Early and late clinical landmarks of corneal dystrophies.

Corneal dystrophies (CDs) represent a heterogenous group of genetic diseases (Lisch and Weiss, 2019). The International Committee of Classification of Corneal Dystrophies (IC3D) distinguishes between 22 distinct forms of corneal dystrophy (CD) which are predominantly autosomal dominant, although autosomal recessive and X-chromosomal dominant and recessive patterns do exist. A detailed corneal examination of as many affected family members as possible can show the phenotypic differences of the various generations. There are few publications which describe the different CDs with regard to the early and late phenotypes. According to early and late phenotype, three types of CD are generally classified: (1) Thirteen CDs with early and late clinical landmarks. However, it must be pointed out that the different penetrances of the gene often leads to quantitative differences in the corneal phenotype in peers in distinct generations of the same family. (2) Seven CDs with late onset and very little progression of the corneal changes. (3) Two CDs with congenital haze which can be interpreted as the final phenotype of this dystrophy. This applies to autosomal dominant and recessive inheritance.

[Corneal dystrophies]. / Les dystrophies de cornée.

Degenerative or hereditary corneal diseases are sometimes difficult to discriminate. Corneal dystrophies affect approximately 0.09 % of the population. They are identified by the IC3D classification based on their phenotype, genotype and evidence gathered for their diagnosis. Practically, the ophthalmologist manages functional symptoms, such as recurrent erosions, visual loss and amblyopia, photophobia, foreign body sensation, and sometimes pain and aesthetic concerns. Medical treatments consist of drops to promote healing, ointments, hyperosmotic agents and bandage contact lenses. Less invasive surgical treatments are used as second line therapy (phototherapeutic keratectomy, lamellar keratectomy). More invasive procedures may eventually be utilized (lamellar or penetrating keratoplasty). Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases. Some rare dystrophies require coordinated and comprehensive medical care.

Corneal dystrophies.

Degenerative or hereditary corneal diseases are sometimes difficult to discriminate. Corneal dystrophies affect approximately 0.09% of the population. They are identified by the IC3D classification based on their phenotype, genotype and evidence gathered for their diagnosis. In practice, the ophthalmologist manages functional symptoms such as recurrent erosions, visual loss and amblyopia, photophobia, foreign body sensation, and sometimes pain and aesthetic concerns. Medical treatments consist of drops to promote healing, ointments, hyperosmotic agents and bandage contact lenses. Less invasive surgical treatments are used as second line therapy (phototherapeutic keratectomy, lamellar keratectomy). More invasive procedures may eventually be utilized (lamellar or penetrating keratoplasty). Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases. Some rare dystrophies require coordinated and comprehensive medical care.

The Genetics and Pathophysiology of IC3D Category 1 Corneal Dystrophies: A Review.

Corneal dystrophies are a group of inherited disorders affecting the cornea, many of which lead to visual impairment. The International Committee for Classification of Corneal Dystrophies has established criteria to clarify the status of the various corneal dystrophies, which include the knowledge of the underlying genetics. In this review, we discuss the International Committee for Classification of Corneal Dystrophies category 1 (second edition) corneal dystrophies, for which a clear genetic link has been established. We highlight the various mechanisms underlying corneal dystrophy pathology, including structural disorganization, instability or maladhesion, aberrant protein stability and deposition, abnormal cellular proliferation or apoptosis, and dysfunction of normal enzymatic processes. Understanding these genetic mechanisms is essential for designing targets for therapeutic intervention, especially in the age of gene therapy and gene editing.

Contact Lens Applications and the Corneal Dystrophies: A Review.

The cornea is precious to sight. Its intricate cellular arrangement and physiology enable it to be transparent and refractive. Corneal dystrophies (CDs) impact vision at various decades of life depending on the dystrophy at hand. Left untreated, visual ramifications ensue. This review article will summarize the current knowledge of the various CDs and the relatively controversial classification based on new genetic knowledge and clinical and histological characteristics. The application of contact lenses, both soft and rigid, has a place in the care and rehabilitation of these unique corneas.

Corneal Dystrophies: Overview and Summary.

In this chapter, I shall discuss the genetics, mode of inheritance and molecular origin of several corneal dystrophies.

UTILIZATION OF FUNDUS AUTOFLUORESCENCE, SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY, AND ENHANCED DEPTH IMAGING IN THE CHARACTERIZATION OF BIETTI CRYSTALLINE DYSTROPHY IN DIFFERENT STAGES.

PURPOSE: To characterize Bietti crystalline dystrophy (BCD) in different stages using multiple imaging modalities. METHODS: Sixteen participants clinically diagnosed as BCD were included in the retrospective study and were categorized into 3 stages according to fundus photography. Eleven patients were genetically confirmed. Fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging features of BCD were analyzed. RESULTS: On fundus autofluorescence, the abnormal autofluorescence was shown to enlarge in area and decrease in intensity with stages. Using spectral domain optical coherence tomography, the abnormalities in Stage 1 were observed to localize in outer retinal layers, whereas in Stage 2 and Stage 3, more extensive retinal atrophy was seen. In enhanced depth imaging, the subfoveal choroidal layers were delineated clearly in Stage 1; in Stage 2, destructions were primarily found in the choriocapillaris with associated alterations in the outer vessels; Stage 3 BCD displayed severe choroidal thinning. Choroidal neovascularization and macular edema were exhibited with high incidence. IVS6-8del17bp/inGC of the CYP4V2 gene was the most common mutant allele. CONCLUSION: Noninvasive fundus autofluorescence, spectral domain optical coherence tomography, and enhanced depth imaging may help to characterize the chorioretinal pathology of BCD at different degrees, and therefore, we propose staging of BCD depending on those methods. Physicians should be cautious of the vision-threatening complications of the disease.

Staging of development in Terrien's degeneration based on corneal curvatures detected by optical coherence tomography.

PURPOSE: We aimed to explore a new classification system based on the change of focal corneal curvatures and corneal thickness in Terrien's corneal degeneration with optical coherence tomography. METHODS: This was a cross-sectional study. Ninety eyes of 59 patients with Terrien's degeneration were examined with slit lamp biomicroscopy, Orbscan II corneal tomography and the Visante OCT system, and were staged according to Süveges's classification. RESULTS: The ratio of female to male patients was 1.57:1. The ratio of bilateral to unilateral lesions was 1.27:1. The occurrence of bilateral lesion was higher in males than in females (x(2) = 7.791, p = 0.005). There was no difference in the mean age between female and male patients (t = 1.859, p = 0.068), or between patients with bilateral and unilateral lesions (t = 1.797, p = 0.078).The minimum corneal thickness at the thinnest point (MinCT) and anterior curvature of the peripheral cornea were almost normal in the initial stages of disease. The anterior curvature was flattened when MinCT became less than 0.56 mm, returned to normal when MinCT was no more than 0.24 mm, and bowed forward when MinCT was no more than 0.13 mm. The posterior corneal curvatures were bowed forward from their normal curvatures in 42 of 90 eyes when MinCT was no more than 0.41 mm. These eyes' MinCT ranged from 0 to 0.41 mm. There was a strong correlation between change of corneal curvatures and MinCT (r = -0.943, p < 0.01). A new classification of six stages based on corneal curvatures is proposed for evaluating the development of Terrien's degeneration. Statistically, there was a moderate correlation between either the Süveges staging or the new staging and the width and circumference of corneal lesions, visual acuity, and simulated keratometric value (all r < 0.6). The correlation of MinCT with the new classification based on corneal curvatures was higher than that with Süveges's classification (r 1 vs. r 2 , -0.943 vs. -0.801). CONCLUSION: The proposed new classification based on focal corneal curvatures is closely associated with corneal thinning, is valuable for evaluating the development of Terrien's degeneration and may enhance surgical planning.

[The revised newest IC³D classification of corneal dystrophies]. / Die revidierte neueste IC³D-Klassifikation der Hornhautdystrophien.

PURPOSE: This report suggests how corneal dystrophies (CDs) should be diagnosed at the slit lamp and specifies the new IC(3)D classification of CDs in 2015 which incorporates new information. METHODS: IC(3)D reviewed all peer-reviewed articles on CDs 2008 to 6/2014. Corneal dystrophy templates and anatomic classifications were updated. RESULTS: To detect landmarks for correct classification of CDs, opacity patterns and opacity units are determined at the slit lamp. Opacity patterns are described as (1) horizontal extension, (2) vertical extension ("depth") and clarity of the (3) cornea in between. Horizontal extension is assessed using a broad beam, vertical extension using a bright, thin slit lamp beam in high magnification. For assessment of opacity units, examination using retroillumination with dilated pupil is indispensable! This is especially true for epithelial and endothelial CDs. With a better review of the cellular origin of CDs, a new anatomic classification is proposed: 1. epithelial and subepithelial; 2. epithelial-stromal transforming growth factor beta-induced (TGFBI); 3. stromal; 4. endothelial dystrophies. Epithelial recurrent erosion dystrophies include three epithelial dystrophies (Franceschetti CD, dystrophia Smolandiensis, and dystrophia Helsinglandica) and are differentiated against TGFBI dystrophies, also associated with recurrent epithelial erosion. The chromosome locus of Thiel-Behnke CD is only located on 5q31. The entity previously called Thiel-Behnke on chromosome 10q24 may be a unique corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is an autosomal recessive disorder. The autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to be a unique entity and most cases appear to be similar to other reported dystrophies, particularly posterior polymorphous corneal dystrophy (PPCD). CONCLUSIONS: The 2015 revision of IC(3)D classification includes an updated anatomic classification more accurately describing TGFBI dystrophies to affect multiple layers. Some entities, e.g., Grayson Wilbrandt, Meretoja syndrome, and CHED2 are removed. All authors and reviewers should adhere to this classification of CDs!

IC3D classification of corneal dystrophies--edition 2.

PURPOSE: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. METHODS: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. RESULTS: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity "Epithelial recurrent erosion dystrophies" 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). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. CONCLUSIONS: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

[Update on corneal dystrophies: new insights following first publication of the IC3D classification]. / Update Hornhautdystrophien: Neues nach der Erstveröffentlichung der IC3D-Klassifikation.

In this review we summarise the new insights into corneal dystrophies following publication of the IC3D classification in 2008. Topics covered are new mutations, new clinical/histological phenotypes, first descriptions of known mutations in previously not mentioned ethnic groups, new dystrophic entities after modern corneal surgery and potentially new types of conservative therapy.

Granular corneal dystrophy: a novel approach to classification and treatment.

PURPOSE: The purpose of this case report is to review granular corneal dystrophy (GCD) and examine the new paradigm in its classification and treatment. CASE REPORT: A 49-year-old white male patient reported yearly for monitoring of GCD. He had an ocular surgical history in the left eye for penetrating keratoplasty in 1989 and phototherapeutic keratectomy with mitomycin C for graft recurrence of stromal bread-crumb opacities 17+ years later in 2002. At his last examination, the patient's vision and comfort was stable in each eye, with minimal recurrence of granular opacities in the left surgical eye, stable granular opacities in the right eye, no recurrent corneal erosion symptoms in either eye, and best spectacle-corrected vision of 20/40 OD and 20/30 OS. CONCLUSIONS: GCD is a Category 1, Stromal, TGFBI-associated corneal dystrophy. Although it is classified as a stromal dystrophy, research suggests the possibility that the granular opacities have an origination to the corneal epithelium with a migratory effect to the corneal stroma. Patients with Groenouw I, like the one in this report, usually do not have severely compromised vision. When vision is significantly affected or recurrent corneal erosion occurs, despite first- and second-line treatments, viable management options thereafter include photokeratectomy and other new surgical treatments such as femtosecond deep anterior lamellar keratoplasty and femtosecond laser-assisted keratoplasty. Future advancements in diagnostic technology, immunohistologic and genetic testing, medications, and surgery will allow for advancements in treating and managing patients with GCD.

Corneal dystrophies and genetics in the International Committee for Classification of Corneal Dystrophies era: a review.

Many of the corneal dystrophies have now been genetically characterized, and a system was established in 2008 by The International Committee for Classification of Corneal Dystrophies (IC3D) in an attempt to standardize the nomenclature. IC3D provided a classification system whereby all dystrophies can be categorized on the basis of the underlying genetic knowledge. Since that time, further work has established even more phenotypic and allelic heterogeneity than anticipated, particular for Fuchs endothelial corneal dystrophy and posterior polymorphous dystrophy. Using genome-wide association studies, a number of genes are now implicated both in normal corneal quantitative traits, such as central corneal thickness, as well as in disease. There is also a trend towards functional characterization of the genetic variants involved to elucidate the pathophysiology of these entities. This review article will provide an overview of the knowledge to date, with an emphasis on findings since the IC3D classification was published in 2008.

Classification of posterior polymorphous corneal dystrophy as a corneal ectatic disorder following confirmation of associated significant corneal steepening.

IMPORTANCE: The identification of steep corneal curvatures in a significant percentage of patients with posterior polymorphous corneal dystrophy (PPCD) confirms this previously reported association and suggests a role for the ZEB1 protein in keratocyte function. OBJECTIVE: To determine whether PPCD is characterized by significant corneal steepening. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at university-based and private ophthalmology practices of 38 individuals (27 affected and 11 unaffected) from 23 families with PPCD. EXPOSURE: Slitlamp examination and corneal topographic imaging were performed for individuals with PPCD and unaffected family members. Saliva or blood samples were obtained from each individual for DNA isolation and ZEB1 sequencing. Corneal ZEB1 expression was measured using immunohistochemistry. MAIN OUTCOMES AND MEASURES: Percentage of individuals affected with PPCD and controls with an average keratometric value greater than 48.0 diopters (D) in each eye; the mean keratometric value averaged for both eyes of individuals with PPCD and controls; and the correlation of ZEB1 mutation with keratometric value. RESULTS: ZEB1 coding region mutations were identified in 7 of the 27 affected individuals. Ten of the 38 individuals (26.3%) had average keratometric values greater than 48.0 D OU: 10 of 27 individuals with PPCD (37.0%; 6 of 7 individuals with ZEB1 mutations [85.7%] and 4 of 20 individuals without ZEB1 mutations [20.0%]) and 0 of 11 unaffected individuals (P = .04 for unaffected vs affected individuals; P = .004 for individuals with PPCD with vs without ZEB1 mutation). The mean keratometric value of each eye of affected individuals (48.2 D) was significantly greater than that of each eye of unaffected family members (44.1 D) (P = .03). Affected individuals with ZEB1 mutations demonstrated a mean keratometric value of 53.3 D, which was significantly greater than that of affected individuals without ZEB1 mutations (46.5 D; P = .004). Fluorescence immunohistochemistry demonstrated ZEB1 expression in keratocyte nuclei. CONCLUSIONS AND RELEVANCE: Abnormally steep corneal curvatures are identified in 37% of all individuals with PPCD and 86% of affected individuals with PPCD secondary to ZEB1 mutations. ZEB1 is present in keratocyte nuclei, suggesting a role for ZEB1 in keratocyte function. Therefore, ZEB1 may play a role in both corneal stromal and endothelial development and function, and PPCD should be considered both an endothelial dystrophy and an ectatic disorder.