Segmental overgrowth and aneurysms due to mosaic PDGFRB p.(Tyr562Cys)

Abstract

Activating variants in the platelet‐derived growth factor receptor β gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next‐generation sequencing‐based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB‐activating variants through literature search. The conditions caused by PDGFRB‐activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant‐related phenotypes are present. Whole‐body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6‐ to 12‐month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

“…In addition, there are likely somatic mutations underlying IA formation, at least in part, necessitating the large-scale analysis of IA lesional tissue. 50,51 By acquiring and studying IA tissue, we may rigorously evaluate theories of IA formation. Advances in endoluminal biopsy techniques will enable comprehensive analysis of IA genetic mechanisms.…”

Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations

“…With this evidence, it is tempting to speculate that loss of function mutations in the PDGF-BB/PDGFRβ axis might be associated with the development of AVMs. As a matter of fact, pathogenic variants of PDGFRB have been described associated with fusiform cerebral aneurysms (Karasozen et al, 2019;Chenbhanich et al, 2021;Parada et al, 2022) and in a small subset of patients with brain AVMs (Gao et al, 2022). Surprisingly, the pathogenic variants identified as Frontiers in Physiology frontiersin.org associated with brain aneurysms result in gain of function of PDGFRβ (Wenger et al, 2020).…”