| description |
Blue Rubber Bleb Nevus syndrome (Bean syndrome, BRBN) is a rare, severe congenital disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations (VMs); gastrointestinal lesions are pathognomonic. We discovered somatic TEK mutations in 15 of 17 individuals with BRBN, and five of six patients with multifocal VMs. In contrast to common unifocal VM that is most often caused by a p.(Leu914Phe) change, multifocal forms are predominantly caused by double cis mutations, identical in all lesions from a given individual: The combination p.([Thr1105Asn;Thr1106Pro]) is recurrent in BRBN and p.([Tyr897Cys;Arg915Cys]) is recurrent in multifocal VM. Both cause ligand-independent activation of TIE2 when expressed in human umbilical vein endothelial cells (HUVECs). In keeping with their associated phenotypes, mutations identified in BRBN and multifocal VM increase survival, invasion and colony-formation of HUVECs. |