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Benign yellow-dot maculopathy: case report and review of the literature

Published:January 23, 2023DOI:https://doi.org/10.1016/j.jcjo.2023.01.002
      The differential diagnosis for yellow macular dots is extensive and includes toxic, genetic, degenerative, and idiopathic etiologies. In many cases, these conditions are progressive, result in decreased central visual acuity, and can be associated with systemic findings. A thorough history, examination, and multimodal visualization techniques, including optical coherence tomography (OCT), fluorescein angiography (FA), and fundus autofluorescence (FAF), are often used to diagnose these conditions.
      • Kovach JL
      • Isildak H
      • Sarraf D.
      Crystalline retinopathy: unifying pathogenic pathways of disease.
      Benign yellow-dot maculopathy, however, is a recently characterized asymptomatic, typically bilateral macular phenotype.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      To our knowledge, only 45 cases from 28 families in 5 reports that have been described in the literature. Thus far there is no definite etiology of this condition, but it appears to have a sporadic or autosomal-dominant inheritance pattern without an identified causative gene.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      • Mishra AV
      • Pollmann AS
      • Choudhry N
      • Demmings E
      • Gupta RR.
      Unilateral benign yellow dot maculopathy.
      • Moisseiev E.
      Benign yellow dot maculopathy.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      • Ninet L
      • David T
      • Gascon P.
      Multimodal imaging for benign yellow dot maculopathy.
      Herein we describe another case of benign yellow-dot maculopathy in a young Hispanic male who remained stable through 2-year follow-up and review the literature surrounding this rare entity.
      A 17-year-old Hispanic male was referred to the retina clinic for evaluation of a possible macular dystrophy. He had no visual complaints, and his past ocular history was significant for mild myopia in both eyes. His past medical history was significant for depression treated with aripiprazole. He also had a history of a suicide attempt 3 years earlier after ingesting approximately 75 Aspirin tablets and 5 aripiprazole tablets. He had no history of intravenous drug use. His family history was nonrevealing for any inherited ocular disorders. His best-corrected visual acuity (BCVA) was 20/20 in both eyes with normal intraocular pressures and no relative afferent pupillary defect. Visual fields, ocular motility, and anterior-segment examination were unremarkable. His funduscopic examination revealed multiple perifoveal fine, discrete yellow spots bilaterally (Fig. 1A, B). The retinal periphery was unremarkable. OCT was normal bilaterally (Fig. 1E, F). Because the patient was asymptomatic, he was observed with no electroretinography (ERG) or FA. On examination 2 years later, the patient's BCVA remained 20/20. He remained asymptomatic, and his fundus examination (Fig. 1C, D) and OCT images (Fig. 1G, H) remained stable. FAF demonstrated hyper-autofluorescent foci corresponding to the yellow lesions seen on clinical examination (Fig. 1I, J). No further work-up, including genetic testing, was pursued.
      Fig 1
      Fig. 1Fundus photography of right (A) and left eyes (B) on initial presentation. Fundus photography of right (C) and left eyes (D) at repeat examination 2 years after initial examination revealing stable yellow dots in both maculae. Unremarkable optical coherence tomography of the maculae of the right (E) and left eyes (F) on initial examination. Optical coherence tomography of the maculae of the right (G) and left eyes (H) remaining unchanged at repeat examination 2 years after the initial examination. Fundus autofluorescence revealing hyper-autofluorescent dots in both maculae on repeat examination in the right (I) and left eyes (J)
      The differential diagnosis for yellow dots within the macula includes drug toxicities (e.g., canthaxanthin), inherited diseases (e.g., oxalosis, Bietti crystalline dystrophy), degenerative (e.g., drupelets or medium-sized drusen seen in age-related macular degeneration), and idiopathic conditions.
      • Kovach JL
      • Isildak H
      • Sarraf D.
      Crystalline retinopathy: unifying pathogenic pathways of disease.
      • Drenser K
      • Sarraf D
      • Jain A
      • Small KW.
      Crystalline retinopathies.
      • Ferris 3rd, FL
      • Wilkinson CP
      • Bird A
      • et al.
      Clinical classification of age-related macular degeneration.
      Degenerative changes such as drupelets would be unlikely given the symmetrical foveal location, the age of the patient, and the normal OCT images and hyper-autofluorescence seen on FAF.
      • Ferris 3rd, FL
      • Wilkinson CP
      • Bird A
      • et al.
      Clinical classification of age-related macular degeneration.
      • Ly A
      • Nivison-Smith L
      • Assaad N
      • Kalloniatis M.
      Fundus autofluorescence in age-related macular degeneration.
      Because the patient did not have a known family history of retinal disease, a toxic etiology was initially considered given the recent Aspirin and aripiprazole overdose, but neither have been reported to cause crystalline retinopathy.
      • Faure C
      • Audo I
      • Zeitz C
      • Letessier JB
      • Robert MP.
      Aripiprazole-induced chorioretinopathy: multimodal imaging and electrophysiological features.
      • Zhu W
      • Wu Y
      • Xu D
      • et al.
      Aspirin use and risk of age-related macular degeneration: a meta-analysis.
      However, after 2 years of follow-up, these findings were seen to be more characteristic of a recently described phenotype—benign yellow-dot maculopathy. Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      described a series of 36 patients from 23 unique families in the initial report of benign yellow-dot maculopathy in 2017. In their report, 33 of 36 patients were asymptomatic, with the other 3 patients experiencing visual symptoms that were not attributable to these macular findings. Funduscopic findings included bilateral discrete yellow dots at the level of the retinal pigment epithelium (RPE). Additionally, these dots tended to be evenly distributed around the fovea or in the nasal parafoveal region. There were no other retinal findings.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      Since this report, 9 additional cases have been described with similar presentations,
      • Moisseiev E.
      Benign yellow dot maculopathy.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      • Ninet L
      • David T
      • Gascon P.
      Multimodal imaging for benign yellow dot maculopathy.
      with Mishra et al. describing the first case of unilateral benign yellow-dot maculopathy.
      • Mishra AV
      • Pollmann AS
      • Choudhry N
      • Demmings E
      • Gupta RR.
      Unilateral benign yellow dot maculopathy.
      Our patient shared similar characteristics with those described in the literature, such as bilateral nonprogressive maculopathy, no visual impairments, and multiple yellow dots evenly distributed in the perifoveal macula. In the 45 cases described in the literature, the median age of the patients was 16 years (range, 5–69 years), which is like our patient's age on initial presentation. This phenotype favoured females (67%) versus males (33%). BCVA was excellent overall in these patients, with 64% of eyes having 20/20 vision (Table 1). Ophthalmic imaging findings are essential when evaluating these rare macular phenotypes. In the cases described in the literature, OCT of the macula was performed in 58% and was normal in 58% and showed ellipsoid zone irregularity in 23% and RPE irregularity in 19%. FA was only obtained in 13% of patients and revealed early hyperfluorescence of the dots (50%), normal FA (33%), and mild unilateral RPE irregularities with window defect (17%). FAF was obtained in 64% of patients, and all showed hyper-autofluorescence of the dots. ERG was obtained in 49% of patients, and all were normal except from 1 patient who was mildly abnormal. Pattern ERG was abnormal in 2 of these patients. Our patient's unremarkable OCT findings and hyper-autofluorescent dots on FAF were similar to those of the other patients described in the literature. It is likely that these hyper-autofluorescent dots on FAF are due to photoreceptor and RPE dysfunction that has been previously reported. Because of the size and non-progressive nature of these dots, the focal changes in the photoreceptors and RPE are unlikely to be visually significant and undetectable on many of our imaging modalities, which explains the unremarkable imaging findings reported in the literature. Demographically, our patient is a Hispanic male, and this has not yet been described in the literature.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      • Mishra AV
      • Pollmann AS
      • Choudhry N
      • Demmings E
      • Gupta RR.
      Unilateral benign yellow dot maculopathy.
      • Moisseiev E.
      Benign yellow dot maculopathy.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      • Ninet L
      • David T
      • Gascon P.
      Multimodal imaging for benign yellow dot maculopathy.
      Table 1Summary of demographic data of patients presenting with benign yellow-dot maculopathy in the literature
      Case numberAuthor(s)AgeFamilySexBCVA OD (LogMAR)BCVA OS (logMAR)
      1Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      51F00
      2Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      281F0–0.08
      3Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      501F–0.08–0.08
      4Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      142M–0.080
      5Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      432F0.180.18
      6Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      453F–0.08–0.08
      7Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      63M–0.08–0.08
      8Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      154F0.780.78
      9Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      184F00
      10Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      454F0.180.18
      11Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      104M–0.08–0.08
      12Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      225F–0.08–0.08
      13Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      5F00
      14Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      76F00
      15Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      6M
      16Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      596F
      17Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      117F00
      18Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      7M
      19Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      78F00
      20Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      458F00
      21Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      138M00
      22Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      89F00
      23Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      610M0.70.8
      24Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1011F00
      25Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      512F00
      26Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1013F00
      27Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1214F0.40
      28Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1415M0.080.14
      29Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1516F00
      30Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1517M00
      31Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      2818M00
      32Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      2819F–0.08–0.08
      33Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      2920F00
      34Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      821F00
      35Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      1622F00
      36Borman et al.
      • Borman AD
      • Rachitskaya A
      • Suzani M
      • et al.
      Benign yellow dot maculopathy: a new macular phenotype.
      5.523F00
      37Murro et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      4324M00
      38Murro et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      3424M00
      39Murro et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      6924F00
      40Murro et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      5525M00
      41Murro et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      5325F00
      42Mishra et al.
      • Murro V
      • Mucciolo DP
      • Giorgio D
      • et al.
      Multimodal imaging of benign yellow dot maculopathy.
      ,
      Unilateral presentation only in the right eye.
      2526M00
      43Moisseiev
      • Moisseiev E.
      Benign yellow dot maculopathy.
      2427M0.10
      44Moisseiev
      • Moisseiev E.
      Benign yellow dot maculopathy.
      27F00
      45Ninet et al.
      • Ninet L
      • David T
      • Gascon P.
      Multimodal imaging for benign yellow dot maculopathy.
      3828F00
      46This study1729M00
      BCVA, best-corrected visual acuity
      low asterisk Unilateral presentation only in the right eye.
      Limitations of this report include the single case, the lack of ophthalmic examinations prior to the Aspirin overdose, and the lack of the examinations of family members. Because this phenotype is typically asymptomatic, it is possible that our patient's family members have similar findings that have previously gone undiagnosed, especially without routine examination. Genetic testing was not performed, which may have helped elucidate a specific causative gene locus.
      In conclusion, there is a paucity of literature on benign yellow-dot maculopathy. Including our case, only 46 total cases have been described in the literature to date. It is possible that this entity is underreported in the literature because patients may not present for routine examination given that they are typically asymptomatic. Because no known etiology has been described thus far, we recommend examining family members of patients presenting with this phenotype, obtaining a thorough history of the patient and his or her family, and considering genetic testing. While this condition has not been shown to significantly affect visual acuity, we believe that it is important to increase awareness of this phenotype, allowing ophthalmologists to keep this in the differential diagnosis when evaluating patients with similar presentations and to prevent misdiagnosis.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this correspondence.

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