Aniridia is a condition in which the iris is completely or partially absent due to a congenital predisposition. Although called “aniridia,” the root of the iris often remains in the most peripheral part of the angle.
In 2017, it was designated as a specified intractable disease under the Intractable Disease Act of the Ministry of Health, Labour and Welfare 1). Patients diagnosed with a specified intractable disease and judged to have a severity classification of grade III or higher are eligible for medical expense subsidies, with a maximum out-of-pocket amount set according to income 2).
| Item | Content |
|---|---|
| Prevalence | 1 in 64,000 to 96,000 people1) |
| Sex difference | None1) |
| Bilateral involvement | 60–90%1) |
| Inheritance pattern (familial) | Approximately 2/3 of all cases (autosomal dominant inheritance) |
| Sporadic | Approximately 1/3 of all cases |
| Wilms tumor association (sporadic cases) | Approximately 30% (WAGR syndrome) 3) |
Epidemiological studies in Sweden and Norway report a prevalence of approximately 1 in 90,000 people3). Detailed ophthalmic evaluation of 43 cases with PAX6 gene mutations showed that the degree of iris dysplasia varies depending on the type of mutation3).
About two-thirds of cases are autosomal dominant, with a 50% chance of inheritance from an affected parent to a child. The remaining one-third are sporadic with no family history. In sporadic cases, there is a risk of WAGR syndrome, which includes Wilms tumor (kidney tumor), so genetic testing for PAX6 and WT1 genes is recommended.
Because the iris is missing or incomplete, the pupil does not function and cannot regulate the amount of light entering the eye. This causes severe photophobia. Additionally, poor fixation due to foveal hypoplasia often leads to horizontal nystagmus appearing early in life.
Congenital complications (present at birth)
Iris abnormalities: ranging from partial atrophy to complete absence
Macular hypoplasia: present in almost all cases. Foveal pit absent, macular pigment indistinct. Major limiting factor for visual acuity
Nystagmus: mainly horizontal nystagmus. Caused by macular hypoplasia
Strabismus: occurs due to poor vision
Acquired complications (develop with growth)
Cataract: Occurs in about 80% of cases. Develops in 50–85% by age 20.
Glaucoma: Occurs in 50–75% of cases. Rare in infancy, progresses during adolescence.
Limbal stem cell deficiency (LSCD): Often normal in early childhood, but corneal stromal opacity and vascular pannus progress with age.
| Complication | Frequency/Timing | Impact on visual function |
|---|---|---|
| Foveal hypoplasia | Almost all cases (congenital) | Major limiting factor for visual acuity. No effective treatment. |
| Cataract | Approximately 80% (acquired)1) | Worsening of visual acuity and photophobia |
| Glaucoma | 50–75% (acquired)1) | Irreversible visual field loss if progressive |
| Limbal stem cell deficiency | Onset and progression after growth3) | Corneal stromal opacity → severe vision loss |
| Nystagmus | Congenital (almost all cases) | Poor fixation |
| Strabismus | Congenital to infancy | Risk of amblyopia |
The PAX6 gene is expressed not only in ocular tissues but also in the central nervous system, pancreatic islets of Langerhans, and olfactory epithelium. Hypoplasia of these tissues can lead to various extraocular complications 1).
Visual prognosis is generally poor, often around 0.1. However, depending on the degree of foveal hypoplasia and the presence of complications, it can range from 0.1 to 0.7. Currently, there is no effective treatment for foveal hypoplasia, and it is the main limiting factor for vision. Appropriate refractive correction and low vision care can improve quality of daily life.
Aniridia is caused by loss of function (haploinsufficiency) of one allele of the PAX6 gene located on the short arm of chromosome 11 (11p13). It results from a 50% reduction in functional gene dosage. Abnormalities in both alleles are thought to be embryonic lethal1).
PAX6 is a master control gene encoding a transcription factor that governs organ differentiation during embryonic development, regulating various other transcription factors. Abnormalities in PAX6 lead to various congenital anomalies throughout the eye (such as aniridia, Peters anomaly, and foveal hypoplasia).
The types of gene mutations are often premature truncated codon (PTC) types such as nonsense and frameshift mutations, and missense mutations have also been reported 1). In sequencing analysis of isolated aniridia, PAX6 mutations are detected in approximately 85% of cases 2).
The PAX6 gene is adjacent to the WT1 gene, a tumor suppressor gene, on chromosome 11p13. In sporadic cases, a contiguous gene deletion can cause WAGR syndrome, which includes Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation 3). Approximately 30% of sporadic cases develop early bilateral Wilms tumor by age 5.
PAX6 genetic testing is necessary to confirm a definite diagnosis, and especially in sporadic cases, genetic testing for PAX6 and WT1 is recommended to assess Wilms tumor risk. Testing should combine DNA sequencing with MLPA/CMA and be performed under appropriate genetic counseling.
The diagnostic criteria and severity classification 1) for aniridia are shown below, along with category classification.
| Diagnostic Category | Combination of Diagnostic Criteria |
|---|---|
| Definite | Meets any of A + B1 + E, and excludes C |
| Probable (1) | Meets any of A + B1 + F, and excludes C |
| Probable (2) | Meets any of A + B1 + B2, and excludes C |
| Probable (3) | Meets any of A + B1 + B3, and excludes C |
| Possible | Meets any of A + B1, but C cannot be completely excluded |
A. Symptoms
B. Examination Findings
C. Differential diagnosis (diseases to be excluded)
D. Extraocular complications associated with PAX6 gene mutation (e.g., agenesis of the corpus callosum, epilepsy)
E. Pathogenic mutation in the PAX6 gene or deletion of the 11p13 region (genetic testing)
F. Familial occurrence (autosomal dominant inheritance in 2/3 of cases)
| Test | Purpose/Details |
|---|---|
| Slit-lamp examination | Assessment of iris dysplasia severity (basis of diagnosis) |
| Fundus examination and OCT | Evaluation of macular hypoplasia (absence of foveal pit, indistinct macular pigment) |
| Gonioscopy | Evaluation of angle dysgenesis and adhesion between persistent iris root and trabecular meshwork |
| Intraocular pressure measurement (regular) | Glaucoma screening. Perform regularly from adolescence. |
| Abdominal ultrasound | Wilms tumor screening (sporadic cases, every few months, especially until age 5) |
| Genetic testing | Identification of PAX6 gene mutation or 11p13 deletion (required for definite diagnosis) |
In children, examination under general anesthesia may be necessary.
The basic approach involves confirming iris dysplasia with slit-lamp microscopy and evaluating foveal hypoplasia with OCT. A definitive diagnosis can be made with PAX6 genetic testing, and in sporadic cases, WT1 gene analysis is also performed. It is important to differentiate from herpetic iris atrophy, traumatic iris defect, iris coloboma, Rieger anomaly, and ICE syndrome.
Iris dysplasia, foveal hypoplasia, microphthalmia, and nystagmus are currently not amenable to intervention, and observation is the basic approach. Treatment targets include keratopathy, cataract, glaucoma, photophobia, and low vision 2).
| CQ | Treatment Target | Recommendation |
|---|---|---|
| CQ1 | Corneal stromal opacity → Corneal transplantation | Weakly recommended against performing |
| CQ2 | Corneal epithelial stem cell deficiency → surgery | Weakly recommended to perform |
| CQ3 | Cataract → surgery | Weakly recommended to perform |
| CQ4 | High intraocular pressure/glaucoma → treatment | Strongly recommended to perform |
| CQ5 | Low vision care | Strongly recommended to perform |
| CQ6 | Photophobia → Treatment | Strongly recommended to perform |
Corneal stromal opacity (CQ1): Weakly recommend not performing corneal transplantation2). Visual improvement from corneal transplantation is limited due to complications of aniridia. Long-term visual prognosis is often poor due to worsening glaucoma and progressive graft failure. Full-thickness corneal transplantation for corneal opacity often does not lead to visual improvement, and attention should be paid to the high rejection rate. In severe cases, the decision to perform should be made after carefully considering the balance of benefits and harms.
Limbal stem cell deficiency (LSCD, CQ2): Weakly recommend surgical treatment2). Specifically, keratolimbal allograft (KLAL) or cultivated oral mucosal epithelial transplantation (COMET) can be expected to achieve some degree of ocular surface reconstruction3). When corneal stromal opacity is present, combining corneal transplantation is often useful for visual improvement2).
Cataract surgery is weakly recommended 2). Cataracts develop in 50–85% of patients by age 20, and surgery is planned based on the severity of opacity and photophobia.
Perform after providing sufficient explanation of the risks associated with surgery.
Glaucoma treatment is strongly recommended2). A stepwise approach is taken as follows.
Many cases are resistant to drug therapy, and tube shunt surgery may be a good option4). Since visual field damage from glaucoma is irreversible, early intraocular pressure control is key to preserving visual function.
First, drug therapy with eye drops and oral medications is performed, but many cases are drug-resistant. If ineffective, outflow reconstruction surgery (goniotomy or trabeculotomy) is considered, followed by trabeculectomy or long tube surgery (glaucoma implant surgery). Long tube surgery requires facility certification. Cyclophotocoagulation is a last resort when other treatments fail. Regular intraocular pressure monitoring is essential.
Low vision care and treatment for photophobia are strongly recommended 2).
The PAX6 gene is a master control gene that encodes a transcription factor governing organ differentiation during the embryonic period. It is expressed from the early eye and regulates various transcription factors. Loss of function of one allele of PAX6 (haploinsufficiency) causes congenital abnormalities throughout the eye (aniridia, Peters anomaly, macular hypoplasia, etc.).
PAX6 mutations are often of the PTC type such as nonsense and frameshift mutations, and missense mutations have also been reported1). Studies on genotype-phenotype correlation have shown that the severity of ophthalmic findings differs depending on the type of mutation3).
PAX6 is expressed not only in the eye but also in the central nervous system, pancreatic islets of Langerhans, and olfactory epithelium, and extraocular complications due to hypoplasia of these tissues (agenesis of the corpus callosum, epilepsy, anosmia, glucose intolerance) may occur1).
Two pathways are considered in the pathogenesis of glaucoma associated with aniridia.
Glaucoma rarely presents in infancy and progressively develops in adolescence with growth. It may occur in an open state due to angle dysgenesis or present as glaucoma due to angle closure.
Pathologically, corneal epithelial stem cell dysfunction is observed, leading to abnormalities in the epithelium and Bowman’s membrane, and the formation of a vascularized pannus. Hypoplasia of the palisades of Vogt progresses to conjunctival invasion and keratinization 1).
The cornea in aniridia is thicker than in healthy individuals. The cornea is often normal in early childhood, but with growth, corneal stromal opacity and LSCD develop, causing vision loss. In a 14-year single-center study (738 eyes), aniridia was the most common cause of LSCD, accounting for 30.9% of cases 6).
Studies on long-term prognosis report that visual prognosis is generally poor, but there are individual differences depending on the type and severity of complications5).
With the widespread use of next-generation sequencing (NGS), the detection rate of PAX6 mutations in isolated aniridia is approximately 85% 2). Chromosomal microarray (CMA) is more sensitive than conventional chromosome testing for detecting 11p13 microdeletions, contributing to improved diagnostic accuracy for WAGR syndrome 2).
Long-term outcomes of cultivated oral mucosal epithelial transplantation (COMET) are accumulating 2). For the Boston type I keratoprosthesis, visual improvement is achieved in 65–93% of cases in the short term (17–28.7 months), but decreases to 43.5% at 4.5 years, according to reports 2).
The HumanOptics CustomFlex ArtificialIris is a custom-made silicone artificial iris device that is useful for reducing photophobia and improving appearance, but as of 2024, it is not approved in Japan. Molecular targeted therapy targeting PAX6 haploinsufficiency is currently at the research stage and has not yet reached clinical application 3).
