Download Familial Congenital Heart Disease

Familial Congenital Heart Disease
I. Genetic and Environmental Factors
By KATHRYN H. EHLERS, M.D.,
AND MARY ALLEN ENGLE, M.D.
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ditions such as endocardial fibroelastosis,
idiopathic myocardiopathy, muscular subaortic
stenosis, or Wolff-Parkinson-White syndrome,
in all of which a familial incidence has been
reported.'
The 48 families included 108 members with
congenital heart disease. Fifty-five of the
affected individuals were female. The types
of malformations covered the range of congenital heart disease, with the most frequently
noted ones being those which are most common in the general population: ventricular
septal defect alone in 19 patients, atrial septal
defect of the secundum type in 16 patients,
tetralogy of Fallot or its variants in 17
individuals, and patent ductus arteriosus in
10 patients. The diagnoses are listed in table
1, where the families are divided into four
groups, A to D, according to the relationship
of the affected members. Abbreviated pedigrees of the 48 families are reproduced in
figure 1.
In group A, siblings were affected in 23
families (table LA and fig. 1A). Three sibs
had congenital heart disease in each of three
families. In 20 families, two sibs were affected,
and in two of these families (A 7 and A 18)
an additional relative, a cousin, also had congenital heart disease. The average number
of live-born children in these families was
four. Among the total number of sibs in the
23 families, 49 had a cardiac anomaly and
54 did not. The high proportion of affected
to unaffected individuals may have been due
in part to voluntary limitation of family size
after the birth of the second child with heart
disease. Yet in several families (nos. 6, 9, 11, 13,
15, and 21), two or more healthy children
were subsequently born to those parents.
In group B with 12 families, a parent and
one or more of the children had congenital
heart disease (table LB and fig. LB). In six
W HILE REMARKABLE advances have
been made during the past two decades
in the diagnosis and medical and surgical
management of congenital heart disease, little
progress has been made in understanding
etiology. With the hope that new information
might be gained about environmental factors,
genetic constitution, and their interplay, we
have directed our attention to a group of
families in which there were multiple instances
of cardiac anomaly.
From more than 100 families with such a
history, 48 were selected for study because
the presence of the defect could be proven
in two or more family members. Undoubtedly some of the other families also had multiple
instances of congenital heart disease, and
there may have been additional members with
cardiac malformations in the study group, but
these were excluded if proof of the malformation, by cardiological examination, surgery,
or autopsy was lacking. Unfortunately, for
members of earlier generations, such proof
was usually not available. None of the individuals had a congenital heart defect as part
of a recognized syndrome known to be associated with chromosomal aberration, such
as Turner's syndrome or the autosomal trisomies. Nor did any have a single gene disorder
with cardiovascular involvement, such as
Marfan's, Hurler's, or the Ellis-van Creveld
syndrome. There were no instances of conFrom the Department of Pediatrics, The New York
Hospital-Comell University Medical Center, New
York, New York.
The study was supported in part by the American
Heart Association, and the Tompkins County, New
York, and Essex County, New Jersey, chapters of the
American Heart Association.
This study was undertaken during the tenure of
Dr. Ehlers' research fellowship of the American Heart
Association.
Circulation, Volume XXXIV, September 1966
503
EHLERS, ENGLE
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Circulation, Volume XXXIV, September 1966
FAMILIAL CONGENITAL HEART DISEASE
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families the mother and one of her children
were affected and in two instances a mother
and two of her children had congenital heart
defects. A father and two children all had
congenital heart malformation in two pedigrees. In one family, (B 7) the father, his
only child, and his maternal first cousin had
congenital cardiac defects. The affected children were fraternal twins in family B3 and
identical twins in family B 4. Family B 1
represents the only one with congenital heart
disease of a similar type (atrial septal defect)
possibly occurring in three generations. The
paternal grandfather died at age 43 because
of an atrial arrhythmia and congestive heart
failure attributed to "mitral stenosis"; the
same diagnosis had originally been made in
the father. Unfortunately, no postmortem
examination was available.
Group C includes five families in which
first cousins had cardiac malformations (table
1C and fig. IC). In the eight families in
group D, aunts, uncles, or more distant
cousins were affected (table ID and fig. ID).
One of the individuals (D 8a) in this latter
group had an affected second cousin on both
the maternal and paternal sides of the family.
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Analysis of Cardiac Malformations
It was difficult in categorizing the malformations to decide whether intrafamilial de-
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507
fects were similar or dissimilar. A malformation
present at birth, and therefore congenital, may
change during the patient's lifetime. Examples
are the spontaneous closure of ventricular
septal defects and the natural development
of pulmonic stenosis in patients with ventricular septal defects even to the point of transformation into the cyanotic form of tetralogy
of Fallot. This makes it difficult not only to
decide on intrafamilial similarity but also to
determine the true familial incidence of congenital heart disease.
In some families, it was easy to judge the
anomalies as identical; for example, families
A 2, A 12, B 1, and B 8 had secundum-type
atrial septal defects, and families A 18, A 20,
B 6 and B 10 had patent ductus arteriosus
as the only defect. In other families, the
508
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Figure 1
Abbreviated pedigrees according to relationship of members affected with congenital heart
disease. A. Families of group A with sibs affected. B. Families of group B with parent and
one or more children affected. C. Families of group C with first cousins agected. D. Families
of group D with more distant relatives affected. E. Key to symbols used in pedigrees.
malformations appeared quite dissimilar, as
for instance, in families A 5, B 5, B 9, C 3,
and C 4, in which one member of each family
had coarctation of the aorta and the other
member had a different defect. Judgment of
concordance or the lack of it was more difficult, however, when malformations were multiple and only one part of the anomaly was
common to each affected member (that is,
family A 3 with an abnormality of the mitral
valve in each but with the other anomalies
similar in A 3a and c but not in A 3b).
Several methods of analyzing defects for
concordance have been used. Campbell2 chose
as the criterion the presence or absence of
cyanosis, while recognizing that this often
depended on the severity of a malformation
or the stage at which a particular malformation was considered or both. Miller and Zervopoulos3 divided the anomalies embryologically
into "early" (transposition complexes, tetralogy
of Fallot, and truncus), those which originated
at the time of rotation and involution of the
bulbus cordis, and "late" (patent ductus arteriosus, coarctation, and atrial septal defect),
those which occur at or after the time of
Circulation, Volume XXXIV, September 1966
FAMILIAL CONGENITAL HEART DISEASE
509
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Figure 1B
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Figure IC
1
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male or female with congenital
cardiac anomaly
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spontaneous abortion
twins, dizygotic
twins, probably monozygotic
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chromosomal complement analyzed;
no abnormality detected
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Figure 1D
Circueation, Volume XXXIV, SePtember 1966
%
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index patient
Figure 1E
EHLERS, ENGLE
510
completion of septation. It seems, however,
that our knowledge regarding the factors responsible for specific cardiac malformations
and the times at which such factors can
adversely influence morphogenesis is still too
incomplete for us to categorize defects in this
way.
Recognizing the limitations, we classified
malformations in two ways, on an anatomic
basis and also according to the presence or
absence of a septal defect. From the anatomic
classification (table 2), cardiac malformations
within one family appear as likely to be
as to be similar, except possibly
case of parent and child involvement.
the numbers are too small to be more
dissimilar
in the
Here
than suggestive of greater familial homogeneity.
The malformations were also classified
(table 3) according to whether a septal defect
was or was not present, irrespective of associated malformations. The 24 families with
all affected members having some defect in
septation were further subdivided into those
in which all had an atrial septal defect, or
a ventricular septal defect, or one or the other
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Table 2
Intrafamilial Classification of Congenital Heart Disease According to Anatomy
Families
with:
Sibs
affected
(group A)
Parent and one or
more children
affected
(group B)
Other
relatives
affected
(groups C and D)
Total
number
of families
Malformations
9*
25
5*
11*
similar
Malformations
23
8
3
12
dissimilar
*Malformations similar in two of three affected individuals in families A 3, B 4, and C 2.
Table 3
Intrafamilial Classification of Congenital Heart Disease According to Presence or
Absence of Separation Defect (with or without Associated Cardiac Malformation)
Sibs
Families with:
Septal defect present
in all affected members:
Ventricular septal
defect in all
Atrial septal defect
in all
Atrial septal defect
in 1 or more and
ventricular septal
defect in other or
others
Septal defect absent in
all affected members:
Malformation similar
Malformation dissimilar
Septal defect present in
1 or more but not in all
affected members
Malformations not completely clarified
affected
(group A)
Total
Other relaParent and one
number of
or more children
tives affected
families
affected (group B) (groups C and D)
10
6
8
24
5
4
5
14
4
2
1
7
1
0
2
3
5
5
3
3
1
1
9
9
0
0
0
0
6
2
3
11
2
1
1
4
Circulation, Volume XXXIV, September 1966
FAMILIAL CONGENITAL HEART DISEASE
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type of defect. Of the nine families in which
no affected member had a septal defect, the
cardiac malformations were identical within
each family. In only 11 families were the
cardiac malformations dissimilar by this method of analysis, in that a septal defect was
present in one or more but not in all of the
affected members. Thus, this type of classification resulted in more intrafamilial defects
being classified as similar.
Both of these methods may result in malformations which are functionally quite variable being categorized as similar. This functional variability, however, may not be
etiologically important. Even in the same
anomaly, function varies with severity. These
methods may also lead to the classification
as dissimilar of defects that may have been
alike at birth. For instance, in family A 10,
did the brother have spontaneous closure of
his ventricular septal defect as he acquired infundibular pulmonic stenosis? These attempts
at classification illustrate some of the problems and raise the question of whether it is
meaningful to try to determine similarity
even if it could be done with certainty. An
identical anomaly can result from a variety
of causes (for example, patent ductus in
certain families or from maternal rubella),
and the same etiological agent can produce
varied anomalies (for example, patent ductus
arteriosus or ventricular septal defect or other
cardiac defects in babies whose mothers had
rubella early in pregnancy).
Analysis of Families
Ethnic Groups
Thirty-six families were of mixed Caucasian
stock including two of Puerto Rican origin.
There were three Negro families and nine
Jewish families. No Mongoloid families were
represented.
Consanguinity
None of the individuals affected was the
offspring of a first-cousin marriage, but in
one family (A 12) with two siblings with
atrial septal defect the parents were second
cousins. In one pedigree with cousin involvement (D4), the grandparents of D4b were
Circulation, Volume XXXIV, September 1966
Sll
said to be "distant cousins." In another pedigree (D 2), the great grandparents of D 2a
were first cousins, and the paternal grandparents of D 2b were more distant cousins.
Twins
In the 48 families there were four sets of
twins in which either one or both of the pair
had congenital heart disease. In family B 4,
the mother (a) with acyanotic ventricular
septal defect and moderate pulmonic stenosis
had twin daughters (b and c), each with a
ventricular septal defect, one of whom required treatment for cardiac failure in infancy.
These twins are considered to be identical
in that they agreed in 17 blood group antigens and were similar in respect to other
genetic traits for which they were examined.
In family D 8, twin D 8c had an atrial
septal defect and her sister, probably an
identical twin on the basis of similar major
blood group and Rh factor and appearance,
had no cardiac defect. Family B 3 consisted
of a father and his fraternal twin children,
all of whom had supravalvular aortic stenosis.
In a fourth family (C 1) in which first
cousins had congenital cardiac malformations,
the fathers appeared to be identical twins and
the male cousin had a twin sister with no
heart defect.
Outcome of Pregnancy
Pregnancy in the families of groups A, B,
and C resulted in a high incidence of congenital heart disease and of fetal loss (table
4), whether the parent did or did not have
a cardiac defect. Three other individuals (A
12a, A 12b and D la) were more fortunate
as parents; each of six pregnancies resulted
in a healthy child.
The incidence of stillbirth and abortion in
the general population is not known, but
most estimates place it in the range of 6 to
20% of all pregnancies, with a mean of approximately 10%.4 5 A fetal wastage of 27% in
group B is consistent with that of 24% reported by Neill and Swanson6 in patients with
congenital heart disease who had 122 miscarriages in 508 pregnancies. The greatest
fetal loss in that report was associated with
EHLERS, ENGLE
512
Table 4
Outcome of Pregnancy
Congenital
Families
Pregnancies
heart
disease
Fetal loss
Live-born
101
29
49
10
18.0
20.6
29
16
27.0
10
Parents without congenital heart disease
125
23
Group A
34
10
Group C
Parent with congenital heart disease
37
12
Group B
(%)
(1-12a)
our study none
of the affected parents were cyanotic, although two had ventricular septal defect with
systemic pressure in the right ventricle and
a balanced shunt (B 4a and D la).
cyanosis in the mother. In
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Noncardiac Malformations
All recognized abnormalities of other syswere recorded. A comprehensive survey
was not made to discover silent anomalies of
the gastrointestinal or genitourinary systems
by roentgenological techniques.
In the individuals with congenital heart
disease, other malformations were detected
tems
in 22 or 22% (table 1). This is similar to
the increased incidence reported by others,
who found rates around 5 to 20%.7-11
Abnormalities of the hand were present in
six individuals. In a Negro family A 16, a
brothber and a sister with complete heart block
had polydactyly as did three of their five
sibs, two of their maternal uncles, and their
maternal grandmother.12 Another family B 8
of interest in that the mother and daughter had secundum-type atrial septal defects
(fig. 2, left and right), now surgically repaired,
and both also had multiple anomalies of the
was
Figure 2
Preoperative roentgenograms of chest of mother, B 8a (left) and daughter, B 8b (right)
showing enlargement of heart, main pulmonary artery, and branches. Note unusual bowing
of clavicles, which in both subjects is associated with marked laxity of the shoulder girdle.
Circulation, Volume XXXIV, September 1966
513
FAMILIAL CONGENITAL HEART DISEASE
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Figure 3
Abnormalities of hands of the mother on the left and daughter on the right in family B 8.
hands, arms, and shoulder girdle (figs. 3 and
4). This association of malformations was originally reported by Holt and Oram and
subsequently further detailed by others.'3 14
Inguinal hernias were found in six patients.
Family B 3 was of especial interest in this
regard in that the father and his fraternal
twin children with supravalvular stenosis all
had bilateral inguinal hernias, as did his
father and mother. Other anomalies included
mental deficiency in two (A 13b and D 2b),
strabismus in A 6b and B 4a, encephalocele in
A ic, visceral heterotoxy and agenesis of the
spleen in A 8b, and genitourinary and skeletal anomalies in A lla.
Among the sibs of the 108 persons with
congenital heart disease, noncardiac malformations occurred in 15 (14%). Data from
other workers showed a lower incidence of
1 to 3% in normal sibs when only one child
in the family had a heart defect.9' 10
In children born to parents with congenital
heart disease, the risk of noncardiac defects
is not clear. Among the 35 live-born children
of 15 parents with congenital heart disease
in this study, no other anomalies were-noted.
Neil and Swanson6 reported 22 instances of
noncardiac malformation in the children resulting from 508 pregnancies in which one
Circulation, Volume XXXIV, September 1966
Figure 4
Roentgenograms of hands of daughter, B 8b, showing
bilateral hypoplastic phalanges of the thumb with
absence of the normal skin segmentation between
the thumb and hand. The first metacarpals are hypoplastic. Not shown are the other skeletal anomalies:
slight bilateral subluxation of radii at the elbows and
spina bifida of the upper part of the sacrum. (Roentgenograms of forearms and hands of the mother,
B 8a, are not shown but reveal absence of the left
thumb, abnormalities of the carpal bones, and shortening and bowing of the left ulnar and rudimentary
radius. Changes in the right arm and hand are less
marked.)
514
EHLERS, ENGLE
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parent had congenital heart disease. Campbell9 reported the occurrence of noncardiac
lmalformation in 4.4% of 90 children born to
individuals with congenital cardiac malformation.
Birth Weight and Length of Gestation
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>of the affected and unaffected individuals did
not differ from the general population.
Parental Age and Birth Order
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In considering parental ages and birth order
22 families (A I to 18 and B l to 4) with
either two or three sibs affected with congenital heart disease were analyzed. Groups
cn
0 |B, C and D were too small to be analyzed
4separately, and it did not seem appropriate
to consider all the families as one large group.
Mean maternal and paternal ages calculated
for the 47 affected individuals of the 22 families did not differ significantly from that calculated for the comparison group of 43 unaffected normal sibs in these same families
(table 5). When the raw figures were
analyzed by the method of Penrose15 to take
into account the factor of family size, these
nonsignificant differences were confirmed. No
age disparities between parents could be
detected for either the normal sibs or for
those with congenital heart disease.
Birth order is another variable which might
influence abnormalities in offspring. Because
of the close correlation of birth rank with
l i
mmaternal and paternal ages, a method of
separating the respective influences of these
factors was devised by Penrose.15 17 By using
this method, an expected mean birth rank
was*°calculated
for individuals with congenital
|
[
heart disease as 3.4, whereas the actual birth
E
rank was 3.5 with a standard error of 0.3.
Therefore, agreement with the assumption
O t X Sof random occurrence of affected individuals
was supported. This lack of relation of
parental ages or birth rank to occurrence of
congenital heart disease in two or more members of one family is consistent with the
lack of relation found in nonfamilial cases
of congenital cardiac malformation.9
Circulation, Volume XXXIV, September 1966
515
FAMILIAL CONGENITAL HEART DISEASE
Seasonal Incidence of Births
The seasonal incidence of births was analyzed for all families with either two or three
children with congenital heart disease (A 1
to 23 and B to 4). While births of individuals
with congenital cardiac anomalies were fairly
evenly divided between the first and second
halves of the year (30 from January to June
and 27 from July to December), more of
their normal sibs were born in the second
half of the year (36 of 55).
Complications of Pregnancy
An attempt was made to obtain
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a detailed
gestational history for each affected person
and his normal sibs. It was apparent that
in most instances such information obtained
retrospectively, often at long intervals after
the pregnancies, was incomplete and inaccurate. Efforts to contact the physicians or
hospitals for review of records also proved
unsatisfactory because of incomplete recording of medications and gestational events.
None of the pregnancies took place in an
area of high altitude, and there was no unusual exposure to radiation. Of the pregnancies
that resulted in a cardiac anomaly, 12 were
complicated by first-trimester bleeding. There
were two instances of "flu" in the first trimester and none of rubella. Types of medications taken during pregnancy, except for
vitamin and mineral supplement, were often
not known. We thought it unusual, though
perhaps of no significance, that in two families
with sibs affected with congenital cardiac
malformations (A 5 and A 11) the mothers
had epilepsy and were taking two or more
medications for control of seizures. To our
knowledge there is no increased risk of congenital malformation in the offspring of
women with seizure disorders, whether receiving anticonvulsant medication or no
therapy.
In the- literature, few prospective studies
are available in which an attempt was made
to tabulate gestational events (in particular,
medications, illness, diet, and the character
of the placenta) and correlate them with
the occurrence of fetal death or with defects
in the offspring.1820 Only the first of these
Circulation, Volume XXXIV, September 1966
studies provided repeated examinations of the
infants to 6 to 12 months of age. The prospective study should yield accurate documentation of gestational events but has the
disadvantage that, when the incidence of the
condition is as low as that of congenital
cardiac defects, an enormous number of
pregnancies must be considered to yield
statistically significant results. Pooling of data
from multiple sources could be helpful, providing the data are collected in a uniform
manner and the offspring are examined not
just through the first year of life but also
around the ages of 2 and of 5 years.
Chromosomal Studies
Of 35 families in which the chromosomal
complement could be analyzed in the index
case (the first member of the family with
congenital heart disease to be so studied),
and in other affected and unaffected relatives,
four families were found to have slight
morphological variations in the autosomes
that were identifiable in more than one generation. The detection and possible significance
of these observations are discussed in Part II
of this report.21
Comment
Possibly, in the future, an increased understanding of some aspects of etiology of
congenital cardiac anomalies, especially when
there is familial clustering of defects, may
lead to modifications that could prevent deformity. The studies in these families with
multiple occurrences of heart disease show
how much more information is needed concerning environmental and genetic influences.
We plan to keep these families under observation, as new members are added, as new
families are added, and as newer methods of
studying environmental and genetic factors
are developed.
Summary and Conclusions
A group of 48 families in which multiple
instances of cardiac anomalies occurred was
examined to see whether any environmental
or genetic factors, acting singly or together,
could be found to account for the increased
familial incidence of defect.
EHLERS, ENGLE
516
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The cardiac malformations included the
range of congenital heart disease, with the
most frequent being those which are common
in the general population. Among t-he families
with congenital heart disease in sibs, and in
the families in which a parent and a child had
a cardiac defect, half of the children had
congenital heart disease. Noncardiac anomalies
occurred in 20% of those with a cardiac defect
and in 10% of their sibs, an increased incidence
for both.
No environmental factors could be identified
but prospective studies are needed to correlate
events of the pregnancy with normal or abnormal development.
Although genetic factors seem to be important, we were unable to muster evidence to
favor any one genetic hypothesis. Studies of
chromosomes disclosed small morphological
variations in a few of the families. These
are discussed in Part II of this report.
Acknowledgment
We are grateful to Dr. Melvin S. Schwartz and
Mr. Joseph J. Brogan, Jr., of the Division of Biometrics, Cornell University Medical College, for the
statistical analyses relating to parental age, birth
rank, and the seasonal incidence of birth.
7. MACMAHON, B., MCKEOWN, T., AND RECORD.
R. G.: Incidence and life expectation of
children with congenital heart disease. Brit
Heart J 15: 121, 1953.
8. RICHARDS, M. R., MERRITT, K. K., SAMUELS,
M. H., AND LANGMANN, A. G.: Congenital
malformations of the cardiovascular system in
a series of 6053 infants. Pediatrics 15: 12,
1955.
9. CAMPBELL, M.: Causes of malformations of the
heart. Brit Med J 2: 895, 1965.
10. LAMY, M., DEGROUCHY, J.,
1 1.
12.
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Circulatioe, Volume XXXIV, September 1966
Familial Congenital Heart Disease: I. Genetic and Environmental Factors
KATHRYN H. EHLERS and MARY ALLEN ENGLE
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Circulation. 1966;34:503-516
doi: 10.1161/01.CIR.34.3.503
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