Retinal Dystrophy With Or Without Macular Staphyloma

A number sign (#) is used with this entry because of evidence that retinal dystrophy with or without macular staphyloma (RDMS) is caused by homozygous or compound heterozygous mutation in the C21ORF2 gene (CFAP410; 603191) on chromosome 21q22.

Biallelic mutation in C21ORF2 also causes a syndromic form of retinal dystrophy associated with axial spondylometaphyseal dysplasia (SMDAX; 602271).

Clinical Features

Khan et al. (2015) studied 3 female probands from unrelated consanguineous Saudi Arabian families who had early-onset retinal dystrophy with macular staphyloma, but without high myopia. The probands were first noted to have decreased vision at age 3 to 6 years, and vision worsened over time. At ages 39, 30, and 12 years, all 3 had similar retinal findings, with dystrophic changes including retinal pigment epithelium (RPE) mottling and vessel narrowing, macular staphyloma despite only mild myopia or high hyperopia, and nonrecordable responses on electroretinography (ERG). The 12-year-old girl also exhibited short stature and truncal obesity, but x-rays of hands, hips, and upper legs did not reveal any bone abnormalities.

Suga et al. (2016) reported a Japanese brother and sister with isolated retinal dystrophy. The sister presented at age 48 years with declining vision that she had noticed over the previous several years, as well as photoaversion. Visual acuity was 20/200 bilaterally. Funduscopy showed bull's-eye maculopathy with annular degeneration of the retina and RPE within the vascular arcades, and mild attenuation of retinal vessels. Visual field testing showed large central scotomas bilaterally. Rod and flash ERGs were reduced, and cone and flicker ERGs were nonrecordable, consistent with cone-rod dystrophy. Ocular coherence tomography (OCT) revealed abnormally laminated retina and extinguished ellipsoid zone. Over 21 years of follow-up, retinal degeneration had gradually progressed with the appearance of a few small areas of clumped pigment. At age 69, her best corrected visual acuity was 20/500 in the left eye and 20/1000 in the right eye, although she could walk unassisted using her peripheral vision. Her older brother noted night blindness in high school followed by visual field restriction, and he was diagnosed with retinitis pigmentosa (RP) in his late twenties. He was legally blind at 40 years of age, and lost light perception at age 60. Examination at age 64 showed diffuse degeneration of the fundi and nonrecordable ERGs bilaterally. Nuclear cataracts had progressed to mature cataracts, making it difficult to determine whether he had late-stage RP or cone-rod dystrophy.

Molecular Genetics

Abu-Safieh et al. (2013) performed exome sequencing in 10 simplex and 23 multiplex cases of retinal dystrophy and identified a 1-bp deletion in the C21ORF2 gene (603191.0003) in a patient (CR-F024) diagnosed with cone-rod dystrophy, who was later also found to have skeletal abnormalities (Wheway et al., 2015; see 602271). By direct sequencing in 7 patients from a replication cohort with autozygome patterns overlapping the C21ORF2 gene, Abu-Safieh et al. (2013) identified homozygosity for a splice site mutation (603191.0006) in 1 patient with retinal dystrophy. No clinical details were provided.

In 3 female probands from unrelated consanguineous Saudi Arabian families, who had early-onset retinal dystrophy with macular staphyloma, Khan et al. (2015) identified homozygosity for mutations in the C21ORF2 gene: 2 of the patients, aged 30 and 39 years, carried the same 31-bp deletion (603191.0004), whereas the youngest patient, a 12-year-old girl who also exhibited short stature and truncal obesity, was homozygous for a missense mutation (C61Y; 603191.0005).

By serial mutation analysis in a cohort of 163 Chinese probands diagnosed with cone-rod dystrophy, Huang et al. (2016) identified potentially pathogenic mutations in 93 (57.1%) of the probands, including a 10-year-old boy (patient QT803) who was compound heterozygous for a 12-bp insertion and a splice site mutation in the C21ORF2 gene. The proband had poor foveal reflex bilaterally, and ERGs showed severely reduced rod responses and extinguished cone responses.

In 147 Japanese families with inherited retinal diseases, Suga et al. (2016) performed whole-exome sequencing and identified homozygosity for a missense mutation in the C21ORF2 gene (Y107C; 603191.0011) in a brother and sister with retinal dystrophy, diagnosed as cone-rod dystrophy in the sister and retinitis pigmentosa in the brother. Neither exhibited macular staphyloma. From the same cohort, Suga et al. (2016) also detected biallelic C21ORF2 mutations in 2 Japanese sibs with RP associated with short stature and narrow thorax (see SMDAX, 602271).