Aniridia

Key Points at a Glance

Aniridia is a rare congenital disorder characterized by varying degrees of iris deficiency, with a prevalence of approximately 1 in 40,000 to 1 in 100,000.
Most cases are caused by haploinsufficiency due to heterozygous mutations in the PAX6 gene, with autosomal dominant inheritance accounting for about two-thirds of cases.
Foveal hypoplasia is present in nearly all cases, leading to nystagmus and reduced visual acuity (corrected visual acuity around 0.1 to 0.2).
Glaucoma, cataracts, and aniridia-associated keratopathy (AAK) are late-onset and progressive complications, making regular follow-up essential.
Sporadic aniridia may indicate WAGR syndrome (Wilms tumor, genitourinary abnormalities, and intellectual disability), requiring genetic testing and abdominal ultrasound for renal tumor screening.
There is no curative treatment; management focuses on low vision care to maximize residual vision and individual treatment for each complication.
In 2017, it was classified as a designated intractable disease, and patients with severity grade III or higher are eligible for medical expense subsidies ⁷⁾.
Ongoing management is required for keratopathy, cataracts, glaucoma, low vision care, and photophobia ⁸⁾.

1. What is Aniridia?

Aniridia is a rare congenital disorder characterized by varying degrees of iris hypoplasia or absence. The term “aniridia” is a misnomer, as remnants of iris tissue are almost always detectable by gonioscopy or ultrasound biomicroscopy (UBM).

The prevalence is approximately 1 in 40,000 to 1 in 100,000, with no significant racial or sex differences reported ¹⁾. It is classified under ICD-10 code Q13.1.

Aniridia is a panocular disease affecting not only the iris but also the cornea, lens, angle, fovea, and optic nerve ¹⁾, presenting various vision-threatening ocular complications. Visual prognosis is generally poor, with corrected visual acuity often around 0.1. Pupillary reflexes are absent, but accommodative responses are preserved, and 60–90% of cases are bilateral.

The following three phenotypes are recognized.

Isolated Aniridia

Frequency: Approximately 2/3 of all cases.

Inheritance: Autosomal dominant (AD).

Features: Caused by PAX6 gene mutation. No systemic symptoms. Penetrance is complete but expressivity is variable.

WAGR Syndrome

Frequency: A subset of sporadic cases.

Inheritance: Contiguous deletion of PAX6 and WT1.

Features: Associated with Wilms tumor, genitourinary abnormalities, and intellectual disability. Tumor risk is up to 50%.

Gillespie Syndrome

Frequency: Approximately 2% of all cases.

Inheritance: ITPR1 gene mutation.

Features: Accompanied by cerebellar ataxia and intellectual disability. Characteristic iris abnormality with fixed dilated pupils is distinctive³⁾.

Sporadic aniridia accounts for about 1/3 of all cases and is caused by a de novo deletion of 11p13 including PAX6. If the deletion extends to the adjacent WT1 gene, it causes WAGR syndrome¹⁾. 25–30% of sporadic aniridia patients develop Wilms tumor, with a reported relative risk of 67.

PAX6 is a master control gene for eye formation and is involved in the development of the eye, neural tube, olfactory bulb, pancreatic islets of Langerhans, and olfactory epithelium. It manifests with loss of function of one allele (haploinsufficiency), and biallelic abnormalities are embryonic lethal. In 2017, it was designated as a specified intractable disease under the Intractable Disease Act, and patients with severity grade III or higher (see Diagnosis and Testing section for details) are eligible for medical expense subsidies⁷⁾.

Q Can aniridia occur even if there is no family history?

Sporadic (new mutation) cases account for about one-third of all cases and can occur without a family history. Since sporadic cases may indicate WAGR syndrome, genetic testing and abdominal ultrasound screening for Wilms tumor are important.

2. Main Symptoms and Clinical Findings

Anterior segment photograph of aniridia. The iris is nearly absent, with a markedly large pupil and red reflex.

Law SK, et al. Asymmetric phenotype of Axenfeld-Rieger anomaly and aniridia associated with a novel PITX2 mutation. Mol Vis. 2011. Figure 2. PMCID: PMC3102021. License: CC BY.

Anterior segment photograph showing near-complete absence of the iris, with only a thin remnant of iris at the corneal periphery. The pupillary area is markedly enlarged, revealing a red reflex, representing a typical clinical finding of aniridia.

Subjective Symptoms

Most cases of aniridia are detected at birth due to iris and pupil abnormalities, or in infancy due to nystagmus.

Photophobia (sensitivity to light): Due to the absence of the iris, the amount of light entering the eye cannot be regulated, causing severe photophobia.
Nystagmus: Horizontal pendular nystagmus associated with foveal hypoplasia typically appears within the first 6 weeks of life.
Reduced visual acuity: Due to foveal hypoplasia, best-corrected visual acuity is usually limited to around 0.1 to 0.2.

Clinical Findings

The phenotype varies between and within families, but differences between the right and left eyes are usually small.

Iris: Ranges from near-complete absence to mild hypoplasia. Mild cases may present with a normal-appearing pupil, but abnormalities can be detected by iris transillumination.
Foveal hypoplasia: Present in nearly all cases, characterized by a diminished foveal reflex, hypopigmentation of the macula, and retinal vessels crossing the foveal area. OCT shows absence of the foveal pit ¹⁾.
Cataract: Congenital anterior polar opacities are common, and visually significant opacities eventually develop in 50–85% of cases, usually within the first 20 years of life ⁶⁾. It is reported to occur in about 80% of cases.
Glaucoma: Reported incidence ranges from 50% to 75%. It typically develops in late childhood or adulthood, making regular intraocular pressure assessment throughout childhood essential. Two mechanisms are considered: increased resistance to aqueous outflow in the trabecular meshwork, and adhesion of residual peripheral iris to the trabecular meshwork leading to angle-closure glaucoma.
Aniridia-associated keratopathy (AAK): Progressive corneal opacification occurs, with an incidence of 20% to 80%. Peripheral corneal thickening and neovascularization progress toward the center ²⁾. The cornea is thicker than in healthy individuals. The cornea is clear in childhood, but conjunctival invasion gradually progresses with age, forming a vascularized pannus.
Lens subluxation: Uncommon, typically displaced upward ¹⁾. The zonules of Zinn are fragile.
Optic nerve hypoplasia: Occurs in about 10% of cases.
Refractive error and strabismus: Often associated with high refractive errors; esotropia is the most common deviation.
Ptosis: Bilateral ptosis is seen in up to 10% of cases.

Q What is the visual acuity in aniridia?

Due primarily to foveal hypoplasia, corrected visual acuity is often around 0.1 to 0.2 (20/200 to 20/100). Visual prognosis is particularly poor when macular hypoplasia is present. Refractive correction and low vision care from infancy are important for visual development.

Extraocular complications

PAX6 is expressed not only in ocular tissues but also in the central nervous system, pancreatic islets of Langerhans, and olfactory epithelium, so the following extraocular complications may occur ⁸⁾.

Wilms tumor: In WAGR syndrome, the incidence is 0% to 26.9%; about 30% of sporadic cases develop by age 5 ⁸⁾
Genitourinary abnormalities: 0% to 33.3% ⁸⁾
Intellectual disability: 0% to 50% ⁸⁾
Central nervous system abnormalities: Pineal gland absence 30%, severe brain malformation 10%
Corpus callosum agenesis, epilepsy, anosmia, glucose intolerance: Reflect the multi-organ expression of PAX6
Systemic complications of WAGR syndrome: dental anomalies 35%, musculoskeletal abnormalities 13%, hyposmia 5%, diabetes 7%, etc.⁸⁾

Key factors determining visual function are glaucoma, macular hypoplasia, nystagmus, keratopathy, cataract, and iris hypoplasia. Since visual field and acuity loss due to glaucoma are irreversible, intraocular pressure management is the most important aspect of follow-up⁸⁾.

3. Causes and Risk Factors

Most cases of congenital aniridia are caused by heterozygous mutations in the PAX6 gene located on the short arm of chromosome 11 (11p13). Haploinsufficiency is the main mechanism of PAX6-related disease¹⁾.

The PAX6 gene is a master control gene for eye formation and plays important roles in the development of the eye, neural tube, olfactory bulb, and pancreas. Two copies of PAX6 are required for normal eye development, and loss of function of just one copy leads to aniridia¹⁾.

In a cohort study of Chinese patients, causative mutations in the PAX6 gene were identified in 96.9% of cases¹⁾. In typical aniridia, mutations that induce nonsense-mediated mRNA decay (NMD) or large deletions are detected in 96% of cases¹⁾.

Pathologically, smooth muscle is absent except at the iris root, and there is developmental abnormality of the angle. Functional abnormalities of corneal epithelial stem cells lead to abnormalities in the epithelium and Bowman’s layer, with formation of a vascularized pannus.

The breakdown of PAX6 mutations causing the aniridia phenotype is shown below.

Mutation type	Frequency
Nonsense mutation	Approximately 39%
Frameshift mutation	Approximately 25%
Splice site mutation	Approximately 13%
Missense mutation	Approximately 12%

Run-on mutations (C-terminal extension mutations) account for about 5% and produce an abnormally elongated PAX6 protein due to conversion of a stop codon into a coding codon ⁶⁾. C-terminal extension mutations are often associated with severe iris hypoplasia and profound visual impairment ¹⁾⁶⁾.

Gene mutations are often of the PTC type, and missense mutations have also been reported ⁷⁾. Regarding the utility of genetic testing, mutations are detected in nearly 85% of isolated aniridia cases by Sanger sequencing or NGS. Additionally, deletions within the PAX6 gene or its cis-regulatory region are detected in nearly 15% of cases by MLPA or CMA ⁸⁾.

Wang (2023) newly identified a frameshift mutation c.640_646del (p.R214Pfs*28) and reported a case presenting with complete iris defect, foveal hypoplasia, lens subluxation, and retinal detachment ¹⁾.

Ratna et al. (2022) identified a run-on mutation c.1268A>T (p.*423L) in an Indian family. Affected individuals presented with complete aniridia, nystagmus, foveal hypoplasia, AAK, superior lens subluxation, high myopia, and optic atrophy, demonstrating a severe phenotype due to C-terminal extension mutation ⁶⁾.

Risk of WAGR syndrome

In sporadic aniridia, large deletions involving the WT1 gene in addition to PAX6 cause WAGR syndrome. The risk of Wilms tumor in cases with WT1 deletion is up to 50% ¹⁾. If WAGR syndrome is suspected, genetic testing can confirm PAX6 and WT1 deletions, enabling Wilms tumor risk assessment and monitoring for developmental delay ⁸⁾. Evaluation of the WT1 region by genetic testing is essential, and 30% of sporadic cases develop Wilms tumor by age 5. Because the WT1 gene is located near PAX6, deletion of both on chromosome 11 short arm (11p13 deletion) results in aniridia complicated by Wilms tumor.

Genetic basis of Gillespie syndrome

Gillespie syndrome is caused by heterozygous dominant-negative mutations or biallelic mutations in the ITPR1 gene ³⁾. To date, 37 cases with molecular diagnosis have been reported, and the Gly2554 residue is known as a hotspot ³⁾.

4. Diagnosis and Examination Methods

Diagnostic Criteria

Based on the diagnostic criteria for aniridia (2020), the diagnosis is confirmed according to the following criteria⁷⁾.

A. Symptoms

Bilateral visual impairment
Photophobia

B. Examination Findings

Slit-lamp microscopy: Iris dysplasia ranging from partial iris atrophy to complete iris defect
Fundus examination/OCT: Foveal hypoplasia (indistinct macular pigment, foveal pit, and foveal avascular zone)
Slit-lamp microscopy: Limbal stem cell deficiency, corneal opacity
Slit-lamp microscopy: Cataract (present in approximately 80% of cases)
Ultrasound/MRI/CT: Microphthalmia
Nystagmus
Intraocular pressure measurement: Glaucoma (occurs in 50–75% of cases due to angle dysgenesis)

C. Differential Diagnoses

Iris atrophy due to prior infection with Herpesviridae
Iris defect after trauma or intraocular surgery
Iris coloboma associated with incomplete closure of the optic cup fissure
Rieger anomaly
Iridocorneal endothelial (ICE) syndrome

E. Genetic testing: Pathogenic mutation in the PAX6 gene or deletion of the 11p13 region

Diagnostic categories⁷⁾:

Definite: A (any) + B1 + E, exclude C
Probable: ① A + B1 + F (familial occurrence), ② A + B1 + B2, ③ A + B1 + B3
Possible: A + B1 only

Severity classification

The severity classification for intractable disease designation is defined in the following four stages⁷⁾.

Severity	Definition
Grade I	Unilateral involvement, contralateral eye normal
Grade II	Both eyes affected, corrected visual acuity in the better eye 0.3 or better
Grade III	Both eyes affected, corrected visual acuity in the better eye 0.1 or better but less than 0.3
Grade IV	Both eyes affected, corrected visual acuity in the better eye less than 0.1

Even for grades I to III, if accompanied by visual field narrowing due to glaucoma or other conditions (central residual visual field within 20 degrees on Goldmann I/4 target), the severity shifts up by one grade. Severity grade III or higher is eligible for medical expense subsidies ⁷⁾.

Clinical Diagnosis

Clinical diagnosis is easy if iris defects or hypoplasia are confirmed by slit-lamp microscopy. Gonioscopy or ultrasound biomicroscopy is used to evaluate residual iris tissue. The presence or absence of developmental abnormalities of the anterior chamber angle is also checked.

Ophthalmic Examination

The following ocular complications are systematically evaluated:

Foveal hypoplasia: OCT is used to evaluate the presence or absence of a foveal pit. A typical finding is normal retinal thickness with absence of a foveal pit.
Intraocular pressure: Measured regularly throughout childhood. Onset varies widely, from congenital glaucoma to adult-onset glaucoma.
Cornea: Evaluate the presence and progression of AAK. Central corneal thickness is often increased ⁶⁾.
Lens: Check for anterior polar cataract, cortical cataract, and subluxation.
Optic nerve: Evaluate for hypoplasia or coloboma.

Genetic Testing

The most important goal in the genetic evaluation of aniridia is to confirm whether the PAX6 deletion extends to the WT1 gene ¹⁾. Whole-exome sequencing and MLPA are used to evaluate mutations and deletions in the PAX6 and WT1 regions ¹⁾²⁾.

Systemic Screening

Abdominal ultrasound: Screening for Wilms tumor. For sporadic cases, follow-up every few months is recommended.
Head MRI: Evaluate for abnormalities of the olfactory bulb, cerebellum, and corpus callosum.
Developmental assessment: Evaluate cognitive and behavioral function.

Q Is genetic testing always necessary?

In sporadic aniridia, assessment of Wilms tumor risk due to WT1 gene deletion is directly linked to prognosis ¹⁾. Even in familial cases, due to phenotypic variability, genetic testing for definitive diagnosis and genetic counseling is recommended.

5. Standard Treatment

There is no curative treatment for aniridia. Management focuses on low-vision care to maximize residual vision and individual treatment for each complication ⁸⁾.

Management of Corneal Disease (AAK)

Corneal transplantation for stromal opacification should be considered cautiously ⁸⁾.

Corneal transplantation may provide short-term visual improvement, but improvement is limited due to concurrent conditions such as macular hypoplasia. Long-term visual prognosis is poor due to progression of glaucoma and graft failure.

Rejection rate for full-thickness corneal transplantation: 64% (Kremer report)
Graft failure rate of two-stage full-thickness transplantation after limbal transplantation: 30% (Holland report)¹²⁾
Anatomical retention rate of Boston KPro: 77–100% (mid-term), 87% (4.5-year long-term)
Postoperative glaucoma after Boston KPro: high rate of 14.3–88%
Retroprosthetic membrane formation after Boston KPro: 13.3–61%

Surgical treatment should be considered for corneal epithelial stem cell deficiency⁸⁾.

Allogeneic limbal transplantation: mean logMAR visual acuity improved from 1.4 to 0.35 in 6 cases (12 eyes) over 64.4 months of follow-up¹²⁾
Cultured oral mucosal epithelial cell sheet transplantation: corneal transparency achieved in 76.4% of 17 eyes, visual improvement in 88.2%¹¹⁾
Combined corneal transplantation is useful for visual improvement when corneal stromal opacity is present
Caution is needed for systemic side effects (renal impairment, glucose intolerance) associated with long-term use of immunosuppressive drugs

Cataract Surgery

Cataract surgery should be considered based on the degree of opacity and photophobia⁸⁾.

Cataracts develop in 50–85% of patients by age 20. Surgery is planned according to the severity of opacity and photophobia. Visual improvement has been reported in 66–100% of surgical cases, but the following points require attention.

Postoperative worsening of glaucoma: 26.9–50%
Cases requiring glaucoma surgery: 4–40%
Anterior Fibrosis Syndrome (AFS): occurred in 6.4% of 155 eyes (all female)¹⁵⁾
Risk of decreased corneal endothelial cell density
Anterior capsulotomy of 6 mm or less may function as a pupil due to fibrosis

Because the zonules of Zinn are fragile, intraocular lens insertion requires careful consideration.

Hu et al. (2024) performed phacoemulsification assisted by chandelier retroillumination in two cases of congenital aniridia with severe AAK. Although conventional intraoperative visualization was difficult due to corneal opacity, posterior illumination enabled clear visualization of the lens and anterior capsule, and corrected visual acuity improved to 20/200 and 20/1000 at 3 weeks postoperatively ⁴⁾.

Glaucoma management

Glaucoma is directly linked to visual prognosis, so aggressive treatment is necessary ⁸⁾.

After the onset of glaucoma, management is based on the following 5-step algorithm.

Medical therapy: Beta-blockers, sympathomimetics, and prostaglandin (PG) analogs are effective. Brimonidine (alpha-adrenergic agonist) is contraindicated in children under 2 years due to risk of central nervous system depression. If corneal epithelial damage is a concern, use preservative-free formulations.
Outflow reconstruction surgery (goniotomy/trabeculotomy): Recommended as the initial surgery ¹⁶⁾. Prophylactic goniotomy has also been reported. However, it may be ineffective in cases where residual iris covers the trabecular meshwork.
Filtering surgery (trabeculectomy): Only a few short- to medium-term reports exist. Outcomes tend to be poor in pediatric eyes, with postoperative ocular hypotony occurring in about 25% of cases ¹³⁾. Postoperative malignant glaucoma has also been reported.
Glaucoma implant surgery (tube shunt surgery): Baerveldt and Ahmed devices are available. For phakic eyes, tube insertion should be directed tangentially rather than toward the center of the cornea. Good intraocular pressure control can be expected.
Cyclodestructive procedures: Last resort. Cyclocryotherapy has been reported to result in ocular hypotony in many cases. Due to ciliary body hypoplasia, the risk of hypotony is higher than in normal eyes.

Q Is glaucoma treatment in aniridia different from that in typical glaucoma?

Because the underlying cause is an abnormality in the development of the angle, a different approach from that for typical open-angle glaucoma is necessary. The first choice is outflow reconstruction surgery, followed by tube shunt surgery as a good option. Brimonidine is contraindicated in children under 2 years of age, and the use of antimetabolites may worsen AAK, so careful judgment is required ⁸⁾.

Low vision care

Low vision care should be introduced early ⁸⁾.

Refractive correction is fundamental, and the rate of myopia complication is reported to be 64% or higher.

Optical visual aids: corrective glasses, magnifiers, tinted glasses, low vision glasses (spectacle type and focus-adjustable type)
Non-optical visual aids: large-print textbooks, book stands, lighting adjustments, typoscopes, tablet devices, video magnifiers ¹⁷⁾
During school age, selection and training in the use of visual aids according to visual function, as well as arrangement of the learning environment, are necessary.
Cooperation with welfare, education, and employment-related facilities according to life stage is important.

Management of photophobia

Treatment of photophobia is important for maintaining visual function development and quality of life ⁸⁾.

Tinted glasses: Prescribe after selecting the color that most reduces photophobia using trial lenses.
Soft contact lenses (SCLs) with artificial iris: They have an effect of reducing nystagmus. Early light-shielding treatment may contribute to improvement of fixation and visual acuity development.
Outdoors, use wide-brimmed hats or parasols; indoors, use indirect lighting.
Artificial iris implantation: There is also a method of inserting an artificial iris simultaneously with cataract surgery ⁵⁾.
When using contact lenses, carefully monitor for the presence of corneal epithelial stem cell deficiency.

Educational Support and Intractable Disease System

Most patients can attend regular classes, but support such as enlarged textbooks, tablet devices, and book stands is necessary. Options include attending classes for visually impaired students or using childcare and educational consultations at schools for the blind or special support schools for visual impairments.

Since April 2017, this condition has been designated as a specified intractable disease. Therefore, even without a physical disability certificate, patients with severity level III or higher are eligible for medical expense subsidies and assistive device provision ⁷⁾. Eligible assistive devices include corrective glasses, tinted glasses, contact lenses (including those with artificial iris), low-vision glasses, white canes for the visually impaired, and artificial eyes.

6. Pathophysiology and Detailed Pathogenesis

Structure and Function of the PAX6 Gene

PAX6 spans 22 kb of genomic DNA containing 14 exons and encodes 422 amino acids ¹⁾. It has two DNA-binding domains (paired domain and paired-type homeodomain), and the C-terminal PST (proline-serine-threonine-rich) domain functions as a transcriptional activator.

PAX6 regulates cell proliferation, differentiation, migration, and adhesion. Its targets include PAX6 itself as well as genes encoding lens crystallins and corneal keratins. Expression continues in the adult retina, lens, and cornea. PAX6 is one of the master control genes governing organ differentiation during the embryonic period.

Mechanism of Haploinsufficiency

Most PAX6 mutations cause haploinsufficiency through nonsense-mediated mRNA decay (NMD) ¹⁾. Mutations introducing a premature termination codon (PTC) (nonsense mutations, frameshift mutations, and most splice mutations) result in the typical aniridia phenotype.

Conversely, if the PTC is located in the final exon or within the last 50 bp of the penultimate exon, it may escape NMD, leading to translation of a truncated protein and potentially a severe phenotype ¹⁾.

A rare case has been reported where a PAX6 nonsense mutation c.282C>A (p.Cys94*) and trisomy 21 coexisted in the same patient. The PAX6 mutation occurred de novo, resulting in complete bilateral aniridia, congenital glaucoma, AAK, and foveal hypoplasia ²⁾.

Genotype–Phenotype Correlation

Although a clear genotype–phenotype correlation has not been established, several trends are known ¹⁾.

Mutations that induce NMD and large PAX6 deletions typically present with classic aniridia
Run-on, missense, and some splice mutations may show milder iris hypoplasia
C-terminal extension mutations are associated with a severe phenotype (marked iris hypoplasia and severe visual impairment)¹⁾⁶⁾

Mechanisms of angle and glaucoma development

In the gonioscopic series by Grant and Walton, the iris stroma initially extends anteriorly over the trabecular meshwork, forming adhesion-like attachments that gradually become sheet-like and eventually lead to angle closure¹⁴⁾. This mechanism is the primary cause of glaucoma development. Pathologically, the underlying basis is a deficiency of smooth muscle sparing the iris root and developmental abnormalities of the angle.

Molecular mechanisms of AAK

AAK is primarily caused by limbal stem cell deficiency (LSCD), but abnormal differentiation and adhesion of corneal epithelium, conjunctival cell invasion, and insufficient tear production also contribute. Deficiency of matrix metalloproteinase 9 (MMP-9), regulated by PAX6, leads to fibrin accumulation and inflammatory cell infiltration, resulting in loss of transparency due to disorganized collagen arrangement in the stroma.

AAK is classified into five stages. Stage I shows abnormalities only in the peripheral epithelium, Stage II shows centripetal epithelial changes (not reaching the center), Stage III shows epithelial changes in the central cornea and superficial neovascularization in the periphery, Stage IV shows superficial neovascularization of the entire cornea, and Stage V shows epithelial abnormalities and deep stromal scarring of the entire cornea¹⁰⁾.

There is a relationship between PAX6 mutation status and the progression of AAK. In patients with PTC or C-terminal extension mutations, AAK progresses in an age-dependent manner, whereas other mutation types may present with non-progressive keratopathy¹¹⁾.

Pathophysiology of Gillespie syndrome

Gillespie syndrome is caused by mutations in the ITPR1 gene³⁾. ITPR1 is a member of the IP3 receptor family, forming Ca²⁺ release channels and localizing to the endoplasmic reticulum. Dominant-negative mutations affect the formation and maintenance of the iris sphincter muscle, leading to characteristic iris hypoplasia around the pupil and fixed mydriasis.

In a literature review of Gillespie syndrome by Ciaccio et al. (2024), analysis of 33 molecularly confirmed cases revealed that motor development is delayed but improves over time, intellectual disability is not present in all cases (17% have normal intelligence), and neurological signs are non-progressive³⁾.

7. Latest research and future perspectives

Expansion of the genetic mutation spectrum

With the widespread use of whole-exome sequencing, new PAX6 mutations continue to be identified. As of 2018, 491 mutations were registered in the Human PAX6 Mutation Database, and approximately 250 new mutations have been reported since then ¹⁾. Mutations in non-coding regions are also being identified as causes of aniridia, offering hope for elucidating cases that could not be diagnosed with conventional testing ⁹⁾.

Advances in Cataract Surgery Techniques

For cataract surgery in cases with severe AAK, visualization techniques using chandelier retroillumination are useful ⁴⁾. This technique enables safe phacoemulsification even in patients with Grade 3–4 severe AAK, and postoperative visual improvement has been achieved.

Genotype and Clinical Course Prediction

It is becoming clear that the progression pattern of AAK differs depending on the type of PAX6 mutation. With decreasing costs of genetic testing, predicting clinical course based on mutation type and early intervention are becoming realistic options.

Genetic Diversity and Complex Phenotypes

In cases of combined aniridia and trisomy 21, relatively mild courses have been reported despite the coexistence of both conditions ²⁾. Understanding the impact on phenotype when multiple genetic disorders coexist in the same patient may provide important insights for future personalized medicine.

Molecular Targeted Therapy and Gene Therapy

The application of read-through drugs (ataluren) for PTC-type mutations in aniridia is being investigated at the basic research level ⁸⁾. Regarding PAX6 gene therapy, basic research on gene supplementation using AAV-PAX6 vectors in Sey mutant mouse models is ongoing. Future clinical trials are anticipated.

Corneal Regenerative Medicine and Artificial Iris

Clinical trials of iPS cell-derived corneal epithelial cell sheet transplantation are being conducted domestically and internationally, attracting attention as a new treatment for AAK ⁸⁾. For artificial irises (e.g., CustomFlex Artificial Iris), clinical experience is accumulating overseas. Contact lenses with artificial irises are covered by insurance as prosthetic devices.

Registry Studies and Future Prospects

Accumulating large-scale registry data in Japan to understand the actual situation and improve the quality of evidence are important future tasks ⁸⁾. Optimization of AAK progression prediction and early intervention based on individual genetic mutations is expected.

8. References

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