Corneal Myofibromatosis caused by novel activating variants in PDGFRB responsive to Imatinib.

Abstract

Purpose : Two benign-appearing corneal tumors were characterized by histologic, genetic and functional examinations as corneal myofibromas. Disease-causing mutations and susceptibility to targeted treatment were analyzed.

Methods : Two unrelated males, aged 18 and 13 years, born to non-consanguineous parents presented with white corneal opacifications, photophobia, glare sensitivity and reduced vision. In infancy, both patients had nodular skin lesions consistent with infantile myofibromatosis, which was confirmed by histology in Patient 1. There was no evidence of Kosaki overgrowth or Penttinen syndrome. Slit lamp biomicroscopy, anterior segment OCT and surgical tumor excision by lamellar keratectomy with Mitomycin C (MMC) were performed. Histopathologic evaluation using conventional and immunohistochemical stains followed. Genetic testing was carried out on peripheral blood after written informed consent. In Patient 1, Sanger Sequencing of the platelet-derived growth factor receptor-beta (PDGFRB) exon 12 was performed to test for a variant previously found in an affected cousin. In Patient 2, exome-based sequencing of PDGFRB and the neurogenic locus notch homolog protein 3 (NOTCH3) gene was performed. For functional analyses, the PDGFRB variants were transfected into cells, tested for expression, activation and sensitivity to the tyrosine kinase inhibitor imatinib.

Results : Histology was consistent with corneal manifestations of myofibromatosis. Immunohistochemical stainings demonstrated positivity for alpha-smooth muscle actin and b-catenin, a low proliferation rate in Ki-67 (<5%), marginal positivity in Desmin, negative staining for Caldesmon and CD34. In both patients the corneal myofibroma recurred within 4 months requiring re-lamellar keratectomy with MMC. The genetic analysis detected the novel heterozygous mutations PDGFRB c.1766A>G (p.Y589C) in Patient 1 and c.1949C>G (p.S650W) in Patient 2. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor Imatinib. The variants can be classified as ACMG Class 5 (pathogenic).

Conclusions : We describe two cases of corneal myofibromatosis caused by the novel mutations PDGFRB c.1766A>G (p.Y589C) and c.1949C>G (p.S650W). Imatinib sensitivity under laboratory conditions suggests perspectives for targeted therapy preventing recurrences.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.