Commentary: Familial exudative vitreoretinopathy-The masquerade in pediatric retinal disorders.

This issue of IJO features an interventional study discussing the clinical profile, management, and outcomes of pediatric macula-off rhegmatogenous retinal detachment (RRD) secondary to familial exudative vitreoretinopathy (FEVR).[1] FEVR is a rare inherited disorder of retinal angiogenesis, characterized by phenotypic and genotypic heterogenicity.[2] Phenotypic expression may range from the presence of temporal avascular peripheral retina in an asymptomatic patient to extensive subretinal exudation, florid fibrovascular proliferation, retinal folds, tractional retinal detachment (RD) or RRD, or severe retinal dysplasia at birth resulting in severe visual dysfunction and even total blindness.[2] Treatment options include observation, laser photocoagulation or cryotherapy, anti-vascular endothelial growth factor (anti-VEGF) injection and scleral buckle, and/or pars plana vitrectomy (PPV), depending upon the stage of disease at presentation.[2]

Management of RRD in FEVR is complicated by its presentation in younger age as well as by the underlying abnormal vitreoretinal interface, which is more adherent and difficult to completely separate from the retina, resulting in postoperative pre-retinal proliferation and recurrent RD.[3] Unique surgical problems are associated with these RRDs, especially in the presence of associated falciform retinal folds.[3] Where peripheral breaks with falciform folds can be supported on a scleral buckle, posterior retinal breaks in eyes with falciform folds necessitating PPV and large posterior relaxing retinectomies result in particularly dismal outcomes.[3]

Due to phenotypic variability, improper and delayed diagnosis is the biggest hurdle in the management of FEVR. When presenting in the neonatal period, it can masquerade other pediatric retinal disorders like retinopathy of prematurity (ROP) and persistent fetal vasculature (PFV).[2] A small subset of premature infants who exhibit retinal findings more characteristic of FEVR than ROP have been described as ROPER (ROP vs. FEVR) by Gologorsky et al.[4] These eyes behave more like FEVR, with a less predictable and more progressive course of disease in long term.[4] FEVR can mimic PFV, especially if associated with “knifelike retinal folds “extending from the optic disk radially to the peripheral retina and anteriorly to the ciliary processes.[2] It is quite possible for a patient to have advanced FEVR findings in one eye and grossly normal other eye, further creating confusion with PFV. The stalk in PFV, unlike the falciform fold in FEVR, is not typically a retinal fold, but a hyaloid stalk of persistent vascular tissue that extends from the optic nerve to the posterior lens surface.[5]

Accurate diagnosis of FEVR is best done by careful clinical examination coupled with fundus fluorescein angiography (FFA) and genetic testing wherever possible. FFA enhances the diagnostic sensitivity because subtle vascular changes in the periphery or even in the posterior pole can easily be overlooked by a routine fundus examination.[2] Wide-field retinal imaging is particularly helpful to detect asymptomatic family members.

Because of phenotypic variations, genetic testing may become essential in some cases to establish the diagnosis. The inheritance pattern of FEVR may be autosomal dominant (AD; most common), autosomal recessive (AR), or X-linked recessive (XL-R), and the common genes implicated so far include NDP, FZD4, LRP5, TSPAN12, ZNF408 and KIIF11.[267] The first four genes result in mutations in the “Norrin/b-catenin signaling pathway,” which plays a pivotal role in vascular morphogenesis in the eye.[2] KIF11, localized to the spindle microtubules, is involved in the mitotic progression and growth of the retinal vessels.[6] The ZNF408 protein has been implicated in abnormal retinal vascularization and trunk vascularization in zebrafish.[7] While almost all patients with NDP mutations are reported to have a severe presentation, milder phenotypes ranging from stage 2 to stage 5 have been seen in eyes with LRP5 mutations.[8] Disease phenotype is reportedly more bilaterally symmetrical in patients with KIFF11, TSPAN12, and NDP gene mutations compared to patients with LRP5 and FZD4 mutations.[9] Widespread chorioretinal degeneration may additionally be present in cases with KIFF11 and NDP mutations, along with neurodevelopmental delay and microcephaly.[10] Genetic testing in FEVR is important for diagnosis, better understanding of the disease, and prognostication. Knowledge of the gene mutation can also facilitate the molecular prenatal analysis of fetal DNA; this along with antenatal ultrasound can be used to predict FEVR in at-risk babies.[11] Timely intervention in the early neonatal period itself can prevent total blindness in some at-risk babies.

FEVR, a clinically and genetically heterogeneous disorder, requires a high index of suspicion, careful examination, timely management, and long-term follow-up. Increased genetic testing in these patients will further improve our understanding of the disease. Awareness and education of parents as well is of paramount importance to reduce the risk of bilateral total blindness due to FEVR.