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Familial Incidence of Atrial Septal Defect A Report of Four Siblings and Review of the ~iterature* Herman I . Libshitz, M.D., and Klemens H . Barth, M.D. Four siblings with atrial septal defects confirmed at operation are reported. They represent the largest sibship with isolated ASD reported to date. Familial aggregation of ASD has been found in single generatioas, and some kindreds have been traced through several generations. Inheritance follows the multifactorial mode primarily but in certain families autosomal dominant transmission is evident. Emphasis is placed on awareness of this congenital heart disease that could result in earlier diagnosis of unsuspected cases in other family members and appropriate genetic counseling. n estimated 0.7 percent of all live infants born A in the United States have congenital heart disease.' Of these, approximately 10 percent have atrial septal defects ( ASD ) .2 Familial aggregation of ASD has been reported since 1935.3This study concerns a single generation of four siblings, all of whom had isolated atrial septal defects. There is no parental burden, and there have been no offspring to date (Fig 1). All four underwent corrective operation. 2/6 systolic ejection murmur was heard at the left sternal border, and the second heart sound was split. The ECC showed sinus rhvthm., a PR-interval of .15 seconds. no evidence of left axis deviation and an incomplete right-bundlebranch-block ( RBBB ) . The chest radiograph revealed a normal cardiac silhouette and slightly dilated pulmonary vessels. Combined cardiac catheterization and angiocardiography showed findings consistent with an atrial septal defect of the secundurn type. The pulmonary arterial pressures were normal. The pulmonary systemic flow ratio (Qp/Qs) was 2:l. Subsequent operation confirmed a secundurn defect 2.5 cm in size. The trunk of the pulmonary artery was found dilated but without valvular or infundibular stenosis. No . Pedigree Neither parent had evidence of heart disease on routine cardiac workup during hospitalization for unrelated diseases. The mother was 30 years of age at her first pregnancy. She gave birth to five children, four of whom will be discussed below. The third, a girl, died at two years of age from heart failure and bronchopneumonia. A diagnosis of congenital heart disease was made, but the type was unknown. No autopsy was performed. This 29-year-old patient, the product of an uncomplicated pregnancy, with a history of asthma and various allergies was admitted to Thomas Jefferson University Hospital for evaluation of a systolic heart murmur. Physical examination showed no abnormalities except for cardiac findings. A grade 'From The Department of Radiology, Thomas Jefferson University Hospital, Philadelphia. Manuscript received June 18; revision accepted Au ust 23 Reprint requests: Dr. Libshitz, Department of ~ a d i o $ lei~~, ferson Hospital, Philadelphia 19107 age 39 Typhoid 2 3 , age 4 age 2 heart failure 0 = female = male Shaded symbols=ASD FIGURE 1. Pedigree of family. CHEST, VOL. 65, NO. 1, JANUARY, 1 9 7 4 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20946/ on 05/05/2017 FAMILIAL INCIDENCE OF ATRIAL SEPTAL DEFECT murmur and an accentuated pulmonary second sound. When he was three years of age, bulging of the left chest wall was noted. ECG changes of RBBB developed. The PR-interval was .14 seconds. There was no evidence of left axis deviation. A chest radiograph showed an enlarged heart and increased pulmonary blood flow. He was further observed, with the diamosis of ASD. Emotional and mental retardation became " evident and a diagnosis of childhood schizophrenia was made at age six. Because his cardiac status deteriorated, he underwent catheterization at 11 years of age. ASD was confirmed, with Qp/Qs ratio of 2 : l . A year later a 4-cm ostium secundurn defect was closed, with no associated cardiac malformations noted. The body did well physically after operation. other cardiac defects were present. The patient was well after operation. The patient was known to have a heart murmur since she was six years of age. Her physical development was normal. She first noted dyspnea and chest pain on exertion at 26 years of age. She was referred to Presbyterian-University of Pennsylvania Medical Center for cardiac evaluation. On physical examination cardiac findings were a grade 4/6 systolic murmur at the left sternal border, and a split second pulmonic sound. The ECC showed sinus rhythm, a PRinterval of .16 seconds, incomplete RBBB, and no evidence of left axis deviation. The chest radiograph was compatible with right ventricular outflow tract enlargement and showed prominent dilatation of pulmonary arteries. Cardiac catheterization demonstrated a large atrial septal defect, small infundibular and small pulmonary valvular pressure gradients, but normal pulmonary artery pressures. The Qp/Qs ratio was 2.4:l. Subsequent closure of a secr~ndumtype atrial septal defect, 2 x 3 cm, was performed. No associated cardiac defects were found. The patient was well after operation. Quite commonly ASD is associated with other VSD ~ and pulmonary cardiac m a l f o r m a t i ~ n s . ~ stenosis appear to be most frequent. This is also the case in Richer'sS series of five siblings with ASD. The two cases which were confirmed at operation showed a ventricular septal defect (VSD) and pulmonary stenosis, respectively, as associated defects. In our series ASD was the only defect (Table 1). The fifth sibling who died at two years of age in congestive heart failure had in all likelihood a complex heart abnormality. This is believed to be true because the mortality for ASD is only 0.7 percent in the first d e ~ a d e . ~ None of our patients had features of the skeletalvascular ( Holt-Oram ) syndrome. This syndrome described in 1960 by Holt and Oram includes skeletal malformations of the radial portion of the forearm and hand, and also of the palate, clavicles, and sternum. The cardiac malformation is often but not always a septum secundum defect. This syndrome is transmitted in the autosomal dominant m ~ d e . ~ * ~ - ' ~ Transmission of the skeletal anomalies varies, and may only be apparent by pectus exca~atum.~ Except for one report of four siblings with septum primum defects," only the secundum type ASD has been reported to date. This might be explained by the relative infrequency of the primum defect. Aggregation of ASD in siblings of one or in several generations of a family seems most frequently to This 24-year-old patient was first noted to have a heart murmur at age 6 on routine examination. He was then admitted to Children's Hospital of Philadelphia ( CHOP), where physical examination revealed slight bulging of the left anterior chest, and a harsh grade 4/6 systolic heart murmur loudest over the left sternal border. ECC showed sinus rhythm, a .15 second PR-interval, right axis deviation and RBBB. Cardiac catheterization and angiocardiography confirmed a large ASD and suggested partial anomalous pulmonary venous return into the right atrium. Advice for corrective operation was not followed initially. In the next two years he developed easy fatigability and failed to thrive. Recatheterization after two and one-half years confirmed the previous findings with Qp/Qs ratio of 4 : l . A chest radiograph at this time showed cardiomegaly as well as a typical pulmonary overload pattern. At operation almost complete absence of atrial septum was found. The defect extended within 1 cm of the orifice of the sriperior vena cava. There was no other cardiac defect. Radiographic changes persisted after operation, so that three years after closure of the large septal defect cardiac catheterization was repeated to exclude persisting left-to-right shunt. No shunt was found. The patient was born prematurely (weight 1.3572 kg). He was observed at CHOP, and he was found to have a systolic Table 1-Findings X-Ray Patient,, No. Changes in the Four Siblings with Atrial Septa1 Defects * ECG PR Interval, Sec. Age a t Heart Catherieation Pulmonary Systemic Flow ratio Qp/Q8 Pulmonary Wedge Pressure Findings a t Operation Diameter Associated of ASD (Cm) Malformations 1 minimal 0.15 29 2:l normal 2.5 none 2 moderate 0.16 27 2.4:l normal 2x3 none 3 pronounced 0.15 8 4:l normal "large" none 4 pronounced 0.14 11 2:l normal 4 none 'Changes on chest roentgenograms: minimal: slight hypervascularity in both lungs; moderate: hypervascularity in both lungs and prominence of the main pulmonary trunk; pronounced: marked pulmonary hypervascularity and gross cardiac enlargement. CHEST, VOL. 65, NO. 1, JANUARY, 1974 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20946/ on 05/05/2017 LIBSHITZ, BARTH be the result of both genetic and environmental iduences (multifactorial inheritance).12J3 In Nora'sls series of 308 patients with ASD and VSD, 26 percent of the children had ASD, an incidence 37 times greater than that in the general population. Zetterqvist14 and Johann~on'~studied the pedigrees of two families with clustering of ASD and found inheritance following the autosomal dominant mode. No visible chromosomal aberrations were found.16 However, only a few kindreds with apparently dominant mode of inheritance are reported.14 The distinction between the types of inheritance becomes important for genetic counseling. Some means of predicting the mode of inheritance have been explored from a single generation, especially for the case of dominant autosomal transmission. Arnarasingham and Fleming1' first pointed out the association between ASD and A-V conduction defect in a father and two of his children (identical twins). In another report of several generations of a family including 16 members with ASD and A-V conduction defects, Bizzarro et all8 concluded that this combination of findings is typical for autosomal dominant transmission and enables prediction of this mode of inheritance for future offspring. The validity for this concept is conjectural. None of Zetterqvist'ss 16 cases of one kindred had prolonged A-V conduction. On the other hand, ASD, either sporadic or familial in origin, is in 5 to 15 percent of cases associated with an A-V conduction d e f e ~ t . ~ It has been sKwn that ASD, a common congenital heart defect, occurs not only sporadically but has an increased incidence in certain families. Better appreciation of the familial aspects of ASD by all physicians involved in the care of such patients will permit earlier diagnoses of unsuspected cases in other family members. Appropriate genetic counseling will also be possible. ACKNOWLEDGMENTS: Appreciation is ex ressed to Patricia F. Borns, M.D., Senior Radiologist, ~hilBren'sHospital of Philadelphia, for the data and permission to use cases 3 and 4, and to Robert G. Trout, M.D., Chief of Thoracic and Cardiovascular Surgery, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, for the data and permission to use case 2. 1 Richards MR, Merrit KK, Sarnuek MH, et al: Congenital malformations of the cardiovascular system in a series of 6,053 infants. Pediatrics 15: 12,1955 2 Nadas AS: Pediatric Cardiology (ed 2 ) Philadelphia, WB Saunders Co., 1963, p 792 3 Leech CB: Congenital heart disease: Clinical analysis of 75 cases from Johns Hopkins Hospital. J Pediatr 7:802839, 1935 4 Campbell M, Polani PE: Factors in the aetiology of atrial septal defects. Br Heart J 23:477, 1961 5 Richer TJ, Gallen WJ, Friedberg DZ: Familial atrial septal defect in a single generation. Br Heart J 34:198200,1972 6 Zetterqvist P, Turesson J, Johansson BW, et al: Dominant mode of inheritance in atrial septal defect. Clin Genet 2:78-86, 1W1 7 Campbell M: Natural history of atrial septal defect. Br Heart J 32:820-826, 1970 8 Antia AU: Familial skeletal cardiovascular syndrome ( Holt-Oram) in a polygamous African family. Br Heart J 32:241-244, 1970 9 Holt M, Oram S: Familial heart disease with skeletal malformations. Br Heart J 22:236-242, 1980 10 McKusick VA: Medical Genetics 1960. J Chronic Dis 14:100, 1961 11 Yao JKY, Thompson MW, Tursler GA, et al: Familial atrial septal defect of the primum type. Can Med Assoc J 98:218-219, 1968 12 Nora JJ, McNamara DG, Fraser FC: Hereditary factors in atrial septal defect. Circulation 35:448-456, 1967 13 Nora JJ: Risk to offspring of parents with congenital heart defects. JAMA 209:2052-2053, 1969 14 Zetterqvist P: Multiple occurrence of atrial septal defect in a family. Acta Paediatr S a n d 49:741, 1960 15 Johansson BW: Inheritance of atrial septal defect. Lancet 1:1224-1225, 1967 16 Book JA: Association between congenital heart malformation and chromosomal variations. Acta Paediatr Scand 50:217-227,1961 17 Amarasingham R, Fleming HA: Congenital heart disease with arrhythmia in a family. Br Heart J 29:78-82, 1967 18 Bizzarro RO: Familial atrial septal defect with prolonged atrioventricular conduction. Circulation 41:677-683, 1970 CHEST, VOL. 65, NO. 1, JANUARY, 1974 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20946/ on 05/05/2017