aniridia means  without iris  in greek . however , this disorder is panocular , taking its name from the noticeable iris hypoplasia observed in most cases . this anatomical defect ranges from an almost complete absence of the iris with an enlarged and irregular pupil mimicking a coloboma to small slit - like defects in the anterior layer , which can be detected only by transillumination slit lamp biomicroscopy . the aforementioned clinical feature is associated with foveal hypoplasia resulting in reduced visual acuity that is almost always present , as well as with early onset nystagmus . in addition , such progressive corneal problems are often complicated by the presence of punctate erosion , corneal opacification , and keratopathy2 ) . aniridia is caused by mutations in the paired box gene-6 ( pax6 ) , which is essential for eye development3 ) . the wilms tumor , aniridia , genital abnormalities , and mental retardation ( wagr ) syndrome is a representative syndromic form of aniridia , and is caused by contiguous gene deletion of both pax6 and the adjacent wilms tumor 1 ( wt1 ) gene5 ) . in the current study , we conducted mutational analysis of the pax6 gene in familial cases of autosomal dominant congenital aniridia and found premature termination of pax6 protein translation . we found a family , in which four members in three consecutive generations were affected by congenital aniridia ( fig . peripheral blood genomic dna was obtained from 6 members of the family ( i-2 , ii-1 , ii-2 , ii-3 , iii-1 , and iii-2 ) . this study was approved by the ethics committee of jeju national university hospital and seoul national university hospital , and was conducted in accordance with the declaration of helsinki . written consent was obtained for every subject after the nature of the study was explained . the index case was an 18-month - old girl ( subject iii-2 in the pedigree ) . the patient was born via caesarean section at full term gestation and her birth weight was 3.6 kg ( 50th75th percentiles ) . bilateral aniridia , nystagmus , and foveal hypoplasia were detected at birth . at the age of 18 months , her weight and height were 10.2 kg and 79.7 cm ( 10th25th percentiles ) , respectively . a development screening test using the korean - ages and stages questionnaires for infant / toddler health examinations through the national health insurance co. represented the normal developmental milestones . subject ii-2 , currently 34 years old , had bilateral aniridia with nystagmus since birth and secondary glaucoma , lens subluxation , and cataracts that had developed subsequently . she underwent cataract surgeries at the age of 17 and 33 years in both eyes , respectively . she also underwent glaucoma surgery with an ahmed valve to reduce high intraocular pressure in the right eye at the age of 34 years . currently , her visual acuity is 0.15 and 0.1 in the right and left eyes , respectively . mutation analysis through direct sequencing of the pax6 gene revealed a heterozygous nonsense mutation in exon 7 ( c.365c > a ) causing premature termination at the 122nd codon of pax6 protein , in all the available affected members ( fig . it is known that almost all patients with aniridia have mutations in the pax6 gene . the resultant pathogenic mechanism is haploinsufficiency of pax6 protein , i.e. , loss of function of one allele resulting in a 50% reduction of overall protein activity6 ) . however , a heterozygous mutation in the pax6 cis - regulatory element ( simo ) that resides in an intron of the adjacent elp4 gene has been reported in one case7 ) . in our study , a nonsense mutation p.ser122 , was detected in exon 7 of the pax6 gene in a family with autosomal dominant congenital aniridia . to our knowledge , the p.ser122 mutation in exon 7 of the pax6 gene has not been previously described in korea , but one case has been reported elsewhere8 ) . at present , a total of 417 substitution variants in pax6 , mostly with mutations in exons 5 , 6 , and 9 , have been identified . among the mutations , there are 33.3% nonsense and 17.7% missense mutations , respectively ( pax6 mutation database , http://lsdb.hgu.mrc.ac.uk/home.php?select_db=pax6 ) . there is no definite correlation between the clinical phenotype and the location of pax6 mutations9 ) . however , in korean patients with congenital aniridia , pax6 mutations have been reported more frequently in exons 7 and 8101112 ) . furthermore , over 90% of the mutations in korean patients were truncating mutations , including nonsense mutations ( 50% ) , splicing errors , deletion and insertion mutations , while missense mutations accounted for 7% of the mutations11 ) . glaucoma , which is an important factor for visual acuity in patients with aniridia , generally develops in late childhood , and is rare in infants1013 ) . therefore , routine ophthalmologic examination for the detection of glaucoma is important to maintain good vision throughout life . in this report , subject iii-2 , who was 18 months old , did not have glaucoma and cataract , while subject ii-2 had to undergo ocular surgery several times due to cataract and glaucoma . in addition , in infant patients with aniridia , it may be difficult to differentiate between isolated aniridia and the wagr syndrome . in young individuals with wagr syndrome , wilms tumor and intellectual disability may not be evident and external genitalia are often normal in female patients14 ) . in order to determine who are at high risk for wilms tumor , our familial aniridia cases show differences in the severity of the phenotype according to age . genetic analysis is important for confirming pax6 mutations in congenital aniridia and for determining whether an affected member is at a high risk of developing a wilms tumor . furthermore , differential diagnosis is needed because aniridia can be associated with a syndromic form in case of a wt1 gene mutation , while epl4 gene mutations also cause aniridia even though the most common cause for isolated aniridia is a pax6 gene mutation15 ) . therefore , case collection is important for correlation between the genotype and phenotype of congenital aniridia in korea .
congenital aniridia is a rare ocular malformation that presents with severe hypoplasia of the iris and various ocular manifestations . 
 most cases of congenital aniridia are known to be related to mutations in the paired box gene-6 ( pax6 ) , which is an essential gene in eye development . 
 herein , we report a familial case of autosomal dominant congenital aniridia with four affected members in 3 consecutive generations and describe the detailed ophthalmologic findings for one of these members . as expected , mutational analysis revealed a nonsense mutation ( p.ser122 * ) in the pax6 gene . 
 thus , our findings reiterate the importance of pax6 mutations in congenital aniridia .