Journal List > J Korean Ophthalmol Soc > v.57(9) > 1010400

Hahn, Kim, and Lim: Clinical Features and Molecular Characteristics of Korean Patients with Congenital Aniridia

Abstract

Purpose

To introduce clinical features and molecular characteristics of Korean patients with congenital aniridia.

Methods

Patients with iris hypoplasia were diagnosed clinically as congenital aniridia and were included in the study. Best corrected visual acuity (BCVA) and associated ocular abnormalities (including severity of iris hypoplasia, nystagmus, keratopathy, and foveal hypoplasia), and findings in optical coherence tomography were analyzed. PAX6 analysis, multiplex ligation-depend-ent probe amplification (MLPA), genomic molecular karyotyping, and candidate gene sequencing were performed to detect genetic abnormalities.

Results

28 patients from 18 families were included in the study. BCVA varied from hand motion to 20/25. No manifest nystagmus was found in 3 patients, but the rest of the patients had pendular horizontal nystagmus. Keratopathy was found in 23 patients, cataracts in 12 patients, and glaucoma in 4 patients. All patients had foveal hypoplasia, including one case with a subtle phenotype. The PAX6 mutation was detected in 13 families out of 18;2 (p.Trp162Leufs*38, p.Gly409Arg) were novel, 3 families had the miss ensemutation, and 3 families had alargedeletion in the PAX6 gene.

Conclusions

This study adds 2 novel PAX6 mutations related to congenital aniridia to those previously reported. Congenital aniridia is a serious, sight-threatening ocular malformation, but central vision and the degree of iris hypoplasia were highly variable. The PAX6 mutation was detected in 72% of the patients in this study, and there were no specific clinical features differentiating aniridia with and without PAX6 mutations.

References

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Figure 1.
Patients with PAX6 mutation. (A-C) Case 10B carries a run-on mutation of PAX6. (A) Anterior segment image showing iris hypoplasia, about 20% of iris remnants, but no significant keratopathy and cataract. (B) Fundus image showing marked foveal hypoplasia. (C) Loss of foveal depression is seen in optical coherence tomography. (D, E) Case 9B carries a run-on mutation of PAX6. (D) Anterior segment image showing subtle iris hypoplasia. (E) But fundus image demonstrates moderate degree of foveal hypoplasia.
jkos-57-1441f1.tif
Figure 2.
Patients without PAX6 mutation. (A-C) Case 18. (A) Anterior segment image showing mild degree of iris hypoplasia. (B) Subtle foveal hypoplasia was seen in fundus image. (C) Near normal foveal depression was also demonstrated in optical coherence tomography. (D-F) Case 17B. (D) Anterior segment image showing complete abscence of iris. (E) Fundus image showing moderate degree of foveal hypoplasia. (F) Loss of foveal depression was seen in optical coherence tomography.
jkos-57-1441f2.tif
Figure 3.
Familial patients with missense mutation of PAX6. (A, B) Case 8A. (A) Anterior segment image showing moderate degree of iris hypoplasia, peripheral corneal opacity and cataract. (B) Fundus image showing moderate degree of foveal hypoplasia. (C-E) Case 8B (mother of 8A). (C) Anterior segment image showing mild degree of iris hypoplasia and cataract, but no definite corneal opacity. (D) Fundus image showing moderate degree of foveal hypoplasia. (E) Optical coherence tomography also showing flat foveal contour.
jkos-57-1441f3.tif
Table 1.
PAX6 gene analysis in 18 probands
Case PAX6 mutation Consequence Exon/Intron Domain Status/Reference
1A c.128C>T p.Ser43Phe Exon 5 PD Previously reported17
2A c.399 + 1G>A (IVS3 [+1] G>A) Splice defect Intron 7 Linker Previously reported23
3 c.484_485insT p.Trp162Leufs*38 Exon 7 Linker Novel
4A c.622C>T p.Arg208Trp Exon 8 HD Previously reported24
5 c.683–9C>G (IVS8–9C>G) Splice defect Intron 8 HD Previously reported17
6 c.718C>T p.Arg240X Exon 9 HD Previously reported5
7 c.949C>T p.Arg317X Exon 11 PST Previously reported4
8A c.1225G>C p.Gly409Arg Exon 13 PST Novel
9A c.1268A>T p.X423Leu Exon 13 3' Untranslated Region Previously reported25
10A c.1268A>T p.X423Leu*15 Exon 13 3' Untranslated Region Previously reported25
11 Exon 1–4 deletion       MLPA kit P219
12 Whole exon deletion WAGR     MLPA kit P219
13 Whole exon deletion WAGR     MLPA kit P219
14A No mutation found        
15 No mutation found        
16 No mutation found        
17A No mutation found        
18 No mutation found        

PD = paired domain; HD = homeodomain; PST = proline-serine-threonine-rich domain; MLPA = multiplex ligation-dependent probe am-plification; WAGR = Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.

Table 2.
Phenotypic data of the 20 patients having PAX6 mutation
Case Age/ Sex Inheritance Mutation type BCVA Iris anomaly Nystagmus Foveal hypoplasia Keratopathy Others Severity
1A 0.4/F AD Missense FF Iris remnant, ∼70% ++ + +/− Ectropion uvea, corectopia Severe
1B 30/F Mother of 1A Missense 20/80 Iris remnant, ∼50% +++ + +++ Ectropion uvea, corectopia, cataract Moderate
2A 0.4/F AD Splice defect FF Thin rim of iris, ∼10% + + + Moderate
2B 30/F Mother of 2A Splice defect 20/80 Thin rim of iris, ∼10% + + ++ Cataract, glaucoma Moderate
3 3.5/F Sporadic Frameshift 20/200 Near-total absence of iris ++ ++ +/− Null zone nystagmus with face turn Severe
4A 25/F AD Missense 20/300 Iris remnant, ∼80% ++ + +++ Cataract, microcornea Severe
4B 54/F Mother of 4A Missense 20/100 Iris remnant, ∼80% + + ++ Microcornea Moderate
5 4/F Sporadic Splice defect 20/160 Iris remnant, ∼80% OD; thin rim, ∼20% OS +/− + + Ectropion uvea, corectopia Mild
6 3/F Sporadic Nonsense 20/400 Near-total absence of iris + ++ +   Severe
7 18/F Sporadic Nonsense 20/200 Thin rim of iris, ∼10% + + + Cataract Severe
8A 1/M AD Missense FF Iris remnant, ∼50% ++ ++ +++ Ectropion uvea, corneal opacity, cataract Severe
8B 42/F Mother of 8A Missense 20/160 Iris remnant, ∼80% ++ ++ + Cataract, glaucoma Severe
9A 3/M AD Run-on 20/400 Near-total absence of iris ++ ++ + Cataract Severe
9B 26/M Father of 9A Run-on 20/125 Near-full iris ++ ++ ++ Cataract Moderate
10A 2.5/M AD Run-on FF Iris remnant, ∼80% + ++ +/− Iridocorneal adhesion, hearing loss Severe
10B 9/F Sister of 10A Run-on 20/80 Iris remnant, ∼80% + ++ +/− High myopia, hearing loss Moderate
10C 43/M Father of 10A Run-on 20/100 Iris remnant, ∼80% + ++ + Cataract Moderate
11 0.5/M Sporadic Large deletion FF No iris ++ ++ Glaucoma Severe
12 0.5/F Sporadic Large deletion FF No iris ++ ++ WAGR Severe
13 0.3/M Sporadic Large deletion FF Near-total absence of iris ++ ++ +++ WAGR, cataract, glaucoma Severe

BCVA = best corrected visual acuity; AD = autosomal dominant; FF = fix and follow; +++ = severe; ++ = moderate; + = mild; +/− = very subtle or minimal; – = none; WAGR = Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.

Table 3.
Phenotypic data of the 8 patients without PAX6 mutation
Case Age/ Sex Inheritance BCVA Iris anomaly Nystagmus Foveal hypoplasia Keratopathy Others Severity
14A 2/F AD FF No iris +++ ++ Developmental delay Severe
14B 27/F Mother of 14A 20/200 Thin rim of iris, ∼5% +++ ++ ++ Cataract, optic atrophy Severe
15 5/F Sporadic 20/25 No iris +/− +   Very mild
16 4/M Sporadic 20/400 No iris ++ ++   Severe
17A 1/F AD FF Iris remnant, ∼80% ++ ++   Severe
17B 3/M Brother of 17A 20/200 No iris ++ ++ +/−   Severe
17C 31/F Mother of 17A 20/160 Near-total absence of iris ++ ++ ++ Cataract Severe
18 3/M Sporadic 20/200 Iris remnant, ∼80% +/− +/−   Mild

BCVA = best corrected visual acuity; AD = autosomal dominant; FF = fix and follow; +++ = severe; ++ = moderate; + = mild; +/− = very subtle or minimal; – = none.

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