Symposium on Pediatric Cardiology
Association of Congenital Heart Disease with Syndromes or Other Defects
Jacqueline A. Noonan, M.D. *
Children born with congenital heart disease frequently have one or more extracardiac anomalies. When a pattern of malformations, presumably having the same etiology, is recognized, the term malformation syndrome is appropriate. Rubella syndrome, Noonan syndrome, and Holt-Oram syndrome are examples of syndromes frequently accompanied by congenital heart disease. Careful tabulation of associated anomalies may result in a recognized pattern of malformation which, with further delineation, will result in a new syndrome. In this review, I hope to encourage the clinician to look carefully at every child with congenital heart disease for the presence of associated extracardiac defects, disturbance of growth and development, and to ask appropriate questions regarding the prenatal environment and family history. This is how syndromes are recognized. Their recognition is essential for proper management and genetic counseling. Diagnostic and therapeutic advances in congenital heart disease, so far, have exceeded the meager advances made regarding the etiology of cardiac defects. I believe careful studies of large numbers of patients will prove helpful in defining the multiple etiologic factors predisposing to congenital heart disease, so that someday, many of these defects can be prevented. Associated Extracardiac Defects The exact incidence of associated extracardiac defects in children with congenital heart disease is uncertain. Autopsy series report an incidence ranging from 24 to 45 per cent,3B. 56. 75 depending somewhat on the definition of what constitutes a significant malformation. Surprisingly few clinical studies lO , 20, 49, 64 have been carried out. Greenwood et al. 20 studied 1566 consecutive symptomatic infants with congenital heart disease and noted that 25.2 per cent had one or more significant extracardiac anomalies. In a smaller study of 835 patients 49 "Professor and Chairman, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky
Pediatric Clinics of North America - Vol. 25, No.4, November 1978
797
798
JACQUELINE
A.
NOONAN
with congenital heart disease seen in both hospital and outpatient clinic, 29 per cent had at least one associated noncardiac anomaly. Fiftynine of these patients who died were autopsied. Associated anomalies had been noted in 32.2 per cent prior to death and six additional patients were found to have hidden anomalies at the time of autopsy, bringing the total incidence of extracardiac anomalies to 42.4 per cent in the autopsied group. In addition, five patients with known extracardiac anomalies had additional hidden anomalies found at the postmortem examination, including Meckel's diverticulum, hydroureters, and a central nervous system malformation. This postmortem incidence is similar to the 45 per cent incidence of extracardiac anomalies noted by Landtman as in an autopsy study of 777 children with congenital heart disease. The incidence of extracardiac defects varies considerably with the type of cardiac malformation. Greenwood 20 found that more than onethird of the patients with atrioventricularis communis defects, patent ductus arteriosus, atrial septal defect, or malposition defects had associated extracardiac anomalies, whereas those patients with ventricular septal defects, tetralogy of Fallot, corarctation of the aorta, and single ventricle all had an incidence exceeding 20 per cent. On the other hand, extracardiac anomalies are rare in patients with simple Dtransposition of the great arteries. In our study,49 associated extracardiac anomalies occurred more frequently among low birth weight infants, many of whom were small for dates rather than truly premature. Associated anomalies occurred nearly twice as frequently among those infants weighing 2500 grams or less than those above that weight. In a recent study, Levy et al. 40 found that among 132 smallfor-date infants with congenital heart disease, 28.7 per cent had major extracardiac anomalies compared with 19.3 per cent in the normal birth weight group. Among our infants with multiple extracardiac anomalies, over 60 per cent were in the low birth weight group.49 The clinician therefore should be particularly suspicious of an associated defect in the low birth weight infant with congenital heart disease. Table 1 lists a number of malformations easily recognized at birth by careful external examination. It is apparent that with the exception of isolated cleft lip and myelomeningocele, all defects are more common in patients with congenital heart disease. Club feet, hypospadias, and cleft palate occur two to six times more frequently, whereas the other anomalies have at least a lO-fold increase in patients with congenital heart disease. In Greenwood's20 study limited to infants there was a 10- to 20-fold increase in the incidence of tracheosophageal fistula, anal atresia, and omphalocele compared with the findings of McIntosh 43 or Nelson (see Table 1).48 McIntosh4:1 reported that among 5739 births, there were 50' infants with congenital heart disease and four with diaphragmatic hernia. Three of the patients with diaphragmatic hernia were among the group with congenital heart disease,63 suggesting a high association between congenital heart disease and diaphragmatic hernia. Genitourinary malformations are often hidden and may not be recognized during life unless searched for. Of 453 patients 22 with genitourinary malformations, 34 (8 per cent) had congeni-
ASSOCIATION OF CONGENITAL HEART DISEASE WITH OTHER DEFECTS
Table 1.
799
Incidence of Defects in 1000 Births
CONTROL GROUPS OF CONSECUTIVE BIRTHS
PTS. WITH CONGENITAL HEART DISEASE
Down syndrome Cleft palate Cleft palate and lip Cleft lip Club feet Cryptorchidism Hemivertebrae Hypospadias Meningomyelocele Microcephaly Omphalocele Ptosis
McIntosh 5739 Births
Nelson 8684 Births
Noonan 835 Pts.
1.9 0.7 0.7 0.2 5.2 2.9 0.8 2.6 1.2 0.4 0.4 0.5
0.8
32 4.2 4.7
Association of Congenital Heart Disease with Syndromes or Other Defects
Jacqueline A. Noonan, M.D. *
Children born with congenital heart disease frequently have one or more extracardiac anomalies. When a pattern of malformations, presumably having the same etiology, is recognized, the term malformation syndrome is appropriate. Rubella syndrome, Noonan syndrome, and Holt-Oram syndrome are examples of syndromes frequently accompanied by congenital heart disease. Careful tabulation of associated anomalies may result in a recognized pattern of malformation which, with further delineation, will result in a new syndrome. In this review, I hope to encourage the clinician to look carefully at every child with congenital heart disease for the presence of associated extracardiac defects, disturbance of growth and development, and to ask appropriate questions regarding the prenatal environment and family history. This is how syndromes are recognized. Their recognition is essential for proper management and genetic counseling. Diagnostic and therapeutic advances in congenital heart disease, so far, have exceeded the meager advances made regarding the etiology of cardiac defects. I believe careful studies of large numbers of patients will prove helpful in defining the multiple etiologic factors predisposing to congenital heart disease, so that someday, many of these defects can be prevented. Associated Extracardiac Defects The exact incidence of associated extracardiac defects in children with congenital heart disease is uncertain. Autopsy series report an incidence ranging from 24 to 45 per cent,3B. 56. 75 depending somewhat on the definition of what constitutes a significant malformation. Surprisingly few clinical studies lO , 20, 49, 64 have been carried out. Greenwood et al. 20 studied 1566 consecutive symptomatic infants with congenital heart disease and noted that 25.2 per cent had one or more significant extracardiac anomalies. In a smaller study of 835 patients 49 "Professor and Chairman, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky
Pediatric Clinics of North America - Vol. 25, No.4, November 1978
797
798
JACQUELINE
A.
NOONAN
with congenital heart disease seen in both hospital and outpatient clinic, 29 per cent had at least one associated noncardiac anomaly. Fiftynine of these patients who died were autopsied. Associated anomalies had been noted in 32.2 per cent prior to death and six additional patients were found to have hidden anomalies at the time of autopsy, bringing the total incidence of extracardiac anomalies to 42.4 per cent in the autopsied group. In addition, five patients with known extracardiac anomalies had additional hidden anomalies found at the postmortem examination, including Meckel's diverticulum, hydroureters, and a central nervous system malformation. This postmortem incidence is similar to the 45 per cent incidence of extracardiac anomalies noted by Landtman as in an autopsy study of 777 children with congenital heart disease. The incidence of extracardiac defects varies considerably with the type of cardiac malformation. Greenwood 20 found that more than onethird of the patients with atrioventricularis communis defects, patent ductus arteriosus, atrial septal defect, or malposition defects had associated extracardiac anomalies, whereas those patients with ventricular septal defects, tetralogy of Fallot, corarctation of the aorta, and single ventricle all had an incidence exceeding 20 per cent. On the other hand, extracardiac anomalies are rare in patients with simple Dtransposition of the great arteries. In our study,49 associated extracardiac anomalies occurred more frequently among low birth weight infants, many of whom were small for dates rather than truly premature. Associated anomalies occurred nearly twice as frequently among those infants weighing 2500 grams or less than those above that weight. In a recent study, Levy et al. 40 found that among 132 smallfor-date infants with congenital heart disease, 28.7 per cent had major extracardiac anomalies compared with 19.3 per cent in the normal birth weight group. Among our infants with multiple extracardiac anomalies, over 60 per cent were in the low birth weight group.49 The clinician therefore should be particularly suspicious of an associated defect in the low birth weight infant with congenital heart disease. Table 1 lists a number of malformations easily recognized at birth by careful external examination. It is apparent that with the exception of isolated cleft lip and myelomeningocele, all defects are more common in patients with congenital heart disease. Club feet, hypospadias, and cleft palate occur two to six times more frequently, whereas the other anomalies have at least a lO-fold increase in patients with congenital heart disease. In Greenwood's20 study limited to infants there was a 10- to 20-fold increase in the incidence of tracheosophageal fistula, anal atresia, and omphalocele compared with the findings of McIntosh 43 or Nelson (see Table 1).48 McIntosh4:1 reported that among 5739 births, there were 50' infants with congenital heart disease and four with diaphragmatic hernia. Three of the patients with diaphragmatic hernia were among the group with congenital heart disease,63 suggesting a high association between congenital heart disease and diaphragmatic hernia. Genitourinary malformations are often hidden and may not be recognized during life unless searched for. Of 453 patients 22 with genitourinary malformations, 34 (8 per cent) had congeni-
ASSOCIATION OF CONGENITAL HEART DISEASE WITH OTHER DEFECTS
Table 1.
799
Incidence of Defects in 1000 Births
CONTROL GROUPS OF CONSECUTIVE BIRTHS
PTS. WITH CONGENITAL HEART DISEASE
Down syndrome Cleft palate Cleft palate and lip Cleft lip Club feet Cryptorchidism Hemivertebrae Hypospadias Meningomyelocele Microcephaly Omphalocele Ptosis
McIntosh 5739 Births
Nelson 8684 Births
Noonan 835 Pts.
1.9 0.7 0.7 0.2 5.2 2.9 0.8 2.6 1.2 0.4 0.4 0.5
0.8
32 4.2 4.7
