EPHB4 – Capillary Malformation-Arteriovenous Malformation Syndrome Type 2

EPHB4 is a transmembrane tyrosine kinase receptor that regulates endothelial cell signaling. Heterozygous loss-of-function variants in EPHB4 cause an autosomal dominant form of capillary malformation-arteriovenous malformation syndrome, now designated CM-AVM2, characterized by multifocal cutaneous capillary malformations and a risk of fast-flow vascular anomalies, including arteriovenous malformations and fistulas.

Genetic studies have identified 54 unrelated probands with 47 distinct EPHB4 mutations, including premature stop codons, splice-site alterations, and frameshifts, across 5 families that demonstrate cosegregation of vascular lesions (PMID:28687708). A four-generation pedigree and a comprehensive review of 127 patients confirm robust segregation and recurrent de novo events, supporting a definitive gene–disease relationship (PMID:35088870).

The variant spectrum encompasses 27 truncating variants and 20 missense substitutions clustered in the kinase and extracellular domains. Case reports further document pathogenic truncating alleles such as c.2125del (p.Asp709fs) in sporadic CM-AVM2 patients, underscoring haploinsufficiency as the primary mechanism.

Functional assays reveal that EPHB4 variants abolish receptor phosphorylation, leading to hyperactivation of the RAS-MAPK and mTORC1 pathways in vitro. Structural analysis of the EphB4–ephrinB2 interface highlights critical residues required for ligand specificity, and mutant receptors show impaired binding and downstream signaling (PMID:16867992; PMID:28687708).

Clinical observations indicate autosomal dominant inheritance with variable expressivity, including telangiectasia, overgrowth, heart murmur, and congestive heart failure in rare cases. No significant contradictory evidence has emerged; genotype–phenotype correlations remain limited by phenotypic heterogeneity.

Integration of extensive genetic and functional data establishes a definitive association between EPHB4 and CM-AVM2. Identification of pathogenic EPHB4 variants enables genetic diagnosis, informs risk of arteriovenous malformations, and supports targeted surveillance and management strategies.

Key Take-home: EPHB4 haploinsufficiency causes autosomal dominant CM-AVM2 with a definitive gene–disease relationship and clear clinical utility for diagnosis and surveillance.

References

• Circulation • 2017 • Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. PMID:28687708
• Acta dermato-venereologica • 2022 • Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review. PMID:35088870
• The Journal of Biological Chemistry • 2006 • Structural and biophysical characterization of the EphB4*ephrinB2 protein-protein interaction and receptor specificity. PMID:16867992

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