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A child with absent or markedly hypoplastic iris on slit-lamp exam. Often presents with nystagmus and reduced visual acuity in infancy; the iris finding is the obvious clue but it travels with foveal hypoplasia, cataract, glaucoma, and (later) keratopathy. Aniridia is a sentinel finding: the immediate clinical job is to decide whether this is isolated familial aniridia or part of WAGR syndrome, because the second one carries a high lifetime risk of Wilms tumor and changes management on day one.
Two questions structure the work-up:
- Is there a positionally informative parent? Isolated aniridia is autosomal dominant with high penetrance; an affected parent on slit-lamp essentially closes the WAGR question for the proband but the WAGR panel is still done to be safe.
- Is the PAX6 change a point mutation or a contiguous 11p13 deletion? A point mutation in PAX6 causes isolated aniridia. A deletion that takes out PAX6 plus the neighboring WT1 causes WAGR. The two look identical at the slit lamp.
The clinical reflex: every child with aniridia gets an 11p13-targeted chromosomal microarray and renal ultrasound surveillance until WAGR is excluded.
PAX6 haploinsufficiency (the vast majority)
- Isolated familial aniridia (PAX6, AD): point mutations or small intragenic deletions in PAX6 at 11p13. Iris hypoplasia + foveal hypoplasia + early nystagmus + later cataract + glaucoma + keratopathy. Visual acuity typically 20/100 to 20/200. Other ocular structures are normal at birth; keratopathy is a progressive late complication driven by limbal stem cell deficiency.
Contiguous 11p13 deletion (the diagnosis you cannot miss)
- WAGR syndrome (deletion of 11p13 spanning PAX6 + WT1, sporadic, almost always de novo): Wilms tumor (40-50% lifetime risk) + Aniridia + Genitourinary anomalies (cryptorchidism, ambiguous genitalia) + Range of intellectual disability. Larger deletions that include BDNF also cause obesity (WAGRO). Renal ultrasound every 3 months until age 8 is the standard surveillance protocol.
Other syndromic aniridia
- Gillespie syndrome (ITPR1, AD or AR): partial aniridia (scalloped iris remnant rather than complete absence) + cerebellar ataxia + intellectual disability. The iris appearance is the differential clue from classic PAX6 aniridia.
- WAGRO: WAGR + obesity, larger 11p13-p14 deletion including BDNF.
Anterior segment dysgenesis mimics
- Peters anomaly, Axenfeld-Rieger (PAX6, PITX2, FOXC1): central corneal opacity or iris adhesions, not true aniridia, but in the same anterior segment dysgenesis differential.
- Any child with aniridia, regardless of family history → 11p13 microarray and renal ultrasound surveillance until WAGR is excluded. Even in a child of an affected parent, send the microarray. The cost of missing WAGR is a preventable Wilms tumor.
- Aniridia + ambiguous genitalia or cryptorchidism → WAGR until proven otherwise. The genitourinary clue is often what tips this in the newborn.
- Partial iris with a scalloped edge plus ataxia and ID → Gillespie; ITPR1, not PAX6.
- Aniridia + an affected parent on slit-lamp + normal microarray → isolated familial PAX6 aniridia. Genetic counseling is straightforward AD with 50% recurrence.
- Apparent "aniridia" in an isolated child without family history is the highest-yield WAGR scenario.
- Slit-lamp exam of the proband and both parents. Subtle iris hypoplasia in a parent diagnoses isolated familial aniridia and informs counseling.
- Chromosomal microarray with 11p13 resolution as the first genetic test. A normal CMA effectively excludes WAGR; abnormal CMA showing an 11p13 deletion confirms it.
- PAX6 sequencing if CMA is normal, to identify the AD point mutation.
- Renal ultrasound every 3 months from diagnosis through age 8 in any child with aniridia until WAGR has been excluded by microarray.
- Pediatric ophthalmology longitudinal care: IOP monitoring (glaucoma develops in 50-75%), cataract surveillance, keratopathy management, low-vision services, foveal hypoplasia documentation by OCT.
- Endocrine evaluation in WAGR for genitourinary anomalies and growth.
- Aniridia is the textbook example of "always look for the contiguous deletion." A normal-appearing child with aniridia can have WAGR and a high risk of Wilms; the microarray is non-negotiable.
- PAX6 is THE gene for aniridia. Whether the mechanism is a point mutation or a deletion changes everything about the prognosis.
- Glaucoma is the most common cause of vision loss in adolescence in aniridia; routine IOP monitoring matters as much as the systemic surveillance.
- Foveal hypoplasia is why aniridia patients have nystagmus and reduced acuity; the iris finding is the visible clue, not the visual mechanism.