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

Antonia Howaldt, MD; Sandrine Lenglez, BSc; Clara Velmans, MD; Anne Maria Schultheis, MD; Thomas Clahsen, PhD; Mario Matthaei, MD; Jürgen Kohlhase, MD; Christian Vokuhl, MD; Reinhard Büttner, MD; Christian Netzer, MD; Jean-Baptiste Demoulin, PhD; Claus Cursiefen, MD, PhD

Ophthalmology Science (May 2024)

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

Antonia Howaldt, MD,
Sandrine Lenglez, BSc,
Clara Velmans, MD,
Anne Maria Schultheis, MD,
Thomas Clahsen, PhD,
Mario Matthaei, MD,
Jürgen Kohlhase, MD,
Christian Vokuhl, MD,
Reinhard Büttner, MD,
Christian Netzer, MD,
Jean-Baptiste Demoulin, PhD,
Claus Cursiefen, MD, PhD

Affiliations

Antonia Howaldt, MD: Department of Ophthalmology, University of Cologne, Cologne, Germany; Correspondence: Antonia Howaldt, Department of Ophthalmology, University of Cologne, Cologne, Germany.
Sandrine Lenglez, BSc: De Duve Institute, University of Louvain, Brussels, Belgium
Clara Velmans, MD: Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Anne Maria Schultheis, MD: Institute of Pathology, University of Cologne, Cologne, Germany
Thomas Clahsen, PhD: Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Mario Matthaei, MD: Department of Ophthalmology, University of Cologne, Cologne, Germany
Jürgen Kohlhase, MD: Center for Human Genetics, SYNLAB MVZ Humangenetik Freiburg GmbH, Freiburg, Germany
Christian Vokuhl, MD: Institute of Pathology, University Hospital Bonn, Bonn, Germany
Reinhard Büttner, MD: Institute of Pathology, University of Cologne, Cologne, Germany
Christian Netzer, MD: Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Jean-Baptiste Demoulin, PhD: De Duve Institute, University of Louvain, Brussels, Belgium
Claus Cursiefen, MD, PhD: Department of Ophthalmology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

Journal volume & issue: Vol. 4, no. 3
p. 100444

Abstract

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Purpose: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis. Design: Case series with genetic and functional in vitro 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 (PDGFRB) and notch homolog protein 3 gene (NOTCH3) 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 PDGFRB variants was performed in vitro 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 PDGFRB variants, and protein expression analysis. Results: We identified 2 novel, heterozygous gain-of-function variants in PDGFRB 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 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 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 PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Published in Ophthalmology Science

ISSN: 2666-9145 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Ophthalmology
Website: https://www.journals.elsevier.com/ophthalmology-science/

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