This is the first family to be described with just primary lymphedema and a likely pathogenic variant in EPHB4. Either early onset isolated peripheral primary lymphedema is a new separate entity (in addition to LRFH and CM-AVM2) in the increasing family of EPHB4-associated phenotypes, or, based on the proposed disease mechanism elucidated through our functional analysis, the CM-AVM2 phenotype spectrum needs expanding to include primary lymphedema. This evidence concerns the gene EPHB4 and cutaneous mastocytosis.