American Journal of Medical Genetics 40105-106 (1991;)
Brief Clinical Report
Father and Two Children With Total Anomalous Pulmonary Venous Connection Bradley D. Raisher, S. Bruce Dowton, and James W. Grant Edward Mallinckrodt Department of Pediatrics, Division of Cardiology (B.D.R., J.W.G.), and the James S . McDonnell Department of Genetics (S.B.D.), Washington University School of Medicine, St. Louis, Missouri Total anomalous pulmonary venous connection (TAPVC)is a rare form of cyanotic congenital heart disease which, without surgical treatment, has a high mortality in the first year of life. Reports of familial recurrence of TAPVC have involved sibs, first cousins, and twins. This is the first report of TAPVC in a father and his 2 children. The implications for genetic counseling to families with this anomaly and individuals reaching adulthood after repair of TAPVC are considered.
KEY WORDS: Congenital heart disease, total anomalous pulmonary venous connection, autosomal dominantinheritance,genetic counseling
white woman whose pregnancy was complicated by amniotic fluid leakage and bleeding in the 6th month, and a seizure disorder for which she was treated with p heny toin and phenobarbital throughout the pregnancy. Clinical evaluation at 2 weeks of life for duskiness, weight loss, and tachypnea documented cyanosis, a continuous heart murmur at the left base, and hepatomegaly. No minor anomalies were noted. Cardiac catheterization revealed confluence of the pulmonary veins into a common chamber which drained to the superior vena cava via a n ascending left vertical vein. Operative repair was performed by anastornosing the common chamber to the left atrium. He had a n uneventful recovery and is asymptomatic a t age 21.
Patient 2 D.G., son of patient 1, was a term male infant weighing 3,175 g, born in 1988 by vaginal delivery, to a 15year-old primigravid woman, following a n uncomplicated pregnancy and delivery with Apgar scores of 8 and INTRODUCTION 9 at one and 5 minutes, respectively. At 7 weeks of life he Total anomalous pulmonary venous connection was evaluated because of feeding intolerance, tachy(TAPVC), as a n isolated anomaly, occurs in approx- pnea, and duskiness associated with crying, and was imately 0.4-2% of congenital cardiovascular malforma- found to have mild cyanosis, tachypnea, and a grade 11 tions [Lucas and Krabill, 19893. Familial occurrence of systolic murmur at the apex and left sternal border. The TAPVC is rare, although occurrence in sibs [Baron et diagnosis of TAPVC with complete and unobstructed al., 1982; Clarke et al., 1973; Delisle et al., 1976; Gath- drainage to the coronary sinus was established by 2-diman and Nadas, 1970; Kaufman et al., 1972; Milner et mensional echocardiography. Surgical repair of this leal., 1977; Paz and Castilla, 1971; Solymar et al., 19871, sion was performed without complication. Chromofirst cousins [Kaufman et al., 1972; Paz and Castilla, somes were normal (46,XY) at the 450 band stage of 19711, and twins [Delisle et al., 1976; Gleason, 1989; resolution. At 2 years, growth and development are norMilner et al., 19771has been described. The following is mal. the first report suggesting autosomal dominant inheritance of TAPVC in a family in which a parent and his 2 Patient 3 children were affected. D.G., the sister of patient 2, was born at term in 1989 after a n uneventful pregnancy, labor, and delivery and CLINICAL REPORTS weighed 3,458 g. At 3 weeks, during a n episode of prePatient 1 sumed pneumonia and dehydration, she was evaluated R.G. was born in 1969 of non-consanguineous parents because of inadequate weight gain, tachypnea, diaat term, weighing 3,629 g. His mother was a 31-year-old phoresis, vomiting, duskiness, and irritability. On a cardiac evaluation she was found to have pallor, tachypnea, Received for publication August 7, 1990; revision received a Grade I11 systolic murmur at the apex and left base, and a n S, gallop. Echocardiography showed TAPVC November 1, 1990. Address reprint requests to Bradley D. Raisher, M.D., St. Louis with 3 of the pulmonary veins draining into the coroChildren’s Hospital, Division of Pediatric Cardiology, 400 S. nary sinus, and the left upper pulmonary vein connectKingshighway, St. Louis, Mo. 63110. ing to a left ascending vertical vein. She underwent 0 1991 Wiley-Liss, Inc.
106
Raisher et al.
successful repair without complications, and currently is growing and developing normally. The family is of American Indian, Irish, Scottish, and German origin without consanguinity in 4 generations. The paternal grandfather and his 8 brothers reportedly had “heart problems’’ at birth, but these reports were not substantiated by documented medical records. The father’s paternal half-brother also underwent open heart surgery at 6 weeks of life for an unknown lesion; however, medical records are not available. The halfbrother’s only sib is reportedly a healthy normal woman. No other congenital malformations are known in this family.
DISCUSSION This family represents the first report of apparent autosomal dominant transmission of TAPVC, with the father and his only 2 children all having the same anomaly. TAPVC is a rare anomaly which usually occurs sporadically with an incidence of 4-6 : 100,000 live births [Fyler, 19801, and is presumed to be multifactorially determined. &ports of familial recurrence of isolated TAPVC have involved sibs, first cousins, and twins [Baron et al., 1982; Clarke et al., 1973; Delisle et al., 1976; Gathman and Nadas, 1970; Gleason, 1989; Kaufman et al., 1972; Milner et al., 1977; Paz and Castilla, 1971; Solymar et al., 19871. No apparent gender predilection has been evident. In this family, TAPVC is an apparent autosomal dominant trait. The original mutation may have been the paternal grandfather, because at least 2 resulting male children, each with different mothers, had a congenital cardiovascular defect necessitating operative repair. TAPVC has been classified as a disorder of targeted cellular growth [Clark, 19861. Embryologically, the primordial pulmonary vein develops as an endothelial bud from the posterior aspect of the left atrium a t 27-29 days gestation [Neill, 19561. This posterior bud from the left atrium “directs” the incorporation of the common pulmonary venous plexus from the lungs and its absorption into the posterior wall of the left atrium, with subsequent disappearance of all former systemic venous connections. The mechanism by which an inherited abnormality in the incorporation of the common pulmonary vein into the left atrium during embryogenesis cannot be defined from these patients. The severe abnormalities of cardiac organization resulting in the complex cardiovascular malformations of asplenia and atrial situs ambiguous, are associated with a 70%incidence of TAPVC [Stanger et al., 19771. This suggests that signals controlling body symmetry and visceral lateralization may be involved in the connection of the pulmonary veins to the left atrium. The anomalous pulmonary connections occurring in this family are consistent with a
disorder at an unknown genetic locus which facilitates the normal connection of the common pulmonary vein into the left atrium. The location of the anomalous connection is a secondary phenomenon. This is supported by the heterogeneity in the anatomic site of connection of the pulmonary to systemic venous drainage in this family and of the other reports of familial TAPVC [Delisle et al., 1976; Kaufman et al., 1972; Milner et al., 1977; Paz and Castilla, 1971; Soymar et al., 19871. As more pediatric patients undergo cardiac repair and survive to parenthood, physicians must maintain a high index of suspicion for familial recurrences of cardiovascular anomalies. Increased recurrence risks in first degree relatives and families must be taken into account when counseling families with cardiovascular malformations.
REFERENCES Baron P, Gutgesell H, Hawkins E, McNamara D (1982):Infradiaphragmatic total anomalous pulmonary venous connection in siblings. Am Heart J 104:1107-1109. Clarke CP, Edis BD, Danks DM (1973): Familial total anomalous pulmonary venous return. Aust New Zeal J Med (abstr) 3:629. Clark EB (1986):Mechanisms in the pathogenesis of congenital heart defects. In Pierpont ME, Moller JM (eds): “The Genetics of Cardiovascular Disease.” Boston: Martinus-Nijoff, pp 3-11. Delisle G, Ando M, Calder AL, Zuberbuhler JR, Rochenmacher S, Alday LE, Mangini 0, Van Praagh S, Van Praagh R (1976):Total anomalous pulmonary venous connection: report of 93 autopsied cases with emphasis on diagnostic and surgical considerations. Am Heart J 91:99-122. Fyler DC (1980): Report of the New England Fkgional Infant Cardiac Program. Pediatrics 65(2 pt.2):375-461. Gathman GE, Nadas AS (1970): Total anomalous pulmonary venous connection-clinical and physiologic observations of 75 pediatric patients. Circulation 42:143-154. Gleason MM (1989): Concordant total anomalous pulmonary venous connection in dizygotic twins. Am Heart J 118:1338-1340. Kaufman RL, Boynton RC, Hartmann AF, Morgan BC, McAlister WH (1972):Familial studies in congenital heart disease 111:Total anomalous pulmonary venous connection in two sisters and their female maternal first cousin. The Cardiovascular System. Birth Defects: Original Article Series 8:88-91. Lucas RV, Krabill KA (1989):Anomalous venous connections, pulmonary and systemic. In Adams FH, Emmanouilides GC, Riemenschneider TA (eds): “Moss’ Heart Disease in Infants, Children, and Adolescents.” Williams and Wilkins: p 587. Milner S, Levin S, Marchand P, Hitchcock F (1977):Total anomalous pulmonary venous drainage in sibs. Arch Dis Child (letter) 53:984. Neill CA (1956):Development of the pulmonary veins, with reference to the embryology of anomalies of pulmonary venous return. Pediatrics 18:880-887. Paz JE, Castilla EE (1971); Familial total anomalous pulmonary venous return. J Med Genet 8:312-314. Solymar L, Sabel K, Zetterqvist P (1987):Total anomalous pulmonary venous connection in siblings. Acta Paediatric Scand 76:124-127. Stanger P, Rudolph AR, Edwards J E (1977):Cardiac malpositions: An overview based on study of sixty-five necropsy specimens. Circulation 56:159-172.
Brief Clinical Report
Father and Two Children With Total Anomalous Pulmonary Venous Connection Bradley D. Raisher, S. Bruce Dowton, and James W. Grant Edward Mallinckrodt Department of Pediatrics, Division of Cardiology (B.D.R., J.W.G.), and the James S . McDonnell Department of Genetics (S.B.D.), Washington University School of Medicine, St. Louis, Missouri Total anomalous pulmonary venous connection (TAPVC)is a rare form of cyanotic congenital heart disease which, without surgical treatment, has a high mortality in the first year of life. Reports of familial recurrence of TAPVC have involved sibs, first cousins, and twins. This is the first report of TAPVC in a father and his 2 children. The implications for genetic counseling to families with this anomaly and individuals reaching adulthood after repair of TAPVC are considered.
KEY WORDS: Congenital heart disease, total anomalous pulmonary venous connection, autosomal dominantinheritance,genetic counseling
white woman whose pregnancy was complicated by amniotic fluid leakage and bleeding in the 6th month, and a seizure disorder for which she was treated with p heny toin and phenobarbital throughout the pregnancy. Clinical evaluation at 2 weeks of life for duskiness, weight loss, and tachypnea documented cyanosis, a continuous heart murmur at the left base, and hepatomegaly. No minor anomalies were noted. Cardiac catheterization revealed confluence of the pulmonary veins into a common chamber which drained to the superior vena cava via a n ascending left vertical vein. Operative repair was performed by anastornosing the common chamber to the left atrium. He had a n uneventful recovery and is asymptomatic a t age 21.
Patient 2 D.G., son of patient 1, was a term male infant weighing 3,175 g, born in 1988 by vaginal delivery, to a 15year-old primigravid woman, following a n uncomplicated pregnancy and delivery with Apgar scores of 8 and INTRODUCTION 9 at one and 5 minutes, respectively. At 7 weeks of life he Total anomalous pulmonary venous connection was evaluated because of feeding intolerance, tachy(TAPVC), as a n isolated anomaly, occurs in approx- pnea, and duskiness associated with crying, and was imately 0.4-2% of congenital cardiovascular malforma- found to have mild cyanosis, tachypnea, and a grade 11 tions [Lucas and Krabill, 19893. Familial occurrence of systolic murmur at the apex and left sternal border. The TAPVC is rare, although occurrence in sibs [Baron et diagnosis of TAPVC with complete and unobstructed al., 1982; Clarke et al., 1973; Delisle et al., 1976; Gath- drainage to the coronary sinus was established by 2-diman and Nadas, 1970; Kaufman et al., 1972; Milner et mensional echocardiography. Surgical repair of this leal., 1977; Paz and Castilla, 1971; Solymar et al., 19871, sion was performed without complication. Chromofirst cousins [Kaufman et al., 1972; Paz and Castilla, somes were normal (46,XY) at the 450 band stage of 19711, and twins [Delisle et al., 1976; Gleason, 1989; resolution. At 2 years, growth and development are norMilner et al., 19771has been described. The following is mal. the first report suggesting autosomal dominant inheritance of TAPVC in a family in which a parent and his 2 Patient 3 children were affected. D.G., the sister of patient 2, was born at term in 1989 after a n uneventful pregnancy, labor, and delivery and CLINICAL REPORTS weighed 3,458 g. At 3 weeks, during a n episode of prePatient 1 sumed pneumonia and dehydration, she was evaluated R.G. was born in 1969 of non-consanguineous parents because of inadequate weight gain, tachypnea, diaat term, weighing 3,629 g. His mother was a 31-year-old phoresis, vomiting, duskiness, and irritability. On a cardiac evaluation she was found to have pallor, tachypnea, Received for publication August 7, 1990; revision received a Grade I11 systolic murmur at the apex and left base, and a n S, gallop. Echocardiography showed TAPVC November 1, 1990. Address reprint requests to Bradley D. Raisher, M.D., St. Louis with 3 of the pulmonary veins draining into the coroChildren’s Hospital, Division of Pediatric Cardiology, 400 S. nary sinus, and the left upper pulmonary vein connectKingshighway, St. Louis, Mo. 63110. ing to a left ascending vertical vein. She underwent 0 1991 Wiley-Liss, Inc.
106
Raisher et al.
successful repair without complications, and currently is growing and developing normally. The family is of American Indian, Irish, Scottish, and German origin without consanguinity in 4 generations. The paternal grandfather and his 8 brothers reportedly had “heart problems’’ at birth, but these reports were not substantiated by documented medical records. The father’s paternal half-brother also underwent open heart surgery at 6 weeks of life for an unknown lesion; however, medical records are not available. The halfbrother’s only sib is reportedly a healthy normal woman. No other congenital malformations are known in this family.
DISCUSSION This family represents the first report of apparent autosomal dominant transmission of TAPVC, with the father and his only 2 children all having the same anomaly. TAPVC is a rare anomaly which usually occurs sporadically with an incidence of 4-6 : 100,000 live births [Fyler, 19801, and is presumed to be multifactorially determined. &ports of familial recurrence of isolated TAPVC have involved sibs, first cousins, and twins [Baron et al., 1982; Clarke et al., 1973; Delisle et al., 1976; Gathman and Nadas, 1970; Gleason, 1989; Kaufman et al., 1972; Milner et al., 1977; Paz and Castilla, 1971; Solymar et al., 19871. No apparent gender predilection has been evident. In this family, TAPVC is an apparent autosomal dominant trait. The original mutation may have been the paternal grandfather, because at least 2 resulting male children, each with different mothers, had a congenital cardiovascular defect necessitating operative repair. TAPVC has been classified as a disorder of targeted cellular growth [Clark, 19861. Embryologically, the primordial pulmonary vein develops as an endothelial bud from the posterior aspect of the left atrium a t 27-29 days gestation [Neill, 19561. This posterior bud from the left atrium “directs” the incorporation of the common pulmonary venous plexus from the lungs and its absorption into the posterior wall of the left atrium, with subsequent disappearance of all former systemic venous connections. The mechanism by which an inherited abnormality in the incorporation of the common pulmonary vein into the left atrium during embryogenesis cannot be defined from these patients. The severe abnormalities of cardiac organization resulting in the complex cardiovascular malformations of asplenia and atrial situs ambiguous, are associated with a 70%incidence of TAPVC [Stanger et al., 19771. This suggests that signals controlling body symmetry and visceral lateralization may be involved in the connection of the pulmonary veins to the left atrium. The anomalous pulmonary connections occurring in this family are consistent with a
disorder at an unknown genetic locus which facilitates the normal connection of the common pulmonary vein into the left atrium. The location of the anomalous connection is a secondary phenomenon. This is supported by the heterogeneity in the anatomic site of connection of the pulmonary to systemic venous drainage in this family and of the other reports of familial TAPVC [Delisle et al., 1976; Kaufman et al., 1972; Milner et al., 1977; Paz and Castilla, 1971; Soymar et al., 19871. As more pediatric patients undergo cardiac repair and survive to parenthood, physicians must maintain a high index of suspicion for familial recurrences of cardiovascular anomalies. Increased recurrence risks in first degree relatives and families must be taken into account when counseling families with cardiovascular malformations.
REFERENCES Baron P, Gutgesell H, Hawkins E, McNamara D (1982):Infradiaphragmatic total anomalous pulmonary venous connection in siblings. Am Heart J 104:1107-1109. Clarke CP, Edis BD, Danks DM (1973): Familial total anomalous pulmonary venous return. Aust New Zeal J Med (abstr) 3:629. Clark EB (1986):Mechanisms in the pathogenesis of congenital heart defects. In Pierpont ME, Moller JM (eds): “The Genetics of Cardiovascular Disease.” Boston: Martinus-Nijoff, pp 3-11. Delisle G, Ando M, Calder AL, Zuberbuhler JR, Rochenmacher S, Alday LE, Mangini 0, Van Praagh S, Van Praagh R (1976):Total anomalous pulmonary venous connection: report of 93 autopsied cases with emphasis on diagnostic and surgical considerations. Am Heart J 91:99-122. Fyler DC (1980): Report of the New England Fkgional Infant Cardiac Program. Pediatrics 65(2 pt.2):375-461. Gathman GE, Nadas AS (1970): Total anomalous pulmonary venous connection-clinical and physiologic observations of 75 pediatric patients. Circulation 42:143-154. Gleason MM (1989): Concordant total anomalous pulmonary venous connection in dizygotic twins. Am Heart J 118:1338-1340. Kaufman RL, Boynton RC, Hartmann AF, Morgan BC, McAlister WH (1972):Familial studies in congenital heart disease 111:Total anomalous pulmonary venous connection in two sisters and their female maternal first cousin. The Cardiovascular System. Birth Defects: Original Article Series 8:88-91. Lucas RV, Krabill KA (1989):Anomalous venous connections, pulmonary and systemic. In Adams FH, Emmanouilides GC, Riemenschneider TA (eds): “Moss’ Heart Disease in Infants, Children, and Adolescents.” Williams and Wilkins: p 587. Milner S, Levin S, Marchand P, Hitchcock F (1977):Total anomalous pulmonary venous drainage in sibs. Arch Dis Child (letter) 53:984. Neill CA (1956):Development of the pulmonary veins, with reference to the embryology of anomalies of pulmonary venous return. Pediatrics 18:880-887. Paz JE, Castilla EE (1971); Familial total anomalous pulmonary venous return. J Med Genet 8:312-314. Solymar L, Sabel K, Zetterqvist P (1987):Total anomalous pulmonary venous connection in siblings. Acta Paediatric Scand 76:124-127. Stanger P, Rudolph AR, Edwards J E (1977):Cardiac malpositions: An overview based on study of sixty-five necropsy specimens. Circulation 56:159-172.
