Although called aniridia, this disorder is a panocular one taking its name from the noticeable iris hypoplasia seen in most cases. This feature can range from a readily visible, almost complete absence of the iris, through enlargement and ... Although called aniridia, this disorder is a panocular one taking its name from the noticeable iris hypoplasia seen in most cases. This feature can range from a readily visible, almost complete absence of the iris, through enlargement and irregularity of the pupil mimicking a coloboma, to small slit-like defects in the anterior layer seen only on transillumination with a slit-lamp. The effect on vision is similarly variable (Jordan et al., 1992). See also Gillespie syndrome (206700), in which aniridia is associated with cerebellar ataxia and mental retardation.
Shaw et al. (1960) ascertained 176 cases of aniridia in the lower Michigan peninsula. Forty isolated cases were considered mutants. The frequency in Michigan was about 1.8 x 10(-5) and the mutation rate about 4 x 10(-6) per ... Shaw et al. (1960) ascertained 176 cases of aniridia in the lower Michigan peninsula. Forty isolated cases were considered mutants. The frequency in Michigan was about 1.8 x 10(-5) and the mutation rate about 4 x 10(-6) per gamete per generation. Affected persons may be visually handicapped because of nystagmus, cataract or glaucoma. The ratio of affected to normal among the offspring of an affected parent was 38 to 62, a significant difference from 50 to 50. In an economically depressed area of eastern Canada, Gove et al. (1961) identified 77 cases of aniridia descended from an affected woman born in 1824. The aniridias showed approximately a 20% elevation of reproductive activity as compared with the rest of the community, and this community was in turn nearly twice as fertile as the rest of Canada. Elsas et al. (1977) described a large pedigree in which visual acuity of affected members was nearly normal. By contrast, the presence of one or more of the associated ocular abnormalities--cataract, lens dislocation, foveal dysplasia, optic nerve hypoplasia, and nystagmus--contributes to severe reduction in visual acuity. About half of cases develop glaucoma which causes severe ocular pain and, if not treated successfully, can destroy residual vision. Ferrell et al. (1980) studied a large kindred with aniridia in which they described marked phenotypic variability with many persons being unaware of the presence of the trait because they had round pupils and good vision in at least one eye. Thinning of the iris was a manifestation. Ferrell et al. (1980, 1987) erroneously mapped aniridia in this family to chromosome 2 (see MAPPING section). This error was in part due to diagnostic difficulties; diagnosis, especially at an early age, may be difficult in patients with round and central pupils. Both normal and affected irides of such at-risk family members transilluminate in early infancy and do not transilluminate at maturation. This is consistent with the hypothesis that aniridia is a disease of the neuroectoderm with normal acquisition of iris epithelial pigmentation and pupillary musculature, but secondary faulty induction of the 3 neural crest mesenchymal waves into the corneal endothelium and trabecular meshwork, corneal stroma, and iris stroma. The variability in phenotype and the resulting diagnostic difficulties were commented on by Shaw et al. (1960) and Hittner et al. (1980). Glaser et al. (1994) reported a family segregating 3 distinct ocular phenotypes: the mother had defects characteristic of aniridia, including essentially absent irides, bilateral cataracts, decreased visual acuity in both eyes, an irregular searching nystagmus, small corneal diameters, and foveal hypoplasia with extension of blood vessels through the central retinal region. She had no intellectual or neurologic impairment. Similar findings were present in her mother and half brother. The father had developed bilateral cataracts shortly after birth, which progressed and were extracted at ages 38 and 40. A circumferential corneal pannus was first noted at age 50. The irides had a large postsurgical defect but were otherwise normal, and the foveas appeared well developed. Their daughter, who was born by cesarean section at 43 weeks' gestation, had severe craniofacial and central nervous system defects and clinical anophthalmia, and died on the eighth day of life. The head was small with disproportionately large ears. The nose was malformed with a flattened bridge and pinpoint external nares. She also had choanal atresia. Postmortem examination confirmed complete agenesis of the eyes, periocular tissues, optic nerves, and chiasm. The brain was small and misshapen. The cerebral hemispheres were thin and widely separated with a single open ventricular system. Midline fusion occurred focally in the anterior septal area, but the corpus callosum was otherwise absent. The mild extraocular phenotypes reported in the small eye mouse, including olfactory bulb hypoplasia, axon guidance defects, cortical plate hypocellularity, and decreased basal ganglia volume, indicate the possibility of subtle brain alterations in human heterozygotes. This prompted Sisodiya et al. (2001) to screen 14 subjects with aniridia for PAX6 mutations and to use MRI to look for alterations in brain structure. Olfactory capacity was also tested. Because PAX6 governs cellular proliferation and migration of 'later-born' neurons, and because subtle but significant malformation may be detectable only by quantitative MRI, they measured regional brain volumes. Interhemispheric communication is through 2 major pathways, the anterior commissure and the corpus callosum. To determine whether callosal hypoplasia, found in both homozygous small eye mice and the human compound heterozygote (Glaser et al., 1994), also occurs in human heterozygotes, Sisodiya et al. (2001) measured callosal area and found significant reduction in the study group compared with controls. Two subjects with hypoplastic olfactory bulbs had mild or moderate hyposmia. Of the remaining 12 subjects with visually normal olfactory bulbs, only 1 had normal olfaction. Some subjects were previously aware of notably reduced olfaction. The authors noted that anosmia had been reported anecdotally in an aniridia subject (Martha et al., 1995). Absence of the anterior commissure without callosal agenesis had not been reported as a malformative sequence in humans. In a similar study of 24 subjects with ocular abnormalities and PAX6 mutations, including the 14 patients reported by Sisodiya et al. (2001), Mitchell et al. (2003) found absence of the pineal gland in 13 subjects and absence of the AC in 12. The authors noted that neither of these findings had been reported in Pax6 mutant mouse models. Because some of the sporadic cases of aniridia are caused by large chromosomal deletions, which may include the Wilms tumor gene (607102), such patients may have an increased risk of developing Wilms tumor (WT1; 607102). Based on the unique registration of both cancer and aniridia cases in Denmark, Gronskov et al. (2001) were able to make an accurate risk estimate for Wilms tumor in sporadic aniridia. They found that patients with sporadic aniridia had a relative risk of 67 (CI, 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only 2 patients of 5 in whom the Wilms tumor gene was deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor. Recchia et al. (2002) reviewed the usefulness of optical coherence tomography (OCT) in the diagnosis of foveal hypoplasia, which may be seen in aniridia or oculocutaneous albinism (203100), as well as in other syndromes. In a patient with foveal hypoplasia (136520), OCT allowed detailed examination of the macular anatomy, showing preservation of multiple inner retinal layers where there should have been none, indicating that the fovea was thicker than normal. The authors suggested that a more accurate term would be 'foveal dysgenesis,' and proposed that OCT might prove helpful in the evaluation of patients with unexplained visual loss. In 32 eyes of 17 patients with aniridia, Brandt et al. (2004) described markedly increased central corneal thickness: 631.6 +/- 50.8 microns versus 535 microns in normal controls. They suggested that increased central corneal thickness might lead to incorrect estimates of intraocular pressure by applanation techniques and highlighted the importance of monitoring aniridia patients for the development of glaucoma through regular gonioscopy and optic nerve examination. Solomon et al. (2009) reported a 4-year-old boy with prenatally diagnosed trisomy 21 who also had extreme microcephaly, bilateral severe microphthalmia, choanal atresia, smooth philtrum, severe developmental delay, and renal dysplasia with recurrent urinary tract infections; evidence for hypopituitarism included central hypothyroidism, secondary adrenal insufficiency, and a history of cryptorchidism and micropenis, which had been treated with exogenous testosterone. He also had neonatal-onset insulin-dependent diabetes mellitus, but abdominal MRI showed no pancreatic anomalies. Structural abnormalities of the brain by MRI included agenesis of the corpus callosum, midline interhemispheric cyst, hypoplastic pons and vermis, possible Dandy-Walker malformation, dysplastic tectum, pituitary and hypothalamic hypoplasia, and a globular basal ganglia. His mother had bilateral aniridia, glaucoma, and corneal opacification, as well as a dense cataract in the right eye; she also had elevated fasting blood glucose, although she had not been diagnosed with diabetes. There was an extensive family history of autosomal dominant aniridia in her family: her sister, mother, maternal aunt and uncle, and maternal grandfather were all affected. The proband's father had a history of early childhood cataract and eventual blindness, as well as hearing loss. Examination revealed high palate and dental crowding; ophthalmologic examination showed microcornea, right cataract, and left aphakia, as well as subtle iris hypoplasia and corectopia. There was an extensive family history of cataract and hearing loss in his family, affecting 4 maternal aunts and 1 uncle as well as his maternal grandfather. The proband had a brother who had died in infancy, who was described as having very similar structural brain anomalies, clinical anophthalmia, and neonatal diabetes.
Fantes et al. (1992) described a mother and son with aniridia associated with a submicroscopic 11p13 deletion. This was a rare case of an inherited WAGR deletion; the family was ascertained through the son who presented with Wilms ... Fantes et al. (1992) described a mother and son with aniridia associated with a submicroscopic 11p13 deletion. This was a rare case of an inherited WAGR deletion; the family was ascertained through the son who presented with Wilms tumor in a horseshoe kidney. Using fluorescence in situ hybridization (FISH) in cell lines from patients with aniridia, Fantes et al. (1992) found that the candidate aniridia gene is deleted, supporting the murine Pax6 homolog as a strong candidate for the AN gene. Jordan et al. (1992) analyzed the PAX6 gene in cell lines from 2 cases of sporadic aniridia and identified a 2-bp insertion (607108.0001) in one and deletion of an exon (607108.0002) in the other. Hanson et al. (1993) described 4 point mutations in the PAX6 gene (607108) in aniridia patients, both sporadic and familial. They suggested that the frequency at which PAX6 mutations are found is an indication that lesions in PAX6 account for most cases of aniridia. Glaser et al. (1994) analyzed the PAX6 gene in a family with 3 distinct ocular phenotypes, and identified 2 different mutations: the mother, who had aniridia, was heterozygous for an R103X mutation (607108.0005), whereas the father, who had congenital cataracts and late-onset corneal dystrophy, was heterozygous for an S353X mutation (607108.0006). Their severely affected daughter, who had microcephaly, choanal atresia, and bilateral anophthalmia, was compound heterozygous for both mutations. Martha et al. (1995) found 4 different mutations in PAX6 in 1 sporadic and 5 familial cases of aniridia: a previously reported mutation and 3 novel ones. In a family with an affected 32-year-old woman and a 10-year-old daughter, the mother had bilateral erosion of the cornea and blood vessels on the corneas with bilateral cataracts and also had very thin irides (see 607108.0008). In another family with affected father and son, the father had aniridia, glaucoma, cataracts, and macular agenesis (see 607108.0009). In yet another family with affected mother and daughter, the mother but not the daughter also had anosmia (see 607108.0010). In all 6 of the aniridia cases, the mutations were predicted to generate incomplete PAX6 proteins and supported the theory that aniridia is caused by haploinsufficiency of PAX6. Axton et al. (1997) screened DNA from 12 aniridia patients for PAX6 mutations and found a total of 10 mutations from 5 familial and 5 sporadic cases. Mutations were not found in the DNA from 2 patients without a family history. All 10 mutations found resulted in functional haploinsufficiency. Prosser and van Heyningen (1998) reviewed PAX6 mutations. They commented that no locus other than 11p13 has been implicated in aniridia and that PAX6 is clearly the major, if not the only, gene responsible. Prosser and van Heyningen (1998) commented that in a gene with such extraordinarily high sequence conservation throughout evolution, there should be undiscovered missense mutations. These might be associated with unidentified phenotypes. They pointed out that olfactory system anomalies, cerebellar coordination problems, or pancreatic malfunction might be expected and that some mild mutations might give rise to a viable recessive phenotype, most likely in consanguineous families. In a mother and 2 sons who had aniridia, ptosis, and slight to moderate mental retardation, Malandrini et al. (2001) identified a missense mutation in the PAX6 gene (S119R; 607108.0023). The sons also had horizontal nystagmus, behavioral changes, and diffuse hypotonia. Brain MRI in all 3 patients were normal. The authors suggested that the missense mutation was responsible for both aniridia and ptosis, and possibly also for the observed cognitive dysfunction in this family. In a boy with partial aniridia of the left eye presenting as a pseudocoloboma, Morrison et al. (2002) identified heterozygosity for a missense mutation in the PAX6 homeodomain (R242T; 607108.0022). There was no family history of congenital eye malformation. The right eye of the patient was completely normal, and the mutation was subsequently identified in blood DNA from his phenotypically normal mother, suggesting low penetrance. Molecular analysis by D'Elia et al. (2006) revealed that the DNA-binding properties of the R242T homeodomain and the paired domain were not altered; however, the mutation reduced sensitivity to trypsin digestion, resulting in increased mutant protein levels. D'Elia et al. (2006) suggested that the R242T phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage (Schedl et al., 1996). Atchaneeyasakul et al. (2006) described the ophthalmic findings and mutation analyses of the PAX6 gene in 10 Thai aniridia patients from 6 unrelated families. Seven patients developed cataracts and 6 patients developed glaucoma. Mutation analysis demonstrated 4 different truncating mutations, 2 of which were de novo. All mutations resulted in loss of function of the PAX6 protein. Atchaneeyasakul et al. (2006) concluded that their data confirmed inter- and intrafamilial variable phenotypic manifestations of which the underlying mechanisms might be haploinsufficiency or dominant-negative mutations. In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygous mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had neurofibromatosis type I (NF1; 162200) with the typical eye defects of retinal fibroma, optic nerve glioma, and gross Lisch nodules on the iris; in addition, although her eyes were of normal size, she had small corneas, as well as cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation, had initially been diagnosed with Leber congenital amaurosis (LCA; see 204000), but also had features atypical of LCA, including bilateral mild microphthalmia, mild microcornea, and iridocorneal synechiae (see MCOPS5, 610125). Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. - Position Effect Fantes et al. (1995) studied 2 aniridia pedigrees in which the disease segregated with chromosomal rearrangements that involved 11p13 but did not disrupt the PAX6 gene. They isolated YAC clones that encompass the PAX6 locus and found that, in both pedigrees, the chromosomal breakpoint is at least 85 kb distal to the 3-prime end of PAX6. In addition, the open reading frame of PAX6 was apparently free of mutations. Fantes et al. (1995) proposed that the PAX6 gene on the rearranged chromosome 11 is in an inappropriate chromatin environment for normal expression, and therefore that a 'position effect' is the underlying mechanism of the anomaly in these families. Crolla et al. (1996) described another case which also suggested position effect: sporadic aniridia with a translocation t(7;11). By fluorescence in situ hybridization they showed that the breakpoint in 11p13 lay between the PAX6 locus and a region approximately 100 kb distal to PAX6. No detectable deletion was found within PAX6, suggesting that the aniridia may have resulted from the distal chromatin domain containing either enhancers or regulators. Position effect variegation was reviewed by Karpen (1994). Lauderdale et al. (2000) reported 2 submicroscopic de novo deletions of 11p13, located more than 11 kb from the 3-prime end of PAX6, that caused sporadic aniridia in unrelated patients. Clinical manifestations were indistinguishable from cases with chain-terminating mutations in the coding region. Using human-mouse retinoblastoma somatic cell hybrids, the authors showed that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Their findings suggested that remote 3-prime regulatory elements are required for initiation of PAX6 expression. In a 13-year-old boy with aniridia, autism, and mental retardation, Davis et al. (2008) identified a 1.3-Mb deletion approximately 35 kb distal to the last exon of PAX6; the authors noted that the deletion included the 3-prime enhancer regions characterized by Lauderdale et al. (2000) as well as 6 neighboring genes (ELP4, 606985; DPH4, 611072; DCDC1, 608062; DCDC5, 612321; MPPED2; and IMMP1L, 612323). The mutation was presumably inherited from the mother, who had aniridia as well as depression, anxiety, and social awkwardness; DNA was not available for analysis. The unaffected father did not carry the deletion. Crolla and van Heyningen (2002) studied 77 patients with aniridia, referred for cytogenetic analysis predominantly to assess Wilms tumor risk, by FISH using a panel of cosmids encompassing the aniridia-associated PAX6 gene, the Wilms tumor predisposition gene WT1 (607102), and flanking markers in distal chromosome 11p13. Thirty patients were chromosomally abnormal. Cytogenetically visible interstitial deletions involving 11p13 were found in 13 patients, 11 of which included WT1. A further 13 patients had cryptic deletions detectable only by FISH, 3 of which included WT1. Six of these, with deletions less than 500 kb, shared a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4 (606985). Two of these 6 patients were mosaic for the deletion. The remaining 4 patients had chromosomal rearrangements. The proportion and spectrum of chromosome anomalies in 4 of 14 (28.5%) familial and 26 of 63 (41%) sporadic cases were not significantly different. An unexpectedly high frequency of chromosomal rearrangements was associated with both sporadic and familial aniridia in this cohort.