title: Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.
abstract: 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.
authors.affiliation: Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA. lin.angela@mgh.harvard.edu
authors.forename: Angela E
authors.initials: AE
authors.lastname: Lin
authors.forename: Mark E
authors.initials: ME
authors.lastname: Alexander
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Noonan
authors.forename: Jeanne
authors.initials: J
authors.lastname: Baffa
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hopkins
authors.forename: Katia
authors.initials: K
authors.lastname: Sol-Church
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Limongelli
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Michael
authors.initials: M
authors.lastname: Silberbach
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Delrue
authors.forename: Susan M
authors.initials: SM
authors.lastname: White
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hamilton
authors.forename: William
authors.initials: W
authors.lastname: O'Connor
authors.forename: Paul D
authors.initials: PD
authors.lastname: Grossfeld
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Smoot
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
mesh_terms: D000293:Adolescent; D000328:Adult; D018376:Cardiovascular Abnormalities / Q000150:complications* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000150:complications* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D011180:Postmortem Changes; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins