial Dystrophy

To evaluate the immunohistochemical characteristics of human corneas with the diagnosis of Fuchs endothelial dystrophy (FED). Formalin-fixed, paraffin-embedded sections of corneas with the diagnosis of FED (15 patients) and 10 control corneas were stained with hematoxylin-eosin and periodic acid-Schiff (PAS). Adjacent histologic sections were stained with monoclonal antibodies that react with epithelial antigens: pancytokeratin, cytokeratins (CK) 7 and 20 CAM 5.2, epithelial membrane antigen (EMA), and Ber EP4. Eight corneas were stained with antibodies to vimentin, smooth-muscle actin (SMA), and CD 68. The endothelial cells in FED were attenuated and atrophic; some contained pigment consistent with melanin. The endothelial cells stained for pancytokeratin, CK 7, and vimentin in all corneas of FED, whereas variable staining was noted with CAM 5.2. No staining of endothelium was noted with CK 20, EMA, BerEP4, SMA, or CD 68. Some cytokeratins that are normally restricted to true epithelium are present in the endothelium of FED. Epithelial metaplasia of endothelium in FED may represent a nonspecific response of distressed endothelial cells, as previously reported in posterior polymorphous dystrophy, congenital hereditary endothelial dystrophy, and iridocorneal endothelial syndrome.

In vivo confocal microscopy of pre-endothelial deposits

Deposits in various layers of the cornea might result from long-term medical therapy, photorefractive surgery, and longterm use of contact lenses or corneal dystrophies. A 46-year-old woman was referred to our department with the suspected diagnosis of posterior polymorphous dystrophy. Slit-lamp biomicroscopy revealed bilateral small-sized deposits in the posterior part of the cornea. In vivo confocal microscopy was performed to evaluate these deposits in detail. In vivo confocal microscopy of the cornea identified hyperreflec-tive "dot-like" structures in the deep stromal layer and anterior to the endothelial cell layer. The morphology and number of keratocytes of the posterior stroma and of endothelial cells appeared normal. In vivo confocal microscopy is a very useful tool to analyze and visualize pre-endothelial deposits. Because there is no family history of corneal disease, the exact origin of the pre-endothelial deposits in our case remains unclear.

Clinical and microstructural analysis of patients with hyper-reflective corneal endothelial nuclei imaged by in vivo confocal microscopy

The purpose of this study was to determine the significance of hyper-reflective corneal endothelial nuclei imaged by in vivo confocal microscopy. A retrospective analysis was performed using a database of 505 patients that had undergone in vivo confocal microscopy of the cornea. All subjects with hyper-reflective endothelial nuclei were identified and these images were analysed to determine corneal endothelial cell density and morphology. The clinical notes of these patients were reviewed and corresponding data regarding corneal thickness was obtained from a related database of Orbscan II pachymetry. Hyper-reflective endothelial nuclei were identified in 41 eyes of 39 (7.7%) patients. Diagnoses included previous cataract surgery or penetrating keratoplasty, posterior polymorphous dystrophy, Fuchs' endothelial dystrophy and irido-corneal endothelial syndrome. No patients with clinically normal corneas exhibited bright endothelial nuclei. The mean endothelial cell density in this group was 1325±872 cells mm −2 and endothelial density was below age-adjusted normal values in 69.2% of patients. Both cellular polymegathism (coefficient of variation of cell area 33.9±7.4%) and cellular pleomorphism were noted (51.8±9.0% hexagonal cells). The mean central corneal thickness was 582±52 μm. There was no significant difference in endothelial density and morphology compared to cases that had low endothelial density but did not exhibit bright nuclei. In conclusion, this study is the first to investigate the significance of bright endothelial nuclei detected by in vivo confocal microscopy. The strong association with corneal disease states suggests that the most likely explanation for this appearance is the alteration in cellular/nuclear morphology, composition or function.

In Vivo Confocal Microscopy of Posterior Polymorphous Dystrophy

This study was designed to delineate the morphologic features of posterior polymorphous dystrophy (PPD) using in vivo confocal microscopy. Six patients with clinically diagnosed PPD were examined by slit-lamp biomicroscopy, Orbscan II slit-scanning elevation topography, and in vivo confocal microscopy. Endothelial cell densities ranged from 613 to 3,405 cells/mm and endothelial polymegathism was noted in all cases, whereas endothelial pleomorphism was not a prominent feature. Three cases exhibited bright endothelial nuclei. A variety of abnormal curvilinear and vesicular abnormalities were imaged by in vivo confocal microscopy, with lesions ranging between 6 and 159 microm in diameter. Abnormal endothelial cells were visible within some of these lesions. Six cases showed hyperreflectivity at the level of Descemet's membrane around the lesions. Deep stromal keratocytes appeared to aggregate around, or were compressed by, the endothelial lesions in one case. We report the largest case series of PPD imaged by in vivo confocal microscopy. The ability of in vivo confocal microscopy to assess the living cornea over time enables monitoring of disease progression and thus the potential to identify and correlate development of, or changes in, microstructural features. As more data become available, these analyses may enable the formulation of prognostic and diagnostic criteria.

Confocal Microscopy of Posterior Polymorphous Endothelial Dystrophy

To report the in vivo confocal microscopic findings of posterior polymorphous endothelial dystrophy (PPED). Four patients with PPED from 2 unrelated families and 2 asymptomatic children of an index patient were included in this observational case series. The eyes of the 6 subjects were examined by confocal light microscopy. Confocal microscopy demonstrated craters, streaks, and cracks over the corneal endothelium surface. Pleomorphism and polymegathism were present in eyes with PPED. Guttae and clusters of abnormal endothelial cells were also identified in corneas of these PPED patients. These findings were absent in eyes without clinical manifestations of PPED. In vivo confocal microscopy is potentially useful for excluding suspected cases of subclinical PPED. Abnormalities in the Descemet membrane and endothelium were observed.

Inheritance of a NovelCOL8A2Mutation Defines a Distinct Early-Onset Subtype of Fuchs Corneal Dystrophy

To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.

Laser In Situ Keratomileusis in Patients With Posterior Polymorphous Dystrophy

To report short-term results of LASIK in 4 eyes with the vesicular form of posterior polymorphous dystrophy (PPMD). A review was performed of 2 patients with PPMD who underwent bilateral LASIK. Patients were asymptomatic at the time of presentation and had no prior ocular history. Preoperative measurements were made of uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), corneal pachymetry, and endothelial cell density (ECD). All 4 eyes underwent uneventful LASIK. Postoperative measurements of UCVA and BSCVA were performed at follow-up visits 1 day, 1 month, 3 months, and 1 year after surgery, along with pachymetry and ECD measurements at the 3-month and 1-year visits. Results were analyzed. At 1 year, all eyes had an UCVA equal to or better than 20/25 and BSCVA equal to or better than 20/20. There was a small mean endothelial cell loss (2.3%) at 1 year. No adverse events were experienced. Short-term results indicate efficacy and safety of LASIK on eyes with posterior polymorphous dystrophy. Further study is needed to assess long-term outcomes in a larger study population.

Corneal Transplants for the Treatment of Congenital Corneal Opacities

To describe the results of corneal transplants in infants and young children with congenital corneal disorders. The charts of 38 children who underwent corneal transplantation for congenital corneal opacities from 1988 to 1999 at the Hospital for Sick Children, Toronto, Ontario, were reviewed. Parameters reviewed included indication, age at diagnosis and surgery, graft size, graft clarity, repeat surgery, glaucoma pre- and postsurgery, visual acuity, and refraction. Thirty-eight children (63 eyes) underwent 86 corneal transplants. The four most common indications for surgery included posterior polymorphous dystrophy, Peters anomaly, congenital glaucoma, and sclerocornea. Mean follow-up was 40.4 +/- 30.2 months (range, 2-111 months). Seventy-eight percent of the grafts were clear at the final follow-up visit. There were 23 repeat grafts in the entire group. The overall success rate of graft clarity was 78% for children undergoing corneal transplantation for congenitally opaque corneas. Best results were achieved in patients with posterior polymorphous dystrophy, followed by patients with Peters anomaly. Sclerocornea and congenital glaucoma carried a 50% chance of success, with repeated transplants needed for many of the eyes.

Frequency, distribution, and outcome of keratoplasty for corneal dystrophies at a tertiary eye care center in South India.

To report the frequency, outcome, and atypical histology in corneal dystrophies. Corneal buttons of patients diagnosed with corneal dystrophy as noted in the records of the ophthalmic pathology register over a period of 6 years were included in this study. The sections from formalin-fixed, paraffin-embedded tissues were reviewed specifically for the type of deposits, associated degenerations such as amyloid and spheroidal deposits, inflammation, and vascularization. Special stains including Masson trichrome, Congo red, and Alcian blue staining were used whenever required. The medical records were evaluated for demographics, clinical presentation, history of consanguinity, family medical history, and clinical outcome of keratoplasty, which was recorded as clear, recurrence of dystrophy, or graft failure. A clinicopathologic correlation was attempted. A total of 144 patients contributed 181 buttons, accounting for 8.1% of keratoplasties performed during the study period. The mean age of the patients was 34 +/- 19 years (range 3-72 years) with a male:female ratio of 1.6 (89):1 (55). Consanguineous parentage was noted in 26% of cases. History of a similar problem in siblings and other family members was elicited in 33 (22%) and 14 (9.7%), respectively. Dystrophies included macular (29.3%), congenital hereditary endothelial dystrophy (34.8%), Fuchs (16.6%), and lattice (15%); the remaining 11% included granular, gelatinous drop-like, Reis-Bucklers, and posterior polymorphous dystrophy. Associated histologic changes were degenerations (15%), vascularization (4%), and inflammation (2%). At a mean follow-up of 42 months, the graft remained clear in 148 eyes (81.7%), failed in 33 eyes (18.2%), and recurred in 5 eyes (2.8%). Graft survival for all dystrophies at the end of 1 year was 94.3 +/- 1.7%, and at the end of 5 years was 74.4 +/- 4.5%. Atypical histologic features did not affect graft survival. Consanguineous marriages possibly contributed to the increase in macular dystrophy and CHED in South India. The degenerative changes seen could possibly be related to late presentation or unknown environmental factors and do not have an effect on the ultimate graft outcome.

Analysis of COL8A2 gene mutation in Japanese patients with Fuchs' endothelial dystrophy and posterior polymorphous dystrophy.

To determine whether Japanese patients with Fuchs' endothelial corneal dystrophy (FECD) and posterior polymorphous dystrophy (PPMD) carry mutations in the COL8A2 gene, and to investigate the possible pathogenicity of the COL8A2 gene in these corneal dystrophies. DNA analysis of the COL8A2 gene was performed in 15 unrelated Japanese patients with FECD, and 5 patients with PPMD using polymerase chain reaction and direct sequencing. Mutation screenings were also performed in 36 unrelated normal volunteers as controls, as well as slit-lamp and specular microscopy. Two types of heterozygous missense mutations of the COL8A2 gene (R155Q and T502M) in 5 of 15 FECD probands (R155Q, 3/30 chromosomes, 10.0%; T502M, 3/30 chromosomes, 10.0%) were found. No mutation was detected in the coding region of the COL8A2 gene in the remaining 10 patients with FECD nor in any of the 5 patients with PPMD. These two mutations were also found in normal Japanese volunteers (R155Q, 5/72 chromosomes, 6.9%; T502M, 11/70 chromosomes, 15.7%). The chromosomal frequency of the two mutations was not significant between the patients and normal controls. The R155Q and T502M mutations of COL8A2 may not be the causative defect in the Japanese FECD and PPMD patients examined in this study.

An immunohistochemical analysis and comparison of posterior polymorphous dystrophy with congenital hereditary endothelial dystrophy.

To evaluate the immunohistochemical profiles of the abnormal endothelial cells of posterior polymorphous dystrophy (PPMD) and congenital hereditary endothelial dystrophy (CHED). Formalin-fixed, paraffin-embedded sections of seven corneas with the diagnosis of PPMD (seven patients), six corneas with the diagnosis of CHED (four patients), and five control corneas were stained with hematoxylin-eosin. Adjacent histologic sections were stained with monoclonal antibodies that react with pancytokeratin, AE1/AE3, cytokeratin (CK) 7, CK 20, CAM 5.2, and epithelial membrane antigen. The immunoreactivity of the corneal endothelium was assessed by light microscopy. The endothelial cells stained positive for pancytokeratin and CK 7 in seven of seven corneas of patients with PPMD and five of six corneas of patients with CHED; variable positivity was seen to AE1, AE3, and CAM 5.2. The endothelium was uniformly negative to staining by CK 20. The epithelium stained positive with pancytokeratin, AE1, and AE3. All control corneas were negative for pancytokeratin, CK 7, and CK 20. The abnormal endothelium in both PPMD and CHED expresses similar CKs, including CK 7, which is not present in normal endothelium or surface epithelium. This may indicate a shared developmental abnormality in these conditions, as previously suggested by ultrastructural studies and genetic mapping.

Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.