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To describe the incidence, ocular findings, and systemic associations among a population-based cohort of children with coloboma.
The medical records of all pediatric (aged < 19 years) patients diagnosed with ocular coloboma from January 1, 1968, through December 31, 2007, as residents of Olmsted County, Minnesota were retrospectively reviewed.
Thirty-three children were newly diagnosed with ocular coloboma during the 40-year study period for an annual incidence of 2.4 per 100,000 residents < 19 years of age, or a prevalence of 1 in 2077 live births. The median age at diagnosis for the 33 subjects was 3.9 months (range, 2 days to 18.4 years), and 22 (67%) patients had unilateral involvement. Twelve (36%) patients had involvement of the anterior segment only, 13 (39%) of the posterior segment only, and 8 (24%) of both anterior and posterior segments. During a median ophthalmologic follow-up of 9.2 years (range, 13 days to 35.9 years), 19 (58%) had other ocular disorders including amblyopia in 11 (33%) and strabismus in 10 (30%). During a median medical follow-up of 16.8 years, 22 (67%) were diagnosed with a non-ocular disorder, including abnormal development in 12 (36%) and CHARGE syndrome in 4 (12%).
In this population-based study, ocular coloboma occurred in 1 in 2077 live births. More than half were diagnosed with an ocular disorder other than coloboma, including strabismus or amblyopia in approximately one-third of patients. Two-thirds of patients were diagnosed with a non-ocular disorder, including CHARGE syndrome in 1 in 8 patients.
Ocular coloboma is a rare congenital abnormality caused by defective embryogenesis. Most colobomas result from the failed closure of the embryonic or choroidal fissure during the 5th to 7th week of fetal life.1 Colobomas may involve any of the ocular structures, including the iris, zonules and ciliary body, choroid, retina, and optic nerve.2 Colobomas are commonly associated with visual loss for which there is little treatment other than amblyopia management.3 Surgical interventions may be performed for cosmetic reasons or for associated complications such as retinal detachment and cataracts.4–7 Colobomas may be associated with other ocular disorders such as microphthalmia,2,8 a multisystem syndrome such as CHARGE syndrome,3,9,10 or found in isolation.
While there are several population-based prevalence studies of coloboma from Europe,11–14 we are unaware of any reports from the United States. The purpose of this study is to describe the incidence, ocular findings, and systemic conditions observed in a population-based cohort of children < 19 years who were diagnosed with ocular coloboma over a 40-year period.
Institutional Review Board approval at Mayo Clinic and Olmsted Medical Group was obtained for this study. The medical records of all patients 19 years of age or younger who were diagnosed by an ophthalmologist with any form of ocular coloboma as a resident of Olmstead County, Minnesota between January 1, 1968, and December 31, 2007, were retrospectively reviewed. Coloboma was defined generally in this study as having a notch, gap, hole, or fissure in any of the ocular structures. Potential cases were identified using the resources of the Rochester Epidemiology Project, a medical record linkage system designed to capture data on any patient–physician encounter in Olmsted County, Minnesota.15 The population of Olmstead County is relatively isolated from other urban areas and virtually all medical care is provided to its residents by Mayo Clinic, Olmsted Medical Group, and their affiliated hospitals.
A diagnostic code search from these two institutions generated a list of 100 potential patients, including 25 individuals diagnosed with unspecified congenital abnormalities which were determined to be non-colobomatous disorders upon review. Seventeen patients were excluded due to diagnoses of other, non-coloboma congenital abnormalities such as morning glory disc abnormality, corectopia and ectropion uveae. Nine were excluded due to incorrect diagnoses, and 3 were eliminated as having eyelid coloboma. Of the remaining 46 patients, 12 were later found to be non-residents of Olmstead County at the time of their diagnosis, and 1 was diagnosed before 1968. The remaining 33 patients were included in this study.
Demographic characteristics including sex and age at diagnosis were collected for each patient. Data on perinatal, developmental, and medical history, and family history of coloboma were also collected. The ophthalmic record was carefully reviewed for the location of the coloboma, any other structural abnormalities, best-corrected visual acuity, ocular alignment, and refractive error. Any association with CHARGE syndrome and the results of genetic testing were also noted. The ophthalmic record of each patient was reviewed for progression of disease, type of management, and final outcome.
To determine the incidence of ocular coloboma in Olmsted County, annual age- and sex-specific incidence rates were constructed using the age-and sex-specific population figures for this county from the US Census. The 95% confidence intervals were calculated using assumptions based on the Poisson distribution. Because coloboma is a congenital disorder, the birth prevalence was also calculated from the number of births occurring from January 1, 1968, through December 31, 2007, in this county.
Thirty-three new cases of congenital coloboma in children were diagnosed during the 40-year study period for an annual incidence of 2.4 (95% confidence interval: 1.6 to 3.2) per 100,000 patients <19 years, or a live birth prevalence of 1 in 2077. There were 16 girls (48%) and 17 boys (52%). Demographic characteristics for the 33 patients are summarized in Table 1. Twelve (36%) of the 33 patients presented with coloboma in the right eye only, 10 (30%) occurred in the left eye only, and 11 (33%) had bilateral involvement. Twelve (36%) patients had involvement of the anterior segment only, 13 (39%) involved the posterior segment only, and 8 (24%) involved both anterior and posterior segments [Table 2]. The median age at diagnosis for the 33 patients was 3.9 months (range, 2 days to 18.4 years) as shown in Figure 1. The respective median ages at diagnosis by coloboma location are 1.5 months (range, 2 days to 9.4 months), 3.9 months (range, 0.9 to 18.3 months), and 9.1 months (range, 1.5 to 19.6 years) for patients with anterior segment involvement only, both anterior and posterior segment involvement, and posterior segment involvement alone. Eight (24%) of the 33 patients had decreased vision at the initial examination, all of which occurred in the eye(s) with coloboma.
Thirty-two of the 33 study patients had at least 2 ophthalmic exams and were followed for a median of 9.2 years (range, 13 days to 35.9 years). The type and number of ocular abnormalities other than coloboma are shown in Table 3. Nineteen (58%) of the 33 study patients were diagnosed with another ocular disorder. Best-corrected visual acuity at final examination was less than 20/60 in 9 (32%) of the 28 patients with sufficient data, including 8 patients with reduced visual acuity in the same eye(s) affected by coloboma and 1 patient with coloboma unilaterally and bilaterally reduced vision due to retinitis pigmentosa. Eleven (33%) of the 33 patients were diagnosed with amblyopia: 8 were managed by patching while 3 were managed by observation alone; 6 (18%) had amblyopia at the final exam. Ten (30%) of the 33 patients were diagnosed with strabismus: 3 received strabismus surgery while the remaining 7 were merely observed; 7 (21%) had strabismus at the final exam. Five (15%) of the 33 patients had microphthalmia or anophthalmia, 3 (9%) patients had anisometropia, and 7 other eye disorders were diagnosed among 5 additional patients [Table 3].
Table 4 shows the percentages of study patients that had non-colobomatous ocular disorders based on the location of their coloboma. Fifty percent of study patients with iris coloboma alone were diagnosed with amblyopia, compared to 33% of patients with involvement of both anterior and posterior segments, and 17% of patients with involvement of the posterior segment alone. None of the 4 study patients with isolated chorioretinal coloboma were diagnosed with other ocular disorders, while 7 (78%) of the 9 patients with coloboma of multiple ocular structures (all of whom had chorioretinal involvement) were diagnosed with at least one other ocular disorder.
The 33 patients were medically followed for a median of 16.8 years (mean, 17.4; range, 36 days to 51.3 years), and 22 (66%) patients were diagnosed with a non-ocular disorder. The non-ocular medical conditions diagnosed among the 33 study patients are summarized in Table 5, including 12 (36%) with abnormal development, 7 (21%) with heart anomalies, 7 (21%) with ear anomalies, and 6 (18%) with skeletal anomalies. CHARGE syndrome was diagnosed in 4 patients, for a birth prevalence of 1 in 17,000 live births. All 4 CHARGE patients were screened for chromosomal abnormalities with negative results; however, 1 of the 4 underwent specific testing of the CHD7 gene and a frameshift mutation (c.1820insA into exon 3) was found.
This population-based study describes the incidence, ocular findings, and systemic conditions associated with coloboma. During the 40-year study period, coloboma was diagnosed in 33 children for a birth prevalence of 1 in 2077. More than half of the study patients had other ocular disorders including strabismus and amblyopia in one-third. Two-thirds of the patients were diagnosed with a non-ocular disorder, including developmental delay in one-third and CHARGE syndrome in 12% of patients.
Population-based prevalence rates for coloboma range from 3.7 per 100,000 from a Hungarian national registry11 to 8 per 100,000 in Scotland.12 However, these rates are a factor of 10-fold less than the 4.8 per 10,000 live births diagnosed among Olmsted County residents. There are several possible explanations for this difference. First, incomplete capture of all patients is likely in the previous studies because they relied on national registry data. The national registry in Scotland is estimated to include less than two-third of all cases,12 and a one-year verification study in Hungary suggests that the Hungarian registry is incomplete.13 Similarly, a Spanish study, which reported a prevalence of 4.9 per 100,00 live births, is based on a national registry limited to congenital malformations diagnosed in the first three days of life.14 Second, diagnostic criteria may vary over time and between countries. The previous reports are based on diagnoses in the last twenty years whereas this study includes diagnoses up to forty years ago.11,12,14 Third, ethnic differences may contribute to different coloboma prevalence rates in different populations. Finally, we should expect the birth prevalence of coloboma to be higher than the reported prevalence of CHARGE syndrome, at 1 in 8,500 to 15,000,16,17 given that CHARGE patients are a subset of the coloboma population.
While some risk factors, such as increased paternal age, have been associated with the development of coloboma,18,19 other factors, including a short gestational age and low birth weight, have not.20 The mean paternal age for our patients was 32.4 years, although we were unable to determine the mean ages of Olmsted County parents during the 40-year study for comparison. Preterm birth does not appear to be a risk factor for coloboma in this population: 3 (9%) of study patients were born prematurely compared to 12–13% in the general United States population.21 Intrauterine exposure to alcohol has been implicated in coloboma development;22 however, only 1 patient in this study had a documented history of fetal alcohol exposure. A positive family history of coloboma was reported in only 2 (6%) patients, suggesting that genetic factors may be significant in a minority of cases. However, additional study patients may have family members with undiagnosed coloboma. We found no clear gender predominance for ocular coloboma. Finally, while coloboma is a congenital disorder as evidenced by the generally early age at diagnosis as shown in Figure 1, a small proportion of patients appear to be diagnosed around the first decade of life, presumably following failed visual screening.
Coloboma occurred bilaterally in approximately one-third of the study patients. This finding is less than the reported percentages of coloboma patients with bilateral involvement in Scotland and Hungary: 42% and 47.5% respectively.12,13 This difference may be due to a reporting or referral bias favoring bilateral diagnoses. As described previously, incomplete capture is likely in the previous studies due to their dependence upon national registry data.12,13 Unilateral intraocular cases may be more likely to go unnoticed by patients, parents, and physicians.
In this study, 36% of patients had a coloboma of the anterior segment (iris) only, 39% of the posterior segment only, and 24% of both anterior and posterior segments. Bermejo et al reported 55 cases of coloboma, of which 47% involved the iris, 40% were chorioretinal, and 13% were unspecified.14 The higher prevalence of iris coloboma in that study may be explained by their three-day diagnosis window compared to a mean diagnosis age of 4 months in the current study. According to our findings, colobomas of the posterior segment are more likely than those of the anterior segment to be diagnosed at an older age.
Nineteen (58%) of the 33 patients in this study were diagnosed with another ocular disorder. The association of coloboma with other ocular disorders has been reported,2 but there is little data on the prevalence of specific ocular disorders within the coloboma population. In this study, 33% of patients were diagnosed with amblyopia and 30% were diagnosed with strabismus. These percentages are significantly greater than the estimated prevalence rates of amblyopia and strabismus in the general population: 1.6–3.5% and 4–6% respectively.23,24 Retinal detachment was a rare complication of coloboma patients in this study, affecting only 6% of study patients. This is consistent with more recent reports,25 and is less than early estimates of 20–40%26,27 that were likely elevated due to referral bias.
It is difficult to derive conclusions on the prevalence of specific ocular diagnoses among coloboma patients based on such a small sample of subjects. However, amblyopia was diagnosed in 50% of the study patients with an isolated iris coloboma, compared to 17% of patients with a strictly posterior lesion, as shown in Table 4. In addition, none of the patients with an isolated chorioretinal coloboma were diagnosed with other ocular disorders, while 78% of patients with multi-level coloboma were diagnosed with at least one other ocular disorder [Table 4].
The high co-morbidity of coloboma and extra-ocular disorders in this study is consistent with previous reports.1,25,28,29 However, it is difficult to determine the prevalences of specific systemic abnormalities among patients with coloboma given its relatively rare occurrence. In a study of 48 consecutive chorioretinal coloboma patients, Daufenbach et al reported systemic abnormalities in 38% of the patients, including 6 (13%) patients with abnormal development.25 We report a higher percentage of patients (66%) with at least one non-ocular diagnosis and a higher percentage (36%) with abnormal development. Several reasons may account for this difference. First, the mean follow-up age in the study by Daufenbach and coauthors is 6.1 years compared to 17.4 years for the current study. In addition, Daufenbach and co-investigators only included patients with chorioretinal and multi-level colobomata, while the current study included all types of ocular coloboma diagnosed over the 40-year period.
The reported birth prevalence of CHARGE syndrome of approximately 1 in 17,000 in this cohort is lower than the 1 in 8,500 to 15,000 from prior studies.16,17 This difference may be due to several reasons. First, because of the relatively rare occurrence of CHARGE syndrome in this study, adding or subtracting a single study subject would significantly alter the prevalence. Second, an accurate diagnosis of CHARGE syndrome is difficult because there is considerable phenotypic variability, with no single defining clinical feature.30 Moreover, patients in this study with several features of CHARGE but who failed to achieve the diagnosis of CHARGE syndrome further illustrate the difficulty of accurately diagnosing this disorder. According to the criteria established by Blake et al,11 an individual must exhibit 4 major criteria or 3 major and 3 minor criteria to be diagnosed with CHARGE syndrome. In addition to the 4 patients who were clinically diagnosed with CHARGE syndrome, 1 patient exhibited 2 major and 3 minor criteria, and 1 patient displayed 1 major and 2 minor criteria.
There are several limitations to the findings in this study. Its retrospective nature is limited by non-standardized data and incomplete follow-up. Colobomata are often asymptomatic, particularly intraocular lesions that do not affect visual acuity, and may go unnoticed by the patient or the physician. Although the vast majority of patients in Olmsted County are managed by the two medical systems within the community, some residents may have sought care outside of Olmsted County, thereby underestimating the true incidence in this population. In addition, the small number of cases of coloboma in this study population makes characterizing the incidence of coloboma subtypes and associated ocular or systemic conditions difficult. Finally, our ability to generalize these findings nationally and internationally is limited by the demographics of Olmsted County, a relatively homogeneous semi-urban white population.
This study provides population-based data on ocular coloboma diagnosed over a 40-year period. Ocular coloboma occurred in approximately 1 in 2077 live births, a rate that is higher than all prior reports. More than half of the study patients were diagnosed with an ocular disorder other than coloboma, including strabismus or reduced vision in approximately one-third of the patients. Two-thirds of patients were diagnosed with a non-ocular disorder, including CHARGE syndrome in 1 in 8 study patients.
This study was made possible in part by the Rochester Epidemiology Project (Grant #R01-AR30582 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases), and by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.
No authors have any financial/conflicting interests to disclose