Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?

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EPHB4 variants were recently reported to cause capillary malformation–arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant.


Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1.


An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM.


Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.

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  1. 1.

    Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;3:1240–1249.

  2. 2.

    Amyere M, Revencu N, Helaers R, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136:1037–1048.

  3. 3.

    Vivanti A, Ozanne A, Grondin C, et al. Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation. Brain. 2018;141:979–988.

  4. 4.

    Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15:265–269.

  5. 5.

    Revencu N, Boon LM, Mulliken JB, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29:959–965.

  6. 6.

    Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer JF, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012;55:91–95.

  7. 7.

    Wooderchak-Donahue WL, Johnson P, McDonald J, et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation (CM-AVM). Eur J Hum Genet. 2018;26:1521–1536.

  8. 8.

    McDonald J, Wooderchak-Donahue WL, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1.

  9. 9.

    Shovlin C, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91:66–67.

  10. 10.

    Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48:73–87.

  11. 11.

    McDonald J, Bayrak-Toydemir P, Pyeritz R. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011;13:607–616.

  12. 12.

    Wooderchak-Donahue W, McDonald J, O’Fallon B, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93:530–537.

  13. 13.

    Hernandez F, Huether R, Carter L, et al. Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia. Hum Genome Var. 2015;2:15040.

  14. 14.

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760.

  15. 15.

    Li H, Ruan J, Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008;18:1851–1858.

  16. 16.

    McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–1303.

  17. 17.

    Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–3814.

  18. 18.

    Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575–576.

  19. 19.

    Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249.

  20. 20.

    Yu J, Streicher JL, Medne L, Krantz ID, Yan AC. EPHB4 mutation implicated in capillary-malformation-arteriovenous malformation syndrome: A case report. Pediatr Dermatol. 2017;34:e227–e230.

  21. 21.

    Gonzalez CD, Mcdonald J, Stevenson DA, Whitehead KJ, Petersen MG, Presson AP, Ding Q, Wilson KF. Epistaxis in children and adolescents with hereditary hemorrhagic telangiectasia. Laryngoscope, 2018;128:1714–1719.

  22. 22.

    Pahl KS, Choudhury A, Wusik K, et al. Applicability of the Curacao criteria for the diagnosis of hereditary hemorrhagic telangiectasia in the pediatric population. J Pediatr. 2018;197:2017–2213.

  23. 23.

    Kim C, Ko CJ, Baker KE, Antaya RD. Histopathologic and ultrasound characteristics of cutaneous capillary malformations in a patient with capillary malformation—arteriovenous malformation syndrome. Pediatr Dermatol. 2015;32:128–131.

  24. 24.

    Best DH, Vaughn C, McDonald J, et al. Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. J Med Genet. 2011;48:358–360.

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We thank the patients and their families for allowing us to publish their data. We thank members of the ARUP Molecular Genetics and Genomics Clinical Laboratories for assisting in the sequence analysis of these patients. We thank the ARUP Institute for Clinical and Experimental Pathology for funding this work. G.A. was supported by the Scientific and Technological Research Council of Turkey (TUBİTAK) with a 2219-Postdoctoral Research Fellowship.

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Correspondence to Jamie McDonald MS.

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  • capillary malformation
  • CM-AVM
  • EPHB4
  • HHT
  • telangiectasia