Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Activating variants in the platelet-derived growth factor receptor beta (PDGFRB) gene have been linked to various clinical conditions.
• Previously, these conditions were categorized as distinct entities like solitary myofibromas, infantile myofibromatosis, Penttinen syndrome, Kosaki overgrowth syndrome, and fusiform aneurysms.

Observation:

• A case series of 12 patients with PDGFRB activating variants and a literature review revealed significant overlap in clinical features.
• Five patients exhibited features spanning multiple diagnostic categories.
• Seven patients from one family displayed variable expressivity and late-onset disease, including adult-onset manifestations and sudden death in two individuals.

Findings:

• The study supports a spectrum of disorders associated with PDGFRB activating variants, challenging the classification into distinct clinical entities.
• Phenotypic differences are dramatic and correlate with advancing age, specific genotypes, and mosaicism.
• Infants and young children presented with fewer abnormalities, while older individuals exhibited more numerous and age-related features.

Implications:

• Treatment with imatinib in three patients resulted in robust and rapid responses, including in infants with multicentric myofibromas.
• This suggests imatinib as a potential therapeutic option for PDGFRB-related disorders.
• Recognizing PDGFRB variants as a spectrum disorder is crucial for accurate diagnosis and management, considering age-dependent and genotype-specific manifestations.