This retrospective, longitudinal case series included patients diagnosed with URPED, with or without CHRRPE features, at the Ocular Oncology and Medical Retina services of Luigi Sacco Hospital (University of Milan, Milan, Italy) and Macquarie University Hospital (Sydney, NSW, Australia) between July 2011 and July 2025. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of both centers. All procedures complied with national bioethical regulations, and written informed consent was obtained from all participants prior to inclusion.

Diagnosis of URPED and CHRRPE was made by a single ocular oncology-trained retina specialist at each center (M.P. and A.F.), based on established clinical and multimodal imaging features. Consistent with recent literature, the presence of the classic “inverted pattern” between SW-FAF and FA was not considered a mandatory inclusion criterion. ^, Instead, diagnostic confirmation relied on recognition of a broader set of multimodal imaging characteristics across color fundus photography (CFP), SW-FAF, optical coherence tomography (OCT), FA, and ICGA ( Figure 1 , A through E and H through L ), thereby allowing the inclusion of atypical URPED presentations identifiable primarily through ICGA findings. In such cases, diagnosis relied on multimodal concordance with key URPED features, including sectorial inverted patterns between SW-FAF and FA, RPE–BrM separation on OCT, and characteristic lesion delineation on ICGA. ^,,,

Multimodal imaging of an overt a covert unilateral retinal pigment epithelium dysgenesis (URPED) and lesions area assessment. (A) True-color fundus photography (TCFP, Eidon, Centervue/iCare) shows a grayish lesion with well-demarcated, scalloped borders. (B) Near-infrared reflectance (NIR, Spectralis OCT2, Heidelberg Engineering) demonstrates irregular hyperreflectance throughout the lesion area. (C) Fundus autofluorescence (FAF, Spectralis OCT2) reveals the typical URPED pattern, with a markedly hypoautofluorescent core surrounded by hyperautofluorescent margins. (D) Fluorescein angiography (FA, Spectralis HRA2) shows the inverted pattern relative to FAF, with central hyperfluorescence corresponding to the hypoautofluorescent area on FAF and peripheral hypofluorescence matching the hyperautofluorescent borders. (E) Late-phase indocyanine green angiography (ICGA, Spectralis HRA2) highlights the lesion as a well-defined hypofluorescent area, further delineating its margins. (H) TCFP also clearly demonstrates an amelanotic, elevated lesion consistent with a choroidal osteoma. Surrounding the osteoma—and extending inferiorly toward the macular area—a speckled yellow-grayish lesion is visible, corresponding to a covert URPED. (I and J) In this same region, NIR and FAF reveal irregular mild hyperreflectance and mildly decreased autofluorescence, respectively. (K) On FA, the covert lesion is not detectable, whereas ICGA (L and N) reveals it as a progressively increasing hypofluorescent area with scalloped margins. (F, G, M, N) Examples of lesion-area measurement performed on en face imaging using the built-in Heidelberg software tool show good correspondence between FA and late-phase ICGA for the overt URPED (F and G), but marked discrepancies for the covert lesion (M and N). Of note, measurement accuracy is affected both by exudative changes (F and M) and by macular pigment (M).

Alternative diagnoses that may mimic URPED were systematically excluded based on clinical history and multimodal imaging findings, including traumatic RPE alterations (eg, retinopathy sclopetaria), inflammatory chorioretinal scars such as serpiginous choroiditis, and outer retinal disorders such as acute zonal occult outer retinopathy. ^, In cases of diagnostic uncertainty, a senior grader (G.S.) adjudicated the final diagnosis.

At baseline and all follow-up visits, patients underwent best-corrected visual acuity (BCVA) testing (recorded in Snellen equivalent), anterior and posterior segment slit-lamp biomicroscopy, and Goldmann applanation tonometry. Fundus images were acquired using true-color systems (EIDON, CenterVue/iCare, Padua, Italy; or CLARUS 700, Carl Zeiss Meditec) and/or pseudocolor ultrawidefield imaging (Optos California, Optos plc.).

Spectral-domain OCT (SD-OCT), near-infrared reflectance (NIR) imaging, and SW-FAF ( λ = 488 nm, 30° × 30° and 55° × 55° fields) centered on the lesion were obtained at each visit (SPECTRALIS OCT2; Heidelberg Engineering GmbH). FA and ICGA exams were performed at baseline for all patients (30° × 30° and 55° × 55° fields; SPECTRALIS HRA2; Heidelberg Engineering GmbH), with early and late frames acquired within 30 minutes of dye injection. The presence of CNV was initially assessed according to the CONAN criteria for multimodal imaging, including structural OCT, and further confirmed, at the physician’s discretion, on swept-source OCT angiography (SS-OCTA, PLEX Elite 9000; Carl Zeiss Meditec), FA, and ICGA.

All imaging studies were systematically reviewed by two retina specialists with expertise in multimodal imaging (A.I. and F.R.) to define the key clinical features of URPED.

Lesions were categorized as: (1) overt URPED, when clearly detectable by noninvasive imaging modalities such as CFP, NIR, SW-FAF, and OCT; or (2) covert URPED, when ICGA was required for diagnostic confirmation. Among overt cases, three distinct SW-FAF patterns were identified: (1a) scalloped (classic-type), characterized by markedly hypoautofluorescent lesions with smooth scalloped borders and hyperautofluorescent margins; (1b) mottled pattern, showing irregular hypoautofluorescent alterations with isoautofluorescent margins; in some cases, jagged borders with attenuated hypoautofluorescence; (1c) mixed pattern, presenting a combination of scalloped and mottled characteristics. The principal features of these patterns are summarized in Table 1 .

SD-OCT was reviewed in parallel with NIR and SW-FAF imaging to assess specific structural alterations. Particular attention was given to: (1) the separation between the RPE and Bruch membrane (BrM), defined as a diffuse band of moderately hyperreflective material with a clear cleavage plane between the two layers; (2) sawtooth RPE changes, characterized by diffuse, irregular, punctate alterations of the RPE overlying areas of RPE-BrM separation; (3) presence of outer retinal and RPE atrophy, classified as incomplete and complete outer retinal atrophy (iORA, cORA) and incomplete and complete RPE and outer retinal atrophy (iRORA, cRORA), according to the Classification of Atrophy Meeting criteria ; (4) choroidal caverns, identified as hyporeflective cavities with hyperreflective margins located within Haller’s and Sattler’s layers; (5) additional features, including pigment mottling or hyperplasia at lesion borders and vitreoretinal interface abnormalities.

The diagnosis of associated hamartomatous lesions was based on the multimodal integration of these findings across CFP, SW-FAF, OCT, NIR, FA, and ICGA, as required. Early- and late-phase FA and ICGA images, centered on the lesions, were systematically reviewed and compared with SW-FAF and OCT to evaluate for the presence of the inverted pattern and to refine the delineation of the lesion margins. Specifically, the lesion area was independently measured by the two graders at baseline on both SW-FAF and late-phase ICGA images (55° × 55°). At the last available follow-up, measurements were repeated on SW-FAF images only. All measurements were obtained manually using the built-in area measurement tool of the Heidelberg software. In cases where intergrader discrepancy exceeded 10%, a senior grader (M.P.) was consulted to adjudicate the final measurement ( Figure 1 , F and G ; M and N).

All statistical analyses were performed using Stata/MP 18.5 (StataCorp). The distribution of continuous variables was assessed with the Shapiro-Wilk test. Data are reported as mean (SD, SD) for normally distributed variables and as median (IQR, IQR) for non-normally distributed variables. Comparisons of the frequency of associated hamartomatous lesions between overt and covert URPED presentations were conducted using two-tailed Fisher’s exact tests. Interobserver agreement for lesion area measurements was assessed using the intraclass correlation coefficient (ICC), calculated separately for (1) lesion area on baseline SW-FAF, (2) lesion area on baseline late-phase ICGA, and (3) lesion area on SW-FAF at the last follow-up. The ICC was estimated with a two-way random-effects model for absolute agreement, with corresponding 95% CIs (CIs).

Comprehensive clinical data from 10 eyes of 10 patients (7 women, 70%) diagnosed with URPED (9 at Luigi Sacco Hospital) and 2 eyes of 2 patients (1 woman, 50%) diagnosed with CHRRPE and URPED-like features were retrospectively reviewed. The mean age at URPED diagnosis was 35.2 (±13.9) years. All lesions were unilateral and confined to the posterior pole, with predominant peripapillary involvement in 8 cases (80%). The median follow-up duration was 27.5 months (IQR = 56.5 range, up to 160 months).

BCVA in URPED eyes ranged from 20/100 to 20/20 at baseline and from 20/400 to 20/20 at the final visit. Only one eye (10%) experienced a loss of more than three ETDRS lines during follow-up, attributable to CNV development. CNV was detected in four eyes (40%), 2 being present at baseline and 2 developing over the follow-up, without a statistically significant difference between overt (2/7, 28.6%) and covert (2/3, 66.7%) forms ( P =.50).

All CNVs were classified as type 2 lesions, except for one case with a mixed type 1/2 pattern according to CONAN criteria. Demographic and clinical features are summarized in Table 2 .

TABLE 2

Demographics and Clinical Features.

Patient ID	Sex	Age	Eye	URPED Type	FAF Pattern	Location	Initial BCVA	Final BCVA	Follow-up (Mo)	Progression	CNV	Association
1	F	39	LE	Covert	Nonspecific	Posterior pole	20/20	20/20	88	No	Yes	Choroidal osteoma
2	F	51	LE	Overt	Scalloped	Peripapillary	20/63	20/80	75	Yes	Yes	No
3	F	30	RE	Overt	Mottled	Posterior pole	20/20	20/20	20	No	No	No
4	F	54	RE	Overt	Mixed	Peripapillary	20/20	20/20	55	No	No	No
5	M	41	RE	Overt	Scalloped	Peripapillary	20/20	20/20	20	No	No	No
6	M	11	LE	Covert	Nonspecific	Peripapillary	20/20	20/20	66	No	No	Capillary hemangioma
7	F	45	LE	Overt	Mixed	Peripapillary	20/20	20/20	35	No	No	No
8	M	37	RE	Covert	Nonspecific	Peripapillary and posterior pole	20/100	20/400	160	No	Yes	No
9	F	19	LE	Overt	Scalloped	Peripapillary and posterior pole	20/50	–	0	–	No	Capillary hemangioma
10	F	25	LE	Overt	Scalloped	Peripapillary and posterior pole	20/100	–	0	–	Yes	Capillary hemangioma

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