Clinical, Pathological, and Molecular Analyses of
Cardiovascular Abnormalities in Costello Syndrome:
A Ras/MAPK Pathway Syndrome
Angela E. Lin,1* Mark E. Alexander,2Steven D. Colan,2Bronwyn Kerr,3Katherine A. Rauen,4,5
Jacqueline Noonan,6Jeanne Baffa,7Elizabeth Hopkins,8Katia Sol-Church,9Giuseppe Limongelli,10
Maria Christina Digilio,11Bruno Marino,12A. Micheil Innes,13Yoko Aoki,14Michael Silberbach,15
Leslie B. Smoot,2Robert F. Padera,21and Karen W. Gripp8
1Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts
2Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts
3Genetic Medicine, Academic Health Science Centre, Central Manchester Foundation Trust Manchester, UK
4Comprehensive Cancer Center, San Francisco, California
5Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California
6Department of Pediatrics, University of Kentucky Medical Center, Lexington, Kentucky
7Nemours Cardiac Center, Wilmington, Delaware
8Division of Medical Genetics, Wilmington, Delaware
9Department of Biomedical Research, A.I. duPont Hospital for Children, Wilmington, Delaware
10Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy
11Medical Genetics, Bambino Gesu ` Pediatric Hospital, Rome, Italy
12Department of Pediatrics, Pediatric Cardiology, La Sapienza University, Rome, Italy
13Department of Medical Genetics, University of Calgary, Calgary, Canada
14Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
15Department of Pediatrics, Division of Cardiology, Doernbecher Children’s Hospital, Portland, Oregon
16Service de G? en? etique M? edicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
17Genetic Health Services Victoria, Royal Children’s Hospital, Victoria, Australia
18Division of Cardiology, Hospital for Sick Children, Toronto, Canada
19Department of Pathology, University of Kentucky Medical Center, Lexington, Kentucky
20Department of Pediatrics, University of California, San Diego, California
21Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
Received 4 August 2010; Accepted 26 November 2010
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
mutation was p.G12S. A congenital heart defect (CHD) was
pulmonary stenosis. Hypertrophic cardiomyopathy (HCM),
typically subaortic septal hypertrophy, was noted in 37 (61%),
abnormalitiesare importantfeatures of
Angela E. Lin, M.D., Genetics Unit, 185 Cambridge St., Simches 2222,
MassGeneral Hospital for Children, Boston, MA 02114.
Published online 22 February 2011 in Wiley Online Library
? 2011 Wiley-Liss, Inc.
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 tachy-
cardia 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 arrhyth-
mia, but is generally self-limited in the remaining three-fourths
development of severe HCM in infants with Costello syndrome,
and the need for cardiovascular surveillance into adulthood as
Key words: aortic dilation; arrhythmias; cardiovascular malfor-
al tachycardia; Noonan-spectrum syndromes; RASopathy
Costello syndrome (MIM #218040) is a rare multiple anomaly
syndrome [Gripp and Lin, 2009], and beyond infancy, can be
differentiated from phenotypically similar Ras/MAPK pathway
syndromes (‘‘RASopathies’’) [Rauen et al., 2010], that is, Cardio-
(#163950). Other RASopathies which have similar pathogenetic
Noonan syndrome with multiple lentigines (formerly known as
LEOPARD syndrome) (#151100, #611554), capillary malformation-
arteriovenous malformation syndrome (#139150), or neurofibro-
2008; Tidyman and Rauen, 2008; Rauen et al., 2010]. Phenotypic
features of Costello syndrome include polyhydramnios, increased
birth weight, feeding problems, failure to thrive, short stature,
developmental delay, pleasant personality, characteristic facial
appearance, soft skin, papillomata, spatulate fingerpads, deep
palmar creases, joint and skin laxity, kyphoscoliosis, pectus, and
150 genotyped patients have been studied [reviews by Estep et al.,
2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007].
Consensusexpertopinionrecommendsthat Costellosyndrome be
defined solely by HRAS mutations [Kerr et al., 2008], which differs
from the molecular heterogeneity of CFC syndrome and Noonan
Cardiovascular abnormalities are important diagnostic and
management issues for most RASopathies, especially Costello
syndrome, and they have been reported in 60–75% of patients
prior to molecular diagnosis [Lin et al., 2002]. Congenital heart
defects (CHDs), cardiac hypertrophy, usually described as hyper-
trophic cardiomyopathy (HCM) and arrhythmia (especially
non-reentrant atrial tachycardia) were each found in approximately
one-thirdofCostello syndromepatients. Theknock-in G12V Hras
mouse model, though a rare mutation in Costello syndrome, does
[Schuhmacher et al., 2008; Chen et al., 2009].
To extend the delineation of the type, frequency, clinical course
and genotype–phenotype analysis of cardiovascular abnormalities
in Costello syndrome, we report data from a cohort in a clinical
molecular study combined with genotyped published cases. This
comprehensive description provides data for rational decision
making in a rare disease, including the mode and timing of
surveillance. Differentiation of the syndromes of the Ras/MAPK
pathway remains an important task for the clinician. Where
possible, data from this cohort of mutation-positive patients
with Costello syndrome will be compared with mutation-positive
patients with Noonan and CFC syndromes.
Clinical Molecular Study
We analyzed Costello syndrome patients with HRAS mutation
confirmation who were enrolled from July 1, 2003 to June 30,
2007 in an IRB-approved study with informed consent (A. I.
duPont Hospital for Children #2003-006, #2005-051, ‘‘study
patients’’). Patients with clinically diagnosed Costello syndrome
were identified at the 2003, 2005, and 2007 International
Costello Syndrome Meetings through the Costello Syndrome
Family Network and through individual physician referral. Basic
clinical information was obtained by self-report from the families
by a review of cardiac medical records. Most families were also
interviewed by the principal investigator (K.W.G.). Information
et al., 2010]. A few patients had been partially reported prior to
HRAS mutation confirmation [e.g., patient 6 in Dearlove and
How to Cite this Article:
Lin AE, Alexander ME, Colan SD, Kerr B,
Church K,LimongelliG, Digilio MC,Marino
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.
LIN ET AL.
Siwik et al., 1998]. Mutation analysis was performed either as
for Children by an unaffiliated CLIA approved lab.
Literature Review Cohort
We reviewed previously reported patients with adequate clinical
and molecular information with Costello syndrome (HRAS)
[Kerr et al., 2008], and other RASopathies, that is, Noonan
syndrome (PTPN11, SOS1, RAF1), Noonan syndrome with
multiple lentigines syndrome (PTPN11), CFC syndrome (BRAF
mutation only, because of larger patient numbers than MEK1/2),
KRAS mutations, and neurofibromatosis type 1 (NF1). We
focused on large reviewsthat included tables with specific subjects,
cardiac history.Duplicative reports were merged. In theabsence of
a single review of NF1 patients with molecular confirmation
clinically diagnosed with NIH consensus criteria [Lin et al., 2000],
NF1 mutation [Baralle et al., 2003; De Luca et al., 2005].
Diagnosis and Definitions
Patients with Costello syndrome had been managed by their
personal pediatric or adult cardiologist. The study diagnosis
was based on the verbatim description submitted by the parent,
compared to diagnostic tests, cardiology consults, catheterization
procedures (especially interventional and electrophysiologic, EP),
their cardiac symptoms by the parent, often after discussion with
the cardiologist, geneticist and/or senior authors.
Congenital heart defect. A CHD was defined as a structural
defect of the heart and major aortic branches. Cardiac findings
such those associated with prematurity or neonatal patent
foramen ovale, patent ductus arteriosus, or physiologic peripheral
semilunar (usually pulmonary) valve obstruction was based on
the stated diagnosis of the referring cardiologist, categorizing
the peak ejection gradient as mild (<35–40mmHg), moderate
(40–60mmHg), or severe (>60mmHg) [Prieto and Latson,
2008]. We used maximum instantaneous gradient (MIG) from
echocardiography. Attempts were made to classify pulmonary
stenosis by specific location (valvar, subvalvar); ‘‘not specified’’
was presumed to be valvar.
Hypertrophic cardiomyopathy. Hypertrophic cardiomyopa-
thy (HCM) included unexplained (primary) cardiac hypertrophy
[Colan, 2007]. The pattern (distribution), severity of left ventricu-
lar hypertrophy and/or outflow obstruction, and change over time
was based on the verbatim description by the cardiologist or
on the echocardiogram report. Less frequently we used the
cardiologist’s description as paraphrased in the geneticist consul-
tation. Regardless of the term reported by each cardiologist (e.g.,
asymmetric septal hypertrophic, idiopathic subaortic stenosis, or
left ventricular hypertrophy), we used the term HCM with either
subaortic obstruction or mild interventricular septal thickening.
Concentric hypertrophy in the absence of left ventricular outflow
obstruction or hypertension was also noted, but was not the
primary pattern of hypertrophy.
Arrhythmia. Arrhythmias were classified in a standard fashion
using 12-lead surface electrocardiogram (ECG), and in some
cases using 24-hr-Holter monitoring. When only a rhythm strip
tracing from an intensive care unit was reported, a diagnosis was
not recorded. Ectopic atrial tachycardia (EAT) referred to a single
non-sinus atrial focus, whereas multifocal atrial tachycardia
(MAT), also known as chaotic atrial rhythm (CAR), consisted of
the preferred term, and ‘‘serious tachycardia’’ referred to any
sustained atrial tachycardia. A small number of patients had EP
mapping to confirm the ECG diagnoses.
Vascular abnormalities. Data were collected about aortic
dilation and coronary artery anomalies excluding peripheral
arterial anomalies. Systemic and pulmonary hypertension were
noted, but inconsistently reported, thus, they were excluded from
the tally of ‘‘vascular’’ abnormalities.
Pathological review. We conducted an extensive review of
autopsy and biopsy findings in Costello syndrome among
both the study participants and previously reported patients, and
compared these to other RASopathies. Gross and microscopic
data and the presence or absence of myocardial fiber disarray was
Cardiac analysis. Patients were reviewed (by A.E.L.) to
determine the dominant cardiac abnormality, rather than listing
component defects. For example, a patient with moderate valvar
pulmonary stenosis, trivial peripheral pulmonary stenosis, patent
foramen ovale, and‘‘rare’’ premature atrial contractionsonHolter
previous reports have used two methods to determine occurrence,
the frequency of an abnormality was reported as the number of
patients (X) and its proportion to all patients (X%), as well as a
(Y, Y%). Genotype–phenotype analyses focused on mortality and
specific cardiac phenotypes which were common, serious, and/or
unusual. A severity analysis was also performed based on
whether the HCM or valve obstruction was reported as severe;
whether tachycardia was described as persistent, malignant,
requiring treatment past age 1 year, or generally viewed as difficult
to treat; or if a surgical or interventional catheterization procedure
We studied 61 Costello syndrome patients confirmed by HRAS
mutation, 58 patients enrolled in the A.I duPont Hospital for
Children clinical molecular longitudinal study and three deceased
were supplemented with medical records and/or published data.
The lack of records in seven families (three outside the United
States) was due to lack of address or response from family or
physician-of-record. Most (80%) patients were white, and there
488 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(mean age at diagnosis 4.2 years). The current age of this cohort
spanned infancy to the fifth decade, and 13 (21%) study patients
limitation of activity, one had moderate cardiac symptoms and
exercise limitation and the status of two patients is unknown (one
was seriously ill from rhabdomyosarcoma). The overall frequency
of neoplasia (20%) and the most common tumor, rhabdomyosar-
coma (12% of all patients, 58% of those with neoplasia), were
similar to the 15% overall risk for solid tumors which has been
estimated [Gripp and Lin, 2009]. The location of the rhabdomyo-
(1) was typical for the predominance of extra-craniofacial rhabdo-
myosarcoma in Costello syndrome, as was the embryonal cell type
[Gripp et al., 2002]. Neoplasia was not associated with the occur-
basic data were obtained (Table I). Diagnostic testing confirming
whom received it for at least 2 years.
Six (10% of total) deaths in this study (Table II) included two
with sudden death. These occurred in a 51=2-year-old boy with the
common p.G12S mutation and HCM, thickened aortic and mitral
valves and marked myocardial fiber disarray [Supplemental Ap-
a 27-year-old male with severe HCM, non-sustained atrial and
ventricular ectopy and mild ascending aortic dilation (Table III).
Postmortem examination confirmed severe HCM (360g), and
showed myxomatous mitral and tricuspid valves, a fenestrated
thick aortic valve, mildly dilated ascending aorta (normal Sinus
of Valsalva), and a plaque of anterior systolic motion of the mitral
valve (Supplemental Appendix patient 2, Fig. 2). The atria did not
appear abnormal, and the conduction system was not sectioned.
Microscopically, there was myocardial fiber disarray, stenotic
intramyocardial arterioles, and moderate epicardial disease, that
is, premature coronary artery disease (40% narrowing of the right
in the prior year.
Among 85 previously reported patients, there were 17 (20%)
deaths (Table II). At least two were sudden deaths, including a
9-year-old girl with non-obstructive HCM, mild pulmonary
nation [Kerr et al., 2006], and a 3-year-old girl with HCM who
had recovered from resection of a ganglioneuroblastoma and died
during an episode of enterocolitis [Aoki et al., 2005, patient 62].
An additional death which is not listed on Table II since
molecular confirmation had not been obtained. This 47-year-old
man was the first patient reported by Costello [1971, 1977] and
when re-evaluated as an adult was being treated for hypertension
without CHD or HCM on echocardiogram [case 1, Costello, 1996;
in good health (details not available), and died suddenly at home.
His parents declined autopsy examination.
TABLE I. Clinical Features of 61 Patients With Costello Syndrome
Geneticist, either local, or study
Cardiologist, pediatric, or adult
Mixed (2 were African American/white)
Age at diagnosis
By age 1 year
Bladder cell carcinoma
Cancer plus HCM
(%, figures rounded)
1 month to 40 years
7 (1 with ganglioneuroblastoma) (12)
2 bladder cell carcinoma
1 pituitary adenoma
Do not know
Do not know
Do not know
Do not know
GH in 16 pts with HCM
Change in severity HCM
Do not know
GH, growth hormone; HCM, hypertrophic cardiomyopathy.
aComparable data for literature patients includes seven with rhabdomyosarcoma [Aoki et al.,
2005; Estep et al., 2006; Kerr et al., 2006], three with neuroblastoma [Aoki et al., 2005;
Zampino et al., 2007; van der Burgt et al., 2007], one with transitional cell carcinoma
[Estep et al., 2006], and two unspecified tumors [Zampino et al., 2006].
LIN ET AL.
TABLE II. Deaths Among 146 Costello Syndrome Patients: Causes and Associated Cardiovascular Abnormalities
Multiorgan system failure
I. This study (# pts)
a5.5 yrs, HCM, sudden death
2.5 yrs, RMS, embryonal
c1.5 mos, wide QRS
tachycardia (not MAT)
b27 yrs, HCM, aortic dilation,
c14 mos, HCM, MAT
c4 mos, HCM, EAT
II. Literature (# pts)
Aoki et al. ,
pt 37, 18 mos,
Estep et al. ,
Kerr et al. , pt. 7, 25 yrs,
Lo et al. ,
pt 2, 3 mos,
HCM, atrial fibrillation,
sepsis, renal failure
Aoki et al. ,
pt 62, 3 yrs,
HCM, resected ganglio-
neuroblastoma, sudden death
Kerr et al. ,
pt 5, 6 mos,
Lo et al. ,
pt 1, 3 mos,
ASD, HCM, PAT/MAT,
Kuniba et al. .
Kerr et al. ,
pt 11; 6 mos,
HCM, coronary artery
Kerr et al. , pt 10;
Lo et al. , pt 4, 2.5 yrs,
Kerr et al. ,
pt 28, (previously unreported data),
HCM, PACs, sudden death
Kerr et al. , pt 12,
PS, SVT, RMS
van der Burgt et al. ,
pt 1, 1 mo,
van der Burgt et al. ,
pt 2, 14 mos,
van der Burgt et al. ,
pt 3, 7 mos,
Lo et al. ,
pt 3, 3 mos,
HCM, atrial tachy, nos
Smith et al. .
PSV, HCM, MAT
Study and literature, total
ASD, atrial septal defect; EAT, ectopic atrial tachycardia; HCM, hypertrophic cardiomyopathy; MAT, multifocal atrial tachycardia (used as the preferred term, including chaotic atrial rhythm); mos, months; nos, not otherwise specified; PACs,
premature atrial contractions; PAT, paroxysmal atrial tachycardia; PSV, pulmonary stenosis, valvar; RMS, rhabdomyosarcoma; SVT, supraventricular tachycardia; tachy, tachycardia; VT, ventricular tachycardia; wks, weeks; yrs, years.
aLin et al.  and Hinek et al.  (patient 3).
bLin et al. [2008b] (patient 2).
cLin et al.  (patients 1–3).
490AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE III. Pathological Findings in Costello Syndrome (total 11 patients, 10 with HRAS mutations, 6 this study) and Other RASopathies (With Emphasis on Myocardium)
to 0.5 yr),
RV; IVS; LV
Appendix pt 2
27 yrs, M,
6, 18, 21
Severe intimal proliferation, medial
hypertrophy of intramyocardial arterioles.
Thick, myxomatous MV, TV, AV (prominent
fenestrations). Plaque of SAM of MV.
Moderate (40%) atherosclerosis RCA.
Remote subendocardial MI, posterior IVS
Appendix pt 6
11 yrs, F,
Appendix pt 35
14 yrs, M,
Improved after two
Appendix pt 40
[Hinek et al.,
2005, pt 3]
5 yrs, M,
Fragmented elastic fibers. Immunostaining
Appendix pt 43
6 yrs, M,
Appendix pt 59
HCM, BVH; CAR
1 yr, F,
6; 15; 9
Hinek et al.
, pt 1;
Estep et al.
et al. [2008b],
6.5 yrs, M,
7; NS; 15
Conduction system fibrosis at bundle of His
Aoki et al.
, pt 62
3 yrs, F,
Kerr et al.
, pt 11
0.5 Yr, F,
Coronary artery fibromuscular dysplasia,
van der Burgt
et al. , pt 1
3 weeks, M,
Small fiber myopathy, excess muscle
Tomita et al. 
1.5 yrs, F,
Burch et al. 
HCM, symmetric BVH
10 yrs, M,
IVS; LVFW, þþ
2 mos, F,
0.5 yrs, F,
LIN ET AL.
TABLE III. (Continued)
to 0.5 yr),
RV; IVS; LV
2 yrs, M,
0.5 yrs, M,
Noonan and O’Connor
0.5 yr, F,
10 yrs, M,
Intramyocardial coronary artery
Nishikawa et al.
17 yrs, M,
12 yrs, F,
Intramyocardial coronary artery
Skinker et al. 
20 yrs, F,
Abundant myocyte vacuolization
Ishikawa et al. 
HCM, ASH, ASD,
dysplastic PV, SVT
1 yr, F,
Fibromuscular dysplasia of
coronary arteries; intramyocardial coronary artery
Razzaque et al.
 (NS if pt 1
or pt 4)
NS if, pt 1 (17 yrs) or
pt 4 (3 wks)
Roberts et al.
 (2 pts)
2 yrs, F,
4 yrs: Death, SBE
4 valves dysplastic, 8mm ASD
Mild PS, HCM, grade
3 PVOD noted shortly
21 yrs, M,
Coronary artery intimal thickening, early
fibrosis ‘‘consistent with HCM’’
ASD, PS repaired in
20 yrs: SVT,
22 yrs, M,
ASD, atrial septal defect; ASH, asymmetric septal hypertrophy; AV, aortic valve; BVH, biventricular hypertrophy; CAR/CAT, chaotic atrial rhythm/tachycardia; CFC, cardiofaciocutaneous syndrome; CHF, congestive heart failure; EAT, ectopic
atrial tachycardia; Ebstein, Ebstein anomaly; HCM, hypertrophic cardiomyopathy; IVS, interventricular septum; JT, junctional tachycardia; LV, left ventricle; LVFW, left ventricular free wall; MI, myocardial infarcation; MV, mitral valve; NA, notavailable; NOS, not otherwise specified; PV, pulmonary valve; RCA, right coronary artery; RMS, rhabdomyosarcoma; RV, right ventricle; SBE, subacute bacterial endocarditis; SAM, systolic anterior motion; SVT, supraventricular tachycardia;
TV, tricuspid valve; VFib, ventricular fibrillation.
aPersonal communication from Dr. Alek Hinek, Hospital for Sick Children, Toronto.
492 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Overview of Costello Syndrome
Table IV lists the cardiovascular abnormalities in 61 study and
85 previously reported patients with Costello syndrome, and in
selected related RASopathies [references in footnote, details
in Supplemental Appendix]. Nearly all patients with Costello
syndrome in this study and the literature had at least one
any cardiovascular abnormality) of all Costello syndrome patients
had a CHD. In addition to pulmonary valve stenosis or dysplasia
in 12 (20% of total), anomalies of the other valves were seen in
10 (19% of total). There were four patients with isolated valve
without HCM (3), and3 with two or more valve anomaliessuch as
thick mitral/aortic valve and dysplasia of all 4 valves; mitral valve
prolapse/bicuspid aortic valve). Two patients had valve anomalies
associated with various minor CHDs including muscular ventric-
ular septal defect and thick aortic valve (1), and atrial septal
defect with bicuspid aortic valve (1). Septal defects were usually
type unspecified (3), isolated atrial septal defect (1), atrial septal
defect with pulmonary stenosis (2), and combinations (one
each with coarctation, ventricular septal defect, atrial septal
defect; membranous ventricular septal defect, transient polyvalvar
disease). There were no complex CHDs such as heterotaxy, single
ventricle, conotruncal or atrioventricular canal defects. The out-
mild (7/12, 58%). Additional levels of pulmonary obstruction
included 3 with supravalvar pulmonary stenosis, and one patient
with severe sub-pulmonary obstruction as a double-chambered
right ventricle in the setting of HCM and requiring two surgical
required surgical or balloon valvotomy for severe pulmonary
stenosis. Overall, atrial septal defects were uncommon and mild,
only one requiring surgical closure. Patient 48 required a mitral
valve replacement with a porcine valve at age 19 years, which was
avoided valve replacement with aggressive medical management.
Among previously reported patients, there were about half as
many reported CHDs (22% of total; 25% any cardiovascular
was decreased among all patients (8/85, 9%), but identical among
those with a cardiovascular abnormality (8/19, 42%), which may
not be assessed among the literature patients.
Hypertrophic cardiomyopathy. HCM was reported with simi-
lar frequency in this study cohort and previously reported patients
(61–68% of total, 71–76% any cardiovascular abnormality). We
did not consistently solicit a family history of HCM, but none was
reported. Most (23, 38% of total, 62% with HCM) patients had
subaortic septal hypertrophy (reported also as asymmetric
septal hypertrophy, idiopathic subaortic stenosis), with variable
obstruction. Other patterns included global or concentric left
ventricular hypertrophy (n¼14), mild interventricular septal
‘‘thickening’’ (n¼2), or unspecified or variable HCM (n¼4).
One patient had ‘‘biventricular’’ involvement of HCM with a
double-chambered right ventricle. There were no patients with
isolated apical HCM, dilated or noncompaction cardiomyopathy,
Of 37 HCM patients, the clinical course was chronically severe
or progressive in 14 (38%), stabilized in 11 (30%), regressed in
of 37 HCM patients (64% of the 14 with severe or progressive
The age of HCM diagnosis ranged from the rare neonatal
phenotype when it was severe [Hinek et al., 2005; Lo et al.,
2008] to the more common presentation in childhood. Prenatal
3-D ultrasonography who had ‘‘cardiac hypertrophy’’ postnatally
[Kuniba et al., 2009].
A comparison of the association of neoplasia and HCM was
not helpful due to the small number of patients with malignancies
(data not shown).
half of the study patients. Some form of atrial tachycardia was
reported in34(56% oftotal;65% anycardiovascularabnormality)
patients, which includes MAT, and EAT (15, 25% total; 44% of
those with arrhythmia), supraventricular/paroxysmal tachycardia
or junctional tachycardia (7, 11% of total; 24% with arrhythmia),
Late-onset atrial fibrillation with/without flutter occurring in 16-
Costello syndrome, though frequent in many forms of HCM.
Ventricular arrhythmia was limited to the 1.5 months old (patient
1) without HCM who died in the setting of wide QRS tachycardia.
eight patients (13% total, 24% with arrhythmia) the course was
chronically severe or worsened. Three patients had ablation pro-
cedures including two young children (patients 26 and 29) for
hemodynamically important and drug refractory tachycardia; one
induced heart block (Supplemental Appendix patient 36, Fig. 1).
No additional patients underwent an invasive EP study or had an
implantable cardioverter-defibrillator (ICD). Standard medical
therapies were effective in many.
Vascular abnormalities. Mild–moderate aortic root dilation
was documented in four study patients (7% of total; patients 2, 17,
33, 38) in which the maximal age and BSA-adjusted Z score was
3–7.8. In patient 2, the dilation involved the ascending aorta,
noted in one literature patient beginning at age 17 years [patient 4,
Estep et al., 2006] without bicuspid aortic valve, who had been
not available. There were no patients with aortic aneurysm or
LIN ET AL.
TABLE IV. Cardiovascular Abnormalities in Costello Syndrome RASopathies (number patients, %) and Related RASopathies: Type, Frequency, and Outcome
% any CV problem
PS valvar or
5/46, 31%14 only
% any CV problem
ASD2, ASD nos;
% any CV problem
% total CHD
% any CV problem
% total HCM
regressed (4 pts)
494AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE IV. (Continued)
171 pt with
% CV problem
% CV problem
1 (Pt. 4)2
% any CV problem
1 (Pt 32)3
% total pts;
% cardiac pts
ASD2, atrial septal defect, secundum type; ASD nos, atrial septal defect, not otherwise specified; ASH, asymmetric hypertrophy; AVSD, atrioventricular septal defect; CFC, cardiofaciocutaneous; BVH, biventricular hypertrophy; CHD, congenital heart
defect; CV, cardiovascular; HCM, hypertrophic cardiomyopathy; IVS, interventricular septum; LV(H), left ventricular (hypertrophy); LVNC, left ventricular noncompaction; MAT, multifocal atrial tachycardia; MV, mitral valve; NA, not available; NFNS,
Neurofibromatosis-Noonan syndrome; NOS, not otherwise specified; NS, Noonan syndrome; PAC, premature atrial contraction; PAS, pulmonary artery stenosis; PNC, premature nodal contraction; PS(V), pulmonary valve stenosis; PVC, premature
ventricular contraction; PVD, polyvalvar dysplasia (2 or more abnormal valves); SVT, supraventricular tachycardia; subAS, subaortic stenosis; TOF, tetralogy of Fallot; VSD, ventricular septal defect; VT, ventricular tachycardia (NS, non-sustained).
Costello syndrome:1Aoki et al. ,2Estep et al. ,3Kerr et al. ,4van Steensel et al. ;5Zampino et al. ,6van Der Burgt et al. ,7Digilio et al. ,8Limongelli et al. ,9Hou ,10Lo et al. ,
11Piccione et al. ,12Kuniba et al. , and13Smith et al. .
CFC syndrome, BRAF:14Rodriguez et al. ,15Niihori et al. ,16Gripp et al. ,17Narumi et al. , and18Cases in Narumi could not be used for this calculation.
Noonan syndrome (PTPN11):19Tartaglia et al. ,20Sarkozy et al. ,21Zenker et al. ,22Jongmans et al. ,23Kamisago et al. , and24Sznajer et al. .
Noonan syndrome with multiple lentigines (PTPN11):25Legius et al. ,26Yoshida et al. ,27Limongelli et al. ,28Iwasaki et al. , and29Yagubyan et al. .
30Goyal and Aragam  described aortic dilation in a male with clinically diagnosed Noonan syndrome with multiple lentigines, mutation analysis not done.
Noonan syndrome (SOS1):31Zenker et al. [2007a] and32Roberts et al. .
Noonan syndrome (RAF)1:33Pandit et al. ,34Razzaque et al. , and35Kobayashi et al. .
KRAS:36Schubbert et al. ,37Carta et al. ,38Zenker et al. [2007b],39Sovik et al. , and40Kratz et al. .
Neurofibromatosis, type 1:41Lin et al. ,42Baralle et al. , and43De Luca et al. .
44Excluded from the Noonan syndrome analysis are SHOC2 [Cordeddu et al., 2009] and NRAS [five patients, Cirstea et al., 2010].
45‘‘Total patients’’ referred to articles which published tables with sufficient detail to allow classification, that is, the complete literature is not represented since patients reported in summary tables could not be classified. Where indicated, this
referred to ‘‘all patients suitable for review from selected article’’ rather than the grand total.
46Outcome studied only in our longitudinal cohort.
47Shaw et al.  reported ‘‘resolution’’ of HCM in 2 Noonan syndrome patients without genotyping.
LIN ET AL.
The following patients are included as examples of possible
‘‘vasculopathy,’’ but not included in the tally of total patients with
cardiovascular abnormalities. Hypertension required treatment in
one male (patient 55) with moderate-severe HCM, and one young
woman from the literature [patient 4, Estep et al., 2006]. Systemic
blood pressure was not consistently reported, and was normal in
24 (89% of those measured). Idiopathic neonatal pulmonary
hypertension occurred in one study infant (patient 59) with lethal
HCM. One infant who had a p.G12A mutation with severe HCM
had fibromuscular dysplasia of the coronary arteries at autopsy
[patient 11, Kerr et al., 2006].
tissue available for pathologic review. In addition to the initial
description of myocardial fiber disarray in a clinically described
Costello syndrome patient [Tomita et al., 1998], we report 7 (four
with disarray (7/10, 70% of all genotyped pathologic specimens).
bundle of His [patient 1 in Hinek et al., 2005; Estep et al., 2006;
patient 44 in Lin et al., 2008b], coronary artery fibromuscular
dysplasia with nesidioblastosis[patient11in Kerr etal., 2006], and
small fiber myopathy with excess muscle spindle [patient 1 in van
der Burgt et al., 2007]. Atrial fibrosis was not reported. As in
Noonan syndrome and non-syndromic HCM patients, myxoma-
were observed (Fig. 2, patient 2).
The other RASopathies have been also associated with myocar-
dial fiber disarray in 12 clinically diagnosed patients with Noonan
syndrome prior to the availability of mutation analysis and
one patient with a RAF1 mutation (Table III). Three patients
had intramyocardial coronary artery thickening resembling non-
syndromic HCM, and one patient had fibromuscular dysplasia.
Myocardial fiber disarray was reported in two clinically diagnosed
patients with CFC syndrome [Roberts et al., 2006], one of whom
had coronary artery intimal thickening.
Genotype–Phenotype Correlation of HRAS
The vast majority of patients had the p.G12S mutation in both our
study cohort (84%) and the previously reported patients (71%),
with 14 additional non-G12S mutations in 1–6 patients, each
respectively. The p.G12S mutation was present in 13/15 (87%)
patients with serious tachycardia, and one each with the p.G12A
and p.G12C mutation. The small number of patients with less
common mutations prevents a meaningful comparison of the
cardiac phenotype severity. Of the 111 total patients with the
p.G12S mutation, 57% had two or more cardiac abnormalities,
whereas 50% of p.G12C and p.G13C patients had a single defect.
Data from a ‘‘severity comparison’’ analysis are not shown on
Table IV. In descending order, the frequency of patients with any
severe cardiovascular abnormality was 100% for p.A146V (1/1
patient), 50% for p.G13C (2/4 patients), 40% for p.G12C (2/5
FIG. 1. 4½-year-old white male with Costello syndrome and HCM (Supplemental Appendix patient 36): During the electrophysiologic study, the
procedure. There was prompt return of arrhythmia from other anatomically distinct atrial sites and he underwent AV node ablation and pacemaker
placement.Arrows pointingatsurface leadIIandtheintracardiac electrogramMAPdindicate the(II)multiple Pwavemorphologies whichcorrelate
with(MAPd) different electrogram activation andmorphologies wherethe electrogram shifts both relativetiming and morphology,evenwithin this
496 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
patients), 22% for p.G12S (24/111 patients), and 10% for p.G12A
Comparison With RASopathies
Table IV presents detailed data on the Costello syndrome
study patients and previously reported patients and other patients
with one of the RASopathies. The analysis of SOS1 illustrates the
individualized approach for each syndrome and mutation. Since
a smaller series [Narumi et al., 2008] was omitted as per general
methods. A condensed comparison is shown in Table VI based on
study patient data only. In general, the frequency of having any
CFC syndrome (BRAF) and Noonan syndrome (SOS1), to a high
of 94% in Noonan syndrome (RAF1). The frequency (2%) of
cardiovascular problems in NF1 is much less and based on a
clinical survey, not directly comparable. The predominance of
pulmonary stenosis is similar in NF1, whereas HCM has been
reported anecdotally. NF1 was not analyzed further.
Congenital heart defects. Among the RASopathies, CHDs
appear most common (?90% of patients with a cardiac problem)
occur in the majority of CFC syndrome (BRAF) and Noonan
syndrome (RAF1) patients, in all syndromes due to the predomi-
nance of pulmonary valve stenosis. The analysis of CFC syndrome
(BRAF) was less extensive because individual patient data was not
available in each of the CFC reports, thus, the frequency of
pulmonary stenosis (31%) was based on one series [Rodriguez-
our Costello syndrome study patients indicates that it is stable or
resolving in most (86%), although comparable data are not avail-
able for the other syndromes. Subaortic stenosis due to anomalous
insertion of the mitral valve, alone or in association with partial
atrioventricular canal, has been reported in patients with a clinical
greater diversity in the scope of CHDs beyond the septal defects,
frequent valve anomalies, and rare coarctation in Costello syn-
drome was observed in association with each of the Noonan
syndrome genes. We did not pursue an extended analysis of atrial
septal defect because of challenges in case classification.
Hypertrophic cardiomyopathy. HCM occurs with similar
frequency in Costello syndrome (this study and literature review),
Noonan syndrome with multiple lentigines (PTPN11), and
Noonan syndrome (RAF1), and is less common in CFC syndrome
(BRAF), Noonan syndrome (PTPN11, SOS1), and KRAS. In
regression of HCM in 14% (five patients) by well-documented
echocardiographicfollow-up wasalsoreportedinone patientwith
a KRAS mutation [patient 2 in Sovik et al., 2007].
Arrhythmia. Among Costello syndrome patients with a car-
diovascular problem, the frequent occurrence of arrhythmia (65%
FIG. 2. Postmortem examination of Supplemental Appendix patient 2:
(A) Photograph of transverse section of gross heart specimen of
100? original magnification). C: Photomicrograph of
intramyocardial arteriole showing medial hypertrophy, intimal
thickening and luminal narrowing (H&E stained section, 40?
original magnification). These images are characteristic of typical
HCM [Fig. 2, page 1311, Maron, 2002; Figure 56.3, Maron, 2008].
LIN ET AL.
TABLE V. HRAS Mutations Detected in Costello Syndrome: Genotype–Phenotype Analyses Based on Study Patients (n¼61) and/or Literature (n¼85)
Number of patients, N (%)a
Selected cardiovascular abnormality,
N (% pts with mutation), N (% pts with feature)
Aortic root dilation
Number of cardiac
72/111 (64); 72/97 (74)
4/5 (80); 4/61 (7)
0: 8 (16); 1: 14 (27);
>2: 29 (57)
4/9 (44); 4/97 (4)
1: 2 (67); 3: 1 (33)
4/5 (80); 4/97 (4)
1: 1 (50); 3: 1 (50)
4/4 (100); 4/97 (4)
3/4 (75); 3/97 (3)
1/5 (20); 1/61 (2)
1: 1 (50); 2: 1 (50)
2/2 (100); 2/97 (2)
2/3 (67); 2/97 (2)
1/1 (100); 1/97 (1)
1/1/ (100); 1/97 (1)
1/1 (100); 1/97 (1)
1: 1 (100)
1/1/(100); 1/97 (1)
1/1 (100); 1/97 (1)
1/1 (100); 1/97 (1)
1/1 (100); 1/97 (1)
3: 1 (100)
EAT, ectopic atrial tachycardia; HCM, hypertrophic cardiomyopathy; MAT, multifocal atrial tachycardia; pts, patients.
498AMERICAN JOURNAL OF MEDICAL GENETICS PART A
RAF1 mutation approach this in overall frequency (13% among all
patients), or with any atrial tachycardia (31%), one of whom had
EAT [Kobayashi et al., 2010]. The finding of an abnormal electro-
cardiogram with conduction abnormalities in Noonan syndrome
Vascular abnormalities. Aortic dilation has been rarely
reported in patients with Noonan syndrome. Coronary artery
dilation and peripheral aneurysms have been reported in
Noonan syndrome with multiple lentigines [Yagubyan et al.,
2004; Limongelli et al., 2007; Iwasaki et al., 2009], with aortic
dilation in one clinically diagnosed patient [Goyal and Aragam,
This study of Costello syndrome patients with documented HRAS
ties and the frequent occurrence of serious tachycardia, provides
new information about outcome and pathologic findings, and
demonstrates similarities to the other RASopathies.
Congenital Heart Defects
The greater frequency of CHDs in the current study may be due to
the bias of underreporting simple CHDs in the literature, or an
increase due to prospective echocardiographic surveillance. Cost-
ello syndrome is not associated with major complex CHDs in
postnatal life, but it is unknown whether they would be present
in earlier fetal development. Pulmonary stenosis, usually valvar, is
common, and may include muscular subpulmonary obstruction
(related to HCM), as well as supravalvar narrowing. Rare
patients with severe subpulmonary stenosis described as ‘‘double-
chambered right ventricle’’ may have accounted for early reports of
‘‘biventricular’’ cardiomyopathy. Structural mitral valve anoma-
cases in which mitral valve thickening in HCM was associated
with systolic anterior motion of the mitral valve (SAM) and left
ventricular outflow tract obstruction
the first review (two-thirds vs. one-third of all patients) [Lin et al.,
2002] which may reflect more careful documentation, reporting
more serious literature cases, or increased cardiac imaging among
all patients. There is less detailed information about patient age in
directly comparable to the mean age at diagnosis (4.2) or current
may reflect ascertainment, given the multiple reports of neonatal
Lo et al., 2008]. We now include mild interventricular septal
‘‘thickening’’ as HCM since previously unclassified cases have now
been observed to progress to typical HCM. HCM is chronically
severe or deteriorates in over one-third of patients, but in 41% the
progression slows. We are intrigued by the apparent decrease in
HCM in 5 well-imaged patients followed for a mean of 8 years by
pediatric cardiologists familiar with Costello syndrome in whom
the severity was moderate in one (#4) and mild in four (patients 9,
22, 23, 51) patients (ages 7–20, mean 11.8 years). Patients 9 and 23
used GH for fourand 1year, respectively, and discontinuation was
wall thickness with aging has been interpreted as widespread
remodeling in adults with HCM, leading to an understanding that
HCM is not a static disease [reviewed in Maron, 2002].
In sarcomeric HCM, myocardial fiber disarray is significantly
clinically diagnosed [Tomita et al., 1998] and 7 mutation-positive
patients with Costello syndrome, a single patient with a KRAS
mutation, 13 (one genotyped, 12 clinically diagnosed) Noonan
syndrome and two clinically diagnosed CFC syndrome patients.
Although the histologic and gross phenotype of HCM in
Costello syndrome (Fig. 2) is strikingly similar to HCM caused by
TABLE VI. Summary of the Cardiovascular Abnormalities in Costello Syndrome and RASopathies
Serious atrial tachycardia
Frequency score þ to þþþþ corresponds to 20–80%; (þ) Imples ‘‘rare’’.
Based on total patients to reference cardiac abnormality (not total cases).
HCM, hypertrophic cardiomyopathy; PS, pulmonary stenosis; VT, ventricular tachycardia.
LIN ET AL.
sarcomeric protein coding mutations [Maron, 2002, Fig. 2], the
from the structural protein in the latter. HCM in the RASopathies
et al., 2008], which may mean that the mutant is not a completely
comparable animal model [Chen et al., 2009]. The mice have
cardiomyocyte hypertrophy and concentric left ventricular hy-
pertrophy in the setting of hypertension. Right ventricular hyper-
trophy with subpulmonary obstruction is rare in Costello
syndrome, and may reflect right-sided HCM. Despite the high
frequency (60%) of HCM in Costello syndrome, it is relatively
unfamiliar to non-geneticists and non-pediatric cardiologists
compared to Noonan syndrome. The presence of severe, often
MAT in children is usually idiopathic; however, it may occur with
lung disease, or postoperatively with a CHD [Dodo et al., 1995;
common syndrome association. The cause of MAT in Costello
dent arrhythmia, unassociated with severe pulmonary stenosis or
HCM. The current autopsies did not report atrial fibrosis. There
were no reports of microdissection of the conduction system to
validate Mori et al.’s  observation of ‘‘degeneration of the
conduction system’’ in which abnormalities of the conduction
pathways led to the atrioventricular node. The existing mouse
model does not exhibit tachycardia [Schuhmacher et al., 2008;
Chen et al., 2009]. Atrial tachycardia may be a functional conse-
quence of diastolic dysfunction in adults with HCM where in-
creased filling pressure is associated with increased atrial stretch
leading to dysrhythmia [Brembilla-Perrot et al., 1997]. However,
the proportion of patients having an arrhythmia (almost all atrial
tachycardia) was similar whether or not there was HCM (12/16,
75% without HCM vs. 22/28, 78% with HCM). No patient had
patients were followed for ventricular ectopy and ‘‘wide QRS
tachycardia’’ (atrial or ‘‘ventricular’’).
The literature tends to be biased towards the severe forms of
Costello syndrome, such as the fetal phenotype [Kuniba et al.,
2009; Lin et al., 2009; Smith et al., 2009] and lethal infantile
presentation [Hinek et al., 2005; Digilio et al., 2007; Limongelli
et al., 2008; Lo et al., 2008], thus, our study patients expand the
diagnosis of Costello syndrome is more likely to be missed in early
lethal cases when infants with hypertrophic cardiomyopathy
and hypotonia may be diagnosed as having a metabolic or
mitochondrial disease. Limited data about the functional status
of adolescents and adults was obtained from parents reporting
‘‘mild’’ symptoms in most cases. Several parents suggested their
anxiety, sedentary lifestyle, or having a musculoskeletal problem.
The recent death of a 27-year-old male with moderately severe
HCM contrasts with the clinical assessment of him as ‘‘mildly
symptomatic’’ and having an active lifestyle. Risk assessment and
management for sudden death in pediatric patients with HCM, in
general, remainsanenormouschallenge [Colan etal.,2007;Colan,
2008]. Current data arederived from adult series and derivation of
pediatric-specific recommendations is hampered by diverse etiol-
ogies, age-specific mortality risks, and greater therapeutic risks.
be used as an epidemiologic measure, merely the first general
description of mortality in Costello syndrome. Our study does not
inclusion of the three prenatally diagnosed patients who later
died [Lin et al., 2009]. Despite these weaknesses in ascertainment,
we noted that most (10 of 23, 43%) deaths occurred in infants
less than 1 year. Four (17%) deaths occurred in children, and two
(9%) in young men with HCM (one who also had pulmonary
in Costello syndrome has not been fully elucidated. A small study
with preliminary data on the safety of growth hormone in Costello
syndrome has been presented [Rauen et al., 2008].
Comparison to Other RASopathies
as having Noonan syndrome. Both can present with HCM of
variable severity, including severe infantile HCM [Hinek et al.,
2005; Limongelli et al., 2007; Lo et al., 2008]. Infants with Costello
syndrome are less likely to have severe pulmonary stenosis, or
CHDs currently distinguishes Costello syndrome from Noonan
Fallot or atrioventricular septal defect have been reported occa-
sionally [Lin et al., 2000; Sarkozy et al., 2003; Pandit et al., 2007;
Razzaque et al., 2007]. The predominance of valve dysplasia and
paucity of cardiac malformation is consistent with the view that
NF1 was delineated first and is more common, it can be viewed as
the prototype ‘‘multiple dysplasia syndrome’’ [Riccardi, 2010],
although Noonan syndrome is probably the model of the heart
There are inadequate data in this review to compare HCM in
CFC and Costello syndrome. Anecdotal experience (J.N.) suggests
that severe subaortic obstruction requiring surgical treatment is
due to RAF1 mutations [Kobayashi et al., 2010] and in Noonan
severe, and longitudinal studies are needed to delineate a compari-
son to Costello syndrome. The resolution by echocardiographic
criteria of HCM in five patients with Costello syndrome is not
unique among RASopathies, and requires monitoring across the
spectrum of RASopathies in longitudinal studies.
500AMERICAN JOURNAL OF MEDICAL GENETICS PART A
The association of Costello syndrome with non-reentrant atrial
CFC or Noonan syndrome when other phenotypic features are
supportive, but should not be viewed as a pathognomonic feature
[Lin et al., 2002, 2009; Gripp et al., 2006]. CFC syndrome has been
reported with supraventricular tachycardia [Rodriguez-Viciana
et al., 2006], unspecified arrhythmia, or atrial tachycardia
we hypothesize that the non-reentrant tachycardias will be identi-
fied in the other RASopathies. Careful evaluations are needed to
determine if ventricular arrhythmias occur in Costello syndrome.
mias, potentially related to HCM (hypertrophy, fibrosis, and
probably disarray) are well-documented, and supraventricular
arrhythmias are attributed to HCM and dilated left atrium. A
in young children and Noonan syndrome with multiple lentigines
witholder patients withconductiondefectsorventriculararrhyth-
mia associated with HCM is not meaningful (Table IV), but they
represent the RASopathies currently with the most frequent and
distinctive ‘‘arrhythmia phenotypes.’’
Mild aortic dilation in Costello syndrome was not related to
of an intrinsic vasculopathy. Prospective surveillance in the other
RASopathies is needed to determine if aortic dilation, coronary
artery dysplasia and hypertension (systemic and pulmonary) con-
screening for this widespread problem.
Nearly 80% of patients with Costello syndrome have the HRAS
p.G12S mutation, with 14 additional mutations in 1–6 patients,
each, rendering genotype–phenotype correlation an ongoing
challenge. Mutations in HRAS p.G12C and p.G12D may
represent a severe phenotype of HCM and infant death
[Lo et al., 2008] based on five and four patients, respectively.
Discordance between the facial/developmental phenotype and
the heart is suggested by the two patients with an attenuated
phenotype [Gripp et al., 2008]. A mildly affected boy with a
p.T58I (patient 50) mutation had only mitral valve prolapse,
whereas a girl with a p.A146V (patient 43) mutation had an
unspecified self-limited tachycardia and rapidly progressive HCM
which required myectomy at 41=2years (myocardial fiber disarray
noted on biopsy).
Cardiac hypertrophy, cutaneous overgrowth, and neoplasia in
Costello syndrome suggest a gain-of-function mutation, interest-
ingly the same mechanism for PTPN11 mutations in NS [Tartaglia
et al., 2001]. The notion that HCM in Costello syndrome is driven
transgenic mouse model where targeted expression of an H-
Ras-G12V mutant has Costello syndrome features and develops
significant cardiac hypertrophy [Zheng et al., 2004]. A zebrafish
model of Costello syndrome expressing oncogenic H-RASV12 also
had thicker heart walls [Santoriello et al., 2009], but the observed
defects in early heart morphogenesis cannot be directly compared
to humans with Costello syndrome (most of whom have the
p.G12S mutation).The mitogen-activated
(MAPK) cascades, p38, JNK, and ERK, have profound effects in
the development of HCM and remodeling [Harris et al., 2004;
Dwyer et al., 2008; Rohini et al., 2010; Streicher et al., 2010].
However, it is important to note that the myocardial phenotypic
heterogeneity is striking. Why 40% of individuals with RAS
ing the patients in whom HCM is absent and present (Fig. 3) may
FIG. 3. Costellosyndromestudypatients(n¼61)classifiedaccordingtothepatternofhypertrophiccardiomyopathyandotherabnormalities.AoDil,
aorta dilation; Arrhy, arrhythmia; CHD, congenital heart defect; HCM, hypertrophic cardiomyopathy.
LIN ET AL.
Study Strengths and Weaknesses
This is the largest prospectively enrolled cohort of patients
with Costello syndrome with molecular confirmation of HRAS
mutation. The cardiology evaluations were performed at various
institutions, including 8 (13%) at 3 pediatric hospitals (4 at
Children’s Hospital of Boston, two at A.I. duPont Hospital for
Children, two at the Hospital for Sick Children, Toronto). Meas-
the absence of consistent indices for ventricular function, gradient
and thickness precludes more than general description of HCM.
Parents of the older patients reported their opinion about exercise
tolerance and cardiac quality of life, in most cases, discussed with
their cardiologist and/or geneticist; none had formal exercise
in aggregate form, we had smaller comparison groups than the
actual number of reported patients. The CFC syndrome analysis
focused only on BRAF mutations, which had thelargest number of
patients, and subsequent studies must include MEK1/2. The
information about the small number of deaths is novel data, but
cannot be viewed as an estimate of mortality prevalence rate,
incidence, or lifetime risk. We did not systematically obtain a
family history of HCM or arrhythmia in the study survey. In most
cases, an astute geneticist or cardiologist would probably have
obtained this information in the course of patient care.
Impact of Study on Guidelines for Evaluation and
Throughout the lifespan of a Costello syndrome person, decision-
making by parents and providers integrates medical, psychosocial,
et al., 2002] to recommend a complete consultation by a skilled
cardiologist for all patients with Costello syndrome at the time of
diagnosis. Whereas previous recommendations were generalized,
the data from this study can guide the timing and frequency,
although all care is still individualized by a personal cardiologist
absence of HCM is a useful feature to understand the clinical and
management ‘‘flow’’ (Figs. 3 and 4).
Newborns who had fetal tachycardia will need a postnatal high
quality 12-lead surface ECG and consideration of Holter monitor-
ing [Lin et al., 2009]; rhythm strips from intensive care units are
usually insufficient for diagnosis. When diagnosis is made in
infancy, serial echocardiograms in the first year of life will
monitor for the possibilityof rapidly progressing HCM.Late onset
HCM is often asymptomatic, and when outflow obstruction is
absent, no murmur will be heard making clinical status unreliable.
Periodic echocardiograms are warranted throughout life. The
onset of serious atrial tachycardia is generally before 1 year of
age. For older children and adolescents, screening echocardio-
graphy should be based on existing findings. Unlike non-
syndromic HCM, the guidelines for echocardiographic screening
in Costello syndrome are not currently based on well-studied risk
stratification [Maron et al., 2003; Colan et al., 2007; Maron, 2008].
In-depth review of pharmacotherapy was beyond the scope of this
article, and patients should be treated by cardiologists using ‘‘best
in the setting of pre-existing HCM, may require more frequent
The risk of sudden death in Costello syndrome relative to other
forms of HCM is unknown. It is appropriate for families to discuss
with their cardiologist the possibility of periodic monitoring
for predictors of sudden death using exercise testing and
FIG. 4. General guidelinesfor management ofCostello syndromepatients. Thefrequencyandtype ofcardiac consultation will depend onthe cardiac
phenotype. ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator.
502 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Holter monitoring, and when justified by risk stratification,
consideration of an ICD in high risk patients (Fig. 4). Exercise
stress testing may play a role in assessing HCM risk (e.g., arrhyth-
The caregivers of adults with syndromes associated with cardiac
abnormalities need assistance in transitioning care from pediatric to
adult cardiologists [Lin et al., 2008a]. Likewise, the families of older
individuals often struggle to find appropriate physicians, which
underscore a responsibility of clinical geneticist to assist in the
transition of their patients through various stages of life [Rauen
and the potential for new onset disease, we advise that cardiology
surveillance be maintained after the second decade, even in the
minority of patients who are thought to be free of cardiac
given to valve dysplasia and late onset tachyarrhythmia.
cardiac abnormalities, though genotype–phenotype correlations
are limited. The Costello syndrome cardiac phenotype overlaps
from fetal life to postnatal presentation, and through childhood
Costello syndrome are serious atrial tachycardia, and mild pulmo-
longitudinal studies. Future studies, especially cardiac specific
mouse models, are needed to evaluate the genetic basis, and to
provide optimal medical and surgical treatment. In anticipation of
a metric if echocardiography can be performed according to
Wethankthefamiliesandparentleaders oftheCostello Syndrome
Family Network for their participation and support. In particular,
but inspire our work. We acknowledge many colleagues who have
cared for individuals, provided suggestions, or assisted us in other
ways including Dr. Lisa Bergesen, Dr. Paul Benke, Dr. Theonia
Boyd, Dr. John Brownlee, Dr. Laurie Demmer, Dr. Patricia
Dickson, Dr. Ira Dubrow, Dr. Lars Erickson, Dr. Anne Fournier,
Dr. John Graham, Dr. Raoul Hennekam, Dr. Alek Hinek, Dr. Jodi
Hoffman, Dr. John Johnson, Dr. Prapti Kanani, Dr. Hiroshi
Kawame, Dr. Mary Kukolich, Dr. Pablo Lapunzina, Dr. Nilima
Malaiya, Dr. Yoichi Matsubara, Dr. John Moeschler, Dr. Maria
Piccione, Dr. Michael Rebodello, Dr. Edwin Rodriquez-Cruz, Dr.
Amarjit Singh, Dr. Alain Verloes, Dr. Joseph Weiss, Dr. Rosanna
Weksberg, Dr. Patricia Wheeler and Dr. Elaine Zackai. Dr. Lin is
indebted to the librarian support of Meaghan Muir and Nhu
Nguyen. As this article was nearing publication, we learned of the
death of Dr. Jack Costello. We recall his important contribution to
pediatrics and genetics.
M, Kato K, Suzuki Y, Kure S, Matsubara Y. 2005. Germline mutations
in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37:
Axelrad ME, Glidden R, Nicholson L, Gripp KW. 2004. Adaptive skills,
Genet Part A 128A:396–400.
Axelrad ME, Nicholson L, Stabley DL, Sol-Church K, Gripp KW. 2007.
Longitudinal assessment of cognitive characteristics in Costello syn-
drome. Am J Med Genet Part A 143A:3185–3193.
GrippKW.2009.Longitudinalcourse ofcognitive, adaptive,andbehav-
ioral characteristics in Costello syndrome. Am J Med Genet Part A
Baralle D, Mattocks C,Kalidas K, Elmslie F,Whittaker J,LeesM, RaggeN,
Patton MA, Winter RM, French-Constant C. 2003. Different mutations
in the NF1 gene are associated with neurofibromatosis-Noonan syn-
drome (NFNS). Am J Med Genet Part A 119A:1–8.
Brembilla-Perrot B, Jacquot A, Beurrier D, Jacquemin L. 1997. Hypertro-
in patients with or without syncope with special reference to the role of
atrial arrhythmias. Int J Cardiol 59:47–59.
Burch M, Mann JM, Sharland M, Shinebourne EA, Patton MA, McKenna
WJ. 1992. Myocardial disarray in Noonan syndrome. Br Heart J 68:
Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb
BD, Tartaglia M. 2006. Germline missense mutations affecting KRAS
J Hum Genet 79:129–135.
Chen X, Mitsutake N, LaPerle K, Akeno N, Zanzonico P, Longo VA,
Mitsutake S, Kimura ET, Geiger H, Santos E, Wendel HG, Franco
A, Knauf JA, Fagin JA. 2009. Endogenous expression of Hras
(G12V) induces developmental defects and neoplasms with copy
number imbalances of the oncogene. Proc Natl Acad Sci USA 106:
Cirstea I, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, Roberts AE,
Lepri F, Merbitz-Zahradnik T, K€ onig R, Kratz CP, Pantaleoni F, Dentici
ML, Joshi VA, Kucherlapati RS, Mazzanti L, Mundlos S, Patton MA,
Silengo MC, Rossi C, Zampino G, Digilio C, Stuppia L, Seemanova E,
Tartaglia M, Zenker M. 2010. A restricted spectrum of NRAS mutations
causes Noonan syndrome. Nat Genet 42:27–29.
Colan SD. 2007. Classification of the cardiomyopathies. Prog Pediatr
Colan SD. Clinical issues in the pediatric hypertrophic cardiomyopathies.
Prog Pediatr Cardiol 2008. 25:27–29.
Orav EJ, Towbin JA. 2007. Epidemiology and cause-specific outcome of
hypertrophic cardiomyopathy in children: Findings from the Pediatric
Cardiomyopathy Registry. Circulation 115:773–781.
Mazzanti L, Digllio MC, Martinelli S, Flex E, Lepri F, Bartholdi D,
Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossl C, Tenconl R,
Zenker M, Merio D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD,
Tartaglia M. 2009. Mutation of SHOC2 promotes aberrant protein
N-myristolyation and causes Noonan-like syndrome with loose anagen
hair. Nat Genet 41:1022–1028.
LIN ET AL.
Costello JM. 1971. A new syndrome. N Z Med J 74:397.
Costello JM. 1977. A new syndrome: Mental subnormality and nasal
papillomata. Aust Paediatr J 13:114–118.
Costello JM. 1996. Costello syndrome: Update on the original cases and
commentary. Am J Med Genet 62:199–201.
Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M,
gene mutations represent the major molecular event underlying neuro-
fibromatosis-Noonan syndrome. Am J Hum Genet 77:1092–1101.
Dearlove O, Harper N. 1997. Costello syndrome. Paediatr Anesth 7:
Denayer E, de Ravel T, Legius E. 2008. Clinical and molecular aspects of
RAS related disorders. J Med Genet 45:695–703.
Digilio MC, Sarkozy A, Capolino R, Chiarini Testa MB, Esposito G, de
Zorzi A, Cutrera R, Marino B, Dallapiccola B. 2007. Costello syndrome:
Clinical diagnosis in the first year of life. Eur J Pediatr 167:621–628.
Dodo H, Gow RM, Hamilton RM, Freedom RM. 1995. Chaotic atrial
rhythm in children. Am Heart J 129:990–995.
Dwyer JP, Ritchie ME, Smyth GK, Harrap SB, Delbridge L, Domenighetti
genetic cardiac hypertrophy in the absence of hypertension. Hypertens
Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA. 2006. HRAS
mutations in Costello syndrome: Detection of constitutional activating
mutationsin codon 12and13and lossof wild-typeallele in malignancy.
Am J Med Genet Part A 140A:8–16.
Goyal SB, Aragam JR. 2006. Aortic root dilatation with redundancy of
mitral and aortic leaflets associated with the LEOPARD syndrome. Int J
Gripp KW, Lin AE. 2009. Costello Syndrome. GeneReviews Updated May
19, 2009. Accessed February 1, 2010.
Gripp KW, Scott CI, Jr., Nicholson L, Figueroa TE. 2000. A second case of
Gripp KL, Lin AE, Stabley DL, Nicholson L, Scott CI, Jr., Doyle D, Aoki Y,
40 patients with Costello syndrome: Genotype and Phenotype analysis.
Am J Med Genet Part A 140A:1–7.
2007. Further delineation of the phenotype resulting from BRAF or
MEK1 germline mutations helps differentiate Cardio-facio-cutaneous
Syndrome from Costello syndrome. Am J Med Genet Part A 143A:
Gripp KW, Innes AM, Axelrad ME, Gillan TL, Parboosingh JS, Davies C,
Leonard NJ, Lapointe M, Doyle D, Catalano S, Nicholson L, Stabley DL,
Sol-Church K. 2008. Costello syndrome associated with novel germline
HRAS mutations: An attenuated phenotype? Am J Med Genet Part A
Gripp KW, Hopkins E, Doyle D, Dobyns WB. 2010. High incidence of
overgrowth associated with HRAS mutations as the likely cause of
structural brain and spinal cord abnormalities. Am J Med Genet Part
Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ. 2004.
Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte
survival in response to pressure overload. Circulation 110:718–723.
Hinek A, Teitell MA, Schoyer L, Allen W, Gripp KW, Hamilton R,
Weksberg R, Lin AE. 2005. Myocardial storage of chondroitin sulfate-
phic cardiomyopathy. Am J Med Genet Part A 133A:1–12.
issues in older patients. Am J Med Genet Part A 152A:84–90.
Ishikawa Y, Sekiguchi K, Akasaka Y, Ito K, Akishima Y, Zhang L, Itoh M,
Ishihara M, Ishii T. 2003. Fibromuscular dysplasia of coronary arteries
resulting in myocardial infarction associated with hypertrophic cardio-
myopathy in Noonan’s syndrome. Hum Pathol 34:282–284.
Iwasaki Y, Horigome H, Takahashi-Igari M, Kato Y, Razzaque MA,
Matsuoka R. 2009. Coronary artery dilatation in LEOPARD syndrome.
A child case and literature review. Cong Heart Dis 4:38–41.
Hall BD, Fries MH, Carey JC. 1998. Costello syndrome: Phenotype,
natural history, differential diagnosis, and possible cause. J Pediatr
Jongmans M, Sistermans EA, Rikken A, Nillessen WM, Tamminga R,
Patton M, Maier EM, Tartaglia M, Noordam K, van der Burgt I. 2005.
Genotypic and phenotypic characterization of Noonan syndrome: New
dataandreview of the literature. Am JMed Genet PartA 134A:165–170.
Kamisago M, Hirayama-Yamad K, Kato T, Imamura S, Joo K, Ando M,
Takao A, Momma K, Nakazawa M, Matsuoka R. 2005.
mutations in the PTPN11 as a cause of cardiac defects associated with
M, editors. Cardiovascular development and congenital malformations.
Molecular and genetic mechanisms. Malden, Massachusetts, USA:
Blackwell Futura Publishing. pp 273–276.
Keane MG, Wiegers SE, Plappert T, Pochettino A, Bavaria JE, Sutton MG.
2000. Bicuspid aortic valves are associated with aortic dilatation out of
proportion to coexistent valvular lesions. Circulation 102:11135–11139.
Kerr B, Eden OB, Dandamudi R, Shannon N, Quarrell O, Emmerson A,
Ladusans E, Gerrard M, Donnai D. 1998. Costello syndrome: Two
patients with embryonal rhabdomyosarcoma. J Med Genet 35:
Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M,
Tang B, Eden OB, O’Sullivan J, De Sandre-Giovannoli A, Reardon W,
Brewer C, Bennett C, Quarell O, M’Cann E, Donnai D, Stewart F,
HennekamR,Cave H,Verloes A,PhilipN,LacombeD, LevyN,Arveiler
B, Black G. 2006. Genotype–phenotype correlation in Costello syn-
drome: HRAS mutation analysis in 43 cases. J Med Genet 43:401–405.
Kerr B, Allanson J, Delrue M, Gripp K, Lacombe D, Lin A, Rauen K. 2008.
The diagnosis of Costello syndrome: Nomenclature in Ras/MAPK path-
way disorders. Am J Med Genet Part A 146A:1218–1220.
Kobayashi T, Aoki Y, Niihori T, Cav? e H, Verloes A, Okamoto N, Kawame
H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N,
Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kur-
504 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F,
Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker
germline KRAS mutations. Am J Med Genet Part A 149A:1036–1040.
Kuniba H, Pooh RK, Sasaki K, Shimokawa O, Harada N, Kondoh T,
Egashira M, Moriuchi H, Yoshiura K, Niikawa N. 2009. Prenatal diag-
nosis of Costello syndrome using 3D ultrasonography amniocentesis
confirmationoftherare HRASmutation G12D.AmJMed GenetPartA
Legault L, Gagnon C, Lapointe N. 2001. Growth hormone deficiency in
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Ge-
willig M, Fryns J-P. 2002. PTPN11 mutations in LEOPARD syndrome. J
Med Genet 39:571–574.
Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P,
Versacci P, Calabro P, De Zorzi A, Di Salvo G, Syrris P, Patton M,
McKenna WJ, Dallapiccola B, Calabro R. 2007. Prevalence and clinical
significance of cardiovascular abnormalities in patients with the LEOP-
ARD Syndrome. Am J Cardiol 100:736.
obstructive biventricular hypertrophy in a patient with Costello syn-
drome: Clinical impact and management. Int J Cardiol 130:e108–e110.
Lin AE, Birch P, Korf B, Schneider GH, Tenconi R, Niimura M, Poyhonen
Friedman JM, the NNFF International Database Participants. 2000.
Cardiac anomalies in neurofibromatosis, type 1(NF1).Am J Med Genet
LinAE, Grossfeld PD, Hamilton R,Smoot L,Proud V, Weksberg R,Gripp
Further delineation of cardiac anomalies in Costello syndrome. Am J
Med Genet Part A 111A:115–129.
J Pediatr 2004. 144:135.
Lin AE, Basson CT, Goldmuntz E, Magoulas PL, McDermott DA, McDo-
nald-McGinn D, McPherson E, Morris CA, Noonan J, Nowak C,
Pierpont ME, Pyeritz RE, Rope AF, Zackai E, Pober BR. 2008a. Adults
with genetic syndromes and cardiovascular abnormalities: Clinical his-
tory and management. Genet Med 10:469–494.
reported Costello syndrome patients. Am J Med Genet Part A 146A:
CI, Hamilton R, Innes AM, Lauzon JL, Sol-Church K, Gripp KW. 2009.
Prenatal features of Costello syndrome: Ultrasonographic findings and
atrial tachycardia. Prenatal Diag 29:682–690.
Lam STS, Kerr B. 2008. Severe neonatal manifestations of Costello
syndrome. J Med Genet 45:167–171.
Marino B, Gagliardi MG, Digilio MC, Polletta B, Grazioli S, Agostino D,
Giannotti A,Dallapiccola B. 1995.Noonan syndrome: Structural anom-
alies of the mitral valve causing subaortic obstruction. Eur J Pediatr 154:
Maron BJ. 2002. Hypertrophic cardiomyopathy: A systematic review.
Maron BJ. 2008. Hypertrophic cardiomyopathy. In: Moss and Adams’
Baltimore: Williams and Wilkins. pp 1172–1195.
Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ,
Seidman CE, Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, Wigle
ED, Task Force on Clinical Expert Consensus Documents. American
College of Cardiology, Committee for Practice Guidelines. European
Society of Cardiology. 2003. American College of Cardiology/European
Society of Cardiology clinical expert consensus document on hypertro-
phic cardiomyopathy. A report of the American College of Cardiology
Coll Cardiol 42:1687–1713.
Mori M, Yamagata T, Mori Y, Nokubi M, Saito K, Fukushima Y, Momoi
MY. 1996. Elastic fiber degeneration in Costello syndrome. Am J Med
MI, Okamoto N, Kurosawa K, Hennekam RCM, Wilson LC, Gillessen-
Kaesbach G, Wieczorek D, Lapunzina P, Ohashi H, Makita Y, Kondo I,
Tsuchiya S, Ito E, Sameshima K, Kato K, Kure S, Matsubara Y. 2007.
syndrome: Overlapping clinical manifestations with Costello syndrome.
Am J Med Genet Part A 143A:799–807.
Narumi Y, Aoki Y, Niihori T, Sakurai M, Cav? e H, Verloes A, Nishio K,
Ohashi H, Kurosawa K, Okamoto N, Kawame H, Mizuno S, Kondoh T,
Kobayashi T, Guliyeva A, Kure S, Matsubara Y. 2008. Clinical manifes-
CFC syndrome. J Hum Genet 53:834–841.
Niihori T, Aoki Y, Narumi Y, Neri G, Cav? e H, Verloes A, Okamoto N,
Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI,
Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G,
Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S,
Matsubara Y. 2006. Germline KRAS and BRAF mutations in cardiofa-
ciocutaneous syndrome. Nat Genet 38:294–296.
Nishikawa T, Ishiyama S, Shimojo T, Takeda K, Kasajima T, Momma K.
1996. Hypertrophic cardiomyopathy in Noonan syndrome. Acta Pae-
diatr Jpn 38:91–98.
Noonan J, O’Connor W. 1996. Noonan syndrome a clinical description
emphasizing the cardiac findings. Acta Paediatr Jpn 38:76–83.
EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR,
Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R,
Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC,
Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. 2007.
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syn-
dromes with hypertrophic cardiomyopathy. Nat Genet 39:1007–1012.
Piccione M, Piro E, Pomponi MG, Matina F, Pietrobono R, Candela E,
Gabriele B, Neri G, Corsello G. 2009. A premature infant with Costello
syndrome due to a rare G13C HRAS mutation. Am J Med Genet Part A
Prieto LR, Latson LA. 2008. Pulmonary stenosis. In: Moss and Adams’
Baltimore: Williams and Wilkins. p 841.
Quezada E, Gripp KW. 2007. Costello syndrome and related disorders.
Curr Opin Pediatr 19:633–644.
Rauen KA, Hefner E, Carrillo K, Taylor J, Messier L, Aoki Y, Gripp KW,
ME,Lin AE,DoyleDA,KerrB,CareyJC,McCormick F,SilvaAJ,Kieran
MW, Hinek A, Nguyen TT, Schoyer L. 2008. Molecular aspects, clinical
aspects and possible treatment modalities for Costello syndrome: Pro-
ceedings from the 1st International Costello Syndrome Research Sym-
posium. Am J Med Genet Part A 146A:1205–1217.
LIN ET AL.
Rauen KA, Schoyer L, McCormick F, Lin AE, Allanson JE, Stevenson DA,
AE, Gelb BD, Shannon K, Gutmann DH, McMahon M, Guerra C, Fagin
JA, Yu B, Aoki Y, Neel BG, Balmain A, Drake RR, Nolan GP, Zenker M,
Bollag G, Sebolt-Leopold J, Gibbs JB, Silva AJ,Patton EE,Viskochil DH,
ings from the 2009 genetic syndromes of the Ras/MAPK pathway: From
bedside to bench and back. Am J Med Genet Part A 152A:4–24.
Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R,
Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y,
Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J,
Higashinakagawa T, Matsuoka R. 2007. Germline gain of-function
mutations in RAF1 cause Noonan syndrome. Nat Genet 39:1013–1017.
Birth Defects Res (Part A) 88:9–14.
Roberts A, Allanson J, Jadico SK, Kavamura MI, Noonan J, Opitz JM,
Young T, Neri G. 2006. Cardiofaciocutaneous syndrome. J Med Genet
Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi
VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS. 2007.
Nat Genet 39:70–74.
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz
the MAPK pathway cause cardio-facio-cutaneous syndrome. Science
Rohini A, Agrawal N, Koyani CN, Singh R. 2010. Molecular targets and
regulators of cardiac hypertrophy. Pharmacol Res 61:269–280.
Santoriello C, Deflorian G, Pezzimenti F, Kawakami K, Lanfrancone L,
d’Adda di Fagagna F, Mione M. 2009. Expression of H-RASV12 in a
proliferating cells. Dis Model Mech 2:56–67.
Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. 2003. Correlation
and LEOPARD syndromes. J Med Genet 40:704–708.
SchubbertS,ZenkerM,RoweSL,Bo € llS,KleinC,BollagG,vanderBurgtI,
Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY,
Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. 2006.
Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:
M. 2008. A mouse model for Costello syndrome reveals an Ang II-
mediated hypertensive condition. J Clin Invest 118:2169–2179.
Shaw SC, Kalidas K, Crosby AH, Jeffery S, Patton MA. 2007. The natural
history of Noonan syndrome: A long-term followup study. Arch Dis
Siwik ES, Zahka KG, Wiesner GL, Limwongse C. 1998. Cardiac disease in
Costello syndrome. Pediatrics 101:706–709.
Skinker DM, Cottrill C, O’Connor W. 1998. Right ventricular biopsy
findings of hypertrophic cardiomyopathy in a patient with Noonan
syndrome. Cardiol Young 8:256–259.
Smith LP, Podraza J, Proud VK. 2009. Polyhydramnios, fetal overgrowth
and macrocephaly: Prenatal ultrasound findings of Costello syndrome.
Am J Med Genet Part A 149A:779–784.
Sol-Church K, Stabley DL, Demmer LA, Agbulos A, Lin AE, Smoot L,
Nicholson L, Gripp KW. 2009. Male-to-male transmission of Costello
syndrome: G12S HRAS germline mutation inherited from a father with
somatic mosaicism. Am J Med Genet Part A 149A:315–321.
two siblings with short stature and neuro-cardio-facio-cutaneous fea-
tures. J Med Genet 44:e84.
Streicher JM, Ren S, Herschman H, Wang Y. 2010. MAPK-activated
in heart. Circ Res 106:1434–1443.
Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, Cav? e H,
Verloes A. The spectrum of cardiac anomalies in Noonan syndrome as a
van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA,
Kucherlapati RS, Gelb BD. 2001. Mutations in PTPN11 encoding the
protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat
HG, Bertola DR, Crosby A, Ion A, Kucherlapati S, Jeffery S, Patton MA,
Gelb BD. 2002. PTPN11 mutations in Noonan syndrome: Molecular
spectrum, genotype–phenotype correlation, and phenotypic heteroge-
neity. Am J Hum Genet 70:1555–1563.
Tidyman WE, Rauen KA. 2008. Noonan, Costello and cardio-facio-cuta-
neoussyndromes: Dysregulation oftheRas-MAPK pathway.Expert Rev
Mol Med 10:e37.
Tomita H, Fuse S, Ikeda K, Matsuda K, Chiba S. 1998. An infant with
Costello syndrome complicated with fatal hypertrophic obstructive
cardiomyopathy. Acta Paediatr Jpn 40:608–611.
CP, Dvorsky R, Ahmadian MR, Zenker M. 2007. Myopathy caused by
HRAS germline mutations: Implications for disturbed myogenic differ-
entiation in the presence of constitutive HRAS activation. J Med Genet
van Steensel MA, Vreeburg M, Peels C, van Ravenswaaij-Arts CM, Bijlsma
G12S in Dutch patients with Costello syndrome. Exp Dermatol 15:
Lock JE, Fyler DC, editors. Nadas’ pediatric cardiology. 2nd edition.
Philadelphia: Saunders Elsevier. pp 484–488.
Wang JN, Wu JM, Tsai YC, Lin CS. 2000. Ectopic atrial tachycardia in
children. J Formosa Med Assoc 99:766–770.
White SM, Graham JM, Jr., Kerr B, Gripp K, Weksberg R, Cytrynbaum C,
Reeder CL, Stewart FJ, Edwards M, Wilson M, Bankier A. 2005. The
adult phenotype in Costello syndrome. Am J Med Genet Part A 136A:
Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti A.
2004. LEOPARD syndrome: A new polyaneurysm association and an
update on the molecular genetics of the disease. J Vasc Surg 39:897–
Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. 2004.
Two novel and one recurrent PTPN11 mutations in LEOPARD syn-
drome. Am J Med Genet Part A 130A:432–434.
Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA,
De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA,
Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri
Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kresse W, Tietze HU,
Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A. 2004. Genotype–
phenotype correlations in Noonan syndrome. J Pediatr 144:268–274.
506AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Download full-text
Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S,
Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP,
Horn D, Kutsche K. 2007a. Expansion of the genotypic and phenotypic
spectrum in patients with KRAS germline mutations. J Med Genet 44:
HG, Gaspar H, Hofbeck M, Gillessen-Kaesbach G, Koch A, Meinecke P,
Mundlos S, Nowka A, Rauch A, Reif S, von Schnakenburg C, Seidel H,
Wehner LE, Zweier C, Bauhuber S, Matejas V, Kratz CP, Thomas C,
Kutsche K. 2007b. SOS1 is the second most common Noonan gene but
plays no major role in cardio-facio-cutaneous syndrome. J Med Genet
Jr., Chien KR, Lederer JW, Wang Y. 2004. Sarcoplasmic reticulum
calcium defect in Ras-induced hypertrophic cardiomyopathy heart. Am
J Physiol Heart Circ Physiol 286:H424–H433.
LIN ET AL.