A m e r i c a n Journal of Medical G e n e t i c s 36:175-177 (1990)
Brief Clinical Report Interrupted Aortic Arch w p e B1 in a Brother and Sister: Suggestion of a Recessive Gene Rainer Pankau, Johannes Funda, and Armin Wessel Departments o f Pediatrics ( R.P.), and Pediatric Cardiology ( J . F . 4 .W.1, University Hospital of Kiel, Kiel, Federal Republic of Germany
We report on the occurrence of an identical form of interrupted aortic arch and ventricular septal defect in a brother a n d sister whose parents are not consanguineous. The first child died on the 7th day of life without surgery 3 years ago; the second underwent surgical correction on the 5th day of life and is doing well.
KEY WORDS: siblings (female/male)
INTRODUCTION Congenital heart defects occur in about 0.8% of all newborn infants [Fuhrmann and Vogel, 19821and such defects may be combined with other congenital malformations. They are caused by diseases during pregnancy, chromosome aberrations, and multifactorial determination. Monogenic inheritance is a factor in only a few cases of congenital heart defect. We report on 2 sibs, a boy and a girl, who had an interrupted aortic arch type B1 with aberrant right subclavian artery, persistent ductus arteriosus, hypoplasia of the aortic root and ascending aorta, ventricular septal defect, atrial septal defect, and pulmonary hypertension. This type of complex congenital heart defect may be due to a recessive gene. CLINICAL REPORTS Patient 1 M.H. (male)was born spontaneously after 38 weeks of gestation in an out-of-townclinic (birth weight 3,750 kg, length 52 cm, head circumference (OFC) 36 cm, Apgar score 9-10-10).He was the 4th child of unmarried, but healthy and non-consanguineous parents (age of the mother 27 years, of the father 32 years). Pregnancy was complicated by EPH-gestosis and hydramnios. After birth t,achypnea and a tachycardia without Received for publication February 17, 1989; revision received October 19, 1989. Address reprint requests to Rainer Pankau, M.D., Dept. Pediatrics, Schwanenweg 20, D-2300 Kiel 1, Federal Republic of Germany.
0 1990 Wiley-Liss, Inc.
heart murmur became obvious. With suspicion of a congenital heart defect the baby was referred to our hospital on day 4.On admission tachypnea, acrocyanosis,and a systolicmurmur with maximal loudness in the 3rd and 4th intercostal space were evident. The 2nd heart sound was split and peripheral pulses were weak. Heart catheterization showed an interrupted aortic arch type B1 combined with the other defects mentioned above (Fig. 1).The disorder was considered nonoperable, and the baby died at age 7 days. Autopsy confirmed the diagnosis and excluded other extracardial anomalies.
Patient 2 The 5th pregnancy was complicated by mild maternal diabetes untreated because of lack of cooperation. After 38 weeks of gestation T.H. (female) was born spontaneously without any medical assistance at home and afterwards was referred to the local hospital (birth weight: 4.790 kg, length 56 cm, OFC 36 cm). On day 2 cyanosis, tachypnea (about 100 per minute), tachycardia (160 beats per minute), and a loud systolic murmur were recognized. The baby was admitted to our hospital on day 3 of life. The initial examination showed mild cyanosis, tachydyspnea, and tachycardia. A loud systolic murmur was audible in the 3rd intercostal space and the peripheral pulses were weak. Catheterization revealed the same findings as in her brother M.H. (Fig. 2). Chromosomes were normal (46,XX). The ophthalmologic examination demonstrated no pathologic findings. The heart defect was corrected on day 5 of life, the postoperative course was uneventful, and the baby is in good condition now. DISCUSSION The New England Regional Infant Cardiac Program reported 2,251 infants with congenital heart disease [Fyler et al., 19801. Of those 179 had a coarctation (8%). Of this special group 21 had an interrupted aortic arch. Thus, this complex congenital malformation amounts to about 1%of all congenital heart defects (0.9%)[Fyler et al., 19801. Depending on the site of interruption, Celoria and Patton [1959] classified the different forms of interrupted aortic arch into the 3 main types: A, B, and C. According to van Praagh et al. [19711type B is the most common type.
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Fig. 1. Angiocardiograms from M.H. in the posterior-anterior view. a: Dye injection into the left ventricle (LV)demonstrates that the ascending aorta (Ao)ends with the right (RCC) and left (LCC) carotid artery. The aortic arch is interrupted. Right ventricle and pulmonary arteries (PA) opacified via ventricular septal defect. b: Injection in the descending aorta shows the course of the aberrant right subclavian artery (RS).
R C C LCC
A
RCC LCC
Fig. 2. Digital subtraction angiocardiograms (posterior-anterior view) from T.H. demonstrating identical congenital heart defects as shown in Figure 1a.b. After dye injection into the left ventricle (LV) ascending aorta and both carot'ld arteries opacify, while the aortic arch is interrupted. Right ventricle (RV)and pulmonary artery (PA) stained via the ventricular septal defect. After entering the descending aorta (aorta desc.) via the ductus Botalli the aberrantright subclavian artery (A. lusoria) and normal left subclavian artery (A. subclavia li.) are opacified. Abbreviations: A. carotis: carotid artery; re.: right; li.: left; LA: left atrium; endyst.: endsystolic.
LCC
C
0
RCC
RCC
LCC
Fig. 3. Classification of interrupted aortic arch. 5 p e s A, B, C after Celoria and Patton [19591. Subtype B1 as found in the 2 sibs demonstrated here. Abbreviations: PA: pulmonary artery; AO: ascending aorta; PDA: persistent ductus arteriosus; RPA, LPA: right, left pulmonary artery; RCC, LCC: right, left common carotid artery; RS, LS: right, left subclavian artery.
Interrupted Aortic Arch Moller and Edwards [1965]gave an overview of about 105 cases with interrupted aortic arch. In 11/105 the ascending aorta ended in 2 carotid arteries with left and right subclavian arteries originating from the descending aorta. This special subgroup of type B may be called type B1. According to the description above we found this type (Bl) combined with other cardiac anomalies (ventricular and atrial septal defect) in a n identical manner in 2 sibs (Fig. 3). It might be argued that this congenital malformation is related to the diabetes during pregnancy. This is also suggested by a birth weight of 4.790 kg and the clinical appearance as a n infant of a diabetic mother in the case of T.H. Day and Inslay [19761 report a risk of about 12% to infants of diabetic mothers of congenital malformation. This is considerably higher than the risk of 6% found in a control group [Day and Inslay, 19761. The risk for congenital heart defect is especially high, involving mainly ventricular septal defect, transposition of the great arteries, and also coarctation. However, since diabetes was absent in the first pregnancy it is unlikely that this metabolic disease was the cause of the cardiovascular defects seen in these sibs. An exogenous cause seems unlikely. In the face of normal chromosomes and the normal non-cardiac phenotype in the 2nd child, the probability of a chromosome abnormality as the cause for the defects is low. Multifactorial determination may be responsible for such cardiovascular defects.
177
Monogenic inheritance offers a simple and plausible explanation for the appearance of identical cardiovascular defects in sibs. This theory is supported by a report of Levin e t al. [19731, who described this form of interrupted aortic arch (type B1) with ventricular septal defect in monozygotic (M2) twins. However, in addition, those patients had retinal coloboma which were absent in a t least the 2nd of our patients. In our case a recessive gene seems likely. To the best of our knowledge, this is the first report of a n interrupted aortic arch type B1 with ventricular and atrial septal defect in sibs differing in sex and age.
REFERENCES Celoria GC, Patton RB (1959): Congenital absence of the aortic arch. Am Heart J 58:407-413. Day RE, Inslay J (1976): Maternal diabetes mellitus and congenital malformation. Arch Dis Child 51:936-938. Fuhrmann W. Vogel F (1982):“Genetische Familienberatung. Ein Leitfaden fur Studenten und Arzte.” Berlin: Springer-Verlag, p 107. Fyler DC, Buckley LP, Hellenbrand WE, Cohn HE, Kirklin JW, Nadas AS, Cartier JM, Breibart MH (1980): Report of the New England regional infant cardiac program. Pediatrics [Suppll 65:375-461. Levin DL, Muster AJ, Newfeld EA, Paul MH (1973):Concordant aortic arch anomalies in monozygotic twins. J Pediatr 83:459-461. Moller J H , Edwards HE (1965): Interruption of aortic a r c h Anatomic patterns and associated cardiac malformations. Am J Radio1 95:557-572. van Praagh R, Bernhard WF, Rosenthal A, Parisi LF, Fyler DC (1971): Interrupted aortic arch: Surgical treatment. Am J Cardiol 27:200-211.
Brief Clinical Report Interrupted Aortic Arch w p e B1 in a Brother and Sister: Suggestion of a Recessive Gene Rainer Pankau, Johannes Funda, and Armin Wessel Departments o f Pediatrics ( R.P.), and Pediatric Cardiology ( J . F . 4 .W.1, University Hospital of Kiel, Kiel, Federal Republic of Germany
We report on the occurrence of an identical form of interrupted aortic arch and ventricular septal defect in a brother a n d sister whose parents are not consanguineous. The first child died on the 7th day of life without surgery 3 years ago; the second underwent surgical correction on the 5th day of life and is doing well.
KEY WORDS: siblings (female/male)
INTRODUCTION Congenital heart defects occur in about 0.8% of all newborn infants [Fuhrmann and Vogel, 19821and such defects may be combined with other congenital malformations. They are caused by diseases during pregnancy, chromosome aberrations, and multifactorial determination. Monogenic inheritance is a factor in only a few cases of congenital heart defect. We report on 2 sibs, a boy and a girl, who had an interrupted aortic arch type B1 with aberrant right subclavian artery, persistent ductus arteriosus, hypoplasia of the aortic root and ascending aorta, ventricular septal defect, atrial septal defect, and pulmonary hypertension. This type of complex congenital heart defect may be due to a recessive gene. CLINICAL REPORTS Patient 1 M.H. (male)was born spontaneously after 38 weeks of gestation in an out-of-townclinic (birth weight 3,750 kg, length 52 cm, head circumference (OFC) 36 cm, Apgar score 9-10-10).He was the 4th child of unmarried, but healthy and non-consanguineous parents (age of the mother 27 years, of the father 32 years). Pregnancy was complicated by EPH-gestosis and hydramnios. After birth t,achypnea and a tachycardia without Received for publication February 17, 1989; revision received October 19, 1989. Address reprint requests to Rainer Pankau, M.D., Dept. Pediatrics, Schwanenweg 20, D-2300 Kiel 1, Federal Republic of Germany.
0 1990 Wiley-Liss, Inc.
heart murmur became obvious. With suspicion of a congenital heart defect the baby was referred to our hospital on day 4.On admission tachypnea, acrocyanosis,and a systolicmurmur with maximal loudness in the 3rd and 4th intercostal space were evident. The 2nd heart sound was split and peripheral pulses were weak. Heart catheterization showed an interrupted aortic arch type B1 combined with the other defects mentioned above (Fig. 1).The disorder was considered nonoperable, and the baby died at age 7 days. Autopsy confirmed the diagnosis and excluded other extracardial anomalies.
Patient 2 The 5th pregnancy was complicated by mild maternal diabetes untreated because of lack of cooperation. After 38 weeks of gestation T.H. (female) was born spontaneously without any medical assistance at home and afterwards was referred to the local hospital (birth weight: 4.790 kg, length 56 cm, OFC 36 cm). On day 2 cyanosis, tachypnea (about 100 per minute), tachycardia (160 beats per minute), and a loud systolic murmur were recognized. The baby was admitted to our hospital on day 3 of life. The initial examination showed mild cyanosis, tachydyspnea, and tachycardia. A loud systolic murmur was audible in the 3rd intercostal space and the peripheral pulses were weak. Catheterization revealed the same findings as in her brother M.H. (Fig. 2). Chromosomes were normal (46,XX). The ophthalmologic examination demonstrated no pathologic findings. The heart defect was corrected on day 5 of life, the postoperative course was uneventful, and the baby is in good condition now. DISCUSSION The New England Regional Infant Cardiac Program reported 2,251 infants with congenital heart disease [Fyler et al., 19801. Of those 179 had a coarctation (8%). Of this special group 21 had an interrupted aortic arch. Thus, this complex congenital malformation amounts to about 1%of all congenital heart defects (0.9%)[Fyler et al., 19801. Depending on the site of interruption, Celoria and Patton [1959] classified the different forms of interrupted aortic arch into the 3 main types: A, B, and C. According to van Praagh et al. [19711type B is the most common type.
176
Pankau et al.
Fig. 1. Angiocardiograms from M.H. in the posterior-anterior view. a: Dye injection into the left ventricle (LV)demonstrates that the ascending aorta (Ao)ends with the right (RCC) and left (LCC) carotid artery. The aortic arch is interrupted. Right ventricle and pulmonary arteries (PA) opacified via ventricular septal defect. b: Injection in the descending aorta shows the course of the aberrant right subclavian artery (RS).
R C C LCC
A
RCC LCC
Fig. 2. Digital subtraction angiocardiograms (posterior-anterior view) from T.H. demonstrating identical congenital heart defects as shown in Figure 1a.b. After dye injection into the left ventricle (LV) ascending aorta and both carot'ld arteries opacify, while the aortic arch is interrupted. Right ventricle (RV)and pulmonary artery (PA) stained via the ventricular septal defect. After entering the descending aorta (aorta desc.) via the ductus Botalli the aberrantright subclavian artery (A. lusoria) and normal left subclavian artery (A. subclavia li.) are opacified. Abbreviations: A. carotis: carotid artery; re.: right; li.: left; LA: left atrium; endyst.: endsystolic.
LCC
C
0
RCC
RCC
LCC
Fig. 3. Classification of interrupted aortic arch. 5 p e s A, B, C after Celoria and Patton [19591. Subtype B1 as found in the 2 sibs demonstrated here. Abbreviations: PA: pulmonary artery; AO: ascending aorta; PDA: persistent ductus arteriosus; RPA, LPA: right, left pulmonary artery; RCC, LCC: right, left common carotid artery; RS, LS: right, left subclavian artery.
Interrupted Aortic Arch Moller and Edwards [1965]gave an overview of about 105 cases with interrupted aortic arch. In 11/105 the ascending aorta ended in 2 carotid arteries with left and right subclavian arteries originating from the descending aorta. This special subgroup of type B may be called type B1. According to the description above we found this type (Bl) combined with other cardiac anomalies (ventricular and atrial septal defect) in a n identical manner in 2 sibs (Fig. 3). It might be argued that this congenital malformation is related to the diabetes during pregnancy. This is also suggested by a birth weight of 4.790 kg and the clinical appearance as a n infant of a diabetic mother in the case of T.H. Day and Inslay [19761 report a risk of about 12% to infants of diabetic mothers of congenital malformation. This is considerably higher than the risk of 6% found in a control group [Day and Inslay, 19761. The risk for congenital heart defect is especially high, involving mainly ventricular septal defect, transposition of the great arteries, and also coarctation. However, since diabetes was absent in the first pregnancy it is unlikely that this metabolic disease was the cause of the cardiovascular defects seen in these sibs. An exogenous cause seems unlikely. In the face of normal chromosomes and the normal non-cardiac phenotype in the 2nd child, the probability of a chromosome abnormality as the cause for the defects is low. Multifactorial determination may be responsible for such cardiovascular defects.
177
Monogenic inheritance offers a simple and plausible explanation for the appearance of identical cardiovascular defects in sibs. This theory is supported by a report of Levin e t al. [19731, who described this form of interrupted aortic arch (type B1) with ventricular septal defect in monozygotic (M2) twins. However, in addition, those patients had retinal coloboma which were absent in a t least the 2nd of our patients. In our case a recessive gene seems likely. To the best of our knowledge, this is the first report of a n interrupted aortic arch type B1 with ventricular and atrial septal defect in sibs differing in sex and age.
REFERENCES Celoria GC, Patton RB (1959): Congenital absence of the aortic arch. Am Heart J 58:407-413. Day RE, Inslay J (1976): Maternal diabetes mellitus and congenital malformation. Arch Dis Child 51:936-938. Fuhrmann W. Vogel F (1982):“Genetische Familienberatung. Ein Leitfaden fur Studenten und Arzte.” Berlin: Springer-Verlag, p 107. Fyler DC, Buckley LP, Hellenbrand WE, Cohn HE, Kirklin JW, Nadas AS, Cartier JM, Breibart MH (1980): Report of the New England regional infant cardiac program. Pediatrics [Suppll 65:375-461. Levin DL, Muster AJ, Newfeld EA, Paul MH (1973):Concordant aortic arch anomalies in monozygotic twins. J Pediatr 83:459-461. Moller J H , Edwards HE (1965): Interruption of aortic a r c h Anatomic patterns and associated cardiac malformations. Am J Radio1 95:557-572. van Praagh R, Bernhard WF, Rosenthal A, Parisi LF, Fyler DC (1971): Interrupted aortic arch: Surgical treatment. Am J Cardiol 27:200-211.
