Foveal hypoplasia grading in 95 cases of congenital aniridia: correlation to phenotype and PAX6 genotype

Congenital aniridia is caused by a mutation in the PAX6 gene [1] and is characterized by partial or complete absence of iris tissue. Apart from the hypoplasia of iris tissue, other ocular features such as foveal hypoplasia, nystagmus, aniridia-related keratopathy, Peters anomaly, Axenfeld-Rieger anomaly and glaucoma are seen in these eyes [1,2]. Cases have been reported with persistent pupillary membranes [3] and iris strands [4].

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The specific clinical features of congenital aniridia in the childhood

Russian Pediatric Ophthalmology ◽

10.18821/1993-1859-2016-11-3-121-129 ◽

2016 ◽

Vol 11 (3) ◽

pp. 121-129 ◽

Cited By ~ 1

Author(s):

Anna Aleksandrovna Voskresenskaya ◽

N. A Pozdeyeva ◽

T. A Vasil'eva ◽

O. V Khlebnikova ◽

R. A Zinchenko

Keyword(s):

Visual Acuity ◽

Children And Adolescents ◽

Newborn Infants ◽

Federal State ◽

Ophthalmological Examination ◽

State Institute ◽

Familial Type ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

And Gender

Aim. The objective of the present study was to elucidate the specific features of the clinical picture of congenital aniridia in the children and adolescents and determine the frequency of complications of this pathology in the Russian Federation. Materials and methods. The study involved 37 children and adolescents at the age below 18 years (74 eyes) who were recruited from 37 unrelated families and diagnosed as having congenital aniridia at the Cheboksarsky branch of S.N. Fedorov Federal State Institute of Eye Microsurgery. All the children underwent the comprehensive ophthalmological examination based at this institution that included determination of the patients’ age and gender, diagnostics of keratopathy, cataract and glaucoma, measurements of foveal hypoplasia and hypoplasia of the optical nerve. In addition, visual acuity (VA) and the type of refraction were determined, gonioscopy and central keratopachymetry were performed on each patient. Results. The age of the patients varied from 2 months to 18 years (median: 3 years). The familial type of inheritance of congenital aniridia was documented in 16 patients whereas sporadic cases of this pathology were detected in 21 (56.7%) children. Microcornea and microphthalmus occurred in 4 and 2 eyes respectively. WAGR syndrome was diagnosed in 9.5% of the patients presenting with sporadic aniridia. Visual acuity was estimated at => 0.1 in 52% of the cases; it was => 0.3 in three patients. Abnormal refraction was documented in 88.3% of the children, marked hypermetropia was diagnosed in 15% of the examined eyes. The signs of aniridic keratopathy in the newborn infants and young children(aged below 3 years) were found in 64% of the cases. The youngest age at which the signs of aniridic keratopathy were apparent was 14 months. Cataract of different severity was documented in 77% of the eyes, glaucoma in 22.6%, foveal hypoplasia in 94%, and nystagmus in 86.5% of the eyes. The thickness of the central cornel region in the children at the age from 6 months to 2 years was 635+-47 microns compared with 606+-43 microns in the patients from 3 to 18 years of age. Conclusion. Congenital aniridia is a progressive panocular pathology affecting various structures of the eye and leading to the impairment of the visual function from the very early life.

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Spectral-domain optical coherence tomography foveal morphology as a prognostic factor for vision performance in congenital aniridia

European Journal of Ophthalmology ◽

10.1177/1120672118818352 ◽

2018 ◽

Vol 30 (1) ◽

pp. 58-65 ◽

Cited By ~ 4

Author(s):

Pilar Casas-Llera ◽

Ana Siverio ◽

Gemma Esquivel ◽

Cristina Bautista ◽

Jorge L Alió

Keyword(s):

Optical Coherence Tomography ◽

Visual Acuity ◽

Outer Segment ◽

Spectral Domain ◽

Ophthalmological Examination ◽

Optical Coherence ◽

Corrected Visual Acuity ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Best Corrected Visual Acuity

Background: Patients with congenital aniridia usually have some degree of foveal hypoplasia, thus representing a limiting factor in the final visual acuity achieved by these patients. The purpose of this study was to analyze whether the foveal morphology assessed by spectral-domain optical coherence tomography may serve as a prognostic indicator for best-corrected visual acuity in congenital aniridia patients. Methods: Observational two-center study performed between January 2012 and March 2017 in the pediatric ophthalmology department at Vissum Alicante and Vissum Madrid, Spain. A total of 31 eyes from 19 patients with congenital aniridia were included. After a complete ophthalmological examination, a high-resolution spectral-domain optical coherence tomography with a three-dimensional scan program macular protocol was used. A morphological grading system of foveal hypoplasia was used varying from grade 1 in which there is a presence of a shallow foveal pit, extrusion of inner retinal layers, outer nuclear layer widening, and a presence of outer segment lengthening to grade 4 in which none of these processes occur. Results: No correlation between central, mid-peripheral, and peripheral macular thickness and logMAR best-corrected visual acuity was found. The presence of outer segment lengthening was associated with better best-corrected visual acuity with a median best-corrected visual acuity, 0.30 logMAR, whereas the absence of this morphologic feature was associated with poorer VA with a median best-corrected visual acuity of 0.61 logMAR (p < 0.001). Conclusion: Foveal hypoplasia morphology can predict the best-corrected visual acuity. Specifically, the morphologic optical coherence tomography feature that is related to a better best-corrected visual acuity in congenital aniridia patients is the presence of outer segment lengthening.

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Detection of a novel PAX6 mutation in a Chinese family with multiple ocular abnormalities

10.21203/rs.3.rs-32697/v4 ◽

2021 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Genetic Mutations ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background: Aniridia is a congenital,panocular disease affecting the cornea,anterior chamber angle,iris,lens,retina and optic nerve.PAX6 loss-of-function mutations were the most common cause of aniridia.Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities,with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This study aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family. Methods: The proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing,with Next Generation Sequencing being used to confirm these results. Results: A novel mutation(c.114_119delinsAATTTCC:p.Pro39fs)in the PAX6 gene was identified in subjects III-2 and III-3 in these family,and both of these subjects exhibited completeaniridia,cataracts,glaucoma,high myopia,and foveal hypoplasia. Conclusions We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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Detection of a novel PAX6 mutation in a Chinese family with multiple ocular abnormalities

10.21203/rs.3.rs-32697/v3 ◽

2020 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Pax6 Gene ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background: Aniridia is a congenital, panocular disease affecting the cornea, anterior chamber angle, iris, lens, retina and optic nerve. PAX6 loss-of-function mutations were the most common cause of aniridia .Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities, with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This s tudy aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family. Methods: The proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing, with Next Generation Sequencing being used to confirm these results. Results: A novel mutation (c.114_119delinsAATTTCC:p.Pro39fs) in the PAX6 gene was identified in subjects III-2 and III-3 in these family, and both of these subjects exhibited complete aniridia, cataracts, glaucoma, high myopia, and foveal hypoplasia. Conclusions: We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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Congenital Aniridia: Clinic, Genetics, Therapeutics, and Prognosis

International Scholarly Research Notices ◽

10.1155/2014/305350 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Pedro Calvão-Pires ◽

R. Santos-Silva ◽

F. Falcão-Reis ◽

A. Rocha-Sousa

Keyword(s):

Gene Expression ◽

Visual Acuity ◽

Prognostic Factors ◽

Clinical Characteristics ◽

Rare Condition ◽

Posterior Segment ◽

Eye Lens ◽

Pax6 Gene ◽

Congenital Aniridia ◽

Foveal Hypoplasia

Congenital aniridia is a rare condition related to a deficiency in the PAX6 gene expression, which may occur as a result of a family inheritance or a sporadic occurrence. Additionally, this condition may occur as an isolated ocular phenotype or in association with a systemic syndrome. The most common abnormality is iris hypoplasia; however, a panocular disease which also affects the cornea, anterior chamber of the eye, lens, and the posterior segment with presence of optic nerve and foveal hypoplasia is also evident. The development of keratopathy, glaucoma, and cataract is frequent and its presence has implications in the patient’s visual acuity. Managing aniridia is challenging since the focus is on treating the previously mentioned disorders, and the outcomes are often disappointing. In this paper, we shall review the epidemiology, pathophysiology, and clinical characteristics of patients with aniridia. We shall also make a review of the therapeutic options for the several conditions affecting this syndrome and consider the genetics and prognostic factors.

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Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia

Pharmaceutics ◽

10.3390/pharmaceutics13010007 ◽

2020 ◽

Vol 13 (1) ◽

pp. 7

Author(s):

Celia Djayet ◽

Dominique Bremond-Gignac ◽

Justine Touchard ◽

Philippe-Henri Secretan ◽

Fabrice Vidal ◽

...

Keyword(s):

Oxidative Degradation ◽

Ophthalmic Solution ◽

Eye Drops ◽

Iris Defect ◽

Drug Loss ◽

Congenital Aniridia ◽

Microbiological Stability ◽

Foveal Hypoplasia ◽

Preservative Free ◽

Oily Solution

Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22–25 °C might facilitate clinical research in aniridia.

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Detection of a novel PAX6 variant in a Chinese family with multiple ocular abnormalities

BMC Ophthalmology ◽

10.1186/s12886-022-02256-7 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Genetic Variants ◽

Chinese Family ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Whole Exome ◽

Novel Variant ◽

Health Related ◽

Congenital Aniridia ◽

Foveal Hypoplasia

Abstract Background Aniridia is a congenital, panocular disease that can affect the cornea, anterior chamber angle, iris, lens, retina and optic nerve. PAX6 loss-of-function variants are the most common cause of aniridia, and variants throughout the gene have been linked to a range of ophthalmic abnormalities. Furthermore, particular variants at a given site in PAX6 lead to distinct phenotypes. This study aimed to characterize genetic variants associated with congenital aniridia in a Chinese family. Methods The proband and family underwent ophthalmologic examinations. DNA was sampled from the peripheral blood of all 6 individuals, and whole-exome sequencing was performed. Sanger sequencing was used to verify the variant in this family members. Results A novel variant (c.114_119delinsAATTTCC: p.Pro39llefsTer17) in the PAX6 gene was identified in subjects II-1, III-1 and III-2, who exhibited complete aniridia and cataracts. The proband and the proband’s brother also had glaucoma, high myopia, and foveal hypoplasia. Conclusions We identified that a novel PAX6 frameshift heterozygous deletion variant is the predominant cause of aniridia in this Chinese family. Trial registration We did not perform any health-related interventions for the participants.

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Detection of a novel PAX6 mutation in a Chinese family with multiple ocular abnormalities

10.21203/rs.3.rs-32697/v1 ◽

2020 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Genetic Mutations ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background Aniridia is a congenital,panocular disease affecting the cornea,anterior chamber angle,iris,lens,retina and optic nerve.PAX6 loss-of-function mutations were the most common cause of aniridia.Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities,with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This study aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family.MethodsThe proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing,with Next Generation Sequencing being used to confirm these results.Results A novel mutation(c.114_119delinsAATTTCC:p.Pro39fs)in the PAX6 gene was identified in subjects III-2 and III-3 in these family,and both of these subjects exhibited completeaniridia,cataracts,glaucoma,high myopia,and foveal hypoplasia.Conclusions We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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Analysis of genotype–phenotype correlations in PAX6-associated aniridia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106172 ◽

2020 ◽

pp. jmedgenet-2019-106172 ◽

Cited By ~ 2

Author(s):

Tatyana A. Vasilyeva ◽

Andrey V. Marakhonov ◽

Anna A. Voskresenskaya ◽

Vitaly V. Kadyshev ◽

Barbara Käsmann-Kellner ◽

...

Keyword(s):

Genetic Variants ◽

Autosomal Dominant ◽

Regulatory Region ◽

Missense Mutations ◽

Loss Of Function ◽

Exact Test ◽

Pathogenic Variants ◽

Different Types ◽

Congenital Aniridia ◽

Foveal Hypoplasia

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher’s exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini–Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3′-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

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