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.     

Rare case of XX/XY mosaicism and trisomy 13 in early prenatal diagnosis

Coexistence of XX/XY sex mosaicism and autosomal trisomy in prenatal diagnosis is particularly rare. Herein, we report the first, to our knowledge, case of a fetus with cyclopia, ambiguous genitalia and a 47,XX,+13,inv9[47]/47,XY,+13[13] karyotype detected at 13 weeks of gestation after chorionic villus sampling. Molecular analysis after prenatal diagnosis suggests that this is a case of sex mosaicism coexisting with trisomy 13, rather than chimera.     

Clinical outcome and follow-up of the first reported case of Russell-Silver syndrome with the unique combination of maternal uniparental heterodisomy 7 and mosaic trisomy 7

BACKGROUND: Russell-Silver syndrome (RSS) has been associated with maternal uniparental disomy (UPD) for chromosome 7 although the etiology of the syndrome is still unknown. Cases of RSS associated with maternal UPD7 have involved isodisomies, heterodisomies, and mixed isodisomy with heterodisomy simultaneously. This publication is a follow-up report of the postnatal clinical outcome of the first prenatally suspected case of combined mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 (UPD7). CASE: The diagnosis of RSS in the proband was suspected prenatally because trisomy 7 mosaicism (47,XX,+7[13]/46,XX[19]) and maternal uniparental heterodisomy 7 were both found in amniotic fluid cells. Cord blood karyotype analysis showed only disomic cells (46,XX[50]), whereas postpartum chorionic villus analysis was completely trisomic for chromosome 7 (47,XX,+7[19]). Postnatally, the diagnosis of RSS was confirmed by physical findings, her trisomy 7 mosaicism was confirmed by cytogenetic analysis of her skin biopsy (47,XX,+7[9]/46,XX[20]) and her UPD7 was confirmed on both peripheral blood and skin biopsy using microsatellite markers. During infancy, the proband experienced growth deficiency, persistent hypoglycemia, and psychomotor developmental delay. CONCLUSIONS: Trisomic rescue as a life-saving mechanism, with subsequent chromosomal mosaicism in combination with UPD may occur more frequently in RSS than has been reported. Systematic testing of cases suspected prenatally or postnatally would be informative regarding the individual contribution of each factor. Imprinting, loss of heterozygosity for recessive genes, and mosaicism may explain the short stature, asymmetry, and the variable expression of the phenotype. The contribution of these mechanisms to the syndrome should be evaluated in these cases.     

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.     

A rare case: mosaic trisomy 22.

A 9-year-old female child of healthy parents (mother: 43 years, father: 44 years) was referred to our center because of severe mental retardation. While pedigree analysis was not contributory, two older sibs were normal and healthy. Physical examination revealed facial dysmorphism, microcephaly and hyperflexibility of all joints. Her chromosome constitution showed a mosaic pattern; mos 46,XX[98]/47,XX,+22[2]. So skin biopsy was performed and mosaic trisomy 22 was confirmed with FISH analysis (46,XX[73]/47,XX,+22[27]). Physical features of this case seemed consistent with her mosaic constitution. This report would be a demonstrative example to show the significant contribution of FISH in states of mosaicism.     

Prenatal diagnosis of mosaicism identified in amniotic fluid cell cultures

Chromosomal mosaicism in prenatal diagnosis is an important problem to be solved immediately and the probable phenotypic reflections should be explained to the family. We report two numerical and two structural mosaicisms detected in amniocyte cultures. The first fetus had a 47,XY,+mar[10]/46,XY[10] karyotype. The marker chromosome was shown to be derived from chromosome 15 by FISH method. The newborn had intrauterine growth retardation and cerebral thrombosis and died at the 29th day of age. The second fetus had a 45,X[4]/46,XX[26] karyotype. The parents refused cordocentesis and decided to terminate pregnancy in the 21st week. The third case, presented with bilateral large choroid plexus cysts, had a 46,XX, dup(1)(q22-q32)[9]/46,XX[21] karyotype. The parents' karyotypes were normal and the pregnancy was aborted in the 23rd week of gestation. The second structural abnormality was reported as 46,XX,t(6;11)(q23; p13)[3]/46,XX[20]. The mosaicism was detected in only one flask. The parents decided to continue pregnancy and cordocentesis could not be performed due to the fetal and placental position. The baby was born at term. Peripheral blood lymphocyte culture resulted in a 46,XX normal karyotype. Information and risks were explained to all families during genetic counseling. Mosaicism in prenatal diagnosis needs both detailed examination and follow up, since clinical findings depend on the type of abnormality.     

Mosaic down syndrome with a marker: molecular cytogenetic characterization of the marker chromosome

Down syndrome is a complex disorder characterized by well defined and distinctive phenotypic features. Approximately 2-3% of all live-born Down individuals are mosaics. Here we report a boy with suspected Down syndrome showing mosaicism for two different cell lines where one cell line is unexpected. The cytogenetic analysis by G-banding revealed a karyotype of 47 XY+21 [20]/46,X+marker [30]. Further, molecular cytogenetic analysis with spectral karyotyping identified the marker as a derivative of Y chromosome. The delineation of Y chromosomal DNA was done by quantitative real-time PCR and aneuploidy detection by quantitative fluorescence PCR. The Y-short tandem repeats typing was performed to estimate the variation in quantity as well as to find out the extent of deletion on Y chromosome using STR markers. Fluorescence in situ hybridization using Y centromeric probe was also performed to confirm the origin of the Y marker. Further fine mapping of the marker was carried out with three bacterial artificial chromosome clones RP11-20H21, RP11-375P13, RP11-71M14, which defined the hypothetical position of the deletion. In our study we defined the extent of deletion of the marker chromosome and also discussed it in relation with mosaicism. This is the first report of mosaic Down syndrome combined with a second de novo mosaic marker derived from the Y chromosome.     

Ring chromosome 15: characterization by array CGH

Ring chromosome 15 [r(15)] is an uncommon finding with less than 50 patients reported. Precise genotype–phenotype correlations are problematic because of the difficulties in determining the extent of euchromatic loss, the level of mosaicism, and the influence of the timing of ascertainment. We report two discordant examples of r(15) patients. In the first case, prenatal diagnosis of a de novo r(15) was made during the second trimester: mos 46,XX,r(15)(p11.2q26)[32]/45,XX,-15[13]/47,XX,r(15)(p11.2q26)x2[3]/46,XX,dic r(15)(p11.2q26p11.2q26[1]/46,XX[2]. Postnatal follow-up revealed extremely small stature, heart defects, and developmental delay. Patient 2 was a 31-year-old short-statured female who was living independently: 46,XX,r(15)(p11q26). Both cases showed loss of the 15q subtelomeric region by fluorescence in situ hybridization (FISH). To investigate the discordance in phenotypes between the two patients, we undertook array comparative genomic hybridization (array CGH) analyses to more fully characterize the deletions associated with these otherwise structurally indistinguishable r(15) chromosomes from conventional cytogenetic analyses and fluorescence in situ hybridization (FISH) studies. By array CGH, patient 1 showed deletion of multiple contiguous clones predicting an approximately 6 Mb deletion of distal 15q. In contrast, patient 2 showed loss of just the 15q subtelomeric clone and an interstitial clone by array CGH confirming that the severity of the phenotype correlated with the size of the deletion at the molecular level. These cases illustrate the utility of array CGH characterization for determining the size of the associated deletion in ring chromosomes and for facilitating phenotype–genotype correlations.     

Complex mosaicism in sex reversed SRY+ male twins

Sex reversal is characterized by discordance between genetic and phenotypic sex. Most XX males result from an unequal interchange between X and Y chromosomes during paternal meiosis, therefore transferring SRY to the X chromosome, which explains the male development in the presence of an otherwise normal female karyotype. We present here the case of sex reversed SRY+ male twins with several cell lines. They consulted for infertility. The presence of SRY on an X chromosome was demonstrated by FISH. Their respective karyotypes were: 46,X,der(X)t(X;Y)(p22.3;p11.2)[249]/45,X [12]/45,der(X)t(X;Y)(p22.3;p11.2)[11]/47,XX,der(X)t(X;Y) (p22.3;p11.2)[1]/47,X,der(X)t(X;Y)(p22.3;p11.2)x2[1]/50, XX,der(X)t(X;Y)(p22.3;p11.2)x4[1]/46,XX[1] for the first twin (SH-1) and 46,X,der(X)t(X;Y)(p22.3;p11.2)[108]/45,X [3]/47,XX,der(X)t(X;Y)(p22.3;p11.2)[2]/45,der(X)t(X;Y) (p22.3;p11.2)[1]/47,X,der(X)t(X;Y)(p22.3;p11.2)x2[1] for the second twin (SH-2). There are three different types of XX males: 1) with normal genitalia, 2) with genital ambiguity, and 3) XX true hermaphrodites. The phenotype of the twins presented in this report is consistent with what is generally seen in XX SRY+ males: they have normal genitalia.     

Chromosomal mosaicism in amniotic fluid cell cultures.

Over the past 6 years, using in situ processing methods, we have identified 32 cases of mosaicism in amniotic fluid cell cultures prepared from 1,100 samples. Two of these (45,X/46,XX and 46,XX/47,XX, + 21) were called true mosaics because multiple colonies demonstrated the same abnormal chromosome complement, and on subsequent evaluation of the newborn blood or fetal tissues, mosaicism was confirmed. Of the remaining cases, 29 were designated as pseudomosaics because only single or partial colonies exhibited an aberrant chromosome complement, 12 having a trisomy 2 line. In the final case, a double trisomy was demonstrated in only one of eight colonies in the first culture, but in the culture from a repeat sample an additional two colonies showed the same double trisomy. Since no abnormal cells were observed in infant blood, it was postulated that the mosaicism may only have been present in the extraembryonic tissues. It is our conviction that the use of these cloning methods should diminish the danger of misdiagnosis in genetic amniocentesis.     

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.     

Karyological characteristics of Down's syndrome: clinical and theoretical aspects

These data have been collected from St. Petersburg Down Syndrome Register that comprises information on 1778 liveborn children with the Down syndrome, including three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223 cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44 cases (3.6%), including 21 males and 24 females, and among these one familial case of mosaicism in a daughter and in a healthy mother. Of 70 cases of translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1 inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free trisomy 21 was associated with structural or numerical anomalies: 46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21, 47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families parental mosaicism was shown or suspected. In 6 families one parent had chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in mothers and an additional small marker in a father. In cases confirmed cytogenetically an increased sex ratio was shown (679 males and 551 females, SR = 1.23), but it was not shown in patients not tested cytogenetically (264 males and 275 females, SR = 0.96, different from the expected 297 males and 242 females, P < 0.01).     

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.     

Inherited ring chromosome 8 without loss of subtelomeric sequences

We report the first case of inherited ring chromosome 8 syndrome without loss of subtelomeric sequences. The proband is a 6 1/2-year-old boy with short stature, microcephaly, mild mental retardation, and behavioral problems including hyperactivity and attention deficit. His mother presented the same physical features but intelligence was normal. Family history also revealed an uncle and a grandmother, with short stature and microcephaly. Moderate mental retardation was reported in the uncle. Karyotypes and fluorescence in situ hybridization (FISH) analyses were performed on peripheral blood lymphocytes for both child and mother. The child's karyotype was reported as 46,XY,r(8)(p23q24.3)[24]/45,XY,-8[2] and the mother's karyotype 46,XX,r(8)(p23q24.3)[22]/45,XX,-8[2]/47,XX,r(8)(p23q24.3), +r(8)(p23q24.3)[1]. FISH studies showed no deletion of subtelomeric sequences for both child and mother indicating that no or little chromosomal euchromatic material has been deleted. These findings indicate that ring chromosome 8 without loss of subtelomeric sequences can be inherited and that carriers in a same family present with cognitive function ranging from mild mental retardation to normal intelligence.     

Tetrasomy 9p mosaicism associated with a normal phenotype in two cases

Tetrasomy 9p is a rare chromosomal syndrome and about 30% of known cases exhibit mosaicism. Approximately 50 of the reported cases with tetrasomy 9p mosaicism show a characteristic facial appearance, growth failure, and developmental delay. However, 3 patients with mosaicism for isochromosome 9p and a normal phenotype have also been reported. We report 2 additional cases of clinically normal young females with tetrasomy 9p mosaicism, one of whom also exhibited X chromosome aneuploidy mosaicism leading to an overall of 6 different cell lines. STR analysis performed on this complex mosaic case indicated that the extra isochromosome was of maternal origin while the X chromosome aneuploidy was of paternal origin, indicating a postzygotic event.     

A child with mosaicism for deletion (14)(q11.2q13)

In this case report we describe a child with a de novo deletion in the (q11.2q13) region of chromosome 14. The child presented with dysmorphic features - anophthalmia, microcephaly, and growth retardation. Cytogenetic studies showed mosaicism. The karyotype was 46,XX,del(14)(q11.2;q13) [16] /46,XX [9]. We compared the features observed in this child with that of others with the same deletion reported in scientific literature and found that this is the first report of a child mosaic for this deletion. It is also the first time it has been reported in association with anophthalmia.     

Prenatal diagnosis of a 46,XX,inv(12)pat/47,XX,i(Xq),inv(12)pat

Summary A 46,XX,inv(12)pat/47,XX,i(Xq),inv(12)pat was diagnosed prenatally in a 36-year-old woman whose husband was a known carrier of a pericentric inversion of chromosome 12. The diagnosis was confirmed in fetal tissue. Terminal bromodeoxyuridine (BrdU) labelling demonstrated that in the line with 46 chromosomes one X was late replicating, while one X and the i(Xq) were late replicating in 100% of the cells with 47 chromosomes. We present the first case of this type of sex chromosome mosaicism. Genetic counseling presented difficulties since it was not possible to predict the fetal phenotype.     

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.     

An XX male with a 46,XX/47,XX,+Y(q12→qter) karyotype

Summary We describe a male with the karyotype 46,XX/47, XX,+Y(q12qter), which may be interpreted as due to an insertion (Y;X)(Yq11Yq12;Xp22) or to mosaicism, 46,XX/47, XX,+Y(12qter). In any case, some of the H-Y determining genes may be located on the long arm of the Y chromosome.