Epidemiology

The prevalence and annual incidence of ND are not known but more than 400 cases have been described. No ethnic predilection has been found. Affected patients are almost always male, while females are carriers.

Clinical description

The ocular findings in affected males are usually bilateral and symmetrical. The iris, anterior chamber, and cornea may be normal at birth but greyish-yellow elevated masses, or "pseudogliomas", are often observed behind the lens along with retinal vascular dysgenesis and leukocoria. Partial or complete retinal detachment develops within the first few weeks or months of life. In infancy and childhood, patients may develop cataracts, nystagmus, anterior/ posterior synechiae, band keratopathy, and a shallow anterior chamber with increased intraocular pressure. Phthisis bulbi (shrinking of the globe) is found later on, along with opacified corneas and sunken orbits. Vision varies from light perception to congenital complete blindness. Most affected males develop progressive asymmetrical sensorineural hearing loss starting in childhood (median age of onset is 12 years). Hearing loss may be severe and bilateral by mid-adulthood. Developmental delay and intellectual disability are found in about 20-30% of patients. Some have cognitive and psychosocial behavioral disorders, including psychosis. Other associated manifestations are highly variable and include growth failure, microphthalmia, a chronic seizure disorder (10% of cases), peripheral vascular disease (peripheral ulcers) and erectile dysfunction, Very rare cases of carrier females with retinal findings, such as retinal detachment, abnormal retinal vasculature with associated vision loss or mild sensorineural hearing loss, have been reported.

Etiology

Norrie disease is caused by mutations in the Norrie disease (pseudoglioma) NDP gene (Xp11.4-p11.3). A large number of disease-causing mutations have been identified. NDP encodes the norrin protein, involved in the vascular development of the eye and ear.

Diagnostic methods

Diagnosis is based on the characteristic clinical ocular findings and can be confirmed by molecular genetic testing of NDP. No biochemical or functional assays are available.

Differential diagnosis

Differential diagnosis includes retinoblastoma in cases with unilateral pseudoglioma, and other disorders related to NDP mutations such as retinopathy of prematurity, persistent hyperplastic primary vitreous, and familial exudative vitreoretinopathy (see these terms).

Antenatal diagnosis

Prenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family.

Genetic counseling

Norrie disease is inherited in an X-linked manner. Rare de novo mutations have been reported. Genetic counseling should be offered to affected families.

Management and treatment

Many patients have complete retinal detachment at birth making treatment for preservation of sight difficult. Those that do not have complete retinal detachment may benefit from surgery or laser therapy. Enucleation of the eye may be required in rare cases. Hearing aids should be provided to correct hearing loss and cochlear implantation can be considered. Supportive therapy should be provided for behavioral disorders.

Prognosis

Overall health is generally good in patients with ND. Life expectancy may however be reduced due to general risks associated with the disabling manifestations of the disease.

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