Differences

This shows you the differences between two versions of the page.

--- fevr [2023/03/12 13:45] – Scott Larson
+++ fevr [2026/09/17 13:00] (current) – [Downloadable Resources] Scott Larson
@@ Line 1: / Line 1: @@
 ====== Exudative Vitreoretinopathy (EVR) ======
-aka. Familial Exudative Vitreoretinopathy (FEVR)//
+aka. Familial Exudative Vitreoretinopathy (FEVR)\\
 A disorder characterized by incomplete development of retinal vasculature. There is a wide variety of clinical appearances and severity but the pathology is the result of retinal ischemia. The disease is characterized by the development of hyper permeable blood vessels, neovascularization, vitreoretinal traction, retinal folds and retinal detachments.
 ===== Types =====
-  * Type 1 - Criswick-Schepens Syndrome
+  * [[https://omim.org/entry/133780?search=%23%20133780&highlight=133780|Type 1]] - Criswick-Schepens Syndrome
     * Autosomal Dominant
     * Gene: [[https://www.ncbi.nlm.nih.gov/gene/8322|FZD4]]
-    * Chromosome: [[https://omim.org/geneMap/11/792?start=-3&limit=10&highlight=792|11q14.2]]
+    * Chromosome location: [[https://omim.org/geneMap/11/792?start=-3&limit=10&highlight=792|11q14.2]]
-    *
+  * [[https://omim.org/entry/305390?search=%23%20305390&highlight=305390|Type 2]]
+    * X-linked recessive
+    * Gene: [[https://www.ncbi.nlm.nih.gov/gene/?term=Homo+sapiens+norrin+cystine+knot+growth+factor+NDP|NDP gene]]
+  * [[https://omim.org/entry/605750?search=%25%20605750&highlight=605750|Type 3]]
+    * Autosomal Dominant
+    * Chromosome location: 11p13-p12 (approximately 30 cM from the EVR1 locus)
+  * [[https://omim.org/entry/601813?search=601813&highlight=601813|Type 4]]
+    * Autosomal Recessive
+    * Gene: [[https://www.ncbi.nlm.nih.gov/gene/4041|LRP5]]
+    * Chromosome location: 11q13.2
+  * [[https://omim.org/entry/613310|Type 5]]
+    * Autosomal Dominant
+    * Gene: TSPAN12
+    * Chromosome location 7q31.31
+  * [[https://omim.org/entry/616468|Type 6]]
+    * Autosomal Dominant
+    * Gene: ZNF408
+    * Chromosome Location: 11p11.2
+  * [[https://omim.org/entry/617572|Type 7]]
+    * Autosomal Dominant
+    * Gene: CTNNB1
+    * Chromosome Location: 3p22.1
+===== 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.
+==== Gene-specific features ====
+^ 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 | — |
+=== Key caveats ===
+  * **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.
+===== Genetic Testing and Family Screening (Newly Diagnosed FEVR) =====
+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.
+=== Genetic testing of the proband ===
+  * **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).
+=== Determine inheritance to guide cascade testing ===
+  * 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.
+=== Clinical/angiographic screening (independent of genetics) ===
+  * **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.**
+=== Surveillance and counseling ===
+  * **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.
+===== Pediatric Screening Age and Examination Under Anesthesia (EUA) =====
+**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.
+=== When to begin and how often ===
+  * **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.
+=== Role of examination under anesthesia (EUA) ===
+  * **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.
+=== Practical caveats ===
+  * 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.
+===== References =====
+  - [[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]]
-===== Genetics =====
-  * Autosomal Dominant Mutations
-    * [[https://www.ncbi.nlm.nih.gov/gene/8322|FZD4]]
-    * [[https://www.ncbi.nlm.nih.gov/gene/4041|LRP5]] - [[https://omim.org/entry/601813|OMIM entry]]
-  * Autosomal Recessive Mutations
-    * [[https://www.ncbi.nlm.nih.gov/gene/4041|LRP5]]
-  * X-linked Recessive Mutations
-    * [[https://www.ncbi.nlm.nih.gov/gene/?term=Homo+sapiens+norrin+cystine+knot+growth+factor+NDP|NDP gene]]
-===== Resources =====
-  * {{ ::autosomal_dominant_vitreoretinopathy_ober_1980.pdf |Autosomal dominant exudative vitreoretinopathy. Ober et al. 1980}}
+{{tag>syndrome}}

syndrome