TY - JOUR
T1 - Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome
T2 - A Ras/MAPK pathway syndrome
AU - Lin, Angela E.
AU - Alexander, Mark E.
AU - Colan, Steven D.
AU - Kerr, Bronwyn
AU - Rauen, Katherine A.
AU - Noonan, Jacqueline
AU - Baffa, Jeanne
AU - Hopkins, Elizabeth
AU - Sol-Church, Katia
AU - Limongelli, Giuseppe
AU - Digilio, Maria Christina
AU - Marino, Bruno
AU - Innes, A. Micheil
AU - Aoki, Yoko
AU - Silberbach, Michael
AU - Delrue, Marie Ange
AU - White, Susan M.
AU - Hamilton, Robert M.
AU - O'Connor, William
AU - Grossfeld, Paul D.
AU - Smoot, Leslie B.
AU - Padera, Robert F.
AU - Gripp, Karen W.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Aortic dilation
KW - Arrhythmias
KW - Cardiovascular malformation
KW - Chaotic atrial rhythm
KW - Congenital heart defect
KW - Ectopic atrial tachycardia
KW - HRAS
KW - Hypertrophic cardiomyopathy
KW - Multifocal atrial tachycardia
KW - Noonan-spectrum syndromes
KW - RASopathy
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U2 - 10.1002/ajmg.a.33857
DO - 10.1002/ajmg.a.33857
M3 - Article
C2 - 21344638
AN - SCOPUS:79952017072
SN - 1552-4825
VL - 155
SP - 486
EP - 507
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 3
ER -