A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib.

Abstract

PurposeHeterozygous germ-line activating mutations in PDGFRB cause Kosaki and Penttinen syndromes and myofibromatosis. We describe a 10-year-old child with a germ-line PDGFRB p.N666H mutation who responded to the tyrosine kinase inhibitor imatinib by inhibition of PDGFRB.MethodsThe impact of p.N666H on PDGFRB function and sensitivity to imatinib was studied in cell culture.ResultsCells expressing the p.N666H mutation showed constitutive PDGFRB tyrosine phosphorylation. PDGF-independent proliferation was abolished by imatinib at 1 μM concentration. Patient fibroblasts showed constitutive receptor tyrosine phosphorylation that was also abrogated by imatinib with reduced proliferation of treated cells.This led to patient treatment with imatinib at 400 mg daily (340 mg/m2) for a year with objective improvement of debilitating hand and foot contractures, reduced facial coarseness, and significant improvement in quality of life. New small subcutaneous nodules developed, but remained stable. Transient leukopenia, neutropenia, and fatigue resolved without intervention; however, mildly decreased growth velocity resulted in reducing imatinib dose to 200 mg daily (170 mg/m2). The patient continues treatment with ongoing clinical response.ConclusionTo our knowledge, this is one of the first personalized treatments of a congenital disorder caused by a germ-line PDGF receptor mutation with a PDGFRB inhibitor.

• Authors: Dinel Pond, Florence A Arts, Nancy J Mendelsohn, Jean-Baptiste Demoulin, Gunter Scharer, Yoav Messinger
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 20 Issue 1 Pg. 142-150 (01 2018) ISSN: 1530-0366 [Electronic] United States
• PMID: 28726812 (Publication Type: Case Reports, Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Imatinib Mesylate
• PDGFRB protein, human
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Alleles
• Amino Acid Substitution
• Gain of Function Mutation
• Genetic Testing
• Germ-Line Mutation
• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Infant
• Magnetic Resonance Imaging
• Male
• Megalencephaly (diagnosis, genetics, surgery)
• Myofibromatosis (congenital, diagnosis, drug therapy, genetics)
• Pharmacogenetics
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, genetics)
• Treatment Outcome