Table of Contents

• Objectives

• Risk Factors Found In Congenital Heart Disease And Chromosomal Aneuploidy

• Embryogenesis Of The Cardiovascular System And The Development Of Cardiac Anomalies

• Aneuploidy

• Cardiovascular Malformations Seen In Trisomy 21,18, 13, And Turner Syndrome

• Cardiovascular Malformations In Chromosome Deletion Syndromes: Williams Syndrome And Digeorge Syndrome

• Abnormalities Associated With Other Major "Cardiac" Syndromes: Noonan Syndrome And Holt-Oram Syndrome

• Summary

• References

• CME Quiz

Objectives

• Name the risk factors found in congenital heart disease and chromosomal aneuploidy

• Name the most common heart defects found in patients with maternal diabetes

• Describe the development of the endocardial cushion of the heart

• Describe the incidence and variations in congenital heart disease in a fetus diagnosed with Trisomy 21

• Name the different locations a ventricular septal defect may occur in the heart

• Describe the most common congenital heart defects found in patients with Turner Syndrome

• Name the most common cardiac abnormality found in patients with Williams syndrome

Risk Factors Found In Congenital Heart Disease And Chromosomal Aneuploidy

Congenital heart disease is the most common form of birth defect, affecting 8.8 in 1,000 newborns every year. (Hoffman, Christianson) At least 50% of the congenital heart cases are minor and are surgically corrected; the remainder account for over half of the deaths from congenital abnormalities in childhood. Many factors may affect the incidence of congenital heart disease. The maternal age increases the prevalence of congenital heart disease. The inclusion of a bicuspid aortic valve (incidence 10 in 1000 live births) and number of premature neonates with a patent ductus arteriosus or ventricular septal defect also raise the overall incidence of congenital heart disease. When patent ductus arteriosus is removed from the figures, the incidence is 3.7 in 1000 live births. (Boughman, Berg, Astemborski)

The risk factors for fetuses with congenital heart disease may be grouped into two main categories, fetal factors and maternal factors. Fetal factors include: chromosomal abnormalities, extracardiac anatomic abnormalities, nonimmune hydrops fetalis, fetal cardiac arrhythmia, or suspected cardiac anomaly on routine ultrasound. The maternal factors include: family history of congenital heart disease, maternal metabolic disorders, or maternal teratogen exposure.

The association of genetic predisposition to cardiac defects is receiving more attention as a result of fetal echocardiographic early diagnosis, surgical interventions and advances, and greater sophistication of cytogenetic and molecular genetic techniques.

"As with all birth defects, chromosomal aneuploidy should be suspected in any newborn with congenital heart disease. The association of heart disease with a specific pattern dysmorphic features may suggest a syndrome. Maternal history will identify those associated with the known teratogens. Clinical examination will identify those liable to be associated with a chromosomal deletion not apparent to routine karyotype analysis. A combination of family history and dysmorphic features can identify a further group of heart defects associated with monogenic syndromes. In a small proportion of isolated heart defects, the pedigree is sufficient to recognize monogenic inheritance. The rest must be addressed in the clinic using empirical data from traditional family studies." (Burn & Goodship, p. 767)

Common Teratogens*

*(Data from Nora and Nora, 1983 and Lammer, et.al. 1985)

Embryogenesis Of The Cardiovascular System And The Development Of Cardiac Anomalies

The primitive heart begins as a pair of endocardial heart tubes that develop before the end of the third week and begin to fuse together to form the primitive cardiovascular system. The cardiac tube grows rapidly, bulging forward in the midline. The pulsatile structure produces a circulation even before valve development has begun. The heart has four primary developing areas: an inlet or atrium, a central dilatation or ventricle, the bulbous cordis leading to the single outlet artery - the truncus arteriosus. The heart bends to the right, secondary to differential growth of the right and left sides of the tube. The heart is functional by the end of the fifth week of fetal development as it is converted from a simple primary tube to a four-chamber, valved organ. The circulation of blood begins by the end of the third week as a tubular heart starts to beat. The cardiovascular system is the first organ to reach a functional state in the embryo.

By eight weeks gestation, the cardiovascular system has completely developed and the cardiac motion is used by the sonographer as a sign of fetal viability. The fetal head is to the right, the fetal body to the left. Amniotic fluid surrounds the fetus within the gestational sac.

The embryo obtains sufficient nourishment during the second week of development by diffusion of nutrients from maternal blood flow. The placenta oxygenates the venous blood, (later known as the inferior vena cava), entering the heart. Much of the blood flows into the left side of the atrium to form the vascular left-sided stream that supplies the brain. The deoxygenated blood from the head and upper body forms most of the right-sided flow. These two streams of blood flow through the ventricle to the outflow tract. The blood flow is smooth and laminar to allow for normal septal growth between the atria and the ventricles; the correct positioning of the endocardial cushions allow the septae to meet in the center at the crux of the heart. The septum primum and small septum secundum separates the left and right atria. The fossa of the foramen ovalae provides a hole between the two atria for blood to circulate. The fossa is covered by the flap of the foramen ovalae. The flap opens into the left atria during fetal life; after birth the pressure in the left heart forces the flap to close. If the hole remains open, or if the septum secundum is too small, a hole persists and becomes a secundum atrial septal. defect. If the primum septum does not form, the hole becomes a septum primum atrial septal defect. The venous return to the heart enters a sinus venosus in early embryo development. This chamber becomes part of the superior posterior wall of the right atrium. If this process is incomplete, a gap persists in the superior portion of the atrial septum, the sinus venosus atrial septal defect.

The endocardial cushions have a superior and inferior border that grow towards each other to separate the opening between the atria and ventricle. Cardiac valves form within the endocardial cushion; the mitral valve is on the left while the tricuspid valve is on the right. Failure of this division may lead to the development of a dysplastic valve or single atrioventricular valve formation with a septal defect above and/or below it. This atrioventricular septal defect or endocardial septal defect may be partial or complete and usually appears with specific clinical features and genetic associations (primarily Trisomy 21).

The two ventricles develop from the single ventricle (left) and the bulbous cordis (right). As the heart loop rotates the central tubular structure, a "left-right" type orientation is formed with the fetal heart. The interventricular septum grows from the apex of the heart in a cranially direction to separate the right from the left ventricle. Failure of this growth process may result in an opening between the two ventricles, ventricular septal defect. The myocardium is the primary muscle of the ventricular heart wall which contributes to the systolic and diastolic pumping action of the cardiac chambers. The right ventricle is more coarsely trabeculated than the left ventricle. Occasionally, tiny muscular holes may occur within the ventricular septum (muscular ventricular septal defects) which usually close spontaneously after birth. The failure of equal and appropriate growth of the two ventricles may result from abnormal heart looping, abnormal inlet orifices, or obstruction of the outlet vessels. The most serious of these malformations is the hypoplastic left heart. Other anomalies such as hypoplastic right ventricle, aortic or mitral atresia, tricuspid or pulmonic atresia, and great vessel malrotations may also be detected inutero.

The great vessels consist of the aorta and pulmonary trunk. The ascending aorta arises from the original midline outflow tract; the aortic arch is the persistent left fourth aortic arch. An interrupted aortic arch occurs when this development fails to occur. This results in the descending aorta connected to the heart via the ductus arteriosus. This defect is often associated with anomalies involving the branchial arch and neural crest derivatives.

The ductus arteriosus connects the pulmonary artery to the descending aorta at the level of the left subclavian artery. It constricts after full term birth to allow the pulmonary circulation to open. If it remains open after birth (especially in premature infants) it is termed a persistent ductus arteriosus.

Aneuploidy

ACardiovascularneuploidy is an abnormality of the chromosomes that implies "not a good set". Any deviation from the diploid number of 46 chromosomes is called aneurploidy. The cells may be hypodiploid (usually 45) or hyperdiploid (usually 47 to 49). Cytogeneticists tend to apply the term to numerical departures from the norm: monosomies, trisomies, and tetrasomies. The three most common trisomies are worthy of detailed discussion together with the only common examples on monosomy (Turner syndrome) and tetrasomies, (Cat Eye syndrome: heart failure, total anomalous pulmonary venous return; and Pallister-Killian syndrome: atrial and ventricular septal defects, coarctation of the aorta, aortic stenosis, patent ductus arteriosus). (Burn and Goodship, p.772)

The majority of fetuses with cardiac defects and chromosomal abnormalities have associated extracardiac abnormalities. The occurrence of associated extracardiac abnormalities in fetuses with cardiac defects and chromosomal abnormalities ranges from 50% to 70%. In the fetus with an isolated cardiac abnormality, the incidence of chromosomal abnormalities is still significantly increased (15%-30%), and thus appropriate genetic counseling is warranted. (Abuhamad, p.3)

Cardiovascular Malformations Seen In Trisomy 21,18, 13, And Turner Syndrome

TRISOMY 21 (Down Syndrome). This chromosomal defect has the highest association between major heart abnormalities and chromosomal defect. At least 40% of Trisomy 21 children will have heart defects; furthermore, 50% of those children with heart abnormalities will specifically be affected with atrial ventricular septal defects (AVSDs).

The AVSDs are subdivided into two forms: complete and incomplete defects. The incomplete defect is also know as the ostium primum atrial septal defect (the inferior wall of the atrial septum has not developed). Frequently an associated abnormality is found in the anterior leaflet of the mitral valve (cleft leaflet) in which the somewhat dysplastic anterior leaflet is malformed and divided into two leaflets. The cleft leaflet is usually somewhat thickened and does not close completely, allowing blood to regurgitate or leak backwards from the left ventricle into the left atrium, or across the primum septal defect, into the right atrium. Thus, there are two separate atrioventricular orifices with a communication pathway between the left ventricle and the right atrium (secondary to the cleft mitral leaflet and primum atrial septal defect). The right atrioventricular valve is usually normal.

A complete AVSD is characterized by a common or single atrioventricular valve with multiple leaflets. The anterior and posterior leaflets may be "overriding" or "bridging" the interventricular septum across the large muscular ventricular septal defect. An ostium primum atrial septal defect is present as well. Atrioventricular regurgitation is often present secondary to the dysplastic development of the valve leaflets.

Complete AVSDs are frequently associated with cardiac malposition (mesocardia means the heart is found in the middle of the thorax; while dextracardia shows the cardiac apex pointing to the right side of the thorax instead of the left). These abnormalities may account for the associated atrioventricular block that is frequently associated with complete AVSDs.

Other cardiac malformations that may be seen with AVSDs include coarctation of the aorta, conotruncal abnormalities (tetralogy of Fallot), double outlet right ventricle, transposition of the great arteries), and pulmonary stenosis or atresia.

Both the tricuspid (anterior) and mitral (posterior) valves are directed toward the left ventricular cavity (double inlet). A ventricular septal defect allows blood to cross into the right heart.

Complications may arise in the fetus depending upon the severity of the atrioventricular valve dysplasia, degree of valvular incompetence, and the size of the endocardial cushion defect. Increased incompetence (regurgitation) from the dysplasia atrioventricular valve into the atrial cavities leads to congestive heart failure and pericardial effusion.

TRISOMY 18 (Edwards Syndrome). This is the second most common autosomal aneuploidy after Down syndrome with a very poor prognosis. Common cardiovascular malformations included ventricular septal defect , atrioventricular septal defect , double outlet right ventricle, and hypoplastic left heart.

This four chamber image shows a dominant right heart with a very small, hypertrophied left heart; the foramen ovalae is still patent during fetal life to provide circulation into the left heart. The mitral and/or aortic valve is usually atretic or very dysplastic and therefore blood cannot enter or exit the left ventricle.

The high membranous ventricular septal defect is the most common congenital heart abnormality. In embryology, the ventricular septum grows from the apex of the heart in a cranial direction. The septum is commonly divided into a muscular and membranous portion. The muscular portion of the septum is thick and trabeculated, while the membranous septum is thin and more likely to not close completely in utero. The ventricular septum may be further classified as an "inlet" or "outlet" component. During ventricular filling (diastole), the atrioventricular valve opens and blood flows from the atrium into the ventricle, touching the posterior or "inlet" part of the septum. During ventricular outflow (systole), the ventricle contracts to force the blood out of the apex of the ventricle into the outflow tract (aorta or pulmonary artery). This is the "outlet" portion of the septum. Trisomy 21 is associated with "inlet" septal defects, while Trisomy 18 and 13 are more likely associated with "outlet" defects (i.e., tetralogy of Fallot, transposition of the great arteries, truncus arterious, double outlet right ventricle).

TRISOMY 13 (Patau Syndrome). The incidence of Trisomy 13 is 1/7000 births. Again the prognosis is poor, with many dying in the neonatal period. Cardiac malformations include atrial and ventricular septal defect and cardiac malposition (especially dextrocardia).

This is the normal size and position of a four chamber heart in a 21 week fetus. The apex of the heart points "leftward", the left atrium is closest to the aorta (small circular structure that lies anterior and to the left of the echogenic spine). The crux of the heart is well seen as the interventricular and intratrial septae equally divide the right and left sides of the heart. The horizontal line of the crux (shorter line) demarcates the tricuspid (anterior) and mitral (posterior) valves.

45 X (Turner Syndrome). This is the only viable human monosomy (45X). Cardiovascular malformation includes ventricular septal defect, coarctation of the aorta, bicuspid aortic valve, hypoplastic left heart, mitral valve prolapse, and idiopathic aortic root dilatation.

Coarctation of the aorta is a discrete shelflike lesion usually present near the left subclavian artery at the site of the ductal arteriosus insertion. It may be focal or tubular hypoplasia of a long segment of the isthmus of the aortic arch. A two leaflet or bicuspid aortic leaflet is found in nearly a third of patients with coarctation of the aorta. Other anomalies associated with coarctation may include hypoplasia of the left sided heart valves (mitral stenosis, or dysplasia; aortic stenosis or dysplasia). In the fetus, the aorta may appear normal in size near the left subclavian artery because of the patent ductus arteriosus communication. A mild narrowing of the descending aorta may not reveal changes in the Doppler waveform (normal flow should not exceed 1.8m/sec), as the ductus constricts after birth, the pressures in the left heart increase significantly to cause a increased velocity in the descending aorta (at the left subclavian artery) in a neonate with coarctation.

Cardiovascular Malformations In Chromosome Deletion Syndromes: Williams Syndrome And Digeorge Syndrome

WILLIAMS SYNDROME. Williams syndrome is characterized by elfin facies and a learning disability with a "cocktail party manner" so called because of a readiness to converse in a friendly outgoing fashion but with little content. The cardiovascular malformations include supravalvular aortic stenosis and peripheral pulmonary artery stenosis. Supravalvular aortic stenosis may be due to one of three defects: a membrane above the sinuses of Valsalva, a localized narrowing of the ascending aorta (hourglass deformity), or a diffuse narrowing involving the aortic arch and branching arteries (tubular variety).

The type of supravalvular stenosis found in Williams syndrome is localized or diffuse. The lesion presents as a "coarctation" or hypoplasia of the ascending aorta with varying degrees of intimal hyperplasia. The appearance is more "hourglass" dilatation of the ascending aorta.

Peripheral pulmonic stenosis is more difficult to detect in utero as this narrowing occurs at the end branching of the right and left pulmonary arteries. The presence of peripheral pulmonary stenosis may complicate the clinical course of the neonate diagnosed with Williams syndrome and supravalvular aortic stenosis.

DiGEORGE SYNDROME. Cardiac malformation, especially problems with the outflow tract, are a key feature of DiGeorge syndrome. Burn and Goodship reviewed cases of DiGeorge syndrome and suggested a useful acronym would be CATCH 22: cardiac defect, abnormal facies, T-cell deficit, cleft palate, hypocalcemia due to 22q11 deletion. "The most important development in our understanding of the causes of heart malformation since the discovery of trisomy 21 has been the discovery that 22q11 deletion is associated with a wide spectrum of heart malformations and is the most common autosomal deletion known." (Burn and Goodship, p. 774)

Abnormalities Associated With Other Major "Cardiac" Syndromes: Noonan Syndrome And Holt-Oram Syndrome

NOONAN SYNDROME. Children with Noonan syndrome present with very specific features: valvar pulmonary stenosis, short stature, mild learning difficulties, and dysmorphic appearance. In addition, pectus excavatum/ carinatum with wide spaced nipples may be present along with other features. Cardiac defects are present in two-thirds of children with Noonan syndrome with over half presenting with pulmonary stenosis. The pulmonic valve is dysplastic and may be seen to doom into the right ventricular outflow tract. Other cardiac defects associated with this condition include atrial septal defect, asymmetric septal hypertrophy (ASH), and persistent ductus arteriosus. A small percentage of patients may have a ventricular septal defect.

HOLT-ORAM SYNDROME. This syndrome is characterized by underdevelopment of the shoulder girdle with triphalangeal thumb and cardiac defects. At least 50% of the cardiac malformations include a secundum ASD with a few patients presenting with ventricular septal defect, atrioventricular septal defect, and truncus arteriosus. This syndrome is an autosomal dominant trait.

Summary

Advances in molecular genetics and echocardiographic evaluation of the fetal heart has allowed the perinatologist to understand the development of the fetus throughout the gestational period. Clinical research has demonstrated specific cardiac abnormalities that are associated with specific aneuploidies and chromosomal defects. This discussion has focused on the more prevelant cardiac defects seen with specific trisomies and syndromes.

The early detection of fetal cardiac anomalies has improved dramatically with advancement in diagnostic ultrasound instrumentation. Fetal cardiac movement, rhythm and chambers may be seen as early as five weeks with the endovaginal transducer. Detailed cardiac examinations may be performed between 16-20 weeks gestation to provide information for the perinatologist to counsel the patient on the best method of treatment for the fetus.

References

Abuhamad, A.. A Practical Guide to Fetal Echocardiography. Lippincott - Raven, 1997. Philadelphia.

Boughman, J., Berg, K. and Astemborski, J. "Familial risks of congenital heart disease in a population based epidemiologic study". Am J Med Genetics 1987: 26: 839-49.

Callen, Peter. Ultrasonography in Obstetrics & Gynecology, Third Edition. W.B. Saunders Co., 1994. Philadelphia.

Emery, David, Connor, J. Michael, and Pyeritz, Reed. Principles and Practice of Medical Genetics, Third Edition. Churchill Livingstone, 1996, New York.

Fitzgerald, M.J.T. and Fitzgerald, M. Human Embryology. Bailliere Tindall, 1994. Philadelphia.

Hagen-Ansert, Sandra L. Textbook of Diagnostic Ultrasonography, Vol. II, Fourth Edition. Mosby, 1995. St. Louis.

Hoffman, J. and Christianson, R. "Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol 1978: 42:641.

Lammer, E.J. Chen, D.T., Hoar R.M.. "Retinoic acid embryopathy". N Engl J Med 313:837-841. 1985.

Moore, Keith L. Before We Are Born. Basic Embryology and Birth Defects, Third Edition. W.B. Saunders, 1989. Philadelphia.

Moore, Keith L. Essentials of Human Embryology. B.C. Decker Inc., 1988. Toronto.

Nichols, D.G., Cameron, D.E., Greeley, W.J., Lappe, D.G., Ungerleinder, R.M., and Wetzel, R.C.. Critical Heart Disease in Infants and Children. Mosby, 1995, St. Louis.

Nora J.J., Nora A.H. "Genetic Epidemiology of Congenital Heart Diseases". Prog. Med Genet 5:91-137. 1983.

Romero. R., Pilu, G., Jeanty, P., Ghidini, A., and Hobbins, J.. Prenatal Diagnosis of Congenital Anomalies, Appelton & Lange, 1988. Norwalk,CT.

Excellent source for congenital heart lesions and embryological diagrams:

• University of Kansas Medical Center Web Site
• Take Quiz