Norrie disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Norrie disease is an inherited eye disorder that leads to blindness in male infants at birth or soon after birth. It causes abnormal development of the retina, the layer of sensory cells that detect light and color, with masses of immature retinal cells accumulating at the back of the eye. As a result, the pupils appear white when light is shone on them, a sign called leukocoria. The irises (colored portions of the eyes) or the entire eyeballs may shrink and deteriorate during the first months of life, and cataracts (cloudiness in the lens of the eye) may eventually develop.

About 30 percent of individuals with Norrie disease develop progressive hearing loss, and 30 to 50 percent of people affected experience developmental delays in motor skills such as sitting up and walking. Other problems may include mild to moderate intellectual disability, often with psychosis, and abnormalities that can affect circulation, breathing, digestion, excretion, or reproduction.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the NDP gene cause Norrie disease. The NDP gene provides instructions for making a protein called norrin. Norrin participates in the Wnt cascade, a sequence of steps that affect the way cells and tissues develop. In particular, norrin seems to play a critical role in the specialization of retinal cells for their unique sensory capabilities. It is also involved in the establishment of a blood supply to tissues of the retina and the inner ear, and the development of other body systems.

In order to initiate the Wnt cascade, norrin must bind (attach) to another protein called frizzled-4. Mutations in the norrin protein interfere with its ability to bind to frizzled-4, resulting in the signs and symptoms of Norrie disease.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder.

In rare cases, however, carrier females have shown some retinal abnormalities or mild hearing loss associated with Norrie disease. Females with one NDP gene mutation who show features of Norrie disease do so because of a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently turned off (inactivated) in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, so that each X chromosome is active in about half the body's cells. This means that in females with an NDP gene mutation, the X chromosome with an NDP gene mutation is active in about half of cells, and the X chromosome with the normal NDP gene is active in about half. Because X-inactivation leads to some cells that produce functional norrin protein and some cells that do not, females can have some features of Norrie disease.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Norrie disease is a rare disorder; more than 400 cases have been reported in the scientific literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal retinal vascular morphology · Very frequent (99-80%)

A structural abnormality of retinal vasculature.

Blindness · Very frequent (99-80%)

Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.

Cataract · Very frequent (99-80%)

A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Chorioretinal abnormality · Very frequent (99-80%)

An abnormality of the choroid and retina.

Corneal opacity · Very frequent (99-80%)

A reduction of corneal clarity.

Deeply set eye · Very frequent (99-80%)

An eye that is more deeply recessed into the plane of the face than is typical.

Hypoplasia of the iris · Very frequent (99-80%)

Congenital underdevelopment of the iris.

Hypotelorism · Very frequent (99-80%)

Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).

Other findings in the same source

From: Orphanet

Additional reported features include Macrotia (Very frequent (99-80%)); Microphthalmia (Very frequent (99-80%)); Narrow nasal bridge (Very frequent (99-80%)); Neoplasm of the eye (Very frequent (99-80%)); Sclerocornea (Very frequent (99-80%)); Vascular neoplasm (Very frequent (99-80%)); Anterior chamber synechiae (Very frequent (99-80%)); Abnormal cochlea morphology (Frequent (79-30%)); Abnormal repetitive mannerisms (Frequent (79-30%)); Abnormal vitreous humor morphology (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Norrie disease is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Norrie disease. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.