Whitney L Wooderchak-Donahue1,2, Gulsen Akay1,3, Kevin Whitehead4, Eric Briggs1, David A Stevenson5, Brendan O'Fallon1, Matthew Velinder6, Andrew Farrell6, Wei Shen1, Emma Bedoukian7, Cara M Skrabann7,8, Richard J Antaya9, Kate Henderson10, Jeffrey Pollak10, James Treat11, Ronald Day12, Joseph E Jacher13, Mark Hannibal13, Kelly Bontempo14, Gabor Marth6, Pinar Bayrak-Toydemir1,2, Jamie McDonald15,16. 1. ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. 2. Department of Pathology, University of Utah, Salt Lake City, UT, USA. 3. Zeynep Kamil Training and Research Hospital, Istanbul, Turkey. 4. Division of Cardiovascular Medicine, Department of Medicine, HHT Center, University of Utah, Salt Lake City, UT, USA. 5. Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA. 6. USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA. 7. Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 8. Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 9. Departments of Dermatology and Pediatrics and HHT Program, Yale University School of Medicine, New Haven, CT, USA. 10. Department of Radiology and Biomedical Imaging, and HHT Program, Yale University School of Medicine, New Haven, CT, USA. 11. Dematology Section, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 12. Division of Pediatric Cardiology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. 13. Department of Pediatrics and Communicable Diseases, Division of Pediatric Genetics, Metabolism &Genomic Medicine, University of Michigan, Ann Arbor, MI, USA. 14. Advocate Children's Hospital, Park Ridge, IL, USA. 15. Department of Pathology, University of Utah, Salt Lake City, UT, USA. Jamie.mcdonald@hsc.utah.edu. 16. Department of Radiology, HHT Center, University of Utah, Salt Lake City, UT, USA. Jamie.mcdonald@hsc.utah.edu.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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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