Corneal Abnormalities in Congenital Aniridia: Congenital Central Corneal Opacity Versus Aniridia-Associated Keratopathy

Corneal Abnormalities in Congenital Aniridia: Congenital Central Corneal Opacity Versus Aniridia-associated Keratopathy

HYO KYUNG LEE, MEE KUM KIM, AND JOO YOUN OH

PURPOSE: To clinically characterize and compare 2 ONGENITAL ANIRIDIA IS A DISORDER CHARACTER- types of corneal abnormalities in patients with congenital ized by hypoplasia or absence of the iris at birth. aniridia: (1) congenital central corneal opacity from birth Because it is caused by the haploinsufficiency of CPax6 1,2 (CCO) and (2) aniridia-associated keratopathy (AAK) the gene, which is crucial for eye development, that develops progressively with age. congenital aniridia is often associated with a variety of DESIGN: Retrospective cohort study. ocular malformations including abnormalities in the METHODS: Medical records of Korean patients who cornea, anterior chamber angle, lens, optic nerve, and were diagnosed with congenital aniridia at Seoul National retina.3–6 Corneal abnormalities in congenital aniridia University Hospital between 1991 and 2016 were may manifest as dense central corneal opacification reviewed. Prevalence of corneal abnormalities (CCO present at birth, that is, congenital central corneal and AAK), other ocular and systemic comorbidities, opacity (CCO).4,7,8 Alternatively, the central cornea is severity of AAK depending on the age, logarithm of the clear at birth, but corneal lesions start in the corneal minimum angle of resolution (logMAR) visual acuities, periphery with conjunctival tissue overriding the limbus and types and results of surgical intervention were and progressively grow onto the peripheral and central collected. cornea. This condition is known to be caused by a 9–12 RESULTS: Among a total of 275 eyes (138 patients), deficiency in the limbal stem cell niche and termed as 13% (35 eyes, 20 patients) had CCO and 25% (68 aniridia-associated keratopathy (AAK).13,14 eyes, 35 patients) developed AAK. The AAK became Congenital aniridia is a rare disease with a prevalence of prominent at a mean of 21.6 years of age, and the severity 1:64 000 to 1:96 000.4,15 Therefore, there have been very progressed with age. Glaucoma was more prevalent in few large-scale studies on corneal abnormalities in patients aniridia patients with CCO (74%), compared to those with congenital aniridia although corneal abnormalities with AAK (37%) (P [ .0003). Cataract frequently are commonly associated with congenital aniridia. In this occurred in patients with AAK (78%), who required study, we investigated the incidence, clinical characteris- cataract surgeries at mean 26.6 years. The logMAR visual tics, and progression of corneal abnormalities in 275 eyes acuity was worse in patients with CCO (2.04 ± 0.71) of 138 Korean patients with congenital aniridia. Specif- than in those with AAK (1.29 ± 0.62) (P < .0001). ically, we herein identified and characterized 2 distinct Penetrating keratoplasty was performed in 6 eyes with types of corneal abnormalities (CCO and AAK) and CCO, and the graft survival was 33.3% during mean compared clinical characteristics and visual prognosis be- 45 months of follow-up (range 14–79 months). tween the 2 groups. CONCLUSIONS: In total, 13% of aniridia patients had CCO at birth, while 25% progressively developed clinically significant AAK with age. The visual outcome was worse in patients with CCO than in those with METHODS AAK. (Am J Ophthalmol 2018;185:75–80. Ó 2017 Elsevier Inc. All rights reserved.) THIS IS A RETROSPECTIVE REVIEW OF PATIENTS WHO WERE diagnosed with congenital aniridia at Seoul National Uni- versity Hospital, Seoul, South Korea, from August 2, 1991 to July 8, 2016. The retrospective review of medical charts was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 1707-175-874). Supplemental Material available at AJO.com. Medical records and anterior segment photographs were Accepted for publication Oct 22, 2017. From the Department of Ophthalmology and the Laboratory of Ocular reviewed for patient demographics (age, sex), laterality of Regenerative Medicine and Immunology, Biomedical Research Institute, the disease, systemic comorbidities (congenital heart Seoul National University Hospital, Seoul, South Korea. anomaly, hearing impairment, Wilms’ tumor, cryptorchi- Inquiries to Joo Youn Oh, Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110- dism, or mental retardation), combined corneal abnormal- 744, South Korea; e-mails: [email protected]; [email protected] ities (CCO, AAK, stage of AAK), other ocular

0002-9394/$36.00 © 2017 ELSEVIER INC.ALL RIGHTS RESERVED. 75 https://doi.org/10.1016/j.ajo.2017.10.017 TABLE 1. Stage of Aniridia-associated Keratopathy TABLE 2. Demographics and Ocular Characteristics of Patients With Congenital Aniridia Stage Characteristics Demographic Parameter Result 0 or 1 Clear cornea or mild cloudiness in the periphery/limbus with vessel ingrowth No. of eyes/patients 275/138 2 Opacifications with ingrowth of vessels, not Patient sex, female:male (n) 73:65 disturbing visual acuity Age at final follow-up (y), mean 6 SD 19.3 6 15.6 3 Difficulties to investigate retina because of Ocular comorbidities, no. of eyes (no. of patients, %) marked central keratopathy with opacification of the corneal stroma and Foveal hypoplasia 260 (130, 94.5%) centripetal ingrowth of vessels, reduced Nystagmus 220 (110, 80.0%) visual acuity Cataract 164 (87, 59.6%) 4 Opacification of entire cornea Glaucoma 63 (33, 22.9%) 5 End stage, thick opaque pannus, fully Spontaneous retinal detachment 6 (5, 2.2%) vascularized cornea Corneal opacities 103 (55, 37.4%) CCO 35 (20, 12.7%) With AAK 19 (13, 6.9%) comorbidities (foveal hypoplasia, nystagmus, cataract, Without AAK 16 (11, 5.8%) glaucoma, retinal detachment), logarithm of the minimum AAK without CCO 68 (35, 24.7%) angle of resolution (logMAR) visual acuities, and ocular Visual outcome (logMAR), mean 6 SD (range) surgeries (cataract extraction, glaucoma surgery, corneal transplantation). Furthermore, corneal abnormalities Best-ever visual acuity 1.17 6 0.54 (0.05–3) 6 were divided into 2 distinct subgroups of corneal opacities: Visual acuity at last follow-up 1.21 0.66 (0–3) (1) dense central corneal opacity present from birth Ocular surgeries, no. (%) of eyes/age at surgery (y) (mean 6 SD)a

(CCO), as determined by anterior segment photographs Cataract surgery 50 (18.2%)/21.3 6 14.4 taken within the first month of birth, and (2) progressive Glaucoma surgery 18 (6.6%)/8.6 6 17.5 conjunctivalization and opacification from the periphery Penetrating keratoplasty 6 (2.2%)/1.5 6 1.7 to the central cornea (AAK). The severity of AAK was graded clinically into 5 stages (range 0–5) as previously sug- AAK ¼ aniridia-associated keratopathy; CCO ¼ central gested (Table 1),13 and >_ stage 2 AAK was defined as AAK corneal opacity at birth; logMAR ¼ logarithm of the minimum angle of resolution. and analyzed for data acquisition because stage 1 AAK was a difficult to differentiate from stage 0 in our medical records. If repetitive surgeries were done in a patient, the age at the first surgery was included. Data are presented as mean 6 SD. GraphPad Prism soft- ware (GraphPad, La Jolla, California, USA) was used for statistical analysis. Comparisons of qualitative variables in 6 eyes (2.2%). Cataract surgeries were performed in 50 were made by Pearson x2 test or Fisher exact test, and eyes (18.2%) at a mean age of 21.3 years, and glaucoma sur- logMAR visual acuities were compared between 2 groups geries were done in 18 eyes (6.6%) at a mean age of 8.6 by 2-tailed Student t test. The correlation between 2 vari- years. ables was tested by using Pearson r coefficient and 2-tailed Overall, clinically significant corneal abnormalities were P value. A P value < .05 was considered statistically signif- found in 103 eyes of 55 patients (37.4%). Thirty-five eyes of icant. 20 patients (12.7%) had dense CCO. Sixty-eight eyes of 35 patients (24.7%) did not have CCO at birth, but gradually developed AAK. The best-ever visual acuity was 1.17 6 RESULTS 0.54 logMAR (range: 0.05–3 logMAR), and the visual acuity at the last follow-up was 1.21 6 0.66 logMAR (range: 0– PATIENT DEMOGRAPHICS AND OCULAR CHARACTERIS- 3 logMAR). TICS: A total of 275 eyes of 138 patients with congenital aniridia were enrolled in the study. Demographic data CORNEAL OPACITIES: CENTRAL CORNEAL OPACITY VS and ocular characteristics of patients are summarized in ANIRIDIA-ASSOCIATED KERATOPATHY: Out of 275 eyes Table 2. Seventy-three patients were female and 65 male. of 138 patients having congenital aniridia, 35 eyes of 20 pa- The mean age at the last follow-up was 19.3 years. The tients (12.7%) had CCO, and 68 eyes of 35 patients most common ocular findings combined with aniridia (24.7%) developed AAK during the follow-up (Figure 1). were foveal hypoplasia and nystagmus, which were present Among 35 eyes with CCO, progressive conjunctivalization in 260 (94.5%) and 220 (80.0%) eyes, respectively. Cata- from the corneal periphery, characteristic of AAK, was ract was combined in 164 eyes (59.6%) and glaucoma in observed in 19 eyes (54.3%) during the follow-up 63 eyes (22.9%). Spontaneous retinal detachment occurred (Table 2). This is significantly higher compared to the

76 AMERICAN JOURNAL OF OPHTHALMOLOGY JANUARY 2018 FIGURE 1. Representative photographs of corneal opacities combined with congenital aniridia. (Left) Central dense corneal opacification present from birth. (Center, Right) Anterior segment photographs of the same patient with aniridia-associated keratopathy at the age of 19 years (Center) and 22 years (Right). Note that keratopathy progressed from the periphery to the center of the cornea with time. prevalence of AAK in aniridia eyes without CCO (68 of 240 eyes, 28.3%, Table 2)(P ¼ .002). Demographics, TABLE 3. Characteristics of Congenital Aniridia Patients ocular characteristics, and visual outcome in CCO and Combined With Aniridia-associated Keratopathy or AAK patients were presented and compared in Table 3. Congenital Central Corneal Opacity CCO was bilateral in 15 patients and unilateral in 5 patients, whereas AAK was bilateral in 33 patients and uni- Characteristics AAKa CCOb P Value lateral in 2 (P ¼ .0857). CCO equally involved both No. of eyes/no. of patients 68/35 35/20 sexes (female:male ¼ 10:10), and AAK predominantly Bilateral:unilateral 33:2 15:5 .0857 involved female (female:male ¼ 22:13) (P ¼ .3524). The Sex (female:male) 22:13 10:10 .3524 prevalence of combined systemic congenital disorders was Age at diagnosis (y), 21.6 6 16.5 At birth not different between the 2 groups (P ¼ .7311). mean 6 SD Nystagmus was frequently found in aniridia patients both Age at final visit (y), 30.4 6 17.6 9.5 6 6.0 6 with CCO (71.4%) and with AAK (82.4%). Glaucoma was mean SD 6 6 < more prevalent in aniridia patients with CCO, compared to Visual acuity at last follow-up 1.29 0.62 2.04 0.71 .0001 (logMAR), mean 6 SD those with AAK: 26 eyes out of 35 (74.3%) having CCO Systemic comorbidities, no. 7 (20.0%) 3 (15.0%) .7311 and aniridia were diagnosed with glaucoma, while 25 of (%) of patients 68 eyes (36.8%) having AAK and aniridia developed glau- Ocular comorbidities, no. (%) of eyes coma (P ¼ .0003). Thirteen eyes (37.1%) with aniridia and Nystagmus 56 (82.4%) 25 (71.4%) .2001 CCO underwent glaucoma surgeries at the age of 0.3 6 0.3 Cataract 53 (77.9%) years, and 4 eyes with AAK (5.9%) had glaucoma surgeries Glaucoma 25 (36.8%) 26 (74.3%) .0003 at the age of 30.4 6 21.8 years (P ¼ .0049). The presence of Ocular surgeries, no. (%) cataract was difficult to examine in aniridia patients with of eyes CCO owing to dense central stromal opacity. However, Cataract surgery 27 (39.7%) 6 the development of cataract was a prominent feature in pa- Age at cataract surgery 26.6 11.9 6 tients with AAK, because 53 out of 68 eyes with AAK (y), mean SD Glaucoma surgery 4 (5.9%) 13 (37.1%) (77.9%) developed cataract during the follow-up. Cataract Age at glaucoma 30.4 6 21.8 0.3 6 0.3 .0049 surgeries were performed in 27 eyes (39.7%) with AAK at surgery (y), mean 6 SD 6 the age of 26.6 11.9 years, an indication that cataract PK 6 (74.3%) became visually significant in AAK patients at a mean of Age at PK (y), 1.5 6 1.7 26.6 years of age. mean 6 SD The visual prognosis was significantly worse in patients with CCO, compared to those with AAK. The best- AAK ¼ aniridia-associated keratopathy; CCO ¼ central ¼ corrected logMAR visual acuities at last follow-up were corneal opacity; logMAR logarithm of the minimum angle of resolution; PK ¼ penetrating keratoplasty. 2.04 6 0.71 in CCO patients and 1.29 6 0.62 in AAK pa- a P < AAK group includes patients who had clear central cornea at tients ( .0001). birth but progressively developed AAK. bIn CCO group, the central corneal opacity was present from AGE-DEPENDENT PROGRESSION OF ANIRIDIA- birth. ASSOCIATED KERATOPATHY: Out of 240 aniridia eyes without CCO, 172 (71.7%) had a mild stage of AAK (stage <_1); 43 (17.9%) were stage 2 and 14 (5.8%) stage 3 The first diagnosis of >_ stage 2 AAK was made by the age (Table 4). The visual acuities deteriorated as the stage of 25 years in 70.6% of patients (Figure 2). The mean age at progressed (Table 4). the time of >_ stage 2 AAK detection was 21.6 years, and the

VOL. 185 CORNEAL ABNORMALITIES IN CONGENITAL ANIRIDIA 77 TABLE 4. Age and Visual Acuity of Aniridia Patientsa Depending on the Stage of Aniridia-associated Keratopathyb

Stage Number (%) of Eyes Age at Final Stage Determination (y) Age at Last Visit (y) VA at Last Visit (logMAR)

0 or 1 172 (71.7%) - 18.1 6 14.0 (2–64) 1.06 6 0.58 (0.05–3.00) 2 43 (17.9%) 17.0 6 13.8 (0–59) 25.1 6 14.8 (7–65) 1.08 6 0.44 (0.22–2.00) 3 14 (5.8%) 35.7 6 16.4 (15–63) 42.3 618.4 (19–73) 1.47 6 0.74 (0.52–3.00) 4 9 (3.8%) 35.2 6 15.1 (20–54) 40.8 6 17.7 (23–62) 1.89 6 0.67 (1.00–3.00) 5 2 (0.8%) 21.0 (21) 24.0 (24) 1.46 6 0.34 (1.22–1.70) Total 240 21.7 6 16.1 (2–73) 1.15 6 0.60 (0.05–3.00)

AAK ¼ aniridia-associated keratopathy; logMAR ¼ logarithm of the minimum angle of resolution; VA ¼ visual acuity. Data are mean 6 SD (range), unless otherwise speciﬁed. aExcluded were the data from aniridia patients with central corneal opacity from birth. bAAK group includes patients who had clear central cornea at birth but progressively developed AAK.

FIGURE 2. Cumulative number of patients depending on the age when clinically evident aniridia-associated keratopathy (stage 2 or higher) was first detected. Approximately 70.6% of patients were first diagnosed with ‡stage 2 aniridia-associated keratopathy by 25 years of age. The mean age at the detection FIGURE 3. Correlation between the stage of aniridia- of ‡stage 2 aniridia–associated keratopathy was 21.6 ± 16.5 associated keratopathy and the age of a patient when each stage years, and the median age was 18.5 years. was determined. A positive correlation was significant (R [ 0.2596, P < .0001). R represents Pearson r coefficient.

median age was 18.5 years (Figure 2). These findings sug- (1 eye), and re-epithelialization failure leading to graft gest that AAK progressively developed and became clini- opacification (1 eye) (Table 5). cally evident in the second and third decades of life in patients with congenital aniridia (Figure 2). Moreover, the stage of AAK increased along with the age of patients (Table 4). Similarly, a significant positive correlation was DISCUSSION found between the age of patients and the stage of AAK (R ¼ 0.2596, P < .0001) (Figure 3). Together, these results OUR DATA DEMONSTRATE THAT CORNEAL OPACITIES WERE indicate that AAK deteriorated with age. present in 37.4% of congenital aniridia patients in a form of either CCO (12.7%) or clinically evident >_stage 2 AAK CORNEAL TRANSPLANTATION FOR CENTRAL CORNEAL (24.7%). These 2 types of corneal abnormalities combined OPACITY IN ANIRIDIA PATIENTS: Penetrating kerato- with congenital aniridia were clinically distinct in several plasty (PK) was performed at mean 1.5 6 1.7 years of age ways. First, the onset of CCO was at birth, whereas AAK in 6 eyes with CCO in aniridia patients. A detailed descrip- developed in the teens and early 20s. Second, CCO mani- tion of each patient is shown in Table 5. The grafts survived fested as dense opacification in the central cornea. By in 2 eyes (33.3%) during the mean 45.0 6 24.2 months of contrast, in AAK, fibrovascular opaque pannus started in follow-up (range 14–79 months), and the median survival the corneal periphery and progressed over the corneal sur- time was 37 months (Figure 4). The causes of graft failure face to involve the central cornea, which is consistent with included corneal infection (2 eyes), endothelial rejection limbal stem cell deficiency.9–14 Third, unilateral cases were

78 AMERICAN JOURNAL OF OPHTHALMOLOGY JANUARY 2018 TABLE 5. Summary of Aniridia Patients who Underwent Penetrating Keratoplasty for Congenital Central Corneal Opacity

Graft Failure (F) or Cause for Rejection-free Survival Ocular 3Other Ocular Surgery Patient No. Sex Laterality Age at PK Survival (S) graft failure Time (mo) Comorbidities (Age)

1 M OD 4 years F Infection 37 CG, C, N TLE þ Ahmed (2 months) 2 M OS 2 years F Rejection 38 CG, C, N TLE þ Ahmed (2 months) 3 F OS 4 months F Infection 11 C, N Cataract surgery (2 years) 4 F OD 2 years S 51 CG, N Glaucoma surgery (1 year) 5 M OD 5 months S 23 C Cataract surgery (5 months) 6 F OD 10 months F Epithelialization 1 C, N Cataract surgery failure (10 months)

C ¼ cataract; CG ¼ congenital glaucoma; N ¼ nystagmus; PK ¼ penetrating keratoplasty; TLE ¼ trabeculectomy.

more common in aniridia patients with CCO (25% in CCO vs 5.7% in AAK), with borderline significance (P ¼ .0857). Fourth, aniridia patients with CCO were significantly associated with a higher rate of glaucoma, compared to those with AAK (74.3% vs 36.8%) (P ¼ .0003). Lastly, the visual outcome was worse in aniridia patients combined with CCO than in AAK patients (P < .0001). Central corneal opacity at birth is also a finding characteristic of Peters anomaly. Therefore, aniridia patients with CCO might represent a combination of 2 forms of anterior segment dysgenesis: Peters anomaly and aniridia. In our study, CCO equally involved male and female subjects, and 25% of cases were unilateral. These findings are similar to what has been previously reported in patients with Peters anomaly. A recent review of literature on Peters anomaly FIGURE 4. Kaplan-Meier survival curve of corneal grafts in revealed that 32.8% of cases were unilateral and the ratio aniridia patients with congenital corneal opacity. The graft sur- 7 between male and female was similar. Alternatively, vival rate was 33.3%, and the median survival time was CCO may be the early presentation of stage 4/5 AAK. 37 months. Careful examination of the limbus and corneal epithelium would be needed in aniridia patients with CCO to differentiate the combined Peters anomaly from early, advanced AAK. In addition to corneal opacities, there were other ocular Unlike AAK of later onset, CCO can cause sensory abnormalities commonly associated with aniridia. In our deprivation amblyopia. Therefore, early and proper man- patients with congenital aniridia, cataract was present in agement is important for vision in patients with aniridia 59.6% and glaucoma in 22.9%. Cataract and glaucoma sur- combined with CCO. However, the graft survival rate after geries were performed at a mean of 21.3 and 8.6 years, PK was 33.3% in our patients, which was lower than the respectively. These findings suggest that clinically signifi- success rate of PK (53%w87.5%) previously reported in cant cataract and glaucoma developed in the first and sec- patients with Peters anomaly.7,16 The poor surgical ond decades of life in aniridia patients. Similarly, AAK was outcome may be the result of combined limbal deficiency of later onset, and its severity progressed with age, as shown in aniridia patients or related to severe genetic defects as in our study and others.13,17 Hence, regular surveillance for reflected by co-presence of CCO and aniridia. Further ef- late-onset ocular abnormalities such as cataract, glaucoma, forts to improve the graft success and visual outcome in and AAK would be required for patients with congenital aniridia patients with CCO would be necessary. aniridia.

VOL. 185 CORNEAL ABNORMALITIES IN CONGENITAL ANIRIDIA 79 The prevalence of keratopathy in aniridia patients analysis. The overall prevalence of AAK including stage (37.4%) was low in our study in comparison to previous re- 1 is, therefore, inconclusive in the present study. Another ports, because the prevalence of AAK has been reported possibility is that keratopathy might have not yet mani- between 46% and 100%.5,6,18–20 There are several fested in our patients. In our study, the mean and median possibilities to account for this difference. One is that age of aniridia patients at the time of detection of >_stage signs and symptoms of keratopathy might have been 2 AAK was 21.6 and 18.5 years, respectively, and the stage undetected in early stages in our patients, leading to of AAK deteriorated with age. Therefore, it is possible that underestimation of the prevalence of AAK. Because the prevalence of AAK would increase in our population in AAK has an insidious onset and progresses from the the longer follow-up. periphery to the center, the visual acuity is not severely In conclusion, we herein characterized and compared 2 affected until the terminal stage, when the opacity types of corneal opacities combined with congenital aniri- involves the central cornea. Moreover, in our hospital, dia. They have clinically distinct features in terms of dis- aniridia patients have been regularly followed up by ease onset, progression, ocular comorbidity and its pediatric ophthalmologists and are referred to corneal severity, and visual outcome. Our study involving a large specialists once clinically evident AAK develops. number of patients with congenital aniridia has clinical im- Therefore, it is possible that early-stage AAK might have plications in that it provides clinicians with longitudinal been overlooked in our patients. To exclude this bias in data that would help evaluate and manage patients with the study, we included AAK of stage 2 or higher for this rare and challenging disease.

FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO ﬁnancial disclosures: Hyo Kyung Lee, Mee Kum Kim, and Joo Youn Oh. All authors attest that they meet the current ICMJE criteria for authorship.

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