American Journal of Medical Genetics 83:378–381 (1999)
Cardiac Anomalies in the
Simpson-Golabi-Behmel Syndrome
Angela E. Lin,1* Giovanni Neri,2 Rhiannon Hughes-Benzie,3 and Rosanna Weksberg4
1
Genetics and Teratology Unit, Massachusetts General Hospital, Boston, Massachusetts
2
Istituto di Genetica Medica, Facolta di Medicina e Chirugia “A. Gemelli,” Università Cattolica del Sacro Cuore,
Rome, Italy
3
Children’s Hospital of Eastern Ontario, Ottawa, Canada
4
Division of Clinical Genetics, Hospital for Sick Children, Toronto, Canada
Diverse cardiac abnormalities have been re-
ported in patients with the Simpson-Golabi-
Behmel syndrome (SGBS), and it is sus-
pected that they are related to the appar-
ently high incidence of early death. To
clarify the incidence and significance of the
various cardiac abnormalities, we reviewed
101 SGBS patients (89 from the literature, 12
new). All were male, except for one clearly
affected female patient with translocation
X;1 [Punnett, 1994: Am J Med Genet 50: 391–
393]. Ninety-six of 99 (97%) patients had the
classic phenotype of macrosomia and typi-
cal “coarse” face. Thirty-six patients (36%)
had a cardiac abnormality, of whom 26 (26%)
had a cardiovascular malformation (CVM).
After excluding 24 patients with insufficient
clinical data, these percentages among the
77 informative cases were 47% and 34%, re-
spectively. When grouped according to a
mechanistic classification, most cases (20/
26, or 77%) were class II CVMs (attributed to
altered embryonic intracardiac flow). Other
cardiac abnormalities included cardiomy-
opathy (n = 4) and electrocardiogram (ECG)
conduction or rhythm abnormalities (n =
12); three of the affected patients (25%) also
had a CVM. Among 92 informative cases,
there were 29 (32%) deaths, a figure that ex-
cludes seven elective terminations. Among
the 25 patients younger than 3 years, death
was associated with a cardiac abnormality
in six (23%). GPC3 mutation analysis using
Southern blot testing and polymerase chain
reaction amplification was performed for 37
of 101 (37%) patients. A mutation was de-
tected in 26 of the 37 patients tested (70%),
12 of whom (46%) had a cardiac abnormality.
*Correspondence to: Angela E. Lin, M.D., Genetics and Tera-
tology Unit, Massachusetts General Hospital, Boston, MA 02114.
E-mail: lin.angela@mgh.harvard.edu
Received 6 August 1998; Accepted 18 December 1998
© 1999 Wiley-Liss, Inc.
We conclude that cardiac abnormalities of
any type are common in SGBS (almost one-
half of informative cases), with CVMs seen
in one-third of cases. The heterogeneous
ECG abnormalities in this survey must be
viewed with caution, since they may repre-
sent a genuine component of the syndrome
or reporting bias. Determining the true
prevalence and natural history of cardiac
abnormalities in SGBS will require a larger
number of patients and more consistent
prospective cardiac evaluations. There are
sufficient data to recommend a baseline
echocardiogram and ECG in SGBS patients.
Data are insufficient to define a cardiac
phenotype/molecular correlation. Am. J.
Med. Genet. 83:378–381, 1999.
© 1999 Wiley-Liss, Inc.
KEY WORDS: Multiple congenital anomaly/
MR syndrome; arrhythmias;
Wiedemann-Beckwith syn-
drome; cardiomyopathy; car-
diovascular malformation;
congenital heart defect; mac-
rosomia; overgrowth syn-
drome; Simpson-Golabi-
Behmel syndrome
INTRODUCTION
Over the past 10 years, there has been a rapid in-
crease in the clinical and molecular delineation of the
Simpson-Golabi-Behmel syndrome (SGBS) [Hughes-
Benzie et al., 1996], a distinctive X-linked macrosomia/
multiple congenital anomaly syndrome caused by mu-
tation of the GPC3 gene [Pilia et al., 1996]. The phe-
notype of this condition consists of macrosomia,
“coarse” face, macroglossia, hepatosplenomegaly, and
nephromegaly. Specific orofacial anomalies include hy-
pertelorism, cleft palate with or without cleft lip, ear-
lobe creases, midline groove in the tongue or lower lip,
and wide mouth with dental malocclusion. Other

anomalies include supernumerary nipples, hernias
(umbilical, inguinal, diaphragmatic), exomphalos, re-
nal dysplasia, cryptorchidism, hypospadias, broad
hands and feet, polydactyly, syndactyly, hypoplasia of
the distal phalanx and nails, and vertebral or rib de-
fects. Performance is usually normal, but there can be
developmental delay or mental retardation. Diverse
heart abnormalities have been reported frequently,
and it is suspected that they are related to the appar-
ently high incidence of early death [König et al., 1991;
Gurrieri et al., 1992]. Because of the potentially serious
nature of cardiac abnormalities in SGBS, we reviewed
the literature and contributed new patients to delin-
eate the incidence and types of cardiac abnormalities in
SGBS and to clarify the potential relationship of car-
diac abnormalities to early death.
PATIENTS AND METHODS
We reviewed the clinical information of 101 patients;
89 of these cases were previously reported [Simpson et
al., 1975; Golabi and Rosen, 1984; Opitz, 1984; Behmel
et al., 1984 and 1988; Tsukahara et al., 1984; Kajii and
Tsukahara, 1984; Lurie and Ilyina, 1987; Opitz et al.,
1988; Neri et al., 1988; LeMerrer et al., 1989; König et
al, 1991; Kaarianen et al., 1991; Hughes-Benzie et al.,
1992b, 1994, and 1996; Schroer, 1992; Garganta and
Bodurtha, 1992; Gurrieri et al., 1992; Harrod, 1992;
Chen et al., 1993; Chueh et al., 1993; Olney and Opitz,
1993; Punnett, 1994; Saul et al., 1994; Terespolsky et
al., 1995; Vance and Probert, 1995; Reitnauer et al.,
1998; Lapunzina et al., 1998]. Twelve new patients
were contributed by R.H.-B. (n ⳱ 4) and R.W. (n ⳱ 8).
All patients were male, except for one clearly affected
female patient with translocation X;1 [Punnett, 1994].
In many reports, it was difficult to determine whether
a manifestation was truly absent, not sought by the
examiner, not applicable, or not reported for the sake of
brevity. We judged the cardiac status to be “unknown”
when the clinical information was inadequate to estab-
lish the presence or absence of a cardiac abnormality.
Cardiac anomalies were classified as cardiovascular
malformation (CVM), cardiomyopathy, or electrocar-
diogram (ECG) abnormality. The CVMs were grouped
using a mechanistic classification [Clark, 1990, 1995]
based on postulated abnormalities of fetal develop-
ment, such as altered mesenchymal tissue migration
(class I: conotruncal, aortic arch defects), intracardiac
blood flow (class II: atrial septal defect [ASD], ventricu-
lar septal defect [VSD], patent ductus arteriosus, ob-
structive lesions of the right and left heart), cell death
(class III: muscular VSD, Ebstein anomaly), extracel-
lular matrix (class IV: atrioventricular canal defects),
and abnormal targeted growth (class V: anomalous pul-
monary veins). Cardiomyopathy was recorded as hy-
pertrophic or dilated. ECG abnormalities included dys-
rhythmias (tachycardia, bradycardia, ectopy) and
heart block (first, second, third, bundle branch). Mis-
cellaneous cardiac abnormalities included endocardial
fibroelastosis (EFE), ejection click, and murmur. GPC3
mutation analysis was performed using Southern blot
testing and polymerase chain reaction amplification of
intra-exonic sequences [Pilia et al., 1996].
Cardiac Abnormalities in SGB Syndrome 379
RESULTS
Among the 101 patients thus defined, there were
seven elective terminations, one stillbirth, 29 patients
younger than 1 year old, 40 between 1 and 18 years old,
15 older than 18 years, and nine of unspecified age. The
SGBS phenotype was considered classic in 96 of 99
(97%); macrosomia was present in 87 of 97 (89%) and
mental retardation in 14 of 55 (25%). A cardiac abnor-
mality of any type was noted in 36 of 101 (36%) total
patients and in 36 of 77 (47%) informative patients. A
CVM occurred in 26 of 101 (26%) total patients and in
26 of 36 (72%) of those with any cardiac abnormality.
There was one patient with d-transposition of the great
arteries, the sole class I CVM. Most malformations (n
⳱ 15) were class II CVMs. This group included five
patients with membranous VSD (isolated or with other
CVMs), five patients with pulmonic stenosis (two cases
of pulmonic stenosis, location unspecified; one of valvar
pulmonic stenosis; one of dysplastic pulmonic valve;
one of pulmonary artery stenosis), and one patient each
with aortic coarctation, ASD, aortic stenosis, patent
ductus arteriosus, and tricuspid valve prolapse with
bicuspid aortic valve. Five other patients had a VSD of
unspecified location. Five patients had an unspecified
CVM. Assuming that the unspecified VSDs were prob-
ably membranous, a common anatomic type of VSD,
then the frequency of class II CVMs was 20 of 25 (77%).
Cardiomyopathy was diagnosed in four patients
(4%). In two patients, there was no CVM. In one patient
with a dysplastic pulmonic valve, the left-sided hyper-
trophic cardiomyopathy was probably an independent
abnormality. The myocardium was hypertrophic in
three cases (biventricular in two and left-sided in one)
and dilated in one case associated with subaortic VSD.
EFE was found in one patient. Murmurs were reported
in 12 patients, unrelated to the defined CVMs; one pa-
tient had a systolic click.
ECG abnormalities of any type occurred in 12 pa-
tients (12% of the total patients, 33% of those with any
cardiac abnormality, and 16% of the informative cases).
There were varying levels of heart block in nine pa-
tients (first-degree atrioventricular block in three,
bundle branch block in five, unspecified atrioventricu-
lar block in one). Additional ECG abnormalities in-
cluded one case each of biventricular repolarization ab-
normalities, right bundle branch block/premature ven-
tricular beats/ventricular tachycardia, and ectopic
atrial tachycardia. Of 12 patients with a conduction
abnormality, three (25%) had an underlying CVM.
Excluding seven elected terminations, there were 29
deaths among the 101 total patients (27%), and 29 of 92
(32%) informative cases. Of the 29 deaths, we counted
one stillbirth, 16 neonates, nine patients younger than
5 years old, and three patients older than 20 years.
Nine of 29 (31%) deaths were associated with any type
of cardiac abnormality (seven CVMs, one bilateral hy-
pertrophic cardiomyopathy, one partial right bundle
branch block). Two of the seven deaths associated with
a CVM could probably be attributed to the structural
malformation, that is, d-transposition of the great ar-
teries and coarctation of the aorta with subpulmonic
stenosis, respectively. The patient with subaortic VSD,
380 Lin et al.

TABLE I. Cardiac Status and GPC3 Mutation Analysis in 101 Patients With
Simpson-Golabi-Behmel Syndrome*
Cardiac abnormality
GPC3
Mutation Present Absent Unknown Total
a
Detected 12 (32%) 10 4 26 (26%)
Not detected 7 (18%)b 0 2 11 (11%)
Not analyzed 19 (50%) 29 18 64 (64%)
Total 38 (100%) 39 24 101 (100%)
*Thirty-seven patients were analyzed.
a
First-degree atrioventricular block (n ⳱ 2), ventricular septal defect (location not specified) (n ⳱ 2), one case
each of left ventricular hypertrophy/right bundle branch block, partial right bundle block, ectopic atrial tachy-
cardia, ventricular septal defect/atrial septal defect, subaortic stenosis/membranous ventricular septal defect/
pulmonic stenosis, membranous ventricular septal defect/right pulmonary artery stenosis/patent ductus arte-
riosus, branch pulmonary stenosis, aortic stenosis.
b
One case each of ventricular septal defect/dilated sinuses of Valsalva/left-sided cardiomyopathy/
tachyarrhythmias, first-degree atrioventricular block, patent ductus arteriosus, pulmonic stenosis, dysplastic
pulmonic valve/left-sided hypertrophic cardiomyopathy, tricuspid valve prolapse/bicuspid aortic valve, not speci-
fied.

dilated sinuses of Valsalva, left-sided cardiomyopathy,
and severe tachyarrhthymias died of congestive heart
failure, the result of a combination of structural, myo-
cardial, and arhythmogenic abnormalities [Gurrieri et
al., 1992]. Two of the seven CVM deaths were associ-
ated with a VSD, and two were unspecified. Among the
26 youngest patients who died (less than 3 years), six
(23%) had an underlying cardiac abnormality.
GPC3 mutation analysis was positive in 26 of the
total 101 (26%) and 26 of the 37 patients (70%) tested
(Table I). Twelve (46%) of these 26 GPC3-positive pa-
tients had a cardiac abnormality. Comparing the types
of cardiac abnormalities in the small number of pa-
tients, the CVM+/GPC3+ group (12 patients) did not
differ from the CVM+/GPC3− group (7).
DISCUSSION
In SGBS, cardiac abnormalities of any type were in-
deed common (almost one-half of informative cases).
Cardiovascular malformations were present in one-
fourth of all patients, one-third of informative patients,
and almost three-fourths of those with a cardiac abnor-
mality. Almost all were flow-related defects, that is,
simple ASDs and VSDs or simple valve anomalies. Of
interest was the paucity of complex CVMs, such as
conotruncal CVMs (only one patient with d-
transposition of the great arteries), single ventricle (no
patients), and heterotaxy (no patients). One patient
[V-6, Hughes-Benzie et al., 1992] had a “transposed
inferior vena cava and descending aorta,” suggesting
an abnormality of situs but lacking the complex intra-
cardiac CVMs of classic heterotaxy.
The 12% incidence of heterogeneous ECG abnormali-
ties must be viewed with caution. This figure may rep-
resent an intriguing genuine component of the syn-
drome or reporting bias. In some instances, conduction
abnormalities and dysrhythmias might be considered
primary “micromalformations” of the conduction sys-
tem or might arise as the result of myocardial dysfunc-
tion in the form of cardiomyopathy or ischemia. Simi-
larly, the patients with cardiomyopathy were too few
and inadequately defined to draw meaningful conclu-
sions.
Excluding seven elective terminations, 29% of the
SGBS patients in this series died. Nine (31%) had a
cardiac abnormality (in most cases a CVM). However,
data are insufficient to state that any type of CVM
increases mortality among SGBS patients. Neverthe-
less, when the cardiac abnormalities were serious, the
cause of death was likely related to them. The GPC3
mutation was present in most patients (26/37) studied
by Southern blot and polymerase chain reaction ampli-
fication analysis. This high rate may reflect a sampling
bias of the literature and of family studies in which the
initial molecular analysis studied the most classic pa-
tients. In the future, heteroduplex analysis may pro-
vide confirmation in additional patients. At present,
the data are insufficient to speculate about whether
there is a cardiac phenotype/molecular correlation.
SGBS has many similarities to the Wiedemann-
Beckwith syndrome (WBS) [Hughes-Benzie et al.,
1992], and patients with SGBS have been included in-
advertently in reviews of WBS [Niikawa et al., 1986;
Harrod, 1993]. Comparing the patterns of cardiac ab-
normalities in the two syndromes could facilitate diag-
nosis if distinctive patterns existed. An oft-quoted
study of WBS conducted at one pediatric cardiology
center noted a cardiac abnormality in 12 of 13 (92%)
patients, seven of whom (54%) had a CVM [Greenwood
et al., 1977]. An additional five of 13 (38%) had cardio-
megaly or cardiomyopathy. In contrast to the high in-
cidence in that biased sample, two other surveys of
WBS reported a cardiac abnormality in approximately
one-third of patients [Niikawa et al., 1986; Pettenati et
al., 1986]. Single case reports of WBS patients describe
focal cardiomyopathy with ectopic atrial tachycardia
[Kuehl et al., 1986], reversible hypertrophic cardio-
mypathy [Ryan et al., 1986], and lethal hypertrophic
cardiomyopathy [Chitayat et al., 1992]. Based on the
small numbers of reported patients, the incidence of
CVM is about the same in both syndromes. Gauging
the true incidence of cardiomyopathy in either condi-
tion is even more difficult. An accurate comparison of
cardiac abnormalities in SGBS and WBS is not yet pos-
sible. Determining the prevalence and natural history
of cardiac abnormalities in SGBS will require a larger
number of patients and more consistent prospective
cardiac evaluations. There are sufficient data to recom-

mend a baseline cardiology consultation, including
echocardiogram and ECG in SGBS patients.
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