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Genetic counseling for congenital heart defects
CURRENT LITERATURE AND CLINICAL ISSUES
Genetic counseling for congenital heart defects Optimal genetic counseling for any congenital malformation requires (1) a thorough understanding of the anatomy, management, and outcome of the particular defect, (2) identification of associated anomalies or syndromes, (3) ascertainment of other affected family members and careful pedigree delineation for prediction of familial risks, and (4) options for prenatal diagnosis. In the past 10 years, since guidelines for counseling of structural congenital heart defects were first presented] we have witnessed important developments in the understanding of its mechanisms, medical and surgical management, and genetic influences. A reappraisal of the approach to genetic counseling for this birth defect is therefore indicated. Herein, we review recent publications on this topic and formulate a strategy suitable for pediatric cardiologists, geneticists, and pediatricians for counseling patients and families with CHDs. MECHANISMS DEFECTS
OF CONGENITAL HEART
The nomenclature employed for classifying structural congenital cardiac malformations may be based on presumed ernbryotogic events 2 Or on their anatomic characteristics and location? In addition to these systems, CHD may be approached from the viewpoint of disordered embryonic mechanisms? Five developmental mechanisms (ectomesenchymal tissue, cardiac hemodynamics, cellular death, extracellular matrix determination, disordered targeted growth) are likely to play a role in causing cardiac malformations. The specific cardiac defects involved are heterogeneous but share the disordered mechanism. The traditional use of the earlier classifications, although helpful in naming complex cardiac defects, may have obscured important pathogenic relationships. TREATMENT DEFECTS
OF C O N G E N I T A L H E A R T
Enormous strides have been made in the surgical palliation and repair of CHDs, especially complex ones. With improved surgical techniques and methods for intraoperarive myocardial preservation, primary repair" in infancy is now possible and is often preferred for certain lesions (tetralogy of Fallot, truncus arteriosus, interruption of the
aortic arch, Complete common atrioventricular canal, transposition of the great arteries)? '6 Tricuspid atresia, Single ventricle, and hypoplastic left-heart syndrome cannot be truly "corrected," but palliation can be provided. 7,8 Because Of the increase in the number of patients who survive to adulthood and the consequent possibility of childbearing, the necessity for genetic counseling is greater than before. CHD ECM
Congenital heart defect Extracardiac malformation
'[
ASSOCIATED DEFECTS Extracardiac malformations occur in approximately 25% of live-born patients with structural CHD, 9 many of whom have identifiable malformation syndromes. Previous cytogenetic studies 1~ of patients with CHD were performed before the current era of chromosoma! banding and high-resolution analysis. More recently, 12% of all infants with CHD were found to have chromosomal abnormalities? 2 Thus a formal genetic evaluation, including karyotype, is often warranted for children with CHD and dysmorphic features. Postmortem examination Of a deceased child with a CHD is of critical importance for the detection of any previously unsuspected ECM, which may then allow recognition of a syndrome and more accurate counseling. FAMILY HISTORY A meticulous pedigree should be obtained to determine whether any other relatives are affected with a CHD, and attempts should be made tO document this information with medical records or diagnostic tests. A formal cardiology consultation may be required for siblings or parents with questionable murmurs of unspecified origin to ascertain whether a congenital defect is present and, if so; whether it is identical, similar, or unrelated to the patient's lesion. If first-degree relatives have a CHD, the risk of recurrence is greater, especially if the defect is concordant (i.e., of similar mechanistic origin). Prospective clinical and echocardiographic studies of first-degree relatives of patients with complete common atrioventricular canal 13 and isolated hypoplastic left-heart syndrome ~4 have 1105
110 6
Lin and Garver
The Journal of Pediatrics December 1988
F A M I L I A L RISKS
Table, Sibling precurrence rates for CHD* Category of disordered cardiac embryonic mechanism Cell migration abnormality (conotruncal) Truncus arteriosus Transposition of great arteries Double-outlet right ventricle Tetrali~gy of Fallot Type B interrupted aortic arch VSD (type I, supracristal, malalignment) Flow lesions Hypoplastic left-heart syndrome Coarctation Aortic stenosis, valvar Bicuspid aortic valve Patent ductus arteriosus Secundum atrial septal defect Pulmonic stenosis, valvar Pulmonary atresia VSD (type II, membranous) Cell death Ebstein anomaly VSD (type IV, muscular) Extracellular matrix Atrioventricular canal VSD (type III, canal type, inlet) Targeted growth APVR, total APVR, partial Single atrium Other
Sibling (%) 0/1 0/24 0/8 0/22 0/1 0/2
5/38 (13.5) 3/37 (8.1) 0/12 1/9 (11.!) 1/ 13 (7.7) 1/31 (3.2) 3/3,3 (9.t) 0/8 5/86 (5.8) 0/10 0/9 0/10 0 0/12 0/1 0/1 1/37 (2.8)
APVR, Anomalouspulmonaryvenous return; VSD, ventricular septal
defect. *Modified from BoughmanJA, Berg KA, AstemborskiJA, et al. Am J Med Genet 1987;26:839. resulted in diagnosis of previously unsuspected CHDs that were clinically less significant than the proband's CHD but were part of the same spectrum (e.g., atrioventricular canal-type septal defects and left axis deviation, left ventricular outflow obstruction, respectively). Additional prospective family studies using two-dimensional echocardiography will be useful for assessing familial prevalence more completely. The impact on the family of a child with a CHD and the effect on subsequent pregnancies has been demonstrated. A decrease in reproduction in families of living infants may occur, or a deceased infant may be "replaced" with another child) s If a patient has a CHD in association with a mendelian malformation syndrome (e.g., dysplastic pulmonie valve stenosis in Noonan syndrome), relatives should be evaluated for evidence of that Syndrome even if they have no evidence of CHD,
A recent study found that the prevalence of structural CHD in live-born infants is 3.7/1000, somewhat less than that in previous studies (5.5 to 8:6/1000). 16 In the earlier studies the diagnosis of CHD was often made on clinical criteria alone. However, the rate of confirmed CHD in the study by Ferencz et al. 16 was relatively similar to previous rates of 4 or 5/1000 live births. 16 Congenital heart defects have been thought to have multifactorial origins] 7 with genetic and environmental influences. However, the familial occurrence of virtually all forms of CHD has been noted, as-23 Monogenic inheritance with autosomal recessive or dominant transmission has been postulated. The purebred keeshond, beagle, and poodle dog strains have an increased frequency of CHD, a finding that supports the notion of strong genetic influences. 24, 25 For a family with one affected Child, the empiric recurrence risk of having another sibling with CHD was previously thought to be 1% to 3%, 1 in accordance with a multifactorial model. Recent information from a large retrospective study (with concurrent ascertainment) suggests that familial precurrence rates (i.e., frequency of CHD in relatives of probands with isolated CHD) may be greater for certain groups of cardiac defects when they are classified by the type of disordered mechanism (Table).4. 26 Although the overall sibling precurrence rates for all types of CHD was similar to that previously reported (1.8%), there was a marked increase in the rate for obstructive lesions of the left side of the heart (related to disordered cardiac hemodynamics). The familial rate of obstructive defects of the left side of the heart was fourfold to sixfold greater. The following sibling precurrence rates were noted: 14% for hypoplastic left-heart syndrome, 11% for bicuspid aortic valve, and 8% for coarctation of the aorta. 26 The recurrence risk to offspring of parents with CHD was initially reported to be between 2% and 4%, depending on the lesion, if one parent was affected. 27 This risk tripled if both parents were affected or if there was one affected parent and an affected child. In a recent large prospective cohort study, Whittemore et al. 28 noted a much higher recurrence risk of 14.2% in children of women with CHD. Similarly, Rose et al. 29reported an 8.8% incidence of CHD in children born to parents with certain defects. A high recurrence risk (1 0% to 14%) in children of parents with complete atrioventricular canal was found by Emanuel et al? ~ These and other studies were comprehensively reviewed by Nora and Nora, 31 who emphasized this increase in recurrence risks for offspring of affected mothers, raising the possibility of cytoplasmic maternal
Volume 113 Number 6
Genetic counseling for congenital heart defects
transmission. It is of interest that Whittemore32 recently expressed concern about her inability to substantiate this hypothesis of increased maternal risk after performing additional follow-up studies of offspring of both affected mothers and affected fathers. In some instances, it is probable that the genetic factors in multifactorially produced CHD play a stronger role. For example, in a study of two rare CHDs, Pierpont et al. 33 found a sibling recurrence risk of 2.1% in probands with all types of interruption of the aortic arch, and 6.6% in
plex)? 2,36 Approximately 90% of mothers of fetuses with trisomy 21 syndrome in whom the chromosomal abnormality was diagnosed by amniocentesis karyotyping chose termination of pregnancy?7 In those instances, termination was based on the abnormal karyotype, not on the presence of the CHD.
truncus arteriosus. Familial recurrence was more frequently associated with interrupted aortic arch (type B) and complex truncus arteriosus. These authors suggested that monogenic inheritance may play a role in the recurrence of these CHD. 33 Empiric recurrence risk figures derived from population-based studies, however, do not distinguish between the majority of cases of CHD and those with the stronger genetic trends; the figures represent "averaged" values. PRENATAL DIAGNOSIS Although the bulk of prospective genetic counseling concerns the assessment and communication of recurrence risk, a prerequisite to the decision to bear children should be the provision of information about prenatal diagnosis and referral to appropriate specialists. A few of these aspects will be discussed. At many centers, fetal echocardiography beginning at 16 weeks gestation can be offered if either parent or previous offspring has a CHD or if the mother has a risk factor predisposing the fetus to CHD (e.g., affected first-degree relative, maternal lithium ingestion, maternal diabetes). 34 If a CHD is identified, the parents should be counseled, possibly in conjunction with a pediatric cardiologist, regarding the specific cardiac anatomy and current medical or surgical management options. Knowledge of actual fetal status, rather than an estimated empiric risk, will help the parents make a decision concerning continuation of the pregnancy.35 If a significant complex CHD is detected, the "worst case" scenario of a critically ill newborn infant should be considered and provisions for treatment discussed. Delivery should occur in proximity to a tertiary care neonatal unit that would be able to provide tracheal intubation, mechanical ventilation, and prostaglandin infusion. The prenatal detection of certain highly distinctive cardiac defects, especially when associated with other ECMs, warrants fetal chromosomal analysis to determine the possibility of an associated syndrome (e.g., common atrioventricular canal in Down syndrome, 'interrupted aortic arch [type B] in DiGeorge malformation corn-
1107
GENETIC COUNSELING Too often, genetic counseling for families of children with CHD is not addressed as a specific issue. The initial interaction between the parents of a newborn infant with CHD and the cardiologist usually occurs in the setting of an intensive care unit during a period of parental stress and anxiety, when future childbearing is not an immediate issue. Subsequent visits to the cardiology clinic are concerned primarily with evaluating the child's cardiac status and plans for treatment. Extracardiac malformations suggestive of malformation syndromes are sometimes not recognized, and referrals to geneticists may not be made. Rarely is there sufficient time to address all of the genetic aspects of CHD. Such a discussion may occur at a later date with a geneticist or genetic counselor if the mother seeks prenatal counseling before a subsequent pregnancy. A cardiologist is rarely present at that session. Ideal genetic counseling would be provided by a geneticist knowledgeable about cardiac defects and outcome or by a pediatric cardiologist with an awareness and willingness to address genetic issues. The benefits of genetic counseling for parents of children with CHD has been demonstrated? 8 Unfortunately, genetic counseling for isolated CHD (i.e., unassociated with a malformation syndrome) may be transmitted as generalized advice, with the use of an overall recurrence risk for first-degree relatives of 3% to 5%39or 2% to 4%.4oInstead, the recurrence risk for siblings should be based on the affected child's specific anatomic defect and the presence of other affected siblings. In some families, mendelian rather than multifactorial transmission will be suggested. Furthermore, a parent with a CHD should be counseled that the risk of affected mothers 7 having a child affected with a CHD may be in the range of 8% to 14%, although additional studies will be needed to confirm this rate. Prenatal diagnosis in the form of fetal eehocardiography, usually accompanied by amnioeentesis for karyotype, is a valuable adjunct for counseling. Because of the rapid expansion of knowledge of the genetics of CHD, these considerations represent our current position, which may be altered in the future. In other areas of genetics, research has shifted from the purely clinical to the molecular level. In pediatric cardiology, well-designed epidemiologic studies, n' ~6.~6replacing small-
1108
Lin and Garver
er, uncontrolled and anecdotal reports, now play a n import a n t role in elucidating the genetic aspects of C H D . Perhaps in the future we may be able to use the techniques of "reverse" genetics for the instances, albeit u n c o m m o n , of familial C H D . This approach would i m p l e m e n t segregation and linkage analyses to establish a c h r o m o s o m e m a p position for the gene of interest. We express our deep appreciation to Drs. Charlotte Ferencz, Joann Boughman, and Edward Clark for their critical review of this article.
Angela E. Lin, MD Kenneth L. Garver, MD, PhD Department of Medical Genetics The Western Pennsylvania Hospital Pittsburgh, PA 15224 REFERENCES
1. Nora J J, Nora AH. The evolution of specific genetic and environmental counseling in congenital heart diseases. Circulation 1978;57:205. 2. VanPraagh R. Terminology of congenital heart disease: glossary and commentary. Circulation 1977;56:139. 3. Shinebourne EA, Anderson RH. Current paediatric cardiology. Oxford: Oxford University Press, 1980. 4. Clark EB. Pathogenesis of cardiac malformations. In: Pierpont ME, Moller JH, eds. Genetics in cardiovascular disease. Norwell, Mass.: Martinus Nijhoff, 1987:3-11. 5. Turley K, Mavroudis C, Ebert PA. Repair of congenital cardiac lesions during the first week of life. Circulation 1982;66(suppl I):I-214. 6. Ebert PA, Turley K. Surgery for cyanotic heart disease in the first year of life. J Am Coil Cardiol 1983;1:274. 7. Humes RA, Porter C J, Mair DD, Puga F J, Schaff HV, Danielson GK. Intermediate follow-up and predicted survival following the modified Fontan procedures. Am Heart J 1986;112:645. 8. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart syndrome. N Engl J Med 1983;308:23. 9. Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 1975;55:485. 10. Anders JM, Moores EC, Emanuel R. Chromosome studies in 156 patients with congenital heart disease. Br Heart J 1965;27:756. ll. Rohde RA. Chromosomes in heart disease: clinical and cytogenetic studies of sixty-eight cases. Circulation 1966; 34:484. 12. Berg KA, Boughman JA, Astemborski JA, Ferencz C. Implications for prenatal cytogenetic analysis from the Baltimore-Washington study of liveborn infants with confirmed congenital heart defects (CHD). Am J Hum Genet 1986; 39:A50. 13. Disegni E, Pierpont ME, Bass JL, Kaplinsky E. Twodimensional echocardiographic identification of endocardial cushion defect in families. Am J Cardiol 1985;55:1649. 14. Berg KA, Astemborski JA, Boughman JA, Schneider DS, Brenner JI, Clark EB. Heart defects in first degree relatives
The Journal of Pediatrics December 1988
15.
16.
17.
18.
19.
20. 21.
22.
23. 24.
25.
26.
27.
28.
29.
30.
31.
32. 33.
34.
of infants with hypoplastic left heart syndrome (HLHS). Am J Hum Genet 1987;41:A47. Rubin JD, Ferencz C. Subsequent pregnancies in mothers of infants with congenital heart disease. Pediatrics 1985; 76:371. Ferencz C, Rubin JD, McCarter R J, et al. Congenital heart disease: prevalence at live birth--the Baltimore-Washington Infant Study. Am J Epidemiol 1985;121:31. Nora JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart defects: the genetic environmental interaction. Circulation 1968;38:604. Fraser FC, Hunter AD. Etiologic relations among categories of congenital heart malformations. Am J Cardiol 1975; 36:793. Miller ME, Smith DW. Conotruncal malformation complex: examples of possible monogenic inheritance. Pediatrics 1979; 63:890. Shokeir MH. Hypoplastic left heart syndrome: an autosomal recessive disorder. Clin Genet 1971;2:7. McCue CM, Spicuzza TJ, Robertson LW, Mauck HP. Familial supravalvular aortic stenosis. J PEDIATR 1968; 73:889. Brunson SC, Nudel DB, Gootman N, Aftalian B. Truncus arteriosus in a family [Letter to Editor]. Am Heart J 1978;96:419. Boon AR, Roberts DF. A family study of coarctation of the aorta. J Med Genet 1976;13:420. Patterson DF, Pyle RL, Van Mierop L, Melbin J, Olson M. Hereditary defects of the conotruncal septum in keeshond dogs: pathologic and genetic studies. Am J Cardiol 1974; 34:187. Paterson DF, Haskins ME, Schnorr MA. Hereditary dysplasia of the pulmonlc valve in beagle dogs. Am J Cardiol 1981;47:631. Boughman JA, Berg KA, Astemborski JA, et al. Familial risks of congenital heart defect assessed in a population-based study. Am J Med Genet 1987;26:839. Nora J J, Nora AH. Recurrence risks in children having one parent with a congenital heart disease. Circulation 1976; 53:701. Whittemore R, Hobbins JC, Engle MA. Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. Am J Cardiol 1982;50:641. Rose V, Gold R J, Lindsay G, Allen M. A possible increase in the incidence of congenital heart defects among the offspring of affected parents. J Am Coll Cardiol 1985;6:376. Emanuel R, Somerville J, Inns A, Withers R. Evidence of congenital heart disease in the offspring of parents with atrioventricular defect. Br Heart J 1983;49:144. Nora J J, Nora AH. Maternal transmission of congenital heart diseases: new recurrence risk figures and questions of cytoplasmic inheritance and vulnerability to teratogens. Am J Cardiol 1983;59:459. Whittemore R. Maternal transmission of congenital heart disease [Letter]. Am J Cardiol 1988;61:499. Pierpont MEM, Gobel JW, Moiler JH, Edwards JE. Cardiac malformations in relatives of children with truncus arteriosus or interruption of the aortic arch. Am J Cardiol 1988; 61:423. Huhta JC. Use and abuses of fetal echo: a pediatric cardiologist's view. J Am Coil Cardiol 1986;8:451.
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Genetic counseling f o r congenital heart defects
35. Pierpont ME, Moller JH. Congenital cardiac malformations. In: Pierpont ME, Moller JH, eds. Genetics of cardiovascular disease. Norwell, Mass.: Martinus Nijhoff, 1987:21. 36. Wladimiroff JW, Stewart M, Sachs ES, Neirmeijer MF. Prenatal diagnosis and management of congenital heart defect: significanceof associated fetal anomalies and prenatal chromosomal studies. Am J Med Genet 1985;21:285. 37. Adler B, Kushnik T. Genetic counseling in prenatally diagnosed trisomy 18 and 21: psychosocial aspects. Pediatrics 1982;19:94.
38. Halloran KH, Hsia YE, Rosenberg LE. Genetic counseling for congenital heart disease. J PEDIATR1976;88:1054. 39. Kelly TE. Clinical genetics and genetic counseling. Chicago: Year Bood Medical, 1980:375. 40. Micbels VV, Riccardi VM. Congenital heart defects. In: Emery AE, Rimoin DL, eds. Principles and practice of medical genetics. Edinburgh: Churchill Livingstone, 1983: 951.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1988 issues of THE JOURNALOF PEDIATRICSare available to subscribers (only) from the Publisher, at a cost of $46.00 ($62.00 international) for Vol. 112 (January-June) and Vol. 113 (July-December), shipping charges included. Each bound volume contains subject and author indexes, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C.V. Mosby Company, Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, USA/800-325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
1 10 9
Genetic counseling for congenital heart defects Optimal genetic counseling for any congenital malformation requires (1) a thorough understanding of the anatomy, management, and outcome of the particular defect, (2) identification of associated anomalies or syndromes, (3) ascertainment of other affected family members and careful pedigree delineation for prediction of familial risks, and (4) options for prenatal diagnosis. In the past 10 years, since guidelines for counseling of structural congenital heart defects were first presented] we have witnessed important developments in the understanding of its mechanisms, medical and surgical management, and genetic influences. A reappraisal of the approach to genetic counseling for this birth defect is therefore indicated. Herein, we review recent publications on this topic and formulate a strategy suitable for pediatric cardiologists, geneticists, and pediatricians for counseling patients and families with CHDs. MECHANISMS DEFECTS
OF CONGENITAL HEART
The nomenclature employed for classifying structural congenital cardiac malformations may be based on presumed ernbryotogic events 2 Or on their anatomic characteristics and location? In addition to these systems, CHD may be approached from the viewpoint of disordered embryonic mechanisms? Five developmental mechanisms (ectomesenchymal tissue, cardiac hemodynamics, cellular death, extracellular matrix determination, disordered targeted growth) are likely to play a role in causing cardiac malformations. The specific cardiac defects involved are heterogeneous but share the disordered mechanism. The traditional use of the earlier classifications, although helpful in naming complex cardiac defects, may have obscured important pathogenic relationships. TREATMENT DEFECTS
OF C O N G E N I T A L H E A R T
Enormous strides have been made in the surgical palliation and repair of CHDs, especially complex ones. With improved surgical techniques and methods for intraoperarive myocardial preservation, primary repair" in infancy is now possible and is often preferred for certain lesions (tetralogy of Fallot, truncus arteriosus, interruption of the
aortic arch, Complete common atrioventricular canal, transposition of the great arteries)? '6 Tricuspid atresia, Single ventricle, and hypoplastic left-heart syndrome cannot be truly "corrected," but palliation can be provided. 7,8 Because Of the increase in the number of patients who survive to adulthood and the consequent possibility of childbearing, the necessity for genetic counseling is greater than before. CHD ECM
Congenital heart defect Extracardiac malformation
'[
ASSOCIATED DEFECTS Extracardiac malformations occur in approximately 25% of live-born patients with structural CHD, 9 many of whom have identifiable malformation syndromes. Previous cytogenetic studies 1~ of patients with CHD were performed before the current era of chromosoma! banding and high-resolution analysis. More recently, 12% of all infants with CHD were found to have chromosomal abnormalities? 2 Thus a formal genetic evaluation, including karyotype, is often warranted for children with CHD and dysmorphic features. Postmortem examination Of a deceased child with a CHD is of critical importance for the detection of any previously unsuspected ECM, which may then allow recognition of a syndrome and more accurate counseling. FAMILY HISTORY A meticulous pedigree should be obtained to determine whether any other relatives are affected with a CHD, and attempts should be made tO document this information with medical records or diagnostic tests. A formal cardiology consultation may be required for siblings or parents with questionable murmurs of unspecified origin to ascertain whether a congenital defect is present and, if so; whether it is identical, similar, or unrelated to the patient's lesion. If first-degree relatives have a CHD, the risk of recurrence is greater, especially if the defect is concordant (i.e., of similar mechanistic origin). Prospective clinical and echocardiographic studies of first-degree relatives of patients with complete common atrioventricular canal 13 and isolated hypoplastic left-heart syndrome ~4 have 1105
110 6
Lin and Garver
The Journal of Pediatrics December 1988
F A M I L I A L RISKS
Table, Sibling precurrence rates for CHD* Category of disordered cardiac embryonic mechanism Cell migration abnormality (conotruncal) Truncus arteriosus Transposition of great arteries Double-outlet right ventricle Tetrali~gy of Fallot Type B interrupted aortic arch VSD (type I, supracristal, malalignment) Flow lesions Hypoplastic left-heart syndrome Coarctation Aortic stenosis, valvar Bicuspid aortic valve Patent ductus arteriosus Secundum atrial septal defect Pulmonic stenosis, valvar Pulmonary atresia VSD (type II, membranous) Cell death Ebstein anomaly VSD (type IV, muscular) Extracellular matrix Atrioventricular canal VSD (type III, canal type, inlet) Targeted growth APVR, total APVR, partial Single atrium Other
Sibling (%) 0/1 0/24 0/8 0/22 0/1 0/2
5/38 (13.5) 3/37 (8.1) 0/12 1/9 (11.!) 1/ 13 (7.7) 1/31 (3.2) 3/3,3 (9.t) 0/8 5/86 (5.8) 0/10 0/9 0/10 0 0/12 0/1 0/1 1/37 (2.8)
APVR, Anomalouspulmonaryvenous return; VSD, ventricular septal
defect. *Modified from BoughmanJA, Berg KA, AstemborskiJA, et al. Am J Med Genet 1987;26:839. resulted in diagnosis of previously unsuspected CHDs that were clinically less significant than the proband's CHD but were part of the same spectrum (e.g., atrioventricular canal-type septal defects and left axis deviation, left ventricular outflow obstruction, respectively). Additional prospective family studies using two-dimensional echocardiography will be useful for assessing familial prevalence more completely. The impact on the family of a child with a CHD and the effect on subsequent pregnancies has been demonstrated. A decrease in reproduction in families of living infants may occur, or a deceased infant may be "replaced" with another child) s If a patient has a CHD in association with a mendelian malformation syndrome (e.g., dysplastic pulmonie valve stenosis in Noonan syndrome), relatives should be evaluated for evidence of that Syndrome even if they have no evidence of CHD,
A recent study found that the prevalence of structural CHD in live-born infants is 3.7/1000, somewhat less than that in previous studies (5.5 to 8:6/1000). 16 In the earlier studies the diagnosis of CHD was often made on clinical criteria alone. However, the rate of confirmed CHD in the study by Ferencz et al. 16 was relatively similar to previous rates of 4 or 5/1000 live births. 16 Congenital heart defects have been thought to have multifactorial origins] 7 with genetic and environmental influences. However, the familial occurrence of virtually all forms of CHD has been noted, as-23 Monogenic inheritance with autosomal recessive or dominant transmission has been postulated. The purebred keeshond, beagle, and poodle dog strains have an increased frequency of CHD, a finding that supports the notion of strong genetic influences. 24, 25 For a family with one affected Child, the empiric recurrence risk of having another sibling with CHD was previously thought to be 1% to 3%, 1 in accordance with a multifactorial model. Recent information from a large retrospective study (with concurrent ascertainment) suggests that familial precurrence rates (i.e., frequency of CHD in relatives of probands with isolated CHD) may be greater for certain groups of cardiac defects when they are classified by the type of disordered mechanism (Table).4. 26 Although the overall sibling precurrence rates for all types of CHD was similar to that previously reported (1.8%), there was a marked increase in the rate for obstructive lesions of the left side of the heart (related to disordered cardiac hemodynamics). The familial rate of obstructive defects of the left side of the heart was fourfold to sixfold greater. The following sibling precurrence rates were noted: 14% for hypoplastic left-heart syndrome, 11% for bicuspid aortic valve, and 8% for coarctation of the aorta. 26 The recurrence risk to offspring of parents with CHD was initially reported to be between 2% and 4%, depending on the lesion, if one parent was affected. 27 This risk tripled if both parents were affected or if there was one affected parent and an affected child. In a recent large prospective cohort study, Whittemore et al. 28 noted a much higher recurrence risk of 14.2% in children of women with CHD. Similarly, Rose et al. 29reported an 8.8% incidence of CHD in children born to parents with certain defects. A high recurrence risk (1 0% to 14%) in children of parents with complete atrioventricular canal was found by Emanuel et al? ~ These and other studies were comprehensively reviewed by Nora and Nora, 31 who emphasized this increase in recurrence risks for offspring of affected mothers, raising the possibility of cytoplasmic maternal
Volume 113 Number 6
Genetic counseling for congenital heart defects
transmission. It is of interest that Whittemore32 recently expressed concern about her inability to substantiate this hypothesis of increased maternal risk after performing additional follow-up studies of offspring of both affected mothers and affected fathers. In some instances, it is probable that the genetic factors in multifactorially produced CHD play a stronger role. For example, in a study of two rare CHDs, Pierpont et al. 33 found a sibling recurrence risk of 2.1% in probands with all types of interruption of the aortic arch, and 6.6% in
plex)? 2,36 Approximately 90% of mothers of fetuses with trisomy 21 syndrome in whom the chromosomal abnormality was diagnosed by amniocentesis karyotyping chose termination of pregnancy?7 In those instances, termination was based on the abnormal karyotype, not on the presence of the CHD.
truncus arteriosus. Familial recurrence was more frequently associated with interrupted aortic arch (type B) and complex truncus arteriosus. These authors suggested that monogenic inheritance may play a role in the recurrence of these CHD. 33 Empiric recurrence risk figures derived from population-based studies, however, do not distinguish between the majority of cases of CHD and those with the stronger genetic trends; the figures represent "averaged" values. PRENATAL DIAGNOSIS Although the bulk of prospective genetic counseling concerns the assessment and communication of recurrence risk, a prerequisite to the decision to bear children should be the provision of information about prenatal diagnosis and referral to appropriate specialists. A few of these aspects will be discussed. At many centers, fetal echocardiography beginning at 16 weeks gestation can be offered if either parent or previous offspring has a CHD or if the mother has a risk factor predisposing the fetus to CHD (e.g., affected first-degree relative, maternal lithium ingestion, maternal diabetes). 34 If a CHD is identified, the parents should be counseled, possibly in conjunction with a pediatric cardiologist, regarding the specific cardiac anatomy and current medical or surgical management options. Knowledge of actual fetal status, rather than an estimated empiric risk, will help the parents make a decision concerning continuation of the pregnancy.35 If a significant complex CHD is detected, the "worst case" scenario of a critically ill newborn infant should be considered and provisions for treatment discussed. Delivery should occur in proximity to a tertiary care neonatal unit that would be able to provide tracheal intubation, mechanical ventilation, and prostaglandin infusion. The prenatal detection of certain highly distinctive cardiac defects, especially when associated with other ECMs, warrants fetal chromosomal analysis to determine the possibility of an associated syndrome (e.g., common atrioventricular canal in Down syndrome, 'interrupted aortic arch [type B] in DiGeorge malformation corn-
1107
GENETIC COUNSELING Too often, genetic counseling for families of children with CHD is not addressed as a specific issue. The initial interaction between the parents of a newborn infant with CHD and the cardiologist usually occurs in the setting of an intensive care unit during a period of parental stress and anxiety, when future childbearing is not an immediate issue. Subsequent visits to the cardiology clinic are concerned primarily with evaluating the child's cardiac status and plans for treatment. Extracardiac malformations suggestive of malformation syndromes are sometimes not recognized, and referrals to geneticists may not be made. Rarely is there sufficient time to address all of the genetic aspects of CHD. Such a discussion may occur at a later date with a geneticist or genetic counselor if the mother seeks prenatal counseling before a subsequent pregnancy. A cardiologist is rarely present at that session. Ideal genetic counseling would be provided by a geneticist knowledgeable about cardiac defects and outcome or by a pediatric cardiologist with an awareness and willingness to address genetic issues. The benefits of genetic counseling for parents of children with CHD has been demonstrated? 8 Unfortunately, genetic counseling for isolated CHD (i.e., unassociated with a malformation syndrome) may be transmitted as generalized advice, with the use of an overall recurrence risk for first-degree relatives of 3% to 5%39or 2% to 4%.4oInstead, the recurrence risk for siblings should be based on the affected child's specific anatomic defect and the presence of other affected siblings. In some families, mendelian rather than multifactorial transmission will be suggested. Furthermore, a parent with a CHD should be counseled that the risk of affected mothers 7 having a child affected with a CHD may be in the range of 8% to 14%, although additional studies will be needed to confirm this rate. Prenatal diagnosis in the form of fetal eehocardiography, usually accompanied by amnioeentesis for karyotype, is a valuable adjunct for counseling. Because of the rapid expansion of knowledge of the genetics of CHD, these considerations represent our current position, which may be altered in the future. In other areas of genetics, research has shifted from the purely clinical to the molecular level. In pediatric cardiology, well-designed epidemiologic studies, n' ~6.~6replacing small-
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Lin and Garver
er, uncontrolled and anecdotal reports, now play a n import a n t role in elucidating the genetic aspects of C H D . Perhaps in the future we may be able to use the techniques of "reverse" genetics for the instances, albeit u n c o m m o n , of familial C H D . This approach would i m p l e m e n t segregation and linkage analyses to establish a c h r o m o s o m e m a p position for the gene of interest. We express our deep appreciation to Drs. Charlotte Ferencz, Joann Boughman, and Edward Clark for their critical review of this article.
Angela E. Lin, MD Kenneth L. Garver, MD, PhD Department of Medical Genetics The Western Pennsylvania Hospital Pittsburgh, PA 15224 REFERENCES
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35. Pierpont ME, Moller JH. Congenital cardiac malformations. In: Pierpont ME, Moller JH, eds. Genetics of cardiovascular disease. Norwell, Mass.: Martinus Nijhoff, 1987:21. 36. Wladimiroff JW, Stewart M, Sachs ES, Neirmeijer MF. Prenatal diagnosis and management of congenital heart defect: significanceof associated fetal anomalies and prenatal chromosomal studies. Am J Med Genet 1985;21:285. 37. Adler B, Kushnik T. Genetic counseling in prenatally diagnosed trisomy 18 and 21: psychosocial aspects. Pediatrics 1982;19:94.
38. Halloran KH, Hsia YE, Rosenberg LE. Genetic counseling for congenital heart disease. J PEDIATR1976;88:1054. 39. Kelly TE. Clinical genetics and genetic counseling. Chicago: Year Bood Medical, 1980:375. 40. Micbels VV, Riccardi VM. Congenital heart defects. In: Emery AE, Rimoin DL, eds. Principles and practice of medical genetics. Edinburgh: Churchill Livingstone, 1983: 951.
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