A recurrent arcuate retinopathy in familial cone-rod dystrophy secondary to heterozygous CRX deletion

Purpose: To describe an arcuate retinopathy appearance in a familial cone-rod dystrophy and the underlying genetic cause. Methods: Retrospective case series of an affected three-generation family (eight affected members, eight unaffected members) Results: The proband, a 47-year-old male, noted significant visual loss since his early thirties. In addition to central macular atrophic changes, retinal examination was notable for peripapillary atrophy and an arcuate of drusenoid deep yellow lesions in the temporal macula. Spectral-domain optical coherence tomography in the area of the lesions showed regional outer neurosensory retina loss with nasal extension (forming a ring around the central retina) but no drusen. Full-field electroretinography revealed cone-rod dysfunction with an electronegative waveform. Fifteen other available family members were examined, and seven (age range 13-71 years old) showed variable expressivity for similar phenotypic findings, most notably the arcuate lesions in all but the oldest individual who had end-stage atrophy. Exome sequencing of the proband's affected daughter uncovered a heterozygous CRX deletion [NM_000554.4: CRX: c.(100 + 1_101-1)_(c.900 + 1_?)del] that segregated with the disease. Conclusion: An unusual familial cone-rod dystrophy phenotype was associated with heterozygous CRX deletion, a pathogenic variant that had a presumed mechanism of haploinsufficiency. The consistent finding of arcuate temporal macular lesions among affected family members was striking, particularly given the variable expressivity previously associated with CRX-related retinopathy. Additional phenotypic studies are needed to assess how frequently this temporal arcuate retinopathy appearance occurs in individuals harboring a similar deletion who are not from the current family.