Familial exudative vitreoretinopathy

Familial exudative vitreoretinopathy is also called FEVR, Criswick-Schepens syndrome (former name for the autosomal dominant form of the disease) or OMIM 133780.

Familial exudative vitreoretinopathy (FEVR) is an inherited eye disorder characterized by premature arrest of the vascularization of the peripheral retina and significant phenotypic and genotypic variability. The disease affects full-term infants with severity ranging from absence of visual symptoms to total blindness. FEVR belongs to the group of vitreoretinal dystrophies.

FEVR was first described in 1969 by Criswick and Schepens in patients exhibiting clinical manifestations similar to those of retinopathy of prematurity (ROP) but without history of prematurity or oxygen supplementation.

Epidemiology, onset & clinical features


The disease is often described as rare or very rare, through the exact prevalence remains unknown. As many of the affected individuals may be asymptomatic, the prevalence of the disorder may be underestimated. FEVR has been described in all ethnic groups.


FEVR usually occurs in full-term newborns and more frequently manifests in the first decade of life. It may however be detected at various ages, up to 20 years.

Clinical features

FEVR presents with bilateral expression that may be asymmetrical. Hallmark features include avascular peripheral retina and peripheral ischemia, retinal neovascularization, subretinal exudation, formation of an abnormal vitreoretinal interface and retinal detachment. The disease has different degrees of severity, ranging from normal vision to total blindness during the first decade of life. Highly variable expressivity may occur even within the same family.

Three clinical stages may be differentiated:

    • Stage I is a mild degree of the disease in which patients are asymptomatic, but the vitreoretinal interface exhibits alterations such as white with or without pressure and cystoid degeneration as well as avascular areas in the peripheral retina. Less characteristic are vascular ingurgitation and telangectasiae, microaneurisms and arterial-venous shunts.

    • Stage II is a proliferative and exudative stage that is characterized by neovascularization, fibrovascular proliferation and sub- and intra-retinal exudation. Complications (macular ectopia and papillary traction events) may occur due to fibrovascular lesions.

    • In stage III, the scar lesion causes tractional, regmatogenous and exudative total or partial retina detachment and falciform folds (that may be unilateral). Other possible complications include optical atrophy, cataracts, glaucoma and strip keratopathy.


In most cases, FEVR takes a progressive course during childhood and adolescence. The progression usually stops by the age of 20 years. Ocular findings and visual acuity then usually remain stable and patients retain useful vision.

Etiology and pathogenesis

FEVR primary pathology is a premature arrest of retinal vasculogenesis, leading to incomplete vascularisation of the peripheral retina. The secondary complications are mainly due to retinal ischemia.

It is genetically heterogeneous and can be inherited by three inheritance patterns: autosomal dominant (adFEVR), autosomal recessive (arFEVR), and X-linked (XFEV).

The most common mode of inheritance is autosomal dominant. To date, two genes are known to be associated with adFEVR: FZD4 on chromosome 11q14-q21, encoding the protein frizzled-4 (this form of the disease is also named exudative vitreoretinopathy-1, EVR1) and LRP5 on chromosome 11q13.4, encoding low-density lipoprotein receptor-related protein 5 (this form of the disease is also named exudative vitreoretinopathy-4, EVR4). Each of these genes is responsible for about 20 % of the adFEVR cases. A third locus for adFEVR, EVR3 (chromosomal locus 11p13-p12), has been mapped but the gene has yet not been identified.

Mutations in LRP5 also cause arFEVR.

The X-linked FEVR (X-linked recessive FEVR, XFEVR, EVR2) can be caused by mutations in the NDP gene on chromosome Xp11.4 (encoding the protein Norrin), which causes Norrie disease.

The FZD4 and LRP5 genes are implicated in the classic Wnt signaling pathway that plays a key role in the embryonic development including eye development. XFEVR is also caused by mutant Norrin, and Norrin itself has been found to act as a ligand for frizzled-4. This would indicate a possible common molecular mechanism underlying both Norrie disease and FEVR.

Mutations in the FZD4 and LRP5 genes have been found in certain cases of unilateral and bilateral persistent fetal vasculature (PFV) and Coats' disease that also have an overlapping clinical presentation to Norrie disease, FEVR, and ROP. The NDP gene has been shown to play a causal role in Norrie disease, X-linked FEVR, Coat's disease and ROP.

Genotypes-phenotypes correlations have yet not been made. Individuals with adFEVR and mutations in the LRP5 gene have been reported to have reduced bone mass; this finding was not seen in individuals with FEVR who have FZD4 mutations or those with other forms of FEVR.

The highly variable intrafamilial expressivity of FEVR suggests that additional exogenous (environmental, epigenetic) or systemic factors (genetic) factors may play a role in the pathogenesis and presentation of the disease.

Mode of inheritance

Most individuals with adFEVR inherit the altered gene from a parent, although the parent may not have any symptom of the disease. Offspring of an affected individual has a 50 % risk of inheriting the mutation, but more than 50 % (up to 90 %) of individuals with adFEVR can be asymptomatic because of reduced penetrance.

Individual with arFEVR inherits the disease from both parents (each of them carries one copy of the mutated gene) but they do not have the disorder.

When FEVR is caused by mutations in the NDP gene, which is located on the X chromosome, in male individuals (who have only one X chromosome), one altered copy of the gene is sufficient to cause the disease. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. A striking characteristic of X-linked inheritance is that fathers cannot pass the X-linked traits to their sons. Although very rarely, both Norrie disease and XFEVR can occur in women.


Diagnosis is based on clinical presentation, ocular examination, and molecular genetic testing. In asymptomatic or only mildly affected patients, the electroretinogram, electro-oculogram, color vision testing and visual fields may be normal or only mildly abnormal.

Diagnosis is often made when families of patients with suspected or known FEVR are screened. In most infants, FEVR is diagnosed when they are evaluated for failure to fix and follow objects or lights, for pendular nystagmus or heterotropia, or when children and adults notice decreased vision.

Fluorescein angiography has the main diagnostic role. Molecular genetic testing for FZD4 and LRP5 is clinically available. Prenatal diagnosis for pregnancies at increased risk is feasible (analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling at approximately ten to 12 weeks' gestation).

Differential diagnosis

The differential diagnosis of FEVR essentially depends on the stage of the disease. FEVR must be differentiated from ROP, Coats' disease, incontinentia pigmenti, persistent hyperplastic primary vitreous (PHPV), and Norrie disease. Important additional differential diagnoses include high myopia, Eales' disease, juvenile retinoschisis, vitreousand toxocariasis.

Management, follow-up & prognosis


The main objective is the early diagnostic and treatment of the disease. Prevention of the primary manifestations of the disease is not possible at present, but prevention and treatment of manifestations mostly related to the neovascularization process may be achieved by prophylactic cryotherapy or argon laser.

The management of FEVR, however, is a matter of controversy and not all authors defend prophylaxis with photocoagulation or cryocoagulation. According to the majority of researchers, the main indication for prophylactic treatment is peripheral neovascularisation and exudative retinal detachment, although the results of this approach have not been conclusive. Since FEVR has such a variable course, only patients at high risk of progression should receive prophylactic treatment.

Scleral buckling procedures and vitrectomy are used to treat retinal detachment.

Therapies under investigation include angiogenesis inhibitors such as antivascular endothelial growth factor (anti-VEGF) drugs (pegaptanib, bevacizumab).


Children should undergo regular fundus examination to evaluate for development of retinal neovascularization, traction, or exudate.

Family screening (ideally by fundus fluorescein angiography to identify any characteristic lesions) is recommended.

Genetic counseling to young adults who are affected or at risk should be offered.


The clinical course of FEVR is variable, but the most severe forms may be active for life, with variable periods of quiescence. Long-term outcomes for serious disease include severe visual impairment and blindness.


Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol 1969; 68: 578-94.

Kondo H, Qin M, Kusaka S, Tahira T, Hasebe H, Hayashi H, Uchio E, Hayashi K. Novel mutations in Norrie disease gene in Japanese patients with Norrie disease and familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1276-82.

Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP, Craig JE, Tengtrisorn S, Carden SM, Maclean H, Mackey DA. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Experiment Ophthalmol. 2006 Sep-Oct;34(7):682-8.

Toomes C, Downey LM, Bottomley HM, Mintz-Hittner HA, Inglehearn CF. Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. Br J Ophthalmol. 2005 Feb;89(2):194-7.

Toomes C. Familial Exudative Vitreoretinopathy, Autosomal Dominant. December 11, 2008. NCBI Bookshelf GeneReviews. [∂=fevr]


Katia Marazova, MD, PhD,  Prof. José-Alain Sahel, MD, PhD and Dr Caroline Laurent-Coriat, MD, PhD

Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment.