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Familial Incidence of Atrial Septal Defect
A Report of Four Siblings and Review of the ~iterature*
Herman I . Libshitz, M.D., and Klemens H . Barth, M.D.
Four siblings with atrial septal defects confirmed at operation are reported. They
represent the largest sibship with isolated ASD reported to date. Familial aggregation of ASD has been found in single generatioas, and some kindreds have been
traced through several generations. Inheritance follows the multifactorial mode
primarily but in certain families autosomal dominant transmission is evident.
Emphasis is placed on awareness of this congenital heart disease that could result in earlier diagnosis of unsuspected cases in other family members and appropriate genetic counseling.
n estimated 0.7 percent of all live infants born
A
in the United States have congenital heart disease.' Of these, approximately 10 percent have
atrial septal defects ( ASD ) .2 Familial aggregation
of ASD has been reported since 1935.3This study
concerns a single generation of four siblings, all of
whom had isolated atrial septal defects. There is no
parental burden, and there have been no offspring to
date (Fig 1). All four underwent corrective operation.
2/6 systolic ejection murmur was heard at the left sternal
border, and the second heart sound was split. The ECC
showed sinus rhvthm., a PR-interval of .15 seconds. no evidence of left axis deviation and an incomplete right-bundlebranch-block ( RBBB ) . The chest radiograph revealed a
normal cardiac silhouette and slightly dilated pulmonary
vessels. Combined cardiac catheterization and angiocardiography showed findings consistent with an atrial septal defect
of the secundurn type. The pulmonary arterial pressures were
normal. The pulmonary systemic flow ratio (Qp/Qs) was
2:l. Subsequent operation confirmed a secundurn defect 2.5
cm in size. The trunk of the pulmonary artery was found
dilated but without valvular or infundibular stenosis. No
.
Pedigree
Neither parent had evidence of heart disease on routine
cardiac workup during hospitalization for unrelated diseases.
The mother was 30 years of age at her first pregnancy. She
gave birth to five children, four of whom will be discussed
below. The third, a girl, died at two years of age from heart
failure and bronchopneumonia. A diagnosis of congenital
heart disease was made, but the type was unknown. No
autopsy was performed.
This 29-year-old patient, the product of an uncomplicated
pregnancy, with a history of asthma and various allergies was
admitted to Thomas Jefferson University Hospital for evaluation of a systolic heart murmur. Physical examination
showed no abnormalities except for cardiac findings. A grade
'From The Department of Radiology, Thomas Jefferson University Hospital, Philadelphia.
Manuscript received June 18; revision accepted Au ust 23
Reprint requests: Dr. Libshitz, Department of ~ a d i o $ lei~~,
ferson Hospital, Philadelphia 19107
age 39
Typhoid
2
3
,
age
4
age 2
heart
failure
0
= female
= male
Shaded symbols=ASD
FIGURE
1. Pedigree of family.
CHEST, VOL. 65, NO. 1, JANUARY, 1 9 7 4
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FAMILIAL INCIDENCE OF ATRIAL SEPTAL DEFECT
murmur and an accentuated pulmonary second sound. When
he was three years of age, bulging of the left chest wall was
noted. ECG changes of RBBB developed. The PR-interval
was .14 seconds. There was no evidence of left axis deviation.
A chest radiograph showed an enlarged heart and increased
pulmonary blood flow. He was further observed, with the
diamosis
of ASD. Emotional and mental retardation became
"
evident and a diagnosis of childhood schizophrenia was made
at age six. Because his cardiac status deteriorated, he underwent catheterization at 11 years of age. ASD was confirmed,
with Qp/Qs ratio of 2 : l . A year later a 4-cm ostium secundurn defect was closed, with no associated cardiac malformations noted. The body did well physically after operation.
other cardiac defects were present. The patient was well
after operation.
The patient was known to have a heart murmur since she
was six years of age. Her physical development was normal.
She first noted dyspnea and chest pain on exertion at 26 years
of age. She was referred to Presbyterian-University of
Pennsylvania Medical Center for cardiac evaluation. On
physical examination cardiac findings were a grade 4/6
systolic murmur at the left sternal border, and a split second
pulmonic sound. The ECC showed sinus rhythm, a PRinterval of .16 seconds, incomplete RBBB, and no evidence of
left axis deviation. The chest radiograph was compatible with
right ventricular outflow tract enlargement and showed prominent dilatation of pulmonary arteries. Cardiac catheterization
demonstrated a large atrial septal defect, small infundibular
and small pulmonary valvular pressure gradients, but normal
pulmonary artery pressures. The Qp/Qs ratio was 2.4:l.
Subsequent closure of a secr~ndumtype atrial septal defect, 2
x 3 cm, was performed. No associated cardiac defects were
found. The patient was well after operation.
Quite commonly ASD is associated with other
VSD
~
and pulmonary
cardiac m a l f o r m a t i ~ n s . ~
stenosis appear to be most frequent. This is also the
case in Richer'sS series of five siblings with ASD.
The two cases which were confirmed at operation
showed a ventricular septal defect (VSD) and pulmonary stenosis, respectively, as associated defects.
In our series ASD was the only defect (Table 1).
The fifth sibling who died at two years of age in
congestive heart failure had in all likelihood a complex heart abnormality. This is believed to be true
because the mortality for ASD is only 0.7 percent in
the first d e ~ a d e . ~
None of our patients had features of the skeletalvascular ( Holt-Oram ) syndrome. This syndrome described in 1960 by Holt and Oram includes skeletal
malformations of the radial portion of the forearm
and hand, and also of the palate, clavicles, and
sternum. The cardiac malformation is often but not
always a septum secundum defect. This syndrome is
transmitted in the autosomal dominant m ~ d e . ~ * ~ - ' ~
Transmission of the skeletal anomalies varies, and
may only be apparent by pectus exca~atum.~
Except for one report of four siblings with septum
primum defects," only the secundum type ASD has
been reported to date. This might be explained by
the relative infrequency of the primum defect.
Aggregation of ASD in siblings of one or in several generations of a family seems most frequently to
This 24-year-old patient was first noted to have a heart
murmur at age 6 on routine examination. He was then
admitted to Children's Hospital of Philadelphia ( CHOP),
where physical examination revealed slight bulging of the
left anterior chest, and a harsh grade 4/6 systolic heart
murmur loudest over the left sternal border. ECC showed
sinus rhythm, a .15 second PR-interval, right axis deviation
and RBBB. Cardiac catheterization and angiocardiography
confirmed a large ASD and suggested partial anomalous
pulmonary venous return into the right atrium. Advice for
corrective operation was not followed initially. In the next
two years he developed easy fatigability and failed to thrive.
Recatheterization after two and one-half years confirmed the
previous findings with Qp/Qs ratio of 4 : l . A chest radiograph
at this time showed cardiomegaly as well as a typical pulmonary overload pattern. At operation almost complete absence of atrial septum was found. The defect extended within
1 cm of the orifice of the sriperior vena cava. There was no
other cardiac defect. Radiographic changes persisted after
operation, so that three years after closure of the large septal
defect cardiac catheterization was repeated to exclude persisting left-to-right shunt. No shunt was found.
The patient was born prematurely (weight 1.3572 kg). He
was observed at CHOP, and he was found to have a systolic
Table 1-Findings
X-Ray
Patient,, No. Changes
in the Four Siblings with Atrial Septa1 Defects *
ECG PR
Interval,
Sec.
Age a t
Heart
Catherieation
Pulmonary
Systemic
Flow ratio
Qp/Q8
Pulmonary
Wedge
Pressure
Findings a t Operation
Diameter
Associated
of ASD (Cm) Malformations
1
minimal
0.15
29
2:l
normal
2.5
none
2
moderate
0.16
27
2.4:l
normal
2x3
none
3
pronounced
0.15
8
4:l
normal
"large"
none
4
pronounced
0.14
11
2:l
normal
4
none
'Changes on chest roentgenograms: minimal: slight hypervascularity in both lungs; moderate: hypervascularity in both lungs
and prominence of the main pulmonary trunk; pronounced: marked pulmonary hypervascularity and gross cardiac enlargement.
CHEST, VOL. 65, NO. 1, JANUARY, 1974
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LIBSHITZ, BARTH
be the result of both genetic and environmental iduences (multifactorial inheritance).12J3 In
Nora'sls series of 308 patients with ASD and VSD,
26 percent of the children had ASD, an incidence 37
times greater than that in the general population.
Zetterqvist14 and Johann~on'~studied the pedigrees of two families with clustering of ASD and
found inheritance following the autosomal dominant
mode. No visible chromosomal aberrations were
found.16 However, only a few kindreds with apparently dominant mode of inheritance are reported.14
The distinction between the types of inheritance
becomes important for genetic counseling. Some
means of predicting the mode of inheritance have
been explored from a single generation, especially
for the case of dominant autosomal transmission.
Arnarasingham and Fleming1' first pointed out the
association between ASD and A-V conduction defect in a father and two of his children (identical
twins). In another report of several generations of a
family including 16 members with ASD and A-V
conduction defects, Bizzarro et all8 concluded that
this combination of findings is typical for autosomal
dominant transmission and enables prediction of
this mode of inheritance for future offspring. The
validity for this concept is conjectural. None of Zetterqvist'ss 16 cases of one kindred had prolonged
A-V conduction. On the other hand, ASD, either
sporadic or familial in origin, is in 5 to 15 percent of
cases associated with an A-V conduction d e f e ~ t . ~
It has been sKwn that ASD, a common congenital heart defect, occurs not only sporadically but has
an increased incidence in certain families. Better
appreciation of the familial aspects of ASD by all
physicians involved in the care of such patients will
permit earlier diagnoses of unsuspected cases in
other family members. Appropriate genetic counseling will also be possible.
ACKNOWLEDGMENTS: Appreciation is ex ressed to Patricia F. Borns, M.D., Senior Radiologist, ~hilBren'sHospital
of Philadelphia, for the data and permission to use cases 3 and
4, and to Robert G. Trout, M.D., Chief of Thoracic and Cardiovascular Surgery, Presbyterian-University of Pennsylvania
Medical Center, Philadelphia, for the data and permission to
use case 2.
1 Richards MR, Merrit KK, Sarnuek MH, et al: Congenital
malformations of the cardiovascular system in a series of
6,053 infants. Pediatrics 15: 12,1955
2 Nadas AS: Pediatric Cardiology (ed 2 ) Philadelphia, WB
Saunders Co., 1963, p 792
3 Leech CB: Congenital heart disease: Clinical analysis of
75 cases from Johns Hopkins Hospital. J Pediatr 7:802839, 1935
4 Campbell M, Polani PE: Factors in the aetiology of atrial
septal defects. Br Heart J 23:477, 1961
5 Richer TJ, Gallen WJ, Friedberg DZ: Familial atrial
septal defect in a single generation. Br Heart J 34:198200,1972
6 Zetterqvist P, Turesson J, Johansson BW, et al: Dominant
mode of inheritance in atrial septal defect. Clin Genet
2:78-86, 1W1
7 Campbell M: Natural history of atrial septal defect. Br
Heart J 32:820-826, 1970
8 Antia AU: Familial skeletal cardiovascular syndrome
( Holt-Oram) in a polygamous African family. Br Heart J
32:241-244, 1970
9 Holt M, Oram S: Familial heart disease with skeletal
malformations. Br Heart J 22:236-242, 1980
10 McKusick VA: Medical Genetics 1960. J Chronic Dis
14:100, 1961
11 Yao JKY, Thompson MW, Tursler GA, et al: Familial
atrial septal defect of the primum type. Can Med Assoc J
98:218-219, 1968
12 Nora JJ, McNamara DG, Fraser FC: Hereditary factors
in atrial septal defect. Circulation 35:448-456, 1967
13 Nora JJ: Risk to offspring of parents with congenital heart
defects. JAMA 209:2052-2053, 1969
14 Zetterqvist P: Multiple occurrence of atrial septal defect
in a family. Acta Paediatr S a n d 49:741, 1960
15 Johansson BW: Inheritance of atrial septal defect. Lancet
1:1224-1225, 1967
16 Book JA: Association between congenital heart malformation and chromosomal variations. Acta Paediatr Scand
50:217-227,1961
17 Amarasingham R, Fleming HA: Congenital heart disease
with arrhythmia in a family. Br Heart J 29:78-82, 1967
18 Bizzarro RO: Familial atrial septal defect with prolonged
atrioventricular conduction. Circulation 41:677-683, 1970
CHEST, VOL. 65, NO. 1, JANUARY, 1974
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