Posterior Polymorphous Corneal Dystrophy Research Articles

Corneal opacities in children

The corneal opacities in childhood could be either, congenital or acquired. The congenital could either localized/non‐systemic disease, like the congenital hereditary endothelial dystrophy, posterior polymorphous corneal dystrophy, congenital hereditary stromal dystrophy, peters anomaly, congenital anterior staphyloma, sclerocornea, cornea plana, cornea tumours, epibulbar dermoid, or related to systemic/metabolic Disorders like mucopolysaccharidoses, cystinosis, tyrosinemia, schnyder crystalline dystrophy, fetal alcohol syndrome. The acquired corneal opacities could be either traumatic, like traumatic breaks in descemet membrane, corneal blood staining, corneal keloids, or non traumatic like keratoconus, posterior corneal depression, keratoglobus, congenital or infantile glaucoma, Corneal ulcers, Familial dysautonomia (Riley‐Day syndrome), Stevens‐Johnson syndrome and toxic epidermal necrolysis. We will discuss these cases, their clinical picture, work up and management.

The newest IC3D classification of corneal dystrophies

In the year 2015, the International Committee for the Classification of Corneal Dystrophies (IC3D) incorporated new clinical, histopathologic, and genetic information into the former 2008 classification. To this end, the IC3D sighted and evaluated worldwide peer‐reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates including categories 1 to 4 and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added.On the basis of revisiting the cellular origin of corneal dystrophies, a modified anatomic classification was proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial‐stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. The entity “Epithelial recurrent erosion dystrophies ERED” actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI‐induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel‐Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel‐Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so‐called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Anterior segment OCT has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination in order to definitively diagnose them.This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies that more accurately classifies TGFBI dystrophies affecting multiple layers rather than being confined to one corneal layer. At this time, a 3rd edition of the IC3D classification of corneal dystrophies is under way.

Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence.

Pathogenic variants in the highly conserved OVOL2 promoter region cause posterior polymorphous corneal dystrophy (PPCD) 1 by inducing an ectopic expression of the endothelial OVOL2 mRNA. Here we produced an allelic series of Ovol2 promoter mutations in the mouse model including the heterozygous c.-307T>C variant (RefSeq NM_021220.4) causing PPCD1 in humans. Despite the high evolutionary conservation of the Ovol2 promoter, only some alterations of its sequence had phenotypic consequences in mice. Four independent sequence variants in the distal part of the Ovol2 promoter had no significant effect on endothelial Ovol2 mRNA level or caused any ocular phenotype. In contrast, the mutation c.-307T>C resulted in increased Ovol2 expression in the corneal endothelium. However, only a small fraction of adult mice c.-307T>C heterozygotes developed ocular phenotypes such as irido-corneal adhesions, and corneal opacity. Interestingly, phenotypic penetrance was increased at embryonic stages. Notably, c.-307T>C mutation is located next to the Ovol1/Ovol2 transcription factor binding site. Mice carrying an allele with a deletion encompassing the Ovol2 binding site c.-307_-320del showed significant Ovol2 gene upregulation in the cornea endothelium and exhibited phenotypes similar to the c.-307T>C mutation. In conclusion, although the mutations c.-307T>C and -307_-320del lead to a comparably strong increase in endothelial Ovol2 expression as seen in PPCD1 patients, endothelial dystrophy was not observed in the mouse model, implicating species-specific differences in endothelial cell biology. Nonetheless, the emergence of dominant ocular phenotypes associated with Ovol2 promoter variants in mice implies a potential role of this gene in eye development and disease.

Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis

BackgroundThe neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes...

Scratched cornea: Case report on incidental bilateral posterior polymorphous corneal dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is a dominantly inherited corneal endothelial disorder, typically considered bilateral and asymptomatic. We report a case of bilateral PPCD that presented as an incidental finding on routine ophthalmic examination. Related visual prognosis is discussed. A 27-year-old male presented for a routine ophthalmic examination. Visual acuity was recorded for both eyes. A detailed slit-lamp examination and anterior-segment optical coherence tomography (AS-OCT) was done. Best-corrected visual acuity was recorded as 6/6 for both eyes. Slit-lamp examination revealed band-shaped lesions in the inferior quadrant of bilateral corneas, at the junction of Descemet's membrane and corneal endothelium. AS-OCT revealed central corneal thickness as 556 and 544 µm for the right and left cornea, respectively, along with a hyper-reflective lesion at the level of corneal endothelium in the right eye.

Tools of the cornea specialist

To report a case of a successful Descemet's membrane endothelial keratoplasty (DMEK) facilitated by the use of intracameral tissue plasminogen activator (tPA) in a 4-year old with posterior polymorphous corneal dystrophy (PPCD).A 4-year old male was referred for bilateral corneal haze and blurry vision. Patient's exam and genetic testing were consistent with a diagnosis of PPCD. Patient was successfully treated with DMEK augmented by the use of intracameral tPA intraoperatively to combat the anterior chamber fibrin formation that can occur in DMEK.To our knowledge, this case represents the youngest reported successful DMEK procedure and the first case describing the use of intracameral tPA intraoperatively to attenuate the anterior chamber fibrin formation that can occur in DMEK.

Genetics of keratoconus; how realistic is gene therapy?

AbstractKeratoconus (KC) is a complex, non‐inflammatory eye condition that impairs the focusing ability of the eye by progressively thinning and distorting the cornea. Its causes remain elusive, as it is a genetically heterogeneous, multifactorial degenerative disorder. KC follows an autosomal (either recessive or dominant) pattern of inheritance and is associated with genes which interact with environmental, genetic and/or other factors.At present, the only fairly reliable treatment that slows down the progression of KC is cornea collagen cross‐linking. In extreme cases a corneal transplant may be required. This fact alone makes gene therapy for KC, a promising therapeutic approach. Such hopes are bolstered by the biophysical properties of the corneal tissues which include the corneal immune privilege, the transparency of the corneal tissue together with its and ex vivo stability, and the uncomplicated operative approach to the eye anterior chamber. In addition, recent advances in vectors, along with the ability to modulate the corneal milieu in order to ensure a relatively long survival of the target gene and allow its successful translation, further bolster the hopes for successfully treating KC via gene therapy.Over the last two decades, however, genome‐wide association studies and studies on SNP and genetic loci identification have identified more than 50 genomic loci that are implicated in both the dysregulation of the corneal collagen matrix formation and maintenance or the cell differentiation pathways that sustain corneal integrity. Among the most prominent genes involved in KC are the VSX1 gene, which is involved, among others, in posterior polymorphous corneal dystrophy; the SOD1 gene which determines the effects of reactive oxygen species; the ZNF469 gene which is also involved in the Brittle Cornea Syndrome; the TGF8 pathway which is involved in the regulation of the extracellular matrix composition; the TGFI gene which plays a role in cell‐collagen interactions. The roles of the MicroRNAs (especially that of the miRNA 184) and of mitochondrial DNA must, also, be stressed. Recently, we bibliographically identified and documented 18 different KC symptoms and clinical signs and cross referenced them to 24 different genes/genetic loci. It turns out that each of these symptoms is associated with from between 3 and 14 identified KC genes. We similarly identified 49 diseases and/or syndromes that involve at least some of the KC‐implicated genes and cross‐referenced them to these 24 genes. Again, it turns out that each one of the 49 diseases/syndromes is associated with from between 1 and 23 KC‐implicated genes.The complex interrelations among the different biophysical and biochemical processes involved in KC, the multitude of related genomic loci, and the large number of comorbidities, collectively, they cast gene therapy in an unfavourable light as a realistic treatment option for KC., On the other hand, the possible identification of a pivotal role for only a handful of genes, may open the path for gene therapy in KC.

RARE CASE OF ISOLATED ANTERIOR LENTICONUS

Lenticonus is a bulging of the lens capsule and the underlying cortex. The diagnosis of lenticonus is essentially a clinical diagnosis which is made by biomicroscopic examination. According to the localization of the conus a distinction is made between lenticonus anterior and lenticonus posterior. Sometimes isolated, it may be an ocular manifestation of Alport syndrome, a hereditary nephritis accompanied by deafness and other ocular signs such as ecked retinopathy or posterior polymorphous corneal dystrophy. All these manifestations are a result of a genetic defect in type IV collagen, a major component of basal membranes in the human body. The clinical aspects and therapy of anterior lenticonus and Alport syndrome are described, as well as the exploration that must begin when anterior lenticonus is discovered. Preconical lenses are less commonly reported and are ［ ］ more common in Alport syndrome (AS) If a patient with a conical 2 lens in front of eye is observed clinically, the possibility of being an AS patient should be ruled out rst. AS,typically manifested as renal injury (hematuria, proteinuria and progressive renal insufciency), neurosensorineural deafness and eye injury triad, more common in women, but male patients are more seriously ill, and most of them have renal failure before the age of 40. 11%~92% of AS patients have eye injury, of which anterior conus lens and spotted retinopathy are characteristic changes, mostly involving both eyes, usually only when renal failure occurs. Reference to the Flinter standard or the new Gregory standard ,For the family history and eye, ear, and kidneyrelated examinations of patients with suspected AS, clinical diagnosis can usually be established, and combined with pathological examination and collagen molecular immunopathological examination, clinicopathological diagnosis can be established in most cases .

Descemet Membrane Endothelial Keratoplasty (DMEK) for Severe Verrucous Posterior Polymorphous Corneal Dystrophy with Uncommon Clinical and Ultrastructural Findings.

To report a case of severe verrucous posterior polymorphous corneal dystrophy (PPCD) and cataract, which was treated with Descemet membrane endothelial keratoplasty (DMEK) and simultaneous cataract surgery as a triple procedure (Triple-DMEK). A 62-year-old female patient presented to our department for co-evaluation of advanced PPCD with cataract and progressive light sensitivity in both eyes. The clinical examination demonstrated unusual clinical findings with prominent verrucous lesions on the posterior surface of the cornea without corneal decompensation. We performed a Triple-DMEK in case of simultaneous cataract. The corneal tissue was examined by light and transmission electron microscopy. Intraoperatively, it was difficult to remove the verrucous structures completely after classical descemetorhexis. Light microscopic examination demonstrated epithelium-like transformation of the corneal endothelium by immunostaining (cytokeratin AE1/3 staining). Transmission electron microscopy revealed thickening of Descemet's membrane (18.5 to 30.0 µm). The anterior banded layer had a normal structure and was slightly thickened (3.5 to 5.5 µm). A normal posterior non-banded layer (PNBL) was observed but thinned (2.5 to 4.0 µm) or missing. It was followed by an altered PNBL with abnormal fibrillary inclusions, which was strongly and variably thickened (11.0 to 24.5 µm). The corneal endothelium was degenerated, partially absent, and epithelial-like altered. The nodular lesions were found to consist of a few degenerated cells that were embedded in an amorphous extracellular matrix interspersed with collagen fibers, which were not arranged in regular lamellae, forming the corneal stroma. The occurrence of pigment granules among the cellular debris suggested that the cells were endothelial cells. The corrected distance visual acuity improved from 20/50 to 20/30 in the right eye (+ 0.00/- 1.75/157°) and from 20/60 to 20/30 in the left eye (+ 0.00/- 1.75/33°), with significant improvement in light sensitivity. The clinical and ultrastructural findings seem to be an unusual variant of the typical characteristic appearance of a PPCD. This case demonstrates that Triple-DMEK is feasible even in very advanced dystrophic changes of the posterior corneal surface, with good morphological and functional results.

Posterior corneal vesicles are not associated with the genetic variants that cause posterior polymorphous corneal dystrophy.

Posterior corneal vesicles (PCVs) have clinical features that are similar to posterior polymorphous corneal dystrophy (PPCD). To help determine whether there is a shared genetic basis, we screened 38 individuals with PCVs for changes in the three genes identified as causative for PPCD. We prospectively recruited patients for this study. We examined all individuals clinically, with their first-degree relatives when available. We used a combination of Sanger and exome sequencing to screen regulatory regions of OVOL2 and GRHL2, and the entire ZEB1 coding sequence. The median age at examination was 37.5 years (range 4.7-84.0 years), 20 (53%) were male and in 19 (50%) the PCVs were unilateral. Most individuals were discharged to optometric review, but five had follow-up for a median of 12 years (range 5-13 years) with no evidence of progression. In cases with unilateral PCVs, there was statistically significant evidence that the change in the affected eye was associated with a lower endothelial cell density (p = 0.0003), greater central corneal thickness (p = 0.0277) and a steeper mean keratometry (p = 0.0034), but not with a higher keratometric astigmatism or a reduced LogMAR visual acuity. First-degree relatives of 13 individuals were available for examination, and in 3 (23%), PCVs were identified. No possibly pathogenic variants were identified in the PPCD-associated genes screened. We found no evidence that PCVs share the same genetic background as PPCD. In contrast to PPCD, we confirm that PCVs is a mild, non-progressive condition with no requirement for long-term review. However, subsequent cataract surgery can lead to corneal oedema.

Imaging features of posterior polymorphous corneal dystrophy observed by in vivo confocal microscopy

Objective: To identify and analyze imaging features of posterior polymorphous corneal dystrophy (PPCD) by in vivo confocal microscopy (IVCM). Methods: This retrospective case series enrolled 27 eyes of 18 patients (including 10 males and 8 females) who were diagnosed with PPCD at the Department of Ophthalmology in Peking University Third Hospital between January 2013 and December 2019. The mean age was (23.61±14.81) years. There were 9 monocular and 9 binocular cases. All patients were examined by slit-lamp biomicroscopy and IVCM. The visual acuity, the mean endothelial cell density, and the images of IVCM were analyzed in all cases. Results: The mean best-corrected visual acuity was 0.76±0.33, and the mean endothelial cell density was (1 723.6±698.3) cells/mm2. The IVCM images of type 1 PPCD (vesicular lesions) showed hyperreflective, placoid or homocentric lesions at the level of the Descemet's membrane, hyporeflective, oval or round lesions at the level of the Descemet's membrane, and hyporeflective, crater-like lesions at the level of the endothelial cell layer. The IVCM images of type 2 PPCD (band lesions) displayed hyperreflective, band lesions and a fibrous strand structure at the level of the Descemet's membrane, hyporeflective, vesicular lesions at the level of the Descemet's membrane, and hyporeflective, trough-and ridge-like lesions at the level of the endothelial cell layer. The IVCM images of type 3 PPCD (geographic placoid opacities) showed loss of the hexagonal features of endothelial cells and epithelial-like cell transformation. Conclusions: PPCD primarily affects the endothelium and Descemet's membrane. IVCM could highlight the special characteristics of PPCD including hyperreflective lesions at the level of the Descemet's membrane, hyporeflective lesions at the level of the endothelial cell layer, and epithelial-like cell transformation of endothelial cells. IVCM is an invaluable tool for clinical diagnosis and dynamic monitoring of PPCD.

Update on the genetics of corneal endothelial dystrophies.

Corneal endothelial dystrophies are a heterogeneous group of diseases with different modes of inheritance and genetic basis for each dystrophy. The genes associated with these diseases encode transcription factors, structural components of the stroma and Descemet membrane, cell transport proteins, and others. Congenital hereditary endothelial dystrophy (CHED) is associated with mutations in two genes, OVOL2 and SLC4A11, for dominant and recessive forms of CHED, respectively. Mutations in three genes are known to cause posterior polymorphous corneal dystrophy (PPCD). They are OVOL2 (PPCD1), ZEB1 (PPCD3), and GRHL1 (PPCD4). The PPCD2 locus involving the collagen gene COL8A2 on chromosome 1 is disputed due to insufficient evidence. Mutations in the COL8A2 gene are associated with early-onset Fuchs’ endothelial corneal dystrophy (FECD). Several genes have been associated with the more common, late-onset FECD. Alterations in each of these genes occur in a fraction of patients, and the most prevalent genetic alteration in FECD patients across the world is a triplet repeat expansion in the TCF4 gene. Knowledge of the genetics of corneal endothelial dystrophies has considerably advanced within the last decade and has contributed to better diagnosis of these dystrophies as well as opened up the possibility of novel therapeutic approaches based on the molecular mechanisms involved. The functions of genes identified to date provide insights into the pathogenic mechanisms involved in each disorder.

C.-61G>A in OVOL2 is a Pathogenic 5′ Untranslated Region Variant Causing Posterior Polymorphous Corneal Dystrophy 1

The purpose of this study was to investigate the clinical and genetic features of a man and his daughter with posterior polymorphous corneal dystrophy (PPCD), referred to our clinic for Descemet membrane endothelial keratoplasty. No other known relatives were affected. Ophthalmic examination and histology, including electron microscopy, were performed. Genetic testing was conducted by means of whole exome sequencing, and variant analysis was achieved by using an internal in silico pipeline. Molecular tests included a dual-luciferase assay. Slowly progressive blurred vision was reported from childhood by the daughter. The father's symptoms started at age 55. Best-corrected visual acuity was reduced in both patients (0.2-0.4). Slit-lamp examination in both patients revealed bilateral corneal clouding with gray endothelial lesions; other family members had no ophthalmological signs. Descemet membrane endothelial keratoplasty was performed uneventfully in both patients. Histology showed thickened Descemet membrane and abnormal endothelium resembling epithelial-like cells. Both patients carried the OVOL2 5' untranslated region NM_021220.4.c.-61G>A variant in the heterozygous state. This change was associated with increased promoter activity and was not present in the unaffected members of the family. The 5' untranslated region mutation c.-61G>A in OVOL2 has been previously found in 1 individual with PPCD1 and reported as a variant of unknown significance because of insufficient evidence supporting its pathogenicity. Identification of the second family with 2 individuals affected by PPCD1 carrying this change, together with functional data, provides further proofs that it is disease-causing.

Posterior Polymorphous Corneal Dystrophy in a Pediatric Population.

The aim of this study was to evaluate the clinical and topographic features of posterior polymorphous corneal dystrophy (PPCD) in children aged 15 years or younger with a long-term follow-up. Retrospective case series. A retrospective chart review of patients who were diagnosed with PPCD at Boston Children's Hospital from 1999 to 2020 was performed. Data collected included age at the time of diagnosis, slit lamp findings, cycloplegic refraction, best-corrected visual acuity, central corneal thickness, specular microscopy, and corneal topography findings whenever available. Twenty-seven eyes of 19 patients were included (11 unilateral and 8 bilateral cases). Ten patients were girls (52.6%). Left eye was affected in 14 eyes. The mean age at the time of diagnosis was 8.5 ± 3.3 years, with a mean follow-up of 5.3 years. In unilateral cases, there was a statistically significant difference in the endothelial cell density (P = 0.01), coefficient variation (P = 0.03), and hexagonality (P = 0.01) between the affected and the contralateral unaffected eyes. The mean best-corrected visual acuity at initial presentation was 0.8 ± 0.2 compared with 0.9 ± 0.08 in unaffected eyes (P = 0.04). The mean astigmatism was higher in the affected eye (+1.7 diopters) compared with (+1.00) the unaffected eye (P = 0.07). At initial presentation, 7 of 27 eyes had amblyopia, which resolved, either partially or completely, in 5 eyes after treatment. PPCD can present early in children with astigmatism and anisometropic amblyopia. A careful slit lamp examination for children presenting with anisoastigmatism is necessary to diagnose PPCD. Contrary to adults, presentation is often unilateral. Such patients should be followed up regularly with cycloplegic retinoscopy to prevent and treat refractive amblyopia if present.

Clinical features of posterior polymorphous corneal dystrophy in children

Posterior polymorphous corneal dystrophy (PPCD) is a genetically heterogenous endothelial disease characterized by abnormalities of Descemet’s membrane and irregular endothelium with few reports in children. We present the largest case series to-date describing the clinical features of PPCD in children ≤15 years old with long-term follow-up.

Clearing the Haze: Navigating Corneal Refractive Surgery in Patients with Posterior Polymorphous Corneal Dystrophy.

Posterior polymorphous corneal dystrophy (PPCD) is a corneal disorder of the endothelium and Descemet’s membrane. Although reports of corneal refractive surgery including laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and small incision lenticule extraction (SMILE) in PPCD are minimal, these procedures have been shown to be safe and effective in this patient population. Proceeding with corneal refractive surgery in eyes with PPCD raises concerns regarding corneal integrity, including long-term biomechanical instability, risk of ectasia, endothelial cell loss, disease progression, and corneal decompensation. Thus, LASIK, PRK, and SMILE should be considered with caution. This commentary explores the patient characteristics associated with favorable surgical outcomes and factors that weigh against proceeding with refractive surgery.

Expression and Function of ZEB1 in the Cornea.

ZEB1 is an important transcription factor for epithelial to mesenchymal transition (EMT) and in the regulation of cell differentiation and transformation. In the cornea, ZEB1 presents in all three layers: the epithelium, the stroma and the endothelium. Mutations of ZEB1 have been linked to multiple corneal genetic defects, particularly to the corneal dystrophies including keratoconus (KD), Fuchs endothelial corneal dystrophy (FECD), and posterior polymorphous corneal dystrophy (PPCD). Accumulating evidence indicates that dysfunction of ZEB1 may affect corneal stem cell homeostasis, and cause corneal cell apoptosis, stromal fibrosis, angiogenesis, squamous metaplasia. Understanding how ZEB1 regulates the initiation and progression of these disorders will help us in targeting ZEB1 for potential avenues to generate therapeutics to treat various ZEB1-related disorders.

Endothelial cell density in children with posterior polymorphous corneal dystrophy: a longitudinal case-control study.

To evaluate longitudinal endothelial cell characteristics of children with posterior polymorphous corneal dystrophy (PPCD). In this prospective case-control study, children with PPCD were followed with slit-lamp photography and non-contact specular microscopy. Patient's eyes were subdivided according to the clinical subtypes of PPCD (vesicular, band, diffuse, and unaffected) and the number of lesions present on the posterior corneal surface. Findings were then compared with age-matched controls. Thirty eyes of 15 patients with PPCD with a mean age 10.5 ± 3.1 years were analysed. Mean follow-up was 3.0 ± 1.0 years. PPCD morphology was vesicular in 40%, diffuse in 37%, band type in 10% and 13% had no detectable lesions despite contralateral involvement. Fourteen eyes (47%) had ≥5 endothelial lesions. Patients with PPCD had significantly lower endothelial cell densities (ECD) at recruitment (1918.9 ± 666.3 vs. 3340.1 ± 286.5 cells/mm2, p < 0.007) and at final follow-up (1793.1 ± 684.6 vs. 3265.2 ± 304.3 cells/mm2, p < 0.007) compared to age-matched controls. The lowest ECDs were found in eyes with diffuse type PPCD and those with ≥5 posterior corneal lesions, while clinically unaffected eyes in patients with confirmed PPCD in fellow eye had a normal ECD. However, the rates of annual ECD decline were not significantly different between eyes with PPCD in general, between the subgroups of PPCD and the normative groups. Endothelial cell density is significantly reduced among children with PPCD and depends on the clinical subtype and the number of posterior corneal lesions present. However, annual ECD loss is similar between normal eyes and those with PPCD.

Diseases of the corneal endothelium

The corneal endothelial monolayer and associated Descemet's membrane (DM) complex is a unique structure that plays an essential role in corneal function. Endothelial cells are neural crest derived cells that rest on a special extracellular matrix and play a major role in maintaining stromal hydration within a narrow physiologic range necessary for clear vision. A number of diseases affect the endothelial cells and DM complex and can impair corneal function and vision. This review addresses different human corneal endothelial diseases characterized by loss of endothelial function including: Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), bullous keratopathy, iridocorneal endothelial (ICE) syndrome, post-traumatic fibrous downgrowth, glaucoma and diabetes mellitus.

C.‐61G&gt;A in OVOL2 is a pathogenic variant in posterior polymorphous corneal dystrophy 1—a case report

AbstractPurposeTo investigate the clinical and genetic features of a man and his daughter with Posterior polymorphous corneal dystrophy 1 (PPCD1), referred to our clinic for Descemet's Membrane Endothelial Keratoplasty (DMEK). No other known relatives were affected, including the index patient's spouse and their son.MethodsClinical examination was performed by best‐corrected visual acuity (BCVA) testing, slit‐lamp examination (SLE), anterior‐segment optical coherency tomography (OCT) and specular microscopy. Histologic testing and electron microscopy were done. Genetic testing was carried out by means of Whole‐Exome Sequencing (WES), and variant analysis was achieved by an internal in silico pipeline.ResultsSlowly progressive blurred vision was reported from childhood by the daughter. The father's symptoms started approximately ten years prior to consultation. BCVA was 0.2 in both eyes in the father and 0.2/0.4 in the right/left eye in the daughter. SLE in both patients revealed bilateral corneal clouding with focal grey endothelial spots. Corneal edema with Descemet's folds was present. DMEK was performed uneventfully. Histology and electron microscopy showed layered Descemet's membrane and pleomorphic endothelial cells with vacuoles but no microvilli. Genetic analysis revealed the c. ‐61G&gt;A variant in the 5′UTR region of the OVOL2 gene heterozygously, in both patients. This change was not present in the unaffected members of the family.ConclusionsPPCD1 has been linked to mutations in the promoter and the 5′UTR region of OVOL2. The NM_021220.4:c.‐61G&gt;A DNA change was previously reported as a variant of unknown pathogenicity, despite having been identified in another patient with PPCD1. Based on perfect familial co‐segregation, complete absence of this change in all public databases of normal controls, and its identification in two additional individuals with PPCD1, we conclude that c.‐61G&gt;A is a truly pathogenic mutation for this condition.