13.3.10  Treatment

Once the diagnosis of JXRS is made, family screening and genetic counseling are important. Early treatment involves maximizing vision by treating amblyopia, refractive error, or strabismus. Close follow-up in the first decade is important to detect any secondary complications such as vitreous hemorrhage or peripheral retinal detachments. As there are no effective prophylactic techniques for patients with JXRS, observation is important.

Surgery should be considered to treat any sight-­ threatening complications such as retinal detachment or nonclearing vitreous hemorrhage. Rhegmatogenous retinal detachment may require scleral buckling alone; however, if the detachment is associated with vitreous hemorrhage and unsupported retinal vessels, additional pars plana vitrectomy surgery may be necessary. Since vitrectomy in children can be wrought with difficulty given the lack of posterior vitreous detachment and tight posterior hyaloid, performing inner-layer retinectomy to remove vitreoretinal traction can be considered [33, 43, 44].

13.3.11  Complications and Associations

Vitreous hemorrhage is the most common secondary complication of JXRS, found in up to 40% of patients [32, 33, 45]. The vitreous hemorrhage is usually caused by torn unsupported retinal vessels within the peripheral schisis cavity. They may clear spontaneously or lead to dense hemorrhage necessitating surgery. The vitreous hemorrhage may also result from peripheral neovascularization caused by retinal ischemia.

Rhegmatogenous retinal detachments may occur with outer retinal holes and subretinal fluid in up to 22% of patients with X-linked juvenile Retinoschisis [30, 31]. If the retinal detachment is chronic and progressing, pigmented demarcation lines may be evident. Repair of retinal detachments in JXRS is associated with a high rate of proliferative vitreoretinopathy [33, 46].

13.3.12  Social and Family Impact

associated with a poor visual outcome, if patients are closely observed for secondary complications.

13.4  Familial Exudative

Vitreoretinopathy (FEVR)

13.4.1  Introduction

FEVR is a bilateral, autosomal dominant ocular condition due to peripheral retinal vascular abnormalities.

13.4.2  Historical Context

FEVR was first described by Criswick and Schepens in 1969 who reported on six patients from two families. Each patient had bilateral vitreoretinal abnormalities that resembled ROP but with no history of premature birth. The ocular findings were described as peripheral neovascularization with tractional retinal detachment, exudates, folds, and macular dragging (Fig. 13.6) [47].

Gow and Oliver in 1971 reported on 22 patients within three generations of a family, which showed the autosomal dominant mode of transmission and suggested a vascular pathogenesis for the disorder [48]. In 1971, Canny and Oliver showed by fluorescein angiography the avascular nature of the peripheral ­temporal retina in patients with FEVR (Fig. 13.7) [49].

Genetic counseling and evaluation of the carrier status should be considered. JXRS is not necessarily

Fig. 13.6  Macular fold and dragging consistent with FEVR in a patient without a history of prematurity

13.4.3  Overview with Clinical Significance

Typically, the diagnosis of FEVR is made in the first several years of life when patients present with leukocoria or exotropia. Clinical evaluation may require examination under anesthesia depending on the severity of disease and the necessity of diagnostic testing. Decreased visual acuity can be due to macular folds, optic nerve or maculardragging,orexudativeretinaldetachment.Examination of the asymptomatic parents may facilitate the diagnosis if temporal avascular retinal areas can be identified.

a

c

Fig. 13.8  Color photos showing examples of peripheral fundus changes and vascular anomalies in patients with FEVR

13.4.4  Classification

FEVR was classified into three “Stages” in1971 by Gow and Oliver. Stage I is described as peripheral temporal white without pressure and vascular anomalies (Fig. 13.8). Stage II shows dilated tortuous vessels with a peripheral fibrovascular mass and macular or disc dragging toward the periphery (Fig. 13.8). Stage III shows massive subretinal exudation and extensive retinal detachment with vitreous bands [48].

FEVR has also been characterized by angiographic appearance by Miyakubo and Hashimoto. Type I has

b

avascular retinal zones less than two disc diameters with focal arteriovenous shunts and no neovascularization. Type II has an avascular retinal zone greater than two disc diameters with more extensive arteriovenous shunts. Type III has a V-shaped notch in the avascular zone. Type IV has neovascularization associated with the avascular retinal zones. Type V has cicatricial ­disease [50].

Pendergast and Trese (1998) further defined FEVR with a different classification scheme. Stage I patients have avascular retinal periphery without extraretinal vascularization. Stage 2 patients have avascular retinal periphery with extraretinal vascularization, which is further subdivided into 2A without exudates and 2B with exudates. Stage 3 patients have subtotal retinal detachment not involving the fovea with 3A primarily exudative and 3B primarily tractional. Stage 4 patients have subtotal retinal detachment involving the fovea with 4A primarily exudative and 4B primarily tractional. Stage 5 patients have a total retinal detachment while 5A is open funnel and 5B is closed funnel [51].

13.4.5  Genetics

There are at least four genetically mapped loci that underlie the emergence of FEVR (EVR1, EVR2, EVR3, EVR4). FEVR is most commonly an autosomal dominant condition, although X-linked and autosomal recessive forms have also been identified. Initially, by multipoint linkage analysis in two families with autosomal dominant FEVR, a locus for FEVR (EVR1) was mapped to the long arm of chromosome 11 (11q13–q23) [52, 53]. A causally associated disease gene (EVR1) was identified at this locus, which encodes the Wnt receptor known as frizzled-4 (FZD4) (Toomes et al. 2004; Robitaille et al. 2002; Kondo et al. 2003). FZD4 is a seven transmembrane integral membrane receptor containing 537 amino acids. In some pedigrees, the X-linked mode of inheritance of FEVR (EVR2) cosegregates with mutations in the gene responsible for Norrie’s Disease [54, 55] that encodes the protein norrin, a 133-amino acid protein, which has recently been shown to be a ligand for the Wnt FZD4 receptor in vascular endothelium (Chen et al. 1995; Xu et al. 2004). An autosomal recessive pedigree of FEVR (EVR4) allowed linkage to 11q13–14 region and identification of another disease gene for low density lipoprotein receptor related

protein (LRP5) (Jiao et al. 2004). LRP5 is now known to be a surface coreceptor for FZD4 in the Wnt signaling pathways in vascular endothelium. LRP5 is able to bind ligands and promote internalization through receptor mediated endocytosis. Mutations in the LRP5 gene also associate with a different clinical syndrome known as osteoporosis pseudoglioma syndrome (OPPG), which has both skeletaland vision-related phenotypic components, with the visual lesion found as a persistent fibrovascular mass associated with the retina (the “pseudoglioma”) (Gong et al. 2001). The combination of early onset bilateral vitreoretinal pathology in association with skeletal fragility is an index for consideration of LRP5 mutations. Curiously, and due to the protein level association of LRP5 with FZD4 as coreceptors, digenic disease can emerge in which single recessive mutations in each gene promote an emergent phenotype (Qin et al. 2005). For example, the hypothetical combined loss of 50% FZD4 and 50% LRP5 proteins at the cell surface could severely impair formation of the bimolecular coreceptor complex that is essential for Wnt pathway signaling in the vascular endothelium. An additional FEVR locus (EVR3) has been mapped (11p13–p12), but the gene is not yet cloned. The phenotypic expression of FEVR is variable even within a family. While penetrance of FEVR is thought to be nearly 100%, the phenotypic expressivity varies over large range, which includes lack of full temporal retinal vascularization to extensive rhegmatogenous or exudative retinal detachments. Hence, identification of the milder forms of FEVR may be difficult to diagnose, by peripheral IVFA, which is otherwise difficult to perform and especially in children. Unaffected carriers of the disease may be challenging to identify. Broad phenotypic spectrum of disease in FEVR can be understood to relate to the nature of the mutations in the different disease genes and the impact that the discrete mutations have on the level of expression of the protein (e.g., null mutations), the location of missense mutations and their impact on local and global protein structure, and the capacity for mutant proteins to affect the expression level, trafficking, or function of the normal or wild type protein (e.g., dominant negative effect). For example, severe FEVR (EVR2) mutations in the NDP gene occur at highly conserved cysteine residues that are expected to specify the tertiary folding of the protein ligand for the FZD4 Wnt receptor binding pocket. Such norrin mutations likely decrease the affinity of the FZD4 receptor

for norrin and thus perturb Wnt beta-catenin mediated signaling pathways in the vascular endothelium (Drenser et al. 2007; Wu et al. 2007; Riveiro-Alvarez et al. 2005).

13.4.6  Pathophysiology

The primary abnormality in FEVR is a peripheral vascular defect, which secondarily causes exudation and vitreoretinal traction. FEVR is a developmental disorder reflecting an arrest of development of the primary peripheral retinal vasculature and can be associated with failed regression of the primary hyaloid vasculature of the vitreous. The disorder mimics ROP but in patients with no history of premature birth; in fact, mutations in FZD4 have also been identified in patients with ROP. The clinical syndromes of FEVR, ROP, and Norrie disease (ND) share distinct common elements in the failure of development of the primary retinal vasculature and the associated secondary complications that can lead to severe visual sequelae (e.g., vitreoretinal traction bands, leakage and exudate, rhegmatogenous, and exudative retinal detachment). Ischemia and vascular leakage are likely driving forces in the emergence of these sequelae. Given the identification of causally associated mutations in different genes for various forms of FEVR, ND, and ROP, and the fact that these genes underlie the specification of a system of signaling (Wnt signaling pathway) within the vascular endothelium, one can begin to understand how primary molecular failures in a single cell type can ultimately promote the emergence of a spectrum of clinical disease.

The contribution of FZD4 and norrin to the Wnt signaling pathway during retinal vascular development was elegantly demonstrated using mouse models of disease (Xu et al. 2004). In the mouse FZD4 knockout, the primary retinal vascular trunks form along the contour of the emerging retina, but the orthogonal branches that penetrate the retina are unable to form, as in the normal state, the subsequent arborization that generates the secondary retinal vasculature (at level of the outer nuclear layer) and the tertiary retinal vasculature (at level of the inner nuclear layer). In addition, there is delay in regression of the primary hyaloid vasculature. Curiously, the retinal vessels that remain in the FZD4 knockout mouse have a fenestrated vascular endothelium, which is not a property of the mature retinal

­vasculature. This study demonstrated that FZD4 was essential to the normal formation and maturation of the mammalian retinal vasculature. These phenotypic findings were similar to the retinal vascular development found in the male NDP knockout mouse and suggested that norrin could be a FZD4 ligand in the Wnt signaling pathway. Subsequent experiments proved this hypothesis, and even though norrin is not a known Wnt ligand or a member of the Wnt ligand family, it achieves a structure that is able to bind to the surface FZD4 receptor with high specificity and at nanomolar affinity. Given that Wnt receptors are promiscuous with respect to different ligands in different tissues, this is not a surprising finding.

Under unstimulated or resting conditions, the betacatenin cytoplasmic factor is part of a large multiprotein complex. The complex includes the scaffold protein, axin, which holds beta-catenin in proximity to glycogen synthase kinase three to allow phosphorylation. The complex also includes adenomatous polyposis coli (APC), a tumor suppressor, which presents pho­ sphorylated beta-catenin to the proteosome for degradation.Bytheseprocesses,thelevelsofunphosphorylated intact beta-catenin in the cytoplasm are kept very low, and the phosphorylated beta-catenin is unable to interact with the cytoplasmic surface of the Wnt FZD4 receptor and unable to enter the nucleus to stimulate transcription (Néstor et al. 2006). Upon ligand (NDP) binding to the surface Wnt receptor (FZD4) and its coreceptor (LRP5), the receptor achieves an active conformational state, which allows the disheveled protein (Dvl) to bind to the cytoplasmic surface and prevent phosphorylation and degradation of beta-catenin. Cytoplasmic levels of free beta-catenin rise with continued receptor occupation, and the uninhibited protein enters the nucleus of the vascular endothelial cells where it interacts with a member of tre Tcf/Lef transcription factors to form transcriptionally active complexes on a set of genes known to be involved in angiogenesis. These genes include ephrin receptors, VEGF, FGF, interleukin-8, endothelin, and MMP2 and MMP9. The promoter for VEGF gene alone contains seven recognition motifs for the beta-catenin/Tcf-Lef factors. Thus, the failure of vascular development in FEVR, ND, and ROP can be understood from the perspective of failures in regulated angiogenesis modulated by the canonical (discussed above) and noncanonical (not presented) Wnt signaling pathways. The participation of the FZD4, NDP, and LRP5 gene