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Aniridia

Includes: Isolated Aniridia, Wilms Tumor-Aniridia-Genital Anomalies-Retardation (WAGR) Syndrome

, MA, MBBS, MD, FRCOphth and , MA, MBBS, FRCS, FRCOphth.

Author Information
, MA, MBBS, MD, FRCOphth
Consultant Ophthalmologist
Moorfields Eye Hospital
London, United Kingdom
, MA, MBBS, FRCS, FRCOphth
Professor of Ophthalmology
Institute of Ophthalmology and Moorfields Eye Hospital
London, United Kingdom

Initial Posting: ; Last Update: November 14, 2013.

Summary

Disease characteristics. Aniridia is characterized by complete or partial iris hypoplasia usually (but not always) with associated foveal hypoplasia resulting in reduced visual acuity and nystagmus presenting in early infancy. Frequently associated ocular abnormalities (often of later onset) include cataract, glaucoma, and corneal opacification and vascularization. Aniridia may occur either as an isolated ocular abnormality without systemic involvement, caused by mutation of PAX6 or deletion of a regulatory region controlling its expression, or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome, with a deletion of 11p13 involving the PAX6 (aniridia) locus and the adjacent WT1 (Wilms tumor) locus. Individuals with deletion of PAX6 and WT1 are at up to a 50% risk of developing Wilms tumor.

Diagnosis/testing. Aniridia is diagnosed by clinical examination. Sequence analysis of the PAX6 coding region and deletion/duplication analysis to detect PAX6 exonic or whole-gene deletions are used to identify the disease-causing mutation in those with isolated aniridia. High-resolution cytogenetic testing to detect deletions involving 11p13 and FISH testing or deletion/duplication analysis to detect deletions of PAX6 and WT1 are used to identify the underlying disease-causing mechanism in those with the diagnosis of WAGR syndrome.

Management. Treatment of manifestations: Aniridia is treated with spectacle correction of refractive errors, tinted or photochromic lenses to reduce light sensitivity, occlusion therapy for amblyopia, and low-vision aids such as closed-circuit television. Cataract extraction may improve visual acuity in those with dense cataracts. Glaucoma is initially treated with topical anti-glaucoma medication; refractory cases may require surgery (trabeculectomy or drainage tube surgery) or cyclodiode treatment. Corneal disease is treated with lubricants, mucolytics, and punctal occlusion. For severe disease corneo-limbal transplant surgery can be undertaken but carries a high risk of failure and may require lifelong systemic immunosuppression. The rare aniridic fibrosis syndrome is treated with surgery.

Surveillance: Children under age eight years should be monitored every four to six months for refractive errors and amblyopia. An annual ophthalmologic review can detect later-onset eye pathology. Annual glaucoma screening throughout life including measurement of intraocular pressure, optic disc examination, and, when possible, visual field assessment. Monitoring for aniridic fibrosis syndrome with slit lamp examination in those with multiple previous intraocular surgeries. Renal ultrasound examination every three months until age eight years for children with aniridia and a WT1 deletion. Lifelong evaluation of renal function in individuals with WAGR syndrome, especially those with bilateral Wilms tumor. Detailed audiologic evaluation is recommended for children with WAGR or isolated aniridia.

Agents/circumstances to avoid: Intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy; repeated intraocular surgery predisposes to the rare but severe aniridic fibrosis syndrome.

Evaluation of relatives at risk: An eye examination in infancy is recommended for offspring and sibs of individuals with aniridia.

Genetic counseling. Isolated aniridia is inherited in an autosomal dominant manner. Most individuals with isolated aniridia have an affected parent; however, some may have isolated aniridia as the result of a de novo gene mutation. Offspring of an individual with isolated aniridia have a 50% chance of inheriting the PAX6 mutation and developing aniridia. WAGR syndrome caused by a contiguous gene deletion usually occurs de novo; WAGR syndrome caused by a cytogenetically visible deletion may be de novo or may result from transmission by a parent with a balanced chromosome rearrangement. Prenatal testing is possible for pregnancies at increased risk for isolated aniridia if the disease-causing mutation of an affected family member has been identified and for pregnancies at increased risk for WAGR syndrome if a contiguous gene deletion or a cytogenetically visible deletion has been confirmed in the proband.

Diagnosis

Clinical Diagnosis

Aniridia is characterized by complete or partial iris hypoplasia usually (but not always) with associated foveal hypoplasia resulting in reduced visual acuity and nystagmus presenting in early infancy. Frequently associated ocular abnormalities, often of later onset, include cataract, glaucoma, and corneal opacification and vascularization.

Techniques used to identify the ocular abnormalities of aniridia

  • Slit lamp examination. Partial or complete iris absence, iris translucency, or abnormal architecture and pupillary abnormalities may be seen; corneal opacification and vascularization, cataract, and glaucoma can also be detected if present.
  • Fundoscopy (slit lamp or binocular indirect ophthalmoscopy). Absence of or reduction in the normal foveal architecture is frequent; less commonly optic nerve abnormalities such as hypoplasia and coloboma can be detected. Rarely other retinal problems may be seen.
  • Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically.
  • Optical coherence tomography (OCT) may be used to document foveal hypoplasia. Although OCT is difficult to perform in the presence of nystagmus, useful images can be obtained with persistence. Anterior segment OCT can also be used to delineate the detailed anatomy of the anterior segment structures, even in those with corneal opacity [Majander et al 2012].
  • High-frequency ultrasound biomicroscopy (UBM). In infants with corneal opacity or severe corneal edema resulting from associated congenital glaucoma, high-frequency anterior segment ultrasound examination can demonstrate iris hypoplasia and/or absence [Nischal 2007].

Aniridia may occur as one of the following:

  • Isolated aniridia without systemic involvement caused by mutation of PAX6 or deletion of a regulatory region controlling PAX6 expression

    Note: Isolated aniridia may occur in individuals with a positive family history consistent with autosomal dominant inheritance (familial aniridia: 70% of all individuals with aniridia) and in individuals with no family history of aniridia (simplex aniridia, commonly referred to as "sporadic aniridia": 30% of individuals with aniridia) [Valenzuela & Cline 2004].

    OR
  • The Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. WAGR syndrome may be diagnosed on the following findings:
    • A visible deletion of 11p13 found on cytogenetic testing

      OR
    • A submicroscopic deletion involving the PAX6 (aniridia) locus and the adjacent WT1 (Wilms tumor) locus found on FISH testing or heterozygosity testing

      OR
    • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia

      Note: (1) Because Wilms tumor, intellectual disability, and behavioral abnormalities are unlikely to be evident in a very young child with WAGR syndrome, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for these manifestations. (2) The external genitalia are usually normal in females with WAGR syndrome [Fischbach et al 2005].

Testing

Cytogenetic testing. High-resolution cytogenetic testing at the 600-650-band level detects deletions involving 11p13 in up to 20% of individuals with no family history of aniridia. Deletion/duplication analysis typically detects these and smaller deletions and may define breakpoints precisely (Table 1).

Molecular Genetic Testing

Genes

  • Mutations or deletions in PAX6 or its control elements are associated with isolated aniridia.
  • Contiguous gene deletions including PAX6 and WT1 are associated with aniridia and the risk of one or more additional manifestations of WAGR.

Clinical testing

Table 1. Summary of Genetic Testing of Aniridia by Phenotype and Family History

PhenotypeGene 1Test MethodMutations Detected 2Mutation Detection Frequency by Phenotype and Test Method
Family History
NegativePositive
WAGR syndrome 3PAX6 and contiguous genesHigh-resolution cytogenetic testingLarge deletion of 11p1357%NA
PAX6 and WTDeletion/ duplication analysis, including FISH 4Whole-gene deletions14%NA
Isolated aniridia 5 PAX6Sequence analysis of coding regionSequence alterations55%62.5%
Deletion/ duplication analysis 4Exonic deletions and deletions of control regions22% 617% 6

NA = not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Wilms tumor-aniridia-genital anomalies-retardation syndrome. Note: In young individuals, Wilms tumor and intellectual disability may not be evident; in females, external genitalia are often normal.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Isolated aniridia: aniridia without systemic involvement

6. [Robinson et al 2008].

Test characteristics. Information on test sensitivity, specificity, and other test characteristics is available [Clericuzio et al 2011] (full text).

Testing Strategy

To confirm/establish the diagnosis of isolated aniridia vs WAGR. In order to determine which affected individuals are at high risk for the development of Wilms tumor and thus require initiation of the Wilms tumor screening protocol, the following testing algorithm should be considered:

Evaluate the proband with cytogenetic testing, FISH, and/or deletion/duplication analysis of PAX6 and WT1 first when the proband is:

  • An infant with aniridia who is a simplex case (i.e., a single occurrence in the family);

    OR
  • An older individual with aniridia and intellectual disability and/or Wilms tumor and/or genital anomalies.

Evaluate the proband with PAX6 sequence analysis and/or PAX6 deletion/duplication analysis first when the proband:

Identification of a PAX6 sequence alteration, a PAX6 exonic deletion, or deletions of PAX6 control regions confirms the diagnosis of isolated aniridia.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation/deletion in the family.

Clinical Description

Natural History

Aniridia is a panocular disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve. The phenotype is variable between and within families; however, affected individuals usually show little variability between the two eyes. Individuals with aniridia characteristically show nystagmus, impaired visual acuity (usually 20/100 - 20/200), and foveal hypoplasia. Milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur [Hingorani et al 2009]. Other abnormalities include corneal changes, glaucoma, cataract, lens subluxation, strabismus, optic nerve coloboma and hypoplasia, and occasionally microphthalmia.

The reduction in visual acuity is primarily caused by foveal hypoplasia, but cataracts, glaucoma, and corneal opacification are responsible for progressive visual failure. Most children with aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with nystagmus (usually apparent by six weeks of age). Congenital glaucoma rarely occurs in aniridia; in such cases, a large corneal diameter and corneal edema may be the presenting findings. Despite their many ocular problems, most individuals with aniridia can retain useful vision with appropriate ophthalmologic management.

Iris. The most obvious ocular abnormality is iris hypoplasia. The severity varies from a nearly normal iris to almost complete iris absence in which a small stump of residual iris tissue is visible on gonioscopy, anterior segment OCT, or ultrasound biomicroscopy [Okamoto et al 2004]. In less extreme cases, the pupil size may be normal, but there may be loss of the iris surface architecture or the presence of iris transillumination [Hingorani et al 2009]. Other iris changes include partial iris defects (resembling a coloboma) or eccentric or misshapen pupils and iris ectropion [Nelson et al 1984, Willcock et al 2006].

Lens. Congenital lens opacities (especially polar) are common [Gramer et al 2012]. Often there is persistent vascularization of the anterior lens capsule (tunica vasculosa lentis) or remnants of the pupillary membrane. The lens opacities are rarely dense enough to require lens extraction in infancy, but visually significant lens opacities eventually develop in 50%-85% of affected individuals, often in the teens or early adulthood. Lens subluxation or dislocation occurs but is uncommon.

Intraocular pressure. When elevated intraocular pressure is associated with loss of retinal ganglion cells resulting in visual field loss and optic nerve cupping, a diagnosis of glaucoma is made. Both elevated intraocular pressure and glaucoma are common in people with aniridia and may eventually occur in up to two thirds of individuals [Gramer et al 2012]. The onset of glaucoma is usually in later childhood or adulthood; glaucoma in infancy is rare [Gramer et al 2012].

Cornea. Keratopathy (corneal degeneration) is a relatively late manifestation with multifactorial causes including limbal stem cell abnormalities and abnormal wound healing [Ramaesh et al 2005]. Changes vary from mild peripheral vascularization to pan corneal vascularization, opacification, and keratinization. Inadequate tear production is common and exacerbates the ocular surface problems. Central corneal thickness is increased – a finding of uncertain clinical relevance, but which may result in undermeasurement of intraocular pressure on tonometry [Brandt et al 2004, Whitson et al 2005]. Rarely, those with aniridia may have microcornea and, extremely rarely, megalocornea [Lipsky & Salim 2011, Wang et al 2012].

Fovea. Foveal hypoplasia is usually (but not always) present. Findings include reduced foveal reflex, macular hypopigmentation, and crossing of the usual foveal avascular zone by retinal vessels. OCT images can clearly delineate the absence of normal foveal architecture.

Optic nerve. Optic nerve hypoplasia (i.e., the optic nerve head appears abnormally small) may occur in up to 10% and there may be optic nerve colobomata [McCulley et al 2005].

Aniridic fibrosis syndrome. Individuals with aniridia who have a history of multiple ocular procedures (penetrating keratoplasty, intraocular lenses [IOLs], and drainage tube insertion) may rarely develop aniridic fibrosis syndrome in which a fibrotic retrolenticular and retrocorneal membrane arises from the root of the rudimentary iris tissue. This membrane may cause forward displacement of the IOLs, IOL entrapment, and corneal decompensation [Tsai et al 2005].

Retina. Retinal detachment may occur, probably as a consequence of a high myopia or previous intraocular surgery. Very rarely, primary retinal manifestations such as an exudative vascular retinopathy or chorioretinal degeneration may occur [Hingorani et al 2009, Aggarwal et al 2011].

Other ocular manifestations. Affected individuals may have significant refractive errors and may develop a secondary strabismus (squint, eye misalignment).

Central nervous system. Individuals with isolated aniridia may show reduced olfaction and cognition, behavioral problems, or developmental delay. Central nervous system abnormalities (including absence or hypoplasia of the anterior commissure; abnormalities of grey matter in the anterior cingulate cortex, cerebellum, and temporal and occipital lobes; white matter deficits in and reduced volume of the corpus callosum; absence of the pineal gland; and occasionally olfactory bulb hypoplasia) can be demonstrated on MRI [Sisodiya et al 2001, Free et al 2003, Mitchell et al 2003, Ellison-Wright et al 2004, Valenzuela & Cline 2004, Bamiou et al 2007, Abouzeid et al 2009].

Hearing. Central auditory processing difficulties (from abnormal interhemispheric transfer) present in some individuals may cause hearing difficulties. This finding is particularly important in the context of associated visual impairment [Bamiou et al 2007].

WAGR syndrome. Individuals with cytogenetically visible deletions of 11p13 or cryptic deletions of PAX6 and WT1 may develop WAGR syndrome: Wilms tumor-aniridia-genital anomalies-retardation syndrome [Fischbach et al 2005]:

  • Wilms tumor risk for individuals with a cytogenetically visible deletion of 11p13 or a submicroscopic deletion that involves PAX6 and WT1 is probably as high as 50%. Individuals with WAGR syndrome are more likely than those with isolated Wilms tumor to develop bilateral tumors and have an earlier age of diagnosis and a more favorable tumor histology with better prognosis [Halim et al 2012].
  • Aniridia is almost universally present in individuals with such a deletion and typically is severe. However, WAGR without aniridia has been described.
  • Genitourinary abnormalities include cryptorchidism (most commonly, in 60% of males), uterine abnormalities, hypospadias, ambiguous genitalia, streak ovaries, urethral strictures, ureteric abnormalities, and gonadoblastoma.
  • Intellectual disability and behavioral abnormalities in WAGR syndrome are highly variable:
    • Seventy percent of individuals with WAGR syndrome have intellectual disability (defined as IQ <74); other individuals with WAGR syndrome can have normal intellect without behavior problems.
    • Behavioral abnormalities include attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (see Autism Overview), anxiety, depression, and obsessive compulsive disorder.
  • Neurologic abnormalities occur in up to one third of individuals with WAGR syndrome. Findings include hypertonia or hypotonia, epilepsy, enlarged ventricles, corpus callosum agenesis, and microcephaly.
  • End-stage renal disease (ESRD). The risk of later ESRD is significant, relating to Wilms tumor and its surgery, focal segmental glomerulosclerosis, and occasionally renal malformation. The rate of ESRD is 36% with unilateral Wilms tumor and 90% with bilateral Wilms tumor. Approximately 25% of individuals with WAGR syndrome have proteinuria ranging from minimal to overt nephritic syndrome [Breslow et al 2005, Fischbach et al 2005].
  • Obesity. The association of obesity in the WAGR spectrum, for which the acronym WAGRO has been suggested, has been confirmed [Brémond-Gignac et al 2005a].

Affected individuals may also show craniofacial dysmorphism, hemihypertrophy, growth retardation, scoliosis, and kyphosis. Other anomalies reported on occasion include polydactyly and congenital diaphragmatic hernia [Nelson et al 1984, Brémond-Gignac et al 2005b, Manoukian et al 2005, Scott et al 2005] (see Congenital Diaphragmatic Hernia Overview).

Early studies recognized that 30% of individuals with aniridia who had no family history of aniridia developed Wilms tumor within the first five years of life; subsequent studies revealed that the risk may be lower [Gronskov et al 2001]. It is now known that these individuals have WAGR syndrome caused by a contiguous gene deletion encompassing both PAX6 and the nearby Wilms tumor suppressor gene (WT1). Absence of one WT1 allele in the germline in these individuals leads to a high risk (~45%) of Wilms tumor occurring through somatic mutation that results in loss of heterozygosity (LOH) in a single differentiating kidney cell.

Genotype-Phenotype Correlations

Isolated aniridia. Haploinsufficiency (loss of protein function of one allele) of PAX6 can be identified in approximately 90% of individuals with aniridia, with intragenic loss-of-function mutations (often premature termination codons) accounting for two thirds and deletions or chromosomal rearrangements in PAX6 or regulatory elements for one third of cases [Gronskov et al 2001, Robinson et al 2008]. PAX6 haploinsufficiency produces classic and severe aniridia with a high incidence of sight-reducing pathology such as optic nerve malformations, glaucoma, cataract and corneal changes [Kleinjan & van Heyningen 1998, Prosser & van Heyningen 1998, Gronskov et al 1999, Hanson et al 1999, Lauderdale et al 2000, van Heyningen & Williamson 2002, Chao et al 2003, Tzoulaki et al 2005, Dansault et al 2007, Hingorani et al 2009].

PAX6 missense mutations, particularly those which 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 [Hingorani et al 2009]. Missense mutations may also result in related disorders (see Table 2) such as foveal hypoplasia, autosomal dominant keratitis, developmental abnormalities of the optic nerve, and Peters anomaly, sometimes associated with neurodevelopmental abnormalities.

C-terminal extension (CTE) mutations, which generate a longer protein product, are associated with a moderately severe aniridic phenotype with poor vision, keratopathy, and cataracts; however, individuals with CTE mutations are less likely to have glaucoma and are more likely to have preservation of iris tissue than individuals who have null mutations [Hingorani et al 2009, Aggarwal et al 2011]. The rare reports of significant non-foveal retinal abnormalities (exudative retinopathy, chorioretinal degeneration) are all associated with CTE mutations, for reasons which are not clear [Hingorani et al 2009, Aggarwal et al 2011].

Although the phenotype can be variable within a family, individuals usually show little difference between the two eyes. The causes for this variation in phenotype among individuals with the same mutation are unknown [Negishi et al 1999].

WAGR syndrome is caused by either cryptic or cytogenetically visible deletions involving varying amounts of 11p that include band 11p13 with PAX6 and neighboring genes. The loss of WT1 produces genitourinary and renal abnormalities and predisposes to Wilms tumor, which results from loss of heterozygosity (LOH). Deletion of one copy of PAX6 causes aniridia. The exact gene loss responsible for intellectual disability is uncertain [Fischbach et al 2005] but the phenotypic spectrum is determined by the identity of the genes involved in the deletion, with more severe cognitive impairment typically associated with larger deletions [Fischbach et al 2005, Xu et al 2008].

Penetrance

Penetrance is 100%.

Prevalence

The prevalence of aniridia is 1:40,000 to 1:100,000. No racial or sexual differences are recognized.

The prevalence of WAGR syndrome is approximately 1:500,000.

Differential Diagnosis

Rieger anomaly, a form of anterior segment mesenchymal dysgenesis, is characterized by severe iris atrophy, corectopia (displaced pupils), iris holes, and, frequently, childhood-onset glaucoma. Rieger anomaly may be distinguished from aniridia by the presence of posterior embryotoxon (visible Schwalbe's line seen as a white line just inside the corneal limbus) with attached iris strands, relatively good visual acuity, and the absence of nystagmus or foveal abnormality.

Iris coloboma is a developmental defect resulting in a focal absence of the iris and a keyhole-shaped pupil; the rest of the iris is normal. Chorioretinal coloboma may be associated. Most iris colobomas are not associated with reduced visual acuity or nystagmus unless accompanied by a large posterior coloboma that involves the optic nerve and fovea; such large chorioretinal colobomas are apparent on fundoscopic examination.

Gillespie syndrome, characterized by partial iris hypoplasia, cerebellar ataxia, and intellectual disability, can be distinguished from aniridia by a characteristic iris configuration in Gillespie syndrome showing a scalloped pupillary edge with iris strands extending onto the anterior lens surface [Nelson et al 1997].

Oculocutaneous albinism (OCA) and ocular albinism typically present in early infancy with nystagmus but a structurally complete iris, typical diffuse iris transillumination (resulting from reduced pigment in the iris pigment epithelium), hypopigmented fundus, and, in the case of OCA, skin and hair hypopigmentation, which distinguish these disorders from aniridia (see Oculocutaneous Albinism Type 1, Oculocutaneous Albinism Type 2, Oculocutaneous Albinism Type 4, and X-Linked Ocular Albinism).

The other causes of nystagmus and poor vision in infancy (e.g., retinal dysplasia, retinal dystrophy, congenital cataracts, optic nerve hypoplasia, congenital infections) lack the iris changes seen in aniridia.

Causes of partial or complete absence of iris tissue in adults include trauma, prior ocular surgery, and the iridocornealendothelial (ICE) syndromes. The age at onset, medical history, and absence of other ocular features in aniridia should prevent diagnostic confusion with aniridia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluation Following Initial Diagnosis

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

  • Evaluation of visual acuity (not easily performed in infants), 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 presence and degree of corneal involvement, cataract, and glaucoma, as they are potentially treatable causes of further visual reduction; however, they may not appear until later in life.
  • Medical genetics consultation

Treatment of Manifestations

Aniridia. Simple measures are often the most important:

  • Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production.
  • Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film.
  • Occlusion therapy for anisometropic amblyopia or strabismic amblyopia in childhood
  • Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age
  • Advice and help with schooling
  • Social support

Note: Corrective surgery for strabismus can be undertaken but is usually only for cosmetic rather than visual purposes.

Lens. Cataract extraction can significantly improve visual acuity in those with severe lens opacities. It should be remembered that in aniridia visual improvement after surgery is limited by foveal hypoplasia; thus, mild to moderate lens opacities may not require surgery:

  • Children rarely require surgery (lens aspiration or lensectomy).
  • In adults, phacoemulsification can be successful.

Note: (1) A significant number of individuals with aniridia have poor zonular stability, which increases the risk for intraoperative complications and influences the choice of surgical technique and options for IOL implantation [Schneider et al 2003]. (2) The use of various types of black diaphragm aniridic IOLs may reduce glare or light sensitivity but may be associated with a higher rate of surgical complications [Reinhard et al 2000, Menezo et al 2005, Pozdeyeva et al 2005].

Intraocular pressure

  • Glaucoma is usually initially treated with topical anti-glaucoma medication.
  • Surgery is reserved for eyes that do not respond to medical therapy:
    • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in patients with primary glaucoma who undergo the same treatment.
    • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases, although this treatment is increasingly being undertaken as a primary procedure [Khaw 2002, Kirwan et al 2002, Arroyave et al 2003, Lee et al 2010].

Note: (1) Glaucoma presenting in infancy is more difficult to treat. Medical treatment is generally ineffective and surgery is required. Goniotomy and trabeculotomy have a low success rate, but trabeculectomy with or without antimetabolites is often successful [Nelson et al 1984, Okada et al 2000, Khaw 2002]. (2) While goniosurgery has been suggested as a preventive measure, glaucoma never develops in a significant proportion of those with aniridia [Swanner et al 2004].

Cornea

  • Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity.
  • When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [Tiller et al 2003].
  • Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty may be undertaken, but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [Lee et al 2008, Pauklin et al 2010]. However, this therapy is associated with a high risk of failure and lifelong systemic immunosuppression may be required to prevent rejection. Whether the use of cultured oral mucous membrane cells may have a beneficial role is as yet uncertain.

Aniridic fibrosis syndrome. Surgical intervention is recommended at the first sign of aniridic fibrosis syndrome [Tsai et al 2005].

Wilms tumor. See Wilms Tumor Overview.

Prevention of Secondary Complications

Detection of high refractive errors and amblyopia in children will allow therapy to protect or restore the vision

Early detection of ocular hypertension and glaucoma will allow the instigation of therapy to prevent the further loss of visual function.

Protection of the ocular surface with lubricants and lacrimal punctual obstruction may help slow the progression of sight-threatening corneal changes.

Surveillance

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 be able to best access educational materials.

Detection of later-onset eye pathology. Individuals with aniridia should have an annual ophthalmology review to detect problems such as corneal changes 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.

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 [Tsai et al 2005].

Wilms tumor. Children with aniridia and a WT1 deletion require renal ultrasound examinations every three months and follow-up by a pediatric oncologist until they reach age eight years. See Wilms Tumor Overview. (Those without deletion of the WT1 locus are at very low risk for Wilms tumor and do not require such screening [Gronskov et al 2001, Muto et al 2002].)

Renal function. Because of the increased risk for renal impairment in WAGR syndrome, it has been suggested that renal function be evaluated every few years across the lifetime in those with WAGR syndrome, especially those with bilateral Wilms tumor [Breslow et al 2005].

Hearing. Children with WAGR syndrome and isolated aniridia may have abnormal hearing despite a normal audiogram; thus, detailed audiologic evaluation is recommended [Bamiou et al 2007].

Agents/Circumstances to Avoid

It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy [Eden et al 2010], and repeated intraocular surgery does predispose to the rare but severe aniridic fibrosis syndrome. Patients should therefore be counseled about these risks before undertaking such surgery.

Evaluation of Relatives at Risk

It is recommended that offspring and sibs of individuals with aniridia have an eye examination in infancy and be offered the option of genetic counseling and testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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 [Polisetti & Joyce 2013, Menzel-Severing et al 2013].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner.

Risk to Family Members — Isolated Aniridia

Parents of a proband

  • Most individuals diagnosed with isolated aniridia have an affected parent.
  • A proband with isolated aniridia and no family history may have the disorder as the result of a de novo gene mutation or gene deletion.
  • Because the severity of the phenotype may vary greatly among family members, recommendations for the evaluation of parents of a proband with an apparent de novo mutation include examination of both parents for evidence of minor degrees of iris hypoplasia or reduced visual acuity caused by foveal hypoplasia and may include genetic testing.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has isolated aniridia or has an identifiable PAX6 mutation, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If a PAX6 mutation cannot be detected in the DNA of either parent of the proband, germline mosaicism in a parent should be considered. Germline mosaicism for PAX6 intragenic mutations has been reported on rare occasions [Gronskov et al 1999].

Offspring of a proband. Each child of an individual with isolated aniridia has a 50% chance of inheriting the PAX6 mutation and developing aniridia.

Note: In rare instances of mosaicism for the PAX6 mutation in the proband, the risk to offspring may be lower.

Risk to Family Members — WAGR Syndrome

Parents of a proband

  • WAGR syndrome caused by a contiguous gene deletion that includes PAX6 and WT1 that is detected only by FISH testing or deletion/duplication analysis usually occurs de novo; however, rarely an asymptomatic parent may be mosaic for such a deletion; thus, it is appropriate to offer FISH testing or deletion/duplication analysis to both parents.
  • In individuals with WAGR syndrome caused by a cytogenetically visible deletion, it is appropriate to offer cytogenetic testing to both parents to determine if either parent has a balanced chromosome rearrangement.

Sibs of a proband

  • If a parent has a balanced chromosome rearrangement, the risk to the sibs is increased depending on the nature of the chromosome rearrangement.
  • 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.

Offspring of a proband. Individuals with WAGR syndrome caused by a cytogenetic deletion generally do not reproduce.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have isolated aniridia.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing using fetal cells obtained by amniocentesis is usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation is possible under the following circumstances:

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which (1) the disease-causing PAX6 mutation has been identified or (2) a chromosome rearrangement detectable by chromosome analysis or FISH has been demonstrated in a parent.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Aniridia Foundation International (AFI)
    University of Virginia School of Medicine - Department of Ophthalmology
    PO Box 800715
    Charlottesville VA 22908-0715
    Phone: 434-243-3357
    Email: info@aniridia.net
  • Aniridia Network International
    109 Gavin Way
    Colchester CO4 9FR
    United Kingdom
    Phone: +44 01206 842 742 (after 6pm)
    Email: hannah@aniridia.org
  • International WAGR Syndrome Association
    Email: Reachingout@wagr.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Aniridia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PAX611p13Paired box protein Pax-6PAX6 @ The Human Genetics Unit Edinburgh U.K.PAX6

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Aniridia (View All in OMIM)

106210ANIRIDIA; AN
194070WILMS TUMOR 1; WT1
194072WILMS TUMOR, ANIRIDIA, GENITOURINARY ANOMALIES, AND MENTAL RETARDATION SYNDROME; WAGR
607102WT1 GENE; WT1
607108PAIRED BOX GENE 6; PAX6

Molecular Genetic Pathogenesis

PAX6 belongs to the PAX (paired box) family of genes that code for highly conserved DNA-binding proteins believed to be important in controlling organogenesis by altering expression of other genes [van Heyningen & Williamson 2002]. PAX6 is expressed in ocular, neural, nasal, and pancreatic tissue during development. Heterozygous mutations of PAX6 appear to disturb ocular morphogenesis, resulting in aniridia and related ocular phenotypes, and also may produce mild central nervous system defects [Sisodiya et al 2001, Free et al 2003, Ellison-Wright et al 2004, Valenzuela & Cline 2004]. Homozygous or compound heterozygous loss of PAX6 function leads to anophthalmia and central nervous system defects and are often fatal [Hodgson & Saunders 1980, Glaser et al 1994, Schmidt-Sidor et al 2009].

Normal allelic variants. PAX6 occupies 22 kb on chromosome 11p13. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. The longest transcript encoding the longest isoform is NM_000280.4

Pathogenic allelic variants. More than 300 PAX6 mutations have been identified, more than 90% of which are predicted to disrupt transcription or translation and are likely to be pathogenic mutations causing congenital eye disorders [Prosser & van Heyningen 1998, Tzoulaki et al 2005]:

Four CpG dinucleotides in exons 8, 9, 10, and 11 are the most common mutation sites, accounting for 21% of all reported mutations [Tzoulaki et al 2005]. Large deletions that may involve other genes (e.g., WT1) also produce aniridia.

Many mutations have been reported in PAX6, both in aniridia and in related ocular phenotypes including Peters anomaly, foveal hypoplasia, and optic nerve anomalies:

  • Of the PAX6 mutations known to cause aniridia, most lead to loss of protein function and comprise nonsense mutations (39%), splice mutations (13%), frameshifting deletions and insertions (25%), in-frame insertions and deletions (6%), missense mutations (12%), and run-on mutations (5%) [Prosser & van Heyningen 1998, Tzoulaki et al 2005].
  • Of the approximately 30 known mutations for non-aniridia eye disorders, 69% are missense mutations [Tzoulaki et al 2005].

Normal gene product. PAX6 encodes the PAX6 protein, a 422-amino acid protein [NP_000271.1] that acts as a transcription factor. PAX6 contains a paired domain and a paired-type homeodomain, both with DNA-binding capability, separated by a lysine-rich linker region. A C-terminal proline, serine, and threonine-rich (PST) domain acts as a transcriptional activator. PAX6 protein is thought to act as the major controller of ocular development during embryogenesis by effects on cellular proliferation, differentiation, migration, and adhesion; several target genes have been identified [van Heyningen & Williamson 2002]. PAX6 protein expression continues in the adult retina, lens, and cornea and may help maintain good ocular health [Koroma et al 1997, van Heyningen & Williamson 2002].

Various isoforms of PAX6 protein are derived through alternative splicing (PAX6-ex12, PAX6-5a,6', PAX6-5a). The ratios of these isoforms may be critical to normal ocular development [Singh et al 2002].

Abnormal gene product. The molecular consequence of most PAX6 mutations is loss of protein function. This was previously believed to occur primarily through premature protein truncation but is now hypothesized to arise from nonsense-mediated decay [Prosser & van Heyningen 1998, Tzoulaki et al 2005]. Missense mutations are believed to produce proteins with reduced function, and protein modeling predicts that 88% of missense PAX6 mutations can be linked to changes in intrinsic stability (77%) and/or to the ability to bind DNA (30%) [Alibes et al 2010]. This results in the variant ocular phenotypes or (if protein function is greatly reduced) in aniridia. Reduction of expression of alternatively spliced PAX6 protein isoforms can also cause an altered or less severe phenotype [Azuma et al 1999, Vincent et al 2003, Chauhan et al 2004].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Haber DA. Wilms tumor. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 38. Available online. Accessed 11-7-13.
  2. Hingorani M, Hanson I, van Heyningen V. Eur J Hum Genet. 2012;20:1011–7. [PMC free article: PMC3449076] [PubMed: 22692063]
  3. Sheffield VC, Alward WLM, Stone EM. The glaucomas. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 242. Available online . Accessed 11-7-13.

Chapter Notes

Revision History

  • 14 November 2013 (me) Comprehensive update posted live
  • 12 July 2008 (me) Comprehensive update posted to live Web site
  • 15 July 2005 (me) Comprehensive update posted to live Web site
  • 20 May 2003 (me) Review posted to live Web site
  • 2 September 2002 (am) Original submission
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