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.

Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches.

Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.

Smart contact lens: A promising therapeutic tool in aniridia.

OBJECTIVE: The perform pre-clinical testing using optical design tools to simulate the optical quality of a smart artificial iris platform encapsulated in a scleral contact lens. These tools allow us to generate aniridia eye models and evaluate different metrics of visual quality and retinal illumination based on the aperture of the artificial iris based on liquid crystals. METHOD: The OCT imaging technique was used to measure the geometry of the anterior segment in a patient with aniridia and, from these data, the eye model was generated with the Zemax optical design program and specific programs developed in Matlab. Ocular aberrations were calculated and the visual function of the anirida eye model was evaluated in three scenarios: (i) without optical correction, (ii) with correction with a commercial scleral contact lens, and (iii) with correction with an optical lens. Intelligent contact based on artificial iris. RESULTS: Optical quality in patients with aniridia is limited by the magnitude of high-order aberrations. Conventional scleral contact lens design accurately corrects for blur but is unable to compensate for high-order ocular aberrations, especially spherical aberrations. The artificial iris-based smart contact lens design enables virtually all high-order aberrations to be compensated with active control of the pupillary diameter (activation of liquid crystal cells based on ambient lighting). In addition to minimizing high-order aberrations, reducing the pupil size would increase the depth of focus. CONCLUSIONS: This article demonstrates by means of optical simulations the concept of an intelligent artificial iris platform encapsulated in a scleral contact lens and its possible application in patients with aniridia. Furthermore, it allows us to anticipate possible visual results in clinical trials with healthy patients (after application of mydriatic agents) and in patients with aniridia. The results demonstrate a better visual quality and a decrease in retinal illumination.

Congenital aniridia - A comprehensive review of clinical features and therapeutic approaches.

Congenital aniridia is a rare genetic eye disorder with total or partial absence of the iris from birth. In most cases the genetic origin of aniridia is a mutation in the PAX6 gene, leading to involvement of most eye structures. Hypoplasia of the fovea is usually present and is associated with reduced visual acuity and nystagmus. Aniridia-associated keratopathy, glaucoma, and cataract are serious and progressive complications that can further reduce visual function. Treatment of the ocular complications of aniridia is challenging and has a high risk of side effects. New approaches such as stem cell therapy may, however, offer better prognoses. We describe the various ocular manifestations of aniridia, with a special focus on conditions that commonly require treatment. We also review the growing literature reporting systemic manifestations of the disease.

Aesthetics of iris reconstruction with a custom-made artificial iris prosthesis.

Patients with large iris defects not only suffer from functional disadvantages but also from aesthetic limitations. The aim of this study was to evaluate the aesthetic outcome of iris reconstruction using an artificial iris (AI). In this study, 82 eyes of 79 consecutive patients with mostly traumatic partial or total aniridia that underwent iris reconstruction surgery using a custom-made silicone AI (HumanOptics, Erlangen, Germany). Pre- and postoperative photographs of 66 patients were analysed subjectively and objectively. Subjective evaluation was based questionnaires. Objective evaluation included measurement of pupil centration and iris colour analysis. Averaged hues from iris areas were transferred to numerical values using the LAB-colour-system. Single parameters and overall difference value (ΔE) were compared between AI and remaining iris (RI), as well as AI and fellow eye iris (FI). Patients, eye doctors and laymen rated the overall aesthetic outcome with 8.9 ±1.4, 7.7 ±1.1 and 7.3 ±1.1 out of 10 points, respectively. Mean AI decentration was 0.35 ±0.24 mm. Better pupil centration correlated with a higher overall score for aesthetic outcome (p<0.05). The AI was on average 4.65 ±10 points brighter than RI and FI. Aniridia treatment using a custom-made artificial iris prosthesis offers a good aesthetic outcome. Pupil centration was a key factor that correlated with the amount of aesthetic satisfaction. The AI was on average slightly brighter than the RI and FI.

[Severe color change in corneal tattoos: Report of 3 cases (French translation of the article)]. / Modification majeure de la couleur des tatouages cornéens à propos de 3 cas.

INTRODUCTION: Corneal tattooing is a noninvasive technique which appears relatively well-tolerated in the medium term. We report the cases of 3 patients with a significant change in the color of their tattoos performed over 5 years previously. PATIENTS AND METHODS: Three patients with a history of intracorneal tattooing several years previously were studied because of a significant change from their initial color. Each patient's file was reviewed with analysis of slit lamp photographs, OCT and specular microscopy. RESULTS: All three patients experienced a significant color change in their tattoos between 5 and 6 years after surgery. The color had changed to golden-brown. DISCUSSION: Retrospective analysis of the components of the tattoo ink found the presence of iron in the black pigment. We believe that pigments composed of iron oxide are transformed into golden-brown ferric iron oxide in the presence of oxygen in the aqueous environment. The presence of moderate corneal edema in these three cases of multioperated patients could explain, in these specific cases, the occurrence of oxidation typically not described. CONCLUSION: Corneal tattooing remains a simple and very interesting technique when partial or total absence of iris causes significant photophobia. However, the significant changes in color that we report more than 5 years later suggest omitting iron from the dyes used for the cornea and limiting its use in cases of limited endothelial prognosis. A long-term evaluation of corneal tattoos appears necessary.

Aniridia-related keratopathy: Structural changes in naïve and transplanted corneal buttons.

BACKGROUND: To study structural changes in naïve and surgically treated corneas of aniridia patients with advanced aniridia-related keratopathy (ARK). METHODS AND FINDINGS: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation and were now retransplanted and two adult healthy donor control corneas were processed for immunohistochemistry. Antibodies against extracellular matrix components in the stroma and in the epithelial basement membrane (collagen I and IV, collagen receptor α11 integrin and laminin α3 chain), markers of fibrosis, wound healing and vascularization (fibronectin, tenascin-C, vimentin, α-SMA and caveolin-1), cell division (Ki-67) and macrophages (CD68) were used. Naïve ARK, KLAL ARK corneas and transplanted corneal buttons presented similar histopathological changes with irregular epithelium and disruption or absence of epithelial basal membrane. There was a loss of the orderly pattern of collagen lamellae and absence of collagen I in all ARK corneas. Vascularization was revealed by the presence of caveolin-1 and collagen IV in the pannus of all ARK aniridia corneas. The changes observed in decentered and centered transplants were analogous. CONCLUSIONS: Given the similar pathological features of all cases, conditions inherent to the host seem to play an important role on the pathophysiology of the ARK in the long run.

PAX6 aniridia syndrome: clinics, genetics, and therapeutics.

PURPOSE OF REVIEW: Aniridia is a rare and panocular disorder affecting most of the ocular structures which may have significant impact on vision. The purpose of this review is to describe the clinical features, genetics, and therapeutic options for this disease and to provide an update of current knowledge and latest research findings. RECENT FINDINGS: Aside from the ocular features, a variety of associated systemic abnormalities, including hormonal, metabolic, gastrointestinal, genitourinary, and neurologic pathologies have been reported in children with aniridia. Although mutations in PAX6 are a major cause of aniridia, genetic defects in nearby genes, such as TRIM44 or ELP4, have also been reported to cause aniridia. Recent improvement in genetic testing technique will help more rapid and precise diagnosis for aniridia. A promising therapeutic approach called nonsense suppression therapy has been introduced and successfully used in an animal model. SUMMARY: Aniridia is a challenging disease. The progressive nature of this condition and its potential complications require continuous and life-long ophthalmologic care. Genetic diagnosis for aniridia is important for establishing definitive molecular characterization as well as identifying individuals at high risk for Wilms tumor. Recent advancement in understanding the genetic pathogenesis of this disease offers promise for the approaches to treatment.

[Aniridia syndrome: clinical findings, problematic courses and suggestions for optimization of care ("aniridia guide")]. / Aniridiesyndrom : Klinische Befunde, problematische Verläufe und Vorschlag zur Betreuungsoptimierung ("Aniridielotse").

BACKGROUND: Congenital aniridia manifests in different forms: it can be transmitted in an autosomal dominant way, as sporadic aniridia and as part of several syndromes including WAGR (Wilms tumor, aniridia, genitourinary abnormalities and intellectual disability) and WAGRO syndromes (WAGR and obesity). Furthermore, recent research shows that aniridia associated with alterations in the PAX6 gene often shows further systemic implications (e.g. endocrine, metabolic and neurological pathologies). Therefore, PAX6-related aniridia is more and more considered to be and described as aniridia syndrome or PAX6 syndrome. PURPOSE: We present a group of 130 patients with congenital aniridia to enhance awareness of the complexity of the disease. Different to other congenital visual impairments aniridia is characterized by many ocular complications arising during the lifetime which may lead to total blindness (e.g. cataract, aniridic keratopathy and secondary glaucoma). Furthermore, there is a specific surgical risk entity: aniridia fibrosis syndrome and anterior segment fibrosis syndrome (ASFS) which lead to a non-infectious fibrous scarring and membrane formation of the anterior segment, often followed by hypotonia and phthisis. Aniridic glaucoma presents yet another severe complication which is often diagnosed late due to diagnostic problems and which may lead to irreversible optic nerve damage. DISCUSSION: The following approaches might help to improve the lifelong care of aniridia patients and might benefit the aim to lessen the impact of complications in aniridia: topical prophylaxis of aniridic corneal epitheliopathy from a very early age, regular measurement of intraocular pressure starting in young children, annual visual evoked potential (VEP) measurements and routine visual field testing as soon as possible, comprehensive optimization of surgical care independent of department location (only the very best surgeons within their subspecialty should treat the different complications) while one experienced pediatric and low vision ophthalmologist should follow the patient continuously ("aniridia guide" for the patient), thus monitoring the disease and stages of complications and advising the patient where to go for surgical treatment. This low vision ophthalmologist continuously follows the patient's course including adaptation of low vision aids according to the course of the disease, helping the patient concerning integration at school and at the place of work and advising about social and legal compensation possibilities. In addition, the guiding ophthalmologist should inform patients with aniridia about possible systemic manifestations of PAX6 syndrome concerning metabolic and neurological implications and should initiate appropriate investigations when applicable.

[Stage-related therapy of congenital aniridia]. / Stadiengerechte Therapie der kongenitalen Aniridie.

BACKGROUND: The main reasons for the markedly reduced visual acuity in pediatric patients with congenital aniridia are foveal dysplasia and optic nerve hypoplasia. During the lifetime a lack of depth of focus and increased sensitivity to glare due to a partly or completely lacking iris may be accompanied by further complications such as cataracts, various types of glaucoma and corneal opacity. THERAPY: In principal, microsurgical intervention should be as minimally invasive as possible to avoid excessive intraocular fibrosis. It is not advisable to use any type of esthetic iris substitute in phakic eyes. Cataract surgery should be performed via small incisions with a foldable intraocular lens (IOL) but not by using a 10 mm diameter polymethyl methacrylate (PMMA) anirida IOL. The conservative therapy of the often progressive limbal stem cell deficiency of the cornea includes artificial tears containing unpreserved hyaluronic acid, gels, autologous serum and amniotic membrane transplantation. Limbal transplantation of various kinds with and without penetrating keratoplasty and the Boston keratoprothesis type I should be considered only in cases of significant reduction of visual acuity and/or recurrent epithelial defects. Glaucoma surgery should be performed primarily as trabeculotomy. Drainage devices (e.g. Ahmed valve) are suggested as a second line approach. The risk of scarring of the filtering bleb in trabeculectomy with mitomycin C is very high in childhood and adolescence. CONCLUSIONS: The stage-related therapy of congenital aniridia should always be based on a global view of the potentially increasing severity of cataract, glaucoma and corneal limbal stem cell deficiency during the lifetime. Each microsurgical intervention should be performed by the appropriate specialist and should be kept as minimally invasive as possible.

Toward postnatal reversal of ocular congenital malformations.

Aniridia is a panocular disorder that severely affects vision in early life. Most cases are caused by dominantly inherited mutations or deletions of the PAX6 gene, which encodes a transcription factor that is essential for the development of the eye and the central nervous system. In this issue of the JCI, Gregory-Evans and colleagues demonstrate that early postnatal topical administration of an ataluren-based formulation reverses congenital malformations in the postnatal mouse eye, providing evidence that manipulation of PAX6 after birth may lead to corrective tissue remodeling. These findings offer hope that ataluren administration could be a therapeutic paradigm applicable to some major congenital eye defects.

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects.

Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics.

[Aniridia-IOL and artificial iris reconstruction]. / Aniridie-IOL und künstlicher Irisersatz.

Aniridia is defined as missing iris tissue which can be partial, subtotal or total. Characteristic clinical symptoms include photophobia and decreased visual acuity due to an increased light perception. In addition, disturbing cosmetic problems are prevalent. Modern iris reconstruction implants offer visual and cosmetic rehabilitation. Amongst them are aniridia intraocular lenses (IOL), iris segment implants and the "artificial iris". Different overall and pupil diameters are available for total or partial implants. At the same time aphakia or cataract can be treated when using aniridia IOLs. Intra- and extracapsular fixation is possible. The "artificial iris" can be folded and implanted through small incisions. The aesthetic results are improved significantly due to customised colour selection providing increased patient satisfaction postoperatively.

Aniridia.

Aniridia is a rare congenital disorder in which there is a variable degree of hypoplasia or the absence of iris tissue associated with multiple other ocular changes, some present from birth and some arising progressively over time. Most cases are associated with dominantly inherited mutations or deletions of the PAX6 gene. This article will review the clinical manifestations, the molecular basis including genotype-phenotype correlations, diagnostic approaches and management of aniridia.