Retinal vascular abnormalities and dragged maculae in a carrier with a new NDP mutation (c.268delC) that caused severe Norrie disease in the proband Phoebe Lin, MD, PhD, a Suma P. Shankar, MD, PhD, b Jacque Duncan, MD, a Anne Slavotinek, MD, PhD, b Edwin M. Stone, MD, PhD, c,d and Tina Rutar, MD a,e Norrie disease (ND) is caused by mutations in the ND pseudoglioma (NDP) gene (MIM 300658) located at chromosome Xp11.4-p11.3. ND is characterized by abnormal retinal vascular development and vitreoretinal disorganization presenting at birth. Systemic manifes- tations include sensorineural deafness, progressive mental disorder, behavioral and psychological problems, growth failure, and seizures. Other vitreoretinopathies that are associated with NDP gene mutations include X-linked familial exudative vitreoretin- opathy, Coats disease, persistent fetal vasculature, and retinopathy of prematurity. Phenotypic variability associated with NDP gene mutations has been well documented in affected male patients. However, there are limited data on signs in female carriers, with mild peripheral retinal abnormalities reported in both carrier and noncarrier females of families with NDP gene mutations. Here, we report a family harboring a single base-pair deletion, c.268delC, in the NDP gene causing a severe ND phenotype in the male proband and peripheral retinal vascular abnormalities with dragged maculae similar to those observed in familial exudative vitreoretinop- athy in his carrier mother. Case Report A 4-month-old Vietnamese boy presented to the pediatric ophthalmology clinic with failure to track and bilateral leukocoria. He was born to a 35-year- old mother at term with an uneventful prenatal and postna- tal course. Family history was significant for a 32-year-old maternal uncle who was blind since childhood (e-Supple- ment 1, available at jaapos.org). The patient exhibited no response to light and conjugate horizontal nystagmus. He had bilateral retrolental masses. Examination under anes- thesia revealed intraocular pressures of 25 mm Hg in the right eye and 12 mm Hg in the left eye. Both eyes had hor- izontal corneal diameters of 10 mm. The right cornea was clear, and the left cornea had a temporal stromal opacity. The irides were hypoplastic with ectropion uveae, posterior synechiae, and diffuse neovascularization bilaterally. Both lenses were anteriorly displaced. The right anterior cham- ber was flat, and the left was flat temporally and one-half corneal thickness deep centrally. There were visible ciliary processes and yellow retrolental masses with fine vessels in both eyes (Figure 1A, B). Ultrasound biomicroscopy con- firmed flat anterior chambers with lenticular-corneal touch bilaterally (Figure 1C, D). B-scan ultrasonography demon- strated gross vitreoretinal disorganization bilaterally (Figure 1E, F). The patient’s ocular phenotype was consis- tent with Norrie disease (ND). The patient passed his new- born hearing screen and an audiological assessment at age 7 months. He had no developmental delay as of age 7 months. There were no other physical abnormalities detected on examination by a clinical pediatric geneticist. The proband’s mother was born full-term and was asymptomatic with a best-corrected visual acuity of 20/40 in the right eye and 20/30 in the left eye. However, exam- ination and fluorescein angiography revealed straightened retinal vessels and temporally dragged maculae bilaterally. The peripheral retinas were avascular with fibrotic neovas- cular tufts in both eyes (Figure 2). She had no other associ- ated systemic abnormalities by history or examination. Norrie disease pseudoglioma (NDP) gene testing on genomic DNA isolated from white blood cells of both the proband and his mother was performed at the Carver Nonprofit Genetic Testing Laboratory at the University of Iowa (http://www.carverlab.org). The methods used for testing are presented in e-Supplement 2 (available at jaapos.org). Bidirectional sequencing revealed a single base-pair deletion, c.268delC (NM_0000266.3) in exon 3 of the NDP gene in both the proband and mother (e-Supplement 3, available at jaapos.org). This mutation has not been previously reported and is presumed to cause a frameshift in the NDP coding region resulting in a prema- ture stop codon. We computationally analyzed the effect of the single base pair deletion by using an online transla- tional tool (http://www.expasy.ch/cgi-bin/dna_aa). The coding sequence of the mutant DNA resulted in a termi- nally aberrant truncated protein, R90fsX103 (e-Supple- ment 3, available at jaapos.org) with a premature stop codon in the third exon after 13 aberrant amino acids. The premature stop codon occurs in the same exon as the naturally occurring stop codon. Therefore, we predict that this transcript is translated into an aberrant yet trun- cated protein rather than undergoing nonsense mediated degradation. The single base-pair deletion we describe is likely the disease-causing mutation in this family given Author affiliations: a Department of Ophthalmology, University of California, San Francisco; b Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco; c The Howard Hughes Medical Institute, Chevy Chase, Maryland; d The University of Iowa Carver College of Medicine, Iowa City, Iowa; e Department of Pediatrics, University of California, San Francisco Supported by an institutional P30 core grant from the National Institutes of Health, NEI EY002162-31. Reprint requests: Tina Rutar, MD, Department of Ophthalmology, University of California San Francisco, 10 Koret Way, K 301, San Francisco, CA 94143-0730 (email: rutart@vision.ucsf.edu). J AAPOS 2010;14:93-96. Copyright Ó 2010 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2010/$36.00 1 0 doi:10.1016/j.jaapos.2009.11.012 Journal of AAPOS 93