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The association of chromosomal alterations and congenital malformations
EDITOR'S COLUMN
The association of chromosomal alterations and congenital malformations THE
CHROMOSOMAL
ETIOLOGY
of a congenital defect is determined currently by the demonstration of a one-to-one relationship between the chromosomal change and the clinical syndrome. For many of the trisomic and some of the deletion syndromes, this relationship is clearly supported by numerous studies. However, faced with the finding of an unusual chromosomal rearrangement in a malformed infant, it may be difficult to determine whether this chromosomal change is causally related to the phenotype. Almost always, identification has been based on an abnormal phenotype; few studies have been done to determine how frequently the various unusual chromosomal rearrangements may appear in the phenotypically normal population. This issue of the JOURNAL contains two articles (Walzer and associates and Stewart and associates) which are concerned with the frequency of chromosomal alterations in newborn infants. Walzer and associates in Boston performed a modified chromosomal analysis on 2,400 phenotypically normal newborn infants; Stewart and co-workers in London selected for chromosomal analysis 184 newborn infants with minor or major malformations from 2,500 consecutive births. The Walzer study is concerned with variations in the karyotypes of clinically normal infants; the Stewart study with the infrequency of chromosomal abnormalities in infants with congenital malformations. Each points to the difficulty that may be encountered in establishing a causal relation between a chromosomal alteration and a clinical disorder. Vol. 74, No. 3, pp. 490-491
In Table I are listed the number of infants in each series with major numerical or structural alterations of the autosomes. In Stewart's series, 5 of the 184 infants (3 per cent) had such alterations; 3 of these had Down's syndrome and were trisomic for the No. 21 chromosome; 2 had inherited balanced translocations. As the authors point out, the association of the translocations with the malformatlons in the latter 2 infants may be fortuitous since the patients were selected for study because they had a malformation. Further, parents of these infants had the same chromosomal change, but they lacked the malformations. Thus, if infants with known chromosome syndromes are excluded, this study indicates an approximate 1 in 90 chance that a newborn infant with a minor or major malformation will have a chromosomal abnormality. Among 2,400 normal newborn infants, Walzer and co-workers found 7 with significant chromosomal changes, a frequency of about 0.3 per cent. This represents a minimum estimate because of the modified type of analysis. In 6 instances the chromosomal alteration was inherited. The finding of 3 normal infants with an extra small metacentric chromosome is quite unusual and raises questions about reports which suggest that this change may be etiologically related to congenital malformations. It does not, however, exclude the possibiIity that the extra fragment might cause aberrations of cell division which would result in nondlsjunction. The results of these two studies suggest that similar chromosomal alterations may
Volume 74 Number 3
Editor's c o l u m n
4 9 1
T a b l e I. C o m p a r i s o n of the m a j o r n u m e r i c a l a n d s t r u c t u r a l alterations of the autosomes found, in two series of n e w b o r n infants
Findings Pericentric inversion No. 2
Walzer and associates ~ Number I Inherited 1 1
Number 0
Stewart and associates~ I Inherited IType ot malformation -
D/D translocation
2
2
0
-
2/C translocation
1
1
0
-
Extra small metaeentric chromosome
3
2
0
-
D/G translocation
0
-
I
1
Congenital heart disease
D/E translocation
0
-
1
1
Congenital dislocation of hip
7
6
25
2
Totals
*Study group = 2,400 normal newborn infants; cytogenetlc study = minimum of 2 cells examined under microscope. "~Study group = 184 newborn infants with major or minor malformatlons; cytogenetlc study = minimum of 10 cells examined and karyotyoed, SThree infants with Down's syndrome, all with 47 chromosomes, have been omitted from the tabulation.
occur in n o r m a l a n d a b n o r m a l persons, b u t a d d i t i o n a l i n f o r m a t i o n will be necessary to d e t e r m i n e the probability of relationship, if any, to the causation of congenital malformations. F o r genetic counseling w e shall need to know w h e t h e r n o r m a l individuals carrying b a l a n c e d translocations, pericentric inversions, or extra small m e t a c e n t r i c chromosomes are a t a d d i t i o n a l risk in respect t o occurrence of m a l f o r m a t i o n s in their offspring. T h e d a t a of W a l z e r a n d associates suggest that significant v a r i a t i o n can occur in the karyotypes of n o r m a l n e w b o r n infants; the study b y S t e w a r t a n d associates
suggests that b a l a n c e d translocation carriers m a y be at an increased risk for the occurrence of m a l f o r m a t i o n s in their offspring, b u t the study does not establish a relationship. These two p a p e r s are useful in identifying the need for the collection of m o r e d a t a to e v a l u a t e w h i c h c h r o m o s o m a l alterations m a y be related to fetal structural disorders and, w h e n such is the case, the frequency with which these alterations m a y be transm i t t e d to the fetus f r o m the parent. S. W. WRIGHT~ M.D. LOS ANGELES~ CALIF.
The association of chromosomal alterations and congenital malformations THE
CHROMOSOMAL
ETIOLOGY
of a congenital defect is determined currently by the demonstration of a one-to-one relationship between the chromosomal change and the clinical syndrome. For many of the trisomic and some of the deletion syndromes, this relationship is clearly supported by numerous studies. However, faced with the finding of an unusual chromosomal rearrangement in a malformed infant, it may be difficult to determine whether this chromosomal change is causally related to the phenotype. Almost always, identification has been based on an abnormal phenotype; few studies have been done to determine how frequently the various unusual chromosomal rearrangements may appear in the phenotypically normal population. This issue of the JOURNAL contains two articles (Walzer and associates and Stewart and associates) which are concerned with the frequency of chromosomal alterations in newborn infants. Walzer and associates in Boston performed a modified chromosomal analysis on 2,400 phenotypically normal newborn infants; Stewart and co-workers in London selected for chromosomal analysis 184 newborn infants with minor or major malformations from 2,500 consecutive births. The Walzer study is concerned with variations in the karyotypes of clinically normal infants; the Stewart study with the infrequency of chromosomal abnormalities in infants with congenital malformations. Each points to the difficulty that may be encountered in establishing a causal relation between a chromosomal alteration and a clinical disorder. Vol. 74, No. 3, pp. 490-491
In Table I are listed the number of infants in each series with major numerical or structural alterations of the autosomes. In Stewart's series, 5 of the 184 infants (3 per cent) had such alterations; 3 of these had Down's syndrome and were trisomic for the No. 21 chromosome; 2 had inherited balanced translocations. As the authors point out, the association of the translocations with the malformatlons in the latter 2 infants may be fortuitous since the patients were selected for study because they had a malformation. Further, parents of these infants had the same chromosomal change, but they lacked the malformations. Thus, if infants with known chromosome syndromes are excluded, this study indicates an approximate 1 in 90 chance that a newborn infant with a minor or major malformation will have a chromosomal abnormality. Among 2,400 normal newborn infants, Walzer and co-workers found 7 with significant chromosomal changes, a frequency of about 0.3 per cent. This represents a minimum estimate because of the modified type of analysis. In 6 instances the chromosomal alteration was inherited. The finding of 3 normal infants with an extra small metacentric chromosome is quite unusual and raises questions about reports which suggest that this change may be etiologically related to congenital malformations. It does not, however, exclude the possibiIity that the extra fragment might cause aberrations of cell division which would result in nondlsjunction. The results of these two studies suggest that similar chromosomal alterations may
Volume 74 Number 3
Editor's c o l u m n
4 9 1
T a b l e I. C o m p a r i s o n of the m a j o r n u m e r i c a l a n d s t r u c t u r a l alterations of the autosomes found, in two series of n e w b o r n infants
Findings Pericentric inversion No. 2
Walzer and associates ~ Number I Inherited 1 1
Number 0
Stewart and associates~ I Inherited IType ot malformation -
D/D translocation
2
2
0
-
2/C translocation
1
1
0
-
Extra small metaeentric chromosome
3
2
0
-
D/G translocation
0
-
I
1
Congenital heart disease
D/E translocation
0
-
1
1
Congenital dislocation of hip
7
6
25
2
Totals
*Study group = 2,400 normal newborn infants; cytogenetlc study = minimum of 2 cells examined under microscope. "~Study group = 184 newborn infants with major or minor malformatlons; cytogenetlc study = minimum of 10 cells examined and karyotyoed, SThree infants with Down's syndrome, all with 47 chromosomes, have been omitted from the tabulation.
occur in n o r m a l a n d a b n o r m a l persons, b u t a d d i t i o n a l i n f o r m a t i o n will be necessary to d e t e r m i n e the probability of relationship, if any, to the causation of congenital malformations. F o r genetic counseling w e shall need to know w h e t h e r n o r m a l individuals carrying b a l a n c e d translocations, pericentric inversions, or extra small m e t a c e n t r i c chromosomes are a t a d d i t i o n a l risk in respect t o occurrence of m a l f o r m a t i o n s in their offspring. T h e d a t a of W a l z e r a n d associates suggest that significant v a r i a t i o n can occur in the karyotypes of n o r m a l n e w b o r n infants; the study b y S t e w a r t a n d associates
suggests that b a l a n c e d translocation carriers m a y be at an increased risk for the occurrence of m a l f o r m a t i o n s in their offspring, b u t the study does not establish a relationship. These two p a p e r s are useful in identifying the need for the collection of m o r e d a t a to e v a l u a t e w h i c h c h r o m o s o m a l alterations m a y be related to fetal structural disorders and, w h e n such is the case, the frequency with which these alterations m a y be transm i t t e d to the fetus f r o m the parent. S. W. WRIGHT~ M.D. LOS ANGELES~ CALIF.