How to Cite this Article: Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, Baffa J, Hopkins E, Sol-Church K, Limongelli G, Digilio MC, Marino B, Innes AM, Aoki Y, Silberbach M, Delrue M-A, White SM, Hamilton RM, O'Connor W, Grossfeld PD, Smoot LB, Padera RF, Gripp KW. 2011. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome. Am J Med Genet Part A 155: 486–507.
Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome†
Article first published online: 22 FEB 2011
Copyright © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 155, Issue 3, pages 486–507, March 2011
How to Cite
Lin, A. E., Alexander, M. E., Colan, S. D., Kerr, B., Rauen, K. A., Noonan, J., Baffa, J., Hopkins, E., Sol-Church, K., Limongelli, G., Digilio, M. C., Marino, B., Innes, A. M., Aoki, Y., Silberbach, M., Delrue, M.-A., White, S. M., Hamilton, R. M., O'Connor, W., Grossfeld, P. D., Smoot, L. B., Padera, R. F. and Gripp, K. W. (2011), Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome. Am. J. Med. Genet., 155: 486–507. doi: 10.1002/ajmg.a.33857
- Issue published online: 24 FEB 2011
- Article first published online: 22 FEB 2011
- Manuscript Accepted: 26 NOV 2010
- Manuscript Received: 4 AUG 2010
- aortic dilation;
- cardiovascular malformation;
- chaotic atrial rhythm;
- congenital heart defect;
- ectopic atrial tachycardia;
- hypertrophic cardiomyopathy;
- multifocal atrial tachycardia;
- Noonan-spectrum syndromes;
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. © 2011 Wiley-Liss, Inc.