Morphogenetic Model for Radial Streaking in the Fundus of the Carrier State of X-Linked Albinism

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.

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.

Correspondence: Dr Goldberg, Wilmer Eye Institute, 600 N Wolfe St, Maumenee 713, Baltimore, MD 21287 (mgoldbrg@jhmi.edu).

Published Online: March 21, 2013. doi:10.1001/jamaophthalmol.2013.39

Funding/Support: Dr Moshiri is supported by Research to Prevent Blindness. Dr Scholl is supported by the Clark Charitable Foundation.