Congenital Heart Defects

Transcription

1 C H A P T E R 46 Congenital Heart Defects Rocio Moran Department of Pediatric Genetics, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA Nathaniel H Robin Department of Genetics and Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA Congenital heart defects have always had special place among birth defects for clinical geneticists. They are both common and serious with an estimated prevalence of approximately 8 in 1000 births and are the most common cause of birth defect-related death (1). They are often the first anomaly to present in a child and, as many are life threatening, they also typically command the greatest attention. For these reasons, they are the defining birth defect for many genetic syndromes. For example, supravalvular aortic stenosis is linked with Williams syndrome, pulmonary stenosis with Noonan syndrome, and coarctation of the aorta with Turner syndrome. However, only one-third of heart defects present as one component of a genetic syndrome, with the remainder occurring as an isolated finding (2). It is the primary role of the medical geneticist to determine if the congenital heart defect is an isolated finding, or represents one manifestation of an underlying syndrome. A syndrome is typically suspected when the heart lesion is associated with findings identified on the medical, prenatal, or family history, or on physical examination, especially noncardiac major and minor anomalies. When a syndrome is suspected, confirmatory testing may be ordered, be it chromosome analysis, fluorescence in situ hybridization, or analysis of single gene(s) for the syndrome of interest. For other cases with additional findings that are not in a recognizable pattern, array comparative genome hybridization (acgh) should be considered as a comprehensive genetic screening test. For those patients with isolated defects, our understanding of the genetic basis of congenital heart defects remains limited. That is because congenital heart defects are not variable manifestations of a single developmental aberration. Rather, they are an etiologically heterogeneous collection of malformations, with overlapping genetic and environmental factors that contribute to disease presentation. Further hindering genetic discovery is the fact that it is rare for isolated heart defects to present with traditional Mendelian inheritance, so most of the progress in this area has been made using animal models (3). However, a small but growing list of single genes may be analyzed to confirm the clinical suspicion. For those that remain without a diagnosis in both suspected syndromic and isolated congenital heart defects, follow up should be arranged. Making an accurate genetic diagnosis for a patient with a congenital heart defect has several clear benefits including the ability to provide accurate counseling on prognosis, precise causality, and recurrence risk for the patient and the family (4). While the same benefits exist when it is determined that the heart lesion is isolated, there is unfortunately simply less information. Recurrence risk counseling, for example, remains largely unchanged and is based on empirical data (5). Advances in cardiac imaging, cardiac catheterization, electrophysiology, and improving surgical techniques have resulted in the exponential growth of the population of adult patients with congenital heart defects, both syndromic and isolated. As this population transitions from the care of the pediatric provider to the adult provider, it is important for members of the medical team to appreciate the specific needs unique to this population of patients. Long-term follow-up of patients with congenital heart defects has identified additional complications that may represent a continuum of the primary defect and not necessarily acquired as the result of a previous repair. In addition, studies on adult patients with more common genetic syndromes are emerging and personalization of their care to their unique medical needs, depending on specific diagnosis, is necessary to prevent significant morbidity and mortality (6). 2013, Elsevier Ltd. All rights reserved. 169

2 170 CHAPTER 46 Congenital Heart Defects This chapter will provide an overview of congenital heart defects from a perspective most relevant to the clinical geneticist. Classic cardiac embryology will be reviewed along with the specific genes that, when abnormal, are implicated in the development of a specific heart lesion. We will also review the common genetic syndromes that have a cardiac defect as a major manifestation, categorized by etiology: chromosomal/aneuploidy syndromes, segmental chromosomal deletion/ duplication syndromes, single gene mutations, and teratogenic. Also, extensive tables are provided that group syndromes by the type of heart defect. Lastly, recurrence TABLE 46-1 Nonsyndromic CHD Heart Defect Gene Gene Function OMIM Atrioventricular CRELD1 Member of a subfamily of epidermal growth factor-related protein canal GDF1 Member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this protein is involved in the establishment of left right asymmetry in early embryogenesis GJA1 Member of the connexin gene family. Major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development Hypoplastic left heart GJA1 Member of the connexin gene family. Major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development HAND1 Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins Âasymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries Septal defects NKX2.5 Functions in early determination of the heart field and may play a role in formation of the cardiac conduction system CITED2 Inhibits transactivation of HIF1A-induced genes by competing with binding of HIF1a to p300-ch GATA4 Family of zinc-finger transcription factors. Regulates genes involved in embryogenesis and in Double outlet right ventricle Tetralogy of Fallot HAND1 HAND2 Âmyocardial differentiation and function Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins Âasymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins Âasymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries TBX20 Interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5 ACTC1 Actins are highly conserved proteins that are involved in various types of cell motility and is major constituent of the contractile apparatus of the heart MYH6 Encodes the alpha heavy chain subunit of cardiac myosin THRAP2 Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes CFC1 Member of the epidermal growth factor (EGF)-Cripto, Frl-1, and Cryptic (CFC) family. Plays key role in intercellular signaling pathways during vertebrate embryogenesis including left right patterning in the heart GDF1 Member of the BMP family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this Âprotein is involved in the establishment of left right asymmetry in early embryogenesis NKX2.5 Functions in early determination of the heart field and may play a role in formation of the cardiac conduction system GATA4 Member of the GATA family of zinc-finger transcription factors. Thought to regulate genes involved in embryogenesis and in myocardial differentiation and function JAG1 Ligand for the receptor notch NKX2.5 Functions in early determination of the heart field and may play a role in formation of the cardiac conduction system ZFPM2/ Member of the FOG family of transcription factors. Modulates the activity of GATA family proteins FOG GDF1 Member of the BMP family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this Âprotein is involved in the establishment of left right asymmetry in early embryogenesis

3 CHAPTER 46 Congenital Heart Defects 171 TABLE 46-1 Nonsyndromic CHD cont d Heart Defect Gene Gene Function OMIM Bicuspid aortic valve ÂSupravalvular aortic stenosis Transposition of the great arteries Aortic Âcoarctation NOTCH1 Member of the Notch family of proteins which function as a receptor for membrane bound ligands, and may play multiple roles during development ELN Protein product is one of the two components of elastic fibers CFC1 GDF1 THRAP2 THRAP2 Member of the EGF-CFC family. Plays key role in intercellular signaling pathways during vertebrate embryogenesis including left right patterning in the heart Member of the BMP family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this Âprotein is involved in the establishment of left right asymmetry in early embryogenesis Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes TABLE 46-2 Some Common Teratogens Teratogenic Influence Risk of Heart Defect (%) Most Common Type Maternal rubella 35 PDA, peripheral pulmonary arterystenosis, septal defects Maternal diabetes 3 5 VSD, coarctation, TGA Maternal phenylketonuria Tetralogy of Fallot Systemic lupus erythematosus Complete heart block Maternal alcohol abuse Septal defects Hydantoin 2 3 Pulmonary and aortic stenosis, coarctation of aorta, PDA Trimethadione Tetralogy of Fallot, TGA, hypoplastic left heart Thalidomide <5 Tetralogy of Fallot, septal defect struncus arteriosus Lithium Ebstein anomaly, tricuspid atresia ASD Retinoic acid Conotruncal heart defects Cocaine 5 Excess situs disturbance TABLE 46-3 Common Management Issues for Adults with Genetics Syndromes and Cardiovascular Abnormalities: General Information for Primary Care Providers a Syndrome Heart Defect Complications (postoperative unless specified) Chromosome Abnormality 22q11.2 deletion Interrupted aortic arch type B Left ventricular outflow tract obstruction. Residual coarctation Truncus arteriosus Tetralogy of Fallot Right ventricular outflow tract obstruction or insufficiency. Truncal valve regurgitation and stenosis. Right ventricular outflow tract obstruction, including pulmonary artery obstruction, pulmonary regurgitation, right ventricular dilation. Management Depending on degree of obstruction, balloon dilation or surgical correction may be needed. Depending on the degree of right ventricular, or truncal obstruction or regurgitation, surgery may be required, e.g. valve repair or replacement. Depending on degree of obstruction or regurgitation, surgery may be required. Continued

4 172 CHAPTER 46 Congenital Heart Defects TABLE 46-3 Common Management Issues for Adults with Genetics Syndromes and Cardiovascular Abnormalities: General Information for Primary Care Providers a cont d Syndrome Heart Defect Complications (postoperative unless specified) Management Down syndrome Complete AVC b Common atrioventricular valve regurgitation or stenosis. Depending on degree of regurgitation or stenosis, surgery may be required. Residual shunt at the site of the septal defect closure. Depending on size of shunt or residual lesion, surgery may be required. Arrhythmia Postoperative bradycardia, syncope Monitor all cases. May need pacemaker. Mitral valve prolapse, less frequently aortic and Usually asymptomatic. Mitral, aortic and tricuspid regurgitation may develop Auscultation in all individuals;obtain echocardiogram if abnormal. tricuspid prolapse. Coronary artery disease Not known to have increased risk of Routine population screening. angina or myocardial infarction. Turner Syndrome Bicuspid aortic valve Can progress to aortic stenosis. As in general population, there is associated risk of aortic dilatation, aneurysm and rupture. Williams Beuren Syndrome Coarctation Residual obstruction at the site of coarctation repair may lead to hypertension. Some mild coarctation may go undetected until adulthood. Repaired or unrepaired, associated with risk of aortic dilatation, dissection, and rupture. Monitor all cases with meticulous imaging of aortic root using echocardiography or MRI. Depending on severity of obstruction, may require anti-hypertensive medication, interventional catheterization or surgical correction. Aorta requires meticulous imaging using echocardiograph,preferably MRI. Hypertension Can be mild to severe. Seek underlying cause, e.g. unrepaired coarctation. Treat aggressively when hyper-tension is essential since it is a risk factor for aortic dissection. Aortic root dilation ECG abnormalities Supravalvar aortic stenosis, focal or diffuse Long-segment stenosis/ hypoplasia of thoracic or descending aorta ( coarctation ) interventional catheterization Coronary artery stenosis (due to medial hypertrophy or dysplastic Aortic valve leaflet) catheterization (if these Hypertension Treat with antihypertensive Pulmonary artery stenoses (PPS, main branch stenoses) Aortic dissection and rupture area associated with dilatation, although the natural history from dilatation to dissection has not been completely delineated. Aside from predisposition to resting tachycardia, not known to have pathologic arrhythmias. Residual left ventricular outflow tract obstruction Re-stenosis Re-coarctation Coronary insufficiency Can occur at any age Balloon dilatation or stenting for significant obstruction. Complications such as tears or aneurysms reported. Baseline imaging of aorta should be obtained in all individuals; at least one MRI examination may be needed to provide optimal imaging. Imaging should be repeated. Beta-blockade can be useful. Because of observed cardiac conduction and repolarization abnormalities, avoid drugs that increase risk of QT prolongation. Depending on degree of obstruction, surgical correction may be needed. Depending on severity of obstruction, may require anti- hypertensive medication,or surgical correction. Screen coronary patency by echocardiogram (limited sensitivity), CTA, MRA or procedures are indicated). Exercise stress testing is of limited utility due to poor exercise tolerance in most adults with WBS. Screen for renovascular cause. medication.

5 CHAPTER 46 Congenital Heart Defects 173 TABLE 46-3 Syndrome Gene Abnormality Holt Oram Syndrome Common Management Issues for Adults with Genetics Syndromes and Cardiovascular Abnormalities: General Information for Primary Care Providers a cont d Heart Defect ASD, secundum-type, VSD, membranous, muscular ASD, secundum-type, VSD, Membranous, muscular Conduction block Complications (postoperative unless specified) Residual shunt, rarely hemodynamic risk. Potential for stroke. Eisenmenger syndrome Can be progressive; when complete heart block is present, may be associated with atrial fibrillation. Marfan Syndrome Aortic dilatation Aortic dissection, rupture aortic regurgitation TGF-B receptor syndromes Hereditary Hemorrhagic Telangectasia Management Depending on size of shunt, may need surgical closure. Medication for pulmonary hypertension. Need regular monitoring with ECG and 24-hour Holter monitoring in those with known conduction disease for development and/or progression. Severe cases may require permanent pacemaker; antiarrhythmics and anticoagulants (for atrial fibrillation) may be required Prophylactic aortic root repair to prevent dissection (>45 50 mm); valve sparing technique option. Aortic dilatation Progressive dilatation, rupture Prophylactic grafting of any portion of the aorta when the risks of surgery are less than the risks of medical management, or in the case of endorgan ischemia, persistent pain Mitral valve prolapse Mitral regurgitation, heart failure Mitral valve repair or replacement. Aortic dilatation Aortic dissection, rupture Prophylactic aortic root repair to prevention dissection, but using aortic diameter criteria less than what is used for Marfan syndrome (>40 mm instead of 50mm in the adult) Aneuryszm of other major arteries Pulmonary arterio-venous malformations Arterial dissection, rupture Cyanosis; paradoxic embolization leading to stroke or brain abscess Hepatic arterio-venous Cirrhosis; hepatic encephalopathy malformations Noonan Syndrome Pulmonic stenosis Can present in adulthood for the first time; those with previous surgery or balloon angioplasty in childhood can have residual PS and/or pulmonary insufficiency ASD, secundum-type Hypertrophic cardiomyopathy Residual shunt after repair in childhood; some adults have undetected large defect and fatigue symptoms; in combination with pulmonary stenosis may have risk for stroke Right ventricular outflow obstruction; can coexist with a CHD such as pulmonary stenosis; risk of arrhythmias Prophylactic repair Therapeutic or prophylactic embolization of the AVM with coils when the diameter of the feeding artery is 1mm or greater Medical management of liver dysfunction Options for severe pulmonary stenosis include balloon valvuplasty or valve replacement; severe pulmonary insufficiency often requires valve replacement Depending on size of shunt may require surgical closure or closure by a septal occluder device Treatment considerations include surgical myomectomy and beta blockers; careful monitoring for arrhythmias may also include treatment such as amiodarone, pacemaker defibrillator ASD, atrial septal defect; AVC, atrioventricular canal defect; CAVC, complete atrioventricular canal; CHD, congenital heart defects; CTA, CT angiography; ECG, electrocardiographic; VSD, ventricular septal defect. a Guidelines provide general information for primary care providers, but individuals require specific management by cardiologists. In the interest of brevity, each cardiac abnormality for each disorder was not listed. b ASD, VSD and tetralogy of Fallot were not discussed. Antibiotic prophylaxis for subacute bacterial endocarditis should be offered in appropriate doses per standard practice. Lin, A. E.; Basson, C. T., et al. Adults with Genetic Syndromes and Cardiovascular Abnormalities: Clinical History and Management. Genet. Med. 2008, 10 (7),

6 174 CHAPTER 46 Congenital Heart Defects risk counseling will be reviewed, for both syndromic and nonsyndromic lesions. REFERENCES 1. Hoffman, J. I.; Kaplan, S. The Incidence of Congenital Heart Disease. J. Am. Coll. Cardiol. 2002, 39 (12), Ferencz, C., et al. Congenital Cardiovascular Malformations: Questions on Inheritance. Baltimore Washington Infant Study Group. J. Am. Coll. Cardiol. 1989, 14 (3), Srivastava, D. Making or Breaking the Heart: From Lineage Determination to Morphogenesis. Cell 2006, 126 (6), Robin, N. H. It Does Matter: The Importance of Making the Diagnosis of a Genetic Syndrome. Curr. Opin. Pediatr. 2006, 18 (6), Shieh, J. T.; Srivastava, D. Heart Malformation: What Are the Chances It Could Happen Again?. Circulation 2009, 120 (4), Lin, A. E., et al. Adults with Genetic Syndromes and Cardiovascular Abnormalities: Clinical History and Management. Genet. Med. 2008, 10 (7),