Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, even within families, with severely affected patients often registered as blind during infancy, whereas mildly affected ... Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, even within families, with severely affected patients often registered as blind during infancy, whereas mildly affected patients with few or no visual problems may have such a small area of avascularity in their peripheral retina that it is visible only by fluorescein angiography. It is believed that this peripheral avascularity is the primary anomaly in FEVR and results from defective retinal angiogenesis. The sight-threatening features of the FEVR phenotype are considered secondary to retinal avascularity and develop because of the resulting retinal ischemia; they include the development of hyperpermeable blood vessels, neovascularization, vitreoretinal traction, retinal folds, and retinal detachments (summary by Poulter et al., 2010). - Genetic Heterogeneity of Familial Exudative Vitreoretinopathy An X-linked form of familial exudative vitreoretinopathy (EVR2; 305390) is caused by mutation in the NDP gene (300658); EVR3 (605750) maps to chromosome 11p13-p12; EVR4 (601813) can be caused by heterozygous or homozygous mutations in the LRP5 gene (603506) on 11q13.4; and EVR5 (613310) is caused by heterozygous mutations in the TSPAN12 gene (613138) on 7q31.
Familial exudative vitreoretinopathy was first described by Criswick and Schepens (1969) on the basis of 6 patients in 2 kindreds. The findings bore some similarities to retrolental fibroplasia and to Coats disease (see 300216). The changes were slowly ... Familial exudative vitreoretinopathy was first described by Criswick and Schepens (1969) on the basis of 6 patients in 2 kindreds. The findings bore some similarities to retrolental fibroplasia and to Coats disease (see 300216). The changes were slowly progressive. Affected children were otherwise healthy. None was premature or treated neonatally with oxygen. Posterior vitreous detachment with organized membranes were found in all quadrants. Vitreoretinal traction was produced by membranes and resulted in displacement of the macula. Snowflake opacities were scattered through the vitreous humor. Localized retinal detachment and displacements and recurrent vitreous hemorrhages from peripheral new vessels were noted. A brother and sister in 1 family were affected. In the other family, 3 brothers and their maternal uncle were affected. A distant male relative related through females was blind, making X-linked recessive inheritance a possibility. This may be the same as congenital falciform retinal detachment (221900). Gow and Oliver (1971) added another series of cases from an extensively affected kindred. Canny and Oliver (1976) divided the clinical course into 3 stages on the basis of studies of Gow and Oliver's pedigree, which in its updated form showed proved or probable cases in 6 successive generations. Under the designation of peripheral retinal neovascularization, Gitter et al. (1978) probably described the same disorder. Nine members of the family showed wide variability in severity and slow progression. Some eyes progressed to vitreous hemorrhage, secondary cataract, and phthisis bulbi. Two other affected members of the family progressed to total retinal detachment. Penetrance is about 100%, but many patients have very mild disease that is detectable with certainty only by fluorescein angiography (Ober et al., 1980). Progression of fundus changes and threat to vision is rare after age 20 years. The similarity to retinopathy of prematurity (ROP) or retrolental fibroplasia can be striking (Slusher and Hutton, 1979). In studies of a large Dutch kindred, Nijhuis et al. (1979) found fluorescein angiography indispensable in demonstrating the earliest detectable abnormalities of the disorder and in distinguishing affected from unaffected persons. In studies of a large German kindred, Laqua (1980) concluded that FEVR is inherited as an autosomal dominant and is a disease primarily of small peripheral vessels leading to fibrovascular mass lesions. Miyakubo et al. (1982) identified 30 cases in 11 families as well as 4 sporadic cases, all male. In 8 affected members of a family, Feldman et al. (1983) described clinical findings including retinal detachment, fibrovascular masses with dragged disc and macula, neovascular fronds, and intraretinal deposits. Miyakubo et al. (1984) proposed a grading system into 5 types. In the Netherlands, van Nouhuys (1989) observed retinal detachment in 36 (20%) of 180 eyes of 90 persons with FEVR from 17 families. He pointed out that FEVR can give rise to very different types of retinal detachment, such as rhegmatogenous retinal detachment, falciform retinal folds, and exudative retinal detachment. All but one retinal detachment occurred before the age of 30. Traction from vitreous membranes seemed to be the most important cause of retinal detachment; atrophy of the peripheral retina may contribute to the formation of retinal breaks. In 4 eyes of 3 patients from 2 large families with FEVR, van Nouhuys (1981) found congenital retinal fold (ablatio falciformis congenita), which, he suggested, should be considered a sign rather than a diagnosis. The formation of congenital retinal fold is the consequence of a developmental disorder of retinal vasculature during the last few months of intrauterine life and the folds may even develop after birth. The clinical picture and familial occurrence of many cases of congenital retinal fold previously described were suggestive of dominant exudative vitreoretinopathy, which is a rather common disorder. Nishimura et al. (1983) likewise found falciform retinal fold as a sign of FEVR. Ida Mann (1935), writing about congenital retinal fold, suggested that this 'curious and striking congenital abnormality...is not so rare as the paucity of the literature concerning it would suggest.' Familial exudative vitreoretinopathy is reported to have a penetrance of 100%, but clinical features can be highly variable, even within the same family. Severely affected patients may be legally blind during the first decade of life, whereas mildly affected individuals may not be aware of symptoms and may receive a diagnosis only by use of fluorescein angiography. The primary pathologic process in FEVR is believed to be a premature arrest of retinal angiogenesis/vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. This failure to vascularize the peripheral retina is the unifying feature seen in all affected individuals, but, by itself, it usually causes no clinical symptoms. The visual problems in FEVR result from secondary complications due to the development of hyperpermeable blood vessels, neovascularization, and vitreoretinal traction. These features cause a reduction in visual acuity and, in 20% of cases, can lead to partial or total retinal detachment (van Nouhuys, 1991). Ranchod et al. (2011) described the clinical characteristics, staging, and presentation of patients with FEVR in their clinical practice over the foregoing 25 years. They included 273 eyes of 145 patients. Patients were slightly male-predominant (57%) with a mean birth weight of 2.80 kg (range, 740 g-4.76 kg), mean gestational age of 37.8 weeks (range, 25-42) and mean age at presentation of almost 6 years (range, less than 1 month-49 years). A positive family history of FEVR was obtained in 18% of patients. A positive family history of ocular disease consistent with but not diagnosed as FEVR was obtained in an additional 19%. Stage 1 FEVR was identified in 45 eyes, stage 2 in 33 eyes, stage 3 in 42 eyes, stage 4 in 89 eyes, and stage 5 in 44 eyes. Radial retinal folds were seen in 77 eyes, which in 64 were temporal or inferotemporal in location. While the majority of retinal folds extended radially in the temporal quadrants, radial folds were seen in almost all quadrants. Fellow eyes demonstrated a wide variation in symmetry. Ranchod et al. (2011) concluded that the presentation of FEVR might mimic the presentation of other pediatric and adult vitreoretinal disorders, and careful examination is often crucial in making the diagnosis of FEVR.
In affected members of families with the form of FEVR mapping to 11q13-q23, EVR1, Robitaille et al. (2002) identified mutations in the FZD4 gene (604579.0001-604579.0002).
Kondo et al. (2003), Yoshida et al. (2004), and Qin et ... In affected members of families with the form of FEVR mapping to 11q13-q23, EVR1, Robitaille et al. (2002) identified mutations in the FZD4 gene (604579.0001-604579.0002). Kondo et al. (2003), Yoshida et al. (2004), and Qin et al. (2005) identified heterozygous mutations in the FZD4 gene (see, e.g., 604579.0003-604579.0005) in Japanese patients with EVR1. Some asymptomatic parents who carried the mutations showed peripheral retinal avascularization. Qin et al. (2005) reported a Japanese family with digenic inheritance of EVR. Affected individuals had a heterozygous mutation in the FZD4 gene (604579.0003) and a heterozygous mutation in the LRP5 gene (603506.0026). Of 68 probands diagnosed as having autosomal dominant or sporadic FEVR, Robitaille et al. (2011) identified 11 different FZD4 mutations (5 missense, 3 deletions, 1 insertion, 2 nonsense) in 12 probands. Six of these mutations were novel, and none were found in 346 control chromosomes. - Retinopathy of Prematurity In an infant with advanced retinopathy of prematurity, MacDonald et al. (2005) identified heterozygosity for a mutation in the FZD4 gene (604579.0006).