Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

Custom Iris Prosthesis for Subtotal Traumatic Aniridia From Combat Ocular Trauma.

Traumatic aniridia from combat ocular trauma can cause visual disability. A 41-year-old male Army Veteran was referred for evaluation of light sensitivity and glare secondary to subtotal traumatic aniridia of his left eye from an improvised explosive device blast. A custom-made artificial iris prosthesis was implanted in the ciliary sulcus and secured using Gore-Tex sutures. After surgery, the patient reported improvement of his light sensitivity and quality of life. The custom iris prosthesis is a surgical option for visual disability resulting from traumatic aniridia from combat ocular trauma.

Secondary Data Analysis of Inflammation-Related mRNAs in Conjunctival Impression Cytology Samples of Aniridia Patients.

PURPOSE: Aniridia is a rare corneal disease that is often associated with aniridia-associated keratopathy (AAK). In AAK, the conjunctival tissue crosses the limbal border, forming a corneal pannus that extends into the corneal center. With increasing AAK severity, corneal pannus formation, vascularization, and ocular surface inflammation increase. The purpose of this study was to investigate inflammation-related mRNA expression in conjunctival epithelial cells in AAK and its relationship with AAK severity. METHODS: Using impression cytology, bulbar conjunctival cells were sampled from 20 subjects with congenital aniridia and 20 age-matched and sex-matched healthy control subjects. RNA was extracted, and mRNA analyses were performed using microarray, which was evaluated for inflammatory markers. RESULTS: In the analyzed aniridia subjects, 70 deregulated mRNAs encoding proinflammatory or antiinflammatory cytokines or factors associated with chronic inflammation, including increased IL-1, IL-8, and MIP3A/CCL20 mRNA. The most downregulated mRNA was TIMP3, and the most upregulated mRNA was Protein c-Fos.Of the 70 mRNAs, 14 inflammation-related genes were altered only in the mild AAK forms, whereas only 2 mRNAs were altered only in the severe AAK forms (TLR4 and PPARG). CONCLUSIONS: The expression of numerous proinflammatory and antiinflammatory cytokines is deregulated at the ocular surface of aniridia subjects with mild AAK. Thus, early antiinflammatory treatment may prevent or slow down corneal scarring and pannus formation in aniridia subjects.

Co-Occurrence of Congenital Aniridia Due to Nonsense PAX6 Variant p.(Cys94*) and Chromosome 21 Trisomy in the Same Patient.

This study aims to present a clinical case involving the unique co-occurrence of congenital aniridia and Down syndrome in a young girl and to analyze the combined impact of these conditions on the patient's phenotype. The investigation involved comprehensive pediatric and ophthalmological examinations alongside karyotyping and Sanger sequencing of the PAX6 gene. The patient exhibited distinctive features associated with both congenital aniridia and Down syndrome, suggesting a potential exacerbation of their effects. Cytogenetic and molecular genetic analysis revealed the presence of trisomy 21 and a known pathogenic nonsense variant in exon 6 of the PAX6 gene (c.282C>A, p.(Cys94*)) corresponding to the paired domain of the protein. The observation of these two hereditary anomalies offers valuable insights into the molecular pathogenetic mechanisms underlying each condition. Additionally, it provides a basis for a more nuanced prognosis of the complex disease course in this patient. This case underscores the importance of considering interactions between different genetic disorders in clinical assessments and treatment planning.

A novel PAX6 variant as the cause of aniridia in a Chinese patient with SRRRD.

BACKGROUND: The genotype characteristics and their associated clinical phenotypes in patients with aniridia were analyzed to explore pathogenic variants using whole-exome sequencing. METHODS: One patient with aniridia was enrolled at the Beijing Tongren Hospital. Comprehensive ophthalmic and general examinations were performed on the patient. DNA was extracted from the patient, and whole-exome sequencing was performed to identify the causative variant. The pathogenicity of the variant was predicted using in silico analysis and evaluated according to American College of Medical Genetics and Genomics guidelines. Relationships between genetic variants and clinical features were analyzed. RESULTS: In addition to the classical aniridia phenotype showing complete iris aplasia, foveal hypoplasia, and ectopic lentis, the patient also exhibited spontaneous reattachment rhegmatogenous retinal detachment (SRRRD). Whole-exome sequencing identified a novel heterozygous variant, exon8:c.640_646del:p.R214Pfs*28. CONCLUSIONS: The present study broadens the range of genetic variants described in aniridia and presents an aniridia patient with SRRRD.

Aniridic scleral fixation of intraocular lens: The answer to vision loss with photophobia!

Background: 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 to this, disturbing cosmetic problems are prevalent. Even after implantation of an intraocular lens, patients often tend to be unsatisfied. Purpose: The answer to this problem lies in the implantation of an aniridic scleral fixation of intraocular lens (SFIOL), which has a central optical axis that acts as the refractive lens and a peripheral rim of a hyperpigmented area that mimics the iris and hence reduces photophobia. The purpose of the video was to demonstrate the use of black diaphragm intraocular lens (BDIOL) implantation, its surgical steps, and its outcomes. Synopsis: We report one such case where a young patient presented with post-traumatic aniridia with subluxated total cataract and spillover vitreous hemorrhage. He was subjected to a vitrectomy, cataract removal, and placement of an aniridic SFIOL with prolene 9-0 using the four-point fixation method. This gave an extremely gratifying outcome and solved both problems, that is, vision and photophobia. Highlight: Before implantation of the SFIOL, the patients had reduced visual acuity from aphakia and intolerable glare from aniridia. In this case-based approach and with relevant example, we tried to provide a solution for tricky scenarios like co-existing traumatic cataract and traumatic aniridia. The patient showed improved visual acuity and marked glare reduction after black diaphragm SFIOL implantation. Video link: https://youtu.be/atl60WetFsM.

A novel missense variant expands the phenotype and genotype of PAX6-associated foveal hypoplasia accompanied by various manifestations of anterior segment dysgenesis.

BACKGROUND: According to previous reports, PAX6-associated foveal hypoplasia (FH) could usually be accompanied by various anterior segment anomalies including variable iris changes. This study aims to exhibit unusual phenotypes of a novel missense variant of PAX6 from a Chinese pedigree. METHODS: Ophthalmic examinations including slit-lamp biomicroscopy, gonioscopy, ophthalmic ultrasound, ultrasonic biomicroscopy, optical coherence tomography, wide-field fundus imaging, and visual field test were performed to evaluate the clinical manifestations. Whole-exome sequencing (WES) and bioinformatics analysis were conducted in eight members from this pedigree to identify the causative mutation. RESULTS: WES revealed a novel heterozygous substitution of PAX6 (NM_000280.5:c.157G > A, p.(Val53Met) (chr11:31823309 C > T, hg19)), which cosegregated with the phenotype of this pedigree. All the three patients (a pair of fraternal twins and their mother) exhibited bilateral FH and anterior segment dysgenesis (ASD) including microcornea, sclerocornea, obvious symmetrical corectopia, iris stromal dysplasia, goniodysgenesis, and abnormal distribution of fundus blood vessels. The girl of the fraternal twins also demonstrated bilateral temporal deviation of lenses and abnormal tissue membrane connecting anterior chamber angle and lens anterior capsule in the right eye. The mother additionally showed apparent cataract bilaterally and cupping of the optic disc in her left eye. CONCLUSION: A novel missense variant in PAX6 gene was detected in a Chinese pedigree demonstrating bilateral FH and ASD. It is really distinctive that the ASD involves almost all parts of the anterior segment, and bilateral symmetrical corectopia is the most perceptible sign. This study expands the phenotypic and genotypic spectrum of PAX6-associated ocular diseases, and facilitates the understanding of the crucial role that PAX6 plays in the development of the eye. Meanwhile, PAX6 could be considered as a candidate pathogenic gene of bilateral symmetrical corectopia.

[Congenital aniridia patients' experience on their visual impairment in Hungary.] / Veleszületett aniridiás betegek látáskárosodással kapcsolatos tapasztalatai Magyarországon.

INTRODUCTION: Aniridia is a rare congenital panocular disease associated with varying degrees of visual acuity impairment. OBJECTIVE: To assess the experiences of congenital aniridia patients in Hungary, with visual impairment using a questionnaire developed by the ANIRIDIA-NET. PATIENTS AND METHOD: Patients completed the Hungarian version of the 20-item ANIRIDIA-NET questionnaire with our assistance. The questionnaire covered demographic data, the most common complaints caused by the disease, the difficulties caused by low vision in different life situations and the frequency of low vision aids used in daily life. RESULTS: 33 subjects (17 female [51.51%] and 16 male [48.48%]), 16 (48.5%) children and 17 (51.5%) adults completed the questionnaire, with an age of 25.69 ± 17.49 years (5-59 years). Daily photosensitivity was reported by 27 (81.8%), dry eyes by 5 (15.2%), tearing by 4 (12.1%), fluctuating vision by 3 (9.1%), and eye pain by 2 (6.1%) subjects. The majority of respondents said that personal communication with schoolmates (16 [48.5%]) or colleagues at work (11 [33.3%]) never caused difficulties because of their visual impairment. 29 people (87.9%) never needed help with daily routines at home, 24 (72.7%) with getting to school/work and 17 (51.5%) with various activities. 29 people (87.8%) never used low vision aids for communication, 23 (69.7%) for travelling, 20 (60.6%) for participating in social activities, 18 (54.5%) for studying/work. CONCLUSION: Although aniridia is associated with reduced visual acuity, the majority of people with congenital aniridia, especially in childhood, manage to cope with personal communication and various life situations without difficulty, despite their eye complaints. Low vision aids can be an important aid for them as they grow into adulthood and as they age. Orv Hetil. 2023; 164(34): 1342-1349.

Pediatric glaucoma in aniridia in a population of Egyptian children.

PURPOSE: To report on the incidence, characteristics, and treatment of glaucoma in association with aniridia in a population of Egyptian children. METHODS: A retrospective chart review was conducted of children (<18 years of age) presenting with aniridia between 2007 and 2022. Diagnosis of glaucoma was based on cup:disk ratio (>0.3) and IOP (>16 mm Hg). Success of glaucoma surgery was defined as IOP ≤16 mm Hg and stable or regressing cup:disk ratio. RESULTS: A total of 93 eyes of 47 children were included. The mean patient age at presentation was 41.2 ± 44.7 months. The mean intraocular pressure (IOP), corneal diameter, cup:disk ratio, and axial length on presentation were 16.4 ± 10.3 mm Hg, 11.4 ± 1.3 mm, 0.4 ± 0.3, and 22.43 ± 2.6 mm Hg. Of eyes with IOP and cup:disk ratio data at presentation, 23 (30%) were diagnosed with glaucoma. Fourteen eyes underwent surgery after presentation; follow-up data were available for half the remaining eyes. At the final follow-up, glaucoma was present in 20 eyes (49%). Glaucoma surgery was performed in 17 eyes, with a complete or qualified success rate of 82.4% at final follow-up, with 15 eyes having at least 12 months' follow-up. CONCLUSIONS: In this study cohort, children with aniridia presented at around 3 years of age, with glaucoma at presentation in almost one-third of the cases.

[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.

Report on the 2021 Aniridia North America symposium on PAX6, aniridia, and beyond.

The inaugural Aniridia North America (ANA) Symposium was held on the first weekend in November 2021 in Charlottesville, VA, at the University of Virginia. The purpose of this meeting was to bring together an international group of scientists, physicians, patient advocacy groups, and individuals with aniridia to discuss recent advances in knowledge about aniridia and other congenital eye diseases and the development of potential treatments for congenital eye disorders using personalized medicine. Leaders in several areas of eye research and clinical treatment provided a broad perspective on new research advances that impact an understanding of the causes of the damage to the eye associated with aniridia and the development of novel treatments for this and related disorders. Here we summarize the research discussed at the symposium.

Genetic predisposition to ocular surface disorders and opportunities for gene-based therapies.

The ocular surface, comprised of the corneal and conjunctival epithelium, innervation system, immune components, and tear-film apparatus, plays a key role in ocular integrity as well as comfort and vision. Gene defects may result in congenital ocular or systemic disorders with prominent ocular surface involvement. Examples include epithelial corneal dystrophies, aniridia, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome, xeroderma pigmentosum (XP), and hereditary sensory and autonomic neuropathy. In addition, genetic factors may interact with environmental risk factors in the development of several multifactorial ocular surface disorders (OSDs) such as autoimmune disorders, allergies, neoplasms, and dry eye disease. Advanced gene-based technologies have already been introduced in disease modelling and proof-of-concept gene therapies for monogenic OSDs. For instance, patient-derived induced pluripotent stem cells have been used for modelling aniridia-associated keratopathy (AAK), XP, and EEC syndrome. Moreover, CRISPR/Cas9 genome editing has been used for disease modelling and/or gene therapy for AAK and Meesmann's epithelial corneal dystrophy. A better understanding of the role of genetic factors in OSDs may be helpful in designing personalized disease models and treatment approaches. Gene-based approaches in monogenic OSDs and genetic predisposition to multifactorial OSDs such as immune-mediated disorders and neoplasms with known or possible genetic risk factors has been seldom reviewed. In this narrative review, we discuss the role of genetic factors in monogenic and multifactorial OSDs and potential opportunities for gene therapy.

Globe rupture with aphakia, aniridia, secondary glaucoma and late corneal decompensation: A multi-staged approach to management.

Severe blunt ocular trauma may result in immediate and delayed complications requiring appropriate management algorithms. We hereby report a case of globe rupture, aphakia, traumatic aniridia, and secondary glaucoma in a 33-year-old male following road traffic accident. He was treated initially by primary repair followed by novel combined approach of aniridia IOL with Ahmed glaucoma valve implantation. Delayed corneal decompensation required deferred penetrating keratoplasty. After a follow-up of 3.5 years after last surgery, patient maintains good functional vision with stable IOL, clear corneal graft and controlled intraocular pressure. A meticulously planned and staged management approach appears better suited in complex ocular trauma in such scenarios giving a good structural and functional outcome.

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 - Hungarian data of a spectrum disease]. / Congenitalis aniridia ­ egy spektrumbetegség magyarországi adatai.

INTRODUCTION: Congenital aniridia is a rare disease, characterised by the complete or partial absence of the iris, but lesions may be present in all structures of the eye. OBJECTIVE: To determine the prevalence of ocular diseases in congenital aniridia by analyzing patients from a Hungarian centre. PATIENTS AND METHODS: Patients at the Department of Ophthalmology of Semmelweis University, examined between October 2005 and May 2022, have been included. After taking the patients' medical history, a detailed ophthalmological examination has been performed. RESULTS: Of the 82 patients in the database, 33 (age 25.69 ± 17.49 [5-59] years, 17 females [51.51%]) presented for examination and 65 eyes were examined. Nystagmus was found in 45 eyes of 23 patients (69.23%), and the patients' uncorrected distance visual acuity was 0.14 ± 0.128 (0.9 logMAR; 0.63-0.005). The aniridia-associated keratopathy was Grade 0 in 8 eyes (12.3%), Grade 1 in 10 eyes (15.38%), Grade 2 in 16 eyes (24.62%), Grade 3 in 4 eyes (6.15%) and Grade 4 in 25 eyes (38.46%). 30 eyes (46.15%) of 15 patients had secondary glaucoma, 6 eyes (9.2%) of 3 patients were glaucoma suspect. 8 eyes (12.3%) had a clear lens, 44 eyes (67.69%) had cataract, of which 22 (33.84%) were anterior cortical polar cataracts. 13 eyes (20%) were pseudophakic (PCL) and 7 eyes (10.77%) had lens dislocation or zonular insufficiency. Macular hypoplasia was found in 6 eyes of 3 patients (4.6%) and optic nerve head malformation in 2 eyes of 1 patient (3.03%). CONCLUSION: The ocular signs of congenital aniridia are aniridia-associated keratopathy, secondary glaucoma, cataract, macular and optic nerve head hypoplasia. Systematic collaboration of different ophthalmological specialties is required for the management and care of all these ocular abnormalities. Orv Hetil. 2023; 164(4): 148-155.

Isolated aniridia caused by a novel PAX6 heterozygous deletion mediated by multi-exon complex rearrangement.

PURPOSE: Mutations in PAX6 gene (chromosome 11p13) encoding a transcriptional regulator involved in oculogenesis mostly present with aniridia. Aniridia is not uncommon in the Philippines but only limited information is available as yet. The purpose of this study was to present a novel, deletion mediated by complex rearrangement in PAX6 gene causing an isolated aniridia in a Filipino girl. PATIENTS AND METHODS: The patient is an 8-year-old girl who came in due to leukocoria with associated nystagmus and esotropia. She presented with subnormal vision, nystagmus, aniridia, and cataractous lenses in both eyes. The family history reveals presence of the aniridia and cataract with the mother and a sibling. The patient underwent lens extraction without intraocular lens implantation bilaterally, where patient subsequently underwent intraocular lens implantation on her left eye. Systemic workup was performed including whole abdomen, renal ultrasound, blood chemistry, and urinalysis. Targeted cataract panel with WT1 and PAX6 genes revealed a novel, heterozygous PAX6-inherited mutation from the mother. This variant is a complex rearrangement in PAX6 involving partial deletions of exons 3-5, including the initiator codon. Deletions of PAX6 are part of a contiguous gene deletion syndrome - Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability syndrome - and therefore evaluation of the WT1 gene was necessary to rule out this life-threatening syndrome. CONCLUSION: This rare, complex rearrangement of multiple exons and deletions in PAX6 causing an isolated aniridia phenotype is probably the first reported case. The patient was managed by a multidisciplinary team and the guardians were counseled regarding the prognosis and complications.

Surgical correction of corneal opacity and aniridia with penetrating keratoplasty and a new iris prosthesis implant.

PURPOSE: This study is to describe the clinical outcome of penetrating keratoplasty combined with implantation of a novel intraocular lens with an artificial iris, aided by continuous vitreous chamber infusion, in patients with severe aniridia and corneal alterations. METHODS: This was a prospective single-center case series study involving five patients with corneal alterations and aniridia. All subjects underwent simultaneous penetrating keratoplasty and implantation of a new intraocular lens with an artificial iris with the assistance of infusion into the vitreous chamber to regulate intraocular pressure during the surgical procedure. Visual acuity, corneal endothelial cell density, and intraocular pressure assessments were performed in the postoperative period. The final cosmetic outcome of the iris prosthesis placement was also evaluated. RESULTS: In all cases, increased visual acuity and a good aesthetic result were observed in all affected eyes except one in which, despite the excellent aesthetic outcome, the eye was very hypotonic as it had high myopia and had undergone several previous surgeries. CONCLUSION: The single surgical procedure combining implantation of an intraocular lens-iris prosthesis with penetrating keratoplasty is an effective technique for the simultaneous treatment of aphakia and aniridia. However, larger series with longer-term follow-up are needed to definitively establish the benefits of this technique.

Corneal transplantation in aniridia-related keratopathy with a two-year follow-up period, an uncommon disease with precarious course.

PURPOSE: The purpose of this study is to study the frequency, surgical transplantation technique and outcome in patients with aniridia-related keratopathy (ARK) with two-year follow-up period. METHODS: A retrospective registry-study including all ARK cases performed in Sweden and Denmark between 2001 and 2016 and registered in the Swedish Cornea Transplant Registry. RESULTS: A total of 36 eyes of 26 patients were subjected to corneal transplantation due to ARK during 2001 to 2016. Penetrating keratoplasty (PK) was the procedure of choice in 58.3% (n = 21) of the eyes, followed by a combination of PK and limbal stem cell transplantation in 13.9% (n = 5) and keratolimbal allograft in 13.9% (n = 5). Boston keratoprosthesis was used in 8.3% (n = 3), and anterior lamellar keratoplasty in 5.6% (n = 2). Thirteen of the procedures (36.1%) were retransplantations. Two years after surgery 26 cases were available to follow-up of which 16 of the grafts were functioning (61.5%). The median visual acuity showed a trend of improvement from hand motion to counting fingers. CONCLUSIONS: A majority of the ARK cases (61.5%) had a graft providing useful vision for the patient 2 years after corneal transplantation, but the visual gain was modest at best. Longer follow-up time is required to evaluate functional graft outcomes. Despite the introduction of limbal stem cell transplantation as a suitable treatment, PK was the most common surgical method in the present study.