Aniridia

Key Points at a Glance

Aniridia is a rare congenital disorder characterized by varying degrees of iris deficiency, with a prevalence of approximately 1/40,000 to 1/100,000.
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, cataract, 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⁾.
The clinical practice guidelines (2021) present six clinical questions and recommendations regarding keratopathy, cataract, 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 1/40,000 to 1/100,000, with no significant racial or sex differences reported ¹⁾. It is classified as Q13.1 in ICD-10.

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 light reflex is absent, but accommodation is preserved. 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 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 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. It was designated as a specified intractable disease under the Intractable Disease Act in 2017, 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 (de novo) 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 almost completely absent, showing 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 almost complete absence of the iris, with only a thin rim of iris remaining near the cornea. The pupil area is markedly enlarged, revealing a red reflex, representing a typical clinical finding of aniridia.

Subjective Symptoms

Most cases of aniridia are discovered 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 usually appears within 6 weeks after birth.
Reduced visual acuity: Due to foveal hypoplasia, corrected visual acuity is typically limited to 0.1–0.2.

Clinical Findings

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

Iris: Ranges from almost complete absence to mild hypoplasia. Mild cases may present with a normal-appearing pupil, but iris transillumination reveals abnormalities.
Foveal hypoplasia: Present in nearly all cases, characterized by a diminished foveal reflex, hypopigmentation of the macula, and retinal vessels crossing the foveal region. 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 patients.
Glaucoma: Reported incidence ranges from 50% to 75%. It usually develops in late childhood or adulthood, and regular intraocular pressure assessment throughout childhood is essential. Two mechanisms are considered: high resistance to aqueous outflow in the trabecular meshwork, and angle-closure glaucoma due to adhesion of the residual iris in the far periphery to the trabecular meshwork.
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 pannus with blood vessels.
Lens subluxation: Uncommon, usually displaced upward ¹⁾. The zonules of Zinn are fragile.
Optic nerve hypoplasia: Occurs in about 10% of cases.
Refractive error and strabismus: Often accompanied by high refractive error, with esotropia being the most common deviation.
Ptosis: Bilateral ptosis is seen in up to 10%.

Q What is the visual acuity in aniridia?

Due mainly to foveal hypoplasia, corrected visual acuity is often around 0.1 to 0.2. 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 be observed ⁸⁾.

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

Important factors determining visual function are glaucoma, macular hypoplasia, nystagmus, keratopathy, cataract, and iris hypoplasia. Since visual field and visual acuity impairment due to glaucoma is irreversible, intraocular pressure management is the most important aspect of follow-up.⁸⁾

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 disease.¹⁾

The PAX6 gene is a master control gene for eye formation and plays an important role 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 aniridia.¹⁾

In a cohort study of Chinese patients, causative mutations in the PAX6 gene were identified in 96.9% of cases.¹⁾ In typical aniridia, mutations that induce nonsense-mediated mRNA decay (NMD) or large deletions are detected in 96% of cases.¹⁾

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 are observed, leading to abnormalities in the epithelium and Bowman’s membrane, and formation of a vascular-rich 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 mutation	Approximately 13%
Missense mutation	Approximately 12%

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

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

Wang (2023) newly identified a frameshift mutation c.640_646del (p.R214Pfs*28) and reported a case presenting with complete iris absence, 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, indicating a severe phenotype due to C-terminal extension mutation ⁶⁾.

Risk of WAGR Syndrome

In sporadic aniridia, large deletions involving both PAX6 and WT1 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 WT1 is located near PAX6, deletions of the short arm of chromosome 11 (11p13 deletion) involving both genes result in aniridia with 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 have been confirmed by molecular diagnosis, 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 about 80% of cases)
Ultrasound/MRI/CT: Microphthalmia
Nystagmus
Intraocular pressure measurement: Glaucoma (associated in 50-75% due to angle dysgenesis)

C. Diseases to be Differentiated

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, fellow eye normal
Grade II	Both eyes affected, best corrected visual acuity in the better eye ≥ 0.3
Grade III	Both eyes affected, best corrected visual acuity in the better eye ≥ 0.1 and < 0.3
Grade IV	Both eyes affected, best corrected visual acuity in the better eye < 0.1

Even for grades I to III, if accompanied by visual field constriction due to glaucoma, etc. (central residual visual field within 20 degrees with Goldmann I/4 target), the severity shifts up one grade. Severity grade III or higher qualifies for medical expense subsidies ⁷⁾.

Clinical Diagnosis

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

Ophthalmologic Examination

The following ocular complications are systematically evaluated:

Foveal hypoplasia: OCT is used to evaluate the presence of a foveal pit. A typical finding is normal retinal thickness with absence of a foveal depression.
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 determine whether the PAX6 deletion extends to the WT1 gene ¹⁾. Whole-exome sequencing or MLPA is 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 bulbs, cerebellum, and corpus callosum.
Developmental assessment: Evaluate cognitive function and behavior.

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. Clinical guidelines (2021) provide recommendations based on six clinical questions ⁸⁾.

Management of Corneal Disease (AAK)

CQ1: Corneal transplantation for corneal stromal opacity is weakly recommended against ⁸⁾.

Corneal transplantation may provide short-term visual improvement, but improvement is limited due to comorbidities 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 after two-stage full-thickness corneal transplantation following limbal transplantation: 30% (Holland report) ¹²⁾
Anatomical retention rate of Boston KPro: 77–100% (mid-term), 87% (4.5-year long-term)
Glaucoma after Boston KPro: high rate of 14.3–88%
Retroprosthetic membrane formation after Boston KPro: 13.3–61%

CQ2: We weakly recommend surgical treatment for corneal epithelial stem cell deficiency. ⁸⁾

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

Cataract surgery

CQ3: We weakly recommend performing cataract surgery. ⁸⁾

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

Postoperative glaucoma worsening: 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 Zinn zonules are fragile, intraocular lens insertion requires careful consideration.

Hu et al. (2024) performed phacoemulsification under 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, respectively, at 3 weeks postoperatively ⁴⁾.

Management of glaucoma

CQ4: Glaucoma treatment is strongly recommended ⁸⁾.

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

Pharmacotherapy: Beta-blockers, sympathomimetics, and prostaglandin (PG)-related drugs are effective. Brimonidine (alpha-adrenergic receptor 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 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% ¹³⁾. Postoperative malignant glaucoma has also been reported.
Glaucoma implant surgery (tube shunt surgery): Baerveldt and Ahmed devices are available. For tube insertion in phakic eyes, tangential rather than central corneal direction is recommended. 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 healthy eyes.

Q Is glaucoma treatment for aniridia different from that for ordinary glaucoma?

Because the underlying cause is abnormal development of the angle, a different approach from that for primary open-angle glaucoma is needed. Initial treatment 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

CQ5: Low vision care is strongly recommended ⁸⁾.

Refractive correction is fundamental; 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 adjustment, typoscopes, tablet devices, video magnifiers ¹⁷⁾
During school age, selection and training in the use of visual aids according to visual function, and arrangement of the learning environment are necessary.
Cooperation with welfare, education, and employment-related facilities according to life stage is important.

Management of Photophobia

CQ6: Treatment for photophobia is strongly recommended ⁸⁾.

Tinted glasses: Prescribe after selecting the color that most reduces photophobia using trial lenses.
Soft contact lenses (SCL) with artificial iris: They have an effect of reducing nystagmus. Early light-shielding treatment may contribute to improvement of fixation and visual 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 corneal epithelial stem cell damage.

Educational Support and Intractable Disease System

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

Since April 2017, this condition has been designated as a specified intractable disease. Therefore, even if patients do not have a physical disability certificate, those with severity grade 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 that introduce a premature termination codon (PTC) (nonsense mutations, frameshift mutations, and most splice mutations) result in the typical aniridia phenotype.

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

A rare case has been reported in which a PAX6 nonsense mutation c.282C>A (p.Cys94*) and trisomy 21 co-occurred in the same patient. The PAX6 mutation arose de novo and resulted 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 or large PAX6 deletions present with typical aniridia
Run-on, missense, and some splice mutations may show milder iris hypoplasia
C-terminal extension mutations are associated with severe phenotypes (marked iris hypoplasia, severe visual impairment)¹⁾⁶⁾

Angle and Glaucoma Pathogenesis

In the gonioscopy series by Grant and Walton, early anterior extension of iris stroma over the trabecular meshwork forming adhesion-like attachments, gradually becoming sheet-like and eventually leading to angle closure was demonstrated¹⁴⁾. This mechanism is the main cause of glaucoma development. Pathologically, it is based on smooth muscle deficiency sparing the iris root and angle dysgenesis.

Molecular Mechanism of AAK

AAK is mainly 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, and loss of transparency due to disorganized collagen arrangement in the stroma.

AAK is classified into 5 stages. Stage I shows only peripheral epithelial abnormalities, Stage II shows centripetal epithelial changes (not reaching the center), Stage III shows central corneal epithelial changes and peripheral superficial neovascularization, 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 an association between PAX6 mutation status and AAK progression. In patients with PTC or C-terminal extension mutations, AAK progresses in an age-dependent manner, while 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 specific iris hypoplasia around the pupil and fixed mydriasis.

In the literature review of Gillespie syndrome by Ciaccio et al. (2024), analysis of 33 molecularly confirmed cases confirmed 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, which is expected to clarify 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 Prediction of Clinical Course

It is becoming clear that the progression pattern of AAK differs depending on the type of PAX6 mutation. With decreasing costs of genetic testing, prediction of clinical course and early intervention based on mutation type 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 of multiple genetic disorders coexisting in the same patient on the phenotype 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 using AAV-PAX6 vectors for gene supplementation 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 abroad is accumulating. Contact lenses with artificial irises are covered by insurance as prosthetic devices.

Registry Studies and Future Perspectives

According to the clinical practice guidelines (2021), accumulating large-scale registry data in Japan to understand the actual situation and revising the guidelines based on improved evidence quality are positioned as 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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