Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Clinical cytogenetics B. Rafael Elejalde & John M. Opitz To cite this article: B. Rafael Elejalde & John M. Opitz (1978) Clinical cytogenetics, Postgraduate Medicine, 63:2, 179-183, DOI: 10.1080/00325481.1978.11714764 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11714764
Published online: 07 Jul 2016.
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Date: 10 August 2017, At: 16:32
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• Cytogenetics arose from the union of mende lian genetics and cytology. 1* Although chromosomes and the essentials of mitosis and meiosis were discovered almost one century ago, the technical difficulties of obtaining from man preparations sui table for analysis delayed the development of hu man clinicat cytogenetics till 1956. Soon after the disco very of chromosomes, the ''law of constancy'' of chromosome number per cell per species was established2 and the description of meiosis (in Ascaris) by Van Beneden 3 provided the explanation for the operation of the law from one generation to the next. Soon after the rediscovery of Mendel' s law, the relationship between gene segregation and meiotic reduction became obvious, mainly through the work of Boveri 4 and Sutton. 5
Terminology Cytogenetic studies in plants and lower animais, conducted in the first half of this century, yielded many concepts and a complex terminology which is best defined and historically documented in Rieger and associates' 6 dictionary. Chromosomes, like most genes (except those on X and Y), occur in pairs. However, members of a pair are not called alleles but are termed homologues. The half-set of chromosomes of a gamete is called a haploid (n) set, and the whole set of chromosomes in somatic cells is a diploid (2n) set. The presence of more than two sets of chromosomes is polyploidy and is technically considered a balanced (euploid) state (although in man polyploidy is highly deleterious), the 3n state being called triploid, the 4n state tetraploid, and so on. Extra or missing chromosomes or pieces of chromosomes produce an unbalanced state, aneuploidy, which is also thought to be deleterious in man in all instances. The occurrence of one
clinical cytogenetics part 1 B. Rafael Elejalde, MD John M. Opltz, MD University of Wisconsin Madison
This paper is an introduction to the cytogenetic biology of man. lt deals with the role of chromosome abnormalities in prenatal death, malformation syndromes, mental retardation, malformation/mental retardation syndromes, abnormalities of sex determination, sex differentiation and sexual function, cancer, and certain genetic disorders in which chromosome abnormalities are seen commonly. Down syndrome is discussed as an important and common example of a malformation/mental retardation syndrome.
*The complete list of references cited in this article will be published with part 2.
One of a special series of articles on practical genetics coordinated by Dr Opitz. Part 2 of this article, to be published next month, concems clinical aspects of various abnormalities (including data on frequency), chromosome baoding techniques, and indications for and applications of chromosome analysis.
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
179
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
clinical cytogenetics - - - - - - - - - - - - - - - - - - -
Figure- 1. Normal human female (XX) and male (XV) karyotypes.
whole extra chromosome is trisomy, of two extra chromosomes (of one pair) tetrasomy, or of two extra chromosomes of two pairs double trisomy. Pentasomy X (49,XXXXX) bas been observed several times in man. Absence of a chromosome is monosomy, with monosomy X (as in the 45,X UllrichTumer syndrome) not necessarily meaning that an X is missing; in this instance a Y could be missing. If pieces of chromosomes are missing or if extra pieces are present (in individuals with 46 chromosomes), the condition is called deletion or partial trisomy, respectively. A reciprocal exchange of material between two chromosomes is a translocation, and the unbalanced state of one or the other altered chromosome in offspring represents a duplication/deficiency, which may also arise through crossing-over in apericentric inversion.
180
Isochromosomes are said to arise through transverse rather than longitudinal division of the centromere during mitosis or meiosis. If successful fusion of the broken chromosome arms occurs, the resulting chromosome consists of two structurally and genetically identical arms on either side of the centramere. Thus, a woman who bas one normal X but also an isochromosome of the long arm of the X is trisomie for the long arm and monosomic for the short arm of X. Ring chromosomes involve at least two breaks and fusion of the broken ends. Extra fragments may represent deleted chromosomes or small translocation chromosomes. Depending on the position of the centromere (where the chromosome arms are joined and one of the places where the spindle fibers attach), the term metacentric, submetacentric, or acrocentric is used, referring
POSTGRADUATE MEDICINE • February 1978 • Vol. 63 • No. 2
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
to the middle of the chromosome, a point below the middle, or a point close to the tip. Figure 1 shows the normal human female and male karyotypes. Note that in man, chromosome 22 has been arbitrarily given the number 21, and vice versa. Trisomy (and monosomy) is said to arise usually from meiotic nondisjunction (rarely from mitotic nondisjunction), yielding a trisomie and a monosomie cell line. If both cell lines are viable, the individual is a mosaic. If mitotie nondisjunction occurs after a normal cellline is established in the zygote, the individual may be a triple mosaie, eg, 46,XX/45,X/47 ,XXX. Background of Human Studies According to Makino, 1 the first studies on human chromosomes were published by Flemming in 1881. 2 Before 1956, however,
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
chromosome numbers assigned to man were different from th ose used today. Tjio and Levan 7 studied cells from four fetal lungs and established the correct number of human chromosomes as 46. This advance and the ability to perform routine chromosome analysis in man came about through Hsu's 8 use of colchicine to arrest mitosis and through introduction-by Osgood, 9 Hungerford, 10 Nowell, 11 Moorhead, 12 and others--ofblood cultures, phytohemagglutinin stimulation, and hypotonie treatment before fixation. Down Syndrome as Prototype Down syndrome is distressingly common, with an incidence of 1/700 to 1/1 ,000, 13 and is the most common cause of severe mental retardation. It is a true multiple congenital anomalies/mental retardation (MCA/MR) syndrome. Its occurrence is signifieantly as-
181
clinical cytogenetics - - - - - - - - - - - - - - - - - - - · B. Rafael Elejalde John M. Opltz Dr Elejalde is senior project associate, Wisconsin Clinical Genetics Center, University of Wisconsin, Madison.
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
Dr Opitz is professer of medical genetics and pediatries, University of Wisconsin Center for Health Sciences and Medical School, and director, Wisconsin Clinicat Genetics Center.
sociated with increased maternai age, exposure to unusual amounts of x-rays, and a maternai history of spontaneous abortion. It has been found that if one of a pair of monozygous (identical) twins has Down syndrome, the other is invariably affected. But if a dizygous (fraternal) twin has Down syndrome, the other twin is normal. In early studies, familial occurrence of Down syndrome could not be explained on the basis ofmendelian inheritance, since most affected sibs had normal parents. However, the incidence of the syndrome among offspring of affected parents (mothers) was about 58%, and at times cases were widely scattered throughout a family, the affected individuals being connected through normal relatives. Waardenburg 14 and Bleyer 15 first suggested that Down syndrome could be due to a chromosome abnormality, but it was not until 1959 that Lejeune and associates 16 found that their nine patients with Down syndrome each had 47 rather than 46 chromosomes, ie, that they were trisomie for chromosome 21. * Studies of Down syndrome have yielded many data of general cytogenetic importance and data important in genetic counseling. In 1.5% of families with at least one affected child, two or more sibs were found to be affected. For a woman who has had a child with Down syndrome, the risk of having another affected child is qui te low, in the vicinity of 1% to 2%. Whereas the risk of • Actually they were trisomie for chromosome 22, but since the "Down syndrome chromosome'' has become identified as 21, the decision was made to exchange 21 and 22 in the human karyotype.
182
having a child with Down syndrome is much greater for a woman in her late 30s or early 40s than for a woman in her earl y 20s, the risk that a woman will have a second affected child is about the same for women ofboth age groups, ie, the relative risk in this regard is higher for the younger women, whereas for the older group the risk of first occurrence and the risk of recurrence are about the same. Wh y is the risk of having a second affected child higher for the younger women? ln more than half of cases (56%), Down syndrome in two or more sibs represents trisomy in offspring of chromosomally apparently normal parents 17 who may have a "genetic predisposition" to nondisjunction. Infrequently (8% of the time), one parent is a mosaic of normal and trisomie ce ils. 17 If every germ cell in such a parent were trisomie, the maximum recurrence risk would be 50%. Another reason for the higher recurrence risk for younger women and for the familial occurrence of Down syndrome is translocation. Translocation is present in sorne 4.8% of affected persons. 17 Most translocations in
Many data of general cytogenetic importance and information useful in genetic counseling have come from studies of Down syndrome, the most common cause of severe mental retardation. persons with Down syndrome are of an interesting type called Robertsonian translocations. These involve long arms only of acrocentric chromosomes (ie, of21 and of either 22 or one of the D pairs) and strict! y speaking are not balanced in the carriers, who lack the expected small reciprocal translocation chromosome consisting of the two short arms and who have only 45 chromosomes. In the case of the D/G translocations, 21 could be fused with 13, 14, or 15. Most of the time (58.5%), 21 is fused with 14; fusion with 13 or 15 is Jess common (19.5% or 22%, respectively).17 The D/G translocation chromosome looks like aC chromosome. An item important in genetic counseling
POSTGRADUATE MEDICINE • February 1978 • Vol. 63 • No. 2
with regard to the risk of Down syndrome in offspring is the appreciably higher risk in female carriers of D/G translocation. 18 Among the offspring of a carrier father or mother, the proportions will be as follows:
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
Father Mother
Down syndrome
Balanced carriers
Normal
2.4% 11.0%
58.8% 40.0%
38.8% 49.0%
G/G translocations present a different counseling challenge. Carriers of 21/21 translocation are frequently (always?) mosaics
lt la possible for physlclans to diagnose Down syndrome wlth vlrtual certalnty from physlcal tlndlngs ln almost ali cases, even neonatally. Developmental manifestations are specifie to the trlsomy. with a normal cell li ne and have a 100% chance of having affected children. Carriers of 21/22 translocation seem to have a rather small chance of having children with Down syndrome, although exact data are unavailable. In cases of G/G translocations, it is extremely important to use the best baoding techniques to differentiate 21/21 from 21/22 translocations. The majority of D/G and G/G translocations in man arise de nova (55 .14% and 96.15% of the time, respectively). 17 1t is of interest that in D/G cases involving inherited 13/21 translocations the D1 (or 13) trisomy syndrome (due to the translocation) is virtually unknown. Another interesting facet of Robertsonian translocation in Dawn syndrome is the observation that D/D translocations seem to be associated with an increased risk of nondisjunction leading to trisomie Dawn syndrome. Severa! patients with trisomie Dawn syndrome and ba1anced D/D translocation are known to be the offspring of similar carriers, sorne of wh ose pedigrees are extensive and show many known carriers. In sorne 8% of cases of familial Dawn syndrome (couples with two or more affected children), one parent is a D/D translocation carrier. 17
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
Individuals mosaic for Down syndrome may present with two extreme phenotypes and a complete range of intermediate manifestations, namely, as an individual with Down syndrome as severe as in the most severe trisomie cases (and sorne 2. 7% of patients with Down syndrome are mosaics) 17 or as a phenotypically apparently normal individual who has had two or more children with trisomie Down syndrome. Developmentally, Down syndrome is a complex pleiotropic malformation syndrome representing manifestations specifie to the trisomy and an apparently nonspecific increase of many other anomalies. The specjfic manifestations make it possible for physicians to diagnose Down syndrome with virtual certainty from physieal findings in almost ali cases, even neonatally. Probably ali aneuploidy syndromes are associated with an increased risk for neoplasia. The risk for leukemia in Dawn syndrome (20 or so times greater than the general risk) is weil documented. An appreciable proportion (perhaps more than half) of embryos affected by Dawn syndrome die prenatally. Amniocentesis and the option of induced abortion offer the opportunity of reducing drastically the number of infants born with Dawn syndrome.19 Studies of (spontaneously) aborted embryos and fetuses have shawn that chromosome abnormalities, mostly in the form of triploidy, autosomal trisomies, and the XO state, are the most common causes of prenatal death and malformation. Sorne investigators have estimated that at least one third or as many as half 20 of all fertilized human ova may have a chromosome abnormality. Triploid fetuses have a characteristie phenotype and are rarely born alive. The same seems to be true of the two other commonly observed human trisomies, namely, the trisomy 13 and 18 syndromes. • Supported by Grant GM20130 from the National Institute of General Medical Sciences, USPHS. Paper No. 2096 from the University of Wisconsin Genetics Laboratory. Address reprint requests to John M. Opitz, MD, Rm 109, Genetics Bldg, University of Wisconsin, Madison, WI 53706.
183
For a woman who has had a chlld wlth Down syndrome, the rlsk of havlng another affected chlld la qulte low, ln the vlclnlty of 1% to 2%.
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Clinical cytogenetics B. Rafael Elejalde & John M. Opitz To cite this article: B. Rafael Elejalde & John M. Opitz (1978) Clinical cytogenetics, Postgraduate Medicine, 63:2, 179-183, DOI: 10.1080/00325481.1978.11714764 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11714764
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 10 August 2017, At: 16:32
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
• Cytogenetics arose from the union of mende lian genetics and cytology. 1* Although chromosomes and the essentials of mitosis and meiosis were discovered almost one century ago, the technical difficulties of obtaining from man preparations sui table for analysis delayed the development of hu man clinicat cytogenetics till 1956. Soon after the disco very of chromosomes, the ''law of constancy'' of chromosome number per cell per species was established2 and the description of meiosis (in Ascaris) by Van Beneden 3 provided the explanation for the operation of the law from one generation to the next. Soon after the rediscovery of Mendel' s law, the relationship between gene segregation and meiotic reduction became obvious, mainly through the work of Boveri 4 and Sutton. 5
Terminology Cytogenetic studies in plants and lower animais, conducted in the first half of this century, yielded many concepts and a complex terminology which is best defined and historically documented in Rieger and associates' 6 dictionary. Chromosomes, like most genes (except those on X and Y), occur in pairs. However, members of a pair are not called alleles but are termed homologues. The half-set of chromosomes of a gamete is called a haploid (n) set, and the whole set of chromosomes in somatic cells is a diploid (2n) set. The presence of more than two sets of chromosomes is polyploidy and is technically considered a balanced (euploid) state (although in man polyploidy is highly deleterious), the 3n state being called triploid, the 4n state tetraploid, and so on. Extra or missing chromosomes or pieces of chromosomes produce an unbalanced state, aneuploidy, which is also thought to be deleterious in man in all instances. The occurrence of one
clinical cytogenetics part 1 B. Rafael Elejalde, MD John M. Opltz, MD University of Wisconsin Madison
This paper is an introduction to the cytogenetic biology of man. lt deals with the role of chromosome abnormalities in prenatal death, malformation syndromes, mental retardation, malformation/mental retardation syndromes, abnormalities of sex determination, sex differentiation and sexual function, cancer, and certain genetic disorders in which chromosome abnormalities are seen commonly. Down syndrome is discussed as an important and common example of a malformation/mental retardation syndrome.
*The complete list of references cited in this article will be published with part 2.
One of a special series of articles on practical genetics coordinated by Dr Opitz. Part 2 of this article, to be published next month, concems clinical aspects of various abnormalities (including data on frequency), chromosome baoding techniques, and indications for and applications of chromosome analysis.
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
179
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
clinical cytogenetics - - - - - - - - - - - - - - - - - - -
Figure- 1. Normal human female (XX) and male (XV) karyotypes.
whole extra chromosome is trisomy, of two extra chromosomes (of one pair) tetrasomy, or of two extra chromosomes of two pairs double trisomy. Pentasomy X (49,XXXXX) bas been observed several times in man. Absence of a chromosome is monosomy, with monosomy X (as in the 45,X UllrichTumer syndrome) not necessarily meaning that an X is missing; in this instance a Y could be missing. If pieces of chromosomes are missing or if extra pieces are present (in individuals with 46 chromosomes), the condition is called deletion or partial trisomy, respectively. A reciprocal exchange of material between two chromosomes is a translocation, and the unbalanced state of one or the other altered chromosome in offspring represents a duplication/deficiency, which may also arise through crossing-over in apericentric inversion.
180
Isochromosomes are said to arise through transverse rather than longitudinal division of the centromere during mitosis or meiosis. If successful fusion of the broken chromosome arms occurs, the resulting chromosome consists of two structurally and genetically identical arms on either side of the centramere. Thus, a woman who bas one normal X but also an isochromosome of the long arm of the X is trisomie for the long arm and monosomic for the short arm of X. Ring chromosomes involve at least two breaks and fusion of the broken ends. Extra fragments may represent deleted chromosomes or small translocation chromosomes. Depending on the position of the centromere (where the chromosome arms are joined and one of the places where the spindle fibers attach), the term metacentric, submetacentric, or acrocentric is used, referring
POSTGRADUATE MEDICINE • February 1978 • Vol. 63 • No. 2
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
to the middle of the chromosome, a point below the middle, or a point close to the tip. Figure 1 shows the normal human female and male karyotypes. Note that in man, chromosome 22 has been arbitrarily given the number 21, and vice versa. Trisomy (and monosomy) is said to arise usually from meiotic nondisjunction (rarely from mitotic nondisjunction), yielding a trisomie and a monosomie cell line. If both cell lines are viable, the individual is a mosaic. If mitotie nondisjunction occurs after a normal cellline is established in the zygote, the individual may be a triple mosaie, eg, 46,XX/45,X/47 ,XXX. Background of Human Studies According to Makino, 1 the first studies on human chromosomes were published by Flemming in 1881. 2 Before 1956, however,
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
chromosome numbers assigned to man were different from th ose used today. Tjio and Levan 7 studied cells from four fetal lungs and established the correct number of human chromosomes as 46. This advance and the ability to perform routine chromosome analysis in man came about through Hsu's 8 use of colchicine to arrest mitosis and through introduction-by Osgood, 9 Hungerford, 10 Nowell, 11 Moorhead, 12 and others--ofblood cultures, phytohemagglutinin stimulation, and hypotonie treatment before fixation. Down Syndrome as Prototype Down syndrome is distressingly common, with an incidence of 1/700 to 1/1 ,000, 13 and is the most common cause of severe mental retardation. It is a true multiple congenital anomalies/mental retardation (MCA/MR) syndrome. Its occurrence is signifieantly as-
181
clinical cytogenetics - - - - - - - - - - - - - - - - - - - · B. Rafael Elejalde John M. Opltz Dr Elejalde is senior project associate, Wisconsin Clinical Genetics Center, University of Wisconsin, Madison.
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
Dr Opitz is professer of medical genetics and pediatries, University of Wisconsin Center for Health Sciences and Medical School, and director, Wisconsin Clinicat Genetics Center.
sociated with increased maternai age, exposure to unusual amounts of x-rays, and a maternai history of spontaneous abortion. It has been found that if one of a pair of monozygous (identical) twins has Down syndrome, the other is invariably affected. But if a dizygous (fraternal) twin has Down syndrome, the other twin is normal. In early studies, familial occurrence of Down syndrome could not be explained on the basis ofmendelian inheritance, since most affected sibs had normal parents. However, the incidence of the syndrome among offspring of affected parents (mothers) was about 58%, and at times cases were widely scattered throughout a family, the affected individuals being connected through normal relatives. Waardenburg 14 and Bleyer 15 first suggested that Down syndrome could be due to a chromosome abnormality, but it was not until 1959 that Lejeune and associates 16 found that their nine patients with Down syndrome each had 47 rather than 46 chromosomes, ie, that they were trisomie for chromosome 21. * Studies of Down syndrome have yielded many data of general cytogenetic importance and data important in genetic counseling. In 1.5% of families with at least one affected child, two or more sibs were found to be affected. For a woman who has had a child with Down syndrome, the risk of having another affected child is qui te low, in the vicinity of 1% to 2%. Whereas the risk of • Actually they were trisomie for chromosome 22, but since the "Down syndrome chromosome'' has become identified as 21, the decision was made to exchange 21 and 22 in the human karyotype.
182
having a child with Down syndrome is much greater for a woman in her late 30s or early 40s than for a woman in her earl y 20s, the risk that a woman will have a second affected child is about the same for women ofboth age groups, ie, the relative risk in this regard is higher for the younger women, whereas for the older group the risk of first occurrence and the risk of recurrence are about the same. Wh y is the risk of having a second affected child higher for the younger women? ln more than half of cases (56%), Down syndrome in two or more sibs represents trisomy in offspring of chromosomally apparently normal parents 17 who may have a "genetic predisposition" to nondisjunction. Infrequently (8% of the time), one parent is a mosaic of normal and trisomie ce ils. 17 If every germ cell in such a parent were trisomie, the maximum recurrence risk would be 50%. Another reason for the higher recurrence risk for younger women and for the familial occurrence of Down syndrome is translocation. Translocation is present in sorne 4.8% of affected persons. 17 Most translocations in
Many data of general cytogenetic importance and information useful in genetic counseling have come from studies of Down syndrome, the most common cause of severe mental retardation. persons with Down syndrome are of an interesting type called Robertsonian translocations. These involve long arms only of acrocentric chromosomes (ie, of21 and of either 22 or one of the D pairs) and strict! y speaking are not balanced in the carriers, who lack the expected small reciprocal translocation chromosome consisting of the two short arms and who have only 45 chromosomes. In the case of the D/G translocations, 21 could be fused with 13, 14, or 15. Most of the time (58.5%), 21 is fused with 14; fusion with 13 or 15 is Jess common (19.5% or 22%, respectively).17 The D/G translocation chromosome looks like aC chromosome. An item important in genetic counseling
POSTGRADUATE MEDICINE • February 1978 • Vol. 63 • No. 2
with regard to the risk of Down syndrome in offspring is the appreciably higher risk in female carriers of D/G translocation. 18 Among the offspring of a carrier father or mother, the proportions will be as follows:
Downloaded by [Australian Catholic University] at 16:32 10 August 2017
Father Mother
Down syndrome
Balanced carriers
Normal
2.4% 11.0%
58.8% 40.0%
38.8% 49.0%
G/G translocations present a different counseling challenge. Carriers of 21/21 translocation are frequently (always?) mosaics
lt la possible for physlclans to diagnose Down syndrome wlth vlrtual certalnty from physlcal tlndlngs ln almost ali cases, even neonatally. Developmental manifestations are specifie to the trlsomy. with a normal cell li ne and have a 100% chance of having affected children. Carriers of 21/22 translocation seem to have a rather small chance of having children with Down syndrome, although exact data are unavailable. In cases of G/G translocations, it is extremely important to use the best baoding techniques to differentiate 21/21 from 21/22 translocations. The majority of D/G and G/G translocations in man arise de nova (55 .14% and 96.15% of the time, respectively). 17 1t is of interest that in D/G cases involving inherited 13/21 translocations the D1 (or 13) trisomy syndrome (due to the translocation) is virtually unknown. Another interesting facet of Robertsonian translocation in Dawn syndrome is the observation that D/D translocations seem to be associated with an increased risk of nondisjunction leading to trisomie Dawn syndrome. Severa! patients with trisomie Dawn syndrome and ba1anced D/D translocation are known to be the offspring of similar carriers, sorne of wh ose pedigrees are extensive and show many known carriers. In sorne 8% of cases of familial Dawn syndrome (couples with two or more affected children), one parent is a D/D translocation carrier. 17
Vol. 63 • No. 2 • February 1978 • POSTGRADUATE MEDICINE
Individuals mosaic for Down syndrome may present with two extreme phenotypes and a complete range of intermediate manifestations, namely, as an individual with Down syndrome as severe as in the most severe trisomie cases (and sorne 2. 7% of patients with Down syndrome are mosaics) 17 or as a phenotypically apparently normal individual who has had two or more children with trisomie Down syndrome. Developmentally, Down syndrome is a complex pleiotropic malformation syndrome representing manifestations specifie to the trisomy and an apparently nonspecific increase of many other anomalies. The specjfic manifestations make it possible for physicians to diagnose Down syndrome with virtual certainty from physieal findings in almost ali cases, even neonatally. Probably ali aneuploidy syndromes are associated with an increased risk for neoplasia. The risk for leukemia in Dawn syndrome (20 or so times greater than the general risk) is weil documented. An appreciable proportion (perhaps more than half) of embryos affected by Dawn syndrome die prenatally. Amniocentesis and the option of induced abortion offer the opportunity of reducing drastically the number of infants born with Dawn syndrome.19 Studies of (spontaneously) aborted embryos and fetuses have shawn that chromosome abnormalities, mostly in the form of triploidy, autosomal trisomies, and the XO state, are the most common causes of prenatal death and malformation. Sorne investigators have estimated that at least one third or as many as half 20 of all fertilized human ova may have a chromosome abnormality. Triploid fetuses have a characteristie phenotype and are rarely born alive. The same seems to be true of the two other commonly observed human trisomies, namely, the trisomy 13 and 18 syndromes. • Supported by Grant GM20130 from the National Institute of General Medical Sciences, USPHS. Paper No. 2096 from the University of Wisconsin Genetics Laboratory. Address reprint requests to John M. Opitz, MD, Rm 109, Genetics Bldg, University of Wisconsin, Madison, WI 53706.
183
For a woman who has had a chlld wlth Down syndrome, the rlsk of havlng another affected chlld la qulte low, ln the vlclnlty of 1% to 2%.
