From the Ocular Oncology Service, Wills Eye Institute, Philadelphia, Pennsylvania.
Supported by Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS).
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Institute, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107. E-mail: email@example.com
Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by premature arrest of retinal angiogenesis leading to incomplete vascularization of the peripheral retina.1 Symptoms result from retinal traction, exudation, neovascularization, and retinal detachment. In a study of 116 eyes with FEVR, Shukla et al. reported neovascularization in 7%, exudative or tractional retinal detachment in 13%, and rhegmatogenous retinal detachment in 17% of eyes on initial presentation.2
FEVR displays 100% penetrance,3 but it is variably expressed and known to produce a spectrum of clinical presentations ranging from mild disease with a completely asymptomatic patient to severe disease with neovascular glaucoma and blindness, resulting in enucleation. This variation in clinical expressivity is present even among patients within the same family and can be noticed within an individual, with one eye manifesting far advanced FEVR and the opposite eye with minimal disease. Herein we present a case of marked asymmetry in the clinical expressivity of FEVR in a 2-month-old infant.
A 2-month-old male infant developed leukocoria and was referred for possible retinoblastoma. This full-term infant had no history of trauma, and there was no family history of retinoblastoma. Visual acuity was no fix or follow in the right eye and fix and follow in the left eye. Intraocular pressures measured 10.9 mm Hg in the right eye and 15.6 mm Hg in the left eye. There was 45-prism diopter right esotropia with leukocoria, band keratopathy, flat anterior chamber, extensive posterior synechiae, and a fibrotic, disorganized vitreous cavity with barely visible total retinal detachment (Figure). The retinal detachment showed several flecks of calcification on ultrasonography. Fluorescein angiography revealed diffuse hyperfluorescence and staining of the disorganized mass of fibrotic detached retina.
Figure. (A) A 2-month-old male infant with right leukocoria and 45-prism diopter right esotropia. (B) Externally unremarkable left eye. (C) The right eye showed total fibrotic retinal detachment and vitreous hemorrhage. (D) The left eye showed temporal dragging of retinal vessels. (E) B-scan ultrasonography of the right eye demonstrated dense intraocular disorganization, globe shrinkage, and flecks of intraocular calcium. (F) Ultrasonography of the left eye was unremarkable. Fluorescein angiography showed (G) diffuse staining of the disorganized globe in the right eye and (H) V-shaped non-perfusion temporally in the left eye.
Evaluation of the left eye showed subtle retinal dragging temporally and mild retinal pigment epithelial mottling. Fluorescein angiography of the left eye disclosed V-shaped temporal peripheral non-perfusion. These bilateral findings were suggestive of FEVR (Stage 3/Type 5 in the right eye and Stage 2/Type 3 in the left eye). Evaluation of both parents showed normal clinical and fluorescein angiographic findings.
Over 20 months of follow-up, the right eye became hypotonous (intraocular pressure = 4 mm Hg) and phthisical. The left eye remained stable without progression. Genetic testing for NDP, TSPAN12, FZD4, and LRP5 yielded negative results.
In 1969, Criswick and Schepens first described FEVR as a retinal abnormality with features similar to retinopathy of prematurity but without a history of premature birth or perinatal complications.4 In 1971, Gow and Oliver demonstrated autosomal dominant inheritance pattern of FEVR and proposed a three-stage classification system.5 Canny and Oliver added to the classification system (Table 1) and established that peripheral vascular defects rather than vitreoretinal traction was the primary abnormality.1 Over time, several different classification schemes have been developed. A classification combining the clinical and angiographic features of FEVR into five types is currently widely used (Table 2).6
Table 1: Three-Stage Clinical Classification of Familial Exudative Vitreoretinopathy
Table 2: Five-Type Combined Clinical and Fluorescein Angiographic Classification of Familial Exudative Vitreoretinopathy
To date, mutations in four genes have been reported to be responsible for FEVR, including Norrie disease protein (NDP),7 frizzled homolog 4 (FZD4),8 low-density lipoprotein receptor-related protein 5 (LRP5),3 and tetraspanin 12 (TSPAN12).9 The gene products of these are critical components of the Norrin/Fz4/Wnt signaling pathway that is important for retinal vascular development. An abnormality in this pathway leads to maldevelopment of the retinal vessels with features of FEVR. These genes can be inherited in autosomal recessive, X-linked, or, most commonly, autosomal dominant fashion. FZD4 can be a useful tool in screening mild or atypical cases of FEVR.10
There are several different mutations currently known within each of the four genes and new mutations continue to be discovered. FZD4 mutation is positive in 20% to 40% of patients.3 Toomes et al. reviewed 40 patients with clinical features of FEVR in which 20% were positive for FZD4 mutations and 15% were positive for LRP5 mutations.3 A four-generational study of 30 patients with FEVR by Chen et al. demonstrated that 100% of X-linked recessive cases had NDP mutations.7 Nikopoulos et al. studied 11 families with FEVR who were negative for mutations in FZD4, NDP, and LRP5 and found TSPAN12 mutations in 46%.9 Our patient tested negative for known mutations.
FEVR can be distinguished from retinopathy of prematurity by a lack of history of prematurity. It can be distinguished from persistent hyperplastic primary vitreous (persistent fetal vasculature), a classically unilateral condition, by bilateral involvement, absence of microphthalmos and hyaloid artery, and typical fluorescein findings of nonperfusion in FEVR.11
In some circumstances, young age (< 3 years old) at detection is a sign of ultimately progressive disease and poor visual prognosis.11 Those patients who remain nonprogressive by 20 years of age generally remain stable in the long term.5,12 Despite these facts, FEVR is a lifetime disease, and progression might occur following a stable period.
Current management of FEVR involves laser photocoagulation or cryotherapy for active neovascularization or retinal tears.2 Retinal detachment is usually tractional and often requires vitrectomy. Peripheral laser ablation or cryotherapy is employed for eyes with substantial retinal exudation. Recently, bevacizumab has been investigated for treatment for retinal exudation and neovascularization.13
FEVR is a bilateral disease but can be markedly asymmetric as illustrated in our patient. The variety of contributory mutations and variable expressivity likely leads to the broad clinical spectrum. The cause of asymmetric disease presentation in FEVR and its correlation with genetic mutation is not clearly understood. Intrafamilial variability, lack of genotype–phenotype correlations, and asymmetric disease presentation suggest that other genetic, environmental, or stochastic factors play a crucial role in determining disease presentation.10
- Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol. 1976;94:1114–1120. doi:10.1001/archopht.1976.03910040034006 [CrossRef]
- Shukla D, Singh J, Sudheer G, et al. Familial exudative vitreoretinopathy (FEVR): clinical profile and management. Indian J Ophthalmol. 2003;51:323–328.
- Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004;74:721–730. doi:10.1086/383202 [CrossRef]
- Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68:578–594.
- Gow J, Oliver GL. Familial exudative vitreoretinopathy: an expanded view. Arch Ophthalmol. 1971;86:150–155. doi:10.1001/archopht.1971.01000010152007 [CrossRef]
- Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology. 1984;91:1524–1530.
- Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180–183. doi:10.1038/ng1093-180 [CrossRef]
- Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32:326–330. doi:10.1038/ng957 [CrossRef]
- Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86:240–247. doi:10.1016/j.ajhg.2009.12.016 [CrossRef]
- Robitaille JM, Zheng B, Wallace K, et al. The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease. Br J Ophthalmol. 2011;95:574–579. doi:10.1136/bjo.2010.190116 [CrossRef]
- Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995;93:473–521.
- Tasman W, Augsburger JJ, Shields JA, Caputo A, Annesley WH Jr, . Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1981;79:211–226.
- Sisk RA, Berrocal AM, Albini TA, Murray TG. Bevacizumab for the treatment of pediatric retinal and choroidal diseases. Ophthalmic Surg Lasers Imaging. 2010;41:582–592. doi:10.3928/15428877-20100830-03 [CrossRef]
Three-Stage Clinical Classification of Familial Exudative Vitreoretinopathy
|1||White with and without pressure in the temporal peripheral retina|
|Associated with peripheral cystoid degeneration, vitreous bands, and vitreous traction on the retina|
|Usually no abnormal vascular or exudative retinal changes|
|2||Stage 1 changes are present with the addition of:|
Neovascularization between the equator and ora serrata temporally
Associated subretinal and intraretinal exudates and localized detachment of the retina
Fibrovascular temporal lesions exert traction on major retinal vessels resulting in “dragged disc” and “ectopic macula”
Often with decreased visual acuity
|3||Total retinal detachment is usually present due to vitreous fibrosis and traction on the retina|
|Associated with massive subretinal and intraretinal exudates|
|Associated anterior segment changes including cataract formation, atrophy of the iris, neovascular glaucoma, and band keratopathy|
Five-Type Combined Clinical and Fluorescein Angiographic Classification of Familial Exudative Vitreoretinopathy
|1 (Simple)||Presence of an almost uniform avascular zone in the farthest fundus periphery less than 2 disc diameters from ora serrata|
|Vascular engorgement, capillary microaneurysms, arteriovenous shunts, and straightening of vessels confined to temporal sector only|
|2 (Arcuate)||Presence of a wider avascular zone, more than 2 disc diameters, in the farthest periphery than in Type 1|
|Peripheral margin of the vascularized retina is uniform, thus arcuate, in appearance|
|Numerous well-developed arteriovenous shunts along peripheral margin|
|3 (V-shaped)||Avascular zone in farthest periphery is more pronounced and more than 2 disc diameters in width|
|Wedge-shaped avascular zone along temporal meridian|
|Retinal vascular abnormalities, as in Type 1, are present in more prominent states|
|4 (Proliferative)||Sea-fan shaped neovascularization, usually temporally|
|Wide avascular zone in the farthest periphery more than 2 disc diameters in width|
|Neovascularization developing from retinal vessels along farthest vascularized retina temporally with dye leakage from new vessels on fluorescein angiography|
|Deformation of retinal vessels due to dragging occurs in a more pronounced form than the above three types|
|Frequent macular ectopia|
|5 (Cicatricial)||Presence of a solid, cicatricial mass in the pars plana region, usually in the temporal sector|
|Tractional, falciform retinal detachment with macular involvement is common|
|No clear-cut avascular zone in the farthest retinal periphery|