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Familial Exudative Vitreoretinopathy (FEVR): for professionals


Overview

PrevalenceLess than 100 reported cases
InheritanceAutosomal dominant, autosomal recessive, X-linked recessive
Genes involved (OMIM No.)NDP (OMIM: #300658), LRP5 (OMIM: #603506), TSPAN12 (OMIM: #613138), FZD4 (OMIM: #604579), KIF11 (OMIM: #148760), ZNF408 (OMIM: #616454), CTNNB1 (OMIM: #116806),  JAG1 (OMIM:# 601920), RCBTB1 (OMIM: #607347), ATOH7 (OMIM: #609875), ILK (OMIM: #602366)
SymptomsVariable ranging from asymptomatic to vision loss
Ocular FeaturesAvascular peripheral retina
Dragged retinal vessels and macula
Retinal (falciform) folds
Neovascularisation
Subretinal exudates
Retinal detachments
Persistent foetal vasculature
Epiretinal membranes
Peripheral pigmentation
Key InvestigationsFundoscopy
Fluorescein Angiography
Optical Coherence Tomography
OCT Angiography
Ultrasonography
Molecular diagnosisWhole genome sequencing with retinal panel
ManagementOcular
Regular ophthalmology monitoring
Screening of Family Members
Prophylactic laser photocoagulation for avascular retinal areas
Intravitreal anti-VEGF injections

Systemic
Multidisciplinary Support
Bone Health Assessment
Supportive measures with genetic counsellor
Therapies under ResearchFurther studies needed to assess the efficacy of targeting VEGF and angiopoietin-2 receptors in the management of FEVR.

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Clinical phenotype

Familial Exudative Vitreoretinopathy (FEVR) is an inherited retinal disorder characterised by abnormal retinal angiogenesis, leading to incomplete vascularisation of the peripheral retina. It exhibits significant phenotypic variability, ranging from asymptomatic cases to severe vision loss and retinal detachment, often detected via genetic testing and retinal imaging.

Presenting features

Ocular:

  • Abnormal retinal angiogenesis resulting in incomplete vascularisation of the peripheral retina1,2.
  • Highly heterogenous clinical presentation with significant variability even amongst individuals affected in the same family.
  • Frequently asymmetrical appearance between eyes.
  • Severe cases may present with:
    • Bilateral severe congenital blindness due to failure of retinal vascularisation and congenital retinal detachments.
    • Conditions described as ‘retinal dysplasia,’ ‘pseudoglioma,’ and ‘congenital retinal non-attachment.’
    • Leukocoria, often associated with a white fibrous retrolental mass and a shallow anterior chamber.
  • Milder cases may include:
    • Asymptomatic individuals with good visual function.
    • Subtle signs of peripheral retinal avascularity detectable via widefield fluorescein angiography.
    • Many individuals may remain stable, but complications can lead to vision loss.
  • Complications may involve:
    • Secondary subretinal or intraretinal exudation.
    • Fibrovascular proliferation resulting in temporal dragging of the retina, tractional folds, or detachment.
    • Increased risk of rhegmatogenous retinal detachments, typically presenting in the second or third decade of life.
    • Overall retinal detachment occurs in 20%–30% of eyes.

Systemic

  • FEVR can be associated with multisystemic disorders, including:
    • Norrie disease:
      • Linked to defects in the NDP gene.
    • Osteoporosis-pseudoglioma syndrome:
      • Associated with biallelic LRP5 gene mutations.
      • Features severe osteoporosis, recurrent fractures (including vertebrae), craniotabes (skull softening), and microcephaly.
      • Approximately 25% of cases exhibit cognitive impairment.
  • Other systemic manifestations:
    • Osteoporosis in individuals with heterozygous or biallelic LRP5 variants.

Staging for FEVR3:

Fundal appearance

  • Avascular Peripheral Retina: Best seen with wide-angle fluorescein angiography, particularly in asymptomatic individuals. Typically affects the temporal quadrant with a V-shaped “brush-border” demarcation but can extend 360 degrees.4
  • Dragged Retinal Vessels and Macula: Retinal arteries and veins are usually dragged temporally, with straightening of the vessels and temporal dragging of the macula.
  • Retinal (Falciform) Folds: Radial folds, often in the temporal region, seen in 28% of eyes but can occur anywhere.
  • Neovascularisation: Hypoxia of the avascular retina can induce extraretinal neovascularisation.
  • Subretinal Exudates: Variable amounts, with massive exudation potentially mimicking Coats’ disease.
  • Retinal Detachments: Tractional and/or rhegmatogenous detachments occur in 21–64% of cases. In a study, 68% of patients with a detachment in one eye also had some degree of detachment in the other eye.
  • Other Findings:
    • Persistent foetal vasculature.
    • Epiretinal membranes.
    • Peripheral pigmentation, especially near the avascular retina.

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Genetics

  1. NDP (OMIM: 300658)5-13
    • Function: Encodes Norrin, a protein secreted by Müller glia cells in the retina. Norrin binds to the transmembrane protein FZD4 and its co-receptor LRP5, expressed by vascular endothelial cells, playing a crucial role in retinal angiogenesis.
  2. LRP5 (OMIM: 603506)
    • Function: Encodes a single-pass transmembrane protein that is a member of the low-density lipoprotein receptor family. It acts as a co-receptor in the Wnt signalling pathway, essential for retinal angiogenesis.
  3. TSPAN12 (OMIM: 613138)
    • Function: Acts as an additional co-receptor that amplifies FZD4-mediated intracellular signalling, which regulates retinal angiogenesis.
  4. FZD4 (OMIM: 604579)
    • Function: Encodes a transmembrane protein receptor for Norrin with a highly conserved N-terminal cysteine-rich domain and a C-terminal intracellular domain. It plays a key role in the Wnt signalling pathway critical for retinal development.
  5. KIF11 (OMIM: 148760)
    • Function: Encodes a kinesin motor protein involved in spindle dynamics and chromosome movement during cell division.
  6. ZNF408 (OMIM: 616454)
    • Function: Encodes a zinc finger protein thought to be involved in transcriptional regulation.
  7. CTNNB1 (OMIM: 116806)
    • Function: Encodes β-catenin, a key component of the Wnt signalling pathway involved in cell adhesion and gene transcription regulation.
  8. JAG1 (OMIM: 601920)
    • Function: Encodes Jagged-1, a ligand for Notch receptors, playing a critical role in cell fate decisions.
  9. RCBTB1 (OMIM: 607347)
    • Function: Encodes a protein involved in the regulation of the cell cycle and ubiquitination processes.
  10. ATOH7 (OMIM: 609875)
    • Function: Encodes a basic helix-loop-helix transcription factor important for retinal ganglion cell development.
  11. ILK (OMIM: 602366)
    • Function: Encodes integrin-linked kinase, involved in integrin-mediated signal transduction and cell-matrix interactions.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Ophthalmic Examination:
    • Comprehensive assessment of visual acuity, intraocular pressure, and anterior and posterior segment examination.
  2. Fundoscopy:
    • Avascular Peripheral Retina: Typically appreciated with wide-angle fluorescein angiography, showing a V-shaped pattern in the temporal periphery or extending 360 degrees.14
    • Dragged Retinal Vessels and Macula: Retinal arteries and veins appear dragged, usually temporally, with apparent straightening.15
    • Retinal (Falciform) Folds: Radial retinal folds, often in the temporal location.
    • Neovascularisation: Extraretinal neovascularisation due to retinal hypoxia.16
    • Subretinal Exudates: Variable amounts of exudation, potentially mimicking Coats’ disease.
    • Retinal Detachments: Tractional and/or rhegmatogenous detachments in severe cases.
  3. Fluorescein Angiography (FA):
    • Diagnosis and Evaluation: Identifies peripheral avascular retina, telangiectasias, optic disc leakage, arterial tortuosity, peripheral capillary agenesis, anomalous vascularisation, aberrant circumferential vessels, delayed AV transit, choroidal nonperfusion, venous-venous shunting, and central macular oedema.
    • Detection of Leakage: Helps identify exudative phases before clinical exudation, crucial for timely intervention.13
  4. Optical Coherence Tomography (OCT):
    • Posterior Segment Microstructures: Shows posterior hyaloidal organisation, vitreomacular traction, vitreopapillary traction, diminished foveal contour, persistent foetal foveal architecture, cystoid macular oedema, intraretinal exudates, and distortion of the ellipsoid zone.17
    • OCT Angiography (OCTA): Non-invasive imaging modality revealing smaller foveal avascular zones, decreased vascular density in parafoveal areas, and thicker fovea compared to controls. Detects peripheral retinal vascular abnormalities and vitreoretinal traction.
  5. Electroretinography (ERG):
    • Reduction of amplitude of oscillatory potentials, a and b wave of bright white flash ERG, scotopic and photopic b waves. Also reduced Light peak/Dark trough ratio of EOG in some cases.18
  6. Ultrasonography:
    • Retinal detachment: B-scan ultrasonography to evaluate for retinal detachments and vitreoretinal pathology, particularly in cases with poor visualization due to media opacities.
  7. Genetic Testing:
    • Whole genome sequencing with retinal panel

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Diagnosis

Clinical features, family history, and genetic testing aid in confirming the diagnosis of FEVR. Differential diagnoses include retinopathy of prematurity, Norrie disease, and Coats disease.

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Management

Ocular

  1. Regular Ophthalmology Monitoring:
    • Careful dilated fundoscopy and widefield fluorescein angiography are essential.
    • Examination under anaesthetic is often required in young children for diagnosis and imaging.
    • Frequency of examinations depends on patient age and clinical severity.
    • Infants at risk should be examined monthly in the first year of life until diagnosis is clarified.
  2. Screening of Family Members:
    • Screening is recommended for asymptomatic family members, especially in stages 1 and 2.
    • Genetic testing can help identify at-risk individuals.
  3. Preventive Treatment:
    • Prophylactic laser photocoagulation is recommended for avascular retinal areas detected by fluorescein angiography to prevent vision-threatening complications.19
    • Intravitreal anti-VEGF injections may be used as adjunct therapy to laser or surgical management.
  4. Management of Advanced Disease:
    • Stage 1 disease can be observed and followed over time.
    • Stage 2 disease may require laser photocoagulation to promote regression of neovascularisation and resolution of exudation.
    • Surgical intervention (scleral buckling and/or vitrectomy) is necessary for retinal detachments, with laser photocoagulation of the peripheral avascular retina.
    • Stage 3A cases with partial exudative retinal detachments may have favourable outcomes with scleral buckling alone.
  5. Use of Anti-VEGF Therapy:
    • Limited studies suggest intravitreal bevacizumab (IVB) can be used as adjunct therapy for stage 2 or 3A disease.20
    • Anti-VEGF agents may not be effective in advanced cases with tractional retinal detachment.
    • Further studies are needed to assess the efficacy of targeting VEGF and angiopoietin-2 receptors.
  6. Genetics: Referral to ocular genetics service or clinical genetics for whole-genome sequencing.

Systemic

  1. Multidisciplinary Support:
    • Referral to a clinical geneticist for new and atypical cases.
    • Genetic counselling to address the variability of isolated and syndromic FEVR.
    • Families should be informed to notify their physician during pregnancy for early examination of the newborn.
  2. Bone Health Assessment:
    • Patients with known LRP5 mutations should undergo DEXA scans to assess bone mineral density. This should be done via an appropriate specialist referral.21
    • If osteoporosis is detected, referral to specialists for potential bisphosphonate therapy is recommended.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic Counsellors (GCs) and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They inform patients of the diagnosis in a private room and provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research

Current research on FEVR is centred on uncovering the genetic mutations and molecular mechanisms driving the disease, refining diagnostic methods, and exploring therapeutic options. Studies are focused on identifying mutations in key genes involved in retinal vascular development, such as NDP, FZD4, and LRP5. These efforts strive to enhance our understanding of FEVR and lead to innovative clinical interventions.

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Further information and support

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References

  1. Criswick V, Schepens C. Familial Exudative Vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578-594.
  2. Tauqeer Z, Yonekawa Y. Familial Exudative Vitreoretinopathy: Pathophysiology, Diagnosis, and Management. Asia Pac J Ophthalmol (Phila). 2018 May-Jun;7(3):176-182.
  3. Kashani AH, Learned D, Nudleman E, Drenser KA, Capone A, Trese MT. High prevalence of peripheral retinal vascular anomalies in family members of patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(1):262-8.
  4. Ranchod TM, Ho LY, Drenser KA, Capone A, Trese MT. Clinical presentation of familial exudative vitreoretinopathy. Ophthalmology. 2011;118(10):2070-5.
  5. Li Y, Fuhrmann C, Schwinger E, Gal A, Laqua H. The gene for autosomal dominant familial exudative vitreoretinopathy (Criswick-Schepens) on the long arm of chromosome 11. Am J Ophthalmol. 1992;113(6):712-3.
  6. Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32(2):326-30.
  7. Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004;74(4):721-30.
  8. Plager DA, Orgel IK, Ellis FD, Hartzer M, Trese MT, Shastry BS. X-linked recessive familial exudative vitreoretinopathy. Am J Ophthalmol. 1992;114(2):145-8.
  9. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5(2):180-3.
  10. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513-23.
  11. Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum Genet. 2004;75(5):878-84.
  12. Nikopoulos K, Venselaar H, Collin RWJ, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat. 2010;31:656-66.
  13. Black GC, Ashworth JL, Sergouniotis PI, editors. Clinical ophthalmic genetics and genomics. Academic Press; 2022 Jan 18.
  14. Gilmour DF. Familial exudative vitreoretinopathy and related retinopathies. Eye (Lond). 2015;29:1-14.
  15. Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology. 1984;91(12):1524-30.
  16. Kashani AH, Brown KT, Chang E, Drenser KA, Capone A, Trese MT. Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(11):2220-7.
  17. Yonekawa Y, Thomas BJ, Drenser KA, Trese MT, Capone A. Familial Exudative Vitreoretinopathy: Spectral-Domain Optical Coherence Tomography of the Vitreoretinal Interface, Retina, and Choroid. Ophthalmology. 2015;122(11):2270-7.
  18. Ohkubo H, Tanino T. Electrophysiological findings in familial exudative vitreoretinopathy. Doc Ophthalmol. 1987 Apr;65(4):461-9. doi: 10.1007/BF00143048. PMID: 3691294.
  19. Pendergast SD, Trese MT. Familial exudative vitreoretinopathy. Results of surgical management. Ophthalmology. 1998;105(6):1015-23.
  20. Tagami M, Kusuhara S, Honda S, Tsukahara Y, Negi A. Rapid regression of retinal haemorrhage and neovascularisation in a case of familial exudative vitreoretinopathy treated with intravitreal bevacizumab. Graefes Arch Clin Exp Ophthalmol. 2008;246(12):1787-9.
  21. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513-23.

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Updated on May 27, 2024
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