Epidemiology and Genetic Basis of Congenital Heart Disease

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Chapter 418 Epidemiology and Genetic Basis of Congenital Heart Disease

Daniel Bernstein

Prevalence

Congenital heart disease occurs in approximately 0.8% of live births. The incidence is higher in stillborns (3-4%), spontaneous abortuses (10-25%), and premature infants (about 2% excluding patent ductus arteriosus [PDA]). This overall incidence does not include mitral valve prolapse, PDA of preterm infants, and bicuspid aortic valves (present in 1-2% of adults). Congenital cardiac defects have a wide spectrum of severity in infants: about 2-3 in 1,000 newborn infants will be symptomatic with heart disease in the 1st yr of life. The diagnosis is established by 1 wk of age in 40-50% of patients with congenital heart disease and by 1 mo of age in 50-60% of patients. With advances in both palliative and corrective surgery, the number of children with congenital heart disease surviving to adulthood has increased dramatically. Despite these advances, congenital heart disease remains the leading cause of death in children with congenital malformations. Table 418-1 summarizes the relative frequency of the most common congenital cardiac lesions.

Table 418-1 RELATIVE FREQUENCY OF MAJOR CONGENITAL HEART LESIONS *

LESION	% OF ALL LESIONS
Ventricular septal defect	35-30
Atrial septal defect (secundum)	6-8
Patent ductus arteriosus	6-8
Coarctation of aorta	5-7
Tetralogy of Fallot	5-7
Pulmonary valve stenosis	5-7
Aortic valve stenosis	4-7
d-Transposition of great arteries	3-5
Hypoplastic left ventricle	1-3
Hypoplastic right ventricle	1-3
Truncus arteriosus	1-2
Total anomalous pulmonary venous return	1-2
Tricuspid atresia	1-2
Single ventricle	1-2
Double-outlet right ventricle	1-2
Others	5-10

* Excluding patent ductus arteriosus in preterm neonates, bicuspid aortic valve, physiologic peripheral pulmonic stenosis, and mitral valve prolapse.

Most congenital defects are well tolerated in the fetus because of the parallel nature of the fetal circulation. Even the most severe cardiac defects (e.g., hypoplastic left heart syndrome) can usually be well compensated for by the fetal circulation. In this example, the entire fetal cardiac output would be ejected by the right ventricle via the ductus arteriosus into both the descending and ascending aortae (the latter filling in a retrograde fashion), so that fetal organ blood flow would be minimally perturbed. Since the placenta provides for gas exchange and the normal fetal circulation has mixing between more highly and more poorly oxygenated blood, fetal organ oxygen delivery is also not dramatically affected. It is only after birth when the fetal pathways (ductus arteriosus and foramen ovale) begin to close that the full hemodynamic impact of an anatomic abnormality becomes apparent. One notable exception is the case of severe regurgitant lesions, most commonly of the tricuspid valve. In these lesions (e.g., Ebstein anomaly or severe right ventricular outflow obstruction [Chapter 424.7]), the parallel fetal circulation cannot compensate for the volume load imposed on the right side of the heart. In utero heart failure, often with fetal pleural and pericardial effusions, and generalized ascites (nonimmune hydrops fetalis) may occur.

Although the most significant transitions in circulation occur in the immediate perinatal period, the circulation continues to undergo changes after birth, and these later changes may also have a hemodynamic impact on cardiac lesions and their apparent incidence. As pulmonary vascular resistance falls in the 1st several weeks of life, left-to-right shunting through intracardiac defects increases and symptoms become more apparent. Thus, in patients with a ventricular septal defect (VSD), heart failure is often first noticed between 1 and 3 mo of age (Chapter 420.6). The severity of various defects can also change dramatically with growth; some VSDs may become smaller and even close as the child ages. Alternatively, stenosis of the aortic or pulmonary valve, which may be only moderate in the newborn period, may become worse if valve orifice growth does not keep pace with patient growth (Chapter 421.5). The physician should always be alert for associated congenital malformations, which can adversely affect the patient’s prognosis (see Table 416-2).

Etiology

The cause of most congenital heart defects is unknown. Most cases of congenital heart disease were thought to be multifactorial and result from a combination of genetic predisposition and environmental stimulus. A small percentage of congenital heart lesions are related to chromosomal abnormalities, in particular, trisomy 21, 13, and 18 and Turner syndrome; heart disease is found in more than 90% of patients with trisomy 18, 50% of patients with trisomy 21, and 40% of those with Turner syndrome. Other genetic factors may have a role in congenital heart disease; certain types of VSDs (supracristal) are more common in Asian children. The risk of recurrence of congenital heart disease increases if a 1st-degree relative (parent or sibling) is affected.

A growing list of congenital heart lesions has been associated with specific chromosomal abnormalities, and several have even been linked to specific gene defects. Fluorescent in situ hybridization analysis allows clinicians rapid screening of suspected cases once a specific chromosomal abnormality has been identified, although clinical laboratory tests for specific gene defects are still uncommon.

A well-characterized genetic cause of congenital heart disease is the deletion of a large region (1.5-3 Mb) of chromosome 22q11.2, known as the DiGeorge critical region. At least 30 genes have been mapped to the deleted region; Tbx1, a transcription factor involved in early outflow tract development has been implicated as a cause of DiGeorge syndrome. The estimated prevalence of 22q11.2 deletions is 1/4,000 live births. Cardiac lesions associated with 22q11.2 deletions are most often seen in association with either the DiGeorge syndrome or the Shprintzen (velocardiofacial) syndrome. The acronym CATCH 22 has been used to summarize the major components of these syndromes (cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia). The specific cardiac anomalies are conotruncal defects (tetralogy of Fallot, truncus arteriosus, double-outlet right ventricle, subarterial VSD) and branchial arch defects (coarctation of the aorta, interrupted aortic arch, right aortic arch). Congenital airway anomalies such as tracheomalacia and bronchomalacia are sometimes present. Although the risk of recurrence is extremely low in the absence of a parental 22q11.2 deletion, it is 50% if 1 of the parents carries the deletion. More than 90% of patients with DiGeorge syndrome have a microdeletion at 22q11.2. A 2nd genetic locus on the short arm of chromosome 10 (10p13p14) has also been identified, the deletion of which shares some but not all phenotypic characteristics with the 22q11.2 deletion; patients with del(10p) have an increased incidence of sensorineural hearing loss.

Other structural heart lesions that have been associated with specific chromosomal abnormalities include familial secundum atrial septal defect associated with heart block (the transcription factor NKX2.5 on chromosome 5q35), familial atrial septal defect without heart block (the transcription factor GATA4), Alagille syndrome (Jagged1 on chromosome 20p12), and Williams syndrome (elastin on chromosome 7q11). Of interest, patients with ventricular septal defects (VSDs) and atrioventricular septal defects (AVSDs) have been found to have multiple NKX2.5 mutations in cells isolated from diseased heart tissues, but not from normal heart tissues or from circulating lymphocytes, indicating a potential role for somatic mutations leading to mosaicism in the pathogenesis of congenital heart defects. A compilation of known genetic causes of congenital heart disease is presented in Table 418-2.

Table 418-2 GENETICS OF CONGENITAL HEART DISEASE

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