Version 1
: Received: 15 September 2023 / Approved: 18 September 2023 / Online: 19 September 2023 (15:18:40 CEST)
Version 2
: Received: 20 October 2023 / Approved: 23 October 2023 / Online: 23 October 2023 (16:12:29 CEST)
Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function – and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goals of this review are to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
23 October 2023
Commenter:
Kenneth Mitton
Commenter's Conflict of Interests:
Author
Comment:
1. Updates to differentiate non-retinal and retinal pathological variants in protein domain diagrams. These diagrams have been completely recreated using MacVector and Photoshop.
2. Addition of three additional genes with multiple syndromes that may also include FEVR-like pathology.
3. Some additions to text for additional genes. Minor revisions and clarifications.
4. Addition of Bruch's membrane and choroidal vasculature to the retinal layer diagram (Figure 1) to improve the explanation of the inner versus outer blood-retinal barrier for readers not familiar with the retina.
Commenter: Kenneth Mitton
Commenter's Conflict of Interests: Author
2. Addition of three additional genes with multiple syndromes that may also include FEVR-like pathology.
3. Some additions to text for additional genes. Minor revisions and clarifications.
4. Addition of Bruch's membrane and choroidal vasculature to the retinal layer diagram (Figure 1) to improve the explanation of the inner versus outer blood-retinal barrier for readers not familiar with the retina.