Congenital heart disease (CHD) is the most common major birth defect, and yet its etiology remains poorly understood. It is generally accepted that both genetic and environmental factors contribute to abnormal cardiac development. With rapid advances in the field of genetics, specific gene alterations underlying named syndromes or groups of cardiac malformations continue to be identified. Our understanding of both positive and negative environmental influences also continues to evolve. Identifying the etiology of cardiac malformations is important, as environmental changes can aid normal development and information on inheritance patterns and recurrence rates aids early identification of at-risk individuals and informs future plans for individuals and families.

In this chapter, we briefly summarize the current knowledge of environmental and genetic causes of CHD.1,2,3 A brief guide to clinical screening by history, examination, and testing for genetic causes is also presented.

CHD is the most common major birth defect. Estimates of the birth prevalence of CHD range from 4 to 50 cases per 1000 live births depending on the epidemiologic study.1 The variation in estimates is explained in part by differences in study design, case ascertainment, and disease classification. In addition, the advent of ultrasound in the 1980s has resulted in identification of milder abnormalities1 and more accurate classification and prenatal diagnosis. The latter may in fact have led to an increase in pregnancy termination and a decline in birth prevalence.

Multiple environmental risk factors have been implicated in the development of CHD. Although unproven, some occurrences of CHD are potentially preventable through changes in the fetal environment. A select group of environmental risk factors are briefly reviewed in this section, although a growing body of epidemiologic literature is dedicated to this topic (Figure 4-1).

Diabetes

Pregestational diabetes is a known risk factor for CHD as well as abnormal development of other organ systems. Heart defects most often associated with maternal diabetes include conotruncal defects, laterality defects and, less commonly, left ventricular outflow obstructive defects (Table 4-1).3 Hypertrophic cardiomyopathy is commonly associated with maternal diabetes but typically resolves after birth, once exposure to the hyperglycemic fetal environment ceases. The risk of birth defects secondary to diabetes can be reduced with strict glycemic control prior to conception and throughout pregnancy.3 Identification of this risk factor is crucial because the prevalence of type 2 diabetes increases in women of childbearing age.

Maternal Medications

The U.S. Food and Drug Association (FDA) classifies medications according to the risk of birth defects. Many medications have been associated with malformations of the heart, although there are no specific estimates quantifying risk of specific types of heart defects. Examples of therapeutic maternal medications associated with CHD include antiepileptic drugs (eg, phenytoin, hydantoin, valproic acid), vitamin A, sulfa antibiotics, and lithium.4 Examples of nontherapeutic maternal substances associated with CHD include alcohol and, in some cases, possibly tobacco.

Protective Factors

There are multiple lines of evidence suggesting that the use of multivitamins and folic acid supplementation decreases the risk of CHD. Most, but not all, studies demonstrate a reduced incidence of heart defects, such as conotruncal defects and ventricular septal defect (VSD), with prenatal use of multivitamins.5

Approach to Prevention of CHD

Environmental risk factors for CHD continue to be identified, providing opportunities for primary prevention. Recommendations have been published to guide prospective parents on known risk factors and emphasize proper preconceptional care.3

Recommendations include the following:

• Women of childbearing age should take a multivitamin containing folic acid daily.
  
• Prospective mothers should have a preconceptional evaluation of associated medical conditions such as diabetes and metabolic disorders.
  
• Prospective mothers should discuss any medication use with a healthcare professional.
  
• Women should avoid contact with people with febrile illnesses or the flu early in their pregnancy.
  
• Women planning a pregnancy or those already pregnant should cease smoking or ingesting alcohol.

Finally, in order to properly counsel families on recurrence risk, an accurate assessment of genetic risk factors is also required. This may include referral for genetic counseling or clinical genetic evaluation and testing.

The recognition that CHD is present in the context of a genetic syndrome has important implications for the pediatric patient, including the identification and management of multisystem involvement and development. The following provides a brief overview of common genetic syndromes and their associated heart diseases, with a summary of these conditions and their cardinal features in Table 4-2. Table 4-3 provides an overview classified by specific cardiac diseases with a list of genetic syndromes that should be considered at the time of diagnosis.

Down Syndrome (Trisomy 21)

Down syndrome is the most common chromosomal aneuploidy in live births. It most often arises from maternal nondisjunction during meiosis, resulting in 3 copies of chromosome 21. Therefore, the birth prevalence increases with maternal age, from 1 in 1445 live births at age 20 years to 1 in 25 births at age 45 years.6 Down syndrome patients have characteristic dysmorphic features, including upslanting palpebral fissure, epicanthal folds, low nasal bridge, large tongue, brachycephaly and third fontanelle, excess nuchal skin, single palmar crease, and clinodactyly. All patients with Down syndrome have an intellectual disability, although there is a wide range of abilities and functioning. Other common features are outlined in Table 4-2. Cardiac disease is an important feature of Down syndrome. Forty to 50% of patients are affected with CHD, and of those, 40% to 50% have common atrioventricular canal (CAVC), a characteristic lesion of this syndrome.7 Many patients also have variants of CAVC, including incomplete canal with a primum atrial septal defect (ASD) and cleft mitral valve. VSDs, patent ductus arteriosus, ASD, and tetralogy of Fallot (TOF) are all associated, in decreasing order of frequency. Patients with Down syndrome are at increased risk of persistent pulmonary hypertension as neonates and also have an increased risk of developing pulmonary hypertension beyond the neonatal period. This risk is an important consideration in the timely repair of large left-to-right shunt lesions. Currently, the American Academy of Pediatrics health supervision guidelines for children with Down syndrome recommend that all children with Down syndrome undergo cardiac evaluation and echocardiogram at diagnosis.8 Patients with Down syndrome have been shown to have equivalent outcomes for CAVC repair compared with non–Down syndrome patients.

The clinical diagnosis of Down syndrome should be confirmed by karyotype to identify cases arising from an unbalanced translocation (3%-4% of patients) rather than nondisjunction. Parents of a child with a translocation require genetic screening to assess for a balanced translocation, which has a higher recurrence risk of 10% to 15%.

Trisomy 18 (Edward) and Trisomy 13 (Patau) Syndromes

Trisomy 18 (Edward) syndrome results from 3 copies of chromosome 18 in 94% of patients, likely arising from nondisjunction. It occurs in 1 in 6000 live births.6 Greater than 90% of patients have CHD, characteristically VSD and/or polyvalvar disease (Figure 4-2), although 10% have complex CHD. The syndrome is also characterized by intrauterine growth retardation and poor postnatal growth, small facial features, overlapping fingers, rocker bottom feet, short sternum, and renal/genitourinary anomalies.

Trisomy 13 (Patau) syndrome arises from 3 copies of chromosome 13, with translocation seen in up to 20%. The prevalence is 1 in 5000 to 29,000 live births. Patients have multiple congenital anomalies, characteristically holoprosencephaly, microphthalmia, cleft lip and palate, polydactyly, and renal/genitourinary anomalies. CHD is present in 50% to 80% of patients. ASD and VSD are the most common defects; polyvalvar disease is also seen in trisomy 13, although less commonly than in trisomy 18.

Both trisomy 18 and 13 have greater than 90% mortality in the first year of life and are associated with severe mental retardation. The high rate of mortality is postulated to be secondary to central apnea as the cardiac disease in either condition is rarely lethal. In patients who survive the neonatal period, many questions remain about the indications for cardiac surgery. All patients with multiple congenital anomalies and phenotypic features suggestive of trisomy 18 and 13 should undergo a karyotype to confirm the diagnosis and identify chromosomal translocations.

Turner Syndrome

Turner syndrome is present in 1 in 2500 to 3000 live births. The overall incidence is much higher because there is a high frequency of prenatal loss. Monosomy of the X chromosome (45,X) is seen in 50% of cases. Another 5% to 10% of cases have duplication of the long arm with loss of the short arm, and the remainder have mosaicism for 45,X with 1 or more other cell lines, including 46,XX, 47,XXX, and 46,XY.

Patients with Turner syndrome have characteristic physical findings, including short stature, webbed neck and low posterior hairline, narrow maxilla and dental crowding, widely spaced nipples, barrel-shaped thorax, cubitus valgus, hyperconvex nails, and lymphedema of the hands and feet. Multiple organ systems are involved, including renal, endocrine, and musculoskeletal (Table 4-2). Many patients have learning disabilities. There is a spectrum with regard to gonadal dysgenesis, the development of secondary sex characteristics and fertility, and there is some genotype–phenotype correlation, with mosaic forms having a greater incidence of spontaneous menarche. Patients with mosaic forms that include a Y chromosome (5%-6%) are at increased risk of gonadal malignancy.

CHD is present in 17% to 45% of patients with Turner syndrome.6 Left-sided obstructive lesions are characteristic, including bicuspid aortic valve, aortic stenosis, and coarctation of the aorta. Hypoplastic left heart syndrome, mitral valve prolapse (MVP), and total anomalous pulmonary venous return are seen less commonly. Aortic root dilation and dissection are reported in older patients with Turner syndrome; however, this is typically in the context of risk factors including a history of coarctation, bicuspid aortic valve, and hypertension. There is no difference in the natural history of cardiac lesions in patients with Turner syndrome compared to those without. The American Academy of Pediatrics health supervision guidelines for girls with Turner syndrome recommend a pediatric cardiology evaluation at diagnosis. Follow-up is individualized to diagnosis; however, blood pressure should be monitored regularly.9 The diagnosis should be confirmed with karyotype.

22q11.2 Microdeletion Syndrome

22q11.2 microdeletion syndrome encompasses DiGeorge, velocardiofacial, and conotruncal anomaly facial syndromes. With an estimated prevalence of 1 in 4000 to 6000, it is the most common microdeletion disorder yet identified. Although most microdeletions are de novo, they are transmitted in an autosomal dominant fashion in approximately 6% of cases. The most common deletion is large (3 Mb) and encompasses a region coding for more than 30 genes, although smaller deletions in the region have been detected. The TBX1 gene maps into the deleted locus and encodes a transcription factor that participates in cardiovascular development. This gene is deleted in most, but not all, patients with the associated disease phenotype. Missense mutations have also been detected in TBX1 in patients with a DiGeorge phenotype who did not have the microdeletion on fluorescent in situ hybridization (FISH), suggesting that TBX1 haploinsufficiency contributes to the disease phenotype.