Chapter 2

Environmental and genetic conditions associated with heart disease in children

Syndromes associated with maternal conditions

Maternal diabetes mellitus

Fetal alcohol syndrome

Maternal HIV infection

Maternal inflammatory (collagen vascular) disease

Maternal phenylketonuria

Maternal rubella infection

Medications and other agents

Retinoic acid

Lithium

Other drugs and environmental exposures

Syndromes with gross chromosomal abnormalities

Down syndrome (Trisomy 21)

Turner syndrome (45, X; Monosomy X)

Trisomy 18 syndrome

Trisomy 13 syndrome

Syndromes with chromosomal abnormalities detectable by special cytogenetic techniques

DiGeorge syndrome and velocardiofacial syndrome (22q11.2 deletion)

Williams syndrome (Williams–Beuren syndrome)

Other syndromes with familial occurrence

Noonan syndrome and related conditions

Limb/heart syndromes

Clinical genetic evaluation

Family history

Genetic testing

Additional reading

This chapter presents the commonest conditions with an association with congenital heart disease. This area is changing rapidly, particularly with the understanding of genetic mutations in conditions that have traditionally been described only clinically.

Syndromes associated with maternal conditions

Maternal diabetes mellitus

Maternal diabetes mellitus may result in macrosomic, large-for-gestational-age infants who commonly have hypoglycemia and respiratory distress. Ventricular septal defect (VSD), especially a small muscular VSD, may occur, but the classic cardiac problem of the infant of diabetic mother (IDM) is asymmetric hypertrophy of the interventricular septum. This condition can appear dramatic by echocardiography and result in left ventricular outflow obstruction. It almost always regresses completely by several weeks of age.

Fetal alcohol syndrome

Fetal alcohol syndrome may result from even a modest consumption of alcohol during early gestation. The clinical spectrum is broad; classical features include unusual triangular facies, thin upper lip, absent philtrum, and small palpebral fissures, often with microphthalmia; hypoplastic nails; and a variety of neurodevelopmental abnormalities. Cardiac anomalies, usually ASD, VSD or tetralogy of Fallot, occur in 15–40% of affected infants and children.

Maternal HIV infection

Maternal HIV infection has been associated with an increased incidence of congenital malformations, compared with non-HIV-infected mothers. This is independent of antiretroviral therapy during pregnancy. The occurrence of cardiac malformations is about 3% with the usual distribution of anomalies.

Maternal inflammatory (collagen vascular) disease

In the absence of structural cardiac deformities, congenital complete atrioventricular block (CCAVB) is often associated with maternal connective tissue disease, classically systemic lupus erythematosus (SLE). CCAVB may develop from mothers with no history of lupus or related diseases who may have autoantibodies of various types. In clinically well mothers who are antinuclear antibody (ANA) negative, the presence of a Sjogren's syndrome antibody, usually anti-Ro (anti-SS-A), may exist. In these mothers, injury to the developing conduction system and, rarely, the myocardium occurs when these maternal IgG autoantibodies cross the placenta and bind to fetal cardiac tissue. The risk of a mother with SLE giving birth to an infant with complete heart block has been estimated at 1 in 60; if maternal anti-SS-A antibodies are present, the risk is 1 in 20.

Maternal phenylketonuria

If not properly controlled by diet during gestation, maternal phenylketonuria may result in neurologic abnormality in the neonate. Cardiac malformations, usually tetralogy of Fallot, ASD or VSD, occur in 20% of these neonates.

Maternal rubella infection

In the first trimester of pregnancy, maternal rubella infection often results in a newborn of low birth weight with multiple anomalies, including microcephaly, cataracts, and deafness. Hepatosplenomegaly and petechiae may be present in infancy. Cardiac lesions are often present, with patent ductus arteriosus occurring most commonly followed by peripheral pulmonary artery stenosis, VSD, and pulmonary valve abnormalities. Maternal immunization prior to pregnancy prevents these problems.

Medications and other agents

Retinoic acid

Retinoic acid, other retinoids, and possibly very large exogenous doses of vitamin A have been associated with various fetal anomalies, including conotruncal defects and aortic arch anomalies.

Lithium

A common therapy for depression, lithium used during early gestation has been associated with Ebstein's malformation of the tricuspid valve, although recent studies show no consistent or a slight association.

Other drugs and environmental exposures

A variety of other therapeutic and nontherapeutic drugs, and also various environmental exposures, have been associated with some increased risk of cardiac malformation, but the strength and consistency of the association are often weak and the amount and quality of the available data are often limited.

In the following sections, diagnostic features of a variety of syndromes will be described briefly and will include comments on the nature of the associated cardiac anomaly.

Syndromes with gross chromosomal abnormalities

Down syndrome (Trisomy 21)

This syndrome involves complete or partial duplication of chromosome 21 in all or some (mosaic) of the body cells of the affected individual.

Features

Features include slanted eyes, thick epicanthal folds, flattened bridge of the nose, thick, protuberant tongue, and a shortened anteroposterior diameter of the head. Common signs are short, broad hands, short, inward-curved fifth fingers, and a single transverse palmar crease (simian crease), together with a generalized hypotonia, joint hyperextensibility, and small stature.

Cardiac anomalies

Anomalies are found in 40–50% of patients. Approximately, one-third are VSD, one-third are atrioventricular septal defects (usually the complete form), and the remainder consist almost exclusively of PDA, ASD, and tetralogy of Fallot. It is rare to find cardiac lesions other than these five diagnoses, especially aortic stenosis and coarctation of the aorta.

Turner syndrome (45, X; Monosomy X)

In this syndrome, a complete or partial absence of one of the X chromosomes in all or some (mosaicism) of the body cells is found.

Features

Although children have a female appearance, they also show abnormal gonadal development. Characteristically, they are short in stature (rarely over 60 inches or 152 cm), have a stocky build, webbing of the neck, a broad chest with widely spaced nipples, cubitus valgus, a low hairline, and edema of the hands and feet (a striking and diagnostic feature in neonates). Renal defects commonly occur and may be associated with hypertension. Gastrointestinal bleeding occurs rarely but can be catastrophic.

Turner syndrome occurs in 1 in 2500 female live births; it is estimated that 99% of fetuses with 45, X perish in utero.

Cardiac anomalies

Anomalies, almost exclusively obstructive left-sided cardiac lesions, occur in 35–55% of individuals. Coarctation of the aorta occurs in 20% of Turner syndrome patients and accounts for the greatest share (90%) of operations or interventions compared with other defects. Bicuspid aortic valve, with stenosis ranging from minimal to severe, occurs in up to 35% of Turner syndrome patients and may appear without coarctation. Anomalous pulmonary venous connection, hypoplastic left heart syndrome, mitral valve abnormalities, and aortic aneurysm occur less commonly.

Trisomy 18 syndrome

Features

Infants with an extra chromosome 18 have low birth weight, multiple malformations, and severe retardation. Although females live longer than males, these infants usually die within weeks or months of birth. Overlapping of the flexed middle fingers by the second and fifth digits (camptodactyly) is very characteristic of this condition. Other features include micrognathia, low-set ears, rockerbottom feet, umbilical and inguinal hernias, and...