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Norrie disease (ND) is a rare X linked recessive disorder in which affected males are blind at birth or in early infancy. About one third develop progressive sensorineural deafness. In addition, about 25% of affected males have varying degrees of developmental delay. The ocular findings include bilateral retinal folds, retinal detachment, vitreous haemorrhage, and bilateral retrolental masses consisting of haemorrhagic vascular and glial tissue (vitreoretinal dysplasia).
Histopathological examination of the eyes of an 11 week foetus with ND showed no evidence of primary neuroectodermal maldevelopment of the retina, suggesting that later disordered retinal vascular development may be a more likely disease mechanism.1
More than 100 different mutations of the ND gene, NDP, have been identified.2 Germ line mutations in NDP have also been identified in X linked familial exudative vitreoretinopathy (FEVR) and in retinopathy of prematurity (ROP). Somatic NDP mutations have been implicated in retinal telangiectasis (Coats disease). These findings suggest a role for the Norrie protein in normal retinal angiogenesis. The reported association of ND with peripheral vascular disease in affected males in a large Costa Rican pedigree,3 suggests that NDP may also play a role in non-ocular angiogenesis.
We present the second report of Norrie disease associated with peripheral vascular insufficiency, further supporting an angiogenic role for NDP.
A 53 year old man with bilateral congenital glaucoma and vitreoretinal dysplasia underwent ophthalmological review, peripheral vascular examination, and molecular genetic testing. He complained of poor vision since birth. He had undergone an enucleation of his right eye in young adulthood secondary to uncontrolled glaucoma resulting in intractable pain. Vision was hand movement. Anterior segment examination revealed Haab’s striae, a shallow anterior chamber and drainage angle dysgenesis. Marked retinal atrophy and optic nerve head calcified drusen had been noted in his left eye before the development of a dense cataract.
He had no evidence of mental retardation. He had sensorineural deafness and had suffered with bilateral lower leg ulceration secondary to peripheral venous insufficiency for over 30 years, necessitating a varicose vein operation at the age of 19 years. Following surgery he has worn support stockings.
A histopathological study of his right eye revealed hypertrophy of corneal nerves (fig 1), a finding which has not been previously reported in association with ND. The ciliary body was seen to be drawn into a preretinal fibrous band at its posterior limit; while the retina had lost its normal architecture and was severely gliotic with cysts and extensive compact lamellar bone formation (fig 2).
The association of congenital glaucoma, vitreoretinal dysplasia, and sensorineural deafness in this male patient raised the possibility of ND. Mutation screening of NDP revealed a two base pair deletion in exon 2, resulting in a stop codon and truncation, thereby confirming the clinical suspicion of ND. His two affected maternal uncles were also found to have ND associated with peripheral venous insufficiency and lower leg ulceration.
These cases represent further evidence of a potential role of NDP in vascular development. Mutations in NDP have been reported in several retinal disorders which are characterised by vascular abnormalities, including Coats disease, Stage 5 ROP, and X linked FEVR, suggesting that the protein product of NDP, Norrin, may be involved in normal retinal angiogenesis. The association of ND with peripheral venous insufficiency seen in the family reported here and in the Costa Rican pedigree3 suggest that Norrin may also play a role in extraocular angiogenesis.
Further light has been shed on the possible roles of Norrin with the development of an NDP knockout mouse model.4,5 The retinal vasculature is abnormal by postnatal day 9, with abnormal vessels in the inner retina and few vessels in the outer retina.4 The main vasculature of the cochlea, at the stria vascularis, is also abnormal, with eventual loss of two thirds of the vessels. It was therefore proposed that one of the principal functions of Norrin in the ear is to regulate the interaction of the cochlea with its vasculature—further supportive evidence of an important angiogenic role for the Norrie gene.
We present the second report of Norrie disease associated with peripheral vascular disease. This association suggests that NDP has an important role in angiogenesis in the eye and other non-ocular tissues.
We are grateful to the patients who kindly agreed to take part in this study. The mutation analysis was kindly undertaken in the Massachusetts General Hospital Neurogenetics DNA Diagnostic Laboratory (Director: Katherine B Sims MD).
The order in which the authors of this article are listed is incorrect and should read:
Michaelides M, Luthert PJ, Cooling R, Firth H, Moore AT.
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