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

Giuseppe Limongelli, Angelo D'Ambrosio, 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 Messina, Maurizio Marasini, Francesca Cairello, Roberto FormigariMaurizio 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 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years 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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Morbidity
Mortality
Mutation
Survival
Hypertrophic Cardiomyopathy
Noonan Syndrome
Pulmonary Valve Stenosis
Sudden Death
Transducers
Genes
Observational Studies
Young Adult
Retrospective Studies
Regression Analysis

Keywords

  • Journal Article

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Limongelli, G., D'Ambrosio, A., Baban, A., Albanese, S. B., Versacci, P., De Luca, E., ... 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

Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. / Limongelli, Giuseppe; D'Ambrosio, Angelo; Baban, Anwar; Albanese, Sonia B; Versacci, Paolo; De Luca, Enrica; Ferrero, Giovanni B; Baldassarre, Giuseppina; Agnoletti, Gabriella; Banaudi, Elena; Marek, Jan; Kaski, Juan P; Tuo, Giulia; Russo, M Giovanna; Pacileo, Giuseppe; Milanesi, Ornella; Messina, Daniela; Marasini, Maurizio; Cairello, Francesca; Formigari, Roberto; Brighenti, Maurizio; Dallapiccola, Bruno; Tartaglia, Marco; Marino, Bruno.

In: International Journal of Cardiology, Vol. 245, 15.10.2017, p. 92-98.

Research output: Contribution to journalArticle

Limongelli, G, D'Ambrosio, A, Baban, A, Albanese, SB, Versacci, P, De Luca, E, Ferrero, GB, Baldassarre, G, Agnoletti, G, Banaudi, E, Marek, J, Kaski, JP, Tuo, G, Russo, MG, Pacileo, G, Milanesi, O, Messina, D, Marasini, M, Cairello, F, Formigari, R, Brighenti, M, Dallapiccola, B, Tartaglia, M & Marino, B 2017, 'Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results', International Journal of Cardiology, vol. 245, pp. 92-98. https://doi.org/10.1016/j.ijcard.2017.07.068
Limongelli, Giuseppe ; D'Ambrosio, Angelo ; Baban, Anwar ; Albanese, Sonia B ; Versacci, Paolo ; De Luca, Enrica ; Ferrero, Giovanni B ; Baldassarre, Giuseppina ; Agnoletti, Gabriella ; Banaudi, Elena ; Marek, Jan ; Kaski, Juan P ; Tuo, Giulia ; Russo, M Giovanna ; Pacileo, Giuseppe ; Milanesi, Ornella ; Messina, Daniela ; Marasini, Maurizio ; Cairello, Francesca ; Formigari, Roberto ; Brighenti, Maurizio ; Dallapiccola, Bruno ; Tartaglia, Marco ; Marino, Bruno. / Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results. In: International Journal of Cardiology. 2017 ; Vol. 245. pp. 92-98.
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T1 - Cardiac defects, morbidity and mortality in patients affected by RASopathies. CARNET study results

AU - Limongelli, Giuseppe

AU - D'Ambrosio, Angelo

AU - Baban, Anwar

AU - Albanese, Sonia B

AU - Versacci, Paolo

AU - De Luca, Enrica

AU - Ferrero, Giovanni B

AU - Baldassarre, Giuseppina

AU - Agnoletti, Gabriella

AU - Banaudi, Elena

AU - Marek, Jan

AU - Kaski, Juan P

AU - Tuo, Giulia

AU - Russo, M Giovanna

AU - Pacileo, Giuseppe

AU - Milanesi, Ornella

AU - Messina, Daniela

AU - Marasini, Maurizio

AU - Cairello, Francesca

AU - Formigari, Roberto

AU - Brighenti, Maurizio

AU - Dallapiccola, Bruno

AU - Tartaglia, Marco

AU - Marino, Bruno

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/10/15

Y1 - 2017/10/15

N2 - 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 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years 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.

AB - 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 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years 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.

KW - Journal Article

U2 - 10.1016/j.ijcard.2017.07.068

DO - 10.1016/j.ijcard.2017.07.068

M3 - Article

C2 - 28768581

VL - 245

SP - 92

EP - 98

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

ER -