Putting diagnostic accuracy to the test
A confirmed diagnosis of familial exudative vitreoretinopathy aids in several aspects of patient management
Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease that disrupts normal blood vessel formation in the retina. Symptoms can range from mild visual deficits to severe visual impairment or even blindness. Accurate diagnosis of FEVR is challenging because its symptoms—such as retinal detachment and abnormal blood vessels—closely resemble those of other retinal diseases, including retinopathy of prematurity (ROP), Coats disease, and persistent fetal vasculature (PFV). Diagnosis often requires widefield angiography or genetic testing. Due to the overlap of symptoms with other conditions, especially in children, FEVR is frequently misdiagnosed, underscoring the critical role of genetic testing in guiding appropriate management.
Recent research highlighted the role of genetic testing in confirming FEVR diagnoses. The retrospective study reviewed cases from 104 paediatric patients referred with suspected FEVR.1 Genetic testing confirmed FEVR in 55 of these cases, revealing that 60% of patients with confirmed FEVR had initially received incorrect diagnoses. The average age at diagnosis was slightly higher in patients with revised diagnoses compared with those initially diagnosed with FEVR, suggesting diagnostic delays may impact disease progression.
The study identified several conditions commonly misdiagnosed as FEVR. Particularly in cases of late-preterm infants, ROP was the most frequent misdiagnosis, accounting for about 39% of cases.1 Besides genetic testing that can confirm the diagnosis, fluorescein angiography (FA) is valuable imaging technique for differentiating FEVR from ROP, as both conditions share similar clinical presentations, particularly peripheral retinal avascularity and abnormal vessel growth (Figures). In FEVR, the FA typically shows symmetric or many times asymmetric peripheral avascular retina without the distinct ridge formation and the organised vascular pattern seen in ROP. Also, there may be abrupt termination of blood vessels at the vascular-avascular junction with signs of neovascularisation or straightening of peripheral vessels, pinpoint areas of hyperfluorescence and segmental areas of vascular leakage.2
PFV was misdiagnosed in 15% of cases, partly due to the similarities in retinal vascular anomalies between PFV and FEVR1. Key differences help distinguish PFV from FEVR, such as the presence of retinal folds that connect a stalk extending from the optic disc to the posterior lens in PFV—a distinctive structure not found in FEVR. FEVR is a posterior-temporal-anterior retinal fold vs PFV that is from the nerve to the lens. Additionally, PFV lacks a genetic pattern and may show distinct lens abnormalities, such as a thickened or elongated ciliary process and sometimes a shallow anterior chamber, which are not characteristic of FEVR. Recent observations suggest that unilateral PFV may be a bilateral, asymmetric condition, as retinal vascular abnormalities have been detected in most fellow eyes of patients with PFV. FA highlights further distinctions. In PFV, the affected eye may display leakage from persistent vessels, while the fellow eye can exhibit vascular abnormalities and in 67.1% peripheral vessel avascularity, a feature that, while present in both FEVR and PFV, differs in the specific vascular patterns observed.3 OCT adds diagnostic value by revealing a vascularised stalk in the affected eye in PFV and often a Bergmeister papilla in the fellow eye, imaging characteristics that are helpful for accurate differentiation.4
Coats disease, which is misdiagnosed as FEVR in about 7% of cases, shares features with FEVR such as abnormal vascular development and retinal exudation.1 However, Coats disease typically affects only one eye, primarily in young boys, and does not follow a hereditary pattern, whereas FEVR often presents in both eyes. A distinguishing feature of Coats disease is the presence of “light bulb” aneurysms and significant leakage seen on fluorescein angiography, which are not usually observed in FEVR.5 On OCT, Coats disease often reveals extensive intraretinal and subretinal fluid, along with hyperreflective exudates caused by severe vessel leakage. Retinal cysts, outer retinal disruptions, retinal schisis formation and retinal thickening due to chronic exudation are also commonly seen in Coats disease.6, 7
The study emphasised the value of genetic testing as a diagnostic tool to confirm FEVR, especially in cases with atypical presentation. Genetic testing can identify pathogenic mutations in genes associated with FEVR, allowing clinicians to differentiate it from similar conditions. Key genes in FEVR, including LRP5, FZD4, NDP, and TSPAN12, affect vascular development pathways. When mutations in these genes are present, a diagnosis of FEVR becomes more certain.
Genetic testing is recommended for patients with suspected FEVR when patients have ambiguous clinical presentation; when the family history suggests a hereditary condition, even in the absence of obvious symptoms in family members; and in cases in which initial treatments fail or symptoms persist. A confirmed diagnosis of FEVR aids in several aspects of patient management. It enables targeted treatments and family counseling by providing insights valuable for family planning and identifying relatives at potential risk, allowing for early detection and intervention. Additionally, patients with confirmed FEVR require long-term monitoring, even if symptoms are mild initially, as regular imaging and follow-up can detect any progression early on, supporting prompt treatment when necessary.
While genetic testing has clear benefits, there are limitations for its use. First, it can be expensive and may not be accessible, depending on patients' health care coverage. Moreover, not all FEVR cases have identifiable mutations in known genes. In this study, genetic mutations were only found in 53% of phenotypic FEVR cases,1 which is consistent with current literature.
Genetic testing not only prevents misdiagnosis but also helps clinicians tailor treatments, monitor disease progression, and provide valuable family counseling. Given the high rate of initial misdiagnoses, ophthalmologists should consider incorporating genetic testing into their diagnostic workflows for paediatric retinal disorders. This proactive approach can lead to better patient outcomes, especially for those with atypical presentations or a family history suggestive of hereditary eye disease.
References
1. Hudson JL, da Cruz NFS, Kunkler AL, Carletti P, Negron CI, Berrocal AM. Revision of Initial Referral Diagnosis after Genotypic Confirmation of Familial Exudative Vitreoretinopathy. Ophthalmol Retina. 2024;8(10):1029-1031.
2. John VJ, McClintic JI, Hess DJ, Berrocal AM. Retinopathy of Prematurity Versus Familial Exudative Vitreoretinopathy: Report on Clinical and Angiographic Findings. Ophthalmic Surg Lasers Imaging Retina. 2016;47(1):14-19.
3. Laura DM, Staropoli PC, Patel NA, Yannuzzi NA, Nolan RP, Al-Khersan H, Fan KC, Flynn HW Jr, Acon D, Negron CI, Berrocal AM. Widefield Fluorescein Angiography in the Fellow Eyes of Patients with Presumed Unilateral Persistent Fetal Vasculature. Ophthalmol Retina. 2021;5(3):301-307.
4. da Cruz NFS, Sengillo JD, Hudson JL, Carletti P, de Oliveira G, Negron CI, Felder MB, Berrocal AM. Intraoperative OCT Angiography in Pediatric Patients with Persistent Fetal Vasculature. Ophthalmol Retina. 2023;7(12):1109-1115.
5. Jeng-Miller KW, Soomro T, Scott NL, et al. Longitudinal examination of fellow-eye vascular anomalies in Coats’ disease with widefield fluorescein angiography: a multicenter study. Ophthalmic Surg Lasers Imaging Retina. 2019;50(4):221-227.
6. Ashkenazy N, Acon D, Kalavar M, Berrocal AM. Optical coherence tomography angiography and multimodal imaging in the management of coats’ disease. Am J Ophthalmol Case Rep. 2021;23:101177.
7. Scott NL, Cernichiaro-Espinosa LA, Russell JF, Murray TG, Dubovy SR, Berrocal AM. Retinoschisis in Coats Disease: Clinical Picture, Therapeutic Considerations, and Management Outcomes. J Vitreoretin Dis. 2020;5(3):251-257. doi: 10.1177/2474126420954306
