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INTRODUCTION

Enhanced S-cone syndrome is a rare, slowly progres-sive autosomal recessively inherited retinal degenera-tion related to mutations in the NR2E3 gene. Patients often present with night blindness, visual loss and visual field abnormalities. Patients with enhanced S-cone syndrome exhibit a variable clinical pheno-type associated with various degrees of pigmentary changes and foveal schisis. We report a 14-month-old boy with an unusual funduscopic appearance. The diagnosis of enhanced S-cone syndrome was suggested by the pathognomonic electroretino-graphic pattern and was confirmed by the finding of homozygous NR2E3 mutations.

CASE REPORT

A 14-month-old boy was referred to the Department of Ophthalmology, University Hospitals of Leuven, Belgium, with a head tilt and nystagmoid eye move-ments. He was also very frightened in the dark. He was the first-born child to consanguineous Arab parents and was in good general health. There were

no familial ocular problems. Orthoptic examination showed a right divergent squint and a pendular nys-tagmus. Binocularly, the child followed and fixated objects of 2 inches diameter. The anterior segment was normal. Funduscopy showed a very peculiar fundus picture with macular hemorrhages and preretinal fibro-sis. Retinal vessels had a dilated and tortuous aspect. The vitreous was clear, the optic discs and periphery were normal (Figure 1). Cycloplegic refraction showed bilateral hypermetropic astigmatism. The child was immediately referred to the emergency department where a total body X-ray and CT scan of the brain was performed to exclude non-accidental injury; both exams were found to be negative. A blood examination could not demonstrate any bleeding diathesis.

The flash electroretinogram (ERG), performed under general anesthesia, showed the following: the rod-specific ERG was undetectable; the ERG response to a standard single flash had a similar waveform under photopic and scotopic conditions; and the 30-Hz flicker ERG was both delayed and of lower amplitude than the single-flash photopic ERG a-wave (Figure 2).

The diagnosis of enhanced S-cone syndrome was suggested by this uniquely abnormal

Ophthalmic Genetics, 34(1-2), 105–108, 2013© 2013 Informa Healthcare USA, Inc.ISSN: 1381-6810 print/1744-5094 onlineDOI: 10.3109/13816810.2012.726395

Received 15 June 2012; revised 17 August 2012; accepted 26 August 2012Correspondence: Catherine Cassiman, University Hospitals Leuven, Ophthalmology, Kapucijnenvoer 33, Leuven, 3000 Belgium. E-mail: cathycassiman@hotmail.com

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2013

Ophthalmic Genetics

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Peculiar fundus abnormalities and pathognomonic electrophysiological findings in a 14-month-old boy

with NR2E3 mutationsCatherine Cassiman1, Werner Spileers1, Elfride De Baere2, Thomy de Ravel3, and

Ingele Casteels1

1Department of Ophthalmology, University Hospitals of Leuven, Belgium, 2Department of Human Genetics, University of Ghent, Belgium, and 3Department of Human Genetics, University Hospitals of Leuven, Belgium

ABSTRACT

Enhanced S-cone syndrome is a rare, slowly progressive autosomal recessively inherited retinal degeneration related to mutations in the NR2E3 gene. Patients often present with night blindness, visual loss and visual field abnormalities. Patients with enhanced S-cone syndrome exhibit a variable clinical phenotype associ-ated with various degrees of pigmentary changes and foveal schisis. We report a 14-month-old boy with an unusual funduscopic appearance. The diagnosis of enhanced S-cone syndrome was suggested by the uniquely abnormal electroretinographic pattern and was confirmed by the finding of homozygous NR2E3 mutations.

KEYWORDS: Enhanced S-cone syndrome, Night blindness, NR2E3

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electroretinographic pattern and prompted DNA analysis.

Genetic testing of the NR2E3 gene was performed using polymerase chain reaction and bidirectional Sanger sequencing of the coding exons and intron-exon boundaries.

DNA analysis showed homozygous nonsense NR2E3 mutations in exon 4, namely c.373C>T (at protein level p.Arg125X).

The flash ERG and funduscopy were repeated after 10 months. The macular appearance had changed to nummular pigmentary depositions at the level of the retinal pigment epithelium (RPE) (Figure 3).

DISCUSSION

Patients with enhanced S-cone syndrome show a vari-able clinical phenotype.1 They often present with night blindness. Visual acuity varies from normal to severely reduced. Hypermetropia with some degree of astigma-tism is identified in most of them. Funduscopy can be normal, especially in the younger subjects, but typically shows nummular pigmentary clumping at the RPE level, primarily along the vascular arcades.This retinal appearance is associated with the absence of autofluo-rescence outside the vascular arcades, possibly related to the loss of photoreceptors in this region. A similar

nummular pigmentary retinopathy can also be seen in Bardet-Biedl syndrome, in retinitis pigmentosa with preserved para-arteriolar RPE and in non-syndromic retinitis pigmentosa.1

In the early disease process of enhanced S-cone syn-drome, only subtle pigmentary changes, surrounded by white dots may be apparent.

Foveal schisis-like changes is another common pre-sentation, this phenotype is frequently correlated with poor visual acuity.2

The ERG features are pathognomonic: the rod-specific ERG is undetectable and single flash photopic and scotopic responses to the same stimulus have a similar waveform. The 30-Hz flicker ERG is delayed and of lower amplitude than the single-flash photopic a-wave. ERG amplitudes vary between patients, the older patients having lower amplitudes, depending on the severity of degeneration. These ERG responses have been shown to be dominated by short-wavelength-sensitive mechanisms.1

Histopathological data found in one patient showed an absence of rods, but a two-fold increase in the cone population, mainly S-cones. Since progressive retinal dystrophies are characterized by loss of photorecep-tors, the increased number of cones in enhanced S cone syndrome is unique.1

The NR2E3 gene codes for a nuclear receptor that is specific to photoreceptors. One of its principle functions

FIGURE 1 Fundus photographs taken at 14 months of age, under general anesthesia, showing subretinal hemorrhages (full arrow) and fibrosis (interrupted arrows). Left upper and lower image: right eye. Right upper and lower image: left eye.

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FIGURE 3 Fundus photographs taken at the age of 2 years, showing subretinal pigment deposition (arrows) and scarring. Left: right eye. Right: left eye.

FIGURE 2 ISCEV standard Flash ERG performed under general anesthesia. OD: right eye, OS: left eye. A: Light adapted 3.0 ERG: response with low amplitude and broadened a- and b-wave. B: Light-adapted 3.0 flicker ERG: very low amplitude response. C: Dark-adapted 0.01 ERG: no response detectable. D: Dark-adapted 3.0 ERG. E: Dark-adapted 3.0 Oscillatory potentials.

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is to repress the expression of cone-specific genes in rod photoreceptors.3

Mutations in the NR2E3 gene have been associated with a variety of autosomal recessively inherited reti-nal degenerations such as enhanced S-cone syndrome, Goldmann-Favre syndrome and clumped pigmentary retinal degeneration. Some specific NR2E3 mutations cause autosomal dominant retinitis pigmentosa.4

The homozygous mutation in our patient leads to the introduction of a premature stop codon at position 125 of the protein (ref sequence cDNA is NM_014249.2:c.373C>T). Due to the nature of the muta-tion, this can be considered to be a pathogenic mutation. This mutation has been reported once, in a compound heterozygous state in another patient with ESCS.5

The funduscopic appearance of diffuse subretinal bleeding and fibrosis without macular schisis, as found in our patient, has never been reported. We did find two case reports of foveal neovascularization. They both presented at the age of 9 years with decreased vision, subfoveal neovascularization in one eye and cystic maculopathy in the other eye.6,7

Although submacular neovascularization was not detected in our patient, the hemorrhage may suggest that submacular vascular abnormality was present. This submacular vascular abnormality may be one of the clinical characteristics of enhanced S-cone syndrome, which is associated from early in life. Over time, the typical pigmentary changes within the vascular arcades did emerge in our case and the two cases cited.

Enhanced S-cone syndrome should therefore be con-sidered in a young patient with subretinal bleeding and

night blindness. The presence of the pathognomonic ERG establishes the diagnosis and directs appropriate genetic screening and counseling.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

REFERENCES

1. Audo I, Michaelides M, Robson AG, et al. Phenotypic varia-tion in enhanced S-cone syndrome. Invest Ophthalmol Vis Sci 2008 May; 49(5):2082–2093.

2. Vaclavik V, Chakarova C, Bhattacharya S, et al. Bilateral giant macular schisis in a patient with enhanced S-cone syndrome from a family showing pseudo-dominant inheritance. Br J Ophthalmol 2008 Feb;92(2):299–300.

3. Pachydaki S, Klaver C, Barbazetto I, et al. Phenotypic fea-tures of patients with NR2E3 mutations. Arch Ophthalmol 2009;127(1):71–75.

4. Bandah D, Merin S, Ashhab M, Banin E, Sharon D. The spectrum of retinal diseases caused by NR2E3 muta-tions in Israeli and Palestinian patients. Arch Ophthalmol 2009;127(3):297–302.

5. Roorda A, Sundquist S, Solovyev A, Ratnam K, Lujan BJ, Stone EM, Duncan JL. Adaptive Optics Imaging Reveals Supernormal Cone Density in Enhanced S-Cone Syndrome. ARVO 2010, #2934

6. Lam BL, Goldberg JL, Hartley KL, Stone EM, Lui M. Atypical mild enhanced S-cone syndrome with novel compound het-erozygosity of the NR2E3 gene. Am J Ophthalmol 2007;144(1): 157–159.

7. Nakumara M, Hotta Y, Piao C-H, Kondo M, Terasaki H, Miyake Y. Enhanced S-cone syndrome with subfoveal neo-vascularisation. Am J Ophthalmol 2002;133(4):575–577.

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