Chromosomal Abnormalities and Their Relation to Disease

When human chromosome anomalies were first described in 1959, it appeared that specific abnormalities might be correlated with specific syndromes. Mongolism and the D and E syndromes are examples of specific syndromes associated with the presence of an extra autosome. Klinefelter''s syndrome may be associated with a variety of different sex chromosome anomalies including XXY, XXYY, XXXY and XXXXY. The lastnamed variant is the only one that frequently presents features distinguishing it from the others. An XO sex chromosome complex is found in many women with gonadal dysgenesis. However, a variety of mosaicisms have been described in association with this condition, including XO/XX, XO/XXX, XO/XX/XXX, XO/XY and XO/XYY. Extra X chromosomes in phenotypical females do not seem to impair fertility or be consistently associated with congenital anomalies. Two families are described in which chromosome anomalies were found, but the association with defects was irregular. In one family the abnormality involved one of the number 16 chromosomes and in the other it involved one of the small acrocentric chromosomes.     

Mosaic triple X syndrome in a female with primary amenorrhea

BACKGROUND:

Turner''s syndrome is the most common chromosomal abnormality in females, affecting 1 in 2,500 live female births. It is a result of absence of an X chromosome or the presence of a structurally abnormal X chromosome. Its most consistent clinical features are short stature and ovarian failure.

AIM:

The aim of the study was to report a rare case of mosaic triple X syndrome in a female with primary amenorrhea.

MATERIALS AND METHODS:

The chromosomal analysis using GTG banding was carried out, which revealed a mosaicism with 45,XO/47,XXX chromosomal constitution. Fluorescent in situ hybridization was also carried out to further confirm the observation made in the study.

CONCLUSION:

The physical features presented by the female could be due to the 45,XO/47,XXX mosaicism and the karyotype analysis was consistent with the diagnosis and clinical symptoms. Triple X mosaicism was confirmed with conventional and molecular cytogenetic analysis.     

Chromosome studies in a neonatal population

The results of chromosome studies on 6809 consecutive newborn infants are presented. One hundred and one (1.48%) were heterozygous for a marker chromosome, the significance of which is not at present clear. Twenty-two infants (0.32%) had a major chromosome abnormality. Only six of these infants (0.09%) had a clinically recognizable abnormal phenotype (Down''s syndrome). The occult chromosome abnormalities included five sex chromosome abnormalities (one 47,XYY; two 47,XXY; two 47,XXX) and 11 balanced translocations. Seven of these were t(DqDq) and four were reciprocal translocations. The results of the present survey are combined with four other similar neonatal surveys in which a total of 23,328 newborns have been screened. Of these, 117 (0.5%; range 0.65-0.32%) had major chromosome abnormalities. The majority of these (72.7%) would not have been detected at birth without chromosome studies, an important fact in the context of prenatal diagnosis of chromosome disease and the early ascertainment of high-risk families.     

Karyotype and meiotic mechanism in Muga silkmoths,Antheraea compta Roth. and A. assamensis (Helf.) (Lepidoptera: Saturniidae)

The chromosome number in males of Antheraea compta (Wild) and A. assamensis (semi-domesticated) is 30, while in females it is 30 (XY) in A. compta and 29 (XO) in A. assamensis, the latter concomitantly does not reveal sex chromatin in interphase nuclei of both somatic and germ cells. This confirms that the Y chromosome, which forms the sex chromatin in females of A. compta, has been lost in the other species. Meiosis in males shows discrete chiasmata while in females of both species it is achiasmatic. Meiotic details of the species are given and the evolutionary inter-relationship is discussed.     

The Sex Chromosomes in Evolution and in Medicine

The recent emergence of human cytogenetics has a firm foundation in studies on other forms of life. Historical highlights are Mendel''s studies on the garden pea (published in 1865 but lost in an obscure journal until 1900); formulation of cytogenic postulates by Sutton and Boveri (1902-1903); Bridges'' discovery of chromosome abnormalities in Drosophila (1916), followed by numerous similar studies in plants; and demonstration of the chromosomal basis of the syndromes of Down, Klinefelter and Turner in man (1959).The sex chromosomes (XX and XY) evolved from a pair of undifferentiated autosomes of a premammalian ancestor, the X chromosome changing less than the Y as they evolved. Eleven numerical abnormalities of the sex chromosomes are known in man, and knowledge of their effects on development is accumulating. The abnormal complexes range in size from the XO error of Turner''s syndrome to the XXXXY error of a variant of Klinefelter''s syndrome.     

Studying Early Lethality of 45,XO (Turner's Syndrome) Embryos Using Human Embryonic Stem Cells

Turner''s syndrome (caused by monosomy of chromosome X) is one of the most common chromosomal abnormalities in females. Although 3% of all pregnancies start with XO embryos, 99% of these pregnancies terminate spontaneously during the first trimester. The common genetic explanation for the early lethality of monosomy X embryos, as well as the phenotype of surviving individuals is haploinsufficiency of pseudoautosomal genes on the X chromosome. Another possible mechanism is null expression of imprinted genes on the X chromosome due to the loss of the expressed allele. In contrast to humans, XO mice are viable, and fertile. Thus, neither cells from patients nor mouse models can be used in order to study the cause of early lethality in XO embryos. Human embryonic stem cells (HESCs) can differentiate in culture into cells from the three embryonic germ layers as well as into extraembryonic cells. These cells have been shown to have great value in modeling human developmental genetic disorders. In order to study the reasons for the early lethality of 45,XO embryos we have isolated HESCs that have spontaneously lost one of their sex chromosomes. To examine the possibility that imprinted genes on the X chromosome play a role in the phenotype of XO embryos, we have identified genes that were no longer expressed in the mutant cells. None of these genes showed a monoallelic expression in XX cells, implying that imprinting is not playing a major role in the phenotype of XO embryos. To suggest an explanation for the embryonic lethality caused by monosomy X, we have differentiated the XO HESCs in vitro an in vivo. DNA microarray analysis of the differentiated cells enabled us to compare the expression of tissue specific genes in XO and XX cells. The tissue that showed the most significant differences between the clones was the placenta. Many placental genes are expressed at much higher levels in XX cells in compare to XO cells. Thus, we suggest that abnormal placental differentiation as a result of haploinsufficiency of X-linked pseudoautosomal genes causes the early lethality in XO human embryos.     

Karyological study of human spontaneous and medical abortions

80 spontaneous abortions (40 at 6-12 weeks and 40 at 13-32 weeks of pregnancy) and 50 induced abortions (49 at 6-12 weeks and 1 at 18 weeks) were karyotyped. Among spontaneous abortions of the first trimester were found 14 different types of chromosome anomalies. The chromosome complex 48,XY, D+, F+, has not yet been described in the literature and belongs to the eempty embryonic sac 1.0:1.5 cm with a weakly developed trophoblast. Among late-term spontaneous abortions no chromosome anomalies were found. An aberrant karyotype of a 7-8 week induced abortion was revealed as 46, XX/47, XXX (5% of the nuclei with double sex chromatin and 47% with single sex chromatin). Normal karyotypes were distributed according to sex chromosome complex as follows: spontaneous abortions of 6-12 weeks, 18(XY), 8(XX); spontaneous abortions 13-32 weeks, 19(XY), 21(XX); induced abortions, 16(XY), 32(XX). The data revealed a random character in the series of investigations. The absence of the XO monosomies was noted.     

Incidence of major chromosome aberrations in 12,319 newborn infants in Tokyo

Summary In order to ascertain the frequency of chromosome aberrations among newborn infants in Japan, a chromosome survey of a large number of newborn infants is in progress. A consecutive series of 12,319 newborn babies, 6382 male and 5937 female, have been screened for clinical manifestations of autosomal aberrations and for sex chromatin and sex chromosome aberrations. Chromosome studies were carried out on 694 infants with suspected chromosome aberrations. The clinically abnormal infants were screened by conventional staining, and banding techniques have been used in the part of the study performed since 1974. Of the clincally abnormal infants, 25 had abnormal karyotypes, including two males with a 47,XXY complement, one female with a 45,X complement, three male infants with a 47,XYY complement, two with trisomy 13 syndrome, three with trisomy 18 (including one case of mosaicism), eleven with Down's syndrome (including one case of mosaicism), one with B5p partial trisomy, one with cri-du-chat syndrome, and one with Y/D translocation. The overall results are comparable to those of previous population cytogenetic studies only in the autosomal trisomies and sex chromosome abnormalities and in that the observed frequencies were comparable to those found in studies in Caucasians.To whom offprint requests should be sent     

Aberrant chromosomal sex-determining mechanisms in mammals, with special reference to species with XY females

Both mouse and man have the common XX/XY sex chromosome mechanism. The X chromosome is of original size (5-6% of female haploid set) and the Y is one of the smallest chromosomes of the complement. But there are species, belonging to a variety of orders, with composite sex chromosomes and multiple sex chromosome systems: XX/XY1Y2 and X1X1X2X2/X1X2Y. The original X or the Y, respectively, have been translocated on to an autosome. The sex chromosomes of these species segregate regularly at meiosis; two kinds of sperm and one kind of egg are produced and the sex ratio is the normal 1:1. Individuals with deviating sex chromosome constitutions (XXY, XYY, XO or XXX) have been found in at least 16 mammalian species other than man. The phenotypic manifestations of these deviating constitutions are briefly discussed. In the dog, pig, goat and mouse exceptional XX males and in the horse XY females attract attention. Certain rodents have complicated mechanisms for sex determination: Ellobius lutescens and Tokudaia osimensis have XO males and females. Both sexes of Microtus oregoni are gonosomic mosaics (male OY/XY, female XX/XO). The wood lemming, Myopus schisticolor, the collared lemming, Dirostonyx torquatus, and perhaps also one or two species of the genus Akodon have XX and XY females and XY males. The XX, X*X and X*Y females of Myopus and Dicrostonyx are discussed in some detail. The wood lemming has proved to be a favourable natural model for studies in sex determination, because a large variety of sex chromosome aneuploids are born relatively frequently. The dosage model for sex determination is not supported by the wood lemming data. For male development, genes on both the X and the Y chromosomes are necessary.     

Cryptic Subtelomeric Rearrangements and X Chromosome Mosaicism: A Study of 565 Apparently Normal Individuals with Fluorescent In Situ Hybridization

Five percent of patients with unexplained mental retardation have been attributed to cryptic unbalanced subtelomeric rearrangements. Half of these affected individuals have inherited the rearrangement from a parent who is a carrier for a balanced translocation. However, the frequency of carriers for cryptic balanced translocations is unknown. To determine this frequency, 565 phenotypically normal unrelated individuals were examined for balanced subtelomeric rearrangements using Fluorescent In Situ hybridization (FISH) probes for all subtelomere regions. While no balanced subtelomeric rearrangements were identified, three females in this study were determined to be mosaic for the X chromosome. Mosaicism for XXX cell lines were observed in the lymphocyte cultures of 3 in 379 women (0.8%), which is a higher frequency than the 1 in 1000 (0.1%) reported for sex chromosome aneuploidies. Our findings suggest that numerical abnormalities of the X chromosome are more common in females than previously reported. Based on a review of the literature, the incidence of cryptic translocation carriers is estimated to be approximately 1/8,000, more than ten-fold higher than the frequency of visible reciprocal translocations.     

Function of the sex chromosomes in mammalian fertility

The sex chromosomes play a highly specialized role in germ cell development in mammals, being enriched in genes expressed in the testis and ovary. Sex chromosome abnormalities (e.g., Klinefelter [XXY] and Turner [XO] syndrome) constitute the largest class of chromosome abnormalities and the commonest genetic cause of infertility in humans. Understanding how sex-gene expression is regulated is therefore critical to our understanding of human reproduction. Here, we describe how the expression of sex-linked genes varies during germ cell development; in females, the inactive X chromosome is reactivated before meiosis, whereas in males the X and Y chromosomes are inactivated at this stage. We discuss the epigenetics of sex chromosome inactivation and how this process has influenced the gene content of the mammalian X and Y chromosomes. We also present working models for how perturbations in sex chromosome inactivation or reactivation result in subfertility in the major classes of sex chromosome abnormalities.     

The XXXXY Chromosome Anomaly: Report of Three New Cases and Review of 30 Cases from the Literature

The majority of abnormal sex chromosome complexes in the male have been considered to be variants of Klinefelter''s syndrome but an exception should probably be made in the case of the XXXXY individual who has distinctive phenotypic features. Clinical, radiological and cytological data on three new cases of XXXXY syndrome are presented and 30 cases from the literature are reviewed. In many cases the published clinical and radiological data were supplemented and re-evaluated. Mental retardation, usually severe, was present in all cases. Typical facies was observed in many; clinodactyly of the fifth finger was seen in nearly all.Radiological examination revealed abnormalities in the elbows and wrists in all the 19 personally evaluated cases, and other skeletal anomalies were very frequent. Cryptorchism is very common and absence of Leydig''s cells may differentiate the XXXXY chromosome anomaly from polysomic variants of Klinefelter''s syndrome. The relationship of this syndrome to Klinefelter''s syndrome and to Down''s syndrome is discussed.     

Antenatal Diagnosis of an XXX Female: A Dilemma for Genetic Counseling

This report describes the first antenatal diagnosis of an XXX female. Over 150 postnatal cases of XXX females have been described. There is no specific phenotype associated with the sex chromosome abnormality and most such persons are fertile. The frequency of XXX females in mental institutions is 3.9 per 1,000 female subjects whereas the frequency in consecutive newborn infants is 1.1 per 1,000 newborns. Chi-square analysis shows this difference cannot be due to chance. On the other hand, data from consecutive newborn studies suggest that intellectual development in XXX newborns is within normal range. Available evidence favors normal development in XXX female infants although the risk for developmental disabilities may be higher for the XXX than for the XX infant.     

Sex chromosome pairing and sex chromatin bodies in W-Z translocation strains of Ephestia kuehniella (Lepidoptera).

Structure and pairing behavior of sex chromosomes in females of four T(W;Z) lines of the Mediterranean flour moth, Ephestia kuehniella, were investigated using light and electron microscopic techniques and compared with the wild type. In light microscopic preparations of pachytene oocytes of wild-type females, the WZ bivalent stands out by its heterochromatic W chromosome strand. In T(W;Z) females, the part of the Z chromosome that was translated onto the W chromosome was demonstrated as a distal segment of the neo-W chromosome, displaying a characteristic non-W chromosomal chromomere-interchromomere pattern. This segment is homologously paired with the corresponding part of a complete Z chromosome. In contrast with the single ball of heterochromatic W chromatin in highly polyploid somatic nuclei of wild-type females, the translocation causes the formation of deformed or fragmented W chromatin bodies, probably owing to opposing tendencies of the Z and W chromosomal parts of the neo-W. In electron microscopic preparations of microspread nuclei, sex chromosome bivalents were identified by the remnants of electron-dense heterochromatin tangles decorating the W chromosome axis, by the different lengths of the Z and W chromosome axes, and by incomplete pairing. No heterochromatin tangles were attached to the translocated segment of the Z chromosome at one end of the neo-W chromosome. Because of the homologous pairing between the translocation and the structurally normal Z chromosome, pairing affinity of sex chromosomes in T(W;Z) females is significantly improved. Specific differences observed among T(W;Z)1-4 translocations are probably due to the different lengths of the translocated segments.     

Relative DNA content in lymphocytes and buccal mucosa of patients with sex chromosomal anomalies

Cytophotometric estimation of DNA values from human buccal mucosa and lymphocyte culture nuclei shows a difference related to different X chromosomal abnormalities, namely, del X, XO, XXX and XXY. The values in the buccal mucosa in all cases except XXX were similar to the normal XX and XY. In lymphocytes nuclei, however, a steady increase in the DNA content at a significant level could be related to an increase in the number of X chromosomes. The similarity in the DNA values of normal XX and XY controls may be attributed to asynchrony in the replication patterns of X and Y chromosomes.     

Sex chromosome aneuploidy in wild small mammals

We describe four examples of the XO condition in wild mammals. One XO house mouse (Mus musculus domesticus) was caught in nature and subsequently gave birth to three litters in captivity, confirming for wild mice the fertility observed for XO laboratory mice. Two other XO house mice were produced from laboratory crosses of wild-caught mice. An immature XO common shrew (Sorex araneus) was caught in nature; this appears to be the first XO recorded in the order Insectivora. We collected data from researchers studying chromosome variation in house mice and common shrews and found an overall incidence of 0.22% sex chromosome aneuploidy in 4608 mice and 0.05% in 6625 shrews. The discrepancy related to a much higher frequency of XO's in mice than shrews. Single XXY and XYY shrews and an XXX mouse have been recorded in nature.     

Les formules gonosomiques dites aberrantes chez les Mammifères Euthériens

The chromosome complement of the sloth Choloepus hoffmanni Peters has been investigated in mitosis and also in male meiosis. The karyotype for both males and females is characterized by a diploid number of 49 chromosomes. In the male the Y-material is translocated on an autosome but the meiotic behavior of the gonosomes is normal and therefore the sex determining mechanism may be normal too, despite the translocation. The females have an XO sex-chromosome constitution in somatic cells. An hypothesis, based on a slight deviation of a normal phenomenon is proposed to explain as regular such a formula in normal animals. — Relating to these conclusions, other known deviations of the standard XX/XY sex chromosome constitution in placental mammals are discussed (multiple sexchromosomes, composite gonosomes and XO female formula). The general conclusion is that despite an apparent variability of sex chromosome morphology, all placental mammals seem to retain a truly XX/XY sex constitution.     

Le risque chromosomique pour un patient porteur d'une translocation t(X;2) concerne non seulement la translocation mais aussi la ségrégation XY

In men, translocations involving sex chromosomes usually result in azoospermia or sometimes oligospermia. We report the case of a man with oligospermia with a 46,Y,t(X;2)(p21;p25.3) translocation and the specific modalities of management of the couple before ICSI. After genetic counselling, we proposed spermatozoa chromosomal analysis using FISH to evaluate the mode of segregation of the translocation and the risk for the embryo and descendants. This study showed that 34% of spermatozoa were normal or balanced for the chromosomes studied, and 66% of spermatozoa presented a chromosome imbalance related to the translocation and/or involving X and Y chromosome non-disjuction. In view of this result, we decided to perform another FISH analysis to define the increased risk related to the non-disjunction of X and Y chromosomes. Only 60% of 1,000 spermatozoa were normal for X and Y. The chromosome risk for the offspring is not limited to the translocation, as the risk of Klinefelter and Turner syndrome is also increased. In view of these results and the woman's age (42 years old), we advised the couple against ICSI at another genetic counselling session. This case illustrates the value of spermatozoa FISH analysis to evaluate the consequences of a translocation on spermatogenesis. The study should not be limited to the translocation alone, but should also evaluate anomalies of non-disjunction of sex chromosomes that are frequent during normal spermatogenesis, but the risk increases in the case of translocations, especially involving the sex chromosomes.     

Chromosome Analysis before Birth and its Value in Genetic Counselling

Chromosome analysis of amniotic cell cultures was achieved in 29 out of 30 consecutive patients who were referred for genetic counselling during pregnancy. Amniocentesis was performed without any apparent untoward maternal or fetal complication. The only pregnancy terminated was that of a carrier of X-linked granulomatous disease, in whom the amniotic cells showed that the fetus was male and also had Down''s syndrome (trisomy G). Chromosome analysis in the remaining 28 patients showed normal karyotypes. The interval between amniocentesis and a definitive karyotype varied from 7 to 31 (average 18·4) days.The reliability of chromosome analysis from amniotic cell culture and of fetal sex determination by means of the sex chromatin and Y-fluorescence techniques was studied further in amniotic fluid from cases of therapeutic abortion and of rhesus incompatibility. The fetal sex was correctly determined in all cases. It is concluded that antenatal diagnosis of genetic disease by amniocentesis now permits a more practical approach to genetic counselling.