Extra Cardiac Anomalies (ECA) in 2020 Subjects with Congenital Cardiovascular Malformation (CCVM) and Control: Etiological Perspective
Abdullah A. Alabdulgader
The main objective of this research was to analyze the spectrum of Congenital Cardiovascular Mal-formations (CCVM), Congenital Cardiovascular Malformation (ECA), the frequency of extra-cardiac malformations, extra cardiac anomalies and the proportion of chromosome aberrations among live born infants in order to generate hypothetical theories of congenital cardiovascular malformation etiology. It was found that out of 1010 congenital cardiovascular malformation, 288 were affected by extra cardiac anomalies (28.5%). Among the most common congenital cardiovascular malformations, Atrioventricular Septal Defect was associated up to 72% with extra cardiac anomalies while Dextro-transposition of Great Arteries was related only up to 8.7%. The syndromes were the common extra cardiac anomalies (37%) with congenital cardiovascular malformation. Overall, in live born infants, the congenital cardiovascular malformations were quite common and these were often associated with other cardiovascular and extra-cardiac malformations, as well as with chromosome anomalies. However, the complex heart defects such as hypoplastic left heart syndrome and double outlet right ventricle were infrequent in live born infants.
Received: April 24, 2012;
Accepted: April 26, 2012;
Published: August 11, 2012
Various epidemiological studies have shown that in live born infants the incidence
of congenital heart defects is between four and eight per 1000 (Ferencz
et al., 1993, 1985; Hoffman
and Christianson, 1978; Mitchell et al., 1971).
We confirmed, higher incidence of congenital cardiac malformations in Saudi
population, than most of all incidence figures in medical literature, up to
10.67 per 1000 live birth (Alabdulgader, 2001). Samanek
et al. (1985) stated that in stillborn infants, the incidence of
congenital heart defects was 10 times higher than that of live births (Samanek
et al., 1985). The etiology of most Congenital Heart Defects (CHD)
is unknown; only around 15% of them can be attributed to a known cause (Botto
and Correa, 2003). Approximately 5-10% are associated with a chromosome
abnormality, 35% can be linked to defects in single genes and about 2% are attributed
to known environmental factors (Clark, 2001).
According to Ferencz et al. (1993), in Baltimore-Washington
infant study during 1981-1989, the frequency of associated congenital cardiovascular
malformation with extra cardiac anomalies in live births was quite variable
in different studies. e.g., from autopsy series, it ranged from 13-37%, while
from clinical series the range was 9-42%. Overall, these were 27.71% in the
study cases vs. 3.4% in controls (Ferencz et al.,
In fact extra cardiac anomalies incidence is defect specific. Ferencz
et al. (1993) revealed that extra cardiac anomalies is associated
with 9% of cases with dextro-transposition of great arteries, compared to 51%
with atrioventricular septal defect. Congenital cardiovascular malformation
may occur at similar vulnerable time with other systems.
Syndromes such as Noonan, Cornielia De Lange, Holt oarm, Seckle, Vacterl, William
and Marfan are the most common extra cardiac anomalies in congenital cardiovascular
malformation cases: For example down-syndrome is frequent in 9% of the cases,
the most dominant chromosomal group (Ferencz et al.,
1993). The specifity of down syndrome is well associated with certain congenital
cardiovascular malformation (Rowe and Uchida, 1961).
On the other hand, it has been revealed that 75% of the cases are left ventricular
outfow track obstruction (turner syndrome) (Ferencz et
al., 1989b). While it is also being mentioned that 50% of cases affected
with pulmonary stenosis are associated with Noonan syndrome (Van
der Hauwaert et al., 1978). Frequency involvement of congenital
cardiovascular malformation with different body systems (Greenwood
et al., 1975) is presented in descending order as Musclo-skeletal
(8.8%), syndrome (Noonan, Cornielia De Lange, Holt oarm, Seckle, Vacterl, William
and Marfan) (8.5%), central nervous system (6.9%), renal-urinary (5.3%), gastro-intestinal
tract (4.2%), respiratory (3.8%) and hematological (<1%). In general there
is a paucity of extra cardiac anomalies association with Dextro-Transposition
of great artery which amount only to 9% (Losekoot and Becker,
The present study attempts to investigate associations of congenital cardiovascular malformations, frequency of extra cardiac malformations and the proportion of chromosome aberrations among Saudi live born infants contributing to unravel some of the congenital heart defects mysteries.
MATERIALS AND METHODS
During a period of 52 months, congenital cardiovascular malformation clinical findings were performed at Prince Sultan Cardiac Center (PSCC). A total of 1010 live born infants aged between 0-13 years were categorized in 10 groups.
Investigations were carried out using CXR, Echo Cardiograph, Echocardiography w/o Cathartic and surgery, Others procedures include, CT-Scan and Skeletal survey Muscle.
Biopsy, Barium studies, chromosomal analysis and electrophoresis etc, were performed for cytogenetic analysis and determination of chromosomal aberrations. Metabolic screening was also performed. Congenital cardiovascular malformation were defined as gross structural abnormality of the heart or intra-thorasic great vessels that is actually or potentially of functional significance.
Minor extra cardiac anomalies with no potential increase of morbidity and mortality were excluded. Extra cardiac anomalies were categorized into 9 major groups including chromosomal and non chromosomal syndromes.
Statistical analysis: Data management and statistical analysis were
conducted using Statistical Analysis System (SAS/STAT Software,
2004) 2004 version 9.1 computer software package applying conditional logistic
regression and specialized macros for fine matching and stratification (SAS/STAT
For the case-control design, every effort was ensured to match controls to cases based on certain factors in order to minimize inherent variation within these factors. So, for a valid analysis, a modeling technique that correctly incorporates the matched nature of the data was performed. Strength of association was measured by odds ratio and tested statistically (p value of significance less than 0.05).
RESULTS AND DISCUSSION
The congenital cardiovascular malformation spectrums, diagnosed clinically, were ventricular septal defect (35%), atrial septal defect (12%), pulmonary stenosis (10%), patent ductus arteriosus (08%), tetralogy of fallot (05%), atrioventricular septal defect (04%), aortic stenosis (04%), coarctation of the aorta (03%), dextro-transposition of great arteries (02%) and others (18%) as shown in Fig. 1.
Frequency of extra cardiac anomalies, with and without chromosome syndromes, associated with different cardiac lesions are presented in Table 1. In terms of extra cardiac anomalies and congenital cardiovascular malformation association, overall 288 cases (28.5%) were associated with extra cardiac anomalies as compared to 10.6% extra cardiac anomalies incidence in the control (Fig. 2). The odd ratio for this association was highly significant (p<0.05) which amounted to almost 3.0.
|| Distribution of various CCVM lesions in 1010 subjects
|| CCVM and ECA association for cases as compared to control,
ECA: Extra cardiac anomiles
||Frequency of extra cardiac anomalies, chromosomally and non-chromosomally
syndromes associated with different cardiac lesions (congenital cardiovascular
|MK: Musculo-skeletal, RS: Respiratory system, CNS: Central
nervous system, GU: Genito-urinary, GI: Gastro-intestinal, HE: Hematological,
NCH: Non-chromosomal, CH: Chromosomal (Figures in braces show the% for each)
In order of the most frequent extra cardiac anomalies with various congenital cardiovascular malformation categories, these were: Atrioventricular septal defect (72.10%), coarctation of the aorta (51.85%), atrial septal defect (34.68%), tetralogy of fallot (30.44%), pulmonary stenosis (28.125%), patent ductus arteriosus (28.395%), ventricular septal defect (26.2%), aortic stenosis (25.0%), dextro-transposition of great arteries (8.70%) and others (17.877%) as presented in Table 1.
The most frequent of these anomalies involved were the Syndromes(such as Noonan, Cornielia De Lange, Holt oarm, Seckle, Vacterl, William and Marfan) (37.15%), central nervous (15.27%), hematological (12.50%), gastro-intestinal tract (9.02%), musculo skeletal (7.29%), genito urinary (6.25%), others (3.27%) and respiratory (1.04%) as shown in Table 2 and Fig. 3.
Congenital cardiovascular malformation frequencies found in various chromosomally abnormal groups were 26 out of 43 cases of atrioventricular septal defect, 25 of the 355 cases of ventricular septal defect, 5 of the 46 cases of tetralogy of Fallot, 9 out of 81 cases of patent ductus arteriosus, three of the 27 cases of coarctation of the aorta, 11 of 124 of atrial septal defect, a single case of 36 cases of Aortic stenosis and 0 cases of pulmonary stenosis and transposition of great artery (Table 1).
Percentage-wise these were: Atrioventricular septal defect (61%), patent ductus arteriosus (11%), tetralogy of fallot (11%), coarctation of the aorta (11%), atrial septal defect (9%), ventricular septal defect (7%), aortic stenosis (3%), pulmonary stenosis (0%) dextro-transposition of great arteries (0%), others (5%) and total (9%) are presented in Table 1.
Significant statistical associations between specific cardiac lesions and specific body systems are presented in Table 3.
Overall, 81 chromosomally abnormal cases out of 88 were linked with down syndrome.
||Frequency of extra cardiac anomalies in CCMV according to
|| Specific cardiac lesion to specific systems statistical associations
|Significant: **p value<0.05, Highly significant: ***p value<0.001
||Chromosomal syndromes associated with 1010 patients with congenital
None of all these cases had an isolated congenital cardiovascular malformation
(Table 4). These were all either accompanied by other congenital
cardiovascular malformation or extra cardiac anomalies. Distributions of congenital
cardiovascular malformation (Ventricular Septical Defect (VSP), Atrial Septical
Defect (ASD), Atrioventricular Septical Defect (AVSP), Tetralogy of fallot (TOA),
Patent Ductus Arteriosus (PDA) and Others) in these 81 cases was presented in
In contrast, cases with Dextro-transposition of the great arteries, pulmonary
valve stenosis/pulmonary valve atresia, had a normal karyotype.
||Bar diagram comparing cases and controls for the different
systems with corresponding p-value, MK: Musculo-skeletal, Rwsp: Respiratory
system, CNS: Central nervous system, GU: Genito-urinary, GIT: Gastro-intestinal
tract, HEM: Hematological, SYND: Syndrome
||Distributions of various cardiac lesions in 81 mongoloid individuals
Atrioventricular septal defect was the commonest type of congenital heart
defect in cases of chromosome anomaly. This is in agreement with the Baltimore
infant study where trisomy 21 and trisomy 18 were more often associated with
atrioventricular septal defect or ventricular septal defect than with coarctation
of the aorta or tetralogy of Fallot. In the Baltimore study (Ferencz
et al., 1993), 9 of the cases were associated with trisomy 21, 3
with trisomy 18 and 1 with trisomy 22.
The non-chromosomal syndromes diagnosed in congenital cardiovascular malformation population were presented in Table 5.
||Non-chromosomal syndromes in 1010 patients with congenital
Association with extracardiac anomalies: In the present population,
288 cases (28.5%) with congenital cardiovascular malformation also had extra
cardiac anomalies. This high proportion of extra cardiac anomalies reflects
the detailed ultrasonic and comprehensive investigations which took into account
all the presented cases. This is in agreement with the Baltimore infant study
where 27% of the congenital heart defects were associated with extra cardiac
anomalies (Ferencz et al., 1987). Interestingly,
these results were at variance with higher findings of (66%) (Tennstedt
et al., 1999). However, it is worth to mention that their findings
were necropsy-based while the present results were clinically founded.
The most frequent extra cardiac anomalies were found in the central nervous
system, the kidneys, the urinary tract and the genital system and the gastrointestinal
system; malformations of the respiratory system and the skeletal system were
less common. Similar findings were reported by Ferencz et
al. (1993) in the Baltimore infant study where the most frequent extra
cardiac anomalies were in the central nervous system, the eyes, the gastrointestinal
system and the kidneys, urinary tract and genital system, as well as of the
abdominal wall (Ferencz et al., 1987).
It was noted in the Baltimore study (Ferencz et al.,
1993) that majority of cases of transposition of the great arteries and
right and left sided obstructive defects were not associated with extra-cardiac
anomalies, whereas in the present study only two cases of transposition of the
great arteries were associated with an extra cardiac malformation. For malformations
of the outflow tract, a combined ratio of isolated extra cardiac anomalies were
given, 1:2.5 (Lurie et al., 1995).
Chromosome abnormalities: In the present study, overall association
between chromosome abnormalities and cardiac defects was observed in 9% of all
congenital cardiovascular malformation cases. The highest incidence was observed
in atrioventricular septal defect (61%) group followed by patent ductus arteriosus
(11%), tetralogy of fallot (11%), coarctation of the aorta (11%), atrial septal
defect (9%), ventricular septal defect (7%), aortic stenosis (3%), while pulmonary
stenosis (0%), dextro-transposition of great arteries (0%), cases lack any association.
Most of these associations were associated with down syndrome. In the Baltimore
infant study (Ferencz et al., 1987), trisomy
21 was the most frequent abnormality associated with congenital heart defects,
followed by trisomy 18, trisomy 13 and monosomy X (45, X).
In a comparative study (Tennstedt et al., 1999),
ventricular septal defect, atrioventricular septal defect, hypoplastic left
heart and double outlet right ventricle were associated with the highest rates
of chromosome abnormalities, in contrast to cases with simple vascular obstruction
or malformations such as pulmonary valve stenosis/pulmonary valve atresia, tricuspid
atresia and transposition of the great arteries, where there was a low prevalence
of chromosome anomalies.
Prenatal investigations Chaoui et al. (1996)
showed a higher rate of chromosomal abnormalities in fetuses with congenital
heart defects (22%) than among live births. In an analysis of fetuses with heart
defects (Gembruch et al., 1991), the authors found
chromosome abnormalities in 28%. The incidence of congenital heart defects and
chromosome abnormalities in fetuses is higher than in live born infants or stillbirths
as the fetuses often do not survive until birth and are therefore, not included
in statistical data collected by pediatric cardiologists (Allan
et al., 1991, 1994; Copel
et al., 1988). Up to now aborted fetuses have not been included in
investigations of the genetic basis of heart defects (Debrus
et al., 1996).
The molecular/genetic basis of many congenital cardiac defects has been elucidated
in recent years as a result of new insights into the molecular control of developmental
events. The discovery of cardiac regulatory gene networks has allowed for genetic
testing for cardiac disease genes. Progress in molecular techniques has allowed
the discovery of several genetic factors associated with congenital cardiovascular
malformation. For example, conotruncal heart defects such as tetralogy of Fallot,
truncus arteriosus communis, double outlet right ventricle and transposition
of the great arteries, together with various types of ventricular septal defects,
are associated with a micro-deletion on chromosome 22. (Goldmuntz
et al., 1998; Momma et al., 1997,
1995, 1996; Johnson
et al., 1995; Merscher et al., 2001;
McElhinney et al., 2003; Frohn-Mulder
et al., 1999; Lewin et al., 1997;
Takahashi et al., 1995).
Alagille syndrome and Holt-Oram syndrome as single-gene disorders reflect genes responsible for congenital heart defects and for multiple other clinical features.
Mutations in Nkx2-5 cause a spectrum of congenital heart defects (Basson
et al., 1997) including cardiac conduction abnormalities, Ventricular-septal
Defects (VSDs) and Atrial-septal Defects (ASDs). Mutations in Tbx5 are responsible
for Holt-Oram syndrome (Lindsay et al., 2001).
An autosomal dominant disorder associated with structural and functional cardiac
defects and deletion of Tbx1 results in malformations of the cardiac outfow
tract and ventricular-septal defects due to failure in the migration of neural
crest cells to the heart (Merscher et al., 2001).
Mutations in GATA4, some of which disrupt its interaction with Tbx5, cause atrial-septal
defects and ventricular-septal defects (Garg et al.,
2003) and Alagille syndrome (Li et al., 1997).
Deletions in the jagged1 gene which encodes a signaling molecule in the Notch
pathway, have been identified in patients with this syndrome.
In summary congenital cardiovascular malformation and extra cardiac anomalies associations and incidence of frequent chromosomal aberrations in Saudi population reflect importance of underlying genetic factors which may have pleiotropic effects and shared common pathways. In this context molecular and bioinformatic approaches uncovering regulatory gene-networks may provide insights needed to understand cardiogenesis and congenital cardiovascular malformation etiology.
Association of congenital cardiovascular malformation with extra cardiac anomalies is well documented. Out of 1010 congenital cardiovascular malformation, 288 are extra cardiac anomalies affected (28.5%). Atrioventricular septal defect is the most common congenital cardiovascular malformation associated with extra cardiac anomalies (72%) while dextro-transposition of great arteries is the lowest (8.7%). Syndromes such as Noonan, Cornielia De Lange, Holt oarm, Seckle, Vacterl, William and Marfan were the most common extra cardiac anomalies associated with congenital cardiovascular malformation to the level of 37%. Statistically significant association has been proven between some congenital cardiovascular malformation and certain systems. This is an important evidence to the multiple types of genetic factors in the etiology of congenital cardiovascular malformation. Better knowledge of congenital cardiovascular malformation with extra cardiac anomalies and establishment of congenital cardiovascular malformation nationwide registry (which is at its terminal stage now) should solve some of the mysteries of cardiac dysmorphogenesis in human.
The study was supported by a grant from KACST (King Abdulaziz City for Science and Technology) and by a MERIT award to DR. Abdullah A. Alabdulgader principal investigator. Help and support from Dr. Kamal Almubark, consultant pediatric cardiologist during data collection is greatly appreciated.
1: Allan, L.D., G.K. Sharland, A. Milburn, S.M. Lockhart and A.M.M. Groves et al., 1994. Prospective diagnosis of 1006 consecutive cases of congenital heart disease in the fetus. J. Am. Coll. Cardiol., 23: 1452-1458.
2: Allan, L.D., G.K. Sharland, S.K. Chita, S. Lockhart and D.J. Maxwell, 1991. Chromosomal anomalies in fetal congenital heart disease. Ultrasound Obstet. Gynecol., 1: 8-11.
3: Basson, C.T., D.R. Bachinsky, R.C. Lin, T. Levi and J.A. Elkins et al., 1997. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet., 15: 30-35.
4: Botto, L.D. and A. Correa, 2003. Decreasing the burden of congenital heart anomalies: An epidemiologic evaluation of risk factors and survival. Prog. Ped. Cardiol., 18: 111-121.
5: Clark, E.B., 2001. Etiology of Congenital Cardiovascular Malformation: Epidemiology and Genetics. In: Moss and Adams Heart Disease in Infants Children and Adolescents, Allen, H., E. Cark, H. Gutgesell and D. Driscoll (Eds.). 6th Edn., Lippincott Williams Wilkins, Philadelphia, PA., USA., pp: 64-79.
6: Copel, J.A., M. Cullen, J.J. Green, M.J. Mahoney, J.C. Hobbins and C.S. Kleinman, 1988. The frequency of aneuploidy in prenatally diagnosed congenital heart disease: An indication for fetal karyotyping. Am. J. Obstet. Gynecol., 158: 409-413.
7: Debrus, S., A. de Meeus, M.K. Jean and P. Bouvagnet, 1996. Genetics of hereditary cardiopathies. Arch. Mal. Coeur. Vaiss., 89: 619-627.
8: Ferencz, C., C.A. Neill, J.A. Boughman, J.D. Rubin, J.I, Brenner and L.W. Perry, 1989. Congenital cardiovascular malformations associated with chromosome abnormalities: An epidemiologic study. J. Pediatr., 114: 79-86.
9: Ferencz, C., J.A. Boughman, C.A. Neill, J.I. Brenner and L.W. Perry, 1989. Congenital cardiovascular malformations: Questions on inheritance. Baltimore Washington Infant Study Group. J. Am. College Cardiol., 14: 756-763.
10: Ferencz, C., J.D. Rubin, R.J. McCarter, J.A. Boughman and P.D. Wilson et al., 1987. Cardiac and noncardiac malformations: Observation in a population-based study. Teratology, 35: 367-378.
11: Ferencz, C., J.D. Rubin, R.J. Mccarter, J.I. Brenner and C.A. Neill et al., 1985. Congenital heart disease: Prevalence at livebirth. The Baltimore-Washington infant study. Am. J. Epi-Demiol., 121: 31-36.
Direct Link |
12: Frohn-Mulder, I.M., E.W. Swaay, C. Bouwhuis, J.O. van Hemel, E. Gerritsma, M.F. Niermeyer and J. Hess, 1999. Chromosome 22q11 deletions in patients with selected outow tract malformations. Genet. Couns., 10: 35-41.
13: Garg, V., I.S. Kathiriya, R. Barnes, M.K. Schluterman and I.N. King et al., 2003. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature., 424: 443-447.
CrossRef | Direct Link |
14: Goldmuntz, E., B.J. Clark, L.E. Mitchell, A.F. Jawad and B.F. Cuneo et al., 1998. Frequency of 22q11 deletions in patients with conotruncal defects. J. Amer. Coll. Cardiol., 32: 492-498.
15: Greenwood, R.D., A. Rosenthal, L. Parisi, D.C. Fyler and A.S. Nadas, 1975. Extracardiac Abnormalities in infants with congenital heart disease. Pediatrics, 55: 485-492.
Direct Link |
16: Hoffman, J.I. and R. Christianson, 1978. Congenital heart disease in a cohort of 19,502 birth with long-term follow-up. Am. J. Cardiol., 42: 641-647.
17: Johnson, M.C., A.W. Strauss, S.B. Dowton, T.L. Spray and C.B. Huddleston et al., 1995. Deletion within chromosome 22 is common in patients with absent pulmonary valve syndrome. Amer. J. Cardiol., 76: 66-69.
CrossRef | Direct Link |
18: Lewin, M.B., E.A. Lindsay, V. Jurecic, V. Goytia, J.A. Towbin and A. Baldini, 1997. A genetic etiology for interruption of the aortic arch type B. Amer. J. Cardiol., 80: 493-497.
19: Li, L., I.D. Krantz, Y. Deng, A. Genin and A.B. Banta et al., 1997. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet., 16: 243-251.
20: Lindsay, E.A., F. Vitelli, H. Su, M. Morishima and T. Huynh et al., 2001. Tbx1 haploinsu cieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nat., 410: 97-101.
CrossRef | Direct Link |
21: Losekoot, T.G. and A.E. Becker, 1987. Discordant Atrioventricular Connection and Congenitally Corrected Transposition. In: Paediatric Cardiology, Anderson, R.H., F.J. Macartney and E.A. Shinebourne (Eds.). Churchill Livingstone, Edinburgh, pp: 867-887.
22: Lurie, I.W., A.P. Kappetein, C.A. Loredo and C. Ferencz, 1995. Non-cardiac malformations in individuals with outflow tract defects of the heart: The Baltimore-Washington Infant Study (1981-1989). Am. J. Med. Genet., 59: 76-84.
PubMed | Direct Link |
23: McElhinney, D.B., D.A. Driscoll, E.R. Levin, A.F. Jawad, B.S. Emanuel and E. Goldmuntz, 2003. Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies. Pediatrics, 112: e472-e472.
Direct Link |
24: Merscher, S., B. Funke, J.A. Epstein, J. Heyer and A. Puech et al., 2001. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell, 104: 619-629.
CrossRef | PubMed |
25: Mitchell, S.C., S.B. Corones and H.W. Berendes, 1971. Congenital heart disease in 56,109 births. Circulation, 43: 323-332.
Direct Link |
26: Momma, K., C. Kondo and R. Matsuoka, 1996. Tetralogy of Fallot with pulmonary atresia associated with chromosome 22q11 deletion. J. Amer. Coll. Cardiol., 27: 198-202.
27: Momma, K., C. Kondo, M. Ando, R. Matsuoka and A. Takao, 1995. Tetralogy of Fallot associated with chromosome 22q11 deletion. Amer. J Cardiol., 76: 618-621.
28: Momma, K., M. Ando and R. Matsuoka, 1997. Truncus arteriosus communis associated with chromosome 22q11 deletion. J. Amer. Coll. Cardiol., 30: 1067-1071.
29: Rowe, R.D. and I.A. Uchida, 1961. Cardiac malformations in mongolism: A prospective study of 184 mongoloid children. Am. J. Med., 31: 726-735.
30: Samanek, M., J. Goetzova and D. Benesova, 1985. Distribution of congenital heart malformations in an autopsied child population. Int. J. Cardiol., 8: 235-250.
31: SAS/STAT Software, 2004. Version 9.1 of the SAS System for Win. SAS Institute Inc., Cary, NC, USA..
32: Takahashi, K., S. Kido, K. Hoshino, K.Ogawa, H. Ohashi and Y. Fukushima, 1995. Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: A prospective study. Eur. J. Pediatr., 154: 878-881.
33: Tennstedt, C., R. Chaoui, H. Korner and M. Dietel, 1999. Spectrum of congenital heart defects and extracardiac malformations associated with chromosomal abnormalities: Results of a seven year necropsy study. Heart, 82: 34-39.
Direct Link |
34: Van der Hauwaert, L.G., J.P. Fryns, M. Dumoulin and N. Logghe, 1978. Cardiovascular malformations in Turner's and Noonan's syndrome. Br. Heart J., 40: 500-509.
35: Ferencz,C., J.D. Rubin, C.A. Loffredo and C.M. Magee, 1993. The Epidemiology of Congenital Heart Disease, The Baltimore-Washington Infant Study (1981-1989). Perspectives in Pediatric Cardiology, Vol. 4, Futura Publishing Co. Inc., MountKisco, New York, pp: 33-73.
36: Chaoui, R., H. Korner, C. Tennstedt and R. Bollmann, 1996. Prenatal diagnostizierte herzfehlbildungen und assoziierte chromosomenaberrationen. Ultraschall Med., 17: 17-17.
37: Gembruch, U., R. Bald and D. Redel, 1991. Bedeutung der Pranatalen Diagnostik Angeborener Herzfehler. Jahrbuch der Gynokologie und Geburtshilfe. Biermann-Verlag, Munich, pp: 107-118.
38: Alabdulgader, A.A., 2001. Congenital heart disease in 740 subjects: Epidemiological aspects. Ann. Trop. Paediatr., 21: 111-118.