Y-specific DNA sequences in male patients with 46,XX and 47,XXX karyotypes

Y chromosomal DNA sequences were detected in three of four 46,XX males and in one 47,XXX male. One reiterated Y chromosomal sequence, Y-190, was localized by in situ hybridization to the distal short arm of an X chromosome of the 47,XXX male. This result is compatible with the hypothesis that an aberrant X/Y interchange has occurred, most likely during paternal meiosis, and that this interchange accounts for Y chromosomal material and sex reversal in this 47,XXX individual.     

The origin of 47, XXY and 47, XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination

We Investigated the parent and cell division of origin of theadditional sex chromosome in 142 males with a 47,XXY constitutionand 50 females with a 47,XXX constitution. In 66 of the 47,XXYmales the additional chromosome was paternal In origin and in76 It was maternal in origin, while among the 47, XXX femalesonly 5 had an additional paternal X chromosome, the remaining45 having an additional maternal chromosome. Among the 107 maternallyderived aneuploids for whom It was possible to determine thecell division of origin, 73 were the result of a mat Ml error,24 the result of a mat Mil error and 10 the result of a postzygotlc mitotlc (PZM) error Involving the maternal X chromosome.Among those In which the non-disjunction was attributable toan error at the first melotlc division (Ml) we observed threedifferent mechanisms of origin. Approximately 30% were associatedwith complete absence of recombination (nullichiasmate); approximately24% were associated with a normal number of recombinant eventsbut an abnormal distribution of exchanges (perturbed recombination),while approximately 45% were associated with a normal numberand distribution of recombinant events (normochiasmate). Non-disjunctiondue to an error at the second melotic division (Mll) was associatedwith a slight reduction in the total number of recomblnant eventsand an abnormal distribution of exchanges. Thus of the fourdifferent meiotic mechanisms of origin, three were associatedwith an abnormal number and/or distribution of exchange events.There was no evidence of an Increased paternal age in the aneuploidsof paternal origin. Among those of maternal origin there wasa significantly increased maternal age In the aneuplofds resultingfrom an error of mat Ml, but this was restricted to the nullichiasmateand the normochiasmate sub groups. The maternal ages of theMl perturbed recombination sub group, the Mil and the PZM groupwere not increased.     

Motor nerve conduction in 47, XXY and 48, XXYY males, and 47, XXX and 45, X females

Measurements were made of the maximum motor nerve conduction in the median and ulnar nerves of the right forearm for the four sex chromosomally abnormal groups 47, XXY and 48, XXYY males, 47, XXX and 45, X females. The results obtained were compared with male and female control groups (a) from the general population and (b) from a subnormality hospital. No significant differences were detected between the corresponding results for 47, XXY males and subnormal males. The results for the 47, XXY males were different from those for normal and subnormal females, except in the case of motor conduction in the median nerve for the subnormal female group. There is a suggestion of marked differences in motor conduction and distal latency in 48, XXYY males when compared to the two male control groups. 47, XXX females showed significant differences in motor conduction and distal latency when compared to normal females, but not when compared to subnormal females. No significant differences were detected between 45, X females and normal females for any of the variables measured.     

Prenatal diagnosis and 47,XXY

In this contribution, we consider detection of 47,XXY by a variety of available methods. These include traditional invasive procedures, screening with maternal serum analytes and fetal ultrasound, and most recently cell-free fetal DNA. Since its introduction in the late 1960s, prenatal genetic diagnosis has evolved greatly. Serendipitious detection of 47,XXY was not infrequent when prenatal genetic diagnosis routinely involved testing by the invasive procedures CVS and amniocentesis. In 2013 this is much less common and relatively few pregnancies in the U.S. and Europe are tested without prior screening protocols, traditionally maternal serum analyte and fetal ultrasound (NT). These protocols are not designed to identify 47,XXY or other X-chromosome aneuploides and with screening by analysis of cell-free DNA in maternal blood, this situation may or may not be altered. Increased numbers of cases could be detected if intake increases and vendors offer information on 47,XXY. A further consideration is that ability of array CGH to detect microdeletions or microduplications below resolution of a karyotype could make return to direct testing using an invasive procedure attractive. © 2013 Wiley Periodicals, Inc.     

47,XXY with associated bilateral renal agenesis

We describe the case of a 36-week gestational-age male stillborn with bilateral renal agenesis and a 47,XXY karyotype, as well as features of Potter sequence. No other congenital abnormalities were noted. Severe oligohydramnios was diagnosed prenatally at 30 weeks, and cytogenetic analysis was performed postmortem. Urinary tract anomalies are uncommon in association with Klinefelter syndrome. Unilateral renal agenesis has been described. We describe, to our knowledge, the first case of bilateral renal agenesis in association with 47,XXY.     

The behavioral profile of children aged 1–5 years with sex chromosome trisomy (47,XXX, 47,XXY, 47,XYY)

Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early intervention. This study addressed the question of what the behavioral profile of children with SCT aged 1–5 years looks like. In total, 182 children aged 1–5 years participated in this study (N_SCT=87, N_{nonclinical controls} = 95). Recruitment and assessment took place in the Netherlands and the United States. The SCT group was recruited through prospective follow‐up (50%), information seeking parents (31%), and clinical referral (18%). Behavioral profiles were assessed with the child behavior checklist and the ages‐and‐stages social–emotional questionnaire. Levels of parent‐rated problem behavior were higher in children with SCT. Difficulties with overall social–emotional functioning were already present in 1‐year‐olds, and elevated scores were persistent across the full age range. Affective and pervasive developmental behaviors were seen in late toddlerhood and prominent at preschool age. Anxiety, attention deficit, and oppositional defiant behaviors were seen in preschool‐aged children. Within this cross‐sectional study, the developmental trajectory of affective, pervasive developmental, and oppositional defiant behaviors seemed to be different for SCT children than nonclinical controls. Collectively, these results demonstrate the importance of behavioral screening for behavioral problems in routine clinical care for children with SCT from a young age. Social–emotional problems may require special attention, as these problems seem most prominent, showing increased risk across the full age range, and with these problems occurring regardless of the timing of diagnosis, and across all three SCT karyotypes.     

Reduced recombination in maternal meiosis coupled with non-disjunction at meiosis II leading to recurrent 47,XXX

We determined the meiotic origin and the stage of non-disjunction of the extra X chromosomes in two sisters with 47,XXX chromosomal complements. Segregation of the X chromosomes in all family members was analyzed using X-linked short tandem repeat polymorphic (STRP) markers. Densitometric analysis of two STRP markers confirmed that both sisters had three copies of the X chromosome and the extra X chromosomes were maternally derived. Both sisters did not share the same maternal homologue suggesting that the recurrent trisomy is non-homologous X chromosome-specific. Haplotype analysis demonstrated a reduction to homozygosity for markers examined, covering most of the length of the X chromosomes in both sisters. These findings suggested that the extra X chromosomes have derived from meiotic II non-disjunction following a nullitransitional meiosis I (MI). A lack of recombination in the X chromosomes of both sisters suggests a possible maternal genetic defect leading to an erratic recombination at MI. This information may contribute to further understanding of mechanisms leading to X chromosome non-disjunction and may assist in counseling of families with this chromosomal rearrangement.     

PGD in 47,XXY Klinefelter's syndrome patients

The use of ICSI has been a major breakthrough in the treatment of male infertility. Even azoospermic patients with focal spermatogenesis in the testis, may benefit from the ICSI technique in order to father a child. As ICSI use has become more common, centres have introduced infertility treatment for Klinefelter patients. To date, 34 healthy children have been born using ICSI without PGD, and the conception of one 47,XXY fetus has been reported. In view of the possible risk of an increased gonosome number in the spermatozoa of Klinefelter patients, a safer approach--offering these couples ICSI combined with PGD--has been used, and has resulted in the birth of three healthy children. Couples in which the male suffered from Klinefelter's syndrome were first treated in 1995; these patients were offered ICSI + PGD using FISH technology, notably to enumerate the X and Y chromosomes. ICSI + PGD was performed in 32 cycles of 20 couples with spermatozoa originating from a fresh ejaculate (n = 1), testicular biopsy (n = 21) or frozen-thawed testicular biopsy (n = 10). Normal fertilization occurred in 56.0 +/- 22.4% of the successfully injected oocytes. On day 3 of development, 119 embryos from 29 cycles were of sufficient quality to undergo biopsy and subsequent PGD; a positive result was obtained in 113 embryos. Embryos were available for transfer in 26 cycles, with a mean of 1.6 +/- 0.6 embryos per transfer. Eight pregnancies were obtained, and five resulted in a delivery. A total of 113 embryos from couples with Klinefelter's syndrome was compared with 578 embryos from control couples with X-linked disease where PGD was used to determine gender. A significant fall occurred in the rate of normal embryos for couples with Klinefelter's syndrome (54.0%) compared with controls (77.2%). Moreover, a significantly increased risk of abnormalities was observed for sex chromosomes and autosomes; for each autosome separately, this reached significance level for chromosomes 18 and 21 only. Hence, a cautious approach is warranted in advising couples with non-mosaic Klinefelter's syndrome. Moreover, the use of ICSI + PGD or prenatal diagnosis should be carefully considered.     

Development of eight pubertal males with 47,XXY karyotype

The increasing frequency with which the diagnosis of the 47,XXY karyotype is made requires more knowledge of the prognosis of this condition. We present four 47, XXY boys identified at birth and followed since then (Group I), and four 47, XXY boys diagnosed because of physical and/or emotional problems (Group II). Physical, psychological, language, and hormone data are presented. The physical and intellectual profiles for the two groups are similar. This is in contrast to the very poor school and emotional adjustment of the Group II individuals. These boys were definitely more difficult and problematic for their parents when compared to their siblings and to Group I who were un-selected. This further emphasizes that the expression of this karyotype is variable and individuals with behavioral disorders may represent a maladaptive subgroup rather than the entire population of 47,XXY males. Recommendations are given for intervention with attention to learning and language problems, hormone status, and emotional state.     

Hypostatic ulcers in 47,XXY Klinefelter''s syndrome

Hypostatic leg ulcers, probably secondary to vascular insufficiency, were observed in two adult men with 47,XXY Klinefelter's syndrome. The association between leg ulcers and 47,XXY Klinefelter's syndrome deserves increased attention because knowledge of the association may alert clinicians to an otherwise unsuspected chromosome abnormality.     

Personality in 47,XXY males during adolescence

The responses to the High School Personality Questionnaire and the Million Adolescent Personality Inventory of a series of neonatally identified 47, XXY adolescent males and age-matched controls were compared. The extra X males' results indicated that they were more assertive, impulsive and prone to conflict than controls. Individual differences in these characteristics among the extra X cases had little relationship to quality of parenting but were related to indices of pubertal development.     

A patient with a 47, XXY,5p- karyotype

A case is reported of a liveborn with the karyotype 47, XXY,5p -. This is the first known case of a liveborn with apparently both Klinefelter and Cri du Chat syndromes.     

Meiotic behaviour of the sex chromosomes in three patients with sex chromosome anomalies (47,XXY, mosaic 46,XY/47,XXY and 47,XYY) assessed by fluorescence in-situ hybridization

Meiotic studies using multicolour fluorescent in-situ hybridization (FISH) and chromosome painting were carried out in three patients with sex chromosome anomalies (47,XXY; 46,XY/47,XXY and 47,XYY). In the two patients with Klinefelter syndrome, although variable percentages of XXY cells (88.5 and 28.3%) could be found in the pre-meiotic stages, none of the abnormal cells entered meiosis, and all pachytenes were XY. However, the abnormal testicular environment of these patients probably resulted in meiotic I non-disjunction, and a certain proportion of post-reductional cells were XY (18.3 and 1.7%). The fact that none of the spermatozoa were XY also suggests the existence of an arrest at the secondary spermatocyte or the spermatid level. In the XYY patient, most (95.9%) premeiotic cells were XYY. The percentage of XYY pachytenes was 57.9%. The sex chromosomes were either in close proximity (XYY) or the X chromosome was separated from the two Ys (X + YY). A high proportion (42.1%) of post-reductional germ cells were XY. However, only 0.11% of spermatozoa were disomic for the sex chromosomes. In this case, the data suggest the existence of an arrest of the abnormal cells at the primary and the secondary spermatocyte or the spermatid level, giving rise to the continuous elimination of abnormal cells in the germ-cell line along spermatogenesis. The fact that the proportion of diploid spermatozoa was only increased in one of the three cases (XXY) is also suggestive of an arrest of the abnormal cell lines in these patients. The two apparently non-mosaic patients were, in fact, germ-cell mosaics. This suggests that the cytogenetic criteria used to define non-mosaic patients may be inadequate; thus, the risk of intracytoplasmic sperm injection in apparently non-mosaics may be lower than expected.     

Assessment of sex chromosome aneuploidy in sperm nuclei from 47,XXY and 46,XY/47,XXY males: comparison with fertile and infertile males with normal karyotype

Sex chromosome aneuploidy was assessed in spermatozoa from a 47,XXY male and a 46,XY/47,XXY male using three colour fluorescence in-situ hybridization (FISH) and compared with two control groups. The first group included subjects of proven fertility and the second infertile males with normal constitutional karyotype. The frequencies of XX and YY disomic, XY hyperhaploid and diploid spermatozoa were significantly increased in the 47,XXY male compared to subjects from the two control groups (P < 0.0001). For the 46,XY/47,XXY sample, the same results were observed, except that the incidence of YY disomic spermatozoa did not differ significantly from the rate obtained in infertile patients. The frequency of sex chromosome aneuploidy did not differ significantly between the 47,XXY and the 46,XY/47,XXY males, except for XX disomic sperm nuclei which was higher in the 47,XXY patient. The frequency of chromosome 12 disomy was also increased in the two XXY individuals (0.42 and 0.49% respectively; P < 0.0001). The meiotic abnormalities observed in the two XXY patients arose through segregation errors in XY germ cells. The increased number of meiotic non-disjunctions observed in the germ cells of infertile males may be a common feature of the deficient oligo- or azoospermic testis. Patients with Klinefelter's syndrome with oligozoospermia have an increased risk of both sex chromosome and autosome aneuploidy in their progeny.