Benign Yellow Dot Maculopathy

Key Points at a Glance

Highlights of This Disease

• Benign yellow dot maculopathy (BYDM) is a very rare macular phenotype first reported in 2017.
• It is characterized by multiple small yellow-white dots around the fovea, usually asymptomatic with preserved visual acuity.
• Non-progressive; lesions remain stable even during long-term follow-up.
• It is a diagnosis of exclusion; differentiation from similar diseases such as familial drusen and crystalline retinopathy is important.
• Hyperautofluorescence on fundus autofluorescence (FAF) is a characteristic and most sensitive finding.
• The causative gene has not been identified, but it follows a sporadic or autosomal dominant inheritance pattern.
• No treatment is required; only regular follow-up observation is needed.

1. What is benign yellow dot macular degeneration?

Benign Yellow Dot Maculopathy (BYDM) is a new macular phenotype first reported by Dev Borman et al. in 2017¹⁾²⁾³⁾. It is a very rare disease with fewer than 50 reported cases in the literature¹⁾, and as of the report by Santos et al. (2024), a cumulative total of 46 cases have been confirmed²⁾.

The main features of this disease are as follows:

• Age of onset: Often develops in childhood²⁾
• Symmetry: Typically bilateral, but unilateral cases have also been reported¹⁾²⁾³⁾
• Symptoms: Asymptomatic and non-progressive, without visual impairment¹⁾²⁾³⁾
• Inheritance pattern: Sporadic or autosomal dominant¹⁾²⁾³⁾
• Causative gene: Unidentified. Whole-exome sequencing has not detected pathogenic mutations in known macular dystrophy genes¹⁾
• Diagnostic nature: It is a diagnosis of exclusion, made after comprehensively ruling out similar diseases¹⁾

Due to its similarity to macular degeneration and other macular diseases, it is easily misdiagnosed¹⁾, and accurate evaluation using multimodal imaging is key to diagnosis.

Q Is benign yellow dot macular disease hereditary?

A

Both sporadic cases and cases showing autosomal dominant inheritance have been reported. Among the original 36 cases, 13 had a family history³⁾. However, whole-exome sequencing has not identified pathogenic mutations in known macular dystrophy genes, and the causative gene remains unidentified at present¹⁾.

2. Main symptoms and clinical findings

Subjective Symptoms

Most patients are asymptomatic and are often discovered incidentally during routine eye examinations²⁾³⁾.

• Visual acuity: Remains normal. The mean visual acuity in the Santos et al. cohort was 0.04 logMAR (nearly normal)²⁾
• Color vision: Normal³⁾
• Subjective visual field defects: Usually none

Clinical Findings

Multiple small yellowish-white spots around the fovea of the macula are characteristic findings of this disease. These are considered subretinal lesions at the level of the RPE (retinal pigment epithelium)¹⁾²⁾³⁾.

• Distribution: Most are evenly distributed around the fovea¹⁾²⁾. In some cases, they tend to concentrate in the nasal parafoveal area²⁾
• Unilateral cases: Yellow spots tend to extend to the temporal side of the macula¹⁾
• Peripapillary: No atrophy¹⁾
• Peripheral retina and vessels: Normal³⁾

Q Does vision decrease in benign yellow dot maculopathy?

A

In reported cases, no decrease in visual acuity has been observed. The mean visual acuity in the Santos et al. cohort was 0.04 logMAR (almost normal) ²⁾, and all cases remained stable during a mean follow-up of 5.8 years ²⁾. At present, it is not considered a progressive visual impairment disease.

3. Causes and Risk Factors

The etiology is unknown ¹⁾³⁾. Although a genetic background is suggested, the causative gene has not been identified.

Genetic Background

• Inheritance pattern: Sporadic or autosomal dominant ¹⁾²⁾³⁾
• Family history: Family history was present in 13 of 36 original cases ³⁾
• Whole exome sequencing: No pathogenic variants in known macular dystrophy genes¹⁾
• Haplotype sharing analysis: Linkage to the NCMD (North Carolina macular dystrophy) locus was excluded¹⁾

Epidemiological Features

• Sex: More common in women (all 5 cases in Santos et al. were female²⁾, 26 of 36 original cases were female³⁾)
• Age: Often onset in childhood. Mean age in the Santos et al. cohort was 31±16 years²⁾
• Association with systemic diseases or medications: Negative¹⁾

Impact on Daily Life

This is a benign disease without visual impairment. In principle, no restrictions on daily life are necessary, but regular ophthalmological check-ups are recommended to confirm differentiation from other macular diseases.

4. Diagnosis and Examination Methods

BYDM is a diagnosis of exclusion, requiring comprehensive history taking, ophthalmic examination, and multimodal imaging ¹⁾.

Multimodal Imaging Findings

FAF Findings

Fundus autofluorescence (FAF): In all cases, it appears as hyperfluorescence corresponding to the yellow dots. This is the most characteristic and stable finding of BYDM and is most useful for diagnosis. ¹⁾²⁾³⁾

OCT Findings

Optical coherence tomography (OCT): Generally normal findings are common, but some cases have reported EZ (ellipsoid zone)/RPE irregularities. ¹⁾²⁾³⁾

In unilateral cases, RPE-EZ irregularities are more pronounced, while in bilateral cases, normal findings are more common. ¹⁾

The mean subfoveal thickness was within the normal range: 285 μm in the right eye and 273 μm in the left eye, according to Mishra et al. ³⁾

OCTA Findings

OCT angiography (OCTA): Performed in 4 bilateral cases, all normal. ¹⁾

Santos et al. also reported normal OCTA findings. ²⁾

In a unilateral case by Balas et al., subtle choroidal vessel rarefaction at the level of the choriocapillaris was reported. ¹⁾

Other examination findings:

• NIR (near-infrared reflectance): Balas et al. described round hyporeflective lesions ¹⁾, while Mishra et al. reported hyperreflectivity ³⁾
• Electroretinogram (ERG): Normal in 17 of 19 original cases. Two cases showed mild to moderate reduction of the P50 component ³⁾. In Mishra et al., multifocal ERG showed a mild decrease in peak signal intensity in the right eye, but within normal range ³⁾
• Goldmann perimetry: normal³⁾

Comparison of unilateral and bilateral involvement

There are differences in clinical features between bilateral and unilateral cases.

Feature	Bilateral	Unilateral
Sex	Female predominance	More males
Distribution of yellow dots	Perifoveal	Extends to temporal side
OCT findings	Usually normal	RPE-EZ irregularity present

Main differential diagnoses

BYDM is a diagnosis of exclusion, so differentiation from the following diseases is essential.

Disease name	Key differentiating points
Familial drusen	Honeycomb distribution, deposits on Bruch’s membrane
Crystalline retinopathy	Hyper/hyporeflective foci in all layers
Gunn dots	Internal limiting membrane level, peripapillary

The following are also listed as differential diagnoses²⁾: Stargardt disease, Best disease, age-related macular degeneration (AMD), autosomal dominant drusen, drug-induced retinopathy, Bietti crystalline dystrophy, white dot fovea (hyperreflective granules in the inner retinal layer), NCMD (autosomal dominant, complete penetrance bilateral macular degeneration)³⁾.

Q What tests are needed to diagnose benign yellow dot macular degeneration?

A

Since it is a diagnosis of exclusion, multimodal imaging such as fundus examination, FAF, OCT, and OCTA is necessary. Among these, hyperfluorescent findings on FAF are most characteristic of BYDM and are observed in all cases¹⁾²⁾³⁾. Taking a family history and whole exome sequencing are also useful as aids in differential diagnosis.

5. Standard treatment

BYDM is a non-progressive benign disease and does not require treatment. Only regular follow-up is recommended²⁾.

Follow-up results

Santos et al. (2024) conducted a mean follow-up of 5.8 years in a cohort of 5 cases and reported that the lesions remained stable in all cases ²⁾. No changes in visual acuity or morphological findings were observed.

In the case of Balas et al. (2024), no progression of the lesion was observed at the 6-month follow-up visit ¹⁾.

Points to note during follow-up

• Although BYDM is considered non-progressive, the long-term outcome remains unclear due to the limited number of cases.
• Other causes of macular yellow dots (e.g., familial drusen, crystalline retinopathy) can be progressive, so a definitive differential diagnosis is important.
• Regular ophthalmologic examinations are recommended to check for the appearance of new lesions or changes in visual acuity.

Q Does benign yellow dot maculopathy require treatment?

A

Treatment is not necessary. It is a non-progressive, benign disease, and currently only observation is recommended²⁾. Santos et al. reported that all cases remained stable over a mean follow-up of 5.8 years²⁾. However, regular ophthalmological examinations should be continued to ensure reliable differentiation from similar diseases.

6. Pathophysiology and detailed pathogenesis

The pathophysiology of BYDM is currently unknown¹⁾³⁾.

Location and characteristics of lesions

Yellow dots are located as subretinal lesions at the RPE level¹⁾²⁾³⁾. Hyperautofluorescence on FAF suggests lipofuscin accumulation or metabolic abnormalities at the RPE level, but there is no definitive evidence.

Pathophysiological Differences Between Unilateral and Bilateral Cases

Characteristics of Bilateral Cases

Sex: Female predominance

Distribution of yellow dots: Evenly distributed around the fovea

OCT findings: Usually normal. RPE-EZ irregularities are rare¹⁾

OCTA findings: No abnormalities in the choriocapillaris¹⁾

Characteristics of Unilateral Cases

Sex: More common in males (both cases reported so far were male)¹⁾

Distribution of yellow dots: Tendency to extend to the temporal side of the macula¹⁾

OCT findings: RPE-EZ irregularity is more pronounced¹⁾

OCTA findings: Possible subtle changes in the choriocapillaris¹⁾

It has been suggested that there may be differences in etiology and manifestation between unilateral and bilateral cases¹⁾.

Genetic Background

Whole-exome sequencing did not identify any known macular dystrophy gene mutations ¹⁾. Haplotype sharing analysis also ruled out linkage to the NCMD locus ¹⁾. The possibility of including different disease groups with similar phenotypes (genetic heterogeneity) has also been suggested ³⁾.

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7. Latest Research and Future Perspectives (Research-Stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

BYDM has extremely few reported cases in the literature¹⁾, and continuous accumulation of cases is essential for a full understanding of the disease.

Advances in Genetic Research

Balas et al. (2024) noted that conducting larger-scale genetic testing helps identify causative gene mutations¹⁾. Building a repository that integrates imaging and genetic data has been proposed as a key step to deepen disease understanding¹⁾.

Future Challenges

• Elucidation of differences between unilateral and bilateral involvement: Comparative studies of etiology, presentation, and long-term outcomes are needed¹⁾²⁾
• Establishment of a case registry: With fewer than 50 reported cases, building evidence is difficult, and multicenter case collection is required.
• Identification of causative genes: Continuous genetic screening using whole-exome sequencing and next-generation sequencing is expected¹⁾

Santos et al. (2024) reported the third largest cohort in the literature²⁾, and the disease concept is being refined as cases accumulate.

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8. References

1. Balas M, Wong J, Arjmand P. Multimodal Imaging of Unilateral Benign Yellow Dot Maculopathy. J Vitreoretinal Dis. 2024;8(5):597-599.
2. Santos M, Oliveira N, Baptista M, et al. Benign Yellow Dot Maculopathy: A Case Series of Patients With a Recently Discovered Macular Phenotype. Cureus. 2024;16(11):e74652.
3. Mishra AV, Pollmann AS, Choudhry N, Demmings E, Gupta RR. Unilateral benign yellow dot maculopathy. Am J Ophthalmol Case Rep. 2021;22:101068.