A mutation in CRX causing pigmented paravenous retinochoroidal atrophy

Abstract

Introduction:

Mutations in the cone-rod homeobox (CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX.

Case description:

A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull’s eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family.

Conclusion:

This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

Introduction

Rod-cone dystrophies (RCDs) are a form of inherited retinal degeneration that lead to progressive loss of peripheral and night vision, followed by the gradual loss of central vision.¹ Estimated to affect roughly 1 in 4000 individuals, RCDs are a prominent cause of irreversible and currently untreatable vision loss.¹ Diagnosis of RCDs is typically made by a combination of fundus examination and full-field electroretinography (ffERG); however, as most current and future therapies for inherited retinal degenerations tend to be gene specific, molecular genetic sequencing is the most essential test for diagnosis.

To date, roughly 90 genes have been identified in association with RCDs, but many cases remain unsolved.¹ Most cases are inherited in an autosomal recessive fashion, but disease can also be inherited in a dominant or X-linked pattern as well. Among the dominant causes of RCD, mutations in the cone-rod homeobox gene, CRX (OMIM #602225), have been implicated in rare cases.¹ CRX is a photoreceptor specific transcription factor that is essential for photoreceptor differentiation and development.² It is co-expressed with a number of other transcription factors including NRL and NR2E3, which when mutated, have also been implicated in human photoreceptor disease.³ Over 50 pathogenic mutations in the CRX gene have been reported in the literature and are known to cause a variety of phenotypes in addition to RCD, including cone-rod dystrophy (CRD), macular dystrophy, and Lebers congenital amaurosis.⁴ Even among cases of RCD, a wide range of phenotypic variability has been reported and continues to be expanded.

Consequently, in this report, we describe the case of two brothers with an atypical and late presentation of RCD phenocopying pigmented paravenous chorioretinal atrophy (PPRCA) associated with a heterozygous mutation in the CRX gene. PPRCA is a poorly understood retinal degeneration of unclear origin that presents with chorioretinal atrophy and intraretinal pigment migration deposited along the retinal veins.⁵ While the disorder is hypothesized to be caused by an inflammatory etiology, rare cases of familial PPRCA have been described in the literature.^5,6

Case description

A 53-year-old man (P1) presented to the Department of Ophthalmology at Columbia University Irving Medical Center for evaluation of an 8-year history of progressive vision loss and night blindness. The patient denied any past ocular history but had one affected brother with similar symptoms. Visual acuity was best corrected to 20/30 in the right eye and 20/50 in the left eye. Anterior segment examination revealed trace nuclear sclerosis but was otherwise unremarkable. Dilated fundus examination demonstrated a bull’s eye lesion with dense chorioretinal atrophy and intraretinal pigment migration in the nasal fields of both eyes (Figure 1(a), top left, OD and OS). Short-wavelength fundus autofluorescence (SW-AF) revealed an unusual paravenous pattern of atrophy extending nasally past the optic disc as well as along the large vessels of the temporal arcades with a surrounding hyperautofluorescent border (Figure 1(a), top right, OD and OS). Additionally, a second hyperautofluorescent ring was seen surrounding the fovea. Spectral-domain optical coherence tomography (SD-OCT) showed diffuse retinal thinning and loss of the outer retinal layers. Hypertransmission into the choroid (Figure 1(a), bottom, OD and OS) was observed in areas of complete atrophy of external layers; however, although outer nuclear layer thinning and ellipsoid zone disruption was seen in the foveal region, no hypertransimission was observed. SD-OCT at areas corresponding with the hyper-autofluorescent ring demonstrated a sharp transition between healthy and degenerated retina (Figure 2) Full-field electroretinogram (ffERG) revealed a rod-cone pattern of degeneration. The patient underwent whole exome sequencing at the Columbia University Laboratory of Personalized Genomic Medicine revealing a likely pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene. The patient was re-evaluated 10-years later and reported progressive vision loss. Best-corrected visual acuity at this time was 20/80 in the right eye and 20/150 in the left eye. Wide-field color fundus photographs and SW-AF revealed that the atrophy extended far into the nasal periphery with a scalloped pattern of degeneration (Figure 1(b), top right and left, OD and OS). SD-OCT imaging additionally demonstrated progressive retinal thinning as well as new, hyperreflective foci in the perifoveal region (Figure 2(b), bottom, yellow arrows).

Figure 1.

Paravenous chorioretinal atrophy extending nasally. (a) Color fundus photographs (top left, OD and OS) at presentation of P1 revealed paravenous chorioretinal atrophy with intraretinal bone spicule pigmentation extending nasally past the optic disc. Short-wavelength autofluorescence (SW-AF) (top right, OD and OS) demonstrated a similar distribution of atrophy with an atypical hyperautofluorescent ring surrounding the retinal vessels. Spectral domain optical coherence tomography (SD-OCT) (bottom, OD and OS) showed central macular atrophy with diffuse retinal thinning and hypertransmission into the choroid. (b) Wide-field color photographs (top left, OD and OS) and SW-AF (top right, OD and OS) of P1 at a 10-year follow-up revealed that the atrophy extended far into the nasal periphery with a scalloped pattern of degeneration. SD-OCT (bottom, OD and OS) demonstrated progressive retinal thinning. (c) Color fundus photography (top left, OD and OS) and SW-AF (top right, OD and OS) of P2 showed a similar pattern of paravenous atrophy with bone spicule pigmentation extending nasally. SD-OCT images (bottom, OD and OS) showed foveal sparing with parafoveal loss of the retinal architecture.

Figure 2.

Spatial correlation of perivascular hyperautofluorescence and loss of retinal architecture. The boundaries of the atypical hyperautofluorescent border (green arrows) on short-wavelength autofluorescence seen in the proband correspond spatially with the transition zone (green arrows) between healthy and atrophic retina on spectral domain optical coherence tomography. Areas of hyperautofluorescence exhibited retinal thinning and loss of the outer retinal layers. Additionally, intermittent disruptions of the ellipsoid zone corresponding to hyperautofluorescent foci in the SW-AF were observed (asterisks).

The affected brother (P2) of the proband presented as a 48-year-old man with a 1-year history of similar difficulties with vision. Visual acuity was best corrected to 20/20 in both eyes and anterior segment examination was unremarkable. Dilated fundus examination revealed the same pattern of nasal chorioretinal atrophy with prominent intraretinal pigment migration in both eyes (Figure 1(c), top left, OD and OS). SW-AF demonstrated a pattern of perivenous atrophy, more prominent in the inferior than superior field, extending nasally past the optic disc with an incomplete hyperautofluorescent ring seen within the macula (Figure 1(c), top right, OD and OS). SD-OCT showed preserved foveal architecture with perifoveal thinning and loss of the outer retinal layers (Figure 1(c), bottom, OD and OS). ffERG was consistent with a rod-cone pattern of degeneration, and whole exome sequencing revealed the same likely pathogenic variant in the CRX gene (Figure 3). Segregation analysis of the mutation was also performed in an unaffected sister who was not found to have the variant. Dilated fundus examination in the mother and an asymptomatic brother confirmed that they were both unaffected. Seven other asymptomatic siblings were not examined.

Figure 3.

Rod-cone dysfunction in a patient with a heterozygous mutation in the CRX gene. Full-field electroretinogram findings in the affected sibling demonstrated significantly reduced single-flash and 30 Hz flicker cone response amplitudes of 35 μV and 22 μV, respectively and implicit time delays to 29 ms in both eyes. Scotopic rod-specific and maximum responses were attenuated with b-wave amplitudes of 75 μV and 167 μV, respectively. A normal age-match control is illustrated for comparison.

Written informed consent was obtained from patients as per Columbia University Institutional Review Board-approved protocol #AAAB6560. All procedures were reviewed and in accordance with the tenets of the Declaration of Helsinki.

Conclusion

Mutations in the cone-rod homeobox gene, CRX, are a rare cause of inherited retinal degeneration that can lead to autosomal dominant Leber congenital amaurosis, RCD, CRD, or macular dystrophy.⁴ The phenotypic variability of CRX-associated degeneration has been a subject of interest in the past, and cases with unusual characteristics such as regressive flecks or atypical patterns of autofluorescence have been described in the literature.^4,7 The present report expands the known phenotypes of CRX-associated RCD with the case of two brothers who presented with a paravenous pattern of atrophy and intraretinal pigment migration that extended far into the nasal retina. The missense variant identified in the two brothers, c.119G>A:p. (Arg40Gln), occurs at a fully conserved nucleotide and has been previously reported as pathogenic, but the specific phenotype is not known. Additionally, the allele is found at a frequency of 0.00001195 in the general population (gno-mAD), suggesting that it is not a common variant, and in silico tools predict the variant to be probably damaging (PolyPhen) and deleterious (SIFT).

The differential diagnosis for the observed phenotype in these brothers is wide, including cone-rod dystrophy, tuberculosis chorioretinitis, syphilitic chorioretinitis, toxoplasmosis, and sarcoidosis. However, the phenotype bears a particularly striking resemblance to PPRCA, as both present with chorioretinal atrophy and bone spicule pigmentation along the distribution of the retinal veins that can extend nasally past the optic disc.⁵ Previous reports of PPRCA have also described an atypical pattern of hyperautofluorescence on SW-AF surrounding areas of atrophy similar to that seen in this case. Spatial correlation between the hyperautofluorescent halo and a sharp transition zone between healthy and degenerated retina has also been reported (Figure 3).⁸ ffERG testing in this family revealed a rod-cone pattern of degeneration with diminished photopic single flash and 30 Hz flicker amplitudes and decreased scotopic responses. In PPRCA, ffERG findings have been reported to be variable, as cases have been described with more attenuated cone responses than rod responses and vice versa.^5,6 However, apparent differences between the reported phenotype and PPRCA include the progressively worsening visual acuity in these brothers, as well as the history of nyctalopia, which is not characteristic of PPRCA.⁵ Notably, a similar PPRCA-like phenotype was also described by Murro et al. in two patients with recessive NR2E3 associated retinal dystrophy.⁹ The known interactions between both CRX and NR2E3 in photoreceptor differentiation may support a common etiology in the development of this phenotype.

Familial cases of PPRCA have been reported infrequently in the literature, and to date, the only identified genetic etiology of the phenotype is due to bi-allelic mutations in the CRB1 gene, which may cause a similar paravenous pattern of atrophy at an early age.¹⁰ However, while mutations in CRB1 may explain a subset of patients with PPRCA, cases with no identified mutations in CRB1 suggest that other genetic etiologies may also exist. Recent reports in the literature have described cases of patients with unilateral retinitis pigmentosa and PPRCA in the fellow eye, further supporting the possibility of shared genetic etiologies.¹¹ Notably, the few reports of hereditary PPRCA in the literature have suggested that inheritance may occur in an autosomal dominant fashion, which may be consistent with the inheritance seen in this family. There may also be male gender predominance.⁶ While segregation of the variant was confirmed in the two affected siblings and an unaffected sister, the absence of segregation of the variant in the parental samples is a limitation of this study.

In many inherited retinal degenerations, such as Usher syndrome, understanding of genotype-phenotype correlations can provide important prognostic information and help guide diagnosis. However, due to the phenotypic variability of CRX-associated disease, assessing such correlations has proven to be difficult. Prior attempts at genotype-phenotype correlation in CRX-associated disease have hypothesized that disease severity may correlate with the position of the mutation within the gene, but were unable to demonstrate any significant association.⁴ The specific missense variant identified in the two brothers occurs within the third alpha helix of the homeobox domain of CRX. This locus is essential for binding DNA; therefore the variant likely disrupts protein function.¹² Other mutations within the homeobox domain have been implicated in the full spectrum of CRX-associated disease, including RCD, CRD, macular dystrophy, and Lebers congenital amaurosis, suggesting that disease phenotype may not be domain dependent.⁴ Interestingly, Hull et al. have found that all disease-causing variants within the homeodomain are missense variants while all but two pathogenic variants outside of the homeodomain are frameshift mutants.⁴ In this report, the authors describe a case of RCD with paravenous atrophy and intraretinal pigment migration in association with mutation in CRX. While the authors hypothesize that genetic modifiers in genes that are co-expressed with CRX, such as NR2E3, may be responsible for this phenotypic variability, further study is needed to correlate genotypes with the continuously expanding phenotypes of CRX-mediated retinal dystrophy.