A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib.
Genet Med
; 20(1): 142-150, 2018 01.
Article
in En
| MEDLINE
| ID: mdl-28726812
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Germ-Line Mutation
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Amino Acid Substitution
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Receptor, Platelet-Derived Growth Factor beta
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Protein Kinase Inhibitors
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Alleles
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Imatinib Mesylate
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Gain of Function Mutation
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Humans
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Infant
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Male
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2018
Type:
Article
Affiliation country:
United States