Aniridia is defined as a partial or complete absence of the iris. Aniridia can be either congenital or acquired. Congenital aniridia is a rare disease which affects both eyes. It is autosomal dominant in the majority. Most of the other cases of congenital aniridia are sporadic. Sporadic aniridia may correlate with WAGR syndrome (Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation). A minority of congenital aniridia may be transmitted autosomal recessively called as the Gillespie syndrome (aniridia, cerebellar ataxia, and mental retardation).
Research has noted a mutation of the PAX6 gene at the chromosome 11p13 in congenital aniridia.
Acquired aniridia occurs after trauma or ocular surgery.
The exact cause of congenital aniridia is unknown. However, the paired box gene (PAX6) gene at chromosome 11p13 is a crucial factor in pathogenesis. This gene is involved in the development of essential organs including the eye, pancreas, brain, and spinal cord during embryonic development.
The various hypothesis regarding the etiopathogenesis of aniridia include:
Classification of congenital aniridia:
Autosomal dominant congenital aniridia- It consists of at least 2/3rd cases of congenital aniridia and may be present in up to 85% cases with aniridia. This variant is autosomal dominant and the most common form of aniridia; it has complete penetrance but variable expressivity. Thus family members may have different severity of aniridia, ocular involvement, and visual acuity. Some cases may have subtle iris hypoplasia or iris coloboma.
Sporadic congenital aniridia- There is a de novo mutation of the PAX6 gene and may consist of 13% to 33% of cases with aniridia. An important fact is that this variant of aniridia correlates with nephroblastoma (Wilm's tumor) as a part of WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation), also known as Miller's syndrome. The genitourinary anomalies include undescended testes in males and streak gonads (nonfunctional ovaries) and/or bicornuate uterus in females. Intellectual disability includes difficulty in learning and processing information. There might be other manifestations including attention deficit hyperactivity disorder, obsessive-compulsive disorder, depression, and anxiety. There may be craniofacial dysmorphism.
WAGR syndrome occurs as the chromosomal location of the PAX6 gene at 11p13 is very close to WT1 (Wilm's tumor) gene. There is a partial deletion of the short arm of chromosome 11 involving both PAX6 and WT1 in this syndrome. Patients with WAGR syndrome have around 45 to 60% chance of developing nephroblastoma. Approximately 25% to 33% of patients with sporadic congenital aniridia may develop nephroblastoma before 3 years of age.
Autosomal recessive congenital aniridia- It consists of 1% to 3% of the all congenital aniridia cases and is the least common variant of congenital aniridia. It has associations with cerebellar ataxia and mental retardation (Gillespie syndrome).
Aniridia is noted in around 1.8 of 100,000 births. Males and females are equally affected.
Various genes implicated in the pathogenesis of congenital aniridia include:
Aniridia 1 or AN1 (OMIM # 106210)- This results from heterozygous mutation of the PAX6 gene at chromosome 11p13. It is inherited autosomal dominantly, and also includes late-onset corneal dystrophy and congenital cataracts. Other associations include Peters anomaly, reduced smell sensation, hypoplasia of corpus callosum and/or anterior commissure, and the absence of the pineal gland.
Aniridia 2 (AN2) (OMIM # 617141, autosomal dominant) results from mutation of a cis-regulatory element of the PAX6 gene. This regulatory region is at the intron of the adjacent ELP4 gene (11p13).
Aniridia 3 (AN3) (OMIM # 617142, autosomal dominant) is due to a mutation in the TRIM44 gene (11p13).
Gillespie syndrome (OMIM # 206700) occurs due to a mutation of the ITPR1 gene at chromosome 3p26.1.
Research has suggested a probable linkage of autosomal dominant aniridia and acid phosphatase 1 (ACP1) at chromosome 2p.
The histopathology shows arrest of neuroectodermal development which includes absent iris muscles with hypoplasia of iris. There may be dysgenesis of the Schlemm's canal and trabecular meshwork. Hypoplasia of the ciliary body is also noted but is less severe than iris-hypoplasia. Large iris vessels may be present over the anterior surface of the hypoplastic iris. The anterior chamber angle may be normal. There may be incomplete cleavage of the angle or an anomalous development of the angle.
The patients usually complain of photophobia related to the severity of aniridia and poor vision (due to many reasons including foveal hypoplasia and optic nerve head hypoplasia) since early childhood. Parents may bring the child for the abnormal appearance of the eyes.
Nystagmus and strabismus are common due to poor vision since childhood.
Other ocular findings include:
Other associations of aniridia include:
The fundus fluorescein angiogram reveals the lack of a well-defined foveal avascular zone.
Optical coherence tomography in foveal hypoplasia shows the absence of foveal depression and the presence of the inner retinal layers.
In sporadic congenital aniridia, Wilm's tumor must be ruled out by regular ultrasonogram of the abdomen. Also, genetic evaluation for PAX6 and WT1 gene is possible.
Ophthalmic examination of the family members is of utmost importance.
In early childhood, the management includes optimal refractive correction, amblyopia therapy, and correction of squint.
Painted contact lenses may reduce photophobia, improve cosmesis, and improve vision. Tinted contact lenses may also be an option. Such contact lenses also reduce nystagmus. Photochromatic or tinted glasses may be helpful.
The food and drug administration has approved an artificial iris implant. It may improve the disabling glare, light sensitivity during day or night, improve cosmesis and vision-related quality of life. However, there is a risk of development or worsening of glaucoma, and limbal stem cell deficiency. Customflex artificial iris may be used to treat
Glaucoma- The medications usually fail to control glaucoma, and surgical intervention is needed. Glaucoma presenting before 1 year of age is very difficult to treat. Surgery is often necessary for glaucoma by 20 years of age in patients with congenital aniridia. The options for surgical therapy include:
The success of surgical intervention may not be significant. In a study, success rates for various interventions were:
Okada and colleagues noted that 'mean good intraocular pressure control period after the filtering surgery was 14.6 months'. The success rate of trabeculectomy is better in older patients and Nelson and colleagues reported successful trabeculectomies in 11 of 14 cases with the minimum follow-up of 1 year. Ultimately, if other modalities fail to control intraocular pressure, cycloablative therapies may be needed which include diode laser cyclophotocoagulation and cyclocryotherapy. Prophylactic goniotomy may prevent the development of glaucoma in congenital aniridia.
The cataract in aniridia may need extraction. Surgery is difficult due to zonular weakness and fragility of the lens capsule. The eye may be left aphakic, and postoperatively contact lens or aphakic glasses may be prescribed. Special intraocular lens (IOL) for aniridia is available which have a peripheral colored region like iris of different pigmentation. Tinted IOLs are also available which can reduce photophobia. In extreme subluxation, scleral-fixated IOL may be necessary. Surgical trauma may increase the chances of glaucoma, corneal decompensation, and limbal stem cell deficiency.
Phase 0 (subclinical limbal stem cell deficiency and phase 1 (slight limbal stem cell deficiency, less than 2 corneal epithelial erosion or ulcer in last 6months, corneal pannus less than 1mm from limbus, mild watering and photophobia and fluorescein staining abnormality) The dry eye and keratopathy need frequent artificial tear drops (free of preservatives). Antiglaucoma drops with preservatives may worsen the corneal surface.
Phase 2 (Moderate limbal insufficiency, constant redness, watering, and photophobia, more than 3 corneal erosions or ulcers in last 6 months, constant tear film instability, vascular pannus) - amniotic membrane transplant or autologous serum is used.
Phase 3 (severe limba insufficiency, corneal vascularization, loss of vision)- Autologous transplant of limbal epithelial cell is not possible due to bilateral involvement. Management options include:
However, the survival of corneal graft is often poor due to multiple causes including corneal vascularization, limbal stem cell deficiency, severe dry eye, and glaucoma.
The associated squint and ptosis may need correction.
Aniridic fibrosis syndrome needs early surgical intervention to remove the membranes.
Systemic diseases need a collaborative approach of specialists of different subspecialties.
Visual prognosis is usually poor. Up to 86% of patients with aniridia may have a visual acuity of 20/100 or worse in the better eye. The cause of visual decline include
However, members of some families with familial aniridia may have good vision of at least 20/30 in up to 61% of cases.
Aniridia may be complicated by:
All patients with sporadic congenital aniridia should be screened regularly with abdominal ultrasonography for Wilms tumor unless a genetic evaluation rules out mutation or deletion of WT1. A proposed protocol of ultrasound screening is
Diagnosing aniridia and properly managing it requires a team effort. There should be proper coordination between pediatrician, pediatric ophthalmologist, geneticist and pediatric surgeon to reach a conclusion regarding the management plan and to counsel the parents accordingly. The prognosis for most patients as far as visual acuity is concerned is poor.(Level V) Interprofessional collaboration is crucial for better outcomes and reduce mortality of patients with aniridia and systemic diseases. Specifically, sporadic congenital aniridia cases must be screened regularly for Wilm's tumor.
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