Monica R. Khitri
BASICS
DESCRIPTION
• Rare neurodevelopmental disorder of males causing congenital or early infancy blindness from retinal dysplasia, classically characterized by retrolental masses (pseudogliomas) (1)
• Associated with developmental delay, hearing loss, and behavioral abnormalities
• Also known as progressive oculo-acoustico-cerebral degeneration
EPIDEMIOLOGY
• First reported in families from Scandinavia but since reported in almost all ethnic groups
• Affects males predominantly. Very rare female carriers (2)
Incidence
Extremely rare disease that has been reported only in isolated case reports.
RISK FACTORS
Family history of Norrie disease
Genetics
• X-linked recessive disease caused by mutations in the NDP gene at Xp11.4
• More than 70 point mutations, chromosomal rearrangements, frame-shift, and splice site mutations described (3)
– Female carriers may harbor some retinal findings that can range from mild pigmentary changes to retinal detachment, abnormal retinal vasculature, and macular drag. When carrier expression is present, it is usually presumed to be a result of skewed X-chromosome inactivation or chromosomal aberration (2)[C].
GENERAL PREVENTION
• Carrier testing of female relatives can identify individuals at risk of having affected offspring.
• Prenatal testing possible if mutation already identified in an affected family member.
PATHOPHYSIOLOGY
Developmental abnormality of retinal vascularization during embryogenesis causing retinal hypoxia and dysplasia (4)
ETIOLOGY
Norrin, the protein encoded by the NDP gene, has a characteristic cysteine knot motif and is involved in Frizzled-dependent signaling cascade important for vascular development and maintenance of the inner ear and retina. Mutations in the NDP gene cause aberrant retinal vascularization (4)[C].
COMMONLY ASSOCIATED CONDITIONS
Associated with mental retardation, behavioral disturbances, and sensorineural deafness in 30% cases.
DIAGNOSIS
HISTORY
Family history of Norrie disease, congenital male blindness.
PHYSICAL EXAM
• Classic finding: Yellow–grey, elevated retrolental mass (pseudoglioma) visible through a clear lens. These masses are typically composed of dysplastic retina with unbranched retinal vessels. The peripheral retina may be attached, is usually avascular, and can have pigmentary changes.
• May have mild changes at birth followed by progressive changes though infancy and childhood
• Bilateral, often symmetric, dystrophic changes in the retina including retinal detachments or folds.
• Vitreous hemorrhage
• Iris atrophy, posterior synechiae
• Corneal opacities
• Cataracts
• Can get shallowing of anterior chamber and increased intraocular pressure in later stages (1)[C], (3)
DIAGNOSTIC TESTS & INTERPRETATION
Lab
Initial lab tests
Molecular genetic testing of NDP gene mutations can be useful in corroborating diagnosis but cannot definitively exclude disease.
Follow-up & special considerations
• Genetics consult
• Examine mother for evidence of subtle retinal pigmentary changes, retinal folds, peripheral avascular retina.
Imaging
Initial approach
B-scan can be used to characterize the retrolental mass, detect retinal detachments if poor view.
Follow-up & special considerations
Regular ophthalmologic monitoring for glaucoma development, cataracts, retinal detachments, and progression of milder disease.
Diagnostic Procedures/Other
• Audiologic evaluation
• Developmental assessment in early childhood if patient not meeting normal developmental milestones
• Behavioral evaluation as indicated
• Genetic counseling
Pathological Findings
Proliferation of preretinal fibrovascular tissue, retinal detachment and gliosis, disorganized layers of dysplastic retina, defective and dilated retinal vessels (4)
DIFFERENTIAL DIAGNOSIS
• Persistent fetal vasculature syndrome (PFVS)
• Retinopathy of prematurity (ROP)
• Coats disease
• Familial exudative vitreoretinopathy (FEVR)
• Retinoblastoma
• Incontinentia pigmenti
• Isolated or syndromic retinal dysplasia
• Occult child abuse (Shaken baby syndrome)
• Osteopetrosis-pseudoglioma syndrome
TREATMENT
MEDICATION
• None available to treat the primary disease process
• IOP-lowering agents can be used to treat ocular hypertension should it occur. If anterior chamber shallow and angle closed, the modalities may include peripheral iridectomy, lens extraction, trabeculectomy, glaucoma drainage tube, or cyclodestructive procedures.
ADDITIONAL TREATMENT
General Measures
• Most males with classic phenotypic presentation have complete retinal detachments at birth with little visual potential
• Patients diagnosed without a complete retinal detachment may benefit from surgery and/or laser therapy (1)[C],(3)[C]. Treatment should include ablation of the avascular retina and the vascularized line of demarcation.
Issues for Referral
• Consider audiology and/or ENT referral for patients with hearing loss. Some patients may benefit from hearing aids or cochlear implantation.
• Low vision evaluation and support
• Retinal surgery and/or laser therapy for patients lacking complete retinal detachments.
• Cognitive and behavioral therapies as needed
Additional Therapies
If nonfunctional eye, phthisis bulbi, consider a scleral shell to encourage orbital and periocular tissue growth.
COMPLEMENTARY & ALTERNATIVE THERAPIES
None proven or indicated.
SURGERY/OTHER PROCEDURES
• Repair of retinal detachment, release of retinal traction, ablation of avascular retina, and vascularized demarcation zone (1)[C].
• Glaucoma surgery may be needed if increased intraocular pressure.
• Consider enucleation or evisceration if needed to control pain.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Regular ophthalmologic examinations as needed to monitor for retinal detachments, cataract, glaucoma.
• Low vision
Patient Monitoring
Behavioral, developmental, psychiatric, and regular audiologic evaluations.
PATIENT EDUCATION
• Genetic counseling
• Low vision evaluation and aids
• Support and education http://www.norries.org/
PROGNOSIS
• Poor visual prognosis, especially if presentation with complete retinal detachments at diagnosis. Often Hand Motion vision or less.
• Many eyes progress to phthisis bulbi.
COMPLICATIONS
• Retinal detachments
• Glaucoma
• Cataracts
REFERENCES
1. Drenser BA, Fecko A, Dailey W, et al. A characteristic phenotypic retinal appearance in Norrie disease. Retina 2007;27(2):243–246.
2. Lin P, Shankar SP, Duncan J, et al. Retinal vascular abnormalities and dragged maculae in a carrier with a new NDP mutation (c.268delC) that caused severe Norrie disease in the proband. J AAPOS 2010;14:93–96.
3. Wu WC, Drenser K, Trese M, et al. Retinal phenotype-genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Arch Ophthalmol 2007;125(2):225–230.
4. Luhmann UF, Lin J, Acar N, et al. Role of the Norrie disease pseudoglioma gene in sprouting angiogenesis during development of retinal vasculature. Invest Ophthalmol Vis Sci 2005;46(9):3372–3382.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
