Progressive cerebral and coronary aneurysms in the original two patients with Kosaki overgrowth syndrome

Abstract

Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet‐derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular‐type Ehlers‐Danlos syndrome and Loeys‐Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow‐up examinations.

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

“…Western blot analysis has shown that expression of the Tyr562Cys variant is consistent with higher basal levels of pPDGFRB, pSRC, pAKT, and pERK1/2, and PDGFRB phosphorylation can activate downstream signaling ( 26 ). PDGFRB phosphorylation contributed to cerebrovascular dilation and lesions, which is observed to be expressed in vascular smooth muscle cells ( 341 ). More recently, the individual with intracranial aneurysm was observed to have PDGFRB alteration, where the vascular complications like SAH may be associated with PDGFRB hyperactivation ( 342 , 343 ).…”