Intracranial vasospasm with subsequent stroke after traumatic subarachnoid hemorrhage in a 22-month-old child

Clinical and radiographic evidence of subarachnoid hemorrhage (SAH)-related vasospasm is rare in children and has not been reported in infants. In this report the authors present the case of a 22-month-old child who developed clinically symptomatic, radiographically identifiable vasospasm after traumatic SAH. To the authors' knowledge, this is the first report of vasospasm associated with SAH in a child this young. This 22-month-old boy fell and had a dense SAH. He had a history of surgically corrected craniosynostosis and nonsymptomatic ventriculomegaly. The boy was evaluated for occult vascular lesions using imaging; none were found and normal vessel caliber was noted. Ten days later, the child developed left-sided weakness and a right middle cerebral artery infarct was identified. Evaluation disclosed significant intracranial vasospasm. This diagnosis was supported by findings on CT angiography, transcranial Doppler ultrasonography, MR imaging, and conventional angiography. The child was treated using intraarterial verapamil with a good result, as well as with conventional intensive care measures to reduce vasospasm. This report documents the first known case of intracranial vasospasm with stroke after SAH in a patient under the age of 2 years. This finding is important because it demonstrates that the entity of SAH-associated vasospasm can affect the very young, widening the spectrum of ages susceptible to this condition. This case is also important because it demonstrates that even very young children can respond to conventional therapeutic interventions such as intraarterial verapamil. Thus, clinicians need to be alert to the possibility of vasospasm as a potential diagnosis when evaluating young children with SAH.</jats:p

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

ABSTRACTTo elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-functionde novovariants (p=4.79×10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22×10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants inACVRL1,NOTCH1,ITGB1, andPTPN11.ACVRL1variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specificEPHB4kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.</jats:p

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 1