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Cagri Besirli, Joshua Robinson, Ekta Lakhani, Michael Trese; Defective Wnt-signaling is associated with progressive retinopathy in Incontinentia pigmenti (IP). Invest. Ophthalmol. Vis. Sci. 2013;54(15):607.
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To describe the association of a Wnt-signaling mutation with accelerated and progressive proliferative retinopathy in Incontinentia pigmenti (IP).
DNA sequence evaluation of Wnt-signaling pathway genes for mutations in a family with IP and 3-D protein structure prediction analysis of H69Y Frizzled-4 (FZD4) mutation identified in this family.
A 3-day old full-term female infant with a family history of IP was diagnosed with IP after punch biopsy for vesicular skin lesions. Ophthalmic examination and fluorescein angiography showed largely avascular retinal periphery in both eyes with abnormal shunt vessels and dye leakage. Peripheral laser ablation therapy was performed. Repeat ophthalmic evaluations demonstrated progressive capillary dropout and retinopathy, requiring additional laser treatments and prompting mutation analysis for Wnt pathway genes. Direct sequencing of exons and exon-intron boundaries revealed a single-nucleotide change in exon 1 of the FZD4 gene, resulting in Histidine to Tyrosine change on amino acid 69. Protein sequence analysis demonstrated that this amino acid is highly conserved across species and among other members of the Frizzled receptor family. 3-D protein structure prediction revealed that His69 residue resides at a critical location in the ligand-binding domain of FZD4.
Progressive retinopathy in IP may indicate a second genetic hit affecting retinal vascular development. Exome sequencing of Wnt-pathway genes may be a useful clinical adjunct in determining the frequency of ophthalmic examinations and guiding the decision-making for retinal laser treatment in patients with IP. The finding of a second genetic mutation in a patient with IP indicates that genome sequencing for Wnt signaling mutations may improve the diagnosis and treatment of other acquired and inherited pediatric retinal vascular diseases.
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