Clinical Genetics 199 I : 40: I 2- I6
The inheritance of conotruncal malformations: a review and report of two siblings with tetralogy of Fallot with pulmonary atresia ERICA. WULFSBERG', ERICJ. zINTZ2 AND JOHN w. MOORE' 'Medical Genetics/Dysmorphology, 'Department of Pediatrics, National Naval Medical Center, Uniformed Services University of the Health Sciences, Ekthesda, Maryland and 'Pediatric Cardiology, Walter Reed Army Medical Center, Washington, DC, USA Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately I%. It is estimated that 4-5% of CHI1 are associated with chromosome abnormalities, 1-2% are associated with single gene Syndromes, 1-2% are due to known teratogens, with the rest presumably determined multifactorially. We report on a brother and sister with tetralogy of Fallot with pulmonary atresia, and review the inheritance of familial conotruncal anomalies. W? feel the small number of family clusters and the rare instances of consanguinity in non-syndromal conotruncal defects are consistent with multifactorial determination. While it is prudent in counseling families with 2 or more individuals with conotruncal CHD to raise the possibility of single gene inheritance, we believe that current empiric recurrence risk estimates most accurately reflect their risks. Received I2 November 1990, revised 10 January, accepted f o r publication 17 January 1991 Key words: congenital heart defects; conotruncal malformations; genetic counseling; recurrence risk.
Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately 1 % (Nora & Nora 1988). It is estimated that 4 5 % of CHD are associated with chromosome abnormalities, 1-2% are associated with single gene syndromes, 1-2% are due to known teratogens, with the remainder presumably determined multifactorially (Nora 1968, Berini & Kahn 1987). Empiric recurrence risks for siblings of a child with a CHD range from 1-10% depending on the specific malformation and the number of affected first-degree relatives (Nora & Nora 1988). Maternal recurrence
risks are 2-6 times greater than paternal risks (Nora & Nora 1987), raising the possibility that the differences are due to unknown teratogens, cytoplasmic inheritance or possibly genomic imprinting. Family clustering of defects has long been recognized with up to 50% of affected sibs having lesions identical with the proband (Fraser & Hunter 1975), and most of the remainder having lesions that are etiologically related (Nora et al. 1970). A difficulty in genetic counseling for these defects is trying to decide if a family cluster represents single gene inheritance or if the familial recurrences are expected under a multifactorially deter-
13
I N H E R I T A N C E O F C O N O T R U N C A L M A L F O R M AT1 0 N S
mined model. We report a brother and sister with tetralogy of Fallot (TOF) with pulmonary atresia (PA), review other cases of family clustering of conotruncal defects, and speculate on their inheritance. Case Reports
Family History The family pedigree (Fig. 1) is significant for the affected proband (Case I), a 4-yearold brother, also with TOF with PA (Case 2) (Fig. 2), and a healthy 2-year-old brother. There was also a 36-year-old maternal aunt who, as an adult, developed a heart murmur and decreased exercise tolerance. The mother, father and the healthy 2-year-old brother were evaluated by a pediatric cardiologist. Physical examinations, electrocardiograms and echocardiograms were entirely normal. Case 1 A 3280-g black female who was born at term to a 24-year-old gravida 3, para 2
mother and 26-year-old father. The mother denied gestational diabetes or other pregnancy complications and had no known exposure to teratogenic drugs, chemicals or radiation. At age 6 months the patient presented with coughing, post-tussive emesis and diarrhea. The mother reported no cyanosis, respiratory distress or feeding difficulties at home. Physical examination showed a weight of 6.58 kg (25th centile), a height of 66 cm (50th centile) and a head circumference (OFC) of 44 cm (75th centile). Pertinent abnormalities included tachypnea, perioral and peripheral cyanosis, a grade 2/6 systolic murmur and a loud single second heart sound. No other major anomalies and no dysmorphic features were noted. Developmental screening was normal. Echocardiography and cardiac catheterization showed an enlarged right ventricle, the aorta overriding a large VSD, ab-
sence of the main pulmonary artery with the distal pulmonary arteries fed by a patent ductus arteriosus (Fig. 3) and large aortopulmonary collaterals. Following a diagnosis of TOF with PA, the patient had surgery to place a gortex shunt from the distal innominate artery to the right pulmonary artery. Her cyanosis improved and she is currently well, with improved growth. A staged repair of her TOF with PA is anticipated. Case 2 The brother of Case 1 was born at term after an uncomplicated pregnancy. At age 3 months he developed cyanosis, respiratory distress and fever. Persistent cyanosis after treatment for pneumonia resulted in a cardiac evaluation including echocardiography and cardiac catheterization. These studies showed a VSD, PA, small confluent branch pulmonary arteries, large aortopulmonary collaterals and a left aortic arch diagnostic of TOF with PA (Fig. 2). A gortex shunt was placed from the ascending aorta to the main pulmonary artery with resultant improvement in his cyanosis. He remained well and grew normally, until age 4 years when significant cyanosis recurred. Physical examination at that time showed a weight of 18 bg (80th centile), height of 107 cm
b TOF with PA
\
Rg. 1. Family pedigree showing siblings with tetralogy
of Fallot (TOF) with pulmonary atresia (PA).
14
WULFSBERG ET A L .
Flg. 2 Right ventricular angiocardiogram of Case 2 (typical of bath children's defects) showing absence of the main pulmonary artery, large maiaiignment-type VSD and a large aorta overriding the ventricular septum.
(70th centile) and an OFC of 50 cm (25th-50th centile). Pertinent abnormalities included generalized cyanosis, 2-3/4 digital clubbing, loud single second heart sound and a grade 3/6 continuous murmur heard diffusely over the chest and back. No other major anomalies and no dysmorphic features were noted. Developmental screening was nonqal. Repeat cardiac catheterization showed that his collaterals and shunt had become stenotic and his true pulmonary arteries had remained small. A right ventricular outflow tract reconstruction without closure of the VSD was performed. Anticipated future procedures include embolization of the collaterals, angioplasty of the main pulmonary artery and closure of the VSD.
Fig. 3. Aortic angiocardiogram of Case 1 (typical of both children's defects) with the catheter through the right ventricle, VSD and aortlc valve. It shows a rightsided aortic arch with filling of welldeveloped branch pulmonary arteries from aortepulmonary collaterals.
Discussion
Conotruncal septation is tie developmental process that divides the single heart tube into two distinct outflow tracts (Miller & Smith 1979). Using an inbred strain of dogs with a high spontaneous rate of CHD, Patterson et al. (1974) observed a spectrum of cardiac abnormalities in their offspring. These ranged fromsubclinical defects of the crista supraventncularis to complete TOF, and included isolated VSlD and pulmonic stenosis. They concluded this spectrum of defects represented different thresholds along a contin,uum of conotruncal maldevelopment. Fraser & Hunter (1975), using human clinical data, showed family clustering of TOF with pulmonary stenosis, TOF
I N H E R I T A N C E 0 F C O N O T R U N C A L M A L F O R M AT1 0 N S
with transposition of the great vessels and TOF with VSD. They concluded that these lesions were etiologically related and the result of defective conotruncal development. These studies support our current understanding that abnormalities in conotruncal development can cause a spectrum of defects. These include TOF, truncus arteriosus, transposition of the great vessels, and double outlet right ventricle (Rein et al. 1990), with at least some types of isolated pulmonic stenosis and VSD representing formes frustes of conotruncal malformations (Patterson et al. 1974, Fraser & Hunter 1975, Miller & Smith, 1979, Ferencz et al. 1989). Fuhrmann (1968) in a study of 57 families with two or more sibs with CHD found four families with three affected sibs. There were no consanguineous families in his series. All three sibs in the first family had TOF (one with PA). The second family had one child with transposition of the great vessels and the other two with unknown cyanotic CHD. The 3rd family had one child with transposition of the great vessels and the other two sibs with VSD. The 4th family had two sibs with transposition of the great vessels and VSD and a 3rd sib with an unknown heart defect. Fuhrmann (1968) considered these cardiac lesions to be identical (case 1) or etiologically related (cases 2-4) lesions. His computed recurrence risk for families with two affected chddren was 5.5% and he felt multifactorial inheritance best explained his observations. Miller & Smith (1979) described two families that might represent monogenic inheritance of conotruncal CHD. The first family had at least five individuals in two generations with CHD. The congenital defects in that family included isolated pulmonary stenosis in two sisters and one sister’s daughter, TOF with PA in one sister‘s son and a hypoplastic right ventricle with pulmonary stenosis in the other sister’s son.
15
They interpreted these defects as within the spectrum of conotruncal CHD and suggested that this family was consistent with autosomal dominant inheritance. Their second family, whose parents were third cousins, had three sons who died with CHD. One son had TOF and the other two had transposition of the great vessels. They felt this family was consistent with autosomal recessive inheritance. Miller & Smith (1979) concluded that when more than one member of a family is affected with a conotruncal CHD, especially if it occurs in more than one generation, then consideration should be given to single gene inheritance. Der Kaloustian et al. (1985) reported two sisters with CHD similar to our patients, whose parents were first cousins. Because of their identical cardiac defects and the parental consanguinity, Der Kaloustian et al. (1985) proposed autosomal recessive inheritance in that family. DiChiara et al. (1980) reported a father and son with PA and VSD with overriding aorta (TOF with PA). They felt this was most consistent with a multifactorial model of inheritance, although they could not exclude autosomal dominant inheritance. Rein et al. (1990) reported a family in which consanguineous first cousins had two daughters with truncus arteriosus and two more distant relatives with CHD (a first cousin once removed with transposition of the great vessels and a second cousin with double outlet right ventricle). They concluded that there is at least a subgroup of conotruncal malformations with monogenic inheritance. They recommended that families having one member with a conotruncal CHD should be informed of a recurrence risk, “which may be significantly higher than in any other cardiac defect”. We feel the small number of reported family clusters of non-syndromal conotruncal defects is consistent with multifactorial determination. Further, the rare reports of
16
W U L F S B E R G ET A L
consanguinity (Miller & Smith 1979, Der Fraser, F. C. & A. D. W. Huntcr (1975). Etiologic relations among categories of congenital heart Kaloustian et al. 1985, Rein et al. 1990) malformations. Am. J . Cardiol. 36,793-796. might be expected by chance alone and Fuhrmann, W. (1968). Congenital heart disease would also increase the recurrence risk for in sibships ascertained by two affected siblings. Humangenetik 6, 1-1 2. defects under multifactorial determination. Miller, M. E. & D. W. Smith (1979). Conotruncal While it is prudent in counseling families malformation complex: examples of possible with two or more individuals with monogenic inheritance. Pedi,atrics 63. 890-893. conotruncal CHD to raise the possibility Nora, J. J. (1968). Multifactorial inheritance hypothesis for the etiology 01' congenital heart of single gene inheritance, we believe that diseases: the genetic-environmental interaction. current empiric recurrence risk estimates Circulation 38, 604-6 17. (Nora & Nora 1988) most accurately reflect Nora, J. J., C. W. McGill & D. G. McNamara their risks. (1970). Empiric recurrence risks in common Acknowledgements
The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. References Berini, R. Y. & E. Kahn (eds.) (1987). 'Ongenital heart defects. In Clinical Genetics Handbook' Oradell, New Jersey, Medical Economics Books. pp. 138-145. Der Kaloustian. V. M.. H. Ralt. J. Malouf, J. Hatem, M. Slim, A.'Tomeh, J . Khori L F. Kutayli (1985). Tetralogy of Fallot with pulmonary atresia in siblings. Am. J. Med. Genet. 21. 119-122. DiChiara, J. A,, D. R. Pieroni, R. L. Gingell, R. M. Bannerman & P. Vlad (1980). Familial pulmonary atresia. A m . J. Dis. Child. 134. 506-508. Ferenn, C., J. A. Boughman, C. A. Neill, J. I. Brenner & L. W. Perry (1989). Congenital cardiovascular malformations: questions on inheritance. J. Am. Coll. Cardiol. 14, 756763.
and uncommon congenital heart lesions. Teratology 3, 325-330. Nora. J. J. & A. H. Nora (1987). Maternal transmission ofcongenital heart diseases: new recurrence risk figures and the question of cytoplasmic inheritance and vulnerability to teratogens. Am. J. Cardiol. 59, 459-463. Nora, J. J. & A. H. Nora (!,988). Update on counseling the family with a. first-degree relative with congenitai heart dmefect. Am. J . Med. Genet. 29, 137-142. Patterson, D. F., R. L. Pyle, L. V. Mierop, J. Melbin & M. Olson (1974). Hereditary defects of the conotruncal septum in Keeshond dogs: pathologic and genetic studies. Am. J. Cardiol. 34, 187-205. Rein. A. J. J. T.. S. Dollbera Ck R. Gale (1990). Genetics of conotruncal m~lformations:review of the literature and report of a consanguineous kindred with various conotruncal malformations. Am. J. Med. Genet. 36, 353-355.
a
I
Address:
Eric A . Wulfsberg M.D., DepartmPnt of Pediatrics National Naval Medical Center Bethesda Maryland 208I4 USA
,
The inheritance of conotruncal malformations: a review and report of two siblings with tetralogy of Fallot with pulmonary atresia ERICA. WULFSBERG', ERICJ. zINTZ2 AND JOHN w. MOORE' 'Medical Genetics/Dysmorphology, 'Department of Pediatrics, National Naval Medical Center, Uniformed Services University of the Health Sciences, Ekthesda, Maryland and 'Pediatric Cardiology, Walter Reed Army Medical Center, Washington, DC, USA Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately I%. It is estimated that 4-5% of CHI1 are associated with chromosome abnormalities, 1-2% are associated with single gene Syndromes, 1-2% are due to known teratogens, with the rest presumably determined multifactorially. We report on a brother and sister with tetralogy of Fallot with pulmonary atresia, and review the inheritance of familial conotruncal anomalies. W? feel the small number of family clusters and the rare instances of consanguinity in non-syndromal conotruncal defects are consistent with multifactorial determination. While it is prudent in counseling families with 2 or more individuals with conotruncal CHD to raise the possibility of single gene inheritance, we believe that current empiric recurrence risk estimates most accurately reflect their risks. Received I2 November 1990, revised 10 January, accepted f o r publication 17 January 1991 Key words: congenital heart defects; conotruncal malformations; genetic counseling; recurrence risk.
Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately 1 % (Nora & Nora 1988). It is estimated that 4 5 % of CHD are associated with chromosome abnormalities, 1-2% are associated with single gene syndromes, 1-2% are due to known teratogens, with the remainder presumably determined multifactorially (Nora 1968, Berini & Kahn 1987). Empiric recurrence risks for siblings of a child with a CHD range from 1-10% depending on the specific malformation and the number of affected first-degree relatives (Nora & Nora 1988). Maternal recurrence
risks are 2-6 times greater than paternal risks (Nora & Nora 1987), raising the possibility that the differences are due to unknown teratogens, cytoplasmic inheritance or possibly genomic imprinting. Family clustering of defects has long been recognized with up to 50% of affected sibs having lesions identical with the proband (Fraser & Hunter 1975), and most of the remainder having lesions that are etiologically related (Nora et al. 1970). A difficulty in genetic counseling for these defects is trying to decide if a family cluster represents single gene inheritance or if the familial recurrences are expected under a multifactorially deter-
13
I N H E R I T A N C E O F C O N O T R U N C A L M A L F O R M AT1 0 N S
mined model. We report a brother and sister with tetralogy of Fallot (TOF) with pulmonary atresia (PA), review other cases of family clustering of conotruncal defects, and speculate on their inheritance. Case Reports
Family History The family pedigree (Fig. 1) is significant for the affected proband (Case I), a 4-yearold brother, also with TOF with PA (Case 2) (Fig. 2), and a healthy 2-year-old brother. There was also a 36-year-old maternal aunt who, as an adult, developed a heart murmur and decreased exercise tolerance. The mother, father and the healthy 2-year-old brother were evaluated by a pediatric cardiologist. Physical examinations, electrocardiograms and echocardiograms were entirely normal. Case 1 A 3280-g black female who was born at term to a 24-year-old gravida 3, para 2
mother and 26-year-old father. The mother denied gestational diabetes or other pregnancy complications and had no known exposure to teratogenic drugs, chemicals or radiation. At age 6 months the patient presented with coughing, post-tussive emesis and diarrhea. The mother reported no cyanosis, respiratory distress or feeding difficulties at home. Physical examination showed a weight of 6.58 kg (25th centile), a height of 66 cm (50th centile) and a head circumference (OFC) of 44 cm (75th centile). Pertinent abnormalities included tachypnea, perioral and peripheral cyanosis, a grade 2/6 systolic murmur and a loud single second heart sound. No other major anomalies and no dysmorphic features were noted. Developmental screening was normal. Echocardiography and cardiac catheterization showed an enlarged right ventricle, the aorta overriding a large VSD, ab-
sence of the main pulmonary artery with the distal pulmonary arteries fed by a patent ductus arteriosus (Fig. 3) and large aortopulmonary collaterals. Following a diagnosis of TOF with PA, the patient had surgery to place a gortex shunt from the distal innominate artery to the right pulmonary artery. Her cyanosis improved and she is currently well, with improved growth. A staged repair of her TOF with PA is anticipated. Case 2 The brother of Case 1 was born at term after an uncomplicated pregnancy. At age 3 months he developed cyanosis, respiratory distress and fever. Persistent cyanosis after treatment for pneumonia resulted in a cardiac evaluation including echocardiography and cardiac catheterization. These studies showed a VSD, PA, small confluent branch pulmonary arteries, large aortopulmonary collaterals and a left aortic arch diagnostic of TOF with PA (Fig. 2). A gortex shunt was placed from the ascending aorta to the main pulmonary artery with resultant improvement in his cyanosis. He remained well and grew normally, until age 4 years when significant cyanosis recurred. Physical examination at that time showed a weight of 18 bg (80th centile), height of 107 cm
b TOF with PA
\
Rg. 1. Family pedigree showing siblings with tetralogy
of Fallot (TOF) with pulmonary atresia (PA).
14
WULFSBERG ET A L .
Flg. 2 Right ventricular angiocardiogram of Case 2 (typical of bath children's defects) showing absence of the main pulmonary artery, large maiaiignment-type VSD and a large aorta overriding the ventricular septum.
(70th centile) and an OFC of 50 cm (25th-50th centile). Pertinent abnormalities included generalized cyanosis, 2-3/4 digital clubbing, loud single second heart sound and a grade 3/6 continuous murmur heard diffusely over the chest and back. No other major anomalies and no dysmorphic features were noted. Developmental screening was nonqal. Repeat cardiac catheterization showed that his collaterals and shunt had become stenotic and his true pulmonary arteries had remained small. A right ventricular outflow tract reconstruction without closure of the VSD was performed. Anticipated future procedures include embolization of the collaterals, angioplasty of the main pulmonary artery and closure of the VSD.
Fig. 3. Aortic angiocardiogram of Case 1 (typical of both children's defects) with the catheter through the right ventricle, VSD and aortlc valve. It shows a rightsided aortic arch with filling of welldeveloped branch pulmonary arteries from aortepulmonary collaterals.
Discussion
Conotruncal septation is tie developmental process that divides the single heart tube into two distinct outflow tracts (Miller & Smith 1979). Using an inbred strain of dogs with a high spontaneous rate of CHD, Patterson et al. (1974) observed a spectrum of cardiac abnormalities in their offspring. These ranged fromsubclinical defects of the crista supraventncularis to complete TOF, and included isolated VSlD and pulmonic stenosis. They concluded this spectrum of defects represented different thresholds along a contin,uum of conotruncal maldevelopment. Fraser & Hunter (1975), using human clinical data, showed family clustering of TOF with pulmonary stenosis, TOF
I N H E R I T A N C E 0 F C O N O T R U N C A L M A L F O R M AT1 0 N S
with transposition of the great vessels and TOF with VSD. They concluded that these lesions were etiologically related and the result of defective conotruncal development. These studies support our current understanding that abnormalities in conotruncal development can cause a spectrum of defects. These include TOF, truncus arteriosus, transposition of the great vessels, and double outlet right ventricle (Rein et al. 1990), with at least some types of isolated pulmonic stenosis and VSD representing formes frustes of conotruncal malformations (Patterson et al. 1974, Fraser & Hunter 1975, Miller & Smith, 1979, Ferencz et al. 1989). Fuhrmann (1968) in a study of 57 families with two or more sibs with CHD found four families with three affected sibs. There were no consanguineous families in his series. All three sibs in the first family had TOF (one with PA). The second family had one child with transposition of the great vessels and the other two with unknown cyanotic CHD. The 3rd family had one child with transposition of the great vessels and the other two sibs with VSD. The 4th family had two sibs with transposition of the great vessels and VSD and a 3rd sib with an unknown heart defect. Fuhrmann (1968) considered these cardiac lesions to be identical (case 1) or etiologically related (cases 2-4) lesions. His computed recurrence risk for families with two affected chddren was 5.5% and he felt multifactorial inheritance best explained his observations. Miller & Smith (1979) described two families that might represent monogenic inheritance of conotruncal CHD. The first family had at least five individuals in two generations with CHD. The congenital defects in that family included isolated pulmonary stenosis in two sisters and one sister’s daughter, TOF with PA in one sister‘s son and a hypoplastic right ventricle with pulmonary stenosis in the other sister’s son.
15
They interpreted these defects as within the spectrum of conotruncal CHD and suggested that this family was consistent with autosomal dominant inheritance. Their second family, whose parents were third cousins, had three sons who died with CHD. One son had TOF and the other two had transposition of the great vessels. They felt this family was consistent with autosomal recessive inheritance. Miller & Smith (1979) concluded that when more than one member of a family is affected with a conotruncal CHD, especially if it occurs in more than one generation, then consideration should be given to single gene inheritance. Der Kaloustian et al. (1985) reported two sisters with CHD similar to our patients, whose parents were first cousins. Because of their identical cardiac defects and the parental consanguinity, Der Kaloustian et al. (1985) proposed autosomal recessive inheritance in that family. DiChiara et al. (1980) reported a father and son with PA and VSD with overriding aorta (TOF with PA). They felt this was most consistent with a multifactorial model of inheritance, although they could not exclude autosomal dominant inheritance. Rein et al. (1990) reported a family in which consanguineous first cousins had two daughters with truncus arteriosus and two more distant relatives with CHD (a first cousin once removed with transposition of the great vessels and a second cousin with double outlet right ventricle). They concluded that there is at least a subgroup of conotruncal malformations with monogenic inheritance. They recommended that families having one member with a conotruncal CHD should be informed of a recurrence risk, “which may be significantly higher than in any other cardiac defect”. We feel the small number of reported family clusters of non-syndromal conotruncal defects is consistent with multifactorial determination. Further, the rare reports of
16
W U L F S B E R G ET A L
consanguinity (Miller & Smith 1979, Der Fraser, F. C. & A. D. W. Huntcr (1975). Etiologic relations among categories of congenital heart Kaloustian et al. 1985, Rein et al. 1990) malformations. Am. J . Cardiol. 36,793-796. might be expected by chance alone and Fuhrmann, W. (1968). Congenital heart disease would also increase the recurrence risk for in sibships ascertained by two affected siblings. Humangenetik 6, 1-1 2. defects under multifactorial determination. Miller, M. E. & D. W. Smith (1979). Conotruncal While it is prudent in counseling families malformation complex: examples of possible with two or more individuals with monogenic inheritance. Pedi,atrics 63. 890-893. conotruncal CHD to raise the possibility Nora, J. J. (1968). Multifactorial inheritance hypothesis for the etiology 01' congenital heart of single gene inheritance, we believe that diseases: the genetic-environmental interaction. current empiric recurrence risk estimates Circulation 38, 604-6 17. (Nora & Nora 1988) most accurately reflect Nora, J. J., C. W. McGill & D. G. McNamara their risks. (1970). Empiric recurrence risks in common Acknowledgements
The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. References Berini, R. Y. & E. Kahn (eds.) (1987). 'Ongenital heart defects. In Clinical Genetics Handbook' Oradell, New Jersey, Medical Economics Books. pp. 138-145. Der Kaloustian. V. M.. H. Ralt. J. Malouf, J. Hatem, M. Slim, A.'Tomeh, J . Khori L F. Kutayli (1985). Tetralogy of Fallot with pulmonary atresia in siblings. Am. J. Med. Genet. 21. 119-122. DiChiara, J. A,, D. R. Pieroni, R. L. Gingell, R. M. Bannerman & P. Vlad (1980). Familial pulmonary atresia. A m . J. Dis. Child. 134. 506-508. Ferenn, C., J. A. Boughman, C. A. Neill, J. I. Brenner & L. W. Perry (1989). Congenital cardiovascular malformations: questions on inheritance. J. Am. Coll. Cardiol. 14, 756763.
and uncommon congenital heart lesions. Teratology 3, 325-330. Nora. J. J. & A. H. Nora (1987). Maternal transmission ofcongenital heart diseases: new recurrence risk figures and the question of cytoplasmic inheritance and vulnerability to teratogens. Am. J. Cardiol. 59, 459-463. Nora, J. J. & A. H. Nora (!,988). Update on counseling the family with a. first-degree relative with congenitai heart dmefect. Am. J . Med. Genet. 29, 137-142. Patterson, D. F., R. L. Pyle, L. V. Mierop, J. Melbin & M. Olson (1974). Hereditary defects of the conotruncal septum in Keeshond dogs: pathologic and genetic studies. Am. J. Cardiol. 34, 187-205. Rein. A. J. J. T.. S. Dollbera Ck R. Gale (1990). Genetics of conotruncal m~lformations:review of the literature and report of a consanguineous kindred with various conotruncal malformations. Am. J. Med. Genet. 36, 353-355.
a
I
Address:
Eric A . Wulfsberg M.D., DepartmPnt of Pediatrics National Naval Medical Center Bethesda Maryland 208I4 USA
,
