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Asplenia syndrome with congenital heart disease and tetralogy of Fallot in siblings
Asplenia Syndrome with Congenital Heart Disease and Tetralogy of Fallot in Siblings
WALTER SILVER, MD MOSHE STEIER, MD NAKUL CHANDRA, MD, Brooklyn,
MRCP
New York
That congenital heart disease tends to have a familial character has become more widely appreciated. The asplenia syndrome is known to be associated with severe congenital heart disease, and tetralogy of Fallot is known to have a familial tendency. This report describes 2 siblings, of whom the first-born had the asplenia syndrome with congenital heart disease and the second had tetralogy Of Fallot.
Large surveys in the past have shown a clear tendency for congenital heart disease to occur in several family members.1*2 Several investigators have reported tetralogy of Fallot in siblings,3-5 but we know of no previous report in which the asplenia syndrome with congenital heart disease appeared in one sibling and tetralogy of Fallot in the other. This paper describes 2 such siblings and briefly reviews the familial occurrence of congenital heart disease. Case Presentations Case 1: This boy was the product of a 38 week normal pregnancy and delivery and weighed 5 lb, 9 oz at birth. At age 2 months a heart murmur was first detected, and at age 6 months the infant was admitted to the hospital with congestive heart failure. He was treated with digoxin and responded well. We first saw him at age 20 months, when he was alert and in no acute distress but showed peripheral duskiness. Additional positive physical findings included bulging of the left precordium, a systolic ejection click followed by a grade 3/6 harsh ejection systolic murmur along the left sternal border, and a loud single second heart sound. The hematocrit was 43 percent, and Howell-Jolly bodies were found in the
From the Division of Pediatric Cardiology, Maimonides Medical Center, and the Department of Pediatrics of the State University of New York, Downstate Medical Center, Brooklyn, N.Y. Manuscript received April 30, 1971; revised manuscript received August 16, 1971, accepted September 9. 1971. Address for reprints: Walter Silver, MD, Division of Pediatric Cardiology, Maimonides Medical Center, 4802 Tenth Ave., Brooklyn, N.Y. 11219.
red blood cells. The electrocardiogram showed right axis deviation, and right ventricular hypertrophy (Fig. 1). The chest roentgenogram showed an enlarged heart in the left hemithorax (levocardia) with increased pulmonary vascular markings. The stomach gas shadow was located under the right diaphragm, and barium swallow confirmed the position of the stomach on the right side (Fig. 2). At cardiac catheterization a functional single atrium and single ventricle, with transposition of the great vessels and pulmonary hypertension, were found. The pulmonary vascular resistance decreased significantly after oxygen inhalation and intravenous administration of Priscoline@, and the patient was transferred to another hospital for pulmonary artery banding. He died 18 hours after the procedure. Autopsy findings were as follows: (1) Asplenia. (2) Situs inversus viscerum with a left-sided heart. (3) Common atrium with only a solitary strand of tissue bridging the otherwise totally divided atria. The 4 pulmonary veins drained into the morphologic left atrium which was present on the right side. A complete atrioventricular canal was present, and the right ventricle was right-sided (d-loop, ventricular inversion in presence of situs inversus). A double-outlet right ventricle with a bicuspid pulmonary valve and mild subpulmonic stenosis was also found (Fig. 3). The aorta was to the right of the pulmonary artery. (4) Medial hypertrophy and early fibrosis of the pulmonary arteries.
July 11,1972
The American Journal of Cardiology
Volume 30
91
ASPLENIA
SYNDROME-SILVER
ET
AL.
V4R
aVR
Figure 2. Case 1. Chest roentgenogram, revealing an enlarged heart in the left side of the chest, increased pulmonary vascular markings and barium entering a right-sided stomach.
Figure 1. Case I. Electrocardiogram tion and right ventricular hypertrophy.
revealing right axis devia-
Case 2: The sister of Case 1 was the product of a fullterm uncomplicated pregnancy and delivery and is reported to have weighed 3 lb, 7 oz at birth. At age 6 hours she was noted to be cyanotic, and a heart murmur was detected. When we first saw her at age 2 months, she appeared adequately nourished, small for her age, and in no acute distress. She weighed 7 lb and measured 17 inches in length. Peripheral cyanosis increased markedly with crying. Other positive physical findings included a grade 2/6 systolic ejection murmur at the left base followed by a single second sound best heard at the apex. Red blood cell morphology was normal, and the hematocrit was 31 percent. The electrocardiogram revealed right axis deviation and right ventricular hypertrophy (Fig. 4). The chest roentgenogram showed no gross cardiomegaly
with decreased pulmonary vascular markings. The stomach bubble was noted to be on the left (Fig. 5). Cardiac catheterization and angiography revealed the characteristic features of tetralogy of Fallot (Fig. 6). The patient was treated with oral propranolol and at age 9 months she weighed 15 lb and was doing well. Chromosomal studies performed in this patient and in both parents showed normal findings. Family history was noncontributory. The mother’s third pregnancy ended in a spontaneous abortion at 2% months’ gestation. Comment
Familial incidence of congenital heart disease: Richards et a1.6 found that the incidence of congenital heart malformations in the newborn period was 0.83 percent. Similar statistics were recently reported by Mitchell et aI7 In 1955 Polani and Campbell1 reported a frequency of congenital heart disease of 2.26 percent among later born siblings. However, in 1966 Nora and Meyer2 found in a study of 517 families that 3.4 percent of siblings and 1.8 percent of parents were
Figure 3. Case 1. Autopsy specimen of the heart. A, opened to show the origin of the pulmonary artery from the right ventricle. A bicuspid pulmonary valve and minimal subpulmonic stenosis are also present. B, opened to show the origin of the aorta from the right ventricle. An abnormal muscle bundle is also seen. A0 = aorta; MB = muscle bundle; PA = pulmonary artery; RV = right ventricle.
92
July 11, 1972
The American Journal of Cardiology
Volume 30
ASPLENIA
SYNDROME-SILVER
ET AL.
affected. Other reports confirm that the incidence of congenital heart disease in families is significant.3-5,8 The type of congenital heart disease found in siblings or other family members is often the same as that found in the propositus. Campbell9 found this to be the case with tetralogy of Fallot, patent ductus arteriosus, pulmonary valvular stenosis, ventricular septal defect and coarctation of the aorta. Congenital heart disease is sometimes associated with genetically determined syndromes. Included are Down’s syndrome, trisomy 16-8, trisomy 13-15, Turner’s syndrome, Ellis-van Crevald syndrome, glycogen storage disease and Friedriech’s ataxia.lO Some disorders of connective tissue, such as Marfan’s syndrome, Hurler’s syndrome and Ehlers-Danlos syndrome, also are associat.ed with specific types of heart disease. Results of chromosomal studies in the parents and in Case 2 were negative, but given the present cytogenie techniques subtle or minor chromosomal anomalies cannot be excluded.ll Asplenia syndrome:: Up to 1968 approximately 160 cases of asplenia syndrome with congenital heart disease had been reported.lO Campbell3 described a child who had both the clinical findings of tetralogy of Fallot (no hemodynamic studies were performed) and a sibling with congenital heart disease who died at age 5 months. At autopsy situs inversus with complicated congenital hea.rt disease was described, but asplenia was not noted. 0ngley12 described a 3 month old girl with multiple s:pleens, situs inversus, anomalous connection of the pulmonary veins to the right atrium and an anomalous inferior vena cava. Her mother had situs inve:rsus ivith an apparently normal heart. One sibling, a “blue baby,” had died at age 9 weeks. No autopsy was reported. The asplenia syndrome with total anomalous pulmonary venous connection to the right superior vena cava in 2 siblings was reported by Rutenberg.ls Another sibling died with asplenia and cyanotic congenital heart disease. No autopsy was reported. Polhemus
and Schaferf4 reported a case of asplenia with isolated levocardia, car biloculare and severe pulmonary stenosis. The sibling had accessory spleens, and atrioventriculare commune. In both siblings the inversion of the abdominal viscera was incomplete and there was a Meckel’s diverticulum. Situs inversus: Campbell in 196315 in 1,000 patients with malformations of the heart found a girl
Figure 5. Case 2. Chest roentgenogram pulmonary vascular markings.
Figure 6. Case 2. Angiogram taken with the catheter at the tricuspid valve, showing a narrow right ventricular outflow tract and relatively larger aorta than pulmonary artery.
showing decreased
aVR aVL
aVF
v6 Figure 4. Case 2. Electrocardiogram tion and right ventricular hypertrophy.
July 11, 1672
showing right axis devia-
The American Journal of Cardiology
Volume 30
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ASPLENIA
SYNDROME-SILVER
ET AL.
with pulmonary atresia whose sister had situs inversus but no heart disease, and a boy with ventricular septal defect whose brother had situs inversus. The high incidence of situs inversus found among the offspring of marriages between cousins indicated that the anomaly is transmitted recessively.13,16 The parents in our cases are not blood relatives.
Tetralogy of Fallot in the propositus has been described with the following lesions in the siblings: tetralogy of Fallot,s pulmonary stenosis,435 ventricular septal defect,5 atria1 septal defect,5 and transposition of the great vessels.16 Our report is the first to describe asplenia with congenital heart disease in 1 infant and tetralogy of Fallot in a sibling.
References 1. Polani PE, Campbell M: An etiological study of congenital heart disease. Ann Hum Genet 19:209-230.1955 Familial nature of congenital heart dis2. Nora JJ, Meyer TC: eases. Pediatrics 37:329-334, 1966 3. Campbell M: The genetics of congenital heart disease and situs inversus in sibs. Brit Heart J 21:65-80, 1959 Familial as.Pects of 4. Chelus CJ. Rowe GG, Crumpton CW: congenital heart disease. Amer J Cardiol 9:508-514, 1962 A family study of Fallot’s tetrad. Aust Ann Med 5. Pitt DB: ii:i79-183, 1962 Congenital 6. Richards MR, Merrit KK, Samuels MH, et al: malformations of the cardiovascular system in a series of 6,053 infants. Pediatrics 15:12-28. 1955 7. Mitchell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births. Circulation 43:323-332, 1971 A report of congenital heart disease a. Weil MH, Allenstein BJ: in five members of one family. New Eng J Med 265661-667, 1961 of the heart. Brit 9. Campbell M: Causes of malformations Med J 2695-904.1965 10. Rowe RD, Mehrizi A: The Neonate with Congenital Heart
94
July 11, 1972
The American Journal of Cardiology
Disease. Philadelphia, WB Saunders, 1969, p 93, 300-305 11. Dahl G: Chromosomal conditions in congenital heart disease. Acta Paediat Stand 59:65-73, 1970 12. Ongley PA, Titus JL, Khoury GH, et al: Anomalous connection of pulmonary veins to right atrium associated with anomalous inferior vena cava. situs inversus and multiple spleens: a developmental complex. Mayo Clin Proc 40:609624,1965 13. Ruttenberg HD, Neufeld HN, Lucas RV, et al: Syndrome of congenital disease with asplenia. Amer J Cardiol 13:387-406, 1964 14. Polhemus DW, Schafer WB: Congenital absence of the spleen: syndrome with atrioventricularis and situs inversus. Pediatrics 9:696-708, 1952 15. Campbell M: The mode of inheritance in isolated levocardia and dextrocardia and situs inversus. Brit Heart J 25:803ai3,1963 of the great 16. Fuhrman W: A family study in transposition vessels and in tricuspid atresia. Ann Hum Genet 6:14&l-157, 1968
Volume 30
WALTER SILVER, MD MOSHE STEIER, MD NAKUL CHANDRA, MD, Brooklyn,
MRCP
New York
That congenital heart disease tends to have a familial character has become more widely appreciated. The asplenia syndrome is known to be associated with severe congenital heart disease, and tetralogy of Fallot is known to have a familial tendency. This report describes 2 siblings, of whom the first-born had the asplenia syndrome with congenital heart disease and the second had tetralogy Of Fallot.
Large surveys in the past have shown a clear tendency for congenital heart disease to occur in several family members.1*2 Several investigators have reported tetralogy of Fallot in siblings,3-5 but we know of no previous report in which the asplenia syndrome with congenital heart disease appeared in one sibling and tetralogy of Fallot in the other. This paper describes 2 such siblings and briefly reviews the familial occurrence of congenital heart disease. Case Presentations Case 1: This boy was the product of a 38 week normal pregnancy and delivery and weighed 5 lb, 9 oz at birth. At age 2 months a heart murmur was first detected, and at age 6 months the infant was admitted to the hospital with congestive heart failure. He was treated with digoxin and responded well. We first saw him at age 20 months, when he was alert and in no acute distress but showed peripheral duskiness. Additional positive physical findings included bulging of the left precordium, a systolic ejection click followed by a grade 3/6 harsh ejection systolic murmur along the left sternal border, and a loud single second heart sound. The hematocrit was 43 percent, and Howell-Jolly bodies were found in the
From the Division of Pediatric Cardiology, Maimonides Medical Center, and the Department of Pediatrics of the State University of New York, Downstate Medical Center, Brooklyn, N.Y. Manuscript received April 30, 1971; revised manuscript received August 16, 1971, accepted September 9. 1971. Address for reprints: Walter Silver, MD, Division of Pediatric Cardiology, Maimonides Medical Center, 4802 Tenth Ave., Brooklyn, N.Y. 11219.
red blood cells. The electrocardiogram showed right axis deviation, and right ventricular hypertrophy (Fig. 1). The chest roentgenogram showed an enlarged heart in the left hemithorax (levocardia) with increased pulmonary vascular markings. The stomach gas shadow was located under the right diaphragm, and barium swallow confirmed the position of the stomach on the right side (Fig. 2). At cardiac catheterization a functional single atrium and single ventricle, with transposition of the great vessels and pulmonary hypertension, were found. The pulmonary vascular resistance decreased significantly after oxygen inhalation and intravenous administration of Priscoline@, and the patient was transferred to another hospital for pulmonary artery banding. He died 18 hours after the procedure. Autopsy findings were as follows: (1) Asplenia. (2) Situs inversus viscerum with a left-sided heart. (3) Common atrium with only a solitary strand of tissue bridging the otherwise totally divided atria. The 4 pulmonary veins drained into the morphologic left atrium which was present on the right side. A complete atrioventricular canal was present, and the right ventricle was right-sided (d-loop, ventricular inversion in presence of situs inversus). A double-outlet right ventricle with a bicuspid pulmonary valve and mild subpulmonic stenosis was also found (Fig. 3). The aorta was to the right of the pulmonary artery. (4) Medial hypertrophy and early fibrosis of the pulmonary arteries.
July 11,1972
The American Journal of Cardiology
Volume 30
91
ASPLENIA
SYNDROME-SILVER
ET
AL.
V4R
aVR
Figure 2. Case 1. Chest roentgenogram, revealing an enlarged heart in the left side of the chest, increased pulmonary vascular markings and barium entering a right-sided stomach.
Figure 1. Case I. Electrocardiogram tion and right ventricular hypertrophy.
revealing right axis devia-
Case 2: The sister of Case 1 was the product of a fullterm uncomplicated pregnancy and delivery and is reported to have weighed 3 lb, 7 oz at birth. At age 6 hours she was noted to be cyanotic, and a heart murmur was detected. When we first saw her at age 2 months, she appeared adequately nourished, small for her age, and in no acute distress. She weighed 7 lb and measured 17 inches in length. Peripheral cyanosis increased markedly with crying. Other positive physical findings included a grade 2/6 systolic ejection murmur at the left base followed by a single second sound best heard at the apex. Red blood cell morphology was normal, and the hematocrit was 31 percent. The electrocardiogram revealed right axis deviation and right ventricular hypertrophy (Fig. 4). The chest roentgenogram showed no gross cardiomegaly
with decreased pulmonary vascular markings. The stomach bubble was noted to be on the left (Fig. 5). Cardiac catheterization and angiography revealed the characteristic features of tetralogy of Fallot (Fig. 6). The patient was treated with oral propranolol and at age 9 months she weighed 15 lb and was doing well. Chromosomal studies performed in this patient and in both parents showed normal findings. Family history was noncontributory. The mother’s third pregnancy ended in a spontaneous abortion at 2% months’ gestation. Comment
Familial incidence of congenital heart disease: Richards et a1.6 found that the incidence of congenital heart malformations in the newborn period was 0.83 percent. Similar statistics were recently reported by Mitchell et aI7 In 1955 Polani and Campbell1 reported a frequency of congenital heart disease of 2.26 percent among later born siblings. However, in 1966 Nora and Meyer2 found in a study of 517 families that 3.4 percent of siblings and 1.8 percent of parents were
Figure 3. Case 1. Autopsy specimen of the heart. A, opened to show the origin of the pulmonary artery from the right ventricle. A bicuspid pulmonary valve and minimal subpulmonic stenosis are also present. B, opened to show the origin of the aorta from the right ventricle. An abnormal muscle bundle is also seen. A0 = aorta; MB = muscle bundle; PA = pulmonary artery; RV = right ventricle.
92
July 11, 1972
The American Journal of Cardiology
Volume 30
ASPLENIA
SYNDROME-SILVER
ET AL.
affected. Other reports confirm that the incidence of congenital heart disease in families is significant.3-5,8 The type of congenital heart disease found in siblings or other family members is often the same as that found in the propositus. Campbell9 found this to be the case with tetralogy of Fallot, patent ductus arteriosus, pulmonary valvular stenosis, ventricular septal defect and coarctation of the aorta. Congenital heart disease is sometimes associated with genetically determined syndromes. Included are Down’s syndrome, trisomy 16-8, trisomy 13-15, Turner’s syndrome, Ellis-van Crevald syndrome, glycogen storage disease and Friedriech’s ataxia.lO Some disorders of connective tissue, such as Marfan’s syndrome, Hurler’s syndrome and Ehlers-Danlos syndrome, also are associat.ed with specific types of heart disease. Results of chromosomal studies in the parents and in Case 2 were negative, but given the present cytogenie techniques subtle or minor chromosomal anomalies cannot be excluded.ll Asplenia syndrome:: Up to 1968 approximately 160 cases of asplenia syndrome with congenital heart disease had been reported.lO Campbell3 described a child who had both the clinical findings of tetralogy of Fallot (no hemodynamic studies were performed) and a sibling with congenital heart disease who died at age 5 months. At autopsy situs inversus with complicated congenital hea.rt disease was described, but asplenia was not noted. 0ngley12 described a 3 month old girl with multiple s:pleens, situs inversus, anomalous connection of the pulmonary veins to the right atrium and an anomalous inferior vena cava. Her mother had situs inve:rsus ivith an apparently normal heart. One sibling, a “blue baby,” had died at age 9 weeks. No autopsy was reported. The asplenia syndrome with total anomalous pulmonary venous connection to the right superior vena cava in 2 siblings was reported by Rutenberg.ls Another sibling died with asplenia and cyanotic congenital heart disease. No autopsy was reported. Polhemus
and Schaferf4 reported a case of asplenia with isolated levocardia, car biloculare and severe pulmonary stenosis. The sibling had accessory spleens, and atrioventriculare commune. In both siblings the inversion of the abdominal viscera was incomplete and there was a Meckel’s diverticulum. Situs inversus: Campbell in 196315 in 1,000 patients with malformations of the heart found a girl
Figure 5. Case 2. Chest roentgenogram pulmonary vascular markings.
Figure 6. Case 2. Angiogram taken with the catheter at the tricuspid valve, showing a narrow right ventricular outflow tract and relatively larger aorta than pulmonary artery.
showing decreased
aVR aVL
aVF
v6 Figure 4. Case 2. Electrocardiogram tion and right ventricular hypertrophy.
July 11, 1672
showing right axis devia-
The American Journal of Cardiology
Volume 30
93
ASPLENIA
SYNDROME-SILVER
ET AL.
with pulmonary atresia whose sister had situs inversus but no heart disease, and a boy with ventricular septal defect whose brother had situs inversus. The high incidence of situs inversus found among the offspring of marriages between cousins indicated that the anomaly is transmitted recessively.13,16 The parents in our cases are not blood relatives.
Tetralogy of Fallot in the propositus has been described with the following lesions in the siblings: tetralogy of Fallot,s pulmonary stenosis,435 ventricular septal defect,5 atria1 septal defect,5 and transposition of the great vessels.16 Our report is the first to describe asplenia with congenital heart disease in 1 infant and tetralogy of Fallot in a sibling.
References 1. Polani PE, Campbell M: An etiological study of congenital heart disease. Ann Hum Genet 19:209-230.1955 Familial nature of congenital heart dis2. Nora JJ, Meyer TC: eases. Pediatrics 37:329-334, 1966 3. Campbell M: The genetics of congenital heart disease and situs inversus in sibs. Brit Heart J 21:65-80, 1959 Familial as.Pects of 4. Chelus CJ. Rowe GG, Crumpton CW: congenital heart disease. Amer J Cardiol 9:508-514, 1962 A family study of Fallot’s tetrad. Aust Ann Med 5. Pitt DB: ii:i79-183, 1962 Congenital 6. Richards MR, Merrit KK, Samuels MH, et al: malformations of the cardiovascular system in a series of 6,053 infants. Pediatrics 15:12-28. 1955 7. Mitchell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births. Circulation 43:323-332, 1971 A report of congenital heart disease a. Weil MH, Allenstein BJ: in five members of one family. New Eng J Med 265661-667, 1961 of the heart. Brit 9. Campbell M: Causes of malformations Med J 2695-904.1965 10. Rowe RD, Mehrizi A: The Neonate with Congenital Heart
94
July 11, 1972
The American Journal of Cardiology
Disease. Philadelphia, WB Saunders, 1969, p 93, 300-305 11. Dahl G: Chromosomal conditions in congenital heart disease. Acta Paediat Stand 59:65-73, 1970 12. Ongley PA, Titus JL, Khoury GH, et al: Anomalous connection of pulmonary veins to right atrium associated with anomalous inferior vena cava. situs inversus and multiple spleens: a developmental complex. Mayo Clin Proc 40:609624,1965 13. Ruttenberg HD, Neufeld HN, Lucas RV, et al: Syndrome of congenital disease with asplenia. Amer J Cardiol 13:387-406, 1964 14. Polhemus DW, Schafer WB: Congenital absence of the spleen: syndrome with atrioventricularis and situs inversus. Pediatrics 9:696-708, 1952 15. Campbell M: The mode of inheritance in isolated levocardia and dextrocardia and situs inversus. Brit Heart J 25:803ai3,1963 of the great 16. Fuhrman W: A family study in transposition vessels and in tricuspid atresia. Ann Hum Genet 6:14&l-157, 1968
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