Corneal Infantile Myofibromatosis Caused by Novel Activating Imatinib-Responsive Variants in .

Purpose: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis.

Design: Case series with genetic and functional analyses.

Participants: Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated.

Methods: Exome-based panel sequencing for platelet-derived growth factor receptor beta gene () and notch homolog protein 3 gene () was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual variants was performed by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot.

Main Outcome Measures: Sequencing data, immunohistochemical stainings, functional analysis of variants, and protein expression analysis.

Results: We identified 2 novel, heterozygous gain-of-function variants in in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the 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 both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria.

Conclusions: We describe 4 cases of corneal myofibromatosis caused by novel variants with autosomal dominant transmission. Imatinib sensitivity suggests perspectives for targeted therapy preventing recurrences in the future.

Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.