Clinical and Genetic Characteristics of Patients with Peripheral Retinal Flecks in Koreans

Article information

Abstract

Materials and Methods

This is a retrospective case series study of 10 patients (20 affected eyes) with peripheral retinal flecks, presented at the Seoul National University Bundang Hospital (Seongnam, Korea) between 2012 and 2023. The study was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (No. B-2407-912-107), and adhered to the tenets outlined in the Declaration of Helsinki. Informed consent was waived due to the retrospective study design.

We defined retinal flecks as whitish or yellowish deposits that are relatively homogenous in size and spread across the retina. In particular, cases with fovea-sparing retinal flecks were defined as peripheral retinal flecks. Patients included in the study were those under the age of 60 years who exhibited peripheral retinal flecks upon fundus examination. We excluded patients with reticular pseudodrusen frequently accompanied by age-related macular degeneration, as well as those with subfoveal structural destruction such as Stargardt disease and macular dystrophy. Acute or chronic ocular diseases, including chorioretinitis, sclerouveitis and lymphoproliferative disorders, and drug intoxication were excluded. Clinical characteristics included age at diagnosis, sex, corrected visual acuity at initial presentation, systemic diseases, and coexisting ocular problems.

All patients provided a detailed medical history and underwent complete ophthalmological examinations, including slit-lamp biomicroscopy and fundus examinations. Fundus photography and optical coherence tomography (OCT) were performed for all patients. Genetic panel testing to identify causative genes was conducted in seven patients. Additionally, a standard electroretinogram (ERG) was performed in seven patients.

Results

A total of 10 patients (two men and eight women) were enrolled in this study (Table 1). Patients ranged in age from 4 to 59 years (mean, 30.5 years) at presentation and all patients were affected in both eyes. There were five patients with RDH5-related fundus albipunctatus, and one patient was Alport syndrome-related retinopathy. One patient was clinically suspected to be an ocular albinism carrier, and another patient was suspected to have nanophthalmos-related retinopathy.

Table 1

Demographic and clinical features for 10 patients with peripheral retinal flecks

All five patients clinically diagnosed with fundus albipunctatus were genetically confirmed to have RDH5 mutations (cases 1–5). A common characteristic among them was the presence of well-marginated small discrete whitish dots observed on fundus examination, predominantly distributed from proximal to far peripheral retina (Fig. 1A–1P). OCT imaging of the flecked areas revealed subretinal drusenoid deposits penetrating ellipsoid zone (Fig. 2A, 2B). Three of these patients (cases 1–3) reported night blindness symptoms, and all demonstrated decreased or delayed rod response on ERG (Fig. 1).

Fig. 1

Representative images of the right eyes of four fundus albipunctatus patients: (A–D) case 1, (E–H) case 2, (I–L) case 3, and (M–P) case 5. (A,E,I,M) Fundus photography. (B,F,J,N) Optical coherence tomography (OCT). (C,G,K,O) Dark-adapted 0.01 electroretinogram (ERG). (D,H,L,P) Photopic 3.0 ERG. (A–D) Fundus photographs and OCT images show no abnormalities at the macula. Small, well-defined white dots are distributed from the proximal to far peripheral retina. ERG reveals nearly absent rod response. (E–H) White discrete dots are distributed from the proximal to far peripheral retina. OCT shows diffuse disruption of the perifoveal ellipsoid and interdigitation zones, with sparing of the fovea. ERG reveals a severely diminished rod response. (I–L) Small, well-marginated white dots are distributed from the perifovea to the periphery. OCT shows no abnormalities. ERG reveals a diminished rod response with relatively preserved cone response. (M–P) Fundus photography shows foveal depigmentation with scattered small yellowish dots. OCT reveals mild blurring of the subfoveal retinal pigment epithelium without structural disruption. ERG shows nearly normal rod and cone function. R = reference value; C = case eye.

Fig. 2

Cross-sectional image with optical coherence tomography images image over flecks. (A,B) Flecks of fundus albipunctatus patient (case 3) were revealed as subretinal drusenoid deposits penetrating ellipsoid zone and external limiting membrane (arrows). (C,D) Flecks of patient with unknown cause (case 7) were represented as subtle retinal pigment epithelium and interdigitation zone margin blurring without definite deposits over the flecked areas, whose pattern resembles flecked lesion of Alport syndrome (yellow arrowheads). (E,F) Flecks of patient suspected to be a carrier of ocular albinism (case 9) were represented as diffuse retinal pigment epithelium and interdigitation zone margin blurring without definite deposits over the flecked areas (white arrowheads).

Among the five patients with fundus albipunctatus, perifoveal photoreceptor (PR) layer disruption sparing fovea was observed on OCT in two patients (cases 2, 4) (Fig. 1E–1H). One of them (case 2) underwent scatter laser treatment due to branch retinal vein occlusion in the left eye and showed good visual acuity during follow-up. In another patient (case 3), she reported night blindness symptoms in approximately half of their eight siblings, although pedigree analysis was not conducted. In one patient (case 5), macular hypopigmentation was observed with subfoveal retinal pigment epithelium (RPE) blurring without deposits noted on OCT (Fig. 1M–1P). No choroidal neovascularization was detected. On fundus examination, the pattern of fleck appeared as small yellowish dots sprinkled in the mid-periphery. The patient was asymptomatic and ERG results were normal. This finding was incidentally discovered during routine examination, and there was no significant progression observed during a follow-up period of 66 months.

In two patients, their pattern of retinal fleck was similar but showed distinct characteristics differentiating it from RDH5-related fundus albipunctatus (cases 6, 7). Both patients showed white to yellowish flecks in the mid-far peripheral areas, which were poorly marginated with partial overlapping (Fig. 3A). On OCT, subtle RPE and interdigitation zone (IZ) margin blurring without definite deposits over the flecked areas was observed (Fig. 2C, 2D), along with foveal to perifoveal hyperreflective internal limiting membrane (ILM) in the macular area. One patient (case 6) was diagnosed with Alport syndrome in 2003 and genetic testing at that time revealed pathogenic variants in the COL4A5 gene. This patient also presented with recurrent corneal erosion and was suspected of epithelial basement membrane dystrophy. Hearing loss and renal dysfunction consistent with underlying condition were also noted. The other patient (case 7) complained of night blindness symptoms but showed normal findings on ERG. No significant systemic abnormalities were observed, and genetic testing did not identify any suspicious genes associated with Al-port syndrome.

Fig. 3

Funduscopic photo of the left eyes of three patients. (A) Alport retinopathy patient shows poorly marginated with partial overlapped white to yellowish spots over mid to far periphery (case 6). (B) Patient of retinal flecks accompanied with nanophthalmos shows small pisciform yellowish dots distributed at mid to far periphery, also with crowded and blurred optic discs with major arterial tortuosity (case 8). (C) Patient with unknown cause presented with clustered small yellowish dots, and the lesions were unevenly distributed from the perifovea to the mid-far peripheral retina (case 10).

One pediatric patient (case 8) suspected of having retinal flecks accompanied with nanophthalmos, exhibited pisciform small yellowish dots in the mid to far peripheral retina on fundus examination (Fig. 3B). Both eyes showed crowded optic discs with blurred margin and major vascular tortuosity, although optic disc drusen were not observed on disc OCT. Macular OCT findings were normal. Axial lengths measured in 2021 were 18.14 and 17.99 mm in the right and left eyes, respectively, both showing severe hyperopia of over +7 diopters (D). The patient’s mother also had a history of severe hyperopia, but genetic testing was not performed for either individual. ERG showed no specific abnormalities, and the patient demonstrated appropriate visual acuity development for her age despite of condition.

Another pediatric patient (case 9) suspected to be a carrier of ocular albinism, showed yellowish small deposit- like spots overlapping and linked from the parafovea to mid-periphery on fundus examination. These lesions appeared as deposit-like structures on fundus imaging but exhibited diffuse RPE and IZ margin blurring on OCT throughout the macula and flecked areas (Fig. 2E, 2F). Initial examination revealed moderate to severe astigmatism of +1.75 and +3.75 D in the right and left eyes, respectively, but subsequent follow-ups indicated well-developed visual acuity, with corrected visual acuity measured as 20 / 25 in the right eye and 20 / 20 in the left eye during follow-up observations.

A pediatric patient (case 10) with unknown cause presented with clustered small yellowish dots, unlike other cases, and the lesions were unevenly distributed from the perifovea to the mid-far peripheral retina (Fig. 3C). On OCT, PR layer in the macular area was intact, but focal RPE thickening was observed in cross-sectional views of the flecked areas. ERG testing showed no abnormalities. The patient underwent surgery for intermittent exotropia and subsequently achieved corrected visual acuity of 20 / 25 in both eyes.

Fundus autofluorescence (FAF) was performed on 5 out of 10 subjects. In the widefield FAF images of three fundus albipunctatus patients (cases 1, 2, 5) and the other (case 9), no significant increase or decrease in autofluorescence was observed within the fleck areas (Fig. 4A–4D). Especially in one patient (case 7), whose fundoscopic finding resembles Alport retinopathy without genetic confirmation, patchy hypoautofluorescence findings were observed on the widefield FAF images (Fig. 4E). But these findings did not exactly match the location of the flecks when compared with the fundus photo. Fluorescein angiography was performed on three patients, two with fundus albipunctatus (cases 2, 5) and one with Alport syndrome (case 6). Fleck areas showed no enhancement or leakage and, conversely, no specific window defects were observed (Fig. 4F–4H). Indocyanine green angiography imaging was performed in only one patient (case 7), and no particular features related to choroidal blood flow were observed (Fig. 4I).

Fig. 4

Multimodal imaging of the subjects. Fundus autofluorescence images of (A) case 1, (B) case 2, (C) case 5, (D) case 9, and (E) case 7. Fluorescein angiography of (F) case 2, (G) case 5, and (H) case 6. (I) Indocyanine green angiography of case 7.

Genetic panel testing was recommended for all 10 patients. Among them, genetic testing was actually conducted in seven patients, and pathogenic variants were identified in six patients (Table 2). Specifically, four different RDH5 variants were identified. Notably, a rare mutation, c.515G>A (p.Gly172Asp), was found in one patient (case 1), who also had another heterozygous mutation, c.928delins-GAAG (p.Leu310GluVal). Another patient (case 3) exhibited compound heterozygous mutations of c.500G>A (p.Arg167His) and c.832C>T (p.Arg278Ter). Three patients (cases 2, 4, 5) carried homozygous mutations of c.928delinsGAAG (p.Leu310GluVal). In a male patient with Alport syndrome (case 6), a hemizygous nonsense mutation of c.3556C>T (p.Gln1186Ter) in the COL4A5 gene on the X chromosome was identified.

Table 2

Summary of molecular genetic data

Discussion

Retinal fleck is an uncommon finding of retina characterized by whitish or yellow spots. While some flecks are confined to the peripheral retina, others can involve the macula. Various imaging techniques have been utilized to identify structural or electrophysiological defects associated with these conditions, with several related genes reported. In this study, we describe the cases and review various peripheral retinal fleck disorders as reported.

Both fundus albipunctatus and retinitis punctata albescens (RPA) present a flecked retina characterized by discrete, uniform, white-yellowish small spots in the mid-periphery. Fundus albipunctatus typically exhibits a stationary nature and is considered a subgroup of congenital stationary night blindness, while RPA belongs to a subgroup of retinitis pigmentosa and may progress [14,15]. In OCT imaging, homogeneous dome-shaped hyperreflective deposits are observed in the inner RPE layer, projecting into the outer retina, thereby disrupting the ellipsoid zone, external limiting membrane, and outer nuclear layer [15,16]. FAF imaging reveals a low background autofluorescence with a few areas of hyperautofluorescence within the white dots [15].

Patients typically present with symptoms such as night blindness and peripheral visual loss, along with delayed dark adaptation. While visual acuity and color vision are usually normal, dark-adapted ERG often shows marked reductions, which can return to normal after prolonged period of dark adaptation [10]. Light-adapted ERG may appear normal but can exhibit cone abnormalities [10,14]. Fundus albipunctatus associated with the RDH5 gene in an autosomal recessive pattern, encodes the enzyme 11-cis retinol dehydrogenase, crucial for the oxidation of 11-cis retinol to 11-cis retinal. Impaired function of the protein could impair retinoid recycling [17,18]. On the other hand, RPA linked to the RLBP1 gene in an autosomal recessive manner, encodes CRALBP, a protein mainly expressed in RPE and Muller cells, binds to the 11-cis retinol and 11-cis retinal to improve the retinoid cycle [19].

Most patients in this study were incidentally detected during examinations for other conditions or routine checkups. Except two individuals, all were younger than 50 years old; however, those two are believed to have exhibited a similar clinical course of RDH5-related retinal flecks from a young age. Traditionally, RDH5-related fundus albipunctatus was considered to be nonprogressive. But recent studies reported abnormal cone cell function in 38% of patients with RDH5-related fundus albipunctatus and findings of partially reduced cone cell density using adaptive optics scanning laser ophthalmoscopy [18,20].

In our study, phenotypic heterogeneity was observed even among patients with the same RDH5 mutation. On OCT, PR layer disruption was observed bilaterally in two patients (cases 2, 4), while no distinct abnormalities in the PR layer were noted in the others. ERG findings showed preserved cone cell function, consistently, but the degree of rod dysfunction varied. While initial ERG revealed no definitely cone dysfunction (Fig. 1), long-term follow-up is needed to determine whether there will be any onset of macular abnormalities or cone dysfunction.

Alport syndrome is a systemic disease characterized by renal failure, hearing loss, and ocular changes such as corneal dystrophy, anterior lenticonus, and retinopathy [21–23]. It is caused by mutations in the COL4A5 gene (X-linked) or COL4A3 or COL4A4 genes (autosomal recessive), leading to the loss of the α3(IV)-α5(IV) collagen network and thinning of the ILM and RPE layer [24]. Fleck retinopathy is most common retinal feature of Alport syndrome, with a prevalence of most males and 25% in females with X-linked inheritance, or most patients with autosomal recessive inheritance [25]. This condition manifests as whitish-yellow dots and flecks, hyperreflective ILM, and a relatively dull macular reflex in the spared fovea, often referred to as a lozenge. OCT typically shows hyperreflective ILM and RPE, along with temporal retinal thinning [21].

Nanophthalmos is a clinical condition characterized by a small yet structurally normal eye. It can follow sporadic or familial pattern. Patients often present with high to extreme hyperopia, reduced visual acuity, and complications such as angle closure glaucoma. Fundus examination reveals various macular and peripheral retinal features, including optic disc drusen, crowded optic disc, foveoschisis, and chorioretinal folds [26]. Additionally, small yellowish deposits resembling flecks may be observed in the mid-periphery [27]. In our study, the patient (case 8) did not have optic disc drusen but did present with arterial tortuosity along with flecks. There was no foveal lesion, and the patient achieved appropriate visual development with correction.

Benign familial fleck retina (BFFR) is another condition to be diferentiated, which was not observed in our study cohort. Introduced by Sabel Aish and Dajani [28] in the 1980s, BFFR exhibits distinct features from fundus albipunctatus and fundus flavimaculatus, characterized by the presence of yellowish round, linear, or pisciform flecks in the fundus, which can affect the whole fundus but typically do not involve the disc or macula. Most patients with BFFR show no symptoms and exhibit normal dark adaptation, as well as normal perimetric or electrophysiologic finding. The causative gene PLA2G5, inherited in an autosomal recessive manner, encodes group V phospholipase A2 (G5PLA2), an enzyme mediating hydrolysis of the middle ester bond of glycerophospholipids [29].

Another possible group of conditions exhibiting similar to flecks is reticular pseudodrusen, presents in approximately 29% of age-related macular degeneration patients [30]. Fundus examination of reticular pseudodrusen reveals multiple dot-like whitish subretinal structures with blurred margin, often clustered and linked to form a reticular pattern [30]. These deposits are observed in OCT as subretinal drusenoid deposits and sometimes extending into the inner-outer segment junction [31]. Therefore, as observed in our study, when yellow to whitish dots are discretely distributed at relatively young age, and especially if there are symptoms of night blindness or systemic symptoms such as hearing loss, a family history, or OCT findings distinct from subretinal drusenoid deposits like IZ blurring, genetic testing may be beneficial to make differential diagnosis.

In this study, 10 patients with peripheral retinal flecks in 20 eyes were observed. Among the seven patients who underwent genetic testing as reported, RDH5 mutation was observed in five patients and COL4A5 mutation in one patient. One patient did not show any significant reported variants, and genetic testing was not conducted in three patients. All patients eventually had corrected visual acuity of 20 / 40 or better in both eyes, and during a mean follow- up period of 76.5 months, no significant progression of lesions was observed. An interesting finding was that among patients complaining of night blindness, ERG showed abnormal rod responses in those with RDH5 mutation, while patients with unidentified mutations exhibited normal ERG responses. Therefore, conducting both genetic testing and electrophysiological tests in patients with peripheral retinal flecks is crucial in differential diagnosis.

In the study population observed in this research, fundus albipunctatus and Alport syndrome were predominant conditions. Among RDH5 mutations, the c.928delins- GAAG variant was identified in 7 out of 10 (70%) (Table 2), corresponding closely to allele frequencies of around 65% in Japanese studies [10] and 75% in Chinese studies [32]. However, regardless of the presence of this mutation, the variability in night blindness symptoms observed in our study suggests phenotypic variability, consistent with findings from the Japanese study [10].

This study has several limitations. First, the sample size was very small, and genetic testing was only conducted in a subset of the patient population, limiting the ability to obtain conclusive information. Additionally, the difficulty in quantifying the extent, color, and size of retinal flecks made challenges in clear classification. As a result, this condition encompasses a heterogeneous group of disorders. However, despite these limitations, this study is important as it is the first analysis of East Asian patients with peripheral retinal flecks focusing specifically on Koreans, particularly including genetic testing results. In summary, although peripheral retinal fleck disease is rare among Koreans, when these findings are observed in fundus examination, it is beneficial to consider various possibilities such as RDH5-related fundus albipunctatus or Alport syndrome and to proceed with genetic and electrophysiological tests. Additionally, despite reports of night blindness symptoms in some cases, all patients demonstrated satisfactory corrected visual acuity.

Article information Continued