ABSTRACT

Goldmann-Favre syndrome, which is caused by mutation of the NR2E3 gene, is a retinal degenerative disease with a wide spectrum of phenotypic properties. Variations in clinical presentation result in difficulties in differential diagnosis. In this article, Goldmann-Favre syndrome cases with different clinical findings are presented. Clinical characteristics of our cases were reviewed and discussed in light of the literature.

Introduction

Goldmann-Favre syndrome (GFS) is a progressive retinal degeneration that develops due to a mutation in the NR2E3 gene, which has a role in the regulation of cone cell differentiation, and has an autosomal recessive inheritance pattern.^1,2 GFS and enhanced S-cone syndrome represent two distinct entities on a spectrum of retinal degenerative disease caused by mutations in the same gene.³ The fact that these two conditions manifest with very different clinical phenotypes make it difficult to distinguish them from other diseases on the retinal degenerative disease spectrum such as retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy.^2,4,5

In this report, the varying examination findings and clinical characteristics of patients treated in our clinic for GFS are discussed in the context of the literature.

Discussion

GFS was first described by Favre⁶ in two brothers, and Ricci⁷ reported that GFS follows an autosomal recessive inheritance pattern. Genetic studies have revealed that GFS occurs due to a mutation in the NR2E3 gene, which is located on the short arm of chromosome 15.^2,5,8 The NR2E3 gene encodes a retinal nuclear receptor involved in transcription.⁹ This gene regulates the expression of cone-specific genes found in the rods and controls the differentiation of photoreceptors.^9,10 Homozygous mutations in the NR2E3 gene result in increased and uncontrolled cone photoreceptor differentiation (especially S-cone) and a reduced number of rod photoreceptor cells during retinal development.^9,10,11

There are case series demonstrating familial inheritance in the literature.^12,13 Familial inheritance is clearly observed in our first three cases. When taking the family history of the patient in Case 1, we learned that her mother had also had vision problems throughout her life. In addition, there was consanguinity both between the patient’s parents and between the patient and her spouse. This explains how both of her children could have GFS when her spouse did not. It is reported that the phenotype of this disease may vary, despite the presence of similar mutations.^5,8,14 There was also individual variation in the nature and severity of the clinical findings and the complications experienced during follow-up in our first three cases. Studies investigating the causes of this phenotypic variability have been inconclusive.

GFS manifests as night blindness or a progressive decrease in visual acuity during the first decade of life.^4,12 It is typically characterized by hyperpigmented RPE clumps that form along the retinal vascular arcades, areas of chorioretinal atrophy, cystoid or schisis-like changes in the fovea, central or peripheral retinoschisis, vitreous degeneration, and cataract.^1,4 In addition, abnormal dark adaptation and electroretinogram results, progressive visual field loss, and color vision disorders are other accompanying symptoms.^4,12 Nummular lesions with atrophic centers and hyperpigmented borders, called “torpedo-like lesions”, were first described in GFS by Yzer et al.² They reported that these lesions were located in the healthier areas of the retina. We also observed similar lesions in Cases 2, 3, 4, and 5 in our series. The lesions were located at the border of the apparently healthy retina in Cases 3 and 4, but were in the affected retina in Cases 2 and 5. In addition, lesions were especially prominent around the upper retinal vascular arcade in Cases 4 and 5. In GFS, rod photoreceptors are essentially replaced by S-cone photoreceptors.^12,14 There is also a reduction in the number of L- and M-cone cells due to phagocytosis of cone cells by RPE cells and as a result of the NR2E3 gene mutation.¹⁵ Histopathological studies have shown an increase in S-cone cells in both the perimacular area and the peripheral retina.¹⁰ In a postmortem examination, a complete absence of rod cells and twice the normal number of cone cells was observed in the retina, with S-cone cells comprising 92% of all the cone receptors.¹⁵ However, in experimental animal models it has been reported that the cone photoreceptors replacing the rod photoreceptors do not show a diffuse histological distribution, but are concentrated in certain regions.¹⁶ These areas of concentration appear as pseudorosettes in histopathological examination, which may explain the round shape of these degenerative lesions.^2,16,17

Retinoschisis is another distinctive finding of GFS.⁴ Although peripheral retinoschisis is more common in GFS, central retinoschisis may also occur.⁴ In our series, Case 2 had both central and peripheral retinoschisis, while Case 4 exhibited only central retinoschisis. Leakage is not seen on FFA in the area of central schisis.^4,12 However, we noted that the areas of perifoveal leakage observed on FFA in Case 3 were generally consistent with the schisis-like areas observed on OCT. Considering the widespread leakage in the optic disc and at the border of the apparently healthy retina, we believed that the lesions were caused by cystoid macular edema. Leakage is rarely observed in GFS and has been reported in a limited number of cases in the literature. Fishman et al.¹² reported three GFS cases with similar widespread leakage in the posterior pole. The leakage from both the retinal vascular arcades and the optic disc reported in those cases is consistent with the findings in our patient. GFS should be considered in the differential diagnosis of patients with a fundus appearance and leakage on FFA similar to those described.

The patients in Cases 2, 4 and 5 of our series exhibited spots that appeared yellow in color on fundus images and showed hyperautofluoresence on FAF. Similar to findings reported by Yzer et al.², they were located at the borderline between the affected retina and apparently healthy retina. These spots may appear as a result of phagocytosed material found in macrophages.¹⁸

Deterioration of the laminar organization of the retina and retinal thickening on OCT have been reported in the affected retinal area.¹⁹ Composite OCT images from the affected retinal area in Case 4 showed loss of the photoreceptor layer at the boundary of the affected retina, followed by disruption of the laminar structure of the retina and a sudden increase in retinal thickness. The increase in thickness and deterioration of the anatomical structure may be due to the fact that S-cone cells, which are larger than rods, are situated where the rods should be.¹⁹ The relative decrease in choroidal thickness in the area of increased retinal thickness in the patient’s left eye was an interesting finding.

The high phenotypic variability of GFS makes it difficult to distinguish from diseases such as retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy. The less common findings reported in our case series may assist in the differential diagnosis of GFS and improve our understanding the underlying pathophysiological processes.