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Recurrence Risk in CHD
best examples is the relationship between coarctation of the aorta and intracardiac defects. When using my figures on coarctation, Nora and Nora did not mention that three out of five affected children had dissimilar defects. By so doing one may miss an essential point. An excess of left heart obstructions and VSDs among first degree relatives suggests the possibility that such intracardiac defects in the probands - even if insignificant in early postnatal life - may have played an important part in the pathogenesis of the coarctation. The probable mechanism is a redistribution of flow in favor of the ductus at the expense of isthmus flow interacting as an internal environmental factor (or trigger) with a local predisposition for coarctation which may well be polygenic in nature. Clustering of different cardiovascular malformations in one and the same family is known to occur' 7and has been the subject of a recent large-scale study.' The relationship between different types may be purely genetic or due to hemodynamic mechanisms during intrauterine life. In ASD, which was the third type of CHD studied by me, the occurrence of simple dominant inheritance was evident,' and some data suggested the possibility of modified dominance in other families.5 In 1968 Nora2 wrote: "Perhaps no single misconception has more delayed an etiological understanding of congenital heart diseases than this; namely the assumption that a heterogenous category of anomalies could be approached as a single disease." This means that cases of different anatomical types should not be indiscriminately pooled in family studies. I find it equally important, however, to stress that, even within the frame of supposed multifactorial inheritance - or etiology - varying types of CHD and the individual families cannot be supposed to conform with one and the same simple etiological model. In addition to single genes and external environmental factors the antenatal interplay between different parts of the heart and great vessels seems particularly worth of be-
To the Editor: In their recent report concerning the recurrence risk in children having one parent with congenital heart disease, Nora and Nora' compared the observed risk in children with a predicted risk corresponding to the square root of an assumed population incidence for each defect. The consistently good or fair agreement between observed and expected risks was claimed to support the hypothesis that each type of CHD represented one genetic entity independent of other types and that the criteria for multifactorial inheritance according to a simplified mathematical model were satisfied. I think, however, that the presentation of data is somewhat misleading and also the approach unsuitable as a basis for the kind of multicenter cooperation which is necessary in this field because of the generally low risks. First, the findings of defects similar and dissimilar to the index case should be presented separately. An observed risk for dissimilar defects of the same order as the population incidence would suggest that the increase in total risk for CHD is specific, as previously supposed by Nora.2 It would also serve as a test of the reliability of the study, as it is hard to believe that a heart defect in one individual should protect other family members from being affected with other types. A higher figure, on the other hand, would suggest a nonspecific increase in risk. Secondly, the population incidence of each defect should be studied on a population basis rather than calculated by multiplying the relative frequency of each defect in hospital data by a rough estimate of 1% for the total population incidence of CHD irrespective of type. The latter method tends to give too high figures for those easily detected and diagnosed defects which are likely to come under medical care. For example, the incidence of PDA is around 0.06% according to population studies from the USA and northwestern European countries.'' The square root of this is 2.4-2.5% and fits well with my own experience of the risk for PDA in children born to a parent with the same defect.8 After having excluded an expected number of dissimilar defects (3/490 or 0.6 ± 0.3%) and an equal number of PDAs of supposedly specific etiology, I found an observed risk of 12/484 or 2.5 ± 0.7% for isolated, nonsyndromic PDA. The corresponding incidence among the proband siblings was 2.3 + 0.6%. The heritability for children as estimated according to Falconer was 74 + 8%. These observations, the relations between sex and genetic risks, the frequency of concordance for monozygotic twins and available data on the occurrence of CHD among second degree relatives are best explained in terms of multifactorial inheritance. Nora and Nora apparently assume a population incidence for PDA of 0.12%, the square root of which (or 3.5%) makes up their expectation figure for first degree relatives. An observed risk of the same order is attained by including cases belonging to other types as if they all represented PDA. Figures presented in this way cannot be used, alone or pooled with those from other studies, to elucidate the question about a possible increase in risk for other types. As already mentioned, my own data did not suggest any such increase as far as simple PDA is concerned. This gives further support to the view that nonsyndromic PDA is to be regarded as a clinical and genetic entity. The above conclusions about PDA cannot be automatically applied to other types of CHD. Apart from a ductus which is unable to perform its last, self-destroying function, the different parts of the circulatory system are not independent of each other during formation, as they are functioning throughout this period and formation is influenced by normal and abnormal blood flow. Probably one of the
ing considered. PER ZETTERQVIST, M.D. Karolinska Sjukhuset Stockholm, Sweden
References 1. Nora JJ, Nora AH: Recurrence risks in children having one parent with congenital heart disease. Circulation 53: 701, 1976 2. Nora JJ: Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic environmental interaction. Circulation 38: 604, 1968 3. Michell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births. Circulation 43: 323, 1971 4. Carlgren LE: The incidence of congenital heart disease in Gothenburg. Proc Assoc Eur Paed Cardiol 5: 2, 1969 5. Zetterqvist P: A clinical and genetic study of congenital heart defects. M.D. thesis. Institute of Medical Genetics, University of Uppsala, Sweden, 1972 6. Pitt DB: A family study of Fallot's tetrad. Austral Ann Med 11: 179, 1962 7. Zetterqvist P: Accumulation of different congenital heart defects in one pedigree. Clin Genet 2: 123, 1971 8. Fraser FC, Hunter ADW: Etiologic relations among categories of congenital heart malformations. Am J Cardiol 36: 793, 1975 9. Zetterqvist P, Turesson I, Johansson BW, Laurell S, Ohlsson NM: Dominant mode of inheritance in atrial septal defect. Clin Genet 2: 78, 1971
The authors reply: To the Editor: In Baltimore, in May, Dr. Zetterqvist and I had the opportunity to discuss our article on recurrence risks and his intention to send a letter to the editor regarding it. Although there is very little in his letter that relates to the thrust of our article, it does provide an op-
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Recurrence risk in CHD. P Zetterqvist Circulation. 1977;55:555-556 doi: 10.1161/01.CIR.55.3.555 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1977 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/55/3/555.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on May 4, 2015
Recurrence Risk in CHD
best examples is the relationship between coarctation of the aorta and intracardiac defects. When using my figures on coarctation, Nora and Nora did not mention that three out of five affected children had dissimilar defects. By so doing one may miss an essential point. An excess of left heart obstructions and VSDs among first degree relatives suggests the possibility that such intracardiac defects in the probands - even if insignificant in early postnatal life - may have played an important part in the pathogenesis of the coarctation. The probable mechanism is a redistribution of flow in favor of the ductus at the expense of isthmus flow interacting as an internal environmental factor (or trigger) with a local predisposition for coarctation which may well be polygenic in nature. Clustering of different cardiovascular malformations in one and the same family is known to occur' 7and has been the subject of a recent large-scale study.' The relationship between different types may be purely genetic or due to hemodynamic mechanisms during intrauterine life. In ASD, which was the third type of CHD studied by me, the occurrence of simple dominant inheritance was evident,' and some data suggested the possibility of modified dominance in other families.5 In 1968 Nora2 wrote: "Perhaps no single misconception has more delayed an etiological understanding of congenital heart diseases than this; namely the assumption that a heterogenous category of anomalies could be approached as a single disease." This means that cases of different anatomical types should not be indiscriminately pooled in family studies. I find it equally important, however, to stress that, even within the frame of supposed multifactorial inheritance - or etiology - varying types of CHD and the individual families cannot be supposed to conform with one and the same simple etiological model. In addition to single genes and external environmental factors the antenatal interplay between different parts of the heart and great vessels seems particularly worth of be-
To the Editor: In their recent report concerning the recurrence risk in children having one parent with congenital heart disease, Nora and Nora' compared the observed risk in children with a predicted risk corresponding to the square root of an assumed population incidence for each defect. The consistently good or fair agreement between observed and expected risks was claimed to support the hypothesis that each type of CHD represented one genetic entity independent of other types and that the criteria for multifactorial inheritance according to a simplified mathematical model were satisfied. I think, however, that the presentation of data is somewhat misleading and also the approach unsuitable as a basis for the kind of multicenter cooperation which is necessary in this field because of the generally low risks. First, the findings of defects similar and dissimilar to the index case should be presented separately. An observed risk for dissimilar defects of the same order as the population incidence would suggest that the increase in total risk for CHD is specific, as previously supposed by Nora.2 It would also serve as a test of the reliability of the study, as it is hard to believe that a heart defect in one individual should protect other family members from being affected with other types. A higher figure, on the other hand, would suggest a nonspecific increase in risk. Secondly, the population incidence of each defect should be studied on a population basis rather than calculated by multiplying the relative frequency of each defect in hospital data by a rough estimate of 1% for the total population incidence of CHD irrespective of type. The latter method tends to give too high figures for those easily detected and diagnosed defects which are likely to come under medical care. For example, the incidence of PDA is around 0.06% according to population studies from the USA and northwestern European countries.'' The square root of this is 2.4-2.5% and fits well with my own experience of the risk for PDA in children born to a parent with the same defect.8 After having excluded an expected number of dissimilar defects (3/490 or 0.6 ± 0.3%) and an equal number of PDAs of supposedly specific etiology, I found an observed risk of 12/484 or 2.5 ± 0.7% for isolated, nonsyndromic PDA. The corresponding incidence among the proband siblings was 2.3 + 0.6%. The heritability for children as estimated according to Falconer was 74 + 8%. These observations, the relations between sex and genetic risks, the frequency of concordance for monozygotic twins and available data on the occurrence of CHD among second degree relatives are best explained in terms of multifactorial inheritance. Nora and Nora apparently assume a population incidence for PDA of 0.12%, the square root of which (or 3.5%) makes up their expectation figure for first degree relatives. An observed risk of the same order is attained by including cases belonging to other types as if they all represented PDA. Figures presented in this way cannot be used, alone or pooled with those from other studies, to elucidate the question about a possible increase in risk for other types. As already mentioned, my own data did not suggest any such increase as far as simple PDA is concerned. This gives further support to the view that nonsyndromic PDA is to be regarded as a clinical and genetic entity. The above conclusions about PDA cannot be automatically applied to other types of CHD. Apart from a ductus which is unable to perform its last, self-destroying function, the different parts of the circulatory system are not independent of each other during formation, as they are functioning throughout this period and formation is influenced by normal and abnormal blood flow. Probably one of the
ing considered. PER ZETTERQVIST, M.D. Karolinska Sjukhuset Stockholm, Sweden
References 1. Nora JJ, Nora AH: Recurrence risks in children having one parent with congenital heart disease. Circulation 53: 701, 1976 2. Nora JJ: Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic environmental interaction. Circulation 38: 604, 1968 3. Michell SC, Korones SB, Berendes HW: Congenital heart disease in 56,109 births. Circulation 43: 323, 1971 4. Carlgren LE: The incidence of congenital heart disease in Gothenburg. Proc Assoc Eur Paed Cardiol 5: 2, 1969 5. Zetterqvist P: A clinical and genetic study of congenital heart defects. M.D. thesis. Institute of Medical Genetics, University of Uppsala, Sweden, 1972 6. Pitt DB: A family study of Fallot's tetrad. Austral Ann Med 11: 179, 1962 7. Zetterqvist P: Accumulation of different congenital heart defects in one pedigree. Clin Genet 2: 123, 1971 8. Fraser FC, Hunter ADW: Etiologic relations among categories of congenital heart malformations. Am J Cardiol 36: 793, 1975 9. Zetterqvist P, Turesson I, Johansson BW, Laurell S, Ohlsson NM: Dominant mode of inheritance in atrial septal defect. Clin Genet 2: 78, 1971
The authors reply: To the Editor: In Baltimore, in May, Dr. Zetterqvist and I had the opportunity to discuss our article on recurrence risks and his intention to send a letter to the editor regarding it. Although there is very little in his letter that relates to the thrust of our article, it does provide an op-
555 Downloaded from http://circ.ahajournals.org/ by guest on May 4, 2015
Recurrence risk in CHD. P Zetterqvist Circulation. 1977;55:555-556 doi: 10.1161/01.CIR.55.3.555 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1977 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/55/3/555.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on May 4, 2015
