Tall stature, insulin resistance, and disturbed behavior in a girl with the triple X syndrome harboring three SHOX genes: offspring of a father with mosaic Klinefelter syndrome but with two maternal X chromosomes

AIMS: To describe the tall stature and its possible underlying mechanism in a Caucasian girl (age 12 years and 10 months) with 46,XX (28%)/47,XXX (72%) mosaicism and to identify the parental origin of her extra X chromosome. METHODS: The fasting glucose-to-insulin ratio was studied. The karyotypes of the girl and her parents as well as the presence of SHOX copies and the parental origin of her extra X chromosome were assessed. RESULTS: Clinical examination revealed a tall stature and severe acne, and endocrinological/metabolic assessment revealed insulin resistance. Fluorescence in situ hybridization cytogenetic analysis depicted the presence of three SHOX genes in the 47,XXX cell line of the patient. Karyotyping of her parents showed a normal 46,XX karyotype in the mother and 46,XY(93%)/47,XXY(7%) Klinefelter mosaicism in the father. However, DNA analysis unequivocally showed maternal origin of the extra X chromosome of the patient. CONCLUSIONS: This report suggests that SHOX gene triplication may produce a tall stature, even in the presence of preserved ovarian function. X triplication might predispose to insulin resistance and behavioral disorders.     

Triple X Egyptian woman and a Down's syndrome offspring

The 47, XXX karyotype (triple X) has a frequency of 1 in 1000 female newborns. However, this karyotype is not usually suspected at birth or childhood. Female patients with a sex chromosome abnormality may be fertile. In patients with a 47, XXX cell line there appears to be an increased risk of a cytogenetically abnormal child but the extent of this risk cannot yet be determined; it is probably lower in the non-mosaic 47, XXX patient than the mosaic 46, XX/47, XXX one. We describe a new rare case of triple X woman and a Down''s syndrome offspring. The patient is 26 years of age. She is a housewife, her height is 160 cm and weight is 68 kg and her physical features and mentality are normal. She has had one pregnancy at the age of 25 years resulted in a girl with Down''s syndrome. The child had 47 chromosomes with trisomy 21 (47, XX, +21) Figure 1. The patient also has 47 chromosomes with a triple X karyotype (47, XX, +X) Figure 2. The patient''s husband (27 years old) is physically and mentally normal. He has 46 chromosomes with a normal XY karyotype (46, XY). There are neither Consanguinity between her parent''s nor she and her husband.Open in a separate windowFigure 1Karyotype 47, XX + 21 of the daughter of Triple X syndromeOpen in a separate windowFigure 2Karyptype 47, XX + X of the Down syndrome''s mother     

Case report: a successful pregnancy outcome in a patient with non-mosaic Turner syndrome (45, X) via in vitro fertilization

We describe a successful pregnancy outcome in a patient with non-mosaic Turner syndrome (45, X) via in vitro fertilization. The patient achieved a second pregnancy at 35 years of age. The her blood lymphocyte karyotype was examined by G-band and FISH. Furthermore, cumulus cells and her elbow skin cells were evaluated via FISH. Non-mosaic Turner syndrome was determined by G-banding [100 % (50/50) 45, X]. Lymphocytes were shown as 478/500 (95.6 %) cells of X sex chromosome signal, 15/500 (3.0 %) cells of XXX signal, and 7/500 (1.4 %) cells of XX signal. The cumulus cells were mosaic: 152/260 (58.5 %) were X; 84/260 (32.3 %) were XXX, 20/260 (7.7 %) were XX, and 4/260 (1.5 %) were XY. Moreover, skin cells included a mosaic karyotype [47, XXX(29)/46, XX(1)]. We conclude that the collection of a large number of blood lymphocytes can reveal different mosaic patterns (X, XX and XXX) by FISH in spite of non-mosaic Turner syndrome.     

Expression of folate-sensitive fragile sites in lymphocyte chromosomes

Summary The expression of folate-sensitive fragile sites (FS) was analyzed using MTX as a fragility inducer in seven normal subjects [four unrelated persons and three members of one family (father, mother, and son)]; a woman heterozygous for fra Xq27.3 with a 47,XXX karyotype; and her son, affected by the fra-X syndrome. The mean expression of chromosome lesions (CL) other than Xq27.3 was 70.1% (686CL in 978 metaphases), and the coincidence between CL and FS was 68.9%. We propose six new c-fra sites: bands 4q33 and 11q22 because they were found in two members of the same family; band 13q32 because it had a frequency of expression of 3% of metaphases; and bands 3p13, 8q21, and Xq21 because they were observed in four of the nine individuals studied.     

Effect of ftorafur and 5-fluorouracil on the chromosomes of human tumor cell cultures]

The effect of two antitumour drugs, ftorafur (Ft) and 5-fluorouracil (5-FU) on chromosomes of human tumour cells (strain CA-1) was studied in vitro. Since no data on the karyotype of this tumour strain had been published, the chromosome set of the model was investigated at first. Significant quantitative and structural divergence from the normal human male karyotype were observed. Steam line cells contained 47-49 chromosomes, including 9 permanent markers. No Y-chromosome was revealed. Ft and 5-FU hardly injured the chromosomes of CA-1 cells; the level of aberrant metaphases reached 94%. Chromatid deletions and gaps formed the major part of drug-induced cytogenetic abnormalities.     

46,X,i(Xq)/47,XX,+13 mosaicism

A 10-year-old girl with short stature and other features of Turner's syndrome was found to be a mosaic consisting of 46,X,i(Xq) and 47,XX,+13 cell lines, a hitherto undescribed situation. She had none of the clinical features of trisomy 13 syndrome, with a possible exception of postaxial polydactyly of the left foot. Her PHA-stimulated blood lymphocytes and EB virus-transformed B lymphocytes both revealed the Xi(Xq)/XX,+13 mosaicism, while her skin fibroblasts showed an exclusively 46,X,i(Xq) karyotype. Studies using Q-and R-banding heteromorphisms as markers indicated that the patient started as a 13 trisomic zygote resulting from a maternal meiotic error, followed by the loss of chromosome 13 at an early mitotic division. C-banding analysis revealed two C banding blocks in the iso X chromosome, an indication that the chromosome was dicentric. BrdU-Hoechst-Giemsa analysis revealed that the iso X chromosome was late-replicating with both its arms either synchronously or asynchronously replicating. The iso X chromosome was thus designated as idic (Xq)(p11:p11). In view of the presence of the XX cell line, it was concluded that the patient started as an XX,+13 zygote, followed by two mitotic events, the loss of a chromosome 13 and the formation of the iso X chromosome, occurring either simultaneously or in succession.     

Transplantation of bone marrow with constitutional chromosomal anomalies. Cytogenetic studies and clinical implications

We report on two cases of transplantation of bone marrow with constitutional chromosomal anomalies. A female patient with acute myelocytic leukemia (FAB, M 3) in first complete remission received a bone marrow graft from her sister with the karyotype 47 XXX (triple-X-syndrome). A male patient with Ph-positive CML and a constitutional Robertsonian t(14; 15) received HLA and MLC loci compatible bone marrow from his sister who was also a carrier of the Robertsonian t(14; 15). Our findings indicate that transplantation of marrow from donors with balanced chromosomal translocation is possible, although no conclusion can be made regarding long term results as both recipients died early from infectious complications.     

Balanced and unbalanced pericentric inversion of a chromosome 14

Summary Three males with a 46,XX karyotype are described. In two of them, evidence of a Y-containing line was found. In the first case, 1 of 500 lymphocyte metaphases was 47,XXY. In the second, 1 of 400 oral mucosa cells contained a Y body. The proportion of low-grade XX/XXY mosaics found among XX males now stands at about 17%.     

Analysis of chromosomal equipment in spermatozoa of a 46,XY/47,XY/+8 male by means of multicolour fluorescent in situ hybridization: confirmation of a mosaicism and evaluation of risk for offspring

Trisomy 8 is generally associated with chromosomal mosaicism and occurs de novo, with relatively well-defined clinical manifestations, ranging from minimal effects to severe malformations. Mosaicism is often difficult to ascertain and the confirmation of diagnosis requires several chromosomal investigations on a variety of tissues. We present a case of mosaic trisomy 8 fortuitously found in a healthy 30-year-old man during a cytogenetic investigation for several spontaneous abortions: 8% of the lymphocyte metaphases showed a 47,XY,+8 karyotype. Fluorescent in situ hybridization (FISH) with the probes pJM.128 and L1.84 was performed on decondensed interphase spermatozoa. Of the 25 000 analysed cells, 398 spermatozoa (1.59%) exhibited a hybridization pattern compatible with a chromosome 8 disomy; the frequency was higher than in either sperm control populations (0.17% and 0.21%). This result is in agreement with the existence of trisomy 8 mosaicism in the gonads and germ cells. FISH on decondensed interphase spermatozoa spreads is thus an easy non-invasive procedure that can be used to complement mosaicism diagnosis in tissue other than blood. Moreover, FISH provides interesting data for characterizing the risk for offspring. Received: 11 July 1996 / Revised: 26 August 1996     

Cell cycles in human diploid and aneuploid strains

Summary Autoradiographic investigation of the cell cycle of 12 diploid and 12 abnormal human fibroblast strains was carried out. Two cell strains (trisomy 7 and monosomy 21) derived from spontaneous abortuses showed prolongation of the G₂ period accompanied by the shortening of the S period. Other cytogenetically abnormal embryonic strains (trisomy 9, 14 and triploidy) did not deviate from the diploid pattern. Three cell strains (LHC-1-70, LHC-6-70, LHC-411) derived from the patients with karyotypes 47,XXX, 47,XY,+18 and 46,XX,5p—respectivly had embryonic types of proliferation with a short G₂ period. In two other strains from the patients with Down's syndrom the G₂ period was prolonged. There was no statistically significant difference in the parameters of the cell cycle between the control and the strains derived from a patient with Klinefelter syndrom and from a male patient with karyotype 46,XX. The modificatory effect of the chromosomal abnormalities on the parameters of cell cycle is discussed.

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Zusammenfassung Der Zellcyclus von 12 normal diploiden und 12 abnormen menschlichen Fibroblasten-Zellinien wurde untersucht. Zwei Zellinien (Trisomie 7 und Monosomie 21) zeigten eine Verlängerung der G₂-Phase und eine Verkürzung der S-Phase. Zellinien (Trisomie 9, 14 und Triploidie) wichen nicht von der Norm ab. Drei Zellinien (47,XXX; 47,XY,+18; 46,XX,5p-) zeigten eine Verkürzung von G₂. G₂ war dagegen verlängert bei zwei Zellinien von Down-Syndrom. Keine Abweichung fand sich bei einem Klinefelter-Patienten und einem männlichen Probanden mit 46,XX.

     

A de novo reciprocal t(2;18) translocation with regular trisomy 21

A 4-year-old girl with Down syndrome exhibited an autosomal translocation t(2;18) in addition to trisomy 21. An evaluation of GTG-banded metaphases revealed the karyotype 47,XX,t(2;18),21 that was confirmed by using fluorescent in situ hybridization (FISH) probes. This case represents a very rare coincidence of an autosomal aneuploidy and a structural rearrangement. Her parents showed a normal chromosome complement. The translocation must have been an apparently "balanced" one as the proband presented with typical features of Down syndrome alone. The mechanism of origin of this rearrangement along with a nondisjunctional error and its significance are discussed.     

Prenatal diagnosis of trisomy 9.

A male karyotype with trisomy 9 (47,XY,+9) was identified in amniotic fluid cells from a 40-year-old pregnant woman. After termination of the pregnancy by saline abortion, the cytogenetic diagnosis was confirmed in a cell line grown from placental tissue. Microscopic and gross pathological findings in the fetus were compared to 1 case with trisomy 9 and 3 with trisomy 9 mosaicism reported in the literature. A distinct clinical syndrome appears to be associated with this rare autosomal trisomy.     

Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy,high levels of trisomy in trophoblast,and increased risk of fetal intrauterine growth restriction.

Molecular studies were performed on 101 cases of confined placental mosaicism (CPM) involving autosomal trisomy. The origin of the trisomic cell line was determined in 54 cases (from 51 pregnancies), 47 of which were also analyzed for the presence of uniparental disomy (UPD) in the disomic cell line. An additional 47 cases were analyzed for parental origin in the disomic cell line only. A somatic (postmeiotic) origin of the trisomy was observed in 22 cases and included the majority of cases with CPM for trisomy 2, 7, 8, 10, and 12. Most cases of CPM involving trisomy 9, 16, and 22 were determined to be meiotic. Fetal maternal UPD was found in 17 of 94 informative CPM cases, involving trisomy 2 (1 case), 7 (1 case), 16 (13 cases), and 22 (2 cases). The placental trisomy was of meiotic origin in all 17 cases associated with fetal UPD (P = .00005). A meiotic origin also correlated with the levels of trisomy in cultured chorionic villi samples (CVS) (P = .0002) and trophoblast (P = .00005). Abnormal pregnancy outcome (usually IUGR) correlated with meiotic origin (P = .0003), the presence of fetal UPD (P = 4 x 10(-7)), and the level of trisomy in trophoblast (P = 3 x 10(-7)) but not with the level of trisomy in CVS or term chorion. The good fit of somatic errors with the expected results could have been observed only if few true meiotic errors were misclassified by these methods as a somatic error. These data indicate that molecular determination of origin is a useful predictor of pregnancy outcome, whereas the level of trisomy observed in cultured CVS is not. In addition, UPD for some chromosomes may affect prenatal, but not postnatal, development, possibly indicating that imprinting effects for these chromosomes are confined to placental tissues.     

Duodenal atresia in an infant with triple-X syndrome: a new associated malformation in 47,XXX

BACKGROUND: An association between the triple-X syndrome (47,XXX) and gastrointestinal malformations is extremely rare. Most 47,XXX patients present with a normal phenotype, but genitourinary malformations have been described. CASE: We report a case of a child with 47,XXX and duodenal atresia. Antenatal ultrasound scan showed a dilated fetal stomach and upper part of the duodenum (double bubble phenomenon) at 31 weeks of gestation in a 31-year-old woman with polyhydramnion. The amniotic fluid karyotype showed 47,XXX. After a scheduled delivery, duodenal atresia was confirmed and treated with duodeno-duodenostomy. CONCLUSIONS: The possible association of gastrointestinal and genitourinary tract anomalies requires a detailed postnatal clinical investigation and ultrasonographic examination of the abdomen, retroperitoneum, and pelvis on all triple-X syndrome patients.     

Molecular studies of chromosomal mosaicism: relative frequency of chromosome gain or loss and possible role of cell selection.

Studies of uniparental disomy and origin of nonmosaic trisomies indicate that both gain and loss of a chromosome can occur after fertilization. It is therefore of interest to determine both the relative frequency with which gain or loss can contribute to chromosomal mosaicism and whether these frequencies are influenced by selective factors. Thirty-two mosaic cases were examined with molecular markers, to try to determine which was the primary and which was the secondary cell line: 16 cases of disomy/trisomy mosaicism (5 trisomy 8, 2 trisomy 13, 1 trisomy 18, 4 trisomy 21, and 4 involving the X chromosome), 14 cases of 45,X/46,XX, and 2 cases of 45,X/47,XXX. Of the 14 cases of mosaic 45,X/46,XX, chromosome loss from a normal disomic fertilization predominated, supporting the hypothesis that 45,X might be compatible with survival only when the 45,X cell line arises relatively late in development. Most cases of disomy/trisomy mosaicism involving chromosomes 13, 18, 21, and X were also frequently associated with somatic loss of one (or more) chromosome, in these cases from a trisomic fertilization. By contrast, four of the five trisomy 8 cases were consistent with a somatic gain of a chromosome 8 during development from a normal zygote. It is possible that survival of trisomy 8 is also much more likely when the aneuploid cell line arises relatively late in development.     

Mosaicism for trisomy 21 and ring (21) in a male born to normal parents: A case report

We present a case of a ring (21) in a mentally challenged patient with mosaicism for trisomy 21 showing karyotype 47, XY,+21/47,XY,+21(r)/46,XY, born to normal parents. The parents and female sibling were phenotypically normal. This is a unique case report from Central India, on occurrence of trisomy 21 and r (21) in the same individual born to normal parents. Also being documented for the first time is the immuno-FISH analysis revealing differential expression of hTERT and a linked over expression of TRF2 in proband, probably corresponding to a high percentage of acrocentric associations.     

Trisomy 21 mosaicism in two subjects from two generations.

In the course of a chromosome fragility investigation on the cancer prone hereditary disorder xeroderma pigmentosum, a low proportion of cells with a 47,XY,+21 karyotype was found in lymphocyte cultures of a patient not showing any Down syndrome symptom. The presence of trisomy 21 mosaicism was demonstrated also in peripheral blood of the healthy father and confirmed by "chromosome painting" that allowed a rapid detection of chromosomes 21 on metaphase cells and interphase nuclei. The trisomic cell line was not detected in fibroblast cultures. The analysis of chromosome 21 heteromorphism indicated that in both subjects the mosaic could result from either a diploid or an aneuploid zygote. Since in the trisomic cell line of the father and the son the extra chromosome 21 seems to be the same, a predisposition toward mitotic errors (non-disjunction or anaphase lagging) may be postulated, leading to the recurrent gain or loss of a specific chromosome 21. In order to test the hypothesis of an abnormal mitotic behaviour of the chromosome 21, we investigated the centromere separation index and the DNA restriction pattern in Southern blots probed with satellite DNA sequences specific for chromosome 21 centromere. Both the approaches did not reveal any peculiar feature that may account for the genetically determined proneness to mitotic error observed in the family.     

Trisomy recurrence: a reconsideration based on North American data

Few reliable data exist concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome. We collected records from two sources: (1) prenatal diagnoses performed at the Hopital Sainte-Justine in Montreal and (2) karyotype analyses performed at Genzyme. Using the standardized morbidity ratio (SMR), we compared the observed number of trisomies at prenatal diagnosis with the expected numbers, given maternal age-specific rates (by single year). SMRs were calculated both for recurrence of the same trisomy (homotrisomy) and of a different trisomy (heterotrisomy). After all cases with an index trisomy 21 were combined, the SMR for homotrisomy was 2.4 (90% CI 1.6-3.4; P=.0005). For women with both the index trisomy and subsequent prenatal diagnosis at age <30 years, the SMR was 8.0; it was 2.1 for women with both pregnancies at age >/=30 years. For the other index viable trisomies (13, 18, XXX, and XXY) combined, the SMR for homotrisomy was 2.5 (90% CI 0.7-8.0). For heterotrisomy, the SMR after an index trisomy 21 was 2.3 (90% CI 1.5-3.8, P=.0007); the SMR did not vary with maternal age at the first trisomy. When all cases with index viable trisomies were combined, the SMR for heterotrisomy was 1.6 (90% CI 1.1-2.4; P=.04). For prenatal diagnoses following a nonviable trisomy diagnosed in a spontaneous abortion (from Genzyme data only), the SMR for a viable trisomy was 1.8 (90% CI 1.1-3.0; P=.04). The significantly increased risk for heterotrisomy supports the hypothesis that some women have a risk for nondisjunction higher than do others of the same age.     

Karyological stability and microevolution of a cell suspension culture ofBrachycome dichromosomatica (Asteraceae)

A long-term suspension culture ofBrachycome dichromosomatica (2n = 4) was induced from a cotyledon-derived callus. Subcultures were obtained every week up to three years. The bulk of the cultures displayed a stable diploid karyotype, while one cell line evolved with 2n = 5 chromosomes in the 86th reinoculation. No further chromosomal change occurred also in that cell line. It is assumed that the fifth chromosome is the expression of a trisomy 2.The chromatin ultrastructure was of the species-specific chromomeric type in the wild-type line, while the trisomic line displayed more condensed chromatin, what probably indicates a rather inactive state of the extra-chromosome.Brachycome dichromosomatica is suggested to represent an ideal species to follow-up karyotype stability and/or variation in cell culture.As a former student W. N. dedicates this paper in gratitude and admiration to Prof. DrElisabeth Tschermak-Woess on the occasion of her 70th birthday. Prof.Woess with her scientific work has stimulated in an unique manner the study of nuclear structures in plants, of endopolyploidy and polytene chromosomes, and has thus established the basis for the rapidly increasing research in these fields.     

Cytogenetic,FISH and DNA studies in 11 individuals from a family with two siblings with dup(21q) Down syndrome

A Spanish family has previously been described with two siblings with dup(21q) Down syndrome. The father has a normal karyotype. The mother has a microchromosome. Cytogenetic, fluorescence in situ hybridization and DNA studies have now been carried out on the family. Findings include that the mother has three different chromosome anomalies, viz. (1) a chromosome 22 with an unusual pericentromeric region that contains alphoid DNA from chromosomes 21/13 and chromosome 22, (2) an isochromosome 21p in the frequent cell line and (3) an isochromosome 21q in a rare second cell line. A possible explanation is that the mother developed from a zygote with trisomy 21 and that mitotic error in early development resulted in the formation of two cell lines with karyotypes of 47,XX,+i(21p) and 47,XX,+i(21q), respectively. The unusual chromosome 22 represents a hitherto undescribed chromosome anomaly and one possible explanation is a translocation of the short arms between chromosomes 21/13 and 22 in the ancestry of the family. The relationship between the unusual chromosome 22 and the isochromosome formation in the mother is not known. However, all three chromosome anomalies involve the alphoid DNA of chromosome 21/13, indicating that this is not a chance finding.