Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Angela E. Lin, Mark E. Alexander, Steven D. Colan, Bronwyn Kerr, Katherine A. Rauen, Jacqueline Noonan, Jeanne Baffa, Elizabeth Hopkins, Katia Sol-Church, Giuseppe Limongelli, Maria Christina Digilio, Bruno Marino, A. Micheil Innes, Yoko Aoki, Michael Silberbach, Marie Ange Delrue, Susan M. White, Robert M. Hamilton, William O'Connor, Paul D. GrossfeldLeslie B. Smoot, Robert F. Padera, Karen W. Gripp

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated.

Original languageEnglish (US)
Pages (from-to)486-507
Number of pages22
JournalAmerican Journal of Medical Genetics, Part A
Issue number3
StatePublished - Mar 2011


  • Aortic dilation
  • Arrhythmias
  • Cardiovascular malformation
  • Chaotic atrial rhythm
  • Congenital heart defect
  • Ectopic atrial tachycardia
  • HRAS
  • Hypertrophic cardiomyopathy
  • Multifocal atrial tachycardia
  • Noonan-spectrum syndromes
  • RASopathy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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