has material basis in germline mutation in EPHB4 hereditary disease vascular malformation EPHB4-associated vascular malformation spectrum https://github.com/monarch-initiative/mondo/issues/4941 Any vascular malformation in which the cause of the disease is a variation in the EPHB4 gene. Variants in the EPHB4 gene have been observed in individuals with capillary malformation-arteriovenous malformation (CM-AVM) (characterized by the presence of multiple small capillary malformations, mostly on the face and limbs, +/- other arteriovenous malformations or arteriovenous fistulas) as well as with lymphatic malformations, ranging in severity from severe non-immune hydrops fetalis to varicose veins and/or subclinical lymphatic anomalies, even within the same family (PMID:27400125). Evidence suggests that both of these presentations are caused by loss of function, though the exact mechanism by which this occurs is variable; some variants demonstrate reduced expression and defects in subcellular localization with aggregates, others have normal expression levels but reduced tyrosine kinase activity) (PMID:33864021). It has been hypothesized that the different presentations may be due to differences in forward vs. reverse signaling defects, but this remains to be elucidated. [PMID:27400125, PMID:2868770, PMID:30760892, PMID:33864021] MONDO:0700080