Aniridia 

Aniridia is a congenital, hereditary, bilateral, extreme form of iris hypoplasia that may be associated with other ocular defects.[1, 2, 3, 4] It describes an extreme form of iris hypoplasia in which the iris appears absent on superficial clinical examination. However, gonioscopy shows the presence of the iris root. Aniridia is not just an isolated defect in iris development but is a panocular disorder with macular and optic nerve hypoplasia, cataract, and corneal changes that are other anomalies that lead to decreased vision and nystagmus. Visual acuity is generally low but is unrelated to the degree of iris hypoplasia. Glaucoma is a secondary problem causing additional visual loss over time.[5]

Patients with aniridia usually lack a foveal reflex, indicating poor macular development. True aplasia of the optic nerve also can occur. All these patients need specialized management of each individual problem. Because of poor visual acuity and nystagmus, low vision aids are very helpful. Lifelong regular follow-up care is necessary for the early detection of any new problems, especially glaucoma, lens, and systemic problems, so that timely treatment is given.[6] Since the condition has a dominant transmission, proper genetic counseling should be obtained.

Aniridia is shown in the images below.

Aniridia with a vascularized corneal opacity in a young patient.

Centrally placed cataractous lens and aniridia in a pediatric patient.

Clinical manifestations

See the list below:

• Aniridia alone

• Aniridia in association with systemic defects

  • Wilms tumor (20% of cases)[7, 8, 9]

  • Genitourinary abnormalities

  • Mental retardation[10]

• Aniridia in association with ocular defects

  • Albinism

  • Ectopia lentis (50%)

  • Spontaneous lens dislocation

  • Arcus juvenilis

  • Keratoconus

  • Cataract (50-85%)

  • Glaucoma (30-50%)

  • Nystagmus

  • Strabismus

  • Optic nerve hypoplasia (75%)

The pathogenesis of aniridia is attributed to a primary developmental arrest of the neuroectoderm and a secondary alteration of all 3 neural crest waves of the mesenchyme. The functional development of the anterior segment is a complex interrelationship between the neural ectoderm and the neural crest waves of the mesenchyme. The pathogenesis may involve defective formation or excessive regression of various layers of the anterior segment caused by cellular or biochemical aberrations. This explains the combined anterior and posterior segment neural ectodermal and mesenchymal defects. The iris stroma is hypoplastic, indicating an altered third neural crest wave of mesenchyme.

Aniridia occurs as the following:

• Autosomal disorder[11]

• An identifiable chromosome deletion of the short arm of chromosome 11, including band p13[12]

• Sporadic case

The exact defect in iris morphogenesis giving rise to aniridia is unknown. Because the iris pigment epithelium, the iris musculature, the retina, and the optic nerve are derived from neuroectoderm, there may be a common embryologic origin for these anomalies. As an isolated ocular malformation, aniridia is an autosomal dominant disorder, which is caused by a mutation in the PAX6 (paired box gene family) gene.[13, 14, 15]

Patients with aniridia who have a positive family history are not at an increased risk for Wilms tumor. Two genetic loci for aniridia have been identified: one (AN1) on chromosome arm 2p and one (AN2) on chromosome 11.

Patients with aniridia without a positive family history have a 30% chance of developing Wilms tumor, and they represent new mutations for the autosomal dominant gene. About one third of such patients have a mutation that affects the WT and AN2 loci, causing the patient to develop Wilms tumor; the other two thirds of patients have a mutation of just the AN2 locus. Because of the high mortality from Wilms tumor, those patients with the WT and AN2 mutations have a low probability of reproducing, whereas those with just AN2 mutations have normal fertility and, hence, a 50% risk to pass the aniridia gene mutation to each child.

Frequency

United States

At present, aniridia strikes 1 in 60,000 individuals; in Canada, this would represent only 475 individuals based on a present population of 28.5 million. In the United States, studies have shown the incidence to be 1 in 90,000. Based on a population of 265 million, this would represent 2945 people.

International

Aniridia is rare and has an incidence of 1 per 64,000 to 1 per 96,000 live births. About two thirds of these cases are familial.

Mortality/Morbidity

All patients with aniridia are visually handicapped for a lifetime. This already reduced vision is threatened further by such complications as cataract and glaucoma. Those patients with Wilms tumor have a reduced span of life.

Race

Aniridia has no racial predisposition.

Age

Congenital glaucoma and aniridia usually are not associated at birth. The glaucoma develops at either the preteen or the teenage level.

Significant cataracts may occur before puberty. The risk for cataract increases with age, with lens opacities observed in 50-85% of patients during the first 2 decades of life.

The prognosis of aniridia varies from patient to patient.

Unmonitored and untreated elevated intraocular pressure may damage vision.

Cataract may require surgery.

Progressive corneal opacification may need corneal grafting.

Thoroughly educating the patient and parents about aniridia and the associated ocular anomalies and systemic problems is mandatory.

The history of aniridia is straightforward. The condition is discovered early in life, especially in whites. In blacks, the condition might remain undiscovered for a long time until an ophthalmologist examines the eyes for visual problems. The patient presents with the following problems:

• Absence of iris

• Nystagmus

• Strabismus

• Reduced vision

Thorough family history includes the following:

• Specific inquiry about any ocular abnormality and/or low vision

• Dental anomaly

• Protruding umbilicus

• Genitourinary abnormalities (Wilms tumor)

• Mental retardation

Perform a thorough systemic examination of the patient.

A detailed ocular examination in patients with aniridia is sometimes difficult because of photophobia and nystagmus. If slit lamp flash pictures are taken, they can provide detailed information on corneal opacities and blood vessels, the depth of the anterior chamber, the edge of a transparent dislocated lens, the presence or absence of zonular fibers, and the presence of lenticular opacities. Photographs are useful to observe changes in the tissues with the passage of time. A picture session is especially important in children.[16]

The patient might show the following findings:

• Nystagmus

• Strabismus

• Photophobia

• Cornea

  • Pannus (shown in the images below)

    Aniridia with superiorly dislocated cataract.
    Aniridia. Close-up of the superior limbus of same patient as in the image above to show pannus.

  • Epithelial ulcers

  • Aniridic keratopathy

  • Arcus juvenilis

  • Microcornea

• Anterior chamber

  • Best judged with a slit lamp microscope

  • Configuration dependent upon the position of the crystalline lens

• Iris

  • Complete absence of iris on oblique illumination

  • Hypoplasia with irregular pupillary margins (atypical coloboma of pupil)

  • Root of the iris visible on gonioscopy

• Angle of the anterior chamber - Trabecular meshwork may be partially or completely covered by the iris stump.

• Crystalline lens

  • Transparent or opaque

  • Ectopia lentis

  • Completely dislocated lens (shown in the image below)

    In-the-bag intraocular lens. The lens has been displaced superiorly.

• Vitreous - Usually normal

• Fundus

  • Optic nerve hypoplasia

  • Macular reflex dull

  • Glaucomatous cupping

• Intraocular pressure

  • Normal

  • Increased

• Vision - Usually about 20/200 or less

Aniridia is caused by the following:

• An identifiable chromosome deletion of the short arm of chromosome 11, including band p13

• Patients with aniridia who have a positive family history: Two genetic loci for aniridia have been identified, one (AN1) on chromosome arm 2p and one (AN2) on chromosome 11.

• As an isolated ocular malformation, aniridia is an autosomal dominant disorder, which is caused by a mutation in the PAX6 (paired box gene family) gene.

Aniridia can be complicated by the presence or association of other problems, mainly cataract and glaucoma.

Chromosomal deletion is detected by cytogenetic testing with the use of high-resolution banding.

Submicroscopic deletions of the Wilms tumor gene are recognized with a fluorescent in situ hybridization (FISH) technique.

High-resolution chromosome studies are obtained in sporadic cases to determine if there is a deletion of band 11p13.

Serial renal ultrasound examinations are indicated in patients through age 7 years, especially for those with a deletion of band 11p13 or for those with a negative family history of aniridia and normal chromosomes.[17]

Histologically, small portions of the iris are always present; the ciliary body is usually hypoplastic; and the anterior chamber angle may be normal, immature (ie, incompletely developed), or malformed. In eyes enucleated from older patients, extensive peripheral anterior synechiae that cause the iris stump to adhere to the posterior corneal surface have been observed.

Prophylaxis in patients with aniridia is directed toward the prevention of glaucoma, which includes the following:

• Medical treatment with miotics
• Surgical separation of the iris from the trabecular meshwork in selected cases

Limbal stem cell deficiency associated with aniridia can be treated with the following:

• Lubricating drops
• Topical steroid pulses
• Vitamin A ointments
• Autologous serum drops
• Topical bevacizumab drops have been reported in one study. ^[18]
• Limbal stem cell transplantation

The medical treatment of aniridia is directed toward control of intraocular pressure, which includes the topical use of the following:

• Miotics
• Beta-blockers
• Sympathomimetics
• Carbonic anhydrase inhibitors
• Prostaglandin analogues

The chances of failure with local antiglaucoma treatment are high.

Treatment of photophobia and nystagmus in patients with aniridia is as follows:

• Tinted or iris contact lenses
• Tinted spectacle lenses
• Tinted intraocular lenses (IOLs) ^[19]
• By the above measures, reducing the amplitude and frequency of nystagmus is possible.

Refractive errors are treated with careful refraction and complete correction.

Treatment of amblyopia and strabismus in patients with aniridia is as follows:

• Usually, the potential visual acuity in both eyes should be symmetrical.
• When the vision is unequal without structural difference, vigorous amblyopia exercises should be performed in the worst eye.
• Binocularity can be achieved if macular hypoplasia is not severe.
• Strabismus surgery is indicated at an early age.

Management of corneal opacification in patients with aniridia is as follows:

• Limbal stem cell transplantation
• Keratoplasty
• Keratoprosthesis ^[20]

Management of cataract in patients with aniridia is as follows:

• In-the-bag lens implantation in cases without lens dislocation
• Use of opaque intracapsular rings to produce an artificial pupil or use of a large intraocular lens with a clear central optic and an opaque periphery
• In-the-bag IOL placement with intracapsular rings, when there is slight lens displacement
• Lens extraction followed by tinted/artificial pupil scleral-fixated posterior chamber lens
• Lens extraction followed by contact lens correction, if the lens is grossly out of place

Management of glaucoma in patients with aniridia is as follows:

• Goniotomy: This includes prophylactic and early surgical therapy. In early surgical therapy, some risk to the crystalline lens and the zonules exists because the surgery is performed from the anterior approach. ^[21]
• Trabeculotomy is safer than goniotomy. The tissues can be defined more clearly, and accurate surgery can be performed. However, failures are common.
• Filtering procedures: Greater danger of injury to the crystalline lens and disturbance of the vitreous exists because the iris is absent. Nonperforating filtration surgery techniques are safer, because the anterior chamber remains undisturbed. Since glaucoma develops in young patients with aniridia, the intraoperative use of mitomycin is justified. Fugo blade can be used to produce a transconjunctival microfiltration track of 200-300 µm in any part of the angle, away from the lens and the vitreous.
• Laser therapy to angle abnormalities
• Cyclocryotherapy: Endocyclophotocoagulation in selected cases
• Glaucoma valve procedure: The choice of the techniques and the order in which they are used depends upon the peculiarities of the case and the perception of the surgeon.

See the list below:

• Banded chromosome analysis on the patient and both parents

• Linkage analysis when large families are available

• Genetic counseling

Patients with aniridia should have proper genetic counseling.

Patients should have thorough lifelong follow-up care to determine whether glaucoma is present.

Lifelong, regular, and careful follow-up care of aniridia is essential with an ophthalmologist, with particular attention to the ocular surface and glaucoma monitoring and treatment.