EPIDEMIOLOGY Incidence, Ocular Findings, and Systemic Associations of Ocular Coloboma A Population-Based Study

Kelly M. Nakamura, BS; Nancy N. Diehl, BS; Brian G. Mohney, MD

Objective: To describe the incidence, ocular findings, 13 days to 35.9 years), 19 patients (58%) had other ocu- and systemic associations of coloboma in a population- lar disorders, including in 11 (33%) and stra- based cohort of children. bismus in 10 (30%). During median medical follow-up of 16.8 years, 22 patients (67%) were diagnosed as hav- Methods: We retrospectively reviewed the medical rec- ing a nonocular disorder, including abnormal develop- ords of pediatric (aged Ͻ19 years) patients diagnosed as ment in 12 (36%) and CHARGE (coloboma, heart de- having ocular coloboma from January 1, 1968, through fects, , retarded growth and development, December 31, 2007, as residents of Olmsted County, Min- genital abnormalities, and ear anomalies) syndrome in nesota. 4 (12%).

Results: Thirty-three children were newly diagnosed as Conclusions: Ocular coloboma occurred in 1 in 2077 having ocular coloboma (annual incidence, 2.4 per live births. More than half of the patients were diag- 100 000 residents Ͻ19 years old; prevalence, 1 in 2077 nosed as having an ocular disorder other than colo- live births). Median patient age at diagnosis was 3.9 boma, including and amblyopia in approxi- months (range, 2 days to 18.4 years), and 22 patients mately one-third. Two-thirds of patients were diagnosed (67%) had unilateral involvement. Twelve patients (36%) as having a nonocular disorder, including CHARGE syn- had involvement of the anterior segment only, 13 (39%) drome in 1 in 8 patients. of the posterior segment only, and 8 (24%) of both. Dur- ing median ophthalmologic follow-up of 9.2 years (range, Arch Ophthalmol. 2011;129(1):69-74

CULAR COLOBOMA IS A Although there are several population- rare congenital abnor- based prevalence studies of coloboma from mality caused by defec- Europe,11-14 we are unaware of any stud- tive embryogenesis. Most ies from the United States. The purpose colobomas result from of this study was to describe the inci- theO failed closure of the embryonic or cho- dence, ocular findings, and systemic con- roidal fissure during weeks 5 to 7 of fetal ditions observed in a population-based co- life.1 Colobomas may involve any of the hort of children younger than 19 years ocular structures, including the , zon- diagnosed as having ocular coloboma in ules and ciliary body, , , and a 40-year period. .2 Colobomas are commonly as- sociated with visual loss for which there is little treatment other than amblyopia METHODS management.3 Surgical interventions may be performed for cosmetic reasons or for The institutional review boards of the Mayo associated complications, such as retinal Clinic and Olmsted Medical Group approved detachment and .4-7 Colobomas this study. The medical records of all patients Author Affiliations: Mayo may be associated with other ocular dis- 19 years or younger who had their condition Clinic College of Medicine orders, such as ,2,8 or with diagnosed by an ophthalmologist as having any (Ms Nakamura), Mayo Clinic multisystem syndromes, such as CHARGE form of ocular coloboma as a resident of Ol- Division of Biostatistics mstead County between January 1, 1968, and (Ms Diehl), and Department of (coloboma, heart defects, choanal atre- December 31, 2007, were retrospectively re- (Dr Mohney), sia, retarded growth and development, viewed. Coloboma was defined generally in this Mayo Clinic and Mayo genital abnormalities, and ear anoma- study as having a notch, gap, hole, or fissure Foundation, Rochester, lies) syndrome,3,9,10 or they may be found in any of the ocular structures. Potential cases Minnesota. in isolation. were identified using the resources of the Roch-

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 69

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Demographic Characteristics of 33 Children 30 Diagnosed as Having Ocular Coloboma in Olmsted County, 25 Minnesota, 1968-2007 25

Characteristic Findings 20 Sex Male, No. (%) 17 (52) 15 Female, No. (%) 16 (48) a Patients, No. Premature birth, No. (%) 3 (9) 10 Birth weight, term infants, mean, g 3364 b Delivery, No. (%) 5 3 Spontaneous vaginal 22 (71) 2 1 1 1 Cesarean 5 (16) 00 0 Forceps assisted 3 (10) 0-1 1-2 2-3 3-4 4-5 5-10 10-14 15-19 Vacuum assisted 1 (3) Age at Diagnosis, y Apgar score Ͻ5 at 5 min, No. (%) 3 (9) Maternal age at birth, mean, y 28.9 Paternal age at birth, mean, y 32.4 Figure. Age at diagnosis of ocular coloboma in 33 children from Olmsted County, Minnesota, 1968 to 2007. Positive family history of coloboma, No. (%) 2 (6)

a Younger than 37 weeks’ gestational age. velopmental, and medical history and family history of colo- b Data were available for only 31 children. boma were also collected. The ophthalmic record was carefully reviewed for the location of the coloboma, any other struc- tural abnormalities, best-corrected visual acuity, ocular align- Table 2. Location of Ocular Coloboma in 33 Children ment, and refractive error. Any association with CHARGE syn- Diagnosed With It in Olmsted County, Minnesota, 1968-2007 drome and the results of genetic testing were also noted. The ophthalmic record of each patient was reviewed for progres- Patients, No. sion of disease, type of management, and final outcome. Unilateral Bilateral Total No. To determine the incidence of ocular coloboma in Olm- Location of Coloboma Involvement Involvement Total of Eyes sted County, annual age- and sex-specific incidence rates were constructed using the age- and sex-specific population figures Anterior segment, 8412 16 for this county from the US Census Bureau. The 95% confi- iris only Posterior segment dence intervals were calculated using assumptions based on the Chorioretinal only 3 1 4 5 Poisson distribution. Because coloboma is a congenital disor- only 5 3 8 11 der, the birth prevalence was also calculated from the number Chorioretinal and 101 1 of births occurring from January 1, 1968, through December optic disc 31, 2007, in this county. Anterior and posterior segments RESULTS Iris and 202 2 chorioretinal Iris, chorioretinal, 336 9 Thirty-three new cases of congenital coloboma in chil- and optic disc dren were diagnosed during the 40-year study for an an- Total 22 11 33 44 nual incidence of 2.4 (95% confidence interval, 1.6-3.2) per 100 000 patients younger than 19 years, or a live birth prevalence of 1 in 2077. There were 16 girls (48%) and ester Epidemiology Project, a medical record linkage system 17 boys (52%). The demographic characteristics of the designed to capture data on any patient-physician encounter Table 1 15 33 patients are summarized in . Twelve of 33 in Olmsted County. The population of Olmstead County is patients (36%) had coloboma in the right eye only, 10 relatively isolated from other urban areas, and almost all medi- (30%) had coloboma in the left eye only, and 11 (33%) cal care is provided to its residents by the Mayo Clinic, Olm- sted Medical Group, and their affiliated hospitals. had bilateral involvement. Twelve patients (36%) had in- A diagnostic code search of these 2 institutions generated a volvement of the anterior segment only, 13 (39%) of the list of 100 potential patients, including 25 individuals diag- posterior segment only, and 8 (24%) both the anterior nosed as having unspecified congenital abnormalities that were and posterior segments (Table 2). The median age at determined to be noncoloboma disorders on review. Seven- diagnosis for the 33 patients was 3.9 months (range, 2 teen patients were excluded owing to diagnoses of other, non- days to 18.4 years) (Figure). The median age at diag- coloboma congenital abnormalities, such as morning glory disc nosis by coloboma location was 1.5 months (range, 2 abnormality, corectopia, and uveae. Nine individu- days to 9.4 months) for patients with anterior segment als were excluded owing to incorrect diagnoses, and 3 were elimi- involvement only, 3.9 months (range, 0.9-18.3 months) nated as having coloboma. Of the remaining 46 pa- for patients with both anterior and posterior segment tients, 12 were later found to be nonresidents of Olmstead County at the time of their diagnosis, and 1 who received a di- involvement, and 9.1 months (range, 1.5-19.6 years) agnosis before 1968. The remaining 33 patients were included for patients with posterior segment involvement alone. in this study. Eight of 33 patients (24%) had decreased vision at the Demographic characteristics, including sex and age at di- initial examination, all of which occurred in the eye(s) agnosis, were collected for each patient. Data on perinatal, de- with coloboma.

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 70

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Thirty-two of 33 study patients had at least 2 ophthal- mic examinations and were observed for a median of 9.2 Table 3. Incidence of Other Ocular Disorders in 33 Children years (range, 13 days to 35.9 years). The type and number Diagnosed as Having Ocular Coloboma in Olmsted County, Minnesota, 1968-2007 of ocular abnormalities other than coloboma are given in Table 3. Nineteen of the 33 study patients (58%) were Ocular Disorder Patients, No. (%) diagnosed as having another ocular disorder. Best- a corrected visual acuity at final examination was less than Reduced VA 9 (27) Unilaterally reduced VA 20/60 in 9 of the 28 patients (32%) with sufficient data, Unilateral coloboma 6 including 8 patients with reduced visual acuity in the same Bilateral coloboma 0 eye(s) affected by coloboma and 1 with coloboma unilat- Bilaterally reduced VA erally and bilaterally reduced vision due to retinitis pig- Unilateral colobomab 1 mentosa. Eleven of the 33 patients (33%) were diagnosed Bilateral coloboma 2 as having amblyopia: 8 were managed by patching and 3 Amblyopia 11 (33) by observation alone; 6 patients (18%) had amblyopia at Strabismus 10 (30) Esotropia alone 4 the final examination. Ten of the 33 patients (30%) were Exotropia alone 1 diagnosed as having strabismus: 3 received strabismus sur- Hypotropia alone 1 gery, and the remaining 7 were merely observed; 7 pa- Mixed 4 tients (21%) had strabismus at the final examination. Five Structural abnormalities 5 (15) of the 33 patients (15%) had microphthalmia or anoph- Microphthalmia 4 thalmia, and 3 (9%) had anisometropia; 7 other eye disor- 1 Other diagnoses ders were diagnosed in 5 additional patients (Table 3). Anisometropia 3 Table 4 provides the percentages of study patients 2 with noncoloboma ocular disorders based on the loca- 2 tion of their coloboma. Fifty percent of patients (6 of 12) 2 with iris coloboma alone were diagnosed as having am- Hypoplasia of the optic nerve 1 blyopia compared with 33% of patients (3 of 9) with in- Abbreviation: VA, visual acuity. volvement of both the anterior and posterior segments a Best-corrected VA less than 20/60. and 17% of patients (2 of 12) with involvement of the b Patient developed retinitis pigmentosa. posterior segment alone. None of the 4 study patients with isolated chorioretinal coloboma were diagnosed as hav- ing other ocular disorders, whereas 7 of the 9 patients Population-based prevalence rates for coloboma range (78%) with coloboma of multiple ocular structures (all from 3.7 per 100 000 from a Hungarian national regis- of whom had chorioretinal involvement) were diag- try11 to 8 per 100 000 in Scotland.12 However, these rates nosed as having at least 1 other ocular disorder. are a factor of 10-fold less than the 4.8 per 10 000 live The 33 patients were medically observed for a me- births diagnosed among Olmsted County residents. There dian of 16.8 years (mean, 17.4 years; range, 36 days to are several possible explanations for this difference. First, 51.3 years), and 22 patients (67%) were diagnosed as hav- incomplete capture of all patients is likely in the previ- ing a nonocular disorder. The nonocular medical con- ous studies because they relied on national registry data. ditions diagnosed in the 33 study patients are summa- The national registry in Scotland is estimated to include rized in Table 5, including 12 (36%) with abnormal less than two-thirds of all cases,12 and a 1-year verifica- development, 7 (21%) with heart anomalies, 7 (21%) with tion study in Hungary suggests that the Hungarian reg- ear anomalies, and 6 (18%) with skeletal anomalies. istry is incomplete.13 Similarly, a Spanish study14 that re- CHARGE syndrome was diagnosed in 4 patients, for a ported a prevalence of 4.9 per 100 000 live births is based birth prevalence of 1 in 17 000 live births. All 4 patients on a national registry limited to congenital malforma- with CHARGE syndrome were screened for chromo- tions diagnosed in the first 3 days of life. Second, diag- somal abnormalities with negative results; however, 1 of nostic criteria may vary across time and between coun- these 4 patients underwent specific testing of the CHD7 tries. The previous studies11,12,14 are based on diagnoses gene, and a frameshift mutation (c.1820insA into exon in the past 20 years, whereas the present study includes 3) was found. diagnoses up to 40 years ago. Third, ethnic differences may contribute to different coloboma prevalence rates in different populations. Fourth, we should expect the COMMENT birth prevalence of coloboma to be higher than the re- ported prevalence of CHARGE syndrome, at 1 in 8500 This population-based study describes the incidence, ocu- to 15 000,16,17 given that patients with CHARGE syn- lar findings, and systemic conditions associated with colo- drome are a subset of the coloboma population. boma. During the 40-year study, coloboma was diag- Although some risk factors, such as increased pater- nosed in 33 children for a birth prevalence of 1 in 2077. nal age, have been associated with the development of More than half of the study patients had other ocular dis- coloboma,18,19 other factors, including young gesta- orders, including strabismus and amblyopia in one- tional age and low birth weight, have not.11 The mean third. Two-thirds of the patients were diagnosed as hav- paternal age of the present patients was 32.4 years, al- ing a nonocular disorder, including developmental delay though we did not determine the mean ages of Olmsted in one-third and CHARGE syndrome in 12%. County parents during the 40-year study for compari-

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 71

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 4. Patients From Olmsted County With Other Ocular Disorders Based on the Location of Their Coloboma (n=33)

Patients With Noncoloboma Ocular Disorders, No. (%) Total No. Location of Coloboma Amblyopia Strabismus Microphthalmia/Anophthalmia Othera of Patients Iris, unilateral 5 (63) 2 (25) 3 (38) 3 (38) 8 Iris, bilateral 1 (25) 1 (25) 0 0 4 Chorioretinal, unilateral 0 0 0 0 3 Chorioretinal, bilateral 0 0 0 0 1 Optic disc, unilateral 2 (40) 2 (40) 0 1 (20) 5 Optic disc, bilateral 0 1 (33) 0 2 (67) 3 Multiple, unilateralb 1 (17) 3 (50) 2 (33) 1 (17) 6 Multiple, bilateralb 2 (67) 1 (33) 0 1 (33) 3

a Other ocular diagnoses include anisometropia, nystagmus, cataract, retinal detachment, and hypoplasia of the optic nerve. b Multiple coloboma includes colobomas of multiple ocular structures: chorioretinal and optic disc; iris and chorioretinal; or iris, chorioretinal, and optic disc colobomas.

son. Preterm birth does not seem to be a risk factor for opia, and 30% were diagnosed as having strabismus. These coloboma in this population: 9% of study patients (n=3) percentages are significantly greater than the estimated were born prematurely compared with 12% to13% of the prevalence rates of amblyopia and strabismus in the gen- general US population.20 Intrauterine exposure to alco- eral population: 1.6% to 3.5% and 4% to 6%, respec- hol has been implicated in coloboma development21; how- tively.22,23 Retinal detachment was a rare complication in ever, only 1 patient in this study had a documented his- patients with coloboma in this study, affecting only 6%. tory of fetal alcohol exposure. A positive family history This is consistent with more recent studies24 and is less of coloboma was reported in only 2 patients (6%), sug- than early estimates of 20% to 40%,25,26 which were likely gesting that genetic factors may be significant in a few elevated because of referral bias. patients. However, additional study patients may have It is difficult to derive conclusions about the preva- family members with undiagnosed coloboma. We found lence of specific ocular diagnoses in patients with colo- no clear sex predominance for ocular coloboma. Fi- boma based on such a small sample. However, ambly- nally, although coloboma is a congenital disorder as evi- opia was diagnosed in 50% of study patients with an denced by the generally early age at diagnosis (Figure), isolated iris coloboma compared with 17% of patients with a small proportion of patients seem to be diagnosed around a strictly posterior lesion (Table 4). In addition, none of the first decade of life, presumably after failed visual the patients with an isolated chorioretinal coloboma was screening. diagnosed as having other ocular disorders, whereas 78% Coloboma occurred bilaterally in approximately one- of patients with multilevel coloboma were diagnosed as third of the study patients. This finding is less than the re- having at least 1 other ocular disorder (Table 4). ported percentages of patients with bilateral coloboma in- The high comorbidity of coloboma and extraocular volvement in Scotland (42%) and Hungary (47.5%).12,13 This disorders in this study is consistent with previous stud- difference may be due to a reporting or referral bias favor- ies.1,24,27,28 However, it is difficult to determine the preva- ing bilateral diagnoses. As described previously, incom- lences of specific systemic abnormalities in patients with plete capture is likely in the previous studies owing to their coloboma given its relatively rare occurrence. In a study dependence on national registry data.12,13 Unilateral intra- of 48 consecutive patients with chorioretinal coloboma, ocular cases may be more likely to go unnoticed by pa- Daufenbach et al24 reported systemic abnormalities in 38% tients, parents, and physicians. of patients, including 6 (13%) with abnormal develop- In this study, 36% of patients had a coloboma of the ment. We report a higher percentage of patients (67% anterior segment (iris) only, 39% of the posterior seg- [22 of 33]) with at least 1 nonocular diagnosis and a higher ment only, and 24% of both the anterior and posterior percentage (36% [12 of 33]) with abnormal develop- segments. Bermejo and Martı´nez-Frı´as14 reported 55 cases ment. Several reasons may account for this difference. of coloboma, of which 47% involved the iris, 40% were First, the mean follow-up age in the study by Daufen- chorioretinal, and 13% were unspecified. The higher bach et al24 is 6.1 years compared with 17.4 years for the prevalence of iris coloboma in that study may be ex- present study. In addition, Daufenbach et al included only plained by their 3-day diagnosis window compared with patients with chorioretinal and multilevel colobomas, a mean diagnosis age of 4 months in the present study. whereas the present study included all types of ocular According to the present findings, colobomas of the pos- coloboma diagnosed during the 40-year period. terior segment are more likely than those of the anterior The reported birth prevalence of CHARGE syndrome segment to be diagnosed at an older age. of approximately 1 in 17 000 in this cohort is lower than Nineteen of the 33 patients (58%) in this study were the 1 in 8500 to 15 000 from previous studies.16,17 This dif- diagnosed as having another ocular disorder. The asso- ference may be due to several reasons. First, because of the ciation of coloboma with other ocular disorders has been relatively rare occurrence of CHARGE syndrome in this reported,2 but there are few data on the prevalence of spe- study, adding or subtracting a single study patient would cific ocular disorders in the coloboma population. In this significantly alter the prevalence. Second, an accurate di- study, 33% of patients were diagnosed as having ambly- agnosis of CHARGE syndrome is difficult because there is

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 72

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 tomatic, particularly intraocular lesions that do not affect Table 5. Associated Nonophthalmic Disorders Diagnosed visual acuity, and may go unnoticed by the patient or the in 33 Children With Ocular Coloboma in Olmsted County, physician. Although most patients in Olmsted County are Minnesota, 1968-2007 managed by the 2 medical systems in the community, some residents may have sought care outside of Olmsted County, Patients, No. (%) thereby underestimating the true incidence in this popu- Diagnosed as Having lation. In addition, the small number of cases of coloboma Disorder Total CHARGE Syndrome in this study population makes characterizing the inci- Abnormal development 12 (36) dence of coloboma subtypes and associated ocular or sys- Developmental delay 6 3 temic conditions difficult. Finally, the ability to generalize Learning disability 4 0 these findings nationally and internationally is limited by Profound mental retardation 1 1 Moderate mental retardation 1 0 the demographics of Olmsted County, a relatively homo- Heart anomalies 7 (21) geneous semi-urban white population. PDA with ASD 2 0 This study provides population-based data on ocular Ventricular septal defect 1 1 coloboma diagnosed during a 40-year period. Ocular colo- ASD 1 1 boma occurred in approximately 1 in 2077 live births, a ASD with pulmonary valve stenosis 1 0 rate that is higher than that of all previous studies. More PDA 1 0 than half of the study patients were diagnosed as having PDA with PFO 1 0 Ear anomaliesb 7 (21) an ocular disorder other than coloboma, including stra- Recurrent otitis mediaa 74 bismus or reduced vision in approximately one-third. Hearing loss 4 3 Two-thirds of the patients were diagnosed as having a Eustachian tube dysfunction 3 1 nonocular disorder, including CHARGE syndrome in 1 External ear deformity 3 1 in 8 study patients. Deafness 1 0 Seizures 6 (18) 2 Skeletal anomalies 6 (18) Submitted for Publication: December 19, 2009; final re- Scoliosis 4 1 Digital malformationsc 30 vision received April 3, 2010; accepted April 5, 2010. Kyphoscoliosis 1 1 Correspondence: Brian G. Mohney, MD, Department of Kyphosis 1 0 Ophthalmology, Mayo Clinic, 200 First St SW, Roches- Osteogenesis imperfecta 1 0 ter, MN 55905 ([email protected]). Urogenital anomalies 5 (15) Financial Disclosure: None reported. Vesicoureteral reflux 3 0 Funding/Support: This study was supported in part by Crytorchidism 1 0 Micropenis 1 0 the Rochester Epidemiology Project (grant R01- Other anomalies AR30582 from the National Institute of Arthritis and Mus- Cleft palate 2 1 culoskeletal and Skin Diseases) and by an unrestricted Short stature 2 1 grant from Research to Prevent Blindness, Inc. Hypogonadotropic hypogonadism 1 1 Choanal atresia 1 0 Laryngomalacia/tracheomalacia 1 0 REFERENCES

Abbreviations: ASD, atrial septal defect; CHARGE, coloboma, heart 1. Chang L, Blain D, Bertuzzi S, Brooks BP. Uveal coloboma: clinical and basic sci- defects, choanal atresia, retarded growth and development, genital ence update. Curr Opin Ophthalmol. 2006;17(5):447-470. abnormalities, and ear anomalies; PDA, patent ductus arteriosus; PFO, patent 2. Onwochei BC, Simon JW, Bateman JB, Couture KC, Mir E. Ocular colobomata. foramen ovale. Surv Ophthalmol. 2000;45(3):175-194. a Recurrent otitis media is defined as 3 episodes of acute otitis media 3. Levin AV. Congenital eye anomalies. Pediatr Clin North Am. 2003;50(1): within 6 months or 4 or more episodes within 1 year. 55-76. bSome children have multiple anomalies. 4. Blackmon DM, Lambert SR. Congenital iris coloboma repair using a modified c Digital malformations included clinodactyly, camptodactyly, and bifid toes. McCannel suture technique. Am J Ophthalmol. 2003;135(5):730-732. 5. Cionni RJ, Karatza EC, Osher RH, Shah M. Surgical technique for congenital iris coloboma repair. J Cataract Refract Surg. 2006;32(11):1913-1916. considerable phenotypic variability, with no single defin- 6. Gopal L, Badrinath SS, Sharma T, et al. Surgical management of retinal detachments ing clinical feature.29 Moreover, patients in this study with related to coloboma of the choroid. Ophthalmology. 1998;105(5):804-809. several features of CHARGE syndrome but who did not 7. Pal N, Azad RV, Sharma YR. Long-term anatomical and visual outcome of vit- reous surgery for retinal detachment with choroidal coloboma. Indian J Ophthalmol. achieve the diagnosis of CHARGE syndrome further illus- 2006;54(2):85-88. trate the difficulty of accurately diagnosing this disorder. 8. Gregory-Evans CY, Williams MJ, Halford S, Gregory-Evans K. Ocular coloboma: According to the criteria established by Blake et al,16 an in- a reassessment in the age of molecular neuroscience. J Med Genet. 2004;41 dividual must exhibit 4 major criteria or 3 major and 3 mi- (12):881-891. nor criteria to be diagnosed as having CHARGE syn- 9. Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006;43 drome. In addition to the 4 patients who were clinically (4):306-314. diagnosed as having CHARGE syndrome, 1 patient exhib- 10. Guercio JR, Martyn LJ. Congenital malformations of the eye and orbit. Otolaryn- ited 2 major and 3 minor criteria, and another displayed 1 gol Clin North Am. 2007;40(1):113-140, vii. major and 2 minor criteria. 11. Vogt G, Szunyogh M, Czeizel AE. Birth characteristics of different ocular con- genital abnormalities in hungary. Ophthalmic Epidemiol. 2006;13(3):159-166. There are several limitations to the findings in this study. 12. Morrison D, FitzPatrick D, Hanson I, et al. National study of microphthalmia, an- Its retrospective nature is limited by nonstandardized data ophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology. and incomplete follow-up. Colobomas are often asymp- J Med Genet. 2002;39(1):16-22.

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 73

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 13. Vogt G, Puho´ E, Czeizel AE. A population-based case-control study of isolated 22. Moseley M, Fielder AR, eds. Amblyopia: A Multidisciplinary Approach. Philadel- ocular coloboma. Ophthalmic Epidemiol. 2005;12(3):191-197. phia, PA: Elsevier Health Sciences; 2002:73-74. 14. Bermejo E, Martı´nez-Frı´as ML. Congenital eye malformations: clinical- 23. Stidwill D. Epidemiology of strabismus. Ophthalmic Physiol Opt. 1997;17(6):536- epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med 539. Genet. 1998;75(5):497-504. 24. Daufenbach DR, Ruttum MS, Pulido JS, Keech RV. Chorioretinal colobomas in 15. Kurland LT, Molgaard CA. The patient record in epidemiology. Sci Am. 1981;245 a pediatric population. Ophthalmology. 1998;105(8):1455-1458. (4):54-63. 25. Patnaik B, Kalsi R. Retinal detachment with coloboma of the choroid. Indian J 16. Blake KD, Davenport SL, Hall BD, et al. CHARGE association: an update and review Ophthalmol. 1981;29(4):345-349. for the primary pediatrician. Clin Pediatr (Phila). 1998;37(3):159-173. 26. Gopal L, Badrinath SS, Kumar KS, Doshi G, Biswas N. Optic disc in coloboma. 17. Issekutz KA, Graham JM Jr, Prasad C, Smith IM, Blake KD. An epidemiological Ophthalmology. 1996;103(12):2120-2127. analysis of CHARGE syndrome: preliminary results from a Canadian study. Am 27. Maumenee IH, Mitchell TN. Colobomatous malformations of the eye. Trans Am J Med Genet A. 2005;133A(3):309-317. Ophthalmol Soc. 1990;88:123-135. 18. Tellier AL, Lyonnet S, Cormier-Daire V, et al. Increased paternal age in CHARGE association. Clin Genet. 1996;50(6):548-550. 28. Leppig KA, Pagon RA. Phenotypic correlations of ocular coloboma without known 19. Puho´ EH, Vogt G, Csa´ky-Szunyogh M, Metneki J, Czeizel AE. Maternal demo- cause. Clin Dysmorphol. 1993;2(4):322-331. graphic and socioeconomic characteristics of live-born infants with isolated ocu- 29. Jyonouchi S, McDonald-McGinn DM, Bale S, Zackai EH, Sullivan KE. CHARGE lar congenital abnormalities. Ophthalmic Epidemiol. 2008;15(4):257-263. (coloboma, heart defect, atresia choanae, retarded growth and development, geni- 20. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of tal hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 de- preterm birth. Lancet. 2008;371(9606):75-84. letion syndrome: a comparison of immunologic and nonimmunologic pheno- 21. Strömland K, Hellström A. Fetal alcohol syndrome: an ophthalmological and so- typic features. Pediatrics. 2009;123(5):e871-e877. doi:10.1542/peds.2008 cioeducational prospective study. Pediatrics. 1996;97(6, pt 1):845-850. -3400.

Archives Web Quiz Winner

ongratulations to the winner of our August quiz, Michael Colucciello, MD, C South Jersey Eye Physicians, Moorestown, New Jersey. The correct answer to our August challenge was sarcoidosis. For a complete discussion of this case, see the Ophthalmic Images section in the September Archives (Chhablani JK, Manu- sani U, Narayanan R. Severe sarcoid vasculitis in a young patient. Arch Ophthal- mol. 2010;128[9]:1165).

Be sure to visit the Archives of Ophthalmology Web site (http://www.archophthalmol .com) and try your hand at our Clinical Challenge Interactive Quiz. We invite visi- tors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the Archives. The first visitor to e-mail our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also be able to choose one of the following books published by AMA Press: Clinical Eye Atlas, Clinical Retina, or Users’ Guides to the Medical Literature.

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 1), JAN 2011 WWW.ARCHOPHTHALMOL.COM 74

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021