Congenital hypertrophy of the retinal pigment epithelium is a congenital hamartoma of the retinal pigment epithelium. It was named by Buettner in 1975.
The prevalence among routine eye examination patients is 1.2%. There is no sex or racial difference. It is a flat, clearly bordered, solitary pigmented lesion often found in the midperipheral fundus, and it contains lacunae (depigmented areas) within the lesion. It enlarges very slowly, and enlargement is seen in 80% of cases over 5 years. The most common site is the equatorial retina, especially the temporal periphery. Juxtapapillary occurrence is rare, at less than 1%1).
It is classified as ICD-10 Q14.1 (congenital malformations of the retina).
Congenital hypertrophy of the retinal pigment epithelium has the following three variants.
Familial adenomatous polyposis is an autosomal dominant cancer syndrome. Without treatment, almost all patients develop colorectal cancer by middle age. Polyps appear from around age 10, and colorectal cancer develops from around age 15. Colorectal cancer develops in 50% of patients by age 40 and in nearly 100% by age 60. Atypical congenital hypertrophy of the retinal pigment epithelium is the earliest and most common extracolonic manifestation of familial adenomatous polyposis and is seen in up to 90% of patients with familial adenomatous polyposis.
The following are subtypes associated with familial adenomatous polyposis.
It is usually benign, and spontaneous regression and malignant transformation are very rare. However, there are reports of nodular pigmented adenoma and adenocarcinoma arising from congenital hypertrophy of the retinal pigment epithelium. Atypical congenital hypertrophy of the retinal pigment epithelium is associated with familial adenomatous polyposis, and if familial adenomatous polyposis is left untreated, nearly all cases develop colorectal cancer by middle age. Regular follow-up and colonoscopy when needed are important (see the section on standard treatment methods for details).
Congenital hypertrophy of the retinal pigment epithelium is almost always asymptomatic and is found incidentally during routine eye exams. Rarely, if the lesion extends to the fovea, it can cause reduced vision.
Clinical findings vary by variant. The features of the three variants are shown below.
Solitary type
Shape: A single flat, round hyperpigmented lesion.
Color: Light gray to brown to black. The border is smooth or jagged.
Location: Usually located in the retinal equator, and more often in the superotemporal quadrant.
Size: Varies from 100 μm to several optic disc diameters.
Lacunae: May include hypopigmented lacunae or be surrounded by a depigmented halo. Slowly enlarge over time.
Overlying retina: Appears normal.
Clustered type (Bear tracks)
Shape: Multiple lesions arranged in clusters (up to 30 per cluster).
Size: Each lesion is 100–300 μm. Tends to be larger toward the periphery.
Distribution: Limited to one sector or quadrant of the fundus. Typically dark gray to black.
Lacunae/halo: No halo or lacunae. Resembles bear tracks.
Laterality: Unilateral or bilateral (bilateral is rare). Usually no functional impact.
Atypical (FAP-associated)
Size: Smaller than the solitary type (50–100 μm in diameter).
Shape: Irregular shapes such as oval, spindle-shaped, comma-shaped, and fish-tail-shaped.
Distribution: Irregularly distributed throughout the fundus.
Bilateral: Bilateral in 78% of patients. The most important feature suggesting an association with familial adenomatous polyposis.
Lacunae: Large lesions may contain lacunae and may be surrounded by depigmented halos or satellite lesions.
Association with familial adenomatous polyposis: In families with familial adenomatous polyposis, multiple bilateral lesions are almost certainly associated with familial adenomatous polyposis.
Histologically, it shows a monolayer structure packed with large melanosomes inside enlarged retinal pigment epithelial cells (a combination of cell hyperplasia and hypertrophy). In lacunar areas, glial cells replace the retinal pigment epithelium and photoreceptor layer, and Bruch’s membrane thickens. The photoreceptor layer over the lesion degenerates with age, and the outer retinal layers disappear. The choroid, choriocapillaris, and inner retinal layers remain unchanged2).
The solitary type is a single, round, large lesion with lacunae; the grouped type consists of multiple small lesions forming clusters that resemble bear tracks; the atypical type is small, irregular, and distributed bilaterally throughout the fundus, strongly suggesting an association with familial adenomatous polyposis. The combination of bilateral, multiple, and irregular features is especially important for differentiating lesions associated with familial adenomatous polyposis3).
Congenital hypertrophy of the retinal pigment epithelium is a congenital hamartoma, thought to result from abnormal development of the retinal pigment epithelium during embryonic life, but no specific gene mutation has been identified in sporadic solitary and grouped types.
The cause of atypical congenital hypertrophy of the retinal pigment epithelium associated with familial adenomatous polyposis is mutation of the APC (adenomatous polyposis coli) gene located on the long arm of chromosome 5 (5q21-q22). Familial adenomatous polyposis is inherited in an autosomal dominant pattern with high penetrance.
The relationship between the site of APC gene mutations and the phenotype of congenital hypertrophy of the retinal pigment epithelium is as follows.
In familial adenomatous polyposis (Gardner syndrome), along with osteomas and soft-tissue tumors caused by APC gene mutations, dark brown pigmented spots appear on the fundus from childhood in 80% of cases.
For first-degree relatives in families with familial adenomatous polyposis (the high-risk group), fundus screening starting at age 10 is recommended. The average specificity of congenital hypertrophy of the retinal pigment epithelium as a marker for familial adenomatous polyposis has been reported at 89%, and the average sensitivity at 79%3). A combined approach using ophthalmic examination, colonoscopy, and genetic testing is recommended.
Diagnosis is usually made clinically, and additional tests are generally not needed. It can be diagnosed by confirming the characteristic pigmented lesions on the fundus. There are no raised lesions, so distinguishing it from other tumors is relatively easy. Color fundus photography is useful for documentation and follow-up, and a wide-field scanning laser ophthalmoscope is recommended as a screening tool.
The main imaging findings are summarized below.
| Exam | Pigmented area | Lacunar area | Special notes |
|---|---|---|---|
| FAF | Low autofluorescence | No fluorescence (retinal pigment epithelium atrophy) | Depending on the modality, lacunae may show pseudo-hyperfluorescence |
| FA | Fluorescence blockage | Transmitted fluorescence | No fluorescence leakage |
| SD-OCT | The retinal pigment epithelium band is hyperreflective and thickened, with loss of the photoreceptor layer | Thinning and loss of the retinal pigment epithelium layer, increased light transmission | Choroidal thickness beneath the lesion is normal |
| B-scan ultrasound | flat and invisible on ultrasound | — | Important differential point from choroidal melanoma |
Detailed findings are as follows.
The features of the main differential diagnoses are summarized below.
| Disease | Shape/elevation | Ultrasound findings | Key points for differentiation |
|---|---|---|---|
| Choroidal melanoma | Dome-shaped/button-shaped, elevated | B-scan: choroidal excavation present | A-scan: medium to low reflectivity, vascular pulsation |
| Choroidal nevus | Flat to slightly elevated | Medium to high echo | Ill-defined borders, with drusen |
| Congenital hypertrophy of the retinal pigment epithelium | Flat | Not visible on ultrasound | Distinct dark pigmented lesion, lacunae |
Other differential diagnoses include melanocytoma, post-inflammatory scars (such as toxoplasmosis), retinal pigment epithelium proliferation, retinal pigment epithelium adenoma/adenocarcinoma, the black sunburst lesion of sickle cell disease, and CGARPES (polar bear footprints: similar to clustered congenital hypertrophy of the retinal pigment epithelium)1,2). There are also reports of adenoma/adenocarcinoma arising secondarily from congenital hypertrophy of the retinal pigment epithelium. In differentiating it from choroidal melanoma, the presence of retinal feeder vessels and abundant hard exudate deposition are key points.
In general, active intervention is not necessary, and asymptomatic cases are managed with observation. Regular follow-up is recommended1,2).
The following approaches have been reported for rare complications.
Congenital hypertrophy of the retinal pigment epithelium is a noninvasive, rapid, and early phenotypic screening marker for familial adenomatous polyposis3).
A systematic review analyzing 28 studies and 4,451 people reported the following data3).
The screening recommendations are as follows.
In general, observation is sufficient, and regular follow-up is recommended. However, if the lesion rapidly enlarges or nodular change appears, adenoma or adenocarcinoma transformation should be suspected and further evaluation is needed. If rare complications such as choroidal neovascularization occur, symptomatic treatment such as photodynamic therapy may be considered1). Treatment for congenital hypertrophy of the retinal pigment epithelium itself is usually unnecessary.
Histologically, congenital hypertrophy of the retinal pigment epithelium is characterized by a single layer of enlarged retinal pigment epithelial cells densely filled with giant melanosomes.
In atypical congenital hypertrophy of the retinal pigment epithelium associated with familial adenomatous polyposis, localized abnormalities in melanin granule morphology are seen, and it differs microscopically from congenital hypertrophy of the retinal pigment epithelium in the general population. In addition to hypertrophy of the retinal pigment epithelium, proliferation is also present, with retinal infiltration and changes in retinal blood vessels. Multilayered structure or full-thickness retinal involvement may also be seen. It appears tumor-like but is clinically benign3).
The temporal changes in the lesion are as follows.
The APC gene is located on the long arm of chromosome 5 (5q21-q22) and encodes a tumor suppressor protein. The severity of the disease and the presence or absence of extracolonic manifestations are associated with the mutation site. Specific mutations such as codon 1597 have been shown to be associated with other extracolonic manifestations such as desmoid tumors, and not to be accompanied by congenital hypertrophy of the retinal pigment epithelium3).
Congenital hypertrophy of the retinal pigment epithelium enlarges in 46% to 83% of cases during follow-up of at least 3 years. Rare reports describe nodular pigmented adenocarcinoma arising from lesions of congenital hypertrophy of the retinal pigment epithelium. There are also reports of untreated nodular lesions progressing to pedunculated tumors with serous retinal detachment. In addition, peripheral retinal pigment epithelial tumors arising within congenital hypertrophy of the retinal pigment epithelium are said to frequently be accompanied by epiretinal membrane and cystoid macular edema.
Alshalan et al. (2025) reported two cases of juxtapapillary congenital hypertrophy of the retinal pigment epithelium1). They performed multimodal imaging for a 69-year-old woman (left eye, about seven disc areas, nearly circumferential) and a 50-year-old woman (right eye, about six disc areas, superior) and made a definitive diagnosis based on fundus autofluorescence (low autofluorescence throughout the lesions), fluorescein angiography (fluorescence blockage plus transmission through lacunae), and SD-OCT (thickened, hyperreflective retinal pigment epithelium band plus loss of outer retinal structure, flat on B-scan). The reported frequency of juxtapapillary cases is less than 1%.
Qiu et al. (2022) reported a case of a 39-year-old Chinese woman with retinitis punctata albescens (RPA) caused by a PRPH2 gene variant (c.828+2T>C) and coexisting multifocal congenital hypertrophy of the retinal pigment epithelium4). Clustered congenital hypertrophy of the retinal pigment epithelium was seen only in the left eye, and electroretinography showed reduced b-wave amplitude after dark adaptation. Family analysis confirmed the same variant in her mother, son, and daughter, but the fundus findings varied. The PRPH2 gene encodes a photoreceptor-specific membrane glycoprotein and is essential for shaping the rod and cone outer segments. A causal link between congenital hypertrophy of the retinal pigment epithelium and PRPH2 gene variants has not yet been established.
It has been suggested that AI could be used for screening congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis3). There is precedent for AI use in diabetic retinopathy screening, and its application to risk stratification for familial adenomatous polyposis based on congenital hypertrophy of the retinal pigment epithelium in large populations is expected.
