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We read with interest the article published in the ARCHIVES by Chynn and colleagues1 who described a full-term male neonate who had bilateral leukocoria, vascularized retrolental membranes, and hemorrhagic retinal detachments. Histopathological examination of 1 eye at the age of 5 weeks revealed elongated ciliary processes, large retrolental vessels, hemorrhagic retinal detachment, and retinal dysplasia—findings indicative of either Norrie disease (ND) or persistent hyperplastic primary vitreous (PHPV). The authors subsequently performed molecular genetic analysis and identified a 1–base-pair deletion in codon 35 of the ND gene, thereby establishing a diagnosis of ND.
As Chynn's study illustrates, the clinical distinction between sporadic ND without systemic manifestations and bilateral PHPV can be difficult and has led to much confusion, with many authors stating that bilateral PHPV occurs in 10% of cases while others believe that bilateral PHPV is extremely rare or may not exist. In addition, it is common in our experience that genetic screening of children with ocular findings consistent with ND or PHPV is negative for mutations in the ND gene. Since mutations in the ND gene have been identified in patients with ND,2,3 we investigated whether mutations in the ND gene were present in 2 unrelated patients with ocular findings consistent with bilateral PHPV to facilitate the identification and classification of these 2 disorders.
Report of Cases
A 4-year-old healthy Hispanic boy had decreased visual acuity since birth, and developed horizontal jerk nystagmus at approximately 10 weeks of age. Medical, family, and birth histories were unremarkable. On ocular examination, visual acuity was counting fingers in both eyes. Anterior segments were normal and corneal diameters were 10.5 mm OU. Funduscopic examination of the right eye revealed a large fibroglial stalk emanating from the center of the optic disc. Peripapillary vessels were drawn into the stalk and the peripapillary retina was elevated and appeared dysplastic. Similar findings were observed in the left eye.
A healthy, full-term, 2-week-old white boy was referred for bilateral retinal detachments. An alert visual evoked potentials measurement revealed tentative P100 wave forms at appropriate absolute latencies in both eyes. On clinical examination the corneal diameter measured 9.5 mm OD and 10.0 mm OS. Both eyes showed elongated ciliary processes, vascularized retrolental masses, and vitreous hemorrhage. A luxuriantly vascularized stalk extended from the optic nerve to the posterior lens. The underlying retina was completely detached and, apart from a portion of the nasal retina, was almost completely devoid of vasculature. Similar findings were observed in the left eye.
Genomic DNA from both patients was amplified using the polymerase chain reaction with primers designed to amplify exons of the ND gene.2 The polymerase chain reaction products were subcloned and sequenced using standard techniques. In both cases the entire coding region of the ND gene, including splice sites, was sequenced. The results revealed a wild-type sequence in both patients, supporting a diagnosis of bilateral PHPV rather than ND.
Norrie disease is an X-linked recessive syndrome characterized by hemorrhagic retinal detachment, PHPV, retinal dysplasia, and vitreous hemorrhage, with bilateral blindness typically observed at birth. Mild to severe mental retardation and progressive sensorineural hearing loss are common associations.
In contrast with ND, PHPV is a sporadic, nonhereditary malformation of the eye and is not associated with systemic abnormalities. The clinical spectrum of PHPV is broad. In severe cases, microphthalmia, retrolental fibrovascular plaques, retinal detachment, and retinal dysplasia may occur, leading to cataract, secondary glaucoma, and eventually, phthisis. Therefore, when bilateral ocular manifestations are encountered that are consistent with severe PHPV in the absence of a family history and systemic abnormalities, the distinction between bilateral PHPV and ND remains an area of confusion. In the current study, one of the patients had only posterior involvement while the other subject was more severely affected and had both anterior and posterior involvement, simulating ND. In both cases no nucleotide alterations were found in the ND gene.
No genetic or biochemical abnormalities have been identified in cases of PHPV to date. Although the gene(s) responsible for PHPV is unknown, the lack of inheritance and the unilaterality of the disease suggest that sporadic somatic mutations may be responsible for the disease. However, it is conceivable that unilateral PHPV, bilateral PHPV, and ND represent 3 separate clinical entities with unique underlying mechanisms. In addition, we cannot exclude the possibility that unilateral PHPV, or even bilateral PHPV, represent a developmental defect caused by environmental factors during embryogenesis, rather than by genetic factors.
Although we cannot definitively exclude the ND gene as a candidate gene for PHPV, it seems as if, in the 2 cases of bilateral PHPV described in this study, mutations in the ND gene are not responsible for ND. This further suggests that bilateral PHPV and ND are distinct clinical entities. The molecular genetic analysis of DNA from additional patients with ND and bilateral PHPV will be necessary to confirm this hypothesis.
This study was supported in part by grants from the Heed Ophthalmic Foundation, Cleveland, Ohio (Dr Pendergast), and the William Beaumont Hospital Research Institute, Royal Oak, Mich (Dr Shastry).
Dr Pendergast is now with Retina Associates of Cleveland Inc, Beachwood, Ohio.
Corresponding author: Barkur S. Shastry, PhD, Eye Research Institute, Oakland University, Dodge Hall, Room 431, Rochester, MI 48309.
Pendergast SD, Trese MT, Liu X, Shastry BS. Study of the Norrie Disease Gene in 2 Patients With Bilateral Persistent Hyperplastic Primary Vitreous. Arch Ophthalmol. 1998;116(3):381–382. doi:
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