Familial exudative vitreoretinopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Familial exudative vitreoretinopathy is a hereditary disorder that can cause vision loss that worsens over time. This condition affects the retina, the specialized light-sensitive tissue that lines the back of the eye. In people with this disorder, blood vessels do not fully develop at the outer edges (periphery) of the retina, which reduces the blood supply to this tissue. This prolonged reduction in blood supply (chronic ischemia) causes continued damage to the retina and can lead to worsening of the condition.

The signs and symptoms of familial exudative vitreoretinopathy vary widely, even within the same family. In many affected individuals, the retinal abnormalities never cause any vision problems. Other people with this condition develop abnormal vessels that leak. This causes chronic inflammation which, over time, can lead to fluid under the retina (exudate). A reduction in the retina's blood supply causes the retina to fold, tear, or separate from the back of the eye (retinal detachment). The resulting retinal damage can lead to vision loss and blindness. Other eye abnormalities are also possible, including eyes that do not look in the same direction (strabismus) and a visible whiteness (leukocoria) in the normally black pupil.

Some people with familial exudative vitreoretinopathy also have a condition known as osteoporosis-pseudoglioma syndrome, which is characterized by reduced bone density. People with this condition have weakened bones and an increased risk of fractures.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the FZD4, LRP5, and NDP genes cause most cases of familial exudative vitreoretinopathy. These genes provide instructions for making proteins that participate in a chemical signaling pathway that affects the way cells and tissues develop. In particular, the proteins produced from the FZD4, LRP5, and NDP genes appear to play critical roles in the specialization of retinal cells and the formation of blood vessels in the retina and the inner ear. The LRP5 protein also helps regulate bone formation.

Variants in the FZD4, LRP5, or NDP gene disrupt chemical signaling during early development, which interferes with the formation of blood vessels at the periphery of the retina. The resulting abnormal blood supply to this tissue leads to retinal damage and vision loss in some people with familial exudative vitreoretinopathy.

The eye abnormalities associated with familial exudative vitreoretinopathy tend to be similar no matter which gene is altered. However, affected individuals with LRP5 gene variants often have reduced bone mineral density in addition to vision loss. Variants in the other genes responsible for familial exudative vitreoretinopathy do not appear to affect bone density.

Variants in other genes each cause a small number of cases of familial exudative vitreoretinopathy. In other cases, the cause of familial exudative vitreoretinopathy is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Familial exudative vitreoretinopathy has different inheritance patterns depending on the gene involved. Most commonly, the condition results from variants in the FZD4 or LRP5 gene and has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant familial exudative vitreoretinopathy inherit the altered gene from a parent, although the parent may not have any signs or symptoms associated with this disorder.

Familial exudative vitreoretinopathy caused by LRP5 gene variants can also have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

When familial exudative vitreoretinopathy is caused by variants in the NDP gene, it has an X-linked recessive pattern of inheritance. The NDP gene is located on the X chromosome, which is 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 variant would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of the gene, 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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of familial exudative vitreoretinopathy is unknown. It is thought to be rare, although affected people with normal vision may never receive a diagnosis.

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.

Peripheral retinal avascularization · Very frequent (99-80%)

Incomplete peripheral vascular development.

Vitreoretinopathy · Obligate (100%)

Ocular abnormality characterized by premature degeneration of the vitreous and the retina that may be associated with increased risk of retinal detachment.

Abnormality of the optic disc · Frequent (79-30%)

A morphological abnormality of the optic disc, i.e., of the portion of the optic nerve clinically visible on fundoscopic examination.

Falciform retinal fold · Frequent (79-30%)

An area of the retina that is buckled so that a sector-shaped sheet of retina lies in front of the normal retina. This feature is of congenital onset.

Retinal neovascularization · Frequent (79-30%)

In ischemic retinal disease, neovascularization (NV) involves the sprouting of new vessels from pre-existent vessels. Ischemia invariably leads to the upregulation of Vascular Endothelial Growth Factor (VEGF) production. Most frequently the new vessels grow internal to the plane of the retina. However, intraretinal proliferation of new vessels can also occur.

Subretinal fluid · Frequent (79-30%)

Fluid accumulating between the neuroretina and retinal pigment epithelium.

Tractional retinal detachment · Frequent (79-30%)

A type of retinal detachment arising due to a combination of contracting retinal membranes, abnormal vitreoretinal adhesions, and vitreous changes, in the absence of a full-thickness retinal defect.

Reduced visual acuity · Frequent (79-30%)

Other findings in the same source

From: Orphanet

Additional reported features include Blindness (Occasional (29-5%)); Cataract (Occasional (29-5%)); Chorioretinal atrophy (Occasional (29-5%)); Epiretinal membrane (Occasional (29-5%)); Hearing impairment (Occasional (29-5%)); Intellectual disability, mild (Occasional (29-5%)); Lymphedema (Occasional (29-5%)); Macular edema (Occasional (29-5%)); Macular exudate (Occasional (29-5%)); Macular telangiectasia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Familial exudative vitreoretinopathy is Ophthalmology, with a ophthalmologist as the relevant type of clinician. Ophthalmologist; paediatric services for children as appropriate.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

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.

• Which part of the eye or visual pathway is affected?
• What change in vision requires immediate contact with the eye service?
• What are the aims and alternatives of any proposed eye treatment?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Familial exudative vitreoretinopathy. 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.