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  • Aortic and arterial manifestations and clinical features in TGFB3-related heritable thoracic aortic disease: results from the Montalcino Aortic Consortium

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Phenotypes
Original research
Aortic and arterial manifestations and clinical features in TGFB3-related heritable thoracic aortic disease: results from the Montalcino Aortic Consortium
  1. Michelle Su-Anne Lim1,
  2. Dong-Chuan Guo2,
  3. Walter Velasco Torrez2,
  4. Andrew Lai1,
  5. Jonathan Schweber3,
  6. Nikita Garg4,
  7. Julie Fleischer4,
  8. Catherine Boileau5,
  9. Julie De Backer6,
  10. Artur Evangelista7,
  11. Guillaume Jondeau8,
  12. Carine Le Goff9,
  13. Olivier Milleron10,
  14. Laura Muiño-Mosquera11,
  15. Shaine Morris12,
  16. Maral Ouzounian13,
  17. Elena Cervi14,
  18. Julien Marcadier15,
  19. Anthony Caffarelli16,
  20. Sherene Shalhub17,
  21. Reed Pyeritz18,
  22. Angela Yetman19,
  23. Dianna Milewicz20,
  24. Alan C Braverman1
  1. 1Cardiovascular Division, Department of Medicine, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
  2. 2Department of Internal Medicine, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA
  3. 3The Hospital for Sick Children, Toronto, Ontario, Canada
  4. 4Department of Paediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, USA
  5. 5Département de Génétique, Universite Paris Cite, Paris, France
  6. 6Division of Cardiology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  7. 7Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  8. 8CRMR Marfan et apparentés, APHP, Hopital Bichat, Université Paris Cité, Paris, France
  9. 9Laboratory of Vascular Translational Science, Bichat Hospital, Université Paris Cité and Université Sorbonne Paris Nord, Paris, France
  10. 10Centre de Référence Maladies Rares Syndrome de Marfan et apparentés, Hôpital Bichat, Paris, France
  11. 11Department of Paediatrics, Division of Paediatric Cardiology and Center for Medical Genetics, Universitair Ziekenhuis Gent, Ghent, Belgium
  12. 12Division of Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
  13. 13Cardiothoracic Surgery, University of Toronto, Toronto, Ontario, Canada
  14. 1414Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
  15. 15Department of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada
  16. 16Department of Cardiac Surgery, Hoag Memorial Presbyterian Hospital, Newport Beach, California, USA
  17. 17Division of Vascular Surgery, University of Oregon Health Sciences, Portland, Oregon, USA
  18. 18University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  19. 19Department of Paediatrics, Division of Cardiology, University of Nebraska, Children's Hospital, Omaha, Nebraska, USA
  20. 20Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
  1. Correspondence to Professor Alan C Braverman; abraverm{at}wustl.edu

Abstract

Background Pathogenic variants in TGFB3 may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in TGFB3-related disease but there are limited outcomes data on vascular events in this condition.

Methods Clinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) TGFB3 variants enrolled in the Montalcino Aortic Consortium registry were reviewed.

Results 34 individuals (56% male, median age 42 years, IQR 17–49, range 3–74 years) with P/LP TGFB3 variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).

Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32–69 years) with aortic root dilation (41–49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred.

Conclusions TGFB3-related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with TGFB3-related HTAD compared with HTAD due to TGFBR1 or TGFBR2 variants.

  • Aneurysm
  • Cardiovascular Diseases
  • Phenotype
  • Vascular Diseases

Data availability statement

No data are available.

https://doi.org/10.1136/jmg-2024-110251

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    Data availability statement

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    Footnotes

    • DM and ACB are joint senior authors.

    • Contributors MS-AL, DM and ACB planned the work, and drafted the manuscript. DG, WVT and DM performed variant curation and verification. All authors contributed to the acquisition, analysis and interpretation of the data, and revision of the manuscript, and gave final approval of the version to be published. All authors agree to be accountable for all aspects of the work. DM and ACB (senior coauthors) are responsible for the overall content as guarantors.

    • Funding MS-AL and AL were supported by the Neidorff Aortopathy and Master Clinician in Cardiology Fellowship Program at Washington University in St. Louis School of Medicine. ACB’s research is supported by the Pam and Ron Rubin Fund and the Neidorff Aortopathy and Master Clinician Fellowship Program at Washington University in St. Louis School of Medicine. These studies were funded by the NIH R01HL109942, Genetic Aortic Disorders Association Canada and the Temerty Family Foundation to DM.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.