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Familial Congenital Heart Disease I. Genetic and Environmental Factors By KATHRYN H. EHLERS, M.D., AND MARY ALLEN ENGLE, M.D. Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 504 ± + + + + + + -++ -e o0a ++±++± 0 ct 0)CD ± Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 0 Q0- ._ +++ + + ++++± +h +++4++ + ++ ++ + ++ ++ +t- F+ ++ +± + + + + ± + + +-t 0 C bo ._I 0 0 0 0 0 u-0e o b ++ c C) ._ +±±+ .5 UI ± +++ t > = .,~~~~~~~~L 0 PLO~~ C) ce 0> ._ 0 CZ 0 0~~~~~~~~~~~~~C CJ 9-.D 0)~ -. I )CZ C.) (-) .2 ~i ce c c) c C C 44 It) CZ m 1- C X 0)~ CCirculation, Volume XXXIV, September 1966 C\1 WH~ ~Ct_S FAMILIAL CONGENITAL HEART DISEASE + ++ ±++++ ±± + + + ++ + ± Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 ± ++ +± 50o +i+ +±++ +++++±++ + ±++ + + +++ + + + + + + +++ "0 + ++ ±±+++ + + + + + + + + + + c) + + + + ±+ + .( (L) 1- Cc 0 "0 C-4 Cd~0 -4-. 6~4"0 .8R"K. Cd m 1e e^ cn CZ ¢Sd (1)~cQ 4-. > CZ CZ 0 a ;SO; ,0 Ct ;- 66~~~S ¢¢s = ¢ ¢ ¢ o;; ¢ ¢ H6~6 Y Q Q Q QC) > ~ 4-4 -4-4 6 6~ ~ ~c > v v = = v¢ v H v v v H ¢¢ >/ > s U) 60 Vq I-q 6d )oo C0 -.: r-H .0 tS- 6d - 0 00 Circulatuon, Volume XXXIV, September 6)cd 0t c +c Ci 1966 0 e C0i CZ: C' ;L Q ) CZ 1c - 0 C's CO ) 6'a C) C6 ' EHLERS, ENGLE 506 Q 0 ++-- + + -F±-F± ;. CZ + + ± -F 0 U) z Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 +++- +F .4 + + ++ + -F- 0 .0 s<0 0 a<,o 0 C) 0 C)ct /-N Ft v 0 ro P.4 +F -F -F +F ++++t-F-++ . *a 0 0 t. I.-I P.-O 4) CZ F* A- ++++ P-4 4 -FA-+ U v COD ~o ~~ *w ~ " CIaCdC\ -~~~C) Cl) U) nn c °-a ct 00~ ~ T C8 0 Cs IC c ~ E C~ ~ ~~~~~ ClClct l 'a 0l) ZC/) c oU > P.Q>P. -,~ P-4 P-4 > C' 'c C l)cl)xq Cl) In n 0 0~c P'q E. -.,u u I C C E c c > > C's l) r4cl)c Fq > C'E cdf Circulation, Volume XXXIV, September 1966 FAMILIAL CONGENITAL HEART DISEASE 0 .^ _I t 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. . c~CZ + + = ~ +±± + + E 0 CZ -',0 ;-4 CZ C t °~ Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 ±+++ > +± 7~ +-+++++++ + JO > e 1- ¢C II eZ4 .C CO B 0~~ Pi;- Analysis of Cardiac Malformations It was difficult in categorizing the malformations to decide whether intrafamilial de- 4 > = Q>Q¢2 8)1l = EH v v v < A 6Q m 4 E =Co E _~~~~~~~~~~~ > > -- sE _:~ w c) C6 4 4- ta cxs c ;4 c X jm pZ ,fl- September~~~ Circ0ation, $S e 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 I 2 L-J. &-. it * * i * F. it 4* * * OTO 10 ba^~ ** .4** 11 bsH7Aw8TTf Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 + 18 l*l 21 t 0 O F7--Jl-"N L-i- 1-11. El r] .tl 4 . 64.. t 12 ETO 4ito7 15 14 17 4E0_T 1* ** 6 1 9 EHLERS, ENGLE * 8 16 /* 19 6"lb6 i 20 I 22 [27O 23 Ot 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 z 4 TTTTT.t i.t4 at. * 6 5 t #s T4 Et Xb 9 10 11 12 Figure jT ±id Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 Figure 1B 3 ,f * Figure IC 1 3 male or female with congenital cardiac anomaly EJ sex unknown it EtT stillborn male spontaneous abortion twins, dizygotic twins, probably monozygotic i 5at 7 I r,o issue utffspring, number unknown t known dead chromosomal complement analyzed; no abnormality detected ** j chromosomal varient detected * b0 Figure 1D Circueation, Volume XXXIV, SePtember 1966 % X 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 ,,, N o Io 00m $ xlllt , CO m t cI 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 0 o Oo > co0 ci 0 Duration of gestation and weight at birth >of the affected and unaffected individuals did not differ from the general population. Parental Age and Birth Order 6o Zt Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 -+ o 22sC6 t's CZ m co IV tv 0 >~ °°0 a .41 q ; 8 ll |t 6 lln| Zt t n t <+ I11 i <: l| > 0 t°10 CD > -0 0 D> mC.'S< % CZ .t 3 < 4r Z* > 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 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. 13. 14. 15. 16. 1. 2. 3. 4. 5. 6. REFERENCES McKUSICK, V. A.: Genetical view of cardiovascular disease. Circulation 30: 326, 1964. CAMPBELL, M.: Genetics of congenital heart disease and situs inversus in siblings. Brit Heart J 21: 65, 1959. MILLER, R., AND ZERVOPOULOS, E.: Congenital malformation of the heart in siblings. Abstracts of Society for Pediatric Research 1958. Amer J Dis Child 96: 443, 1958. TIETZE, C., GUTTMACHER, A., AND RUBIN, S.: Unintentional abortions in 1497 planned -pregnancies. JAMA 142: 1348, 1950. WARBURTON, D., AND FRAZER, F. C.: Genetic aspects of abortion. Clin Obstet Gynec 2: 22, 1959. NEILL, C. A., AND SWANSON, S.: Outcome of pregnancy in congenital heart disease. Abstract. Circulation 24: 1003, 1961. 17. 18. 19. 20. 21. AND SCHWEISGUTH, O.: Genetic and non-genetic factors in the etiology of congenital heart disease: A study of 1188 cases. Amer J Hum Genet. 9: 17, 1957. BOESON, J. C., MELCHIOR, E. T., AND VENDEL, S.: Extracardiac malformations in children with congenital heart diseases. Acta Paediat (Stockholm) (suppl. 146): 28, 1963. LYNCH, R. J., AND ENGLE, M. A.: Familial congenital complete heart block. Amer J Dis Child 102: 210, 1961. HoLT, M., AND ORAM, S.: Familial heart disease with skeletal malformations. Brit Heart J 22: 236, 1960. ZETTERQUIST, P.: Syndrome of familial atrial septal defect, heart arrhythmia and hand malformation (Holt-Oram) in mother and son. Acta Paediat (Stockholm) 52: 115, 1963. PENROSE, L. S.: Relative aetiological importance of birth order and maternal age in mongolism. Proc Roy Soc (Biol) 115: 431, 1934. PENROSE, L. S. Method of separating the relative aetiological effects of birth order and maternal age, with special reference to mongolian imbecility. Ann Eugenics 6: 108, 1934. PENROSE, L. S.: Familial data on 144 cases of anencephaly, spina bifida and congenital bydrocephaly. Ann Eugenics. 6: 73, 1946. MACINTOSH, R., MERRITT, K. K., RICHARDS, M. R., SAMUELS, M. H., AND BELLOWS, M. T.: Incidence of congenital malformations: Study of 5964 pregnancies. Pediatrics 14: 505, 1954. HEDBERG, K. H.: Maternal conditions in pregnancy and congenital malformations. Acta Paediat (Stockholm) 52: 353, 1963. MCDONALD, A. D.: Maternal health and congenital defect: A prospective investigation. New Eng J Med 258: 767, 1958. GERMAN, J. L., III, EHLERS, K. H., AND ENGLE, M. A.: Familial congenital heart disease: II. Chromosome studies. Circulation 34: 517, 1966. Circulatioe, Volume XXXIV, September 1966 Familial Congenital Heart Disease: I. Genetic and Environmental Factors KATHRYN H. EHLERS and MARY ALLEN ENGLE Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 Circulation. 1966;34:503-516 doi: 10.1161/01.CIR.34.3.503 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1966 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/34/3/503.citation Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. 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