Several authors have suggested that a postzygotic de novo variant in the other allele (“second hit hypothesis”) would be required for the development of the focal lesions associated with the CM-AVM2 disease phenotype.6–8 This mechanism has been shown for other hereditary multifocal vascular malformations such as RASA1-associated CM-AVM1.28–30 However, variable expression of the disease phenotype could also be due to genetic modifiers or polygenic inheritance, therefore, it is necessary to understand whether one or two EPHB4 null alleles will lead to disease. The gene discussed is EPHB4; the disease is vascular malformation.