In 1966, Smith proposed that the term dysmorphology be used to denote the study of abnormalities in morphogenesis, regardless of etiology, timing of origin, or severity. The field has expanded dramatically over the last several decades, as great strides have been made in our understanding of the developmental pathogenesis of many structural defects, including those affecting the cardiovascular system. Congenital anomalies of the cardiovascular system are among the leading causes of morbidity and mortality in infancy and childhood. With an overall incidence between 0.4% and 1% among live-born infants, congenital cardiovascular malformations (CCVMs) or congenital heart defects (CHDs) constitute an etiologically heterogeneous group of birth defects with a variety of known and unknown causes. For most structural cardiovascular malformations, the genetic and biochemical basis for the developmental error is largely unknown. Vigorous research efforts are currently directed at elucidating the genetic, biochemical, and cellular mechanisms involved in normal and abnormal cardiovascular development. An increasing number of specific genes are now implicated in the pathogenesis of congenital cardiovascular malformations in humans and animals. These developments in the dysmorphology and genetics of pediatric heart disease have led to improvements in clinical diagnosis, management, and genetic counseling for individuals and families with congenital heart disease, whether isolated or associated with one or more extracardiac malformations. In this chapter, the etiologic and genetic aspects of congenital cardiovascular malformations will be reviewed, emphasizing those aspects of particular interest to the pediatrician, pediatric cardiologist, and pediatric cardiac surgeon.
APPROACH TO THE CHILD WITH STRUCTURAL DEFECTS
About 4% of all infants have at least one major defect in structural development. A significant proportion of these have congenital cardiovascular malformations, for which the incidence in the general population is between 0.4% and 1%. Furthermore, at least 25% of patients with a congenital heart defect have one or more extracardiac malformations. Cardiologists and cardiac surgeons frequently are involved in the care of patients with multiple malformations involving multiple organ systems. Consultations between the cardiac team and a dysmorphologist or clinical geneticist, play an integral part in the management of affected patients and their families.
A developmental approach to the child with structural defects is depicted in Figure. The ultimate goal of such an approach is to make a specific diagnosis such that accurate prognosis can be predicted, the recurrence risk can be determined, and an appropriate management plan may be formulated. When evaluating an infant or child with a structural defect, it must first be determined whether the defect has a prenatal or postnatal onset. Usually this distinction can be deduced from a careful history and physical examination. The term prenatal onset is used to designate structural abnormalities that are present at birth, whereas postnatal onset is used to designate structural abnormalities that are not present at birth, but rather develop post-natally. Some structural defects are categorized as postnatal in onset even though the genetic alteration responsible for them was present prenatally. Once the distinction between prenatal and postnatal onset has been made, a rational differential diagnosis can be developed, since this determination narrows the diagnostic possibilities considerably.
The vast majority of structural cardiovascular defects have a prenatal rather than postnatal onset. Congenital heart defects may be the result of malformation (abnormal development), disruption (interruption of a normal developmental process), or deformation (the effects of extrinsic mechanical forces on normal development). Although some isolated defects are caused by single gene mutations (e.g., mutations of the elastin gene, ELN, in familial supravalvar aortic stenosis) or known teratogens (e.g., retinoic acid), most currently have no identifiable cause. In the past, most isolated defects were thought to arise from multifactorial influences—a combination of genetic and environmental causes. Recent research efforts have implicated an increasing number of specific genes in the pathogenesis of congenital cardiovascular malformations.
Dysmorphic features and extracardiac malformations are commonly associated with congenital heart defects (25%) and should prompt an evaluation for a possible syndrome. Multiple malformation syndromes arise from chromosomal, genetic, teratogenic (environmental), and unknown causes. For malformation syndromes, the prognosis and recurrence risk for heart disease depend largely on the underlying syndrome diagnosis. In the management of fetuses, infants, children, and adults with congenital cardiovascular malformations, the importance of a genetics evaluation, including consultation with a clinical geneticist and possible cytogenetics evaluation, cannot be overemphasized. When a major cardiovascular malformation is detected prenatally, amniocentesis should be strongly considered, particularly if there is a coexistent extracardiac malformation. In particular, complete atrioventricular canal defects are common in Trisomy 21 syndrome, and conotruncal malformations (truncus arteriosus, tetralogy of Fallot, type B interrupted aortic arch) are common in the chromosome 22 deletion syndrome (velocardiofacial syndrome, DiGeorge sequence), which is associated with genetic abnormalities on the long arm of chromosome 22. In most patients with the chromosome 22 deletion syndrome, a deletion on the long arm of chromosome 22 can be detected by fluorescent in situ hybridization (FISH).
When structural malformations are present at the time of birth (prenatal onset), the diagnostic possibilities should include chromosomal abnormalities, genetically determined syndromes, and environmental disorders due to prenatal exposure to a teratogen. The child was born to a mother who used the acne medi-cation, cis-retinoic acid (Accutane) during her pregnancy. In these infants, malformations present at birth include craniofacial defects, especially anomalies of the ears and the Robin sequence, defects of the central nervous system including hydrocephalus and microcephaly, thymic abnormalities, and a characteristic spectrum of conotruncal malformations including tetralogy of Fallot, double-outlet right ventricle, supracristal ventricular septal defect, and type B interruption of the aortic arch. The retinoic acid embryopathy is an example of the effect of a teratogen on the developing embryo or fetus. In particular, it demonstrates how a specific teratogen can lead to a characteristic spectrum of cardiac lesions, presumably by acting via a common mechanism interfering with conotruncal development. Disorders caused by environmental agents take on a special significance because prevention prior to conception may be feasible. In general, recognizing that a teratogenic agent was the cause of the structural defect means that the recurrence risk is negligible if the mother avoids the use of that agent during subsequent pregnancies. Other teratogens that are known to cause cardiac malformations in humans include alcohol, anticonvulsants (hydantoins, trimethadione, valproic acid, carbamazepine), lithium, thalidomide, warfarin (Coumadin), the rubella virus, maternal diabetes, and maternal phenylketonuria (see following discussions).
A patient with mucopolysaccharidosis type I (MPS I, Hurler syndrome). Although the genetic alteration responsible for MPS I syndrome is present prenatally, the structural abnormalities develop postnatally. This child appeared to be normal at birth, having thrived in utero. By 18 months of age, coarse facial features, cloudy corneas, poor growth, mental deficiency, and multiple skeletal anomalies became evident. Deposition of mucopolysaccharides in cardiac valve tissue, myocardium, and coronary arteries leads to progressive thickening and stiffening of valve leaflets, valvar insufficiency, myocardial dysfunction, sudden death from arrhythmia, and diffuse coronary artery disease. A small subset of individuals with severe MPS I have an early-onset fatal endocardiofibroelastosis.Postnatal onset of these structural defects should focus the diagnostic evaluation on the etiologic possibilities set as they became manifest after birth. They include genetically determined inborn errors of metabolism, degenerative diseases of the central nervous system, and perinatal and postnatal environmental factors such as anoxia, trauma, infection, and drugs.