Cardiac involvement in classical or hypermobile Ehlers–Danlos syndrome is uncommon

Abstract

Purpose

Cardiac–valvular and vascular Ehlers–Danlos syndrome (EDS) have significant cardiovascular issues. The prevalence and significance of such abnormalities in classical (cEDS) or hypermobile EDS (hEDS) remain unclear. We report the prevalence of cardiac abnormalities in patients with cEDS and hEDS.

Methods

We identified 532 pediatric patients with potential EDS evaluated at our institution from January 2014 through April 2019 by retrospective chart review. Ninety-five patients (12 cEDS and 83 hEDS patients) met 2017 EDS diagnostic criteria and had an echocardiogram. One patient was excluded due to complex congenital heart disease, and two were excluded due to lack of images. We reviewed echocardiograms for all structural abnormalities.

Results

Of these 95 patients, 1 had mild aortic root dilation, and 1 had mild ascending aorta dilation in the setting of a bicuspid aortic valve. Eleven patients (11.6%) had a cardiac valve abnormality, all of which were trivial to mild. None of the patients required cardiac intervention.

Conclusion

Our results demonstrate that aortic dilation and valvular anomalies are uncommon in cEDS or hEDS patients. Given the lack of evidence, we do not recommend echocardiographic evaluation and surveillance in patients with cEDS and hEDS in the absence of clinical findings or positive family history.

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Fig. 1
Fig. 2: Z-score calculations for aortic dimensions for patients with classical and hypermobile Ehlers–Danlos syndromes (cEDS/hEDS).
Fig. 3: Lack of association of patient age and aortic Z-scores.

References

  1. 1.

    Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.

    Article  Google Scholar 

  2. 2.

    McKusick VA. The Ehlers–Danlos syndrome. Heritable disorders of connective tissue. 4th ed. St. Louis: CV Mosby; 1972. p. 292–371.

  3. 3.

    Beighton P, de Paepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet. 1988;29:581–594.

    CAS  Article  Google Scholar 

  4. 4.

    Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers–Danlos National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am J Med Genet. 1998;77:31–37.

    CAS  Article  Google Scholar 

  5. 5.

    Cabeen WR Jr, Reza MJ, Kovick RB, Stern MS. Mitral valve prolapse and conduction defects in Ehlers–Danlos syndrome. Arch Intern Med. 1977;137:1227–1231.

    Article  Google Scholar 

  6. 6.

    Leier CV, Call TD, Fulkerson PK, Wooley CF. The spectrum of cardiac defects in the Ehlers–Danlos syndrome, types I and III. Ann Intern Med. 1980;92 (2 Pt 1):171–178.

    CAS  Article  Google Scholar 

  7. 7.

    Dolan AL, Mishra MB, Chambers JB, Grahame R. Clinical and echocardiographic survey of the Ehlers–Danlos syndrome. Br J Rheumatol. 1997;36:459–462.

    CAS  Article  Google Scholar 

  8. 8.

    McDonnell NB, Gorman BL, Mandel KW, et al. Echocardiographic findings in classical and hypermobile Ehlers–Danlos syndromes. Am J Med Genet A. 2006;140:129–136.

    Article  Google Scholar 

  9. 9.

    Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers–Danlos syndrome. J Pediatr. 2011;158:826–830.e1.

    Article  Google Scholar 

  10. 10.

    Wenstrup RJ, Meyer RA, Lyle JS, et al. Prevalence of aortic root dilation in the Ehlers–Danlos syndrome. Genet Med. 2002;4:112–117.

    Article  Google Scholar 

  11. 11.

    Lopez L, Colan SD, Frommelt PC, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr. 2010;23:465–495.

    Article  Google Scholar 

  12. 12.

    Page Children’s Hospital Boston. Z-score calculator. https://zscore.chboston.org. Accessed 27 August 2019.

  13. 13.

    Ward RM, Marsh JM, Gossett JM, Rettiganti MR, Collins RT 2nd. Impact of bicuspid aortic valve morphology on aortic valve disease and aortic dilation in pediatric patients. Pediatr Cardiol. 2018;39:509–517.

    Article  Google Scholar 

  14. 14.

    Tiller GE, Cassidy SB, Wensel C, Wenstrup RJ. Aortic root dilatation in Ehlers–Danlos syndrome types I, II and III. A report of five cases. Clin Genet. 1998;53:460–465.

    CAS  Article  Google Scholar 

  15. 15.

    Ritter A, Atzinger C, Hays B, et al. Natural history of aortic root dilation through young adulthood in a hypermobile Ehlers–Danlos syndrome cohort. Am J Med Genet A. 2017;173:1467–1472.

    Article  Google Scholar 

  16. 16.

    Asher SB, Chen R, Kallish S. Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers–Danlos syndrome and related disorders. Am J Med Genet A. 2018;176:1838–1844.

    Article  Google Scholar 

  17. 17.

    van Karnebeek CD, Naeff MS, Mulder BJ, Hennekam RC, Offringa M. Natural history of cardiovascular manifestations in Marfan syndrome. Arch Dis Child. 2001;84:129–137.

    Article  Google Scholar 

  18. 18.

    MacCarrick G, Black JH 3rd, Bowdin S, et al. Loeys–Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576–587.

    Article  Google Scholar 

  19. 19.

    Zarate YA, Lepard T, Sellars E, et al. Cardiovascular and genitourinary anomalies in patients with duplications within the Williams syndrome critical region: phenotypic expansion and review of the literature. Am J Med Genet A. 2014;164A:1998–2002.

    Article  Google Scholar 

  20. 20.

    Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965–1976.

    CAS  Article  Google Scholar 

  21. 21.

    Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–798.

    CAS  Article  Google Scholar 

  22. 22.

    Yamada K, Watanabe A, Takeshita H, et al. Measurement of serum Tenascin-X in joint hypermobility syndrome patients. Biol Pharm Bull. 2019;42:1596–1599.

    Article  Google Scholar 

  23. 23.

    Petersen JW, Douglas JY. Tenascin-X, collagen, and Ehlers–Danlos syndrome: tenascin-X gene defects can protect against adverse cardiovascular events. Med Hypotheses. 2013;81:443–447.

    CAS  Article  Google Scholar 

  24. 24.

    Rauser-Foltz KK, Starr LJ, Yetman AT. Utilization of echocardiography in Ehlers–Danlos syndrome. Congenit Heart Dis. 2019;14:864–867.

    Article  Google Scholar 

  25. 25.

    Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med. 1999;341:1–7.

    CAS  Article  Google Scholar 

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Acknowledgements

S.L.P. acknowledges funding from the National Heart, Lung, and Blood Institute (K08HL148553).

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Correspondence to Sharon L. Paige MD, PhD.

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Paige, S.L., Lechich, K.M., Tierney, E.S.S. et al. Cardiac involvement in classical or hypermobile Ehlers–Danlos syndrome is uncommon. Genet Med (2020). https://doi.org/10.1038/s41436-020-0856-8

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Keywords

  • Ehlers–Danlos syndrome
  • connective tissue disorders
  • aortopathy
  • aortic dilation
  • echocardiography