Benign Yellow Dot Maculopathy
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Disease Entity
Benign Yellow Dot Maculopathy
Disease
Benign yellow dot maculopathy, first described by Dev Borman et al. in 2017, is a rare condition characterized by bilateral yellow dots in the parafoveal macula.[1] There has been one reported case of unilateral involvement.[2] The condition is non-progressive, and patients have normal visual function.[1] Two further unilateral cases were published independently in 2024, each described by its
authors as the second reported case[3][4]
Epidemiology
Prevalence is unknown, likely due to the condition’s benign nature. A recent literature review demonstrated a 2:1 female-to-male ratio, a median age at diagnosis of 16, and a range 5-69 of reported cases.[1][2][5][6][7][8] Benign yellow dot maculopathy has been reported in those of White, West African, South Asian, African-Caribbean, and Hispanic descent.[1][5] Around 46 cases have been reported till 2023. [5]Subsequent case reports and series have raised the published total to roughly 50.[3][4][9][10][11]The cases have now been reported from Portugal and Palestine.[4][10]A single United Kingdom center identified 25 affected individuals from 19 unrelated families presenting between 2016 and 2023, which suggests the condition is considerably more common than the small published literature implies.The median age at presentation in that cohort was 37 years, with a range of 4 to 54 years, a difference from earlier series that reflects referral and ascertainment patterns rather than a difference in the disease itself.[9]
Risk Factors
Family history is a risk factor, given its association with autosomal dominant inheritance.[1] In the first large study, 'Whole-exome analysis across three unrelated families found no pathogenic variants in known macular dystrophy genes. Haplotype sharing analysis in one family excluded linkage with the North Carolina macular dystrophy (MCDR1) locus.'[1]Haplotype sharing analysis also found no rare exonic variants within the shared segment partially overlapping the MCDR3 locus on chromosome 5p15, and a non-coding regulatory mechanism, as demonstrated for MCDR1 and MCDR3, has been proposed.[1]
A later cohort confirmed vertical transmission, including one instance of male-to-male transmission in a family, examination of 15 first-degree relatives of 8 probands identified 6 further affected individuals.[9]. Next-generation sequencing in a single long-followed case identified only two heterozygous variants of uncertain significance, in ALMS1 and GPR179, neither of which is established as causal.[9]
Pathophysiology
The pathophysiology is unknown. Although some reported cases are sporadic, it is hypothesized that an autosomal dominant inheritance is involved.[1][5]
A structural hypothesis has been proposed on the basis of paired autofluorescence imaging. The dots are hyperautofluorescent on short-wavelength (blue) fundus autofluorescence but hypoautofluorescent on near-infrared autofluorescence.[12] Because short-wavelength autofluorescence predominantly reflects retinal pigment epithelium lipofuscin and near-infrared autofluorescence predominantly reflects melanin, this reciprocal pattern is consistent with a focal absence of melanin within retinal pigment epithelium cells. Reduced melanin would lower the near-infrared signal and would also absorb less of the blue excitation light, thereby enhancing visualization of the underlying lipofuscin, which appears clinically as a yellow dot. This hypothesis also accounts for the essentially normal appearance on optical coherence tomography.[12]
Diagnosis
Benign yellow dot maculopathy usually presents as an incidental finding of bilateral yellow dots in the parafoveal macula on routine fundoscopic examination, as most patients are asymptomatic.[1] Best corrected visual acuity (BCVA) is typically very good, as 64% of reported eyes have 20/20 visual acuity.[5]In a more recent cohort, BCVA was 20/25 or better in every patient once eyes with unrelated ocular pathology were excluded.[9]
History
Patients are typically asymptomatic; this condition is noted on routine funduscopic examination as an incidental finding.Patients are frequently referred with a working diagnosis of early-onset drusen or macular dystrophy, and recognition of the phenotype avoids unnecessary investigation.[9]
Physical Examination
The typical exam finding is bilateral yellow dots in the parafoveal macula, with one reported case of unilateral involvement. Representative images are available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503697/ and here. The clinical features described by Dev Borman et al. include 'All subjects had bilateral symmetric multiple yellow dots at the macula. In the majority, these were evenly distributed throughout the fovea, but in nine subjects they were concentrated in the nasal parafoveal area. The dots were hyperautofluorescent on fundus autofluorescence imaging. OCT imaging was generally normal, but in 6 subjects, subtle irregularities at the inner segment ellipsoid band were seen. Electrophysiological studies identified normal macular function in 17/19 subjects and normal full-field retinal function in all subjects. '[1]
Additional examination findings have been reported since. A yellow peripapillary crescent was present to a varying degree in 17 of the 26 subjects in the original series for whom detailed images were available, while the optic disc was otherwise normal in all.[1]Extension of the dots to and beyond the temporal vascular arcades occurs in a substantial minority: in a cohort of 25 individuals, the dots extended to the arcades in 19 and beyond the arcades in 11.[9]Lesions are not found in the far retinal periphery, which is a useful point of distinction from North Carolina macular dystrophy.[9] Very mild phenotypes consisting of only a few dots occur, particularly in relatives of index patients, and may be dismissed as normal variation in the absence of the family context.[9]
Diagnostic Procedures
There is no specific diagnostic test to diagnose benign yellow dot maculopathy aside from a clinical exam; however, a recent review of the literature reported the following findings using common diagnostic tests in the workup of benign yellow dot maculopathy[5]:
- OCT: no changes, but can demonstrate ellipsoid zone or RPE irregularity. Ellipsoid zone irregularity was seen in 11 of 25 eyes in a later cohort. There is no hyperreflective granulation of the inner retinal layers, a feature that distinguishes this condition from white dot fovea.[3][9]
- Fluorescein angiography: Early hyperfluorescence of the dots and mild RPE irregularities with window defect, without change in size or intensity through the course of the angiogram and without leakage.[1]
- FAF: hyperautofluorescence of the dots
- Near-infrared autofluorescence: the same dots are hypoautofluorescent, the [10]reciprocal of the blue-light appearance.[9]
- OCT angiography: normal.[4]
- Adaptive optics: the dots appear as hyperreflective lesions within the macular cone mosaic.[6]
- Electrophysiology: full-field electroretinography is normal, and the electro-oculogram light rise was normal in 9 of 10 tested subjects in the original series, although a subnormal electro-oculogram and a global reduction in microperimetric sensitivity have been reported in an isolated long-term case.[1][10]
The differential diagnosis for this condition includes the following:
- Autosomal dominant drusen
- Bietti crystalline retinopathy
- Cystinosis
- Fundus flavimaculatus
- North Carolina macular dystrophy
- Oxalosis
- Talc
- Tamoxifen
- Age-Related Macular Degeneration
- Basal laminar drusen
- White dot fovea, The dots were highly reflective on green monochromatic images, were not visible on fluorescein angiography, and appeared hyperreflective in the inner retina using spectral-domain optical coherence tomography. Adaptive optics showed polygonal granules ranging from 1 to 10 μm in size. [13]
- Stargardt disease[4]
- Best disease and pattern dystrophies[4]
- Congenital grouped albinotic spots[4]
- Mitochondrial retinopathy[14]
- Pachydrusen[14]
- Drusen-like lesions beneath the retina in patients with partial lipodystrophy and type II mesangiocapillary glomerulonephritis (MCGN).[15]
Management
Due to the non-progressive and benign nature of this condition, observation is recommended. Other causes of yellow dots in the macula should be considered and treated appropriately.Confident recognition of the phenotype is the principal management step, since accurate diagnosis at first presentation avoids unnecessary genetic testing, repeated imaging, serial follow-up, second-opinion referrals, and the psychological burden of a presumed progressive inherited retinal dystrophy.[9]
Prognosis
Long-term outcomes are currently unknown. The exact etiopathogenesis and differentiation from common differential diagnoses may need more cases with this condition to prove this to be a new entity. Strict diagnostic criteria for this condition are yet to be reported. Various reported cases have different fundus features.[1][2]Stability has now been documented over mean follow-up periods of approximately 3.6 and 5.8 years in recent series, and in individual patients for 18 years and for 12 years, with no morphological or functional progression.[4][8][9][10]
[4]References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Dev Borman, A., Rachitskaya, A., Suzani, M., Sisk, R. A., Ahmed, Z. M., Holder, G. E., Cipriani, V., Arno, G., Webster, A. R., Hufnagel, R. B., Berrocal, A., & Moore, A. T. (2017). Benign yellow dot maculopathy: A new macular phenotype. Ophthalmology, 124(7), 1004–1013. https://doi.org/10.1016/j.ophtha.2017.02.026
- ↑ 2.0 2.1 2.2 Mishra, A. V., Pollmann, A. S., Choudhry, N., Demmings, E., & Gupta, R. R. (2021). Unilateral benign yellow dot maculopathy. American Journal of Ophthalmology Case Reports, 22(101068), 101068. https://doi.org/10.1016/j.ajoc.2021.101068
- ↑ 3.0 3.1 3.2 Balas M, Wong J, Arjmand P. Multimodal Imaging of Unilateral Benign Yellow Dot Maculopathy. J Vitreoretin Dis. 2024 Jun 16;8(5):597-599. doi: 10.1177/24741264241260489. PMID: 39318986; PMCID: PMC11418657.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Santos M, Oliveira N, Baptista M, Arede P, Marques JP, Vaz-Pereira S. Benign Yellow Dot Maculopathy: A Case Series of Patients With a Recently Discovered Macular Phenotype. Cureus. 2024 Nov 28;16(11):e74652. doi: 10.7759/cureus.74652. PMID: 39735063; PMCID: PMC11681434.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Kasetty, V. M., Desai, T. U., & Desai, U. R. (2023). Benign yellow-dot maculopathy: case report and review of the literature. Canadian Journal of Ophthalmology. Journal Canadien d’ophtalmologie. https://doi.org/10.1016/j.jcjo.2023.01.002
- ↑ 6.0 6.1 Murro, V., Mucciolo, D. P., Giorgio, D., Sodi, A., Passerini, I., Pacini, B., Finocchio, L., Virgili, G., & Rizzo, S. (2019). Multimodal imaging of benign yellow dot maculopathy. Ophthalmic Genetics, 40(2), 135–140. https://doi.org/10.1080/13816810.2019.1589529
- ↑ Moisseiev, E. (2018). Benign yellow dot maculopathy. American Journal of Ophthalmology Case Reports, 10, 13–15. https://doi.org/10.1016/j.ajoc.2018.01.040
- ↑ 8.0 8.1 Ninet L, David T, Gascon P. Multimodal Imaging for Benign Yellow Dot Maculopathy. Ophthalmol Retina. 2022;6(4):307. doi:10.1016/j.oret.2021.12.020
- ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 Kiraly P, Birtel J, Ong AY, Ruan C, Fischer MD, Charbel Issa P. Extended phenotypic spectrum of benign yellow dot maculopathy. Eye (Lond). 2025 Jun;39(8):1547-1552. doi: 10.1038/s41433-024-03590-4. Epub 2025 Feb 21. PMID: 39984697; PMCID: PMC12089353.
- ↑ 10.0 10.1 10.2 10.3 10.4 Nunziata A, Del Fabbro S, Antropoli A, Bianco L, Arrigo A, Bandello F, Mansour AM, Parodi MB. 12-YEAR FOLLOW-UP OF A BENIGN YELLOW DOT MACULOPATHY CASE. Retin Cases Brief Rep. 2026 Sep 1;20(5):711-715. doi: 10.1097/ICB.0000000000001810. PMID: 40986785.
- ↑ Alswaiti Y, Mustafa O. Benign Yellow Dot Maculopathy in a Palestinian Child: A Case Report. Case Rep Ophthalmol. 2026 Mar 5;17(1):408-414. doi: 10.1159/000551354. PMID: 42094631; PMCID: PMC13143270.
- ↑ 12.0 12.1 Delori FC, Dorey CK, Staurenghi G, Arend O, Goger DG, Weiter JJ. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci. 1995 Mar;36(3):718-29. PMID: 7890502.
- ↑ Salcedo-Ledesma, A., Ledesma-Gil, G., & Spaide, R. F. (2024). DESCRIBING THE LOCATION AND MORPHOLOGY OF THE DOTS IN WHITE DOT FOVEA USING ADAPTIVE OPTICS. RETINAL Cases & Brief Reports, 18(3), 275–278. https://doi.org/10.1097/ICB.0000000000001403
- ↑ 14.0 14.1 Charbel Issa P, De Silva SR, Pfau K, Birtel J. Differential Diagnosis of Age-Related Macular Degeneration. Klin Monbl Augenheilkd. 2025 Jan;242(1):7-21. English, German. doi: 10.1055/a-2327-8597. Epub 2025 Jan 16. Erratum in: Klin Monbl Augenheilkd. 2025 Jan;242(1):e1. doi: 10.1055/a-2524-5086. PMID: 39820891.
- ↑ D'souza Y, Short CD, McLeod D, Bonshek RE. Long-term follow-up of drusen-like lesions in patients with type II mesangiocapillary glomerulonephritis. Br J Ophthalmol. 2008 Jul;92(7):950-3. doi: 10.1136/bjo.2007.130138. PMID: 18577648.
