Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

Giulio Calcagni, Giuseppe Limongelli, Angelo D'Ambrosio, Francesco Gesualdo, M. Cristina Digilio, Anwar Baban, Sonia B. Albanese, Paolo Versacci, Enrica De Luca, Giovanni B. Ferrero, Giuseppina Baldassarre, Gabriella Agnoletti, Elena Banaudi, Jan Marek, Juan P. Kaski, Giulia Tuo, M. Giovanna Russo, Giuseppe Pacileo, Ornella Milanesi, Daniela MessinaMaurizio Marasini, Francesca Cairello, Roberto Formigari, Maurizio Brighenti, Bruno Dallapiccola, Marco Tartaglia, Bruno Marino

Research output: Contribution to journalArticle

Abstract

Background RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. Methods A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. Results Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20 years, respectively. Restricted estimated mean survival at 20 years follow-up was 19.6 years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age < 2 years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. Conclusions The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.

Original languageEnglish
Pages (from-to)92-98
Number of pages7
JournalInternational Journal of Cardiology
Volume245
DOIs
Publication statusPublished - Oct 15 2017

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Keywords

  • Children
  • Congenital heart defect
  • Hypertrophic cardiomyopathy
  • Noonan syndrome
  • RASopathies

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Calcagni, G., Limongelli, G., D'Ambrosio, A., Gesualdo, F., Digilio, M. C., Baban, A., Albanese, S. B., Versacci, P., De Luca, E., Ferrero, G. B., Baldassarre, G., Agnoletti, G., Banaudi, E., Marek, J., Kaski, J. P., Tuo, G., Russo, M. G., Pacileo, G., Milanesi, O., ... Marino, B. (2017). Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. International Journal of Cardiology, 245, 92-98. https://doi.org/10.1016/j.ijcard.2017.07.068