Clinical Guidance

Isolated aniridia. PAX6 haploinsufficiency produces classic and severe aniridia with a high incidence of sight-reducing pathology including optic nerve malformations, glaucoma, cataract, and corneal changes [, , , , , , , , , ]. PAX6 pathogenic missense variants, particularly those that are in the paired domain and therefore likely to significantly reduce the DNA binding ability, tend to produce atypical/milder or variable-phenotype aniridia with better vision, more residual iris tissue, and a lower frequency of sight-reducing malformations and complications .

Source: GeneReviews — "PAX6-Related Aniridia"

Penetrance

Isolated aniridia has almost complete penetrance. Aniridia in WAGR also has almost complete penetrance. The risk of Wilms tumor is up to 77%.

Source: GeneReviews — "PAX6-Related Aniridia"

Diagnostic Criteria

PAX6-related aniridia includes isolated aniridia without systemic involvement and the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. No formal diagnostic criteria have been published.

Suggestive Findings

PAX6-related isolated aniridia should be suspected in probands who have the following clinical and imaging findings of aniridia with no other associated systemic abnormalities.

Clinical findings

Source: GeneReviews — "PAX6-Related Aniridia"

Differential Diagnosis

Individuals with Aniridia and No Identifiable PAX6 Pathogenic Variant

Heterozygous pathogenic variants in the following genes are included in the differential diagnosis of PAX6-related aniridia:

• FOXC1. Phenocopies exist and include dominant alleles of FOXC1, which can cause diagnostic difficulties .

• PITX2.

• PITX3.

• Unknown.

could not identify the cause of aniridia in 20 individuals despite PAX6, FOXC1, and PITX2 sequence analysis, FISH, and aCGH, suggesting that there may be further genetic heterogeneity with potentially new disease loci and/or novel mutational mechanisms.

Source: GeneReviews — "PAX6-Related Aniridia"

Management Guidelines

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aniridia (whether isolated or part of Wilms tumor-aniridia-genital anomalies-retardation [WAGR] syndrome), the following are recommended:

• Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function.

• Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life.

• Consultation with a clinical geneticist and/or genetic counselor

To establish the extent of disease and needs in an individual diagnosed with WAGR syndrome, the following are recommended:

• Evaluation by a pediatrician to assess growth and feeding

• Evaluation for Wilms tumor

• Evaluation by a urologist for urogenital abnormalities

• Developmental assessment

Treatment of Manifestations

Aniridia. Simple measures are often the most important:

Source: GeneReviews — "PAX6-Related Aniridia"

Clinical Guidance

It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy , and repeated intraocular surgery does predispose to the rare but severe aniridic fibrosis syndrome. Affected individuals should therefore be counseled about these risks before undertaking such surgery.

Source: GeneReviews — "PAX6-Related Aniridia"

Therapies Under Investigation

Ongoing research is investigating the role and success of limbal stem cell transplantation and ocular mucous membrane cell transplantation for keratopathies associated with limbal stem cell failure, including aniridia . A Phase II randomized, double-masked, placebo-controlled study of ataluren in individuals with aniridia caused by pathogenic nonsense variants in PAX6 is under way (ClinicalTrials.gov Identifier: NCT02647359). This is based on preclinical evidence that the small-molecule drug ataluren can effectively suppress the nonsense mutation in the Pax6 mouse model, generating full-length functional protein that reversed the developmental defect following postnatal drug administration . Search ClinicalTrials.

Source: GeneReviews — "PAX6-Related Aniridia"

Surveillance Guidelines

Aniridia

Amblyopia and refractive error. Children younger than age eight years should be monitored every four to six months for refractive errors and detection and treatment of incipient or actual amblyopia (strabismic, refractive, or sensory). Glasses and other visual aids should be provided to optimize access to educational materials. Detection of later-onset eye pathology. Individuals with aniridia should have an annual ophthalmology review to detect issues such as corneal changes, raised intraocular pressure, and cataracts. Glaucoma. Individuals with aniridia should undergo annual glaucoma screening throughout life including:

• Measurement of intraocular pressure;

• Optic disc examination;

• Visual field assessment when possible.

Note: Assessment of the optic disc and visual field may be difficult in the presence of media opacities and nystagmus. Optic disc photography is a useful method of monitoring optic disc changes. Aniridic fibrosis syndrome. Individuals with aniridia with a history of multiple ocular procedures (penetrating keratoplasty, IOLs, and drainage tube insertion) should be monitored for aniridic fibrosis syndrome .

WAGR Syndrome

Wilms tumor. Children with aniridia and a WT1 deletion require kidney ultrasound examinations every three months and follow up by a pediatric oncologist until they reach age eight years. See Wilms Tumor Predisposition. (Those without deletion of the WT1 locus are at very low risk for Wilms tumor and do not require such screening .

Source: GeneReviews — "PAX6-Related Aniridia"