Clinical characteristics: PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual.
WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral issues.
Diagnosis/testing: The diagnosis of PAX6-related aniridia is established in a proband with one of the two following clinical and molecular genetic findings:
Isolated aniridia (i.e., without systemic involvement) and a heterozygous PAX6 pathogenic variant, ranging in size from a single nucleotide (e.g., those resulting in a nonsense, missense, or splice site variant or single-nucleotide deletion or duplication) to a partial- or whole-gene deletion (or in rare instances deletions telomeric to PAX6 that do not include PAX6); or
Aniridia and one or more additional findings of WAGR syndrome and a deletion of PAX6 and the upstream adjacent gene, WT1
Management: Treatment of manifestations:
Aniridia. Correction of refractive errors, use of tinted or photochromic lenses to reduce light sensitivity, occlusion therapy in childhood for amblyopia, use of low-vision aids. Treatment of severe cataracts requires attention to potential complications caused by poor zonular stability. Glaucoma: Initial treatment is usually topical anti-glaucoma medication; surgery is reserved for eyes that do not respond to medical therapy. Ocular surface disease: medical treatment (lubricants, mucolytics, and punctal occlusion) may help slow the progression of corneal opacification. When corneal opacification causes significant visual reduction, penetrating keratoplasty with limbal stem cell transplantation may be considered; however, this has a high risk of failure and possible lifelong systemic immunosuppression to prevent rejection.
WAGR syndrome. Wilms tumor, genital anomalies, and developmental delay / intellectual disability are managed as per standard practice.
Aniridia. Monitor children younger than age eight years every four to six months for refractive errors and detection and treatment of incipient or actual amblyopia; annual ophthalmology follow up of all individuals to detect issues such as corneal changes, raised intraocular pressure, and cataracts.
WAGR syndrome. Children with aniridia and a WT1 deletion require renal ultrasound examinations every three months and follow up by a pediatric oncologist until age eight years. Because of the increased risk for renal impairment in WAGR syndrome (especially in those with bilateral Wilms tumor), lifelong evaluation of renal function is recommended. Developmental progress and educational needs require regular monitoring. Behavioral assessment for anxiety, ADHD, and aggressive or self-injurious behavior as needed.
Agents/circumstances to avoid: Intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy; repeated intraocular surgery predisposes to severe aniridic fibrosis syndrome.
Evaluation of relatives at risk: Early clarification of the genetic status of infants who are offspring or sibs of an individual with PAX6-related isolated aniridia (by either an eye examination or molecular genetic testing for the PAX6 variant in the family) is recommended in order to identify those who would benefit from prompt treatment and surveillance of complications of aniridia.
Genetic counseling: Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner.
Isolated aniridia. ~70% of individuals have an affected parent; ~30% have a de novo PAX6 pathogenic variant or deletion of a regulatory region controlling PAX6 expression. Each child of an individual with isolated aniridia has a 50% chance of inheriting the causative genetic alteration and developing aniridia. In rare instances of mosaicism for the PAX6 pathogenic variant in the proband, the risk to offspring may be lower.
WAGR syndrome is associated with contiguous-gene deletions including PAX6 and WT1. If the proband has a de novo contiguous-gene deletion and neither parent has evidence of mosaicism for the deletion, the risk to sibs is no greater than that in the general population.
When the PAX6 genetic alteration in a family is known, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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