Genetic Overlap Uncovered: Atypical ROP May Mask FEVR or TBD, Urging Genetic Testing for Accurate Diagnosis

Study Overview

• Purpose: To identify underlying genetic diagnoses (familial exudative vitreoretinopathy [FEVR] or telomere biology disorders [TBD]) in preterm infants with atypical retinopathy of prematurity (ROP) using genetic testing and multimodal imaging.
• Design: Retrospective case series conducted at Bascom Palmer Eye Institute from March 1, 2019, to July 30, 2023.
• Inclusion Criteria: Patients with clinical features of ROP but confirmed genetic variants for FEVR or TBD via next-generation sequencing (Invitae; Labcorp Genetics).
• Sample Size: 38 eyes from 19 patients.

• Key Terms Introduced:

  • ROPER: ROP with underlying FEVR.

  • ROPMERE: ROP with underlying TBD.

• Primary Objective: Reinforce the overlap between ROP, FEVR, and TBD, emphasizing the need for genetic testing to guide diagnosis and management.

Demographics and Clinical Characteristics

• Patient Demographics:
  • 15 males (78.9%), 4 females (21.1%).
  • Mean age at first visit: 4.1 years (range: 0.1–23.8 years).
  • Mean age at diagnosis of FEVR/TBD: 5.7 years (range: 0.3–36.7 years).
• Gestational Age:
  • Mean: 29.4 weeks.
  • 11 patients (57.9%) <32 weeks (preterm).
  • 8 patients (42.1%) ≥32 weeks (moderate to late preterm).
• Initial Diagnosis: All patients initially diagnosed with ROP based on clinical presentation.

Genetic Findings

• FEVR (15/19 patients, 78.9%):
  • Most common genetic variants:
    • LRP5: 5/15 (33.3%).
    • FZD4: 3/15 (20%).
    • TSPAN12: 2/15 (13.3%).
    • CTNNA1: 2/15 (13.3%).
    • KIF11, NDP, ZNF408: 1/15 each (6.7%).
• TBD (4/19 patients, 21.1%):
  • Most common genetic variants:
    • CTC1: 3/4 (75%).
    • ACD: 1/4 (25%).
  • Two CTC1 patients were brothers, suggesting familial inheritance.
• Genetic Testing: Positive for pathogenic variants in all cases, confirming FEVR or TBD.

Clinical Findings

• Fundoscopy Findings (at presentation, 38 eyes):
  • Incomplete peripheral vascularization: 34/38 eyes (89.5%).
  • Tortuous vessels: 14/38 eyes (36.8%).
  • Neovascularization: 10 10/38 eyes (26.3%).
  • Retinal detachment (RD): 9/38 eyes (23.7%).
  • Exudation: 6/38 eyes (15.8%).
  • Retinal dragging: 4/38 eyes (10.5%).
  • Vitreous hemorrhage: 3/38 eyes (7.9%).
  • Fovea plana, telangiectatic vessels: 3/38 eyes each (7.9%).
  • Terminal arborization, aneurysmal dilation: 2/38 eyes each (5.3%).
  • Rare findings (1/38 eyes, 2.6% each): vessel straightening, scattered hemorrhages, hyperpigmentary changes, coloboma.
• Fluorescein Angiography (FA) Features:
  • ROPER (FEVR): Irregular vascular sprouts, vessel pruning, pinpoint hyperfluorescence, segmental vascular leakage.
  • ROPMERE (TBD): Aneurysmal dilatation (85.7%), terminal arborization (85.7%), anastomotic loops (85.7%), capillary dropout, vascular changes extending to zone 1.

Treatment and Outcomes

• Treatments:
  • Intravitreal bevacizumab: 24/38 eyes (63.2%).
  • Laser photocoagulation: 25/38 eyes (65.8%).
  • Sub-Tenon’s Kenalog: 19/38 eyes (50%).
  • Pars plana lensectomy/vitrectomy: 2/38 eyes (5.3%).
  • Multiple sessions of laser or bevacizumab often required.
• Visual Acuity (VA):
  • At presentation: 20/200 or better in 10/20 eyes (50%), worse than 20/200 in 8/20 eyes (40%), not measurable in 18 eyes.
  • Final VA: 20/200 or better in 15/26 eyes (57.7%), worse than 20/200 in 11/26 eyes (42.3%).
• Follow-Up: Mean 36.5 months (range: 0–164 months).
• Prognosis: Poor outcomes (VA worse than 20/200 in 42.3%) associated with late presentation, exudative/tractional RD, or vitreous hemorrhage.

Key Differentiators

• ROP vs. FEVR:
  • FEVR: Presence of exudates, persistent disease progression, FA findings (irregular sprouts, vascular leakage).
  • ROP: Typically regresses with treatment or spontaneously.
• ROP vs. TBD:
  • TBD: Systemic features (e.g., dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome), FA findings (aneurysmal dilatation, terminal arborization), severe retinal disease disproportionate to gestational age.
• Indications for Genetic Testing:
  • Early-onset RD.
  • Mixed exudative/ischemic retinopathy.
  • Bilateral Coats-like disease.
  • Poor treatment response or disease recurrence.
  • Severe disease disproportionate to gestational age.

Pathophysiology

• Genetic Overlap:
  • FEVR and ROP: Variants in Wnt/β-catenin pathway (FZD4, LRP5, NDP) linked to severe ROP.
  • TBD and ROP: Bidirectional relationship between telomere biology and Wnt signaling; Wnt agonists may ameliorate telomere shortening in TBD.
• Clinical Spectrum: ROP, FEVR, and TBD may share a spectrum due to overlapping genetic and clinical features.

Clinical Implications

• Genetic Testing: Essential for atypical or severe ROP to identify ROPER or ROPMERE, guiding long-term management.
• Management:
  • Anti-VEGF (bevacizumab) for neovascularization/leakage.
  • Laser photocoagulation for vascular non-perfusion.
  • Surgical repair for RD.
• ROPER/ROPMERE:
  • Unpredictable activation/inactive phases require serial FA and close monitoring.
  • Unlike ROP, these conditions progress despite treatment, necessitating lifelong surveillance.
• ROPMERE-Specific:
  • Early diagnosis critical for genetic counseling, cancer screenings, and symptom-specific treatment.
  • Systemic evaluation based on TBD subtype (e.g., dyskeratosis congenita, Revesz syndrome).

Limitations

• Small sample size (19 patients).
• Lack of functional assays to confirm causality of genetic variants.
• Retrospective design limits comprehensive systemic evaluation.
• Prevalence of FEVR/TBD variants in ROP population remains unclear.

Citation

Da Cruz NFS, Hudson JL, Sengillo JD, et al. Underlying Disease in Atypical Retinopathy of Prematurity. American Journal of Ophthalmology. 2025;274:67-75. doi:10.1016/j.ajo.2025.02.026