Congenital aniridia is a rare bilateral ocular malformation characterized by the partial or complete absence of the iris and is frequently associated with various anomalies, including keratopathy, cataract, glaucoma, and foveal and optic nerve hypoplasia. Additionally, nearly 50% of individuals with congenital aniridia experience symptoms of ocular dryness. Traditional treatment encompasses artificial tears and autologous serum. This study aimed to assess the effectiveness and safety of using platelet rich in growth factors (PRGF) plasma in patients with congenital aniridia and ocular dryness symptoms.
METHODS: The included patients underwent two cycles of a 3-month PRGF treatment. At 6 months, symptomatology was evaluated using the OSDI and SANDE questionnaires, and ocular surface parameters were analyzed.
RESULTS: The OSDI and SANDE values for frequency and severity demonstrated statistically significant improvements (p < 0.05). Ocular redness, corneal damage (corneal staining), and tear volume (Schirmer test) also exhibited statistically significant improvements (p < 0.05). No significant changes were observed in visual acuity or in the grade of meibomian gland loss.
CONCLUSIONS: The use of PRGF in patients with congenital aniridia and ocular dryness symptoms led to significant improvements in symptomatology, ocular redness, and ocular damage. No adverse effects were observed during the use of PRGF.

During life up to 70% of aniridia subjects develop aniridia-associated keratopathy (AAK). AAK is characterized by limbal stem cell insufficiency, impaired corneal epithelial cell differentiation and abnormal cell adhesion, which leads to centripetal spreading vascularization, conjunctivalization, and thickening of the cornea. Our aim was to examine the subbasal nerve plexus and central corneal stromal microstructure in subjects with congenital aniridia, using in vivo confocal laser scanning microscopy CLSM.
31 eyes of 18 patients (55.6% males, mean age: 25.22 ± 16.35 years) with congenital aniridia and 46 eyes of 29 healthy subjects (41.4% males, mean age 30 ± 14.82 years) were examined using the Rostock Cornea Module of Heidelberg Retina Tomograph-III. At the subbasal nerve plexus, corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal total branch density (CTBD), and corneal nerve fiber width (CNFW) were analyzed using ACCMetrics software. Keratocyte density in the anterior, middle and posterior stroma was assessed manually.
The CNFD (2.02 ± 4.08 vs 13.99 ± 6.34/mm2), CNFL (5.78 ± 2.68 vs 10.56 ± 2.82 mm/mm2) and CTBD (15.08 ± 15.62 vs 27.44 ± 15.05/mm2) were significantly lower in congenital aniridia subjects than in controls (p < 0.001 for all). CNFW was significantly higher in aniridia subjects than in controls (0.03 ± 0.004 vs 0.02 ± 0.003 mm/mm2) (p = 0.003). Keratocyte density was significantly lower in all stromal layers of aniridia subjects than in controls (p < 0.001 for all). Stromal alterations included confluent keratocytes, keratocytes with long extensions and hyperreflective dots between keratocytes in aniridia.
Decrease in CNFD, CNFL, and CTBD, as well as increase in CNFW well refer to the congenital aniridia-associated neuropathy. The decreased keratocyte density and the stromal alterations may be related to an increased cell death in congenital aniridia, nevertheless, stromal changes in different stages of AAK have to be further analyzed in detail.

Congenital aniridia is a rare genetic eye disorder characterized by the complete or partial absence of the iris from birth. Various theories and animal models have been proposed to understand and explain the pathogenesis of aniridia. In the majority of cases, aniridia is caused by a mutation in the PAX6 gene, which affects multiple structures within the eye. Treating these ocular complications is challenging and carries a high risk of side effects. However, emerging approaches for the treatment of aniridia-associated keratopathy, iris abnormalities, cataract abnormalities, and foveal hypoplasia show promise for improved outcomes. Genetic counseling plays a very important role to make informed choices. We also provide an overview of the newer diagnostic and therapeutic approaches such as next generation sequencing, gene therapy, in vivo silencing, and miRNA modulation.

OBJECTIVE: 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.
CONCLUSIONS: 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.

OBJECTIVE: Congenital aniridia is a rare disease, which is in most cases related to PAX6 haploinsufficiency. Aniridia associated keratopathy (AAK) also belongs to ocular signs of congenital aniridia. In AAK, there is corneal epithelial thinning, corneal inflammation, vascularization and scarring. In advanced stage AAK, typically, conjunctival epithelial cells slowly replace the corneal epithelium. Based on previous results we hypothesize that alterations of the conjunctival cells in congenital aniridia may also support the corneal conjunctivalization process. The aim of this study was to identify deregulated proteins in conjunctival impression cytology samples of congenital aniridia subjects.
METHODS: Conjunctival impression cytology samples of eight patients with congenital aniridia [age 34.5 ± 9.9 (17-51) years, 50% female] and eight healthy subjects [age 34.1 ± 11.9 (15-54) years, 50% female] were collected and analysed using mass spectrometry. Proteomic profiles were analysed in terms of molecular functions, biological processes, cellular components and pathway enrichment using the protein annotation of the evolutionary relationship (PANTHER) classification system.
RESULTS: In total, 3323 proteins could be verified and there were 127 deregulated proteins (p < 0.01) in congenital aniridia. From the 127 deregulated proteins (DEPs), 82 altered biological processes, 63 deregulated cellular components, 27 significantly altered molecular functions and 31 enriched signalling pathways were identified. Pathological alteration of the biological processes and molecular functions of retinol binding and retinoic acid biosynthesis, as well as lipid metabolism and apoptosis related pathways could be demonstrated.
CONCLUSIONS: Protein profile of conjunctival impression cytology samples of aniridia subjects identifies alterations of retinol binding, retinoic acid biosynthesis, lipid metabolism and apoptosis related pathways. Whether these changes are directly related to PAX6 haploinsufficiency, must be investigated in further studies. These new findings offer the possibility to identify potential new drug targets.

Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.

This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia.

BACKGROUND: 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.
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.
CONCLUSIONS: 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.
Bevezetés: A congenitalis aniridia ritka panocularis betegség, amelyben a szem csaknem minden struktúrája érintett, és a betegek többségének jelentősen csökkent a látóélessége. A congenitalis aniridia szemészeti jelei lehetnek az aniridiához társult keratopathia, másodlagos zöld hályog, szürke hályog, macula- és opticus-hypoplasia, nystagmus. Noha az aniridiához társult keratopathia kifejezés régóta elterjedt az irodalomban, sokféle stádiumbeosztási javaslata került már leírásra. Célkitűzés: Az aniridiához társult keratopathia egyes stádiumainak vizsgálata az irodalomban elérhető stádiumbeosztások szerint, magyarországi aniridiás betegeknél. Betegek és módszerek: 33, congenitalis aniridiás beteg 65 szemét vizsgáltuk (életkor: 25,69 ± 17,49 [5–59] év, 17 nő [51,51%]). Réslámpás vizsgálattal rögzítettük a szaruhártya állapotát, majd Mackman, Mayer, López-García, Lagali stádiumbeosztása alapján osztályoztuk a corneaeltéréseket. Eredmények: A Mackman beosztása szerinti 0. stádiumba 8 szem (12,3%), az 1A stádiumba 0 szem, az 1B stádiumba 38 szem (58,46%), végül a 2. stádiumba 19 szem (29,23%) került. Mayer szerint az I. stádiumba 8 szem (12,3%), a II. stádiumba 38 szem (58,46%), a III. stádiumba 5 szem (7,7%), a IV. stádiumba 7 szem (10,77%), az V. stádiumba pedig 7 szem (10,77%) tartozott. López-García csoportosítása alapján nem került beosztásra 8 szem (12,3%), az 1. stádiumba 20 szem (30,77%), a 2. stádiumba 18 szem (27,7%), a 3. stádiumba pedig 19 szem (29,23%) került. Lagali osztályozása szerint a 0. stádiumba 8 szem (12,3%), az 1. stádiumba 20 szem (30,77%), a 2. stádiumba 18 szem (27,7%), a 3. stádiumba 5 szem (7,7%), a 4. stádiumba pedig 14 szem (21,54%) tartozott. Következtetés: Jelenleg a Lagali és mtsai által kialakított, aniridiához társult keratopathia stádiumbeosztási használatát javasoljuk, hiszen a stádiumbesoroláshoz szükséges vizsgálat könnyen kivitelezhető, a stádiumok kellő részletességgel követik az állapot előrehaladását, segítve a prognózis megítélését, a terápiás terv felállítását. A Lagali szerinti 1. stádiumban az erek legfeljebb 1 mm-rel lépik át a limbust, a 2. stádiumban a centrális 2–3 mm szaruhártya-terület erektől megkímélt. Amikor az erek elérik a szaruhártya centrumát, 3. stádiumról, majd az átlátszatlan, vaskos, egyenetlen cornealis pannus esetén 4. stádiumról beszélünk. Orv Hetil. 2023; 164(27): 1063–1069.

BACKGROUND: 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.
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%).
CONCLUSIONS: 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.
Bevezetés: A congenitalis aniridia ritka betegség, melynek fő jellemzője a szivárványhártya teljes vagy részleges hiánya, azonban a szem összes struktúrájában jelen lehetnek elváltozások. Célkitűzés: Társuló szembetegségek előfordulásának meghatározása congenitalis aniridiában, egy magyarországi centrum betegeinek vizsgálatával. Betegek és módszerek: Munkánkba a Semmelweis Egyetem Szemészeti Klinikáján 2005. október és 2022. május között aniridia diagnózisával vizsgált betegeket válogattunk be. A betegek anamnézisfelvételét követően részletes szemészeti vizsgálatot végeztünk. Eredmények: Az adatbázisban talált 82 betegből 33 jelent meg vizsgálaton (életkor: 25,69 ± 17,49 [5–59] év, 17 nő [51,51%]), és 65 szemet vizsgáltunk. Nystagmust 23 beteg 45 szemén (69,23%) találtunk, a vizsgált betegek korrigálatlan távoli látóélessége 0,14 ± 0,128 (0,9 logMAR; 0,63–0,005) volt. Az aniridiához társult keratopathia 8 szem (12,3%) esetén Grade 0., 10 szem (15,38%) esetén Grade 1., 16 szem (24,62%) esetén Grade 2., 4 szem (6,15%) esetén Grade 3. és 25 szem (38,46%) esetén Grade 4. volt. 15 beteg 30 szeme (46,15%) esetén találtunk szekunder glaucomát, 3 beteg 6 szemét (9,2%) glaucomagyanúsnak ítéltük meg. 8 szem (12,3%) esetén a lencse tiszta volt, 44 szem (67,69%) esetén találtunk szürke hályogot, melyből 22 (33,84%) elülső kérgi polaris szürke hályog volt. 13 szem (20%) volt pseudophakiás (PCL), és 7 szem (10,77%) esetén találtunk lencsediszlokációt vagy zonulainsufficientiát. Maculahypoplasia 3 beteg 6 szeme (4,6%) esetén, papillafejlődési rendellenesség 1 beteg 2 szeme (3,03%) esetén volt igazolható. Következtetés: A congenitalis aniridia szemészeti jelei az aniridiához társult keratopathia, másodlagos zöld hályog, szürke hályog, macula- és opticushypoplasia. A szemészeti eltérések ellátásához és gondozásához a különféle szemészeti szakterületek rendszeres, gondos együttműködése szükséges. Orv Hetil. 2023; 164(4): 148–155.

PAX6 haploinsufficiency causes aniridia, a congenital eye disorder that involves the iris, and foveal hypoplasia. Comprehensive screening of the PAX6 locus, including the non-coding regions, by next-generation sequencing revealed four deep-intronic variants with potential effects on pre-RNA splicing. Nevertheless, without a functional analysis, their pathogenicity could not be established. We aimed to decipher their impact on the canonical PAX6 splicing using in vitro minigene splicing assays and nanopore-based long-read sequencing. Two multi-exonic PAX6 constructs were generated, and minigene assays were carried out. An aberrant splicing pattern was observed for two variants in intron 6, c.357+136G>A and c.357+334G>A. In both cases, several exonization events, such as pseudoexon inclusions and partial intronic retention, were observed due to the creation or activation of new/cryptic non-canonical splicing sites, including a shared intronic donor site. In contrast, two variants identified in intron 11, c.1032+170A>T and c.1033-275A>C, seemed not to affect splicing processes. We confirmed the high complexity of alternative splicing of PAX6 exon 6, which also involves unreported cryptic intronic sites. Our study highlights the importance of integrating functional studies into diagnostic algorithms to decipher the potential implication of non-coding variants, usually classified as variants of unknown significance, thus allowing variant reclassification to achieve a conclusive genetic diagnosis.