EPHB4 Mutation Implicated in Capillary Malformation–Arteriovenous Malformation Syndrome: A Case Report

Abstract

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome, due to inactivating mutations in RASA1 in 68% of cases, is characterized by the development of cutaneous capillary malformations and arteriovenous malformations or fistulas; no known genetic etiology has been identified in patients with CM-AVM syndrome without RASA1 mutations. We present the case of a child with RASA1-negative CM-AVM syndrome with a de novo missense mutation in EPHB4, a transmembrane tyrosine kinase receptor essential for vasculogenesis. Inactivating the mutation in EPHB4 has been shown to upregulate the mitogen-activated protein kinase pathway and the mammalian target of rapamycin complex 1, possibly contributing to the development of vascular malformations.

Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation

“…Very recently, a second form of CM-AVM (CM-AVM2) caused by germline loss-of-function mutations in EPHB4 was reported [24]. CM-AVM2 mimics RASA1-related CM-AVM and also HHT in that clinical features include multifocal CMs, telangiectases, and AVMs [24,25]. With this new discovery, it is likely that cases with CMs and AVMs who tested negative for a RASA1 variant have an EPHB4 variant.…”

DDX24 Mutations Associated With Malformations of Major Vessels to the Viscera

“…For example, mutations of the TEK receptor tyrosine kinase and glomulin genes have been associated with venous malformations (Mendelian Inheritance in Man [MIM] 600195 and 138000), and mutated Fms‐related tyrosine kinase 4 is considered to be the causal gene of certain types of lymphatic malformations (MIM 153100) . In addition, mutations of RAS p21 protein activator 1, ephrin receptor B4, and Krev interaction trapped 1 are found in mixed vascular malformations (MIM 608354 and 116860) . However, the causal genes have been associated rarely with malformations of vessels to the viscera.…”

“…(14) In addition, mutations of RAS p21 protein activator 1, ephrin receptor B4, and Krev interaction trapped 1 are found in mixed vascular malformations (MIM 608354 and 116860). (15)(16)(17)(18) However, the causal genes have been associated rarely with malformations of vessels to the viscera.…”

Six‐year‐old male with a chief complaint of telangiectasias

“…EPHB4 encodes a tyrosine kinase receptor involved in angiogenesis, ephrin type B receptor 4. Loss of EPHB4 generates uncontrolled signaling by the RAS‐MEK‐ERK and RAS‐AKT‐mTORC1 pathways and provides an explanation for the phenotypic similarity to CM‐AVM1 …”

“…2 Interestingly, a decreased incidence of AVMs in CM-AVM2 compared to CM-AVM1 has been reported, which helps explain the absence of AVMs in our patient. 1,7 Given the high flow nature and potential for acute hemorrhage, MRI in high-risk areas like the brain is indicated to evaluate for presence, size, and quality of AVMs. This includes asymptomatic patients who present with cutaneous syndromes that harbor the possibility of AVMs.…”