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.