1. Introduction

• Familial Exudative Vitreoretinopathy (FEVR): inherited retinal vascular disorder with anomalous vascular development.
• Phenotypic heterogeneity: ranges from asymptomatic peripheral avascular retina → severe retinal detachment.
• Differential diagnosis challenge: overlaps with ROP, Norrie disease, Coats disease, persistent fetal vasculature.

Clinical Pearls

• Always consider FEVR in full‑term infants with ROP‑like changes.
• Early diagnosis is critical to prevent irreversible blindness.

Exam Tips

• FEVR vs ROP: FEVR occurs in full‑term infants, ROP in premature infants.

2. Prevalence & Demographics

• Detection rates vary (0.36%–2.32%) in neonatal screening programs (esp. China).
• High misdiagnosis risk: FEVR mimics ROP in full‑term infants.
• Need for large, multi‑regional genetic studies to refine prevalence estimates.

Clinical Pearls

• Prevalence higher in East Asian cohorts.
• Misdiagnosis → delayed treatment.

Exam Tips

• Remember China neonatal screening prevalence ~1.19%.

3. Etiology: Genes & Pathways

• Majority of FEVR genes converge on Norrin/Wnt/β‑catenin signaling.
• Key genes firmly implicated: NDP, FZD4, LRP5, TSPAN12, CTNNB1, CTNNA1.
• Non‑Wnt genes also contribute: KIF11, JAG1, DOCK6, ZNF408, etc.

Clinical Pearls

• Wnt pathway disruption → defective angiogenesis.
• Non‑Wnt genes broaden spectrum (syndromic overlap).

Exam Tips

• Memorize six core Wnt genes: NDP, FZD4, LRP5, TSPAN12, CTNNB1, CTNNA1.

3.1 Wnt Pathway Genes

🔹 NDP (Norrin)

• X‑linked inheritance; severe bilateral disease in males.
• >200 pathogenic variants; impair secretion or receptor binding.
• Female carriers often show vascular changes due to X‑inactivation.

Clinical Pearls

• Female carriers need surveillance.
• Norrin gene therapy shows promise.

Exam Tips

• NDP mutation → advanced stage FEVR in 86% of cases.

🔹 FZD4

• Autosomal dominant inheritance most common.
• Mutation detection rate: 5%–40%.
• Clinical spectrum highly variable: stage 1–5 disease.

Clinical Pearls

• FZD4 mutations often bilateral but asymmetric.
• Mutation hotspots exist but phenotype varies.

Exam Tips

• FZD4 knockout mice → absence of intraretinal capillary beds.

🔹 LRP5

• Most frequently mutated gene in FEVR (13.6%–47.7%).
• Dominant & recessive inheritance; recessive linked to bone density issues.
• Truncating mutations → higher risk of retinal detachment.

Clinical Pearls

• Screen bone mineral density in recessive cases.
• Strong genotype–phenotype correlations.

Exam Tips

• LRP5 mutation → retinal detachment risk ↑ 2.3‑fold.

🔹 TSPAN12

• Fourth most common gene; prevalence up to 12.9%.
• Acts as co‑receptor enhancing Norrin/FZD4/LRP5 signaling.
• Typically bilateral, symmetric, severe disease (≥ stage 4).

Clinical Pearls

• Bilateral symmetry is hallmark.
• Splice‑site mutations common (~16%).

Exam Tips

• TSPAN12 knockout → persistent hyaloid vessels.

🔹 CTNNB1 (β‑catenin)

• Encodes β‑catenin; mutations cause severe bilateral FEVR + syndromic features.
• Often de novo mutations; truncating variants linked to rapid progression.

Clinical Pearls

• Associated with intellectual disability, motor regression.
• Lithium chloride partially restores angiogenesis in models.

Exam Tips

• CTNNB1 knockout → embryonic lethality.

🔹 CTNNA1 (α‑catenin)

• Encodes α‑catenin; mutations cause hyperactivation of Wnt signaling.
• Severe bilateral disease with neovascularization and barrier breakdown.

Clinical Pearls

• Gain‑of‑function mechanism (unlike other genes).
• Causes excessive neovascularization.

Exam Tips

• CTNNA1 knockout → loss of intermediate/deep capillary layers.

🔹 CTNND1 (p120‑catenin)

• Encodes p120‑catenin; stabilizes VE‑cadherin and regulates Wnt signaling.
• Loss‑of‑function → vascular leakage + impaired angiogenesis.

Clinical Pearls

• Dual disruption: adhesion + signaling.
• LiCl can partially restore Wnt activity.

Exam Tips

• CTNND1 mutation → early‑onset leakage phenotype.

3.2 Non‑Wnt Pathway Genes

🔹 KIF11

• Syndromic FEVR: microcephaly + chorioretinal degeneration.
• Mutation frequency ~5.7%.
• Loss‑of‑function truncating mutations predominate.

Clinical Pearls

• Distinct subtype: degenerative + vascular changes.
• Intrafamilial variability common.

Exam Tips

• KIF11 knockout → monopolar spindles, apoptosis.

🔹 DOCK6

• Biallelic mutations → Adams–Oliver syndrome overlap.
• Severe retinal folds/detachment.

Clinical Pearls

• Syndromic overlap with scalp/limb defects.
• Endothelial Cdc42 pathway implicated.

Exam Tips

• DOCK6 mutation → bilateral retinal folds.

🔹 JAG1

• Notch pathway gene; rare but validated contributor.
• Phenotype: peripheral avascular zones, falciform folds, neovascularization.

Clinical Pearls

• Notch signaling regulates tip/stalk balance.
• Severe angiogenic deficits in knockout mice.

Exam Tips

• JAG1 mutation → absence of secondary/tertiary vascular plexuses.

🔹 ZNF408

• Transcription factor; variants cause mild to severe disease.
• Incomplete penetrance common.

Clinical Pearls

• Dominant‑negative effect in cytoplasmic mislocalization.
• Zebrafish models confirm vascular role.

Exam Tips

• ZNF408 mutation → Stage 0–2 disease in many cases.

🔹 DLG1 & RCBTB1

• Candidate genes; pathogenicity inconclusive.
• DLG1 knockout → mild angiogenesis delay.
• RCBTB1 role speculative; not consistently validated.

Clinical Pearls

• Treat as “emerging candidates.”
• Require further validation.

Exam Tips

• Not yet exam‑relevant, but know as “possible genes.”

Future Directions

• Predictive genetics + early screening key to prevention.
• Emerging therapies: gene delivery (Norrin replacement), pathway‑specific interventions.
• Need for large‑scale exome/genome sequencing to uncover unsolved cases.

Clinical Pearls

• Genetic counseling essential.
• Imaging + genotyping refine risk stratification.

Exam Tips

• Future focus: non‑canonical Wnt pathways (planar cell polarity).

4. Clinical Spectrum & Phenotypic Features

• Wide phenotypic heterogeneity: from asymptomatic peripheral avascular retina → severe bilateral retinal detachment.
• Stages (1–5):
  • Stage 1: peripheral avascular retina.
  • Stage 2: neovascularization/exudation.
  • Stage 3: vitreoretinal traction.
  • Stage 4: partial retinal detachment.
  • Stage 5: total retinal detachment.
• Complications: falciform folds, macular dragging, retrolental fibroplasia, cataract, vitreous hemorrhage.
• Interocular asymmetry common, but some genes (e.g., TSPAN12) → bilateral symmetry.

Clinical Pearls

• Early stages may be subtle → require wide‑field angiography.
• Advanced stages often present with leukocoria or strabismus.
• Misdiagnosis as Coats disease or ROP is frequent.

Exam Tips

• Stage 5 = total retinal detachment.
• Macular dragging + falciform folds = classic FEVR hallmark.

5. Imaging Features

• Wide‑field fluorescein angiography (UWFFA): gold standard for detecting peripheral avascular zones.
• OCT/OCTA: reveals vascular anomalies, vitreoretinal traction, macular changes.
• SLO & ultra‑widefield imaging: enhance genotype–phenotype correlation.

Clinical Pearls

• OCTA can detect subtle capillary dropout before clinical signs.
• Imaging critical for differentiating FEVR from mimics (ROP, Coats).

Exam Tips

• UWFFA = best tool for early detection.
• OCTA shows loss of deep capillary plexus in FEVR.

6. Genetic Basis

• Core Wnt pathway genes: NDP, FZD4, LRP5, TSPAN12, CTNNB1, CTNNA1.
• Non‑Wnt genes: KIF11, DOCK6, JAG1, ZNF408, DLG1, RCBTB1.
• Emerging candidates: APCDD1, AXIN1/2, DVL family, ZNRF3, RNF43.
• Genetic heterogeneity: known genes explain ~50% of cases.

Clinical Pearls

• Genetic testing improves diagnostic precision.
• Female carriers often show angiographic changes despite minimal symptoms.

Exam Tips

• LRP5 = most frequently mutated gene.
• KIF11 = syndromic subtype with microcephaly.

7. Therapeutic Approaches

• Laser photocoagulation: for avascular retina/neovascularization.
• Anti‑VEGF therapy: adjunct in neovascular stages.
• Surgery: vitrectomy, scleral buckling for advanced detachment.
• Future therapies: gene therapy (Norrin replacement), pathway‑specific interventions.

Clinical Pearls

• Early intervention preserves vision.
• Anti‑VEGF use must be cautious (risk of traction progression).

Exam Tips

• Laser = first‑line for early stages.
• Vitrectomy indicated in Stage 4–5 disease.

8. Emerging Challenges

• Incomplete genetic yield: ~50% cases unsolved.
• Phenotypic overlap with other pediatric retinopathies complicates diagnosis.
• Need for standardized diagnostic criteria.
• Variable penetrance and expressivity → unpredictable outcomes.

Clinical Pearls

• Multicenter genetic + imaging studies needed.
• Syndromic overlaps (KIF11, DOCK6) must be recognized.

Exam Tips

• Half of clinically diagnosed FEVR cases lack identifiable mutations.

9. Future Directions

• Predictive genetics + neonatal screening → prevention.
• Large‑scale exome/genome sequencing → expand gene list.
• Non‑canonical Wnt pathways (planar cell polarity) underexplored.
• AI‑based imaging analysis may refine early detection.

Clinical Pearls

• Genetic counseling essential for families.
• AI + multimodal imaging = next frontier.

Exam Tips

• Planar cell polarity pathway = future research target.

✅ Key Takeaways

• FEVR = genetically heterogeneous, progressive retinal vascular disorder.
• Core Wnt genes explain ~50% of cases; non‑Wnt genes broaden spectrum.
• Clinical spectrum ranges from subtle avascular retina → total detachment.
• Imaging + genetics are indispensable for diagnosis and risk stratification.
• Therapy tailored to stage; gene therapy and AI diagnostics are future directions.