Clinical background
Aniridia refers to a bilateral malformation of the eye in which the most prominent clinical finding is variable to near-total absence of the iris. The word aniridia is a misnomer since the iris is not totally absent ( Figure 61.1 ) and there are in fact a number of other accompanying ocular abnormalities that result from the underlying genetic defect in one of the master ocular developmental genes, PAX6 . Even in the more severe cases, a stump of tissue is invariably present at the base of the iris, and gonioscopy may be required for its adequate visualization. Careful ocular examination will reveal other abnormalities that include persistent strands of the fetal pupillary membrane, congenital lens opacities that could be cortical, anterior polar, or of other types, ectopia lentis or subluxation of the crystalline lens as a result of poor zonular development, developmental glaucoma, a superficial keratopathy referred to as corneal pannus, persistence of the retina over pars plana, and foveal hypoplasia that is almost universal and leads to decreased visual acuity and nystagmus.
Congenital poor visual function in aniridia results from macular, foveal, and optic nerve hypoplasia. Acquired causes of visual loss in aniridia include the development or progression of cataracts, optic nerve damage from glaucoma, corneal opacification, and anisometropic or strabismic amblyopia. The keratopathy/corneal pannus of aniridia appears late in the first decade of life and is presumably due to insufficient/absent limbal stem cells that depend on the presence of normal PAX6 complement for their development and maintenance. Nystagmus is most likely due to congenital poor visual acuity, although underlying central nervous causes may exist that have not been adequately investigated. There are at least two families in which some members have classical aniridia and other members have atypical iris defects ranging from radial clefts or atypical colobomas and relatively good vision. We have recently described four patients with aniridia, preserved vision, little or no foveal hypoplasia and no detectable mutations in PAX6. Vascular anomalies of the iris have also been described. Aniridia can also occur in association with malformations of the globe such as Peters’ anomaly or congenital anterior staphyloma or with microcornea and subluxated lenses.
Aniridia is associated with systemic abnormalities when it occurs in the context of the well-defined contiguous gene syndrome of “Wilms’ tumor–aniridia–genitourinary abnormalities–retardation” (WAGR) or Miller syndrome ( Box 61.1 ). This type of aniridia is of the nonheritable variety and is always associated with a deletion of band 13 on the short arm of chromosome 11.
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Aniridia is an autosomal-dominant panocular malformative disorder in which the most prominent clinical abnormality is absence of iris tissue
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Poor vision in aniridia results mostly from foveal hypoplasia
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Aniridia results from mutations in the PAX6 gene on 11p13
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The WAGR syndrome of Wilms’ tumor, aniridia, genitourinary malformations and retardation results from deletions of chromosome 11p13
Aniridia can also occur in the context of multisystem malformation syndromes and chromosomal abnormalities such as a ring chromosome 6, pericentric inversion of chromosome 9, the syndrome of multiple ocular malformations, and mental retardation described by Walker and Dyson and Hamming et al, and the syndrome of aniridia and absence of the patella. When iris hypoplasia is not severe, aniridia may be confused with conditions such as Rieger anomaly ( Figure 61.2 ), ectopia lentis et pupillae, atypical coloboma of the iris, or essential iris atrophy (Chandler syndrome).
PAX6 is widely expressed in the central nervous system. Sisodiya et al performed magnetic resonance imaging (MRI) and smell testing in patients with aniridia and showed absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of cases, demonstrating that PAX6 haploinsuffiency causes more widespread human neurodevelopmental anomalies ; Mitchell et al demonstrated widespread structural abnormalities of the brain, including absence of the pineal gland and unilateral polymicrogyria on MRI of 24 patients heterozygous for defined PAX6 mutations. Thompson et al studied 14 patients with PAX6 gene mutations and MRI abnormalities for defects in cognitive functioning. None were found except in a subgroup of patients with agenesis of the anterior commissure who performed significantly more poorly on measures of working memory than those without this abnormality. In another study, brain MRI, central auditory testing, and a questionnaire were administered to a group of 11 children with aniridia. The corpus callosum area was significantly smaller on brain volumetry in patients compared with controls. The anterior commissure was small in 7 cases and was normal in 3 cases on visual inspection of brain MR images. Audiograms showed no abnormalities in any of the children. Central auditory test results were normal in all the controls and were abnormal in all the cases, except for 1 case with a pattern of abnormalities consistent with reduced auditory interhemispheric transfer. The cases had greater difficulty localizing sound and understanding speech in noise than the controls. These findings indicate that, despite normal audiograms, children with PAX6 mutations may experience auditory interhemispheric transfer deficits and have difficulty localizing sound and understanding speech in noise.
Aniridia with cerebellar ataxia and mental retardation is a very rare condition inherited in an autosomal-recessive fashion and known as Gillespie syndrome. Gillespie syndrome is not caused by mutations in PAX6 .
Most recently glucose intolerance and diabetes mellitus have been described in some patients with aniridia and are possibly due to the importance of PAX6 in pancreatic development and function. PAX6 plays an indispensable role in islet cell development. Yasuda et al performed oral glucose tolerance tests in patients with PAX6 mutations and found glucose intolerance characterized by impaired insulin secretion.
Etiology and distribution
Aniridia occurs in 1/50 000 live births. Shaw et al estimated the prevalence of aniridia in the lower peninsula of Michigan in 1960 to be about 1 in 64 000. Approximately two-thirds to three-fourths of patients have at least one other affected family member; the remainder are sporadic.
In one large series of 125 patients, 74 cases were sporadic, 24 were familial, and 14 had the WAGR syndrome, or other malformations. Two cases had chromosome rearrangements involving 11p13, 16 cases had visible deletions, and 16 cases had cryptic deletions identified by fluorescent in situ hybridization (FISH). The frequency of cryptic deletions in familial aniridia was 27% and in sporadic isolated aniridia was 22%. Of the 14 cases referred with WAGR syndrome, 10 (71%) had chromosomal deletions, 2 cryptic, and 8 visible. Of the 13 cases with aniridia and other malformations, 5 (38%) had a chromosomal rearrangement or deletion. In 37 cases with no karyotypic or cryptic chromosome abnormality, sequence analysis of the PAX6 gene was performed. Mutations were identified in 33 cases: 22 with sporadic aniridia, 10 with familial aniridia, and 1 with aniridia and other non-WAGR syndrome-associated anomalies. Overall, 67 of 71 cases (94%) undergoing full mutation analysis had a mutation in the PAX6 genomic region.
Aniridia is caused in most cases by mutations in PAX6 , a homeobox transcription factor on 11p13. There appears to be a correlation between the type of mutation and the clinical phenotype. A classic severe phenotype results from mutations that lead to stop codons and protein haploinsufficiency. Missense mutations cause aniridia as well as other phenotypes, including cataracts, Peters’ anomaly, other types of anterior-segment dysgenesis, and occasionally a clinical picture predominated by keratopathy ( Figure 61.3 ). Rarely, the iris is so well preserved ( Figure 61.4 ) that the phenotype is one of isolated foveal hypoplasia ( Figure 61.5 ). Some patients with mutations in PAX6 have microphthalmia.
Prognosis, prevention, and treatment
Once the clinical diagnosis of aniridia is made, it becomes imperative to determine whether the patient has a mutation inside the PAX6 gene or whether he/she carries a deletion that involves the adjacent Wilms’ tumor gene WT1 . Clinical molecular genetic testing is available and will identify a mutation in more than 75% of cases. Karyotyping has been superseded by microarray analysis, a test that will detect small deletions or chromosomal rearrangements of 11p13 where the PAX6 gene is located. FISH analysis can also be used to detect submicroscopic deletions of 11p13. As a general rule, familial cases have intragenic mutations, while sporadic cases may be due to either PAX6 mutations or to chromosomal deletions that may include adjacent genes and cause the WAGR syndrome. In any patient with aniridia and a negative family history, the risk of developing Wilms’ tumor is 20%. About 1 in 70 patients with Wilms’ tumor have aniridia. The presence of other systemic abnormalities in a sporadic case of aniridia should raise the suspicion of a chromosome 11p deletion or rearrangement. If access to genetic testing is not possible, careful, repeated examination and imaging of the renal system should be performed. Ultrasound examination of the kidneys is done at 6-month intervals supplemented with intravenous pyelography, computed tomography, or MRI to evaluate further any suspicious finding.
Other family members should be examined for the presence of mild degrees of iris hypoplasia as this may indicate dominant inheritance with variable expressivity and circumvent the worries about the potential occurrence of Wilms’ tumor.
The management of ocular problems in patients with aniridia can be very challenging ( Box 61.2 ). Visual acuity is less than or about 20/200 in most patients, but may be as good as 20/20 in patients with aniridia and preserved ocular function. The main cause of acquired visual loss in aniridia is glaucoma, and patients are screened for its presence at regular intervals. The glaucoma in aniridia typically develops in late childhood or in adulthood; however, it may be present in the first year of life. Aniridic glaucoma may be due to trabeculodysgenesis, but a more likely mechanism is occlusion of the filtering angle by an up-pulling of the iris stump. Goniotomy or trabeculotomy may be successful in controlling or preventing aniridic glaucoma ; however, filtering surgery or cyclocryotherapy may be required. Medical therapy should be tried in older individuals with aniridic glaucoma. Cataracts, which develop in most aniridic patients, are extracted if they produce significant further decrease in visual acuity. Some patients have congenital anterior polar cataracts while others have acquired cataracts that usually develop in early adulthood. Ectopia lentis is occasionally found in aniridic eyes and should be looked for before a lensectomy is performed. Finally, penetrating keratoplasty may be required in some instances if progressive keratopathy leads to corneal opacification and to further loss of vision.
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The workup of patients with aniridia includes mutation analysis of the PAX6 gene. If a mutation is found in sporadic patients, a deletion of 11p13 is ruled out and the risk of Wilms tumor becomes that of the general population
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Patients with aniridia are at high risk of developing glaucoma. Intraocular pressure needs to be checked frequently
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Cataracts are common and should only be extracted if vision is expected to improve
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Other family members should be carefully examined, especially in families where the clinical manifestations are mild
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