Female Simplex Carriers of X-Linked Retinal Dystrophies: A Case Series

X-linked inherited retinal dystrophies (IRDs) lead to progressive vision loss in affected males and include choroideremia (CHM), X-linked retinitis pigmentosa (XLRP), and X-linked cone-rod dystrophy (XLCORD). Female carriers may be asymptomatic or manifest disease ranging from mild to severe. Due to the variable manifestation of disease in females, some pedigrees can appear autosomal dominant. However, female carriers presenting as simplex probands are rare and X-linked disease may not be suspected in these cases without genetic testing.

Three affected simplex CHM carriers and six affected simplex XLRP or XLCORD carriers due to variants in RPGR (n = 5) or RP2 (n = 1) were included. Best corrected visual acuity, color fundus photos, fundus autofluorescence (FAF), optical coherence tomography, electroretinography, and Goldmann visual fields were collected. X-chromosome inactivation (XCI) ratios were determined for 4 cases. Age of onset ranged from infancy to 43 years, with nyctalopia as the most common presenting symptom. 4 out of 5 cases with RPGR variants presented with cone or cone-rod dystrophies, while the remaining cases presented with rod-cone dystrophy. XCI analysis revealed extreme skewing in 2 cases who both presented with severe disease. 4 out of 7 cases with FAF demonstrated autofluorescence patterns classic for carrier status. The remaining 3 cases had severe disease and corresponding FAF patterns consistent with their severity.

The absence of family history does not preclude X-linked inheritance in females with retinal dystrophies. Multimodal imaging such as FAF and red-free photos should be included in the workup. As new therapeutic strategies are developed for CHM and RPGR-associated retinal degeneration, including gene therapy, it may become increasingly more important to diagnose symptomatic carriers, as it has been previously shown that earlier intervention is more effective in IRD populations.