Relationship between physical and psychological functioning and health-related quality of life in congenital Aniridia.

PURPOSE: Congenital aniridia is a serious eye disease characterized by absence of iris to various degrees. The aims of this study were to investigate health-related quality of life (HRQoL) in adults with aniridia and assess the relationships between HRQoL, psychological status, ocular health and obesity. METHODS: Twenty-nine adults with congenital aniridia (48% male, aged 18-79 years) participated. HRQoL was measured with SF-36 and the EQ visual analogue scale (VAS). The physical (PCS) and mental (MCS) component summaries of the SF-36 were calculated with higher scores indicating better HRQoL. Symptoms of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Obesity was assessed with the Patient-Reported Outcomes in Obesity (PROS). Sociodemographic characteristics, genetic variants and ocular and medical health variables were also analysed. RESULTS: The participants scored significantly lower in the general health domain of the SF-36 than the general population (65.2 vs. 75.3, p = 0.017). The EQ VAS score was also lower in the aniridia group (64.9 vs. 77.9, p = 0.021). Low PCS score was correlated with presence of ocular pain (p = 0.019), high HADS score (p = 0.017) and high PROS score (p = 0.009). Low MCS score was related to higher educational level (p = 0.038) and high HADS score (p < 0.001). High HADS and PROS scores were both related to low EQ VAS scores. CONCLUSION: Adults with congenital aniridia scored worse on certain measures of HRQoL than the general population. Poorer HRQoL was associated with increased symptoms of anxiety, depression and obesity and with presence of ocular pain.

Quantitative Analysis of the Association Between Follow-Up Duration and Severity of Limbal Stem Cell Deficiency or Visual Acuity in Aniridia.

Purpose: This study aimed to quantitatively analyze the association between follow-up duration and the severity of limbal stem cell deficiency (LSCD) or visual acuity in patients with aniridia. Methods: A total of 52 eyes of 27 patients with aniridia were enrolled at Osaka University Hospital. Medical records were retrospectively reviewed to obtain information on the severity of LSCD and corrected distance visual acuity (CDVA). LSCD severity was based on a modified severity grading scale. We used an ordered logistic regression model to examine the association between follow-up duration and LSCD severity, and a linear regression model with a generalized linear mixed model for the association between follow-up duration and visual acuity. Results: The mean follow-up duration was 5.2 ± 6.3 years. The mean age at the last follow-up visit was 40.5 ± 18.9 years. The mean CDVA was 1.52 ± 1.09 logMAR. At the last follow-up, 1 examined eye (1.9%) was categorized as stage 0, 7 (13.5%) as Ia, 9 (17.3%) as Ib, 5 (9.6%) as Ic, 2 (3.8%) as IIb, 12 (23.1%) as IIc, and 11 (21.2%) as III. Five eyes (9.6%) were unclassifiable. There was a significant association between follow-up duration and LSCD severity (odds ratio per +1 year, 1.41; P < 0.001). CDVA significantly decreased as follow-up duration increased. Each increase of 1 year in the follow-up duration was associated with a mean difference of +0.021 logMAR (95% confidence interval [CI] 0.01-0.03; P < 0.001). Conclusion: We quantitatively demonstrate that LSCD severity and visual impairment significantly progress as follow-up duration increases.

Mutation spectrum of PAX6 and clinical findings in 95 Chinese patients with aniridia.

Purpose: Aniridia is a rare congenital panocular disease caused by mutations in PAX6. The purposes of this study were to clarify the mutation features of PAX6 in a cohort of Chinese patients with aniridia and to describe their clinical characteristics. Methods: We recruited 95 patients from 65 unrelated families clinically diagnosed with aniridia. All patients underwent ophthalmic examinations. Sanger sequencing and multiplex ligation probe amplification of PAX6 were performed to detect intragenic variants and copy number variations (CNVs). Results: We identified 58 disease-causing mutations in PAX6 in 63 families; the detection rate was 96.9%. The 58 mutations included frameshift indels (27.6%), splice site changes (25.9%), nonsense mutations (20.7%), CNVs (19.0%), missense mutations (3.4%), run-on mutations (1.7%), and a synonymous mutation (1.7%). Clinical examinations revealed that 71 patients had complete or almost complete iris loss, 16 patients showed partial iris loss, and six patients had a full iris but with an abnormal structure. Conclusions: The results confirmed that mutations in PAX6 are the predominant cause of aniridia, and the majority are loss-of-function mutations that usually result in classical aniridia. In contrast, missense mutations, run-on mutations, and small numbers of splicing mutations mostly lead to atypical aniridia and an intrafamilial phenotypic variability of iris hypoplasia.

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

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.

Gillespie's Syndrome with Minor Cerebellar Involvement and No Intellectual Disability Associated with a Novel ITPR1 Mutation: Report of a Case and Literature Review.

Variants in the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene have been recently identified as a cause of Gillespie's syndrome, a rare inherited condition characterized by bilateral iris hypoplasia, congenital muscle hypotonia, nonprogressive cerebellar ataxia, and intellectual disability. Here, we describe the clinical and genetic findings in a patient who presented with iris hypoplasia, mild gait ataxia, atrophy of the anterior cerebellar vermis but no cognitive deficits. Whole-exome sequencing (WES) uncovered a heterozygous ITPR1 p.Glu2094Lys missense variant, affecting a highly conserved glutamic acid residue for which other amino acid substitutions have already been reported in Gillespie's syndrome patients. Our data expand both the phenotypic and genetic spectrum associated with Gillespie's syndrome and suggest a mutation hotspot on Glu2094.

Early and late auditory information processing show opposing deviations in aniridia.

Aniridia is a congenital disorder, predominantly caused by heterozygous mutations of the PAX6 gene. While ocular defects have been extensively characterized in this population, brain-related anatomical and functional abnormalities are emerging as a prominent feature of the disorder. Individuals with aniridia frequently exhibit auditory processing deficits despite normal audiograms. While previous studies have reported hypoplasia of the anterior commissure and corpus callosum in some of these individuals, the neurophysiological basis of these impairments remains unexplored. This study provides direct assessment of neural activity related to auditory processing in aniridia. Participants were presented with tones designed to elicit an auditory steady-state response (ASSR) at 22 Hz, 40 Hz, and 84 Hz, and infrequent broadband target tones to maintain attention during electroencephalography (EEG) recording. Persons with aniridia showed increased early cortical responses (P50 AEP) in response to all tones, and increased high-frequency oscillatory entrainment (84 Hz ASSR). In contrast, this group showed a decreased cortical integration response (P300 AEP to target tones) and reduced neural entrainment to cortical beta-band stimuli (22 Hz ASSR). Collectively, our results suggest that subcortical and early cortical auditory processing is augmented in aniridia, while functional cortical integration of auditory information is deficient in this population.

Meibomian gland dysfunction and keratopathy are associated with dry eye disease in aniridia.

AIMS: To investigate the aetiology and characteristics of dry eye disease (DED) in a Nordic cohort of patients with congenital aniridia. METHODS: Thirty-four Norwegian and one Danish subject with congenital aniridia and 21 healthy controls were examined. All subjects underwent an extensive dry eye examination, including evaluation of meibomian glands (MGs) by meibography, measurement of tear production and tear film osmolarity and grading of vital staining of the ocular surface. Moreover, slit-lamp biomicroscopy was undertaken, including grading of aniridia-associated keratopathy (AAK). RESULTS: Mean tear film osmolarity was significantly higher (314±11 mOsmol/L) in patients with aniridia compared with the healthy control group (303±11 mOsmol/L, p=0.002). Vital staining score was higher in the aniridia group (4.3±3.0) compared with healthy controls (2.4±1.6, p=0.02). The degree of staining correlated positively with the stage of AAK (r=0.44, p=0.008) and negatively with corneal sensitivity (r=-0.45, p=0.012). Number of expressible MGs was lower in aniridia subjects (2.9±1.6) than in controls (4.0±1.3, p=0.007). MG loss, staged from 0 to 3, was higher in the aniridia group than in the control group, both in upper eyelid (0.86±0.89 vs 0.10±0.31, p=0.001) and lower eyelid (0.94±0.73 vs 0.30±0.47, p=0.003). Computerised analyses showed thinning (p=0.004) and lower density (p<0.001) of the MGs compared with the healthy population. CONCLUSIONS: Patients with congenital aniridia demonstrate increased tear film osmolarity, ocular surface staining, loss of MGs and lower MG expressibility. We conclude that meibomian gland dysfunction and keratopathy are related to development of DED in aniridia.

Mild aniridia phenotype: an under-recognized diagnosis of a severe inherited ocular disease.

PURPOSE: Aniridia is a rare panocular disorder caused by mutations in the PAX6 gene and characterized mainly by iris hypoplasia. Here, we present six families with a history of low vision/blindness with a previously undiagnosed mild aniridia phenotype with minimal iris changes. METHODS: Retrospective case series of patients diagnosed with a subtle aniridia phenotype characterized by minimal iris abnormalities, foveal hypoplasia, and an identified mutation in PAX6. Data collection from patient's charts included ocular examination findings, visual acuity, refraction, and clinical pictures when available. Genetic analysis was performed by isolation of genomic DNA from peripheral blood. The main outcome was the identification of patients with mild aniridia harboring a PAX6 mutation. RESULTS: In all six families, the phenotype included minimal corectopia and foveal hypoplasia; nystagmus was present in 10 out of 11 patients. A PAX6 mutation was identified in all six families; three of these mutations were identified previously, and three are novel mutations. All the mutations are located within the conventional 128-residue paired domain of PAX6. CONCLUSIONS: A mild form of aniridia should be considered in the differential diagnosis of patients with low vision associated with mild iris abnormalities, nystagmus, and foveal hypoplasia. To ensure an accurate diagnosis of aniridia, minimal pupillary changes and/or incipient keratopathy should be examined. The broad phenotypic heterogeneity among aniridia leads to the fact that eye care clinicians must have a high index of suspicion for the disease when seeing undiagnosed low vision patients, because proper diagnosis can improve management as well as facilitate genetic testing and counselling.

Color Vision in Aniridia.

Purpose: To assess color vision and its association with retinal structure in persons with congenital aniridia. Methods: We included 36 persons with congenital aniridia (10-66 years), and 52 healthy, normal trichromatic controls (10-74 years) in the study. Color vision was assessed with Hardy-Rand-Rittler (HRR) pseudo-isochromatic plates (4th ed., 2002); Cambridge Color Test and a low-vision version of the Color Assessment and Diagnosis test (CAD-LV). Cone-opsin genes were analyzed to confirm normal versus congenital color vision deficiencies. Visual acuity and ocular media opacities were assessed. The central 30° of both eyes were imaged with the Heidelberg Spectralis OCT2 to grade the severity of foveal hypoplasia (FH, normal to complete: 0-4). Results: Five participants with aniridia had cone opsin genes conferring deutan color vision deficiency and were excluded from further analysis. Of the 31 with aniridia and normal opsin genes, 11 made two or more red-green (RG) errors on HRR, four of whom also made yellow-blue (YB) errors; one made YB errors only. A total of 19 participants had higher CAD-LV RG thresholds, of which eight also had higher CAD-LV YB thresholds, than normal controls. In aniridia, the thresholds were higher along the RG than the YB axis, and those with a complete FH had significantly higher RG thresholds than those with mild FH (P = 0.038). Additional increase in YB threshold was associated with secondary ocular pathology. Conclusions: Arrested foveal formation and associated alterations in retinal processing are likely to be the primary reason for impaired red-green color vision in aniridia.

Long-term results after artificial iris implantation in patients with aniridia.

BACKGROUND: The custom-made, flexible artificial iris developed by HumanOptics and Koch can reconstruct the anterior segment of patients with aniridia. The aim of this study was to evaluate the long-term clinical outcome and complication spectrum after artificial iris implantation and the role of the embedded fiber mesh in view of specific complications. METHODS: In this retrospective interventional case series, patients received an artificial iris between 2004 and 2013. Only eyes with a minimum follow-up period of 2 years were included. Indications were congenital, traumatic, or iatrogenic aniridia. The artificial iris was used either with or without embedded fiber mesh for partial or full prostheses. RESULTS: We included 34 patients (mean age 48.8 years; SD ±17.2) with a mean follow-up of 50.0 months (SD ±18.9 months). No repositioning of prostheses was necessary. In cases of keratopathy (17.6 %) visual function increased from baseline mean 1.6 logMAR (SD ±0.7) to 1.2 logMAR (SD ±0.7) after artificial iris implantation. The remaining iris tissue darkened during the follow-up in 23.5 % (83.3 % with and 10.7 % without mesh), 8.8 % developed glaucoma (50 % with and 0 % without mesh) and 14.7 % needed consecutive surgery after prostheses implantation (50 % with and 7.1 % without mesh). In three out of seven trauma cases (42.9 %) silicone oil was spilled into the anterior chamber after 2.5 years on average. CONCLUSION: The artificial iris prosthesis revealed a good clinical outcome in terms of long-term stability, cosmetic appearance, visual function, and represents a good functional iris diaphragm for compartmentalisation. Complications such as glaucoma, darkening of iris tissue, and need for consecutive anterior segment surgery are clearly associated with implants with integrated fiber mesh, but not to those without. Hence, the use of full iris prostheses without embedded fiber mesh, even in cases with remnant iris, and the use of slightly smaller implants than officially recommended may be beneficial.

Accuracy of Intraocular Pressure Measurement With the Icare Tonometer in Children.

PURPOSE: The aim of this study was to evaluate the difference between intraocular pressure (IOP) measurements in children with the Icare tonomer (IT) and applanation (AT), pneumatic (PT), or digital tonometers (TT). DESIGN: A randomized prospective trial of children younger than age 16 attending the pediatric ophthalmology department of Manchester Royal Eye Hospital was conducted. METHODS: Children had IOP measured twice, once with an IT and again with a TT, PT, or AT during the same clinic appointment. RESULTS: Forty-four children (88 eyes) were included, with a mean [range (R)] age of 57 (2-144) months. Twelve eyes had anterior segment pathology (ASP), defined as aniridia, congenital glaucoma, or Peters anomaly. Regardless of the presence or absence of ASP, total mean difference (MD), R, positive bias (PB), and limits of agreement (LOA) between IT and other instruments were as follows: PT: MD = 3.2, R = 0 to 8, PB = 2.9, LOA = -1.0 to 6.9; TT: MD = 2.6, R = 0 to 6, PB = 0.9, LOA = -1.8 to 3.5; and AT: MD = 1.4, R = -3 to 5, PB = 0.6, LOA = -4.2 to 7.3. In eyes with ASP, IT comparisons with PT were as follows: MD = 3.9, R = 0 to 8, PB = 3.9, LOA = -0.9 to 8.8. CONCLUSIONS: In children with ASP, IOP measured with IT is higher than expected when compared with other tonometers, in some cases by up to 8 mm Hg. We found an overestimation of IOP in children using the IT with a positive bias of 4 mm Hg. We propose that the IT overestimates IOP measurements in children compared with standard tonometers. Further work should be carried out on a much larger cohort to establish a suitable correction factor for such children.

Outcomes of a modified capsular tension ring with a single black occluder paddle for eyes with congenital and acquired iris defects: Report 2.

PURPOSE: To evaluate the safety and efficacy of Morcher 96F iris diaphragm implantation to manage small defects of the human iris. SETTING: Jules Stein Eye Institute, UCLA, Los Angeles, California, USA. DESIGN: Prospective nonrandomized interventional case series. METHODS: Demographic, preoperative, and postoperative data of patients who had implantation of the modified capsular tension ring (CTR) and followed to 1 year were reviewed. Safety measures included loss of corrected distance visual acuity (CDVA), perioperative complications, adverse events, and secondary surgical interventions. Efficacy measures included CDVA with glare, daytime and nighttime glare symptom scores, and subjective cosmesis scores. RESULTS: Sixteen patients had CTR implantation. There was a statistically significant improvement in the median CDVA of 2.5 Snellen lines (P < .01), with 4 patients having minor decreases in CDVA for reasons unrelated to the device. There were no intraoperative complications. Three adverse events were reported: 1 ocular hypertension, 1 postoperative retinal detachment, and 1 25-degree rotation of the CTR. There were 4 secondary surgical interventions. There was a statistically significant improvement in the median CDVA with glare of 8 Snellen lines (P < .01), but 2 patients had a decrease in CDVA with glare for reasons unrelated to the device. There were statistically significant improvements in the median daytime and nighttime glare symptom scores of 5 points and 4 points, respectively (both P < .01). There was no change in cosmesis for most patients. CONCLUSION: Iris diaphragm CTR implantation was relatively safe and effective at reducing light and glare sensitivity in eyes with small iris defects. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Aniridic Glaucoma: Long-term Visual Outcomes and Phenotypic Associations.

PURPOSE: The aim of this study was to evaluate long-term visual outcomes in patients with aniridic glaucoma. DESIGN: Retrospective noncomparative observational case series. MATERIALS AND METHODS: A review of medical records of 128 eyes of 64 consecutive patients with aniridic glaucoma, diagnosed after the age of 5 years was analyzed. The parameters studied included age at presentation, family history, baseline intraocular pressure (IOP), type and the number of surgical interventions, and associated comorbidities. PRIMARY OUTCOME MEASURE: Best corrected visual acuity (BCVA) in the better eye. RESULTS: Mean age at presentation was 15.86±10.11 years (range, 5 to 47 y). The average follow-up was 7.69±4.98 years (range, 1 to 17 y). At the final follow up only 18 patients had BCVA better than 6\60 and only 5 patients had BCVA of >6/18. Seventeen of the 64 (26.5%) patients developed phthisis in 1 eye. The final visual outcomes were not associated with age at presentation (P=0.64) or sex (P=0.76); however, those with a higher baseline IOP (P=0.017), those with familial aniridia (P=0.037), and those who underwent more number of surgical interventions had poorer visual outcomes (P=0.004). Kaplan-Meier analysis demonstrated the probability of bilateral blindness to be 69.8% and 97.6% at 5 and 10 years, respectively. CONCLUSIONS: Long-term visual outcomes after therapy among aniridic glaucoma patients remain poor. Higher baseline IOP, the presence of familial aniridia, and a history of greater number of surgical interventions are associated with poorer long-term visual outcomes.

The clinical characterization and surgical correction of blepharoptosis associated with congenital aniridia.

PURPOSE: To document the clinical characteristics and describe our management of patients with blepharoptosis associated with congenital aniridia. METHODS: Consecutive retrospective case series of patients with congenital aniridia seen at a single institution (Cincinnati Eye Institute) from 1963 to 2010. Surgical correction was performed by 2 surgeons (J.A.N. and R.C.K.). RESULTS: Ptosis associated with congenital aniridia is marked with decreased levator function. Significant comorbid ophthalmologic disease was invariably present, particularly aniridia-associated keratopathy. Complications, most often keratopathy, were common, even following conservative correction. CONCLUSIONS: The degree of ptosis is significant, and levator function is typically reduced. Ocular surface viability appears to play a key role in preoperative, intraoperative, and postoperative management. While we are aware that congenital aniridia is rather rare, we believe these recommendations are generalizable to patients with severe ocular surface disease.

Congenital aniridia: long-term clinical course, visual outcome, and prognostic factors.

PURPOSE: To describe the clinical course of congenital aniridia and to evaluate prognostic factors for visual outcome after long-term follow-up. METHODS: The medical records of 120 eyes from 60 patients with congenital aniridia were retrospectively reviewed. The prevalence and clinical course of ophthalmic characteristics, systemic disease, refractive errors, and visual acuity were assessed. Prognostic factors for final visual outcomes were analyzed. RESULTS: Aniridic keratopathy developed in 82 (69%) of 119 eyes. Macular hypoplasia was observed in 70 eyes of 35 patients (91%). Cataract was observed in 63 of 120 eyes (53%). Nystagmus was present in 41 patients (68% of 60 patients) at the initial visit but decreased in five patients (8% of 60 patients). Ocular hypertension was detected in 19 eyes (20% of 93 eyes), six (32% of 19 eyes) of which developed secondarily after cataract surgery. The mean changes in spherical equivalent and astigmatism during the follow-up period were -1.10 and 1.53 diopter, respectively. The mean final visual acuity was 1.028 logarithm of minimal angle of resolution. Nystagmus and ocular hypertension were identified as prognostic factors for poor visual outcome. CONCLUSIONS: Identification of nystagmus and ocular hypertension was important to predict final visual outcome. Based on the high rate of secondary ocular hypertension after cataract surgery, careful management is needed.

Treatment of congenital aniridia associated with subluxated infantile cataract.

A 5 year old boy was presented at Eye clinic University clinical center Tuzla with congenital aniridia in both eyes. Clinical examination revealed visual acuity of 0,08 without correction in right and 0.7 with -5.0 Dsph and -1.0 Dcyl Axx 109° in left eye. Opthalmologic examination showed bilateral aniridia associated with moderate cataract in the right and incipient cataract in the left eye. In the right eye, zonular weakness with incipient capsular displacement and esotropia of Δ6º, were noted. The patient underwent phacoemulsification, implantation of capsular tension ring and Artificial Iris implant in the capsular bag. Phacoemulsification went uneventful and early postoperative recovery was successful with no signs of aniridia-associated keratopathy development and normal values of intra ocular pressure. Patient was not motivated for operation of the left eye and it was corrected with soft contact lens. Six month after the operation visual acuity in the right eye improved to 0.9 with +1.25Dsph and maintained stable in left eye, with complete elimination of esotropia and signs of binocular vision restoration. Small incision cataract extraction with IOL and Artificial Iris implantation in one procedure can be used to correct congenital aniridia and cataract with significant visual function improvement.

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.