Author Affiliations: Department of Ophthalmology, University of California at Davis School of Medicine, Sacramento (Dr Moshiri); and Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University Hospital and School of Medicine, Baltimore, Maryland (Drs Scholl, Canto-Soler, and Goldberg).
Ocular albinism is an X-linked disease characterized in affected males by poor vision, nystagmus, iris transillumination, hypopigmented fundus, foveal hypoplasia, and a decreased proportion of ipsilateral ganglion cell fibers at the optic chiasm. Mutation of the OA1/GPR143 gene on the X chromosome is responsible for this condition. The skin and hair pigmentation appears clinically normal, but skin histologic analysis reveals macromelanosomes in melanocytes.1 Carriers of the condition are rarely symptomatic but often have signs of their carrier status. Female carriers have macromelanosomes in the skin, although they are fewer in number than in affected males. The eyes of carriers often show iris transillumination (80%) and a mud-splattered appearance of the posterior pole with typical pigmentary streaks in the peripheral fundus (92%).2 The pathogenesis of these streaks has not been understood.
A 60-year-old woman was referred for evaluation of nonspecific visual complaints and abnormal fundus pigmentation. She was thought to have a possible retinal dystrophy. The patient's symptoms were limited to difficulty seeing clearly while driving at night and difficulty seeing clearly at near. Both eyes were affected equally, and the symptoms had been present for several months. Her medical history was unremarkable for any chronic medical conditions, and she took no medications. The patient had no significant ocular history. Her family history was significant for a father and a son with ocular albinism. She therefore was an obligate carrier of this disease.
Her distance and near visual acuities were correctable to 20/20 OU. Pupillary reactions were normal, as were intraocular pressures, extraocular movements, confrontational visual fields, and ocular alignment. Slitlamp examination findings were remarkable only for moderate nuclear sclerosis in each eye. No iris transillumination was noted on careful examination. Dilated examination revealed clear media in each eye, pink optic nerves with normal cups, flat maculae, and normal retinal vessels bilaterally. The posterior pole appeared to have a splotchy pattern of pigmentation, as seen on fundus autofluorescence imaging (Figure 1). The peripheral fundus had alternating radial streaks of hyperpigmentation and hypopigmentation (Figure 2A) at the level of the retinal pigment epithelium (RPE), typical of the X-linked ocular albinism carrier state. Fluorescein angiography showed normal retinal vasculature with areas of blocking and window defects corresponding to hyperpigmented and hypopigmented regions, respectively (Figure 2B). Findings on optical coherence tomography of the macula and full-field electroretinography were normal in both eyes. Her visual symptoms were consistent with presbyopia and cataract.
Figure 1. Fundus autofluorescence image of the posterior pole of the right eye of the X-linked ocular albinism obligate carrier, demonstrating the typical mud-splattered appearance of the retinal pigment epithelium. Hypoautofluorescent areas correspond to hyperpigmented areas of retinal pigment epithelium. Similarly, hyperautofluorescent areas correspond to hypopigmented areas on the color fundus photograph.
Figure 2. Color fundus photograph and late-phase fluorescein angiogram. A, Color fundus photograph on a wide-angle instrument of the right eye of the X-linked ocular albinism obligate carrier, demonstrating the typical mud-splattered appearance of the posterior pole and the characteristic alternating hyperpigmented and hypopigmented peripheral streaks at the level of the retinal pigment epithelium. B, Late-phase fluorescein angiogram of the same eye showing normal retinal vasculature, blocking in hyperpigmented areas, and window defects in hypopigmented areas. Hypofluorescent areas correspond to hyperpigmented areas of retinal pigment epithelium. Similarly, hyperfluorescent areas correspond to hypopigmented areas on the color fundus photograph.
Recent studies using 4-dimensional imaging with custom cell-tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying optic cup morphogenesis in the zebra fish shed light on the fundus pattern in our patient. Kwan et al3 identified 2 major RPE cell movements during eye development: pinwheeling and spreading. An initial pinwheel-like movement of RPE cells during the optic vesicle elongation phase gives rise to a discrete RPE domain that can be further subdivided within posterior, central, and anterior subdomains (corresponding to temporal, central, and nasal in humans). Immediately afterward, during optic vesicle invagination, RPE cells corresponding to the temporal and nasal domains undergo a posterior to anterior radial migration (spreading), while RPE cells located in the central domain maintain their relative central position. Kwan and colleagues replicated these studies on chick embryos and found similar movements, thereby suggesting that optic cup morphogenesis may be evolutionarily conserved across vertebrate species. Time-lapse photography3 (also available online at http://www.youtube.com/watch?v=VyJ4M_1HEzY) demonstrates these dramatic movements and migration of RPE precursor cells.
Bodenstein and Sidman4 studied RPE development in mice using pigmented-albino mouse chimeras and X-inactivation mosaics. They found that posterior RPE precursors (corresponding to the central domain in zebra fish) become postmitotic sooner than in peripheral RPE precursors. Therefore, these posterior RPE precursors stay relatively localized, allowing more “cell mixing.” Conversely, peripheral RPE precursors divide more, because they stay mitotically active longer, and add cells in an edge-biased fashion, producing less cell mixing and accounting for groups of clones in the peripheral fundus.
We propose that these morphogenetic movements of RPE precursors during eye development may constitute the basis of the characteristic radial-streaking phenotype observed in carriers of X-linked ocular albinism. This model is based on the premise that female carriers have a mixed population of both pigmented and nonpigmented RPE precursor cells due to lyonization of the X chromosome. During the early stages of optic vesicle development, this mixed population of RPE precursors will undergo pinwheel movements and give rise to temporal, central, and nasal RPE subdomains characterized by a pigmented and nonpigmented mosaic pattern. As development proceeds, the mud-splattered pattern of the posterior pole would originate from the central RPE subdomain through the generation of localized pigmented vs nonpigmented clones by relatively fewer cell divisions and less migratory activity. On the other hand, the radial streaks seen in the periphery would originate from the posterior to anterior migration of RPE cells from the temporal and nasal RPE subdomains as well as the edge-biased pattern and relatively increased mitotic activity of the peripheral clonal cell populations (Figure 3). A computer animation of the proposed model is presented in the
. Further molecular histopathologic analysis in human samples and experiments in knockout mice may lend further evidence in support of this model in mammalian species.
Figure 3. Schematic model of clonal populations of retinal pigment epithelial precursor cells proliferating and migrating in the peripheral fundus to produce the typical pattern of alternating hyperpigmented and hypopigmented streaks at the level of the retinal pigment epithelium. Artist: David Rini, MFA, Department of Art as Applied to Medicine, The Johns Hopkins University School of Medicine, 2012.
Correspondence: Dr Goldberg, Wilmer Eye Institute, 600 N Wolfe St, Maumenee 713, Baltimore, MD 21287 (firstname.lastname@example.org).
Published Online: March 21, 2013. doi:10.1001/jamaophthalmol.2013.39
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Moshiri is supported by Research to Prevent Blindness. Dr Scholl is supported by the Clark Charitable Foundation.
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Radial Streaking in the Fundus of the Carrier State of X-Linked Albinism
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