Sherene Shalhub1, Peter H Byers2, Kelli L Hicks3, Dawn M Coleman4, Frank M Davis4, Giovanni De Caridi5, K Nicole Weaver6, Erin M Miller7, Marc L Schermerhorn8, Katie Shean8, Gustavo Oderich9, Mauricio Ribeiro10, Cole Nishikawa11, Kristofer Charlton-Ouw12, Christian-Alexander Behrendt13, E Sebastian Debus14, Yskert von Kodolitsch14, Devin Zarkowsky15, Richard J Powell16, Melanie Pepin2, Dianna M Milewicz17, Ellen S Regalado17, Peter F Lawrence18, Karen Woo18. 1. Division of Vascular Surgery, Department of Surgery, University of Washington, Seattle, Wash. Electronic address: shalhub@uw.edu. 2. Departments of Pathology and Medicine (Medical Genetics), University of Washington, Seattle, Wash. 3. Division of Vascular Surgery, Department of Surgery, University of Washington, Seattle, Wash. 4. Section of Vascular Surgery, University of Michigan, Ann Arbor, Mich. 5. Department of Cardiovascular and Thoracic Sciences, University of Messina, Messina, Italy. 6. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Divisions of Cardiology and Human Genetics, University of Cincinnati School of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Boston, Mass. 9. Mayo Clinic Division of Vascular Surgery, Rochester, Minn. 10. Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. 11. Department of Surgery, University of California, Davis Medical Center, Sacramento, Calif. 12. Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston, Houston, Tex. 13. Department of Vascular Medicine, University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. Department of Cardiology, University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 15. Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco, San Francisco, Calif. 16. Division of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH. 17. Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Tex. 18. Division of Vascular Surgery, University of California Los Angeles, Los Angeles, Calif.
Abstract
OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
OBJECTIVE:Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.
Authors: Angela F Brady; Serwet Demirdas; Sylvie Fournel-Gigleux; Neeti Ghali; Cecilia Giunta; Ines Kapferer-Seebacher; Tomoki Kosho; Roberto Mendoza-Londono; Michael F Pope; Marianne Rohrbach; Tim Van Damme; Anthony Vandersteen; Caroline van Mourik; Nicol Voermans; Johannes Zschocke; Fransiska Malfait Journal: Am J Med Genet C Semin Med Genet Date: 2017-03 Impact factor: 3.908
Authors: U Schwarze; W I Schievink; E Petty; M R Jaff; D Babovic-Vuksanovic; K J Cherry; M Pepin; P H Byers Journal: Am J Hum Genet Date: 2001-09-27 Impact factor: 11.025
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Authors: F M Pope; G R Martin; J R Lichtenstein; R Penttinen; B Gerson; D W Rowe; V A McKusick Journal: Proc Natl Acad Sci U S A Date: 1975-04 Impact factor: 11.205
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