PERIPHERAL RETINOPATHY IN OFFSPRING OF CARRIERS OF NORRIE DISEASE GENE-MUTATIONS - POSSIBLE TRANSPLACENTAL EFFECT OF ABNORMAL NORRIN

Background: The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) co nsists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proli feration. Norrie disease (congenital retinal detachment), X-linked pri mary retinal dysplasia (congenital retinal fold), and X-linked exudati ve vitreoretinopathy (congenital macular ectopia) are allelic disorder s. Methods: Blood was drawn for genetic studies from members of two fa milies to test for ND gene mutations, Sixteen unaffected family member s were examined ophthamlologically, If any retinal abnormality were id entified, fundus photography and fluorescein angiography was performed . Results: Family A had ND (R109stp), and family B had X-linked exudat ive vitreoretinopathy (R121L), The retinas of II offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had p eripheral inner retinal vascular abnormalities; The retinas of five of fspring of affected males were examined: none of three carrier females and none oi two otherwise healthy males had this peripheral retinal f inding, Conclusions: Peripheral inner retinal vascular abnormalities s imilar to regressed retinopathy of prematurity were identified in seve n offspring of carriers of ND gene mutations in two families. These op hthalmologic findings, especially in four genetically healthy offsprin g, strongly support the hypothesis that abnormal Norrin may have an ad verse transplacental (environmental) effect on normal inner retinal va sculogenesis.