Genetic susceptibility to advanced retinopathy of prematurity (ROP)

Abstract

Retinopathy of prematurity (ROP) is a vascular vitreoretinopathy that affects infants with short gestational age and low birth-weight. The condition is a multifactorial disease and is clinically similar to familial exudative vitreoretinopathy (FEVR), which is a bilateral hereditary eye disorder affecting full-term infants. Both of them are characterized by the abnormal vessel growth in the vitreous that can lead to vitreoretinal traction, retinal detachment and other complications resulting in blindness. Despite the recent advances in diagnosis and treatment, ROP remains a major cause of childhood blindness in developed countries. The etiology of pathogenesis of advanced ROP is currently unknown. In the past, many causative factors such as length of time exposed to supplemental oxygen, excessive ambient light exposure and hypoxia have been suggested but evidence for these as independent risk factors in recent years is not compelling. It is not clear why ROP in a subset of infants with low birth-weight progresses to a severe stage (retinal detachment) despite timely intervention whereas in other infants with similar clinical characteristics ROP regresses spontaneously. Recent research with candidate gene approach, higher concordance rate in monozygotic twins and other clinical and experimental animal studies, suggest a strong genetic predisposition to ROP besides environmental factors such as prematurity. Three genes, which are involved in the Wnt signaling pathway, are mutated in both FEVR and in a small percentage of ROP disorder. However, none of the genetic factors identified thus far in ROP, account for a substantial number of patient population. Future studies involving genomics, bioinformatics and proteomics may provide a better understanding of the pathophysiology and management of ROP.

Figure 1

A schematic illustration of some of the abnormalities associated with advanced ROP. In the early stages, ROP is characterized by an incomplete vascularization of the peripheral retina (panel A), with a sharply demarcated boundary between vascularized and avascularized retina (stage 1). This can progress to an elevated ridge (panel B) that consists of mesenchymal tissue (stage 2). In more advanced stages of the disease, extra-retinal fibrovascular proliferation occurs (panel C) on the posterior border of the ridge (stage 3). In addition to the abnormal vascularization, the normal gelatinous vitreous (panel D) becomes partially liquefied (panel E). While spontaneous regression often occurs, an organization and contraction of vitreous collagen can take place (panel E) which can lead to a retinal fold (panel F) causing partial (panel G) or total retinal detachment (panel H) that represent stages 4 and 5 respectively.

Figure 2

A highly hypothetical pathway that may lead to a cicatricial ROP and a morphologically similar disorder FEVR. De novo gene mutation coupled with environmental factors (e. g. prematurity) may lead to the progression and development of retinal detachment in stage 4 - 5 ROP whereas prematurity alone without gene mutation may lead to an early stage of ROP that may subsequently regress to a normal condition. On the other hand, inherited or de novo mutations without prematurity may result in familial and sporadic FEVR respectively, that develop during the first decade of life.

Figure 3

A schematic representation of the canonical Wnt signaling pathway. Norrin and Wnt act as ligands to bind FZD4 that interact with LRP5. In the absence of Wnt signaling, beta-catenin is phosphorylated and subjected to proteosomal degradation. In the presence of Wnt signaling, beta-catenin accumulates in the cytoplasm and enters the nucleus. Its subsequent interactions with a member of Tcf/Lef family activate the transcription of Wnt target genes. It was also shown that TSPAN12 is a component of the norrin-LRP5-FZD4 signaling complex and enhances the levels of norrin-beta-catenin signaling but not Wnt-beta-catenin signaling. Because of mutations in NDP, FZD4, LRP5 and TSPAN12 genes, abnormal signaling may occur which may result in defective Wnt target genes activation that may give rise to FEVR and ROP pathology. AD = autosomal dominant; AR = autosomal recessive; XL = X-linked recessive; FEVR = familial exudative vitreoretinopathy; ROP = retinopathy of prematurity; NDP = Norrie disease pseudoglioma.