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

Calcagni, Giulio; Limongelli, Giuseppe; D’Ambrosio, A; Gesualdo, Francesco; Digilio, María Cristina; Baban, Anwar; Albanese, Sonia B.; Versacci, Paolo; Luca, Enrica De; Ferrero, Giovanni Battista; Baldassarre, Giuseppina; Agnoletti, Gabriella; Banaudi, Elena; Marek, Jan; Kaski, Juan Pablo; Tuo, Giulia; Russo, Maria Giovanna; Pacileo, Giuseppe; Milanesi, Ornella; Messina, D; Marasini, Maurizio; Cairello, Francesca; Formigari, Roberto; Brighenti, Maurizio; Dallapiccola, Bruno; Tartaglia, Marco; Marino, Bruno

doi:10.1016/j.ijcard.2017.07.068

Cited by 85 publications

(71 citation statements)

References 32 publications

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“…Studies suggest that there are higher risks associated with cardiac interventions for patients with NSD as well as higher rates of re-intervention. 10,52 Thus, being able to accurately ascertain individuals at-risk for NSD may be important prior to intervention. Furthermore, guidelines for referral would optimize genetics resource utilization including clinical evaluation and testing.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis

Anderson

Cnota

James

et al. 2018

Congenital Heart Disease

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Objective:To evaluate the prevalence of Noonan spectrum disorders (NSD) in a pediatric population with valvar pulmonary stenosis (vPS) and identify the clinical characteristics that differentiate those with NSD from those without NSD.Design: A retrospective chart review of 204 patients diagnosed with vPS between 9/1/2012 and 12/1/2016 at a pediatric medical center was performed. The quantitative features of vPS, genetic diagnosis information, and phenotypic characteristics of Noonan syndrome were collected. Chi-square test, Fisher's exact test, t test, Wilcoxon rank-sum test, and ANOVA were used for comparisons among the groups.Logistic regression was used to test for the association between the clinical characteristics and the presence of NSD.Results: Syndromic diagnoses were made in 10% of the children with vPS, with NSD accounting for 6%. Hypertrophic cardiomyopathy (P < .0001), short stature (P < .0001), developmental delay (P < .0001), ophthalmological abnormalities (P < .0001), pectus carinatum/excavatum (P = .01), neurological abnormalities (P = .022), and aortic stenosis (P = .031) were present more often in individuals with NSD compared to nonsyndromic vPS. A logistic regression analysis showed a 4.8-fold increase in odds for NSD for each additional characteristic (P < .0001). Conclusions:At least 6% of the children with vPS have an underlying NSD. Individuals with vPS and NSD were significantly more likely to have additional features known to be associated with NSD than those with vPS without NSD. We conclude that vPS in the presence of one or more significant characteristics should prompt referral for genetic evaluation as a guide to ascertain patients at risk for NSD while optimizing the use of clinical genetics evaluation and potential genetic testing. K E Y W O R D Scongenital heart disease, pulmonary valve dysplasia, rasopathy | 265 ANDERSON et al.

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Section: Introductionmentioning

confidence: 99%

Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis

Anderson

Cnota

James

et al. 2018

Congenital Heart Disease

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“…In the Pediatric Cardiomyopathy Registry study, three patients with NS and HCM were listed in the follow‐up period, but none survived to transplant . Calcagani et al reported a 7‐year‐old patient with NS who underwent heart transplantation, and died of rejection 8 months after transplantation. Al‐Rahawan et al reported a patient with CFC syndrome who underwent heart transplantation at 8 months of age for HCM with heart failure and outflow obstruction.…”

Section: Discussionmentioning

confidence: 99%

“…HCM is known to be more prevalent among individuals with RAF1‐ , RIT1‐ , HRAS‐, and NSML‐associated PTPN11 mutations, with prevalence as high as 80% in some genotypes . While HCM is relatively rare in children under 1 year of age, HCM related to NS most often presents in the first year of life, being the leading genetic cause of HCM in this age group, and a leading cause of morbidity and mortality among infants and children with NS . Children with NS and HCM also have a less favorable outcome when compared with age‐matched children with idiopathic or familial/sarcomeric forms of HCM, with higher mortality (15% at 3 years compared with 11% in isolated HCM), and greater likelihood of heart failure symptoms at presentation .…”

Section: Introductionmentioning

confidence: 99%

“…6 While HCM is relatively rare in children under 1 year of age, HCM related to NS most often presents in the first year of life, being the leading genetic cause of HCM in this age group, and a leading cause of morbidity and mortality among infants and children with NS. [7][8][9] Children with NS and HCM also have a less favorable outcome when compared with age-matched children with idiopathic or familial/sarcomeric forms of HCM, with higher mortality (15% at 3 years compared with 11% in isolated HCM), and greater likelihood of heart failure symptoms at presentation. 7,10 Among children clinically diagnosed with NS who also have HCM, half have a coexisting CHD which, along with arrhythmias, may factor into their higher mortality rate and risk for sudden death.…”

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confidence: 99%

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Cardiac transplantation in children with Noonan syndrome

McCallen

Ameduri

Denfield

et al. 2019

Pediatric Transplantation

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NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS‐specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post‐discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.

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“…It can be related to environmental, infectious and genetic etiologies (Ware, ). CMPs in NS are associated with significant morbidity and mortality, representing a frequent cause of heart failure and mortality, particularly in children and young adults (Calcagni et al, ). Previous reports state that mortality in NS patients is relatively low, but mainly related to severity of cardiac involvement.…”

Section: Introductionmentioning

confidence: 99%

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Baban

Olivini

Lepri

et al. 2019

American J of Med Genetics Pt A

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Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs. K E Y W O R D Scardiomyopathy, RASopathies, SOS1

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

Cited by 85 publications

References 32 publications

Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis

Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis

Cardiac transplantation in children with Noonan syndrome

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

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