Effect of Ritanserin and Duloxetine on the Gene Expression of Primary Aniridia and Healthy Human Limbal Stromal Cells, In Vitro.

INTRODUCTION: In congenital aniridia caused by mutations in paired box 6 (PAX6), PAX6 influences the migration and differentiation of limbal epithelial cells (LECs), thereby playing a pivotal role in aniridia-associated keratopathy. The antidepressants ritanserin and duloxetine affect PAX6 expression in LECs. Limbal stromal cells, which support limbal epithelial stem cells, are crucial in the limbal stem cell niche. This study explores how ritanserin and duloxetine influence gene expression in primary human limbal stromal cells from subjects with congenital aniridia and from healthy subjects, in vitro. METHODS: Primary human limbal stromal cells from corneas affected by aniridia (AN-LSCs) (n = 8) and from healthy corneas (LSCs) (n = 8) were isolated and cultured in either low-glucose serum-free (LGSF) or normal-glucose serum-containing (NGSC) media. Cells were treated with 4 µM ritanserin or duloxetine for 24 h. Quantitative PCR (qPCR) and western blot were used to assess the expression of PAX6, FOSL2, TGF-ß1, ACTA2A1, LUM, COL1A1, COL5A1, DSG1, FABP5 and ADH7. RESULTS: In AN-LSCs with LGSF-medium, ritanserin increased PAX6 messenger RNA (mRNA) (p = 0.007) and decreased TGF-ß1 and FOSL2 mRNA levels (P = 0.005, P = 0.038). In addition, TGF-ß1 protein levels decreased with both treatments (P = 0.02, P = 0.007), and FABP5 protein level increased, using ritanserin (P = 0.019). In LSCs with LGSF-medium, ACTA2A1 mRNA levels decreased using ritanserin and duloxetine (P = 0.028; P = 0.031), while FABP5 mRNA levels increased with ritanserin treatment (P = 0.003). Also, duloxetine use reduced α-SMA protein (P = 0.013) and increased FABP5 protein levels (P = 0.029). In LSCs with NGSC-medium, ritanserin elevated LUM, FABP5 and ADH7 mRNA and protein levels (P = 0.025, P = 0.003, P = 0.047, P = 0.024, P = 0.013, P = 0.039). CONCLUSIONS: The results of our study confirmed that the antipsychotropic drugs ritanserin and duloxetine alter PAX6 and TGF-ß1 gene expression in AN-LSCs cultured in LGSF-medium. These drugs were found to have an impact on retinoic acid signaling pathways and keratocyte characteristic markers both in LSCs and AN-LSCs, using different culture media.

Increased susceptibility of human limbal aniridia fibroblasts to oxidative stress.

Aniridia-associated keratopathy originates from a haploinsufficiency of the transcription factor PAX6 (PAX6+/-). In the corneal epithelium of PAX6+/- mice, a significant increase in oxidized proteins was observed, accompanied by impaired compensation for elevated oxidative stress (OS). The extent to which limbal fibroblast cells (LFCs) are affected by an increased susceptibility to OS in cases of congenital aniridia (AN) has not been determined, yet. Our aim was to examine the impact of OS on antioxidant enzyme expression in normal and AN-LFCs. Following isolation and culture of primary LFCs (n = 8) and AN-LFCs (n = 8), cells were treated with cobalt chloride for 48 h to chemically induce hypoxic conditions and OS. Subsequently, HIF-1α/-2α, PHD1/2, Nrf2, CAT, SOD1, PRDX6, and GPX1 gene expression was examined by qPCR. SOD1, PRDX6, and GPX1 protein levels were assessed from the cell lysate by Western blot. The induction of hypoxia led to reduced HIF-1α gene expression in both fibroblast groups (p≤0.008), while the decrease in PHD1 was limited to AN-LFCs (p = 0.0007). On the other hand, under hypoxic conditions, PHD2 showed higher mRNA expression in AN-LFCs compared to normal LFCs (p = 0.013). As a result of OS, the mRNA levels of Nrf2 (p<0.0001) and the antioxidant enzymes CAT (p = 0.005), SOD1 (p = 0.005), GPX1 (p = 0.002) decreased in AN-LFCs. This was accompanied by an increased protein expression of SOD1 (p = 0.019) and PRDX6 (p=0.0009). In the normal LFC group, the induced extent of OS had no impact on the gene (p≥0.151) and protein expression (p ≥ 0.629) of antioxidant enzymes, except for the GPX1 mRNA level (p = 0.027). AN-LFCs exhibit higher susceptibility to OS than normal LFCs. Therefore, in AN-LFCs, there are sustained alterations in gene and protein expression of antioxidative enzymes even after 48 h of CoCl2 treatment.

Examination of Subbasal Nerve Plexus and Central Corneal Stromal Microstructure in Subjects With Congenital Aniridia, Using in Vivo Confocal Laser Scanning Microscopy.

PURPOSE: During life up to 70% of aniridia subjects develop aniridia-associated keratopathy (AAK). AAK is characterized by limbal stem cell insufficiency, impaired corneal epithelial cell differentiation and abnormal cell adhesion, which leads to centripetal spreading vascularization, conjunctivalization, and thickening of the cornea. Our aim was to examine the subbasal nerve plexus and central corneal stromal microstructure in subjects with congenital aniridia, using in vivo confocal laser scanning microscopy CLSM. METHODS: 31 eyes of 18 patients (55.6% males, mean age: 25.22 ± 16.35 years) with congenital aniridia and 46 eyes of 29 healthy subjects (41.4% males, mean age 30 ± 14.82 years) were examined using the Rostock Cornea Module of Heidelberg Retina Tomograph-III. At the subbasal nerve plexus, corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal total branch density (CTBD), and corneal nerve fiber width (CNFW) were analyzed using ACCMetrics software. Keratocyte density in the anterior, middle and posterior stroma was assessed manually. RESULTS: The CNFD (2.02 ± 4.08 vs 13.99 ± 6.34/mm2), CNFL (5.78 ± 2.68 vs 10.56 ± 2.82 mm/mm2) and CTBD (15.08 ± 15.62 vs 27.44 ± 15.05/mm2) were significantly lower in congenital aniridia subjects than in controls (p < 0.001 for all). CNFW was significantly higher in aniridia subjects than in controls (0.03 ± 0.004 vs 0.02 ± 0.003 mm/mm2) (p = 0.003). Keratocyte density was significantly lower in all stromal layers of aniridia subjects than in controls (p < 0.001 for all). Stromal alterations included confluent keratocytes, keratocytes with long extensions and hyperreflective dots between keratocytes in aniridia. CONCLUSIONS: Decrease in CNFD, CNFL, and CTBD, as well as increase in CNFW well refer to the congenital aniridia-associated neuropathy. The decreased keratocyte density and the stromal alterations may be related to an increased cell death in congenital aniridia, nevertheless, stromal changes in different stages of AAK have to be further analyzed in detail.

[Staging of aniridia-associated keratopathy]. / Az aniridiához társult keratopathia stádiumbeosztása.

INTRODUCTION: Congenital aniridia is a rare panocular disease that affects almost all eye structures leading in most patients to reduced visual acuity. Ophthalmological signs include aniridia-associated keratopathy, secondary glaucoma, cataract, macular and optic nerve head hypoplasia, nystagmus. Although the term aniridia-associated keratopathy has long been used in the literature, various staging proposals have been described. OBJECTIVE: To analyze aniridia-associated keratopathy stages, using available literature classifications, in patients with aniridia in Hungary. PATIENTS AND METHODS: We examined 65 eyes of 33 patients with congenital aniridia (age: 25.69 ± 17.49 [5-59] years, 17 females [51.51%]). We recorded the corneal status by slit-lamp examination and classified the corneal abnormalities according to the Mackman, Mayer, López-García and Lagali staging. RESULTS: According to Mackman's classification, 8 eyes (12.3%) were in stage 0, 0 eye in stage 1A, 38 eyes (58.46%) in stage 1B and 19 eyes (29.23%) in stage 2. According to Mayer, stage I included 8 eyes (12.3%), stage II 38 eyes (58.46%), stage III 5 eyes (7.7%), stage IV 7 eyes (10.77%) and stage V 7 eyes (10.77%). In López-García's classification, 8 eyes (12.3%) could not be grouped, 20 eyes (30.77%) were in stage 1, 18 eyes (27.7%) in stage 2 and 19 eyes (29.3%) in stage 3. Lagali's classification included 8 eyes (12.3%) in stage 0, 20 eyes (30.77%) in stage 1, 18 eyes (27.7%) in stage 2, 5 eyes (7.7%) in stage 3 and 14 eyes (21.54%) in stage 4. CONCLUSION: We recommend using Lagali's staging scheme for aniridia-associated keratoptahy due to its ease of use, detailed progression assessment, and treatment planning. In stage 1 according to Lagali, blood vessels cross the limbus by up to 1 mm, in stage 2 the central 2-3 mm of the corneal area is spared of blood vessels. When the blood vessels reach the center of the cornea, it is stage 3, followed by opaque, uneven corneal pannus in stage 4. Orv Hetil. 2023; 164(27): 1063-1069.

Future directions in managing aniridia-associated keratopathy.

Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.

New horizons in aniridia management: Clinical insights and therapeutic advances.

Congenital aniridia is a rare genetic eye disorder characterized by the complete or partial absence of the iris from birth. Various theories and animal models have been proposed to understand and explain the pathogenesis of aniridia. In the majority of cases, aniridia is caused by a mutation in the PAX6 gene, which affects multiple structures within the eye. Treating these ocular complications is challenging and carries a high risk of side effects. However, emerging approaches for the treatment of aniridia-associated keratopathy, iris abnormalities, cataract abnormalities, and foveal hypoplasia show promise for improved outcomes. Genetic counseling plays a very important role to make informed choices. We also provide an overview of the newer diagnostic and therapeutic approaches such as next generation sequencing, gene therapy, in vivo silencing, and miRNA modulation.

Similarities in DSG1 and KRT3 Downregulation through Retinoic Acid Treatment and PAX6 Knockdown Related Expression Profiles: Does PAX6 Affect RA Signaling in Limbal Epithelial Cells?

Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells (LECs) and conjunctival epithelial cells. The aim of this study was to identify the role of retinol derivates in the differentiation of human LEC and its potential impact on aniridia-associated keratopathy development. Human LEC were isolated from healthy donor corneas and were cultured with retinol, retinoic acid, or pan-retinoic acid receptor antagonist (AGN 193109) acting on RARα, ß, γ (NR1B1, NR1B2 NR1B3) or were cultured with pan-retinoid X receptor antagonist (UVI 3003) acting on RXR α, ß, γ (retinoid X receptor, NR2B1, NR2B2, BR2B3). Using qPCR, differentiation marker and retinoid-/fatty acid metabolism-related mRNA expression was analysed. DSG1 (Desmoglein 1), KRT3 (Keratin 3), and SPINK7 (Serine Peptidase Inhibitor Kazal Type 7) mRNA expression was downregulated when retinoid derivates were used. AGN 193109 treatment led to the upregulation of ADH7, KRT3, and DSG1 mRNA expression and to the downregulation of KRT12 (Keratin 12) and KRT19 (Keratin 19) mRNA expression. Retinol and all-trans retinoic acid affect some transcripts of corneal LEC in a similar way to what has been observed in the LEC of PAX6-aniridia patients with the altered expression of differentiation markers. An elevated concentration of retinol derivatives in LEC or an altered response to retinoids may contribute to this pattern. These initial findings help to explain ocular surface epithelia differentiation disorders in PAX6-aniridia and should be investigated in patient cells or in cell models in the future in more detail.

Long-Term Anatomical and Functional Survival of Boston Type 1 Keratoprosthesis in Congenital Aniridia.

Purpose: To analyze the long-term anatomical survival, functional survival, and complications of Boston type 1 keratoprosthesis (KPro) in the eyes with congenital aniridia-associated keratopathy (AAK). Methods: A retrospective review of 12 eyes with congenital aniridia that underwent a Boston type 1 KPro surgery was conducted. A Kaplan-Meier analysis was performed. Anatomical and functional success criteria were KPro retention and a best corrected visual acuity (BCVA) ≤1.3 LogMAR (≥0.05 decimal) at the end of a follow-up period. Postoperative complications were recorded. Results: The mean preoperative BCVA was 2.1 ± 0.9 (range: 3.8-1) LogMAR, and glaucoma was a comorbidity in all the cases. Five years after the surgery, the overall retention rate was 10/12 (83.3%), and 50% had functional success. Only three (25%) of the 12 cases did not achieve a BCVA ≤1.3 LogMAR. The cumulative probability of anatomical success was 92, 79, and 79% after 1, 5, and 10 years, respectively. The cumulative probability of functional success was 57 and 46% after 1 and 5 years, respectively. The mean anatomical and functional survival time was 10 ± 1.3 (95% IC = 7.5-12.3 years) and 3.8 ± 0.9 years (95% IC = 1.8-5.8 years), respectively. The most common postoperative complication was retroprosthetic membrane (RPM) formation in 8/16 cases (66%). The mean number of complications per case was 2.4 ± 1.8 (0-6). Conclusions: The Boston type 1 KPro is a viable option for patients with AAK with good anatomical and functional long-term results. Glaucoma is an important preoperative condition that affects functional results. Retroprosthetic membrane formation seems to have a higher incidence in this condition.

Pathophysiology of aniridia-associated keratopathy: Developmental aspects and unanswered questions.

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.

An attempt to optimize the outcome of penetrating keratoplasty in congenital aniridia-associated keratopathy (AAK).

PURPOSE: To propose an optimized microsurgical and medical approach to reduce the risk of complications after penetrating keratoplasty (PKP) in patients with aniridia-associated keratopathy (AAK). METHODS: Retrospective observational case series of 25 PKP performed in 16 patients with AAK. Preoperative indications were endothelial decompensation and vascularized scars (68%) or graft failure (32%) due to limbal stem cell deficiency. The optimized approach included a combination of a small corneal graft size (around 7.0 mm), interrupted 10-0nylon sutures, simultaneous AMT as a patch, large bandage contact lens, temporary lateral tarsorrhaphy, postoperative autologous serum eye drops, and systemic immunosuppression. Main outcome measures included: visual acuity, transplant survival, and complications encountered during follow-up of 107 weeks on average. RESULTS: A complete modified keratoplasty scheme was used in 10 of 25 PKP (group 1), while at least one of the modifications was missing in the other 15 PKP (group 2). After 8 weeks of follow-up, the epithelium was closed in 23 eyes. Visual acuity improved in 19 eyes at 6 months of follow-up, and remained stable in six eyes. None of the eyes showed a decrease in visual acuity. At the last post-operative follow-up, this visual improvement persisted in 14 eyes and graft survival rate after 156 weeks (3 years) was 69% in group 1 versus 44% in group 2 (p = 0.39, log-rank test). Secondary corneal neovascularization (8%), scarring (4%), ulcer (4%), or graft rejection (8%) happened mostly in the second group which was missing at least one of the suggested modifications. CONCLUSIONS: PKP in congenital aniridia must be considered as a high-risk keratoplasty. An optimized therapeutic approach seems to be promising in order to reduce the postoperative complication rate in these most difficult eyes.

Dysfunction of the limbal epithelial stem cell niche in aniridia-associated keratopathy.

PURPOSE: Abnormalities in the limbal niche microenvironment have been suggested to be causally involved in aniridia-associated keratopathy (AAK), but histological analyses on the limbal structure and composition in AAK are lacking. Here, we investigated morphologic and molecular alterations of the limbal epithelial stem cell niche in human congenital aniridia. METHODS: The blind, buphthalmic and painful left eye of a 16-year old girl with congenital aniridia and juvenile glaucoma had to be enucleated because of uncontrolled intraocular pressure. The diagnosis of AAK was based on classical clinical features and partial limbal stem cell deficiency in the superior half. Genetic analysis identified a large heterozygous PAX6 gene deletion encompassing exons 11-15 as well as exon 9 of the neighboring ELP4 gene. Three limbal biopsies were taken from the superior, nasal and temporal regions to isolate and cultivate limbal epithelial progenitor cells and subject them to mRNA expression analyses. The globe was vertically bisected and processed for light and transmission electron microscopy and immunohistochemistry. RESULTS: Comparative analysis of the superior and inferior limbal zones showed a gradual degradation of palisade structures associated with the transition from a hyperplastic to an attenuated corneal epithelium, inflammatory cell infiltrations and basement membrane irregularities. The clinically unaffected inferior part revealed no distinct stem cell clusters in the preserved palisade region, but a uniform population of hyperproliferative, undifferentiated progenitor cells in the basal/suprabasal layers of limbal and corneal epithelia, which gave rise to maldifferentiated epithelial cells exhibiting a conjunctival/epidermal phenotype and nuclear-to-cytoplasmic translocation of Pax6. The structure of the limbal niche was fundamentally perturbed, showing marked alterations in extracellular matrix composition, dislocation of atypical melanocytes lacking melanosomes and melanin, aberrant Wnt/ß-catenin and retinoic acid signaling, and massive immune cell infiltration. CONCLUSIONS: Considering the limitations of a single Case study, the findings suggest that ocular surface alterations in AAK are caused by a primary dysfunction and gradual breakdown of the limbal stem cell niche through Pax6-related effects on both melanogenesis and epithelial differentiation.

Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations.

PURPOSE: To investigate corneal phenotype in aniridia-associated keratopathy (AAK) including its earliest manifestations, in relation to PAX6 mutational status. METHODS: 46 subjects (92 eyes) with congenital aniridia from a German registry were examined using slit lamp biomicroscopy, anterior segment optical coherence tomography, contact esthesiometry and in vivo confocal microscopy. Cytogenetic analysis was conducted by Sanger sequencing of PAX6 exons and/or MLPA analysis. Measured parameters included AAK grade, distance-corrected visual acuity (DCVA), central corneal thickness (CCT), corneal sensitivity, subbasal nerve density, mature dendritic cell (DC) density and corneal epithelial phenotype. RESULTS: 46 subjects (age range: 1-64 years) were examined, including 23 (50%) children under the age of 18. Five subjects (11.1%) with absent PAX6 coding mutation (non-PAX6 cases) had mild AAK (Grade 0-1) into the fourth decade of life and maintained corneal epithelial phenotype, greater subbasal nerve density (16.8 mm/mm2 vs. 3.58 mm/mm2, P = 0.01) and better corneal sensitivity (41 ±â€¯11 mm vs. 28 ±â€¯12 mm, P = 0.03) relative to those with PAX6 coding mutations. In five subjects, corneal endothelial cell density ranged from 3245 to 4399 cells/mm2. Independent of mutational status, an increased CCT, over tenfold increased mature DC density and reduced corneal sensitivity characterized all subjects. CONCLUSIONS: PAX6 coding mutations influence AAK phenotype and progression from the earliest stages of life. A minimal keratopathy present in 100% of congenital aniridia cases is independent of the specific mutation and consists of increased corneal thickness, reduced touch sensitivity, and increased ocular surface immune activity.

Clinical and morphological manifestations of aniridia-associated keratopathy on anterior segment optical coherence tomography and in vivo confocal microscopy.

PURPOSE: The study aimed to evaluate clinical and morphological changes in the limbal palisades of Vogt (POV) at different stages of aniridia-associated keratopathy (AAK) and to assess possible utility of anterior segment optical coherence tomography (AS-OCT) for the visualization of limbal progenitor structures as it correlates to laser scanning confocal microscopy (LSCM) data. METHODS: The study involved 32 patients (59 eyes) with congenital aniridia. AAK stage was defined based on biomicroscopy. Assessment of limbal zone and detection of POVs in identical areas was performed by LSCM (HRT3) and AS-OCT (RTVue XR Avanti) using 3D Cornea (En Face mode) and Cornea Cross Line protocols. RESULTS: Intact and changed POVs were found in 8/8 stage 0 eyes, in 1/21 stage I and 2/13 stage II eyes. Spearman's correlation coefficient in assessing the consistency of the POV diagnostic results by LSCM and AS-OCT for the inferior limbus was rS = 0.85 (P < 0.05), for the superior limbus - rS = 0.53 (P < 0.05). AS-OCT was less sensitive for detection of partially present POVs in superior limbus. The negative correlation between AAK stage and POV preservation was determined (rS = -0.5, P < 0.05). There was no correlation between AAK stage and patient age (rS = 0.235, P = 0.209). Three patients with PAX6 3' deletion showed stage 0 AAK with intact or slightly disturbed POVs morphology and transparent cornea. CONCLUSION: AS-OCT may be an additional diagnostic tool for POV visualization in vivo in aniridic patients. Its diagnostic accuracy is subject to selection of anatomic region, nystagmus and the degree of POV degradation.

[Diagnostic capabilities of optical coherence tomography and confocal laser scanning microscopy in studying manifestations of aniridia-associated keratopathy]. / Diagnosticheskie vozmozhnosti opticheskoi kogerentnoi tomografii i lazernoi skaniruiushchei konfokal'noi mikroskopii v izuchenii proiavlenii aniridiinoi keratopatii.

AIM: to investigate the possible use of anterior segment optical coherence tomography (AS-OCT) and laser scanning confocal microscopy (LSCM) for visualization of limbal progenitor structures and epithelial changes at different stages of aniridia-associated keratopathy (AAK) and to analyze genotype-phenotype correlations of corneal damage. MATERIAL AND METHODS: Thirty-four patients (63 eyes) with congenital aniridia (CA) were subjected to epithelial cell density measurement in the central cornea as well as epithelial surface assessment with limbal palisades of Vogt (POV) detection in the corresponding sites of the two corneas. For that, LSCM (HRT3) and AS-OCT (RTVue XR Avanti) were performed. Central corneal and epithelial thicknesses were measured using the Pachymetry protocol. RESULTS: There has been found an increase in the central corneal thickness (CCT) of CA patients, which correlated with the stage of AAK, and a decrease in the central epithelial thickness as compared with healthy subjects (p<0.05). The difference between the basal and wing epithelial cells density in eyes with stages I and II AAK and normal cells density at stage 0 AAK was statistically significant (p<0.05). Intact or disturbed POV were detected in all patients with PAX6 3' deletion. At that, AS-OCT findings highly agreed with LSCM images for both the inferii (rS=0.85, p<0.05) and superior limbi (rS=0.53, p<0.05). A negative correlation was established between the stage of AAK and in vivo morphology of POV (rS=-0.5, p<0.05). However, no correlation was found between the stage of AAK and patient's age (rS=0.169, p=0.174). CONCLUSION: AS-OCT and LSCM are both important diagnostic tools for corneal surface monitoring in patients with limbal stem cells deficiency.

Congenital Aniridia and the Ocular Surface.

Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface, in particular, can be severely affected by a progressive pathology termed aniridia-associated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micro-morphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition.

Congenital aniridia: etiology, manifestations and management.

Congenital aniridia manifests as total or partial absence of the iris caused most commonly by mutations in PAX6, FOXC1, PITX2, and CYP1B1. Recently two new genes, FOXD3 and TRIM44, have also been implicated in isolated studies. We discuss the genotype-phenotype correlations for the main implicated genes. Classic aniridia is a panocular condition, which includes aniridia, cataract, corneal pannus, foveal, and optic nerve hypoplasia associated with mutations in the PAX6 gene. Classical aniridia is due to PAX6 mutations, while other genes contribute to aniridia-like phenotypes. We review the challenges involved in the management of aniridia, and discuss various surgical interventions. The clinical importance of defining the genotype in cases of congenital aniridia has become acutely apparent with the advent of possible therapies for classical aniridia, which are discussed.