Norrie Disease - Clinical Features, Causes, and Management

Introduction:

Norrie disease was first reported by Dr. Norrie, who was an ophthalmologist in Denmark. Norrie disease is a genetic disorder that affects the eye and causes blindness in males after or at birth. Individuals are also affected by hearing loss and cognitive impairment such as behavioral issues, delay in development, and psychotic-like features in which the perceptions are altered. There is no cure for Norrie disease but early intervention can prevent some vision loss. Individuals with this disorder can live life normally but have to face challenges like blindness and hearing loss.

What is Norrie Disease?

Norrie disease is an inherited genetic disorder that occurs due to a mutation in the NDP (norrin cystine knot growth factor NDP) gene which plays an important role in the development of retinal cells. This disease is characterized by loss of vision, retinal detachment, hearing loss, intellectual disability, and psychosis.

What Are the Other Names of Norrie Disease?

Norrie disease is also called:

• Anderson-Warburg syndrome.

• Congenital progressive oculo-acoustico-cerebral degeneration.

• Fetal iritis syndrome.

• Norrie-Warburg syndrome.

• Pseudoglioma congenita.

• Oligophrenia microphthalmus.

• Episkopi blindness.

• Whitnall-Norman syndrome.

What Are the Clinical Features of Norrie Disease?

Norrie disease occurs mostly in males, and in females the symptoms are mild. The clinical features of Norrie disease are:

Eye abnormalities include:

• Abnormal development of the retina (light-sensitive area of nerve tissue which is present at the back of the eye, these nerves receive images and send them to the brain through the optic nerve) which causes a retinal detachment.

• Pseudoglioma (due to retinal detachment grayish-yellow mass which contains immature retinal cells appears in the back of the eye which gives a pseudo (false) appearance of a tumor).

• Microphthalmia (small eyes).

• Blindness.

• Leukocoria (white pupil).

• Shrinkage or deterioration of the iris (the colored part of the eye) or eyeballs which occurs during the first month of life.

• Abnormality of the choroid (the middle part of the wall of the eye).

• Cataracts (opaque area in the lens of the eye).

• Tumor in the eye.

• Deeply set eyes.

• Hypotelorism (reduced distance between eyes).

Other abnormalities include:

• Large ears.

• Narrow nasal bridge.

• Hearing loss.

• Delay in developing motor skills such as walking or sitting.

• Intellectual disability.

• Psychosis, where the perceptions and thoughts are disrupted.

• Abnormalities in breathing, digestion, and reproduction.

• Abnormality in circulation such as venous insufficiency.

• Blood vessel tumor.

• Erectile dysfunction.

• Motor stereotypy (repetitive movements of the arms or hands).

• Seizures (abnormal activity of the brain that causes abnormal movements and emotions).

What Is the Cause of Norrie Disease?

Norrie disease occurs due to a mutation in the NDP gene. Norrie disease is inherited in an X-linked recessive pattern in which the mutated gene is located on the X chromosome. X-linked inheritance cannot be passed down from fathers to sons. In males who carry one X and one Y chromosome, the X-chromosome carries the mutated gene and is sufficient to cause the disease. Whereas in females who carry two X chromosomes, if the mutation is present in one chromosome, she is referred to as a carrier and does not present any symptoms, if mutations are present on both X chromosomes, the female is affected by this disease. Some carrier females may show some retinal abnormality because of the X-inactivation process (turning off of the X chromosome in the somatic cells). The features of this gene include:

• The NDP gene is located on the X chromosome.

• The NDP gene provides instructions in the formation of a protein called norrin.

• Norrin helps in chemical signaling pathways in the development of cells and tissues.

• Norrin plays an important role in Wnt (Wingless-related integration site) signaling pathway which is important for cell division, cell adhesion, cell migration, and other cellular activities.

• Norrin binds to a protein called frizzled-4 receptors (produced by the FZD4 [frizzled class receptor 4] gene) which are present on the outer layer of cells. These help in the developmental process of the eye and other parts of the body.

• Norrin protein plays an important role in specializing the cells of the retina and providing blood supply to it. Norrin also helps in establishing blood supply to the inner ear.

Mutation in the NDP gene can interfere in the binding of Norrin protein with the frizzled-4 receptors which affect the development of the retina, therefore, causing vision loss.

What Is the Differential Diagnosis of Norrie Disease?

The differential diagnosis of Norrie disease includes:

• Retinoblastoma with Unilateral Pseudoglioma: A type of malignant tumor of the retina that occurs in children who are under the age of three. A characteristic feature of this condition is leukocoria also called a cat’s eye reflex. It can be painful in some cases.

• Retinopathy of Prematurity (ROP): A blinding disorder that affects the retina of premature infants. The blood vessels of the retina are not developed completely. Sometimes this condition may lead to scarring, bleeding, vision loss, or retinal detachment.

• Persistent Hyperplastic Primary Vitreous (PHPV): A developmental disorder that affects the eye at birth. The symptoms of this disorder include vision loss and abnormal eye structures.

• Familial Exudative Vitreoretinopathy (FEVR): A genetic disorder that causes retinal dysfunction. This condition disturbs the outer or inner blood-retinal barrier.

• Coats Disease: A disorder that affects the development of blood vessels of the retina. Affected individuals have a loss of vision and retinal detachment.

• Lenz Microphthalmia: An X-linked disorder that is characterized by small eyes or missing eyes, and abnormalities of the skeletal system, ear, fingers, and genitourinary tract.

What Is the Diagnosis of Norrie Disease?

The diagnosis of Norrie's disease includes:

• Detailed patient history including family history, identifying the characteristic features such as vision loss and hearing loss, and a thorough clinical evaluation.

• Genetic testing reveals a mutation in the NDP gene.

What Is the Management of Norrie Disease?

The management of Norrie's disease includes a number of specialty teams such as pediatricians, ophthalmologists, and audiologists.

• Early surgical intervention or the use of a laser can help in preserving some vision.

• Surgical treatments to reattach retinas and remove cataracts.

• Surgical therapy such as lasers, or filtering surgery to reduce intraocular pressure.

• Surgical treatment for the removal of the eye is very rarely done.

• Use of hearing aids in individuals with loss of hearing. If hearing aids are not successful cochlear implant may be done.

Conclusion:

Norrie disease is a rare disorder and affected children should receive specialized education including personalized education and other social, medical, and vocational services so that they can achieve their highest potential. Genetic counseling should be done for individuals with Norrie disease and their family members.