ORPHA: 891; DO: 0111411;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.2 | Exudative vitreoretinopathy 4 | 601813 | Autosomal dominant; Autosomal recessive | 3 | LRP5 | 603506 |
A number sign (#) is used with this entry because familial exudative vitreoretinopathy-4 (EVR4) can be caused by heterozygous, homozygous, or compound heterozygous mutation in the LRP5 gene (603506) on chromosome 11q13.
See also osteoporosis-pseudoglioma syndrome (OPPG; 259770), an allelic disorder with an overlapping phenotype.
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).
For a discussion of genetic heterogeneity of familial exudative vitreoretinopathy, see EVR1 (133780).
Shastry and Trese (1997) reported a family in which the mode of inheritance of FEVR appeared to be autosomal recessive. Affected males and females occurred in 3 separate sibships. The parents were consanguineous in the case of 2 of the sibships.
Two unrelated families with FEVR reported by de Crecchio et al. (1998) likewise showed apparent autosomal recessive inheritance. Compared with autosomal dominant and X-linked recessive inheritance, the presumably recessive form showed earlier onset at birth and a more severe and progressive course.
In an Asian family with FEVR, Price et al. (1996) found linkage to chromosome 11 (maximum 2-point lod score of 5.55 at D11S533) within the region of the EVR1 locus. Although there was consanguinity within the family, the transmission pattern was consistent with autosomal dominant inheritance.
By high-resolution genotyping of the family reported by Price et al. (1996), Toomes et al. (2004) determined that the disease locus was not EVR1, but rather a distinct locus approximately 10 cM centromeric to the FZD4 gene (604579), which represents EVR1. The novel locus, termed EVR4, was within a 15-cM interval on chromosome 11q13 between D11S1368 and D11S937. The findings indicated that there are 2 nearby but distinct loci for FEVR on chromosome 11q.
The transmission pattern of EVR4 is autosomal dominant in some families (Toomes et al., 2004) and autosomal recessive in other families (Jiao et al., 2004).
In affected members of 6 unrelated families with FEVR, Toomes et al. (2004) identified 6 different heterozygous mutations in the LRP5 gene (see, e.g., 603506.0020-603506.0021). One of the families had been reported by Price et al. (1996).
In affected members of the 3 families with autosomal recessive EVR studied by Shastry and Trese (1997) and de Crecchio et al. (1998), Jiao et al. (2004) identified 3 different homozygous mutations in the LRP5 gene: R570Q (603506.0022), R752G (603506.0023), and E1367K (603506.0024). The findings indicated that mutations in the LRP5 gene can cause both autosomal dominant and autosomal recessive EVR.
Qin et al. (2005) identified 9 novel mutations in the LRP5 gene (see, e.g., 603506.0025-603506.0028) in Japanese patients with FEVR. Four families showed autosomal dominant inheritance, and 2 families showed autosomal recessive inheritance. One family was found to have a heterozygous mutation in the LRP5 gene (603506.0026) and a heterozygous mutation in the FZD4 gene (604579.0003) on the same chromosome. Qin et al. (2005) also found that patients with mutations in the LRP5 gene showed reduced bone mineral density and suggested that it is a common feature in patients with EVR4. Qin et al. (2005) proposed that osteoporosis-pseudoglioma syndrome (OPPG; 259770), which is also caused by mutation in the LRP5 gene, and EVR4 are part of a single phenotypic spectrum with both ocular and bone manifestations.
de Crecchio, G., Simonelli, F., Nunziata, G., Mazzeo, S., Greco, G. M., Rinaldi, E., Ventruto, V., Ciccodicola, A., Miano, M. G., Testa, F., Curci, A., D'Urso, M. M., Rinaldi, M. M., Cavaliere, M. L., Castelluccio, P. Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity. Clin. Genet. 54: 315-320, 1998. [PubMed: 9831343] [Full Text: https://doi.org/10.1034/j.1399-0004.1998.5440409.x]
Jiao, X., Ventruto, V., Trese, M. T., Shastry, B. S., Hejtmancik, J. F. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5. Am. J. Hum. Genet. 75: 878-884, 2004. [PubMed: 15346351] [Full Text: https://doi.org/10.1086/425080]
Poulter, J. A., Ali, M., Gilmour, D. F., Rice, A., Kondo, H., Hayashi, K., Mackey, D. A., Kearns, L. S., Ruddle, J. B., Craig, J. E., Pierce, E. A., Downey, L. M., Mohamed, M. D., Markham, A. F., Inglehearn, C. F., Toomes, C. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am. J. Hum. Genet. 86: 248-253, 2010. Note: Erratum: Am. J. Hum. Genet. 98: 592 only, 2016. [PubMed: 20159112] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.012]
Price, S. M., Periam, N., Humphries, A., Woodruff, G., Trembath, R. C. Familial exudative vitreoretinopathy linked to D11S533 in a large Asian family with consanguinity. Ophthal. Genet. 17: 53-57, 1996. [PubMed: 8832721] [Full Text: https://doi.org/10.3109/13816819609057871]
Qin, M., Hayashi, H., Oshima, K., Tahira, T., Hayashi, K., Kondo, H. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum. Mutat. 26: 104-112, 2005. [PubMed: 15981244] [Full Text: https://doi.org/10.1002/humu.20191]
Shastry, B. S., Trese, M. T. Familial exudative vitreoretinopathy: further evidence for genetic heterogeneity. (Letter) Am. J. Med. Genet. 69: 217-218, 1997. [PubMed: 9056564] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970317)69:2<217::aid-ajmg19>3.0.co;2-o]
Toomes, C., Bottomley, H. M., Jackson, R. M., Towns, K. V., Scott, S., Mackey, D. A., Craig, J. E., Jiang, L., Yang, Z., Trembath, R., Woodruff, G., Gregory-Evans, C. Y., Gregory-Evans, K., Parker, M. J., Black, G. C. M., Downey, L. M., Zhang, K., Inglehearn, C. F. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am. J. Hum. Genet. 74: 721-730, 2004. [PubMed: 15024691] [Full Text: https://doi.org/10.1086/383202]
Toomes, C., Downey, L. M., Bottomley, H. M., Scott, S., Woodruff, G., Trembath, R. C., Inglehearn, C. F. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR). Molec. Vis. 10: 37-42, 2004. [PubMed: 14737064]