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Published on: September 20, 2016
A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib
Dinel Pond1, Florence A Arts2, Nancy J Mendelsohn1
1Department of Medical Genetics and Genomics, Children's Minnesota, Minneapolis, Minnesota, USA.
Insights
A child with a rare genetic disorder caused by a PDGFRB mutation showed significant improvement with imatinib treatment. This targeted therapy effectively inhibited the mutated receptor, improving symptoms and quality of life.
Area of Science:
- Genetics
- Pharmacology
- Oncology
Background:
- Germ-line activating mutations in Platelet-Derived Growth Factor Receptor Beta (PDGFRB) are linked to Kosaki and Penttinen syndromes and myofibromatosis.
- Understanding the functional impact of specific PDGFRB mutations is crucial for developing targeted therapies.
Observation:
- A 10-year-old patient presented with a germ-line PDGFRB p.N666H mutation.
- Cells with the p.N666H mutation exhibited constitutive PDGFRB tyrosine phosphorylation and PDGF-independent proliferation.
- Patient-derived fibroblasts confirmed constitutive receptor phosphorylation and increased proliferation.
Findings:
- Imatinib effectively inhibited PDGFRB phosphorylation and PDGF-independent proliferation in cell culture models of the p.N666H mutation.
- Patient treatment with imatinib resulted in objective clinical improvements, including reduced contractures and facial coarseness.
- The patient experienced a significant enhancement in quality of life, with stable subcutaneous nodules and manageable side effects.
Implications:
- This case represents one of the first personalized treatments for a congenital disorder caused by a germ-line PDGFRB mutation using a specific PDGFRB inhibitor.
- Targeted inhibition of PDGFRB with imatinib offers a promising therapeutic strategy for patients with PDGFRB-driven congenital disorders.
- Further research into PDGFRB inhibitors may lead to novel treatments for a spectrum of related genetic conditions.
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.
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