📋 Case Presentation
A 34-year-old woman with Coats Plus Syndrome (CPS) presented for retinal evaluation. Despite 20/20 vision OU and no visual complaints, ultra-widefield OCT angiography (UWF-OCTA) revealed extensive peripheral retinal capillary nonperfusion. The posterior pole appeared normal, underscoring the silent nature of peripheral ischemia in CPS.
Systemic findings included:
- Severe gastrointestinal bleeding
- Normocytic anemia
- Intracranial calcifications
Genetic testing revealed heterozygous variants in CTC1, PUS1, and SOX18, alongside short telomeres, confirming CPS within the spectrum of telomere biology disorders (TBDs).
🔎 ROPER and ROPMERE: Genetic Overlap in Atypical ROP
Recent studies have shown that some infants initially diagnosed with retinopathy of prematurity (ROP) actually harbor underlying genetic disorders that alter disease course and prognosis farabiretina.com.
ROPER (ROP with underlying FEVR)
- Represents infants with ROP who also carry familial exudative vitreoretinopathy (FEVR)-related mutations.
- Key genes implicated:
- LRP5 (low-density lipoprotein receptor-related protein 5)
- FZD4 (frizzled class receptor 4)
- TSPAN12 (tetraspanin 12)
- CTNNA1 (catenin alpha 1)
- KIF11, NDP, ZNF408 (less frequent)
- These genes converge on the Wnt/β-catenin signaling pathway, critical for retinal vascular development.
- Clinical hallmark: atypical, persistent, or aggressive ROP that does not regress as expected.
ROPMERE (ROP with underlying TBD)
- Represents infants with ROP who also have telomere biology disorders.
- Key genes implicated:
- CTC1 (conserved telomere maintenance component 1)
- ACD (adrenocortical dysplasia protein homolog, also known as TPP1)
- These mutations impair telomere maintenance, leading to systemic features (bone marrow failure, pulmonary fibrosis, GI bleeding) and retinal ischemia disproportionate to gestational age.
- Clinical hallmark: aneurysmal dilatation, terminal arborization, and vascular changes extending centrally on fluorescein angiography.
👁️ Imaging and Clinical Implications
- UWF-OCTA is invaluable for detecting subtle peripheral ischemia in both ROPER and ROPMERE.
- Structured classification (ROPER vs ROPMERE) helps clinicians:
- Decide when to order genetic testing.
- Anticipate systemic associations.
- Tailor follow-up intensity and family counseling.
🩺 Broader Systemic Context
- ROPER: Primarily ocular, but genetic overlap with FEVR means lifelong risk of progressive retinal disease, even after ROP regression.
- ROPMERE: Multisystemic, requiring hematology, pulmonology, and gastroenterology input alongside ophthalmology.
📌 Clinical Takeaways
- Genetic testing is essential in atypical or treatment-resistant ROP to uncover ROPER or ROPMERE.
- ROPER genes (LRP5, FZD4, TSPAN12, CTNNA1, KIF11, NDP, ZNF408) → Wnt pathway dysregulation.
- ROPMERE genes (CTC1, ACD/TPP1) → telomere dysfunction.
- Recognizing these overlap syndromes allows for precision medicine: targeted surveillance, systemic evaluation, and family counseling.
📖 Citation
Da Cruz NFS, Hudson JL, Sengillo JD, et al. Underlying Disease in Atypical Retinopathy of Prematurity. Am J Ophthalmol. 2025;274:67-75. doi:10.1016/j.ajo.2025.02.026 farabiretina.com
