The management and the causes of miscarriages present challenges for the obstetrical community as well as for families. In families who have a child with an X and Y chromosomal disorder, the duress of pregnancy loss may be significantly exacerbated. A greater understanding of these mechanisms would inform medical providers and families of children with 47,XXY, or Klinefelter syndrome (KS), and variant disorders (48,XXXY and 49,XXXXY). This study investigates miscarriage incidences across a cohort of mothers of male offspring born with these disorders. Pregnancy history of mothers of male offspring with 47,XXY (KS) or variant disorders was collected. Statistical analyses were performed to determine if these mothers experienced higher incidences of miscarriage than the general population. Mothers reporting miscarriage in the 47,XXY (p = 0.03, d = 0.31) and 48,XXXY (p = 0.02, d = 1.95) groups were significantly older at the time of birth than those who did not report miscarriage. When compared to known statistics of miscarriage in the general population, there was a significant increase in the miscarriages in the 47,XXY (p = 0.04, h = 0.13), 49,XXXXY (p = 0.02, h = 0.23), and combined groups (p < 0.01, h = 0.15). Mothers of children with 47,XXY (KS) and variant disorders are at increased risk of miscarriage compared to the general population based on the findings of this study.

High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs. In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed. The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction. The increase in the number of extra-Xs is associated with a "dose-dependent" progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance.

Klinefelter Syndrome (KS) is the most common aneuploidy in humans (prevalence: 85-250 per 100,000 born males) and is characterized by one or more supernumerary X-chromosomes (47-XXY, 48-XXXY and 49-XXXXY karyotypes). KS is a multisystemic disorder associated to multiple phenotypic features including cardiac abnormalities, infertility, mental retardation, diabetes and increased cancer risk. Using a non-integrative mRNAs reprogramming approach, we generated two iPSC lines 48-XXXY and 49-XXXXY from a non-mosaic 49-XXXXY KS patient carrying a balanced translocation t(4,11) (q35,q23). These iPSC lines provide a unique cellular platform to study the molecular mechanisms underlying KS pathophysiology.

Klinefelter Syndrome (KS) is caused by the presence of a supernumerary X chromosome. Cytogenetic studies revaled that 80-90% of patients carry a 47-XXY karyotype, while 10-20% of cases are represented by mosaic 46-XY/47-XXY and high-grade aneuploidies 48-XXXY and 48-XXYY. The phenotypic traits of KS are highly variable across individuals and include cognitive dysfunction, metabolic dysregulation, osteoporosis, and cardiovascular diseases. Here, we describe the derivation of multiple 47-XXY iPSC lines from three unrelated KS patients to study the impact of supernumerary X chromosome during early development.

Klinefelter Syndrome (KS) is the most frequent X chromosome aneuploidy in males. KS patients with 47-XXY, 48-XXXY and 49-XXXXY karyotypes endure inter-individual phenotypic variabilities including infertility, cardiac diseases, metabolic and psychiatric disorders. We derived iPSC lines from a high-grade 49-XXXXY KS and two healthy donors' fibroblasts. Importantly, the healthy controls XY and XX are direct relatives to KS patients, thus enabling functional comparisons of healthy and disease iPSCs with partially matched genetic backgrounds. These iPSC lines provide an unprecedented cellular tool to study KS pathophysiology at the pluripotent stage as well as during differentiation into disease relevant cell types.