Insight into the causes of congenital heart disease can be gained from analysis of both the fetal as well as the parental genetic and environmental factors.2,16,23 Animal and human models have provided an understanding of the role of a number of gene defects in a variety of transcription factors and signaling molecules that have been discovered to cause various congenital heart defects. These genetic defects range from transcription factors such as NKX2.5, TBX5, GATA4, and FOG2 to signaling molecules PTPN11, JAG1, and CFC1, to entire genetic additions (trisomies 13, 18, and 21) and deletions (monosomy X and long arm of 6Q).16 In addition to the cardiac defects caused by these genetic additions, deletions, or mutations, the Baltimore-Washington Infant Study illustrated that greater than 25% of infants with congenital heart disease have associated noncardiac abnormalities,3,11 with chromosomal abnormalities and well-defined genetic syndromes constituting two thirds of these cases. The major chromosomal defects and syndromes are summarized in Table 81-1, although there are many more recognized deletions with a known association with heart disease (see Chapter 31). The focus of this section is to alert readers to some of the more common genetic and environmental abnormalities that contribute to congenital heart disease and lead them to further references to investigate those described in this chapter. TABLE 81-1 Major Chromosomal and Inherited Syndromes Associated with Heart Defects Infants with syndromes that are clearly related to either an excess or deleted chromosomal material have a pattern of anomalies that tend to be pathogenetically related. Infants who have a cluster of defects that appear in a non-random fashion that do not correspond to either a described syndrome or particular developmental field during cardiogenesis may also be affected with one of several recognized associations such as VACTERL (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula or esophageal atresia, renal agenesis and dysplasia, limb defects)31 or CHARGE syndrome (coloboma, heart disease, choanal atresia, restricted growth and development or other central nervous system anomalies, genital hypoplasia, and ear anomalies or deafness), which has been found to be caused by abnormalities in the CHD7 gene.38 Currently, molecular karyotyping yields an etiologic diagnosis in at least 18% of patients with syndromic congenital heart disease (CHD), but with higher-resolution genetic evaluation available this has resulted in an increasing number of genetic variants of unknown significance.4 The association of congenital heart disease with chromosomal defects, especially trisomies 13, 18, and 21, has been known for many years. Congenital heart defects are not present in all infants with these trisomies; however, they are present in the majority. More than 40% of infants with trisomy 21 have congenital heart disease, and 65% of these have endocardial cushion defects, a proportion many times more common than seen in children with normal chromosomes.13,30 Furthermore, many cardiac defects such as transposition of the great arteries and truncus arteriosus, which are relatively common causes of CHD in infants, are quite rare or unreported in children with trisomy 21. There are numerous well-defined contiguous gene deletion syndromes that have congenital heart defects as part of the phenotype. Williams syndrome is an example of such a genetic disorder. It is associated with a deletion of several contiguous genes on chromosome 7, one of which is the elastin gene.36 Supravalvular aortic stenosis and peripheral branch pulmonary artery stenosis are the most commonly seen heart defects.7 Another well-described chromosomal microdeletion is 22q11 deletion, which is associated with the phenotype of velocardiofacial syndrome24 or DiGeorge syndrome. It has a high prevalence of associated conotruncal heart defects. The sheer number of patients with this chromosomal deletion increased the interest in abnormalities in this chromosome as a cause of other conotruncal defects. Goldmuntz and associates screened 250 consecutive children with conotruncal defects and found that 50% of children with interrupted aortic arch, 35% with truncus arteriosus, and 16% with tetralogy of Fallot had a microdeletion of chromosome 22.14 Children with the “minor” cardiac abnormalities such as right aortic arch and/or an aberrant subclavian artery are also likely to have this chromosomal microdeletion.
Genetic and Environmental Contributions to Congenital Heart Disease
Syndrome
Cardiac Defects
Noncardiac Features
Trisomy 13
ASD, PDA, VSD
Microcephaly; cutis aplasia; holoprosencephaly; cleft lip; microphthalmia; low-set ears; micrognathia; hypotonia; polydactyly; rocker bottom feet; cryptorchidism
Trisomy 18
ASD, ECD, PDA, TOF, VSD
Intrauterine growth restriction; microcephaly; prominent occiput; micrognathia; cleft lip/palate; low-set ears; clenched hands with fingers 1 and 4 overlapping 2 and 3; rocker bottom feet; cryptorchidism; short sternum; pectus carinatum
Trisomy 21
ECD, VSD, ASD
Brachycephaly; epicanthal folds; small ears; upslanting palpebral fissures; transverse palmar crease; protruding tongue; excess nuchal skin; hypotonia; duodenal atresia
CHARGE
TOF, ECD aortic arch anomalies
Coloboma; choanal atresia; cranial nerve dysfunction; ear abnormalities; Mondini defect of the cochlea; absent or hypoplastic semicircular canals; developmental delay; growth deficiency; genital hypoplasia
Deletion 22q11 (DiGeorge, velocardiofacial)
IAA, TF, VSD, truncus arteriosus
Hypocalcemia; palatal abnormalities; immune deficiency; significant feeding and swallowing problems; constipation with or without structural gastrointestinal anomalies; renal anomalies; hearing loss (both conductive and sensorineural)
Holt-Oram
ASD, VSD, COA
Upper-extremity malformations involving radial, thenar, or carpal bones; cardiac conduction defects;
Kartagener
Dextrocardia
Situs inversus; bronchiectasis; asplenia; conductive hearing loss
Loeys-Dietz
Aortic dilatation and/or rupture, MVP
Hypertelorism; craniosynostosis; cleft palate/bifid uvula; pectus excavatum or pectus carinatum; scoliosis; joint laxity; arachnodactyly; talipes equinovarus; velvety and translucent skin; easy bruising; widened, atrophic scars
Marfan
Aortic dilatation, MVP, TVP, pulmonary artery dilatation (proximal)
Arachnodactyly; pectus deformity; hyperextensible joints; high arched palate; ectopia lentis
Neurofibromatosis
PS, aortic dilatation, MVP, HCM34
Café au lait spots; axillary/inguinal freckling; Lisch nodules; cutaneous neurofibromas; anteriolateral tibial bowing
Noonan
PS, HCM28,33
Short, broad neck; low hairline; coagulation defects; pectus deformity; scoliosis; cryptorchidism; lymphatic dysplasia; ptosis; low-set, posteriorly rotated ears
Smith-Lemli-Opitz
TAPVC, AV canal
Prenatal and postnatal growth restriction; microcephaly; underdeveloped external genitalia in males/hypospadias; postaxial polydactyly; 2-3 syndactyly of the toes; poor suck, irritability; failure to thrive; temporal narrowing; epicanthal folds; broad nasal bridge; short nasal root; anteverted nares; cleft palate; low-set, posteriorly rotated ears; micrognathia
Thrombocytopenia- absent radius (TAR)
ASD, TOF15
Thrombocytopenia; bilateral absent radii with thumbs present; long bone abnormalities
Turner syndrome
AS, COA, HLHS32
Broad chest; short, broad neck; lymphedema; hyperconvex nails
Williams syndrome
SVAS, branch pulmonary artery stenosis9
Hypercalcemia; feeding difficulties; failure to thrive; fullness of mouth and eyes; hypotonia; hyperextensible joints; hypertension; hypercalciuria
Chromosomal Defects
Genomic Defects
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