Second Report of the p.Leu874Pro Missense Variant in EPHB4 in a Family With Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM) Syndrome

Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1–2 cm in diameter) capillary malformations of the skin. This disorder has been described as two distinct entities: CM-AVM1 and CM-AVM2. The diagnosis of these disorders has been associated with pathogenic variants in the RASA1 gene for RASA1-CM-AVM, formerly known as CM-AVM1, and, more recently, the EPHB4 genes for EPHB4-CM-AVM, formerly known as CM-AVM2. Affected patients with either type may also have arteriovenous malformations and fistulas, which can cause life-threatening bleeding, congestive heart failure, or neurologic consequences such as stroke. These syndromes are typically either sporadic or inherited in an autosomal dominant manner with variable expressivity. We report a case series of a father and three daughters who have clinically diagnosed EPHB4-CM-AVM syndrome who were found to have a variant of uncertain significance (VUS) in EPHB4 that has only been reported once prior.