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1.
J AAPOS ; 27(6): 357-359, 2023 12.
Article in English | MEDLINE | ID: mdl-37742703

ABSTRACT

Aniridia is an autosomal dominant congenital malformation associated with mutations in the PAX6 gene. It can be associated with deletion in the contiguous WT1 gene, leading to WAGR syndrome, characterized by Wilm tumor, aniridia, genitourinary anomalies, and mental retardation. Persistent fetal vasculature is a developmental malformation caused by incomplete regression of hyaloid vasculature. Most cases of persistent fetal vasculature occur sporadically; however, some inherited forms are described. We report a case of genetically confirmed WAGR associated with congenital cataract and persistent fetal vasculature.


Subject(s)
Aniridia , Intellectual Disability , WAGR Syndrome , Humans , WAGR Syndrome/diagnosis , WAGR Syndrome/genetics , WAGR Syndrome/pathology , Chromosome Deletion , Aniridia/diagnosis , Aniridia/genetics , Aniridia/pathology , Intellectual Disability/genetics , Mutation
2.
BMC Med Genomics ; 16(1): 182, 2023 08 04.
Article in English | MEDLINE | ID: mdl-37542296

ABSTRACT

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.


Subject(s)
Aniridia , Retinal Detachment , Humans , Aniridia/complications , Aniridia/genetics , Aniridia/pathology , East Asian People , Genotype , Homeodomain Proteins/genetics , Mutation , PAX6 Transcription Factor/genetics , Pedigree
3.
Congenit Anom (Kyoto) ; 63(4): 109-115, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37191119

ABSTRACT

Aniridia, which is a rare congenital defect of the eye, consists of iris hypoplasia or aplasia, and additional ocular abnormalities. It is most commonly caused by autosomal dominant PAX6 gene mutations. However, in about 30% of cases, it is associated with chromosomal rearrangements in the 11p13 region. The aim of this study was to identify the potential PAX6 gene variants, which could cause the isolated aniridia. Eight patients with isolated aniridia were included in this study. MLPA analysis allowed in the past to exclude large structural rearrangements of the PAX6 and adjacent genes like WT1. Blood samples were collected from the patients (and their families in familial cases) and genomic DNA was extracted from peripheral blood leukocytes and buccal cells. The amplification of the 11 exons of the PAX6 gene was performed. Bidirectional Sanger Sequencing was conducted for the identification of the potentially pathogenic variants, and for the segregation analysis of the identified variant in the family. The results were analyzed with the use of CodonCode Aligner software. In three patients, aniridia was sporadic, whereas in another five cases, the eye defect was familial. The potentially pathogenic variants in the PAX6 gene were found in 6 out of 8 patients with aniridia. We identified four known (c.781C > T, c.607C > T, and c.949C > T twice), and two novel variants (c.258_265del and c.495_496insG). Point mutations in the PAX6 gene are the most frequent cause of aniridia. The investigation of the genetic background of the disease is essential for patients to evaluate recurrence risk in the offspring.


Subject(s)
Aniridia , Eye Abnormalities , Humans , PAX6 Transcription Factor/genetics , Paired Box Transcription Factors/genetics , Mouth Mucosa/pathology , Aniridia/diagnosis , Aniridia/genetics , Aniridia/pathology , Eye Abnormalities/genetics , Mutation , Homeodomain Proteins/genetics , Pedigree
4.
Histochem Cell Biol ; 158(2): 169-180, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35551459

ABSTRACT

We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/ß-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10-11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against ß-catenin, Wnt5a, Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared with the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, ß-catenin, Hes1, mTOR, and rps6 was higher in the 9-12 wg fetal corneas compared with adult corneas. The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.


Subject(s)
Aniridia , Cornea , Signal Transduction , beta Catenin , Aniridia/metabolism , Aniridia/pathology , Cornea/metabolism , Cornea/pathology , Fetus , Hedgehog Proteins/metabolism , Humans , TOR Serine-Threonine Kinases/metabolism , beta Catenin/metabolism
5.
Biochem Biophys Res Commun ; 582: 100-104, 2021 12 10.
Article in English | MEDLINE | ID: mdl-34700241

ABSTRACT

Aniridia is a panocular inherited rare eye disease linked to heterozygous mutations on the PAX6 gene, which fail to properly produce sufficient protein essential for normal eye development and function. Most of the patients suffer from aniridia-related keratopathy, a progressive opacification of the cornea. There is no effective treatment for this blinding disease. Here we screen for small compounds and identified Ritanserin, a serotonin 2A receptor antagonist, that can rescue PAX6 haploinsufficiency of mutant limbal cells, defective cell migration and PAX6-target gene expression. We further demonstrated that Ritanserin activates PAX6 production through the selective inactivation of the MEK/ERK signaling pathway. Our data strongly suggest that repurposing this therapeutic molecule could be effective in preventing or treating existing blindness by restoring corneal transparency.


Subject(s)
Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 3/genetics , Ophthalmic Solutions/pharmacology , PAX6 Transcription Factor/genetics , Ritanserin/pharmacology , Serotonin Antagonists/pharmacology , Stem Cells/drug effects , Aniridia/drug therapy , Aniridia/genetics , Aniridia/metabolism , Aniridia/pathology , Cell Line , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Repositioning/methods , Epithelium, Corneal/drug effects , Epithelium, Corneal/metabolism , Epithelium, Corneal/pathology , Gene Expression Regulation , HEK293 Cells , Haploinsufficiency , Humans , Limbus Corneae/drug effects , Limbus Corneae/metabolism , Limbus Corneae/pathology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Models, Biological , PAX6 Transcription Factor/agonists , PAX6 Transcription Factor/metabolism , Receptor, Serotonin, 5-HT2A/genetics , Receptor, Serotonin, 5-HT2A/metabolism , Signal Transduction/drug effects , Stem Cells/metabolism , Stem Cells/pathology
6.
Genes (Basel) ; 12(9)2021 09 11.
Article in English | MEDLINE | ID: mdl-34573386

ABSTRACT

Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.


Subject(s)
Eye Diseases, Hereditary/genetics , Glaucoma/etiology , Glaucoma/genetics , Aniridia/genetics , Aniridia/pathology , Collagen Diseases/complications , Collagen Diseases/genetics , Collagen Diseases/pathology , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Eye Diseases, Hereditary/pathology , Glaucoma/pathology , Glaucoma, Angle-Closure/complications , Glaucoma, Angle-Closure/genetics , Glaucoma, Angle-Closure/pathology , Humans , Hyperopia/complications , Hyperopia/genetics , Hyperopia/pathology , Immune System Diseases/complications , Immune System Diseases/genetics , Immune System Diseases/pathology , Metabolic Diseases/complications , Metabolic Diseases/genetics , Metabolic Diseases/pathology , Microphthalmos/complications , Microphthalmos/genetics , Microphthalmos/pathology , Syndrome , Vascular Diseases/complications , Vascular Diseases/genetics , Vascular Diseases/pathology
7.
Genes (Basel) ; 12(5)2021 05 09.
Article in English | MEDLINE | ID: mdl-34065151

ABSTRACT

BACKGROUND: Congenital aniridia is a complex ocular disorder, usually associated with severe visual impairment, generally caused by mutations on the PAX6 gene. The clinical phenotype of PAX6 mutations is highly variable, making the genotype-phenotype correlations difficult to establish. METHODS: we describe the phenotype of eight patients from seven unrelated families with confirmed mutations in PAX6, and very different clinical manifestations. RESULTS: Only two patients had the classical aniridia phenotype while the other two presented with aniridia-related manifestations, such as aniridia-related keratopathy or partial aniridia. Congenital cataracts were the main manifestation in three of the patients in this series. All the patients had nystagmus and low visual acuity. CONCLUSIONS: The diagnosis of mild forms of aniridia is challenging, but these patients have a potentially blinding hereditary disease that might present with a more severe phenotype in future generations. Clinicians should be aware of the mild aniridia phenotype and request genetic testing to perform an accurate diagnosis.


Subject(s)
Aniridia/genetics , Cataract/genetics , Corneal Dystrophies, Hereditary/genetics , Nystagmus, Congenital/genetics , PAX6 Transcription Factor/genetics , Phenotype , Adolescent , Adult , Aniridia/pathology , Cataract/pathology , Child , Corneal Dystrophies, Hereditary/pathology , Female , Humans , Infant , Infant, Newborn , Male , Mutation , Nystagmus, Congenital/pathology
8.
Hum Mutat ; 42(8): 1053-1065, 2021 08.
Article in English | MEDLINE | ID: mdl-34174135

ABSTRACT

Congenital aniridia (AN) is a severe autosomal dominant panocular disorder associated with pathogenic variants in the PAX6 gene. Previously, we performed a molecular genetic study of a large cohort of Russian patients with AN and revealed four noncoding nucleotide variants in the PAX6 5'UTR. 14 additional PAX6-5'UTR variants were also reported in the literature, but the mechanism of their pathogenicity remained unclear. In the present study, we experimentally analyze five patient-derived PAX6 5'UTR-variants: four variants that we identified in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_-117del) and one previously reported (c.-52+5G>C). We show that the variants lead to a decrease in the protein translation efficiency, while mRNA expression level is not significantly reduced. Two of these variants also affect splicing. Furthermore, we predict and experimentally validate the presence of an evolutionarily conserved small uORF in the PAX6 5'UTR. All studied variants lead to the frameshift of the uORF, resulting in its extension. This extended out-of-frame uORF overlaps with the downstream CDS and thereby reduces its translation efficiency. We conclude that the uORF frameshift may be the main mechanism of pathogenicity for at least 15 out of 18 known PAX6 5'UTR variants. Moreover, we predict additional uORFs in the PAX6 5'UTR.


Subject(s)
Aniridia , 5' Untranslated Regions , Aniridia/genetics , Aniridia/pathology , Frameshift Mutation , Humans , Inheritance Patterns , PAX6 Transcription Factor/genetics , RNA, Messenger/genetics
9.
Ophthalmic Genet ; 42(2): 216-217, 2021 04.
Article in English | MEDLINE | ID: mdl-33300417

ABSTRACT

Introduction: Wilms tumor (WT) is the most common renal malignancy of children and can be seen in WAGR syndrome (WT, aniridia, genitourinary anomalies, and intellectual disability). WAGR results from a contiguous gene deletion within the 11p13 region, encompassing the WT1 gene, often responsible for WT development, and the PAX6 gene, responsible for aniridia. Aniridia, a pan-ocular disease resulting from iris hypoplasia, is thought to increase the risk for WT development if their genetic alteration spans both the WT1 and the PAX6 genes on 11p13.Case Description: We describe a unique case of a patient with aniridia secondary to a heterozygous PAX6 nonsense mutation who developed WT despite no additional identifiable germline genetic drivers for this disease.Discussion: Isolated mutations in PAX6 previously have not been associated with increased risk of WT development case raises the question of if surveillance for WT should be continued in patients with aniridia with an isolated PAX6 mutation identified.


Subject(s)
Aniridia/pathology , Codon, Nonsense , Eye Proteins/genetics , Kidney Neoplasms/pathology , PAX6 Transcription Factor/genetics , Wilms Tumor/pathology , Aniridia/complications , Aniridia/genetics , Child, Preschool , Humans , Kidney Neoplasms/complications , Kidney Neoplasms/genetics , Male , Prognosis , Wilms Tumor/complications , Wilms Tumor/genetics
10.
J Med Genet ; 58(4): 270-274, 2021 04.
Article in English | MEDLINE | ID: mdl-32467297

ABSTRACT

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.


Subject(s)
Aniridia/genetics , Eye Abnormalities/genetics , Genetic Predisposition to Disease , PAX6 Transcription Factor/genetics , Adolescent , Adult , Aniridia/epidemiology , Aniridia/pathology , Cataract/epidemiology , Cataract/genetics , Child , Child, Preschool , Eye Abnormalities/epidemiology , Eye Abnormalities/pathology , Female , Genetic Association Studies , Glaucoma/epidemiology , Glaucoma/genetics , Humans , Male , Mutation, Missense/genetics , Pedigree , Young Adult
11.
Exp Eye Res ; 203: 108371, 2021 02.
Article in English | MEDLINE | ID: mdl-33248069

ABSTRACT

Congenital aniridia is caused by heterozygous mutations in the PAX6 gene. In this disease, congenital iris and foveal hypoplasia is associated with juvenile onset cataract, glaucoma, and corneal keratopathy. In rodents, Pax6 mutations result in a congenital reduction in ocular size that is not typically described in human aniridia. Here, the ocular morphometry of aniridia patients is compared with the lens phenotype of Pax6+/tm1/Pgr mice to reveal whether there are species differences in Pax6 regulation of lens development and homeostasis. Ultrasound biometry (UBM) revealed that eleven percent of aniridia patients exhibited mild microphthalmia while the anterior chamber depth of aniridic eyes was significantly reduced from 6 months of age onward. Although aniridic lens thickness was normal from birth, it was significantly decreased in aniridic lenses older than 30. Notably, 86% of aniridic lenses exhibited cataractous changes in this cohort. In addition, a significant proportion of aniridia patients develop lens subluxation as they age associated with reduced lens diameter as measured by anterior segment optical coherence tomography (AS-OCT). Analysis of young adult Pax6+/tm1/Pgr mouse lenses by micro-computed tomography (microCT), bright field and dark field imaging revealed that they are reduced in size but did not exhibit overt cataracts at this age. Overall, this study reveals that congenital microphthalmia as assessed by axial length, or microphakia, as assessed by lens thickness, are not typical in human aniridia, although these are primary manifestations of Pax6 mutations in mice, suggesting that PAX6 regulates some aspects of lens development differently between these species.


Subject(s)
Aniridia/pathology , Cataract/pathology , Lens, Crystalline/pathology , Microphthalmos/pathology , Adolescent , Adult , Aged , Animals , Aniridia/genetics , Anterior Chamber/pathology , Axial Length, Eye/pathology , Cataract/genetics , Child , Child, Preschool , Disease Models, Animal , Female , Humans , Infant , Male , Mice , Mice, Mutant Strains , Microphthalmos/genetics , Microscopy, Acoustic , Middle Aged , PAX6 Transcription Factor/genetics , Phenotype , Slit Lamp Microscopy , Tomography, Optical Coherence , Young Adult
12.
BMC Med Genomics ; 13(Suppl 8): 130, 2020 09 18.
Article in English | MEDLINE | ID: mdl-32948199

ABSTRACT

BACKGROUND: Because of the significant occurrence of "WAGR-region" deletions among de novo mutations detected in congenital aniridia, DNA diagnosis is critical for all sporadic cases of aniridia due to its help in making an early diagnosis of WAGR syndrome. Standard cytogenetic karyotype study is a necessary step of molecular diagnostics in patients with deletions and in the patients' parents as it reveals complex chromosomal rearrangements and the risk of having another affected child, as well as to provide prenatal and/or preimplantation diagnostics. CASE PRESENTATION: DNA samples were obtained from the proband (a 2-year-old boy) and his two healthy parents. Molecular analysis revealed a 977.065 kb deletion that removed loci of the ELP4, PAX6, and RCN1 genes but did not affect the coding sequence of the WT1 gene. The deletion occurred de novo on the paternal allele. The patient had normal karyotype 46,XY and a de novo pericentric inversion of chromosome 11, inv(11)(p13q14). CONCLUSIONS: We confirmed the diagnosis of congenital aniridia at the molecular level. For the patient, the risk of developing Wilms' tumor is similar to that in the general population. The recurrence risk for sibs in the family is low, but considering the possibility of gonadal mosaicism, it is higher than in the general population.


Subject(s)
Aniridia/genetics , Chromosome Deletion , Chromosome Inversion , Chromosomes, Human, Pair 11 , Aniridia/diagnosis , Aniridia/pathology , Child, Preschool , Humans , Male
13.
Curr Eye Res ; 45(10): 1292-1297, 2020 10.
Article in English | MEDLINE | ID: mdl-32141346

ABSTRACT

Purpose: To evaluate the choroidal thickness (CT) in children with congenital aniridia in comparison with age-matched controls. Methods: This was a cross-sectional, observational study that included 64 eyes of 32 children with congenital aniridia (aged 5-12 years) and 80 eyes of 40 healthy subjects who were age-matched. In all subjects, subfoveal choroidal thickness (SFCT) was assessed at 750-µm intervals from the fovea to 1.5 mm in the temporal and nasal directions with spectral-domain optical coherence tomography (SD-OCT). Results: The mean SFCT was 207.67 ± 30.99 µm in the aniridic eyes. This SFCT was significantly thinner than that in control eyes (288.55 ± 30.06 µm) (P < .001). The SFCTs at 1.5 mm and 0.75 mm intervals in the temporal and nasal directions from the fovea were also significantly thinner in eyes with aniridia than control eyes (P < .001).There was a significant negative correlation between the SFCT and axial length in eyes with aniridia (B = -10.60, 95%CI = -19.31~-1.89, P = .017). Conclusions: The subfoveal and parafoveal CTs were significantly thinner in eyes with congenital aniridia than in control eyes. These choroidal changes could open up a new way for the research related to the pathophysiology of congenital aniridia.


Subject(s)
Aniridia/pathology , Choroid/pathology , Adolescent , Aniridia/diagnostic imaging , Child , Child, Preschool , Choroid/diagnostic imaging , Cross-Sectional Studies , Female , Humans , Male , Organ Size , Tomography, Optical Coherence
14.
Mol Genet Genomic Med ; 8(5): e1198, 2020 05.
Article in English | MEDLINE | ID: mdl-32125788

ABSTRACT

BACKGROUND: Congenital aniridia is a severe ocular abnormality characterized by incomplete formation of the iris and many other ocular complications. Most cases are caused by the paired box 6 (PAX6) gene mutations generating premature termination codons (PTCs). METHODS: Ophthalmic examination was performed on a Chinese pedigree with congenital aniridia. The mutation was identified by targeted next-generation sequencing. Nonsense suppression therapy was applied on patient-derived lymphocytes. The PAX6 expression was assayed by real-time polymerase chain reaction and Western blot. RESULTS: Complete aniridia was complicated with horizontal nystagmus, contract, foveal hypoplasia, and microphthalmia. A novel heterozygous c.702_703delinsAT (p.Tyr234*) mutation was found in exon 9 of PAX6, generating a PTC at the homeodomain. There were about 50% reductions of both full-length PAX6 protein and PAX6 mRNA in patient-derived lymphocytes, indicating haploinsufficiency due to nonsense-mediated mRNA decay. Ataluren (PTC124) and geneticin (G418) could induce about 30%-40% translational readthrough. Nonsense suppression therapy restored PAX6 protein to about 65%-70% of unaffected family controls. CONCLUSION: Our data expanded the genetic and phenotypic variations of congenital aniridia, and showed the therapeutic effect of nonsense suppression on this disease using patient-derived cells.


Subject(s)
Aniridia/genetics , INDEL Mutation , Nonsense Mediated mRNA Decay/drug effects , PAX6 Transcription Factor/genetics , Adult , Aniridia/pathology , Cells, Cultured , Child , Female , Gentamicins/pharmacology , Haploinsufficiency , Heterozygote , Humans , Male , Middle Aged , Oxadiazoles/pharmacology , PAX6 Transcription Factor/metabolism , Pedigree
15.
Mol Genet Genomic Med ; 8(4): e1183, 2020 04.
Article in English | MEDLINE | ID: mdl-32056389

ABSTRACT

BACKGROUND: Congenital aniridia involves total or partial hypoplasia of the iris and is due to a deficiency in PAX6 gene expression. WAGR syndrome is comprised of Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability. Numerous genitourinary pathologies may be associated with WAGR syndrome, necessitating an evaluation of the genitourinary anatomy. The WT1 is vital for the development of kidneys, ovaries in females, and testes in males. WT1 gene mutations result in a WT1 protein with a decreased ability to bind to DNA, leading to uncontrolled growth, and cell division in the kidney which permits the development of Wilms tumor. A congenital ureteral valve is an exceedingly rare cause of obstructive uropathy. RESULTS: A renal and bladder ultrasound demonstrated a renal cyst. A voiding cystourethrogram revealed grade 3 vesicoureteral reflux, and a MAG3 renal scan showed ureteropelvic junction obstruction and hydronephrosis. A ureteral stent was inserted at 3 months of age after which the renal cyst resolved. The patient was urinary tract infection-free at 27 months of age. Genetic testing confirmed a heterozygous alteration in PAX6 (c.495delG, p.Thr166Leufs*41) and no abnormalities of WT1, excluding WAGR syndrome. CONCLUSION: The genitourinary risks potentially associated with aniridia necessitate prompt genetic analysis to evaluate for WAGR syndrome.


Subject(s)
Aniridia/genetics , Genetic Testing , PAX6 Transcription Factor/genetics , Urethral Obstruction/genetics , Aniridia/pathology , Child, Preschool , Diagnosis, Differential , Female , Humans , Kidney/diagnostic imaging , Mutation , Syndrome , Urethra/abnormalities , Urethra/diagnostic imaging , Urethral Obstruction/pathology
16.
Brain Res ; 1732: 146698, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32014531

ABSTRACT

PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in PAX6 cause the disorder aniridia in humans and the Small eye trait in mice. Aniridia is a congenital and progressive disorder known for ocular phenotypes; however, recently, consequences of PAX6 haploinsufficiency in the brains of aniridia patients have been identified. These findings span structural and functional abnormalities, including deficits in cognitive and sensory processing. Furthermore, some of these abnormalities are accelerated as aniridia patients age. Although some functional abnormalities may be explained by structural changes, variability of results remain, and the effects of PAX6 heterozygous loss-of-function mutations on neuroanatomy, particularly with regard to aging, have yet to be resolved. Our study used high-resolution magnetic resonance imaging (MRI) and histology to investigate structural consequences of such mutations in the adult brain of our aniridia mouse model, Small eye Neuherberg allele (Pax6SeyNeu/+), at two adult age groups. Using both MRI and histology enables a direct comparison with human studies, while providing higher resolution for detection of more subtle changes. We show volumetric changes in major brain regions of the the Pax6SeyNeu/+ mouse compared to wild-type including genotype- and age-related olfactory bulb differences, age-related cerebellum differences, and genotype-related eye differences. We also show alterations in thickness of major interhemispheric commissures, particularly those anteriorly located within the brain including the optic chiasm, corpus callosum, and anterior commissure. Together, these genotype and age related changes to brain volumes and structures suggest a global decrease in adult brain structural plasticity in our Pax6SeyNeu/+ mice.


Subject(s)
Aniridia/diagnostic imaging , Brain/diagnostic imaging , Neuronal Plasticity/physiology , PAX6 Transcription Factor/genetics , Age Factors , Aging/physiology , Animals , Aniridia/genetics , Aniridia/pathology , Brain/pathology , Disease Models, Animal , Magnetic Resonance Imaging , Mice , Mice, Knockout , Mutation
17.
Genes (Basel) ; 10(12)2019 12 17.
Article in English | MEDLINE | ID: mdl-31861090

ABSTRACT

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed.


Subject(s)
Aniridia/genetics , Eye Proteins/genetics , Genetic Association Studies , PAX6 Transcription Factor/genetics , Aniridia/pathology , Databases, Genetic , Gene Deletion , Haploinsufficiency , Humans , Mutation, Missense , Wilms Tumor/genetics , Wilms Tumor/pathology
18.
Invest Ophthalmol Vis Sci ; 60(13): 4120-4128, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31574536

ABSTRACT

Purpose: To investigate fundus autofluorescence (FAF) and other fundus manifestations in congenital aniridia. Methods: Fourteen patients with congenital aniridia and 14 age- and sex-matched healthy controls were examined. FAF images were obtained with an ultra-widefield scanning laser ophthalmoscope. FAF intensity was quantified in the macular fovea and in a macular ring surrounding fovea and related to an internal reference within each image. All aniridia patients underwent an ophthalmologic examination, including optical coherence tomography and slit-lamp biomicroscopy. Results: Mean age was 28.4 ± 15.0 years in both the aniridia and control groups. Fovea could be defined by subjective assessment of FAF images in three aniridia patients (21.4%) and in all controls (P = 0.001). Mean ratio between FAF intensity in the macular ring and fovea was 1.01 ± 0.15 in aniridia versus 1.18 ± 0.09 in controls (P = 0.034). In aniridia, presence of foveal hypoplasia evaluated by biomicroscopy correlated with lack of foveal appearance by subjective analyses of FAF images (P = 0.031) and observation of nystagmus (P = 0.009). Conclusions: Aniridia patients present a lower ratio between FAF intensity in the peripheral and central macula than do healthy individuals. Both subjective and objective analyses of FAF images are useful tools in evaluation of foveal hypoplasia in aniridia.


Subject(s)
Aniridia/diagnostic imaging , Aniridia/pathology , Fluorescein Angiography/methods , Ophthalmoscopy/methods , Tomography, Optical Coherence/methods , Adolescent , Adult , Case-Control Studies , Child , Female , Humans , Male , Middle Aged , Prospective Studies , Young Adult
19.
J Fr Ophtalmol ; 42(5): 477-484, 2019 May.
Article in French | MEDLINE | ID: mdl-30928242

ABSTRACT

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.


Subject(s)
Color , Cornea/pathology , Postoperative Complications/pathology , Tattooing/adverse effects , Adult , Aged , Aniridia/pathology , Aniridia/therapy , Coloring Agents/adverse effects , Corneal Opacity/pathology , Corneal Opacity/therapy , Female , Follow-Up Studies , Humans , Ink , Male , Middle Aged , Pigmentation/physiology , Retrospective Studies , Time Factors , Treatment Failure
20.
J Ayub Med Coll Abbottabad ; 31(1): 131-133, 2019.
Article in English | MEDLINE | ID: mdl-30868799

ABSTRACT

A foetus affected by a congenital rubella infection can develop congenital rubella syndrome (CRS). Aniridia is the absence of iris, rarely been described in literature in association with CRS, can easily be overlooked, leading to complications e.g. glaucoma and blindness later in life. We report a case of a neonate with CRS and aniridia presenting at a tertiary care hospital.


Subject(s)
Aniridia , Rubella Syndrome, Congenital , Aniridia/etiology , Aniridia/pathology , Female , Humans , Infant, Newborn , Rubella Syndrome, Congenital/complications , Rubella Syndrome, Congenital/diagnosis
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