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| fevr [2025/04/18 14:40] – external edit 127.0.0.1 | fevr [2026/09/17 13:00] (current) – [Downloadable Resources] Scott Larson |
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| * Gene: CTNNB1 | * Gene: CTNNB1 |
| * Chromosome Location: 3p22.1 | * Chromosome Location: 3p22.1 |
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| | ===== Genotype–Phenotype Correlation ====== |
| | A genotype–phenotype correlation exists in FEVR but is **imperfect**, limited by marked intra- and interfamilial variability and incomplete penetrance. The strongest signal (systematic review/meta-analysis of >3,200 individuals) is that **disease severity tracks with the position of the mutated gene in the Norrin/β-catenin signaling cascade**: **NDP > FZD4 > LRP5 > TSPAN12** (Wang et al., PLoS One, 2021). NDP (Norrin ligand) and FZD4 (receptor) are obligatory for pathway activation and produce the most severe phenotypes; LRP5 (co-receptor) and TSPAN12 (auxiliary complex) are non-decisive and yield milder disease. |
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| | ==== Gene-specific features ==== |
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| | ^ Gene ^ Frequency ^ Severity / hallmark ^ Distinguishing features ^ |
| | | **NDP** | ~4.6% | Most severe; ~86% advanced (stage 4–5); single-gene carriers stage 5 | Retinal detachment ~64.5%; X-linked recessive; overlaps Norrie disease | |
| | | **FZD4** | ~11.5% | Second most severe; ~78.6% advanced | ~33% asymmetric between eyes | |
| | | **LRP5** | ~13.6% (most common) | Intermediate; ~86% stage 4–5 in single-gene carriers | RD ~51.9%; **reduced bone mineral density / osteoporosis-pseudoglioma spectrum** (unique); predominates in unilateral disease | |
| | | **TSPAN12** | ~6.7% | Mildest; no stage 5; RD less common (P=0.017) | Retinal fold most common; least asymmetry (~11%) | |
| | | **KIF11** | ~5.7% | Distinct, outside Norrin/β-catenin pathway | Microcephaly-chorioretinopathy syndrome | |
| | | **ZNF408** | ~1.6% | Insufficient data | — | |
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| | === Key caveats === |
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| | * **Marked phenotypic variability** within families and for single variants; genotype cannot reliably predict individual course. |
| | * **LRP5 is the only major FEVR gene with systemic findings** (low bone mineral density, fractures). |
| | * **Laterality skew**: LRP5 predominates in unilateral disease (>50% vs ~one-third bilateral); KIF11 absent from a unilateral Chinese cohort. |
| | * **Copy number variants** produce phenotypes indistinguishable from single-nucleotide variants. |
| | * **Multi-gene (digenic/oligogenic) variants** tend to be more severe, consistent with dose-dependent signaling. |
| | * Molecular diagnosis achieved in only **~40–50%** of clinically diagnosed cases. |
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| | ===== Genetic Testing and Family Screening (Newly Diagnosed FEVR) ===== |
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| | Both **genetic testing of the proband** and **clinical/angiographic screening of at-risk relatives** are recommended. They are complementary: a molecular diagnosis enables cascade testing and counseling, but because a causative variant is found in only ~40–50% of probands, **a negative genetic test does not exclude familial disease**, and imaging-based screening of relatives remains essential. |
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| | === Genetic testing of the proband === |
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| | * **Use an NGS panel** (LRP5, FZD4, TSPAN12, NDP, ZNF408, CTNNB1; expanded panels add KIF11 and overlapping-phenotype genes) rather than sequential single-gene testing. Yield ~40–50% (41.5% in one expanded-panel cohort). |
| | * **Classify variants by ACMG/ClinGen criteria** and reclassify over time. |
| | * **Include KIF11** (distinct microcephaly-chorioretinopathy phenotype with systemic implications). |
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| | === Determine inheritance to guide cascade testing === |
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| | * Most often **autosomal dominant** (LRP5, FZD4, TSPAN12, ZNF408, CTNNB1); also **X-linked recessive (NDP)** and autosomal recessive forms. |
| | * Once the familial variant is known, offer **targeted cascade testing** to first-degree relatives; flag LRP5 carriers for bone mineral density. |
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| | === Clinical/angiographic screening (independent of genetics) === |
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| | * **Dilated exam + wide-field fluorescein angiography (UWF-FA)** in first-degree relatives is the highest-yield step: in one series **58% of asymptomatic relatives had stage 1–2 and 21% had stage 3–5 findings**, despite only 8% reporting positive family history. |
| | * **Do not rely on family history** to select who to screen (positive in <50% of cases). |
| | * **Screen even when the proband appears unilateral.** |
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| | === Surveillance and counseling === |
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| | * **Serial exams** (every ~6 months at experienced centers) with fundus photography and wide-field FA. |
| | * Counsel that FEVR is **progressive and lifelong**; provide genetic counseling for recurrence risk and reproductive planning. |
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| | ===== Pediatric Screening Age and Examination Under Anesthesia (EUA) ===== |
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| | **Screening should begin at birth** (neonatal fundus exam) for at-risk infants, because severe FEVR—especially LRP5- and NDP-associated—is frequently present at birth and can progress rapidly; onset before age 3 carries the worst prognosis. No formal FEVR-specific society schedule was identified; recommendations reflect expert-center practice. |
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| | === When to begin and how often === |
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| | * **Neonatal exam**: dilated fundus exam in the first days of life; one reported pedigree screened by wide-field imaging on postnatal day 3 enabling prophylactic treatment with preserved acuity. |
| | * **Early-childhood vigilance**: toddlers diagnosed before age 3 present mostly with poor visual behavior (33%) or strabismus (26%); only 11% via screening, and ~half already stage 4–5—waiting for symptoms is inadequate. |
| | * **Serial follow-up**: ~every 6 months with fundus photography and wide-field FA; screening continues into adulthood as disease is lifelong. |
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| | === Role of examination under anesthesia (EUA) === |
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| | * **EUA with wide-field imaging/angiography** is the practical method for infants and uncooperative children; earliest findings (peripheral avascularity, neovascularization) are often invisible on bedside fundoscopy. Contact wide-field systems (e.g., RetCam) enable photography and FA; FA informed treatment decisions in 82% and revealed subtle findings in 27% in a pediatric series. |
| | * **Escalate to EUA** when the child cannot be examined awake, for asymmetric/unexplained findings, or when peripheral pathology/treatment need is suspected—allowing same-session laser photocoagulation. |
| | * **Combine with genetic risk stratification**: LRP5 and NDP carriers merit earliest, most aggressive neonatal evaluation; a negative genetic test does not defer imaging-based screening. |
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| | === Practical caveats === |
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| | * Distinguish FEVR from retinopathy of prematurity; some premature infants have FEVR ("ROPER"), so prematurity does not exclude FEVR. |
| | * <50% of affected individuals have a positive family history—do not lower screening thresholds within a pedigree once a proband is identified. |
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| | ===== References ===== |
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| | - [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Autosomal%20Dominant%20Vitreoretinopathy%20Ober_1980.pdf |Autosomal dominant exudative vitreoretinopathy. Ober et al. 1980]] |
| | - [[https://docs.eyefixer.org/vault/Retina/Inherited%20Retinal%20Disease/Familial%20Exudative%20Vitreoretinopathy%20and%20Related%20Retinopathies.pdf |Familial exudative vitreoretinopthy and related retinopathies. Gilmour DF. 2015]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-phenotype+associations+familial+exudative+vitreoretinopathy+systematic+review+meta-analysis|Wang X, et al. Genotype-phenotype associations in FEVR: a systematic review and meta-analysis on >3200 individuals. PLoS One. 2021]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotype-Phenotype+Spectrum+eyeGENE+Familial+Exudative+Vitreoretinopathy+Norrin+beta-catenin|Yaylacioglu Tuncay F, et al. Genotype-phenotype spectrum of eyeGENE patients with FEVR. Invest Ophthalmol Vis Sci. 2025]] |
| | - [[https://medlineplus.gov/genetics/condition/familial-exudative-vitreoretinopathy/|MedlinePlus. Familial exudative vitreoretinopathy. NLM.]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Clinical+Genetic+Features+Familial+Exudative+Vitreoretinopathy+Only-Unilateral+Chinese+Cohort|Tian T, et al. Clinical and genetic features of FEVR with only-unilateral abnormalities in a Chinese cohort. JAMA Ophthalmol. 2019]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Predicting+mild+familial+exudative+vitreoretinopathy+autosomal+dominant+deep+learning|Watanabe W, et al. Predicting mild FEVR with autosomal dominant inheritance using deep learning. Sci Rep. 2026]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Progression+familial+exudative+vitreoretinopathy+long-term+clinical+course+baseline+predictors|Acar AB, et al. Progression in FEVR: long-term clinical course and baseline predictors. Graefes Arch Clin Exp Ophthalmol. 2026]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Novel+Technique+Validating+Copy+Number+Variants+Familial+Exudative+Vitreoretinopathy|Zhang LL, et al. A novel technique for validating copy number variants and its application in FEVR. Hum Mutat. 2025]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Gene+Variant+Spectrum+Probands+Familial+Exudative+Vitreoretinopathy+Expanded+Panel|van der Ende S, et al. Gene variant spectrum in probands with FEVR using an expanded panel. Invest Ophthalmol Vis Sci. 2025]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Diagnosis+Management+Familial+Exudative+Vitreoretinopathy+Lifelong+Progressive+Asymmetric|Wood EH, Drenser KA, Capone A. Diagnosis and management of FEVR: a lifelong, progressive, and often asymmetric disease. JAMA Ophthalmol. 2019]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=High+Prevalence+Peripheral+Retinal+Vascular+Anomalies+Family+Members+Familial+Exudative+Vitreoretinopathy|Kashani AH, et al. High prevalence of peripheral retinal vascular anomalies in family members of patients with FEVR. Ophthalmology. 2014]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Clinical+Genetic+Profiles+Management+Treatment+Outcomes+Familial+Exudative+Vitreoretinopathy|Tao LR, et al. The clinical and genetic profiles, management, and treatment outcomes of FEVR. Surv Ophthalmol. 2026]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Genotypic+Distribution+Clinical+Correlations+Familial+Exudative+Vitreoretinopathy+Single-Center|Soetikno BT, Spoth E, Hartnett ME. Genotypic distribution and clinical correlations in FEVR: a single-center study. Ophthalmol Sci. 2024]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Phenotyping+Genotyping+FEVR+Molecular+Genetics+Clinical+Imaging+Features+Therapeutics|Wang Y, et al. Phenotyping and genotyping FEVR: molecular genetics, clinical and imaging features, and therapeutics. Prog Retin Eye Res. 2025]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Peripheral+central+retinal+vascular+changes+asymptomatic+family+members+familial+exudative+vitreoretinopathy|Ozdek S, Tefon Aribas AB, Atalay HT. Peripheral and central retinal vascular changes in asymptomatic family members of patients with FEVR. Graefes Arch Clin Exp Ophthalmol. 2023]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Molecular+Characterization+FZD4+LRP5+TSPAN12+Familial+Exudative+Vitreoretinopathy|Seo SH, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in FEVR. Invest Ophthalmol Vis Sci. 2015]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Ultra-wide-field+scanning+laser+ophthalmoscopy+asymptomatic+early-stage+familial+exudative+vitreoretinopathy|Lyu J, et al. Ultra-wide-field scanning laser ophthalmoscopy assists detection of asymptomatic early-stage FEVR. Graefes Arch Clin Exp Ophthalmol. 2017]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Novel+Variant+FZD4+Gene+Familial+Exudative+Vitreoretinopathy+Case+Report|Yang B, et al. A novel variant in the FZD4 gene leading to FEVR: a case report and literature review. Medicine (Baltimore). 2025]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Early-Onset+Familial+Exudative+Vitreoretinopathy+Clinical+Characteristics+Management+Outcomes|Kitic N, et al. Early-onset of FEVR: clinical characteristics, management, and outcomes. Retina. 2024]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Ultra-Widefield+Fundus+Fluorescein+Angiography+Pediatric+Retinal+Vascular+Diseases|Temkar S, et al. Ultra-widefield fundus fluorescein angiography in pediatric retinal vascular diseases. Indian J Ophthalmol. 2019]] |
| | - [[https://pubmed.ncbi.nlm.nih.gov/?term=Foveal+hypoplasia+optical+components+familial+exudative+vitreoretinopathy+retinopathy+prematurity|Chen PY, et al. Foveal hypoplasia and optical components in patients with FEVR and retinopathy of prematurity. Sci Rep. 2022]] |
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| ===== Resources ===== | |
| * {{::autosomal_dominant_vitreoretinopathy_ober_1980.pdf |Autosomal dominant exudative vitreoretinopathy. Ober et al. 1980}} | |
| * {{::familial_exudative_vitreoretinopathy_and_related_retinopathies.pdf |Familial exudative vitreoretinopthy and related retinopathies. Gilmour DF. 2015}} | |
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| {{tag>syndrome}} | {{tag>syndrome}} |