A male case with double aneuploidy (48,XXY,+21)

The co-occurrence of two numerical chromosomal abnormalities in same individual (double aneuploidy) is relatively rare and the clinical presentations are variable depending on the predominating aneuploidy or a combination effect of both. Furthermore, double aneuploidy involving both autosomal and sex chromosomes is seldom described. We describe a male patient with typical clinical features of Down Syndrome and his karyotype revealed 48,XXY,+21. The phenotypic characteristics of this child have been discussed in the light of the published reports on double aneuploidies of XXY and trisomy 21.     

Double aneuploidy in three Egyptian patients: Down-Turner and Down-Klinefelter syndromes

The co-occurrence of two numerical chromosomal abnormalities in same individual (double aneuploidy) is relatively rare and its clinical presentations are variable depending on the predominating aneuploidy or a combination effect of both. Furthermore, double aneuploidy involving both autosomal and sex chromosomes is seldom described. In this study, we present three patients with double aneuploidy involving chromosome 21 and sex chromosomes. They all had the classical non disjunction trisomy 21; that was associated with monosomy X in two of them and double X in the other. Clinically, they had most of the phenotypic features of Down syndrome as well as variable features characteristic of Turner or Klinefelter syndrome. Cytogenetic studies and fluorescence in situ hybridization (FISH) analysis were carried out for all patients and their parents. The first patient was a male, mosaic with 2 cell lines (45,X/47,XY,+21) by regular banding techniques and had an affected sib with Down syndrome (47,XY,+21). The second was a female, mosaic (46,X,+21/47,XX,+21) where monosomy X was detected only by FISH in 15 percentages of cells, nevertheless, stigmata of Turner syndrome was more obvious in this patient. The third patient had non mosaic double trisomy; Down-Klinefelter (48,XXY,+21) presented with Down syndrome phenotype. Parental karyotypes and FISH studies for these patients were normal with no evidence of mosaicism. In this report, we review the variable clinical presentations among the few reported cases with the same aneuploidy in relation to ours. Also, the proposed mechanisms of double aneuploidy and the occurrence of non-disjunction in more than one family member are discussed. This study emphasizes the importance of molecular cytogenetics studies for more than one tissue in cases with atypical features of characteristic chromosomal aberration syndromes. To our knowledge, this is the first report of double aneuploidy, Down-Turner and Down-Klinefelter syndromes in Egyptian patients.     

Mosaic double aneuploidy: Down syndrome and XYY

Chromosomal abnormalities are seen in nearly 1% of live born infants. We report a 5-year-old boy with the clinical features of Down syndrome, which is the most common human aneuploidy. Cytogenetic analysis showed a mosaicism for a double aneuploidy, Down syndrome and XYY. The karyotype was 47, XY,+21[19]/48, XYY,+21[6]. ish XYY (DXZ1 × 1, DYZ1 × 2). Mosaic double aneuploidies are very rare and features of only one of the aneuploidies may predominate in childhood. Cytogenetic analysis is recommended even if the typical features of a recognized aneuploidy are present so that any associated abnormality may be detected. This will enable early intervention to provide the adequate supportive care and management.     

An infant with Turner-Down aneuploidy and massive capillary hemangioma of the orbit: a case report with review

We report on a case of double aneuploidy involving Down and Turner cell lines in a female child with a massive capillary hemangioma of the left orbit and mild clinical features of Down syndrome. Cytogenetic findings with G-banding revealed mosaicism in her peripheral blood, i.e. mos45,X[48]/47,XX,+21[28]/46,XX[12/47,XXX[12]. Mosaicism of such nature is rare and to our knowledge the present case is the first reported of Turner-Down double aneuploidy mosaicism associated with an orbital capillary hemangioma. An annotated bibliography of earlier reported cases with documented karyotyping is also included.     

Rare Case of Monozygotic Twins Diagnosed With Klinefelter Syndrome During Evaluation for Infertility

Although neither Klinefelter syndrome nor monozygotic twins are particularly rare (1/667 male births and 3–4/1000 live births, respectively), the occurrence of both in the same pregnancy (ie, identical twins with Klinefelter syndrome) is exceedingly rare and has only been reported three times previously in the literature. This report describes the fourth ever reported case of monozygotic twins with Klinefelter syndrome (who presented to our male fertility clinic with failure to conceive) and sheds interesting light on the reproductive concordance observed with this rare clinical entity. To our knowledge, this is the first reported case of monozygotic twins with Klinefelter syndrome that describes the infertility workup and outcomes of microsurgical testicular sperm extraction.Key words: Klinefelter syndrome, Microsurgical testicular sperm extraction, Azoospermia, Sertoli only syndrome, Germ cell aplasiaKlinefelter syndrome, the most common sex chromosome disorder in men, is the clinical result of an additional X chromosome in human males. This syndrome, which affects an estimated 1 in 667 live male births, most commonly manifests as 47,XXY, but may also take the form of 46,XY/47,XXY (Klinefelter mosaicism), 48,XXXY, or 49,XXXXY.¹ Typical clinical manifestations of the syndrome include primary infertility, atrophic testes, hypergonadotropic hypogonadism, gynecomastia, eunuchoidism, and decreased facial and body hair.¹ This condition often goes undiagnosed in prepubertal boys, and even in adult men, despite the physical hallmarks of the syndrome; many cases come to light only during the evaluation of primary male factor infertility. The andrologist, therefore, plays a central role in the diagnosis, work-up, and management of men with Klinefelter syndrome.With an incidence approximately twice that of Klinefelter (3–4 per 1000 live births worldwide),² monozygotic (identical) twinning occurs when one fertilized egg splits and divides into two embryos. Monozygotic twins have been observed with various karyotypic abnormalities, including trisomy 21,³ trisomy 18,⁴ and trisomy 13.⁵ However, the presentation of monozygotic twins with Klinefelter syndrome (a fertilized egg with a 47, XXY karyotype splitting to produce identical embryos with Klinefelter syndrome) is exceedingly rare. In this report, we discuss one case of identical twin brothers diagnosed with Klinefelter syndrome at our fertility clinic (Glickman Urological & Kidney Institute, Cleveland, OH) as part of a work-up for inability to conceive.     

Screening for aneuploidy in twin pregnancies: maternal age- and race-specific risk assessment between 9-14 weeks.

The aim of this study was to calculate the risk for aneuploidy in twin pregnancies between 9-14 weeks utilizing maternal age, race and dizygotic twinning rates. Using previously published risks for aneuploidy in singletons and twins at the time of amniocentesis and at term, we calculated new risk estimates for twins at 9-14 weeks gestation or at the time of chorionic villus sampling. Using these tables, the risk for trisomy 21 in at least one fetus of a twin gestation in a 32-year-old at 9-14 weeks is 1/285 for Whites and for African-Americans. This is equivalent to the risk for trisomy 21 (1/265) in a 35-year-old woman with a singleton at the same gestational age. The risks for trisomies 18 and 13 also follow similar trends. In counseling women with twin pregnancies at the time of first trimester nuchal translucency screening or chorionic villus sampling, it should be noted that the maternal age-related risk for aneuploidy for a 32-year-old is equivalent to that of a 35-year-old woman with a singleton gestation.     

Double trisomy and transmitted pericentric inversion (48,XXY, +21,inv(22)). Interchromosomal effect

A patient is reported, carrier of a double aneuploidy (trisomy 21 and XXY) associated with a pericentric inversion 22 inherited from the mother. The role of this structural rearrangement at the origin of the double aneuploidy is discussed.     

Double autosomal/gonosomal mosaic aneuploidy: study of nondisjunction in two cases with trisomy of chromosome 8

We report cytogenetic and molecular investigations performed in two cases of mosaic trisomy 8 combined with mosaic sex chromosome aneuploidy. In a 35-year-old female, presenting with short stature, gonadal dysgenesis, and a multiple congenital anomalies/mental retardation syndrome typical of trisomy 8, chromosome analysis from peripheral lymphocytes showed the presence of three cell lines, whose karyotypes were 45,X (59.2%), 46,X,+8 (1.2%), and 47,XX,+8 (39.6%), respectively. The same cell lines were found in a skin fibroblast culture, though in different proportions. The second patient, a 9-month-old male with multiple skeletal abnormalities, showed a 47,XY,+8 and a 47,XXY cell line in both peripheral lymphocytes (61.7% and 38.3%, respectively) and skin fibroblasts (92.8% and 7.2%, respectively). To determine the events underlying the origin of these complex karyotypes we performed Southern blot and polymerase chain reaction (PCR) analysis using polymorphic DNA markers from the X chromosome and from chromosome 8. Both supernumerary chromosomes 8, and, in case 2, the two X chromosomes, appeared to be identical, lacking detectable recombination events. We conclude that, in both cases, the most likely mechanism underlying the origin of the mosaic cell lines was formation of a normal zygote, followed by mitotic errors during early divisions.     

A 48,XXY,+21 Down syndrome patient with additional paternal X and maternal 21

Summary The origin of meiotic nondisjunction of the extra chromosomes X and 21 was studied in a patient with the karyotype 48,XXY,+21 using DNA polymorphisms. The extra chromosome X was the result of paternal first meiotic nondisjunction of X and Y. The extra chromosome 21 was derived from the mother. The meiotic error in the mother most probably occurred in meiosis II. Thus, this is a combination caused by the chance occurrence of two independent events.     

Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births

Summary Data were analyzed on the results of 19675 prenatal cytogenetic diagnoses reported to two chromosome registries on women aged 35 or over for whom there was no known cytogenetic risk for a chromosome abnormality except parental age. The expected rates at amniocentesis of 47,+21; 47,+18; 47,+13; XXX; XXY; XYY; and other clinically significant cytogenetic defects by maternal age were obtained from a regression analysis on the observed rates, using a first degree exponential model. After an adjustment for maternal age, these rates were compared with previously estimated rates by maternal age in live births. The rates of 47,+21 at amniocentesis and live birth are approximately parallel, with the latter about 80% of the amniocentesis rates. The rates of 47,+18 at amniocentesis and live birth are approximately parallel, with the live birth rates about 30% of the amniocentesis rates, consistent with high fetal mortality of 47,+18 after amniocentesis. The rates of 47,+13 at amniocentesis indicate an increase in maternal age that is not as marked as thar previously estimated in live births. The rates at amniocentesis for XXX and XXY increase with maternal age, with the rates of XXY almost identical to those estimated previously in live births, suggesting no late fetal mortality of XXY. The rates of XYY show a slight decrease with maternal age also consistent with little late fetal mortality of XYY. No consistent trend with age is seen for the pooled group of other clinically significant defects.     

Klinefelter's syndrome, mosaic 46,XX/46,XY/47,XXY/48,XXXY/48,XXYY: a case report

A 35-year-old male was investigated for primary infertility. Clinical examination showed an intelligent man with normal facial appearance and moustache and small firm testes. Testicular histopathology revealed marked atrophy of the testes with no spermatogenesis and absence of germ cells. Hormonal profile showed elevated levels of FSH,LH and low levels of testosterone. Chromosome analysis from whole blood culture showed cells with 46,XX/46,XY/47,XXY/48,XXXY/48,XXYY mosaicism. The predominant cell line was 47,XXY (87.86%). 46,XY/47,XXY mosaicism is not uncommon. However, mosaicism of multiple sex chromosome aneuploidy is rarely observed. This is the first report of mosaicism in Klinefelter's syndrome variant with five cell lines.     

Cell-cycle kinetics of cell lines from patients with chromosomal mosaicism

Lymphocyte cultures from five patients with chromosomal mosaicism (two 47,XY,+21/46,XY, one 47,XX,+21/46,XX, one 45,X/46,XX, and one 47,XXY/46,XY) were studied using sister chromatid differential staining technique for cell kinetic evaluation. Aneuploid and normal cell lines were compared to identify changes in cellular proliferation in vitro that could be related to cellular selective advantage and cell-line-proportion changes occurring with age. Comparison of the percentage of cells in different cell generations in 48, 72, and 96 h-cultures shows no differences between the aneuploid and normal cell lines indicating that cell-cycle kinetics is similar in these cells in vitro.     

Dentition of a 48,XYY,+21 male

Summary Although the dentition of a 48,XYY,+21 male showed some typical features of Down's syndrome, metric analysis indicated a marked increase in tooth size particularly for early developing teeth. The extra Y chromosome can influence phenotypic expression, overcoming the superimposed effects of the additional 21 chromosome.     

Abnormalities of human sex chromosomes

Summary The cytogenetic study of a pair of identical, mentally-retarded twins with the chromosome complement 48,XXXY is reported, along with extensive clinical and endocrinological studies of one twin.The genetic and clinical features of 30 reported 48,XXXY individuals were summarized and compared to those of 47,XXY and 49,XXXXY individuals. For 47,XXY the mean maternal age clearly is increased; for 48,XXXY it appears definitely but only slightly increased; and for 49,XXXXY it may not be increased at all. Developmental defects, similar in type, appear to be progressively more marked when an additional 1, 2, or 3 X chromosomes are added to the normal male chromosome complement. 47,XXY individuals may be either normal in intelligence or mentally retarded, whereas severe mental retardation has been present in all those with the complements 48,XXXY and 49,XXXXY.The interesting suggestion of increased twining associated with poly-X male complements is noted.

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Zusammenfassung Die cytogenetische Untersuchung eines Paares eineiiger, geistig zurückgebliebener Zwillinge mit dem Chromosomenstatus 48,XXXY wird dargestellt; bei dem einen Paarling konnten außerdem ausgedehnte klinische und endokrinologische Studien durchgeführt werden.Außerdem wurden die genetischen und klinischen Merkmale der 30 bekannten Fälle mit 48,XXXY dargestellt und mit denen von Patienten mit 47,XXY und mit 49,XXXXY verglichen. Bei Fällen mit 47,XXY ist das mütterliche Alter deutlich erhöht; bei 48,XXXY ist es eindeutig, aber nur leicht erhöht; es sieht so aus, als ob es für 49,XXXXY überhaupt nicht erhöht wäre. Defekte der Entwicklung, die dem Typ nach ähnlich sind, scheinen dem Ausmaß nach desto mehr ausgeprägt zu sein, je mehr X-Chromosomen zusätzlich bei dem normalen männlichen Chromosomensatz vorhanden sind. 47,XXY Individuen können entweder schwachsinnig sein oder eine normale Intelligenz haben; dagegen zeigten alle Fälle mit 48,XXXY und 49,XXXXY einen schweren Schwachsinn.Es wird die interessante Frage aufgeworfen, ob die Zwillingshäufigkeit bei Poly X-Männern erhöht ist.

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Research supported by grants HD 04134, HL 09011, RR-47, AM-11105, and TIAM 53950-11 from the National Institutes of Health.     

Aneuploidy in human spermatozoa

We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2× disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes.     

Acute leukaemia and the same chromosome abnormality in monozygotic twins

Summary Monozygotic twin girls, both of whom had acute undifferentiated leukaemia and a 47,XX,+19 karyotype, are described. The case is discussed in terms of childhood leukaemia and the hypothesis that a single transformation event in utero may be responsible for leukaemia in twins.     

Coincident maternal meiotic nondisjunction of chromosomes X and 21 without evidence of autosomal aysnapsis

Summary A family in which the proband showed phenotypic signs of both the Turner and Down syndromes was studied cytogenetically and with restriction fragment length polymorphisms. The proband's karyotype was 46,X,+21, showing double aneuploidy without any signs of mosaicism. The single X and one chromosome 21 were of paternal origin while two chromosomes 21 were of maternal origin. The nondisjunction of chromosome 21 took place in maternal meiosis II. If it is assumed that the absence of mosaicism renders postzygotic mitotic loss of the X chromosome unlikely, then the X chromosome would have been lost in maternal meiosis I or II. Recombination had occurred between the nondisjoined chromosomes 21. We conclude that double nondisjunction took place in one parent and that asynapsis was not a prerequisite for the autosomal nondisjunction.     

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.     

植物非整倍体研究进展

非整倍体(aneuploid)是指相对于正常个体(euploid)的染色体组增加、减少一条或若干条染色体的生物个体。由于非整倍体个体存在基因剂量效应的不平衡性(gene-dosage imbalance),非整倍体个体往往会表现严重的表型缺陷(aneuploid syndrom),如发育迟缓,个体矮小,难以繁殖后代等。在人类中,最为典型的例子为导致新生儿智力缺陷的唐氏综合症,由额外的一个21号染色体拷贝(部分拷贝)引起。此外,大多数癌细胞类型表型为严重的非整倍体。在大多情况下,非整倍体对于动物及人类是致命的,而植物对于非整倍体则往往表现出较强的耐受力,特别是在异源多倍体植物中。植物非整倍体对于植物的遗传、育种研究有重要意义,在基因及分子标记的物理位置确定,基因转移,连锁群与染色体的对应关系的确立上具有无可比拟的优势。该文综述了近些年来有关植物非整倍体研究的结果,介绍了非整倍体的几种重要成因和有关非整倍体鉴定手段的变迁,阐述了植物非整倍体对个体表型、基因表达以及表观遗传方面的影响,重点讨论了非整倍体在植物进化、基因组序列测定以及遗传改良方面的潜在作用。同时,探讨了植物非整倍体研究的新思路,以及利用非整倍体促进相关植物遗传改良、育种研究的新方法。