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tions in the literature. This patient uniquely presented with a study including fundus autofluorescence and extensive electrophysiology. more dramatic macular pattern at a much later age than an Retina. 2010;30(1):51-62. average patient with CDSRR and had neither nyctalopia nor 3. Michaelides M, Holder GE, Webster AR, et al. A detailed phenotypic study of “cone dystrophy with supernormal rod ERG.” Br J Ophthalmol. dyschromatopsia. This would suggest not only that the 2005;89(3):332-339. heterogeneity of phenotypes for CDSRR is much broader than 4. Wissinger B, Dangel S, Jägle H, et al. Cone dystrophy with supernormal rod the literature indicates but also that the patient’s 2 novel response is strictly associated with mutations in KCNV2. Invest Ophthalmol Vis mutations are mild, having resulted in compound heterozy- Sci. 2008;49(2):751-757. gosity associated with a late presenting phenotype. 5. Wissinger B, Schaich S, Baumann B, et al. Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response. Hum Mutat. 2011;32(12):1398-1406. Tamara Lee Lenis, MD, MS 6. Smith KE, Wilkie SE, Tebbs-Warner JT, et al. Functional analysis of missense Elona Dhrami-Gavazi, MD mutations in Kv8.2 causing cone dystrophy with supernormal rod Winston Lee, MA electroretinogram. J Biol Chem. 2012;287(52):43972-43983. Sri Krishna Mukkamala, MD Mirela Raluca Tabacaru, MD Peripapillary Chorioretinal Lacunae in a Girl Lawrence Yannuzzi, MD With 3q21.3 to 3q22.1 Microdeletion Peter Gouras, MD With Features of Aicardi Syndrome Stephen H. Tsang, MD, PhD Aicardi syndrome is characterized by the classic triad of agenesis of the corpus callosum, seizures, and peripapillary chorio- Author Affiliations: Cleveland Clinic Lerner College of Medicine, Case Western retinal lacunae.1 This disorder occurs exclusively in girls and XXY Reserve University, Cleveland, Ohio (Lenis); Department of Ophthalmology, boys and is presumed to be inherited in an X-linked dominant Columbia University, New York, New York (Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Gouras, Tsang); Department of Pathology and Cell Biology, Columbia pattern, although the causative genes involved have not been University, New York, New York (Lee, Tsang); Vitreous Retina Macula identified. We examined a girl with a microdeletion on chro- Consultants of New York, New York (Mukkamala, Yannuzzi). mosome 3 who was found to have bilateral peripapillary cho- Corresponding Author: Stephen H. Tsang, MD, PhD, Edward S. Harkness Eye rioretinal lacunae with other features of Aicardi syndrome. Institute, 635 W 165th St, Room 218, New York, NY 10032 ([email protected]).

Published Online: September 12, 2013. Report of a Case | A girl was born at 32 weeks’ gestation to a doi:10.1001/jamaophthalmol.2013.4681. mother with preeclampsia via induced vaginal delivery. At Author Contributions: Study concept and design: Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Yannuzzi, Gouras, Tsang. birth, she was noted to have preaxial polydactyly involving her Acquisition of data: Lenis, Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, Yannuzzi, left hand as well as an atrial-septal defect with mild pulmo- Tsang. nary valvular stenosis. At age 18 months, she was evaluated Analysis and interpretation of data: Lenis, Dhrami-Gavazi, Lee, Mukkamala, for speech and motor delay and staring spells. Examination dis- Tabacaru, Yannuzzi, Tsang. Drafting of the manuscript: Lenis, Dhrami-Gavazi, Lee, Mukkamala, Tabacaru, closed a broad flat nasal bridge, epicanthal folds, broad and Gouras, Tsang. wide mouth, retromicrognathia, and truncal hypotonia. A chro- Critical revision of the manuscript for important intellectual content: Lenis, Lee, mosomal microarray study revealed a 6-megabase deletion of Mukkamala, Yannuzzi. chromosome 3, spanning from 3q21.3 to 3q22.1. Obtained funding: Lenis, Mukkamala. Administrative, technical, or material support: Dhrami-Gavazi, Lee, Tabacaru, Ophthalmologic examination showed normal optoki- Yannuzzi, Tsang. netic responses and reactive pupils with no relative afferent Study supervision: Mukkamala, Gouras, Tsang. pupillary defect. She had no strabismus, nystagmus, anterior Conflict of Interest Disclosures: None reported. segment anomalies, or refractive error. Retinal examination Funding/Support: This work was supported by the LuEsther T. Mertz Retinal showed bilateral peripapillary chorioretinal lacunae. In the right Research Center, Manhattan Eye, Ear, and Throat Hospital, Macular Foundation, eye, a normal right optic disc was abutted by a cluster of poorly Inc, core grant 5P30EY019007 from the National Eye Institute, core grant 5P30CA013696 from the National Cancer Institute, and unrestricted funds circumscribed chorioretinal lacunae with hyperpigmented bor- from Research to Prevent Blindness. The Bernard and Shirlee Brown Glaucoma ders superotemporally (Figure 1). In the left eye, a dysplastic Laboratory, Department of Ophthalmology, Columbia University is supported optic disc was encircled by a cluster of well-circumscribed de- by grant R01 EY018213 from the National Institutes of Health, the Foundation pigmented chorioretinal lacunae with variably dense fine pig- Fighting Blindness, Schneeweiss Stem Cell Fund, and the Tistou and Charlotte Kerstan Foundation. Tsang is a member of the RD-CURE Consortium, is a fellow mentation around the borders (Figure 1). The midperipheral of the Burroughs-Wellcome Program in Biomedical Sciences, and has been retinas showed multiple additional streaky areas of focal reti- supported by the Bernard Becker Association of University Professors in nal pigment epithelial depigmentation (Figure 1). Magnetic Ophthalmology Award from Research to Prevent Blindness, the Dennis W. Jahnigen Award from the American Geriatrics Society, the Joel Hoffman resonance imaging showed thinning of the corpus callosum, Scholarship, the Barbara and Donald Jonas Family Fund, and the Professor mildly decreased white matter volume with dilation of the pos- Gertrude Rothschild Stem Cell Foundation. terior aspect of the left lateral ventricle, mild cortical thicken- Role of the Sponsors: The sponsors had no role in the design and conduct of ing with abnormal deep sulcation involving the right parasag- the study; collection, management, analysis, and interpretation of the data; or ittal lobe, and a cavum septum pellucidum (Figure 2). preparation, review, or approval of the manuscript. 1. Gouras P, Eggers HM, MacKay CJ. Cone dystrophy, nyctalopia, and Discussion | In 1946, Krause2 first described the ocular findings supernormal rod responses: a new retinal degeneration. Arch Ophthalmol. 1983;101(5):718-724. of Aicardi syndrome in an infant girl with seizures, develop- 2. Robson AG, Webster AR, Michaelides M, et al. “Cone dystrophy with mental delay, and gray-white plaques in the retina bilaterally. supernormal rod electroretinogram”: a comprehensive genotype/phenotype In 1965, Aicardi et al3 documented the classic findings of this

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Figure 1. Retinal Photographs

A B

C D

High-magnification photographs showing bilateral peripapillary chorioretinal lacunae in the right (A) and left (B) eyes and low-magnification photographs showing multiple midperipheral oblong depigmented areas in the right (C) and left (D) eyes.

Figure 2. Magnetic Resonance Images

A B

A, T1-weighted sagittal magnetic resonance image demonstrating minimal hypoplasia of the corpus callosum (arrow). B, T2-weighted axial magnetic resonance image demonstrating cortical migration anomaly involving the parasagittal right parietal lobe with thickened gyrus (small arrow) abutting the lateral ventricle. There is also bilateral white matter hypoplasia with dilation of the posterior horn of the left lateral ventricle (large arrow) and a cavum septum pellucidum (asterisk).

syndrome in a series of girls with infantile spasms, absence of third cerebral ventricle, cerebral hemispheric asymmetry, the corpus callosum on pneumoencephalogram, and abnor- Dandy-Walker variant, colpocephaly, choroid plexus papillo- mal eye findings (microphthalmia, coloboma, and atrophic cho- mas, and enlargement of the tectum.4,5 Aicardi syndrome may roiditis). The latter finding corresponds to chorioretinal lacu- also be associated with systemic anomalies such as vertebral nae, which consist of well-circumscribed, full-thickness defects malformations (eg, fused vertebrae, scoliosis, spina bifida), cos- limited to the retinal pigment epithelium and choroid, with an tal malformations (eg, absent ribs, fused or bifurcated ribs), intact overlying retina that may appear histologically muscular hypotonia, microcephaly, dysmorphic facies, au- abnormal.1 Subsequent reports documented multiple struc- ricular anomalies, and gastrointestinal tract dysfunction. A con- tural central nervous system abnormalities in Aicardi syn- stellation of facial anomalies (prominent premaxilla, up- drome including cortical migration anomalies (eg, pachygy- turned nasal tip, decreased angle of the nasal bridge, and sparse ria, cortical heterotopia, and polymicrogyria), cysts around the lateral eyebrows) has also been described in Aicardi syndrome.6

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According to the revised diagnostic criteria,6,7 patients can 3. Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasm in flexion, be diagnosed as having Aicardi syndrome when they have 2 callosal agenesis, ocular abnormalities. Electroencephalogr Clin Neurophysiol. 1965;19:609-610. of the classic features with 2 other associated findings. Our pa- 4. Aicardi J. Aicardi syndrome. Brain Dev. 2005;27(3):164-171. tient had some clinical features (muscular hypotonia) and neu- 5. Hopkins B, Sutton VR, Lewis RA, Van den Veyver I, Clark G. Neuroimaging roimaging features (abnormal corpus callosum, neuronal mi- aspects of Aicardi syndrome. Am J Med Genet A. 2008;146A(22):2871-2878. gration abnormalities) of Aicardi syndrome, but they were not 6. Sutton VR, Hopkins BJ, Eble TN, Gambhir N, Lewis RA, Van den Veyver IB. enough to be diagnostic and her facial features did not corre- Facial and physical features of Aicardi syndrome: infants to teenagers. Am J Med spond to those of Aicardi syndrome. Although virtually pathog- Genet A. 2005;138A(3):254-258. nomonic for Aicardi syndrome,1 peripapillary chorioretinal la- 7. Aicardi J. Aicardi syndrome: old and new findings. Int Pediatr. 1999;14:5-8. cunae in girls are seen rarely in other conditions including 8. Warburg M, Heuer HE. Autosomal dominant microcephaly with lacunar autosomal dominant microcephaly with lacunar retinal retinal hypopigmentations. In: Henkind P, ed. Acta XXIV: International Congress hypopigmentations,8 amniotic band syndrome,9 oral-facial- of Ophthalmology. Philadelphia, PA: Lippincott; 1983. digital syndrome,10 and oculoauricular syndrome.11 9. Hashemi K, Traboulsi EI, Chavis R, Scribanu N, Chrousos GA. Chorioretinal lacuna in the amniotic band syndrome. J Pediatr Ophthalmol Strabismus. It is hypothesized that Aicardi syndrome arises from a de 1991;28(4):238-239. 4 novo mutation of a gene on the X chromosome. However, 2 10. Nevin NC, Silvestri J, Kernohan DC, Hutchinson WM. Oral-facial-digital similar cases have been described in patients with a translo- syndrome with retinal abnormalities: OFDS type IX: a further case report. Am J cation of chromosome 3.12,13 Our patient with peripapillary cho- Med Genet. 1994;51(3):228-231. rioretinal lacunae had a deletion on chromosome 3 that com- 11. Schorderet DF, Nichini O, Boisset G, et al. Mutation in the human homeobox prised more than 66 genes, none of which have been associated gene NKX5-3 causes an oculo-auricular syndrome. Am J Hum Genet. 2008;82(5):1178-1184. with chorioretinal lacunae. She also had several features of 12. Ropers HH, Zuffardi O, Bianchi E, Tiepolo L. Agenesis of corpus callosum, Aicardi syndrome, although she did not meet the current di- ocular, and skeletal anomalies (X-linked dominant Aicardi’s syndrome) in a girl agnostic criteria. Because our patient was found to have an in- with balanced X/3 translocation. Hum Genet. 1982;61(4):364-368. terstitial chromosomal microdeletion, we recommend that 13. Donnenfeld AE, Packer RJ, Zackai EH, Chee CM, Sellinger B, Emanuel BS. chromosomal microarray testing be performed in girls with Clinical, cytogenetic, and pedigree findings in 18 cases of Aicardi syndrome. Am chorioretinal lacunae when the neurological and systemic fea- J Med Genet. 1989;32(4):461-467. tures do not fully correspond to those of Aicardi syndrome. COMMENT & RESPONSE Eileen Broomall, MD Deborah Renaud, MD Fundus Autofluorescence Is Not the Best Early Rafif Ghadban, MD Screen for Hydroxychloroquine Toxicity Ralitza Gavrilova, MD To the Editor I was pleased to see pictures of hydroxychloro- Michael C. Brodsky, MD quine toxicity in the recent Ophthalmic Images,1 asare- minder that the problem still exists. However, some readers Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minnesota may draw an erroneous impression from the caption, which (Broomall, Renaud, Gavrilova, Brodsky); Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota (Renaud, Ghadban, Brodsky); Department of Medical suggests that fundus autofluorescence may “be useful to de- Genetics, Mayo Clinic, Rochester, Minnesota (Renaud, Gavrilova). termine whether patients with macular pigmentary change Corresponding Author: Michael C. Brodsky, MD, Mayo Clinic, 200 First St SW, may continue using hydroxychloroquine.” Rochester, MN 55905 ([email protected]). The problem is that the image shows “late” toxicity with Published Online: September 19, 2013. a visible bull’s-eye, and effective screening nowadays should doi:10.1001/jamaophthalmol.2013.4830. detect toxic effects well before any visible fundus changes or Author Contributions: Dr Brodsky had full access to all of the data in the study dark arcuate rings appear on autofluorescence. The early and takes responsibility for the integrity of the data and the accuracy of the data finding in this image is actually the wider hyperfluorescent analysis. Study concept and design: Broomall, Renaud, Ghadban, Brodsky. glow that can be seen before pigmentary damage—but this Acquisition of data: Broomall, Ghadban, Gavrilova, Brodsky. can be subtle and is less reliable as a primary screening tool. Analysis and interpretation of data: All authors. Retinopathy in this patient would have been recognized in Drafting of the manuscript: Broomall, Renaud, Ghadban, Gavrilova. Critical revision of the manuscript for important intellectual content: Renaud, fields and on spectral-domain optical coherence tomography Ghadban, Gavrilova, Brodsky. long before this autofluorescent bull’s-eye became Administrative, technical, or material support: Ghadban. apparent,2,3 and that would have been the optimal time to Study supervision: Renaud, Gavrilova, Brodsky. stop the drug. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported in part by a grant from Research to Michael F. Marmor, MD Prevent Blindness, Inc and by the Mayo Foundation. Role of the Sponsors: The funding agencies had no role in the design and Author Affiliation: Byers Eye Institute at Stanford, Palo Alto, California. conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Corresponding Author: Michael F. Marmor, MD, Byers Eye Institute at Stanford, 2452 Watson Ct, Palo Alto, CA 94303 ([email protected]). 1. Carney SH, Brodsky MC, Good WV, Glasier CM, Greibel ML, Cunniff C. Aicardi syndrome: more than meets the eye. Surv Ophthalmol. 1993;37(6):419-424. Conflict of Interest Disclosures: None reported. 2. Krause AC. Congenital encephalo-ophthalmic dysplasia. Arch Ophthal. 1. Gorovoy IR, Gorovoy MS. Fundus autofluorescence in hydroxychloroquine 1946;36(4):387-44. toxicity. JAMA Ophthalmol. 2013;131(4):506.

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