EVER-Acta lecture: Telomere maintenance and retinal vascularisation

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Abnormal development of the retinal vasculature is an important cause of vision loss in infancy, childhood and, occasionally, in adult life. In addition to retinopathy of prematurity from exposure to oxygen after preterm birth, several genetic defects affecting retinal vascularization have recently been discovered, affecting either Wnt signaling or telomere maintenance. The canonical norrin–beta-catenin pathway of Wnt signaling is deranged by mutations in frizzeld-4 (FZD4), low density lipoprotein receptor-related protein 5 (LRP5), norrin (NDP) and other genes. These lead to vascular leakage, vitreoretinal traction or both in Coats’ disease, familial exudative vitreoretinopathy (FEVR), Norrie’s disease and osteoporosis-pseudoglioma syndrome. Mutations in telomeric repeat-binding factor 1-interacting nuclear factor 2 (TINF2) and CTS telomere maintenance complex component 1 (CTC1) in Revesz syndrome and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) can even cause retinal angiomas. Wnt signaling initially was the suspect for them as well, because all six diseases share more or less widespread retinal avascularity as a hallmark. Indeed, a link between the two pathways is still possible. The manifestations of the telomere-related syndromes are more protean than those of Wnt-related ones, which have no other significant systemic findings than osteoporosis if LRP5 is mutated. The former may lead to a cerebral and intestinal vasculopathy or hepatopathy, all of which can be fatal, and to skin and hair abnormalities. Milder forms can escape diagnosis until adulthood. It is useful to recognize these genetic vasculopathies. Genes for cases which still go unexplained remain to be discovered.

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