Knowledge on rare diseases and orphan drugs

To date, more than 400 cases have been described. Affected patients are almost always male.

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 (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 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 may include growth failure, microphthalmia, varied chronic seizure disorders, 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.

Norrie disease is caused by mutations in the NDP gene (Xp11.4-p11.3), encoding the norrin cystine knot growth factor NDP which is involved in the vascular development of the eye and ear. A large number of disease-causing mutations have been identified.

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. A causative mutation in the NDP gene is recovered in around 85% of male probands. If negative, search for a rearrangement should be conducted.

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.

Prenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family. In rare cases, particularly where there is a family history, ocular abnormalities have been detected on ultrasonography in the third trimester.

Norrie disease is inherited in an X-linked manner. Rare de novo mutations have been reported. Genetic counseling should be offered to affected families. Where a female carries the mutation, there will be a 50% risk that male offspring will inherit the disease, and a 50% risk that female offspring will be carriers. Where a male is affected, male offspring are unaffected whereas female offspring are obligate carriers

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.

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.

Last update: February 2020 - Expert reviewer(s): Pr Patrick CALVAS