High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome.
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ABSTRACT:
SUBMITTER: Davis SM
PROVIDER: S-EPMC7413636 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4-15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners' Parent Rating Scale-Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors.A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.
| S-EPMC3356148 | biostudies-literature
Project description:Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.
| S-EPMC8485146 | biostudies-literature
Project description:Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X-chromosome determines these features of KS are poorly understood, skewed X-chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes. We assessed genomic, methylomic and transcriptomic variation in matched prefrontal cortex and cerebellum samples identifying an individual with a 47,XXY karyotype who was comorbid for schizophrenia and had a notably reduced cerebellum mass compared with other individuals in the study (n = 49). We examined methylomic and transcriptomic differences in this individual relative to female and male samples with 46,XX or 46,XY karyotypes, respectively, and identified numerous locus-specific differences in DNA methylation and gene expression, with many differences being autosomal and tissue-specific. Furthermore, global DNA methylation, assessed via the interrogation of LINE-1 and Alu repetitive elements, was significantly altered in the 47,XXY patient in a tissue-specific manner with extreme hypomethylation detected in the prefrontal cortex and extreme hypermethylation in the cerebellum. This study provides the first detailed molecular characterization of the prefrontal cortex and cerebellum from an individual with a 47,XXY karyotype, identifying widespread tissue-specific epigenomic and transcriptomic alterations in the brain.
| S-EPMC4121369 | biostudies-literature
Project description:Angelman syndrome (AS, OMIM 105830) is a neurogenetic disorder with firm clinical diagnostic guidelines, characterized by severe developmental delay and speech impairment, balanced and behavioral disturbance as well as microcephaly, seizures, and a characteristic electroencephalogram (EEG). The majority of AS cases (70%) are caused by a 15q11.2-q13 deletion on the maternally derived chromosome. The frequency of AS has been estimated to be between 1/10000 and 1/20000. Klinefelter syndrome (KS) occurs due to the presence of an extra X chromosome (karyotype 47,XXY). The main features in KS are small testes, hypergonadotropic hypogonadism, gynecomastia, learning difficulties, and infertility. We present what is, to our knowledge, the first case of a patient with both KS and AS due to a 15q11.2-q13 deletion on the maternally derived chromosome and an extra X chromosome of paternal origin. He showed dysmorphic features, axial hypotonia, and delayed acquisition of motor skills. Early diagnosis is essential for optimal treatment of AS children; this is one of the earliest diagnosed cases of AS probably due to the presence of two syndromes. Clinical findings in this patient here described may be helpful to identify any other cases and to evaluate recurrence risks in these families.
| S-EPMC4212645 | biostudies-literature
Project description:Klinefelter syndrome (KS) is characterized by a masculine phenotype, supernumerary sex chromosomes (usually XXY), and spermatogonial stem cell (SSC) loss in their early life. Affecting 1 out of every 650 males born, KS is the most common genetic cause of male infertility, and new fertility preservation strategies are critically important for these patients. In this study, testes from 41, XXY prepubertal (3-day-old) mice were frozen-thawed. Isolated testicular cells were cultured and characterized by qPCR, digital PCR, and flow cytometry analyses. We demonstrated that SSCs survived and were able to be propagated with testicular somatic cells in culture for up to 120 days. DNA fluorescent in situ hybridization (FISH) showed the presence of XXY spermatogonia at the beginning of the culture and a variety of propagated XY, XX, and XXY spermatogonia at the end of the culture. These data provide the first evidence that an extra sex chromosome was lost during innate SSC culture, a crucial finding in treating KS patients for preserving and propagating SSCs for future sperm production, either in vitro or in vivo. This in vitro propagation system can be translated to clinical fertility preservation for KS patients.
| S-EPMC8745151 | biostudies-literature
Project description:Study questionShould testicular sperm extraction (TESE) in non-mosaic 47,XXY Klinefelter syndrome (KS) patients be performed soon after puberty or could it be delayed until adulthood?Summary answerThe difference in sperm retrieval rate (SRR) in TESE was not significant between the 'Young' (15-22 years old) cohort and the 'Adult' (23-43 years old) cohort of non-mosaic KS patients recruited prospectively in parallel.What is known alreadySeveral studies have tried to define predictive factors for TESE outcome in non-mosaic KS patients, with very heterogeneous results. Some authors have found that age was a pejorative factor and recommended performing TESE soon after puberty. To date, no predictive factors have been unanimously recognized to guide clinicians in deciding to perform TESE in azoospermic KS patients.Study design, size, durationTwo cohorts (Young: 15-22 years old; Adult: 23-43 years old) were included prospectively in parallel. A total of 157 non-mosaic 47,XXY KS patients were included between 2010 and 2020 in the reproductive medicine department of the University Hospital of Lyon, France. However 31 patients gave up before TESE, four had cryptozoospermia and three did not have a valid hormone assessment; these were excluded from this study.Participants/materials, setting, methodsData for 119 patients (61 Young and 58 Adult) were analyzed. All of these patients had clinical, hormonal and seminal evaluation before conventional TESE (c-TESE).Main results and the role of chanceThe global SRR was 45.4%. SRRs were not significantly different between the two age groups: Young SRR=49.2%, Adult SRR = 41.4%; P = 0.393. Anti-Müllerian hormone (AMH) and inhibin B were significantly higher in the Young group (AMH: P = 0.001, Inhibin B: P < 0.001), and also higher in patients with a positive TESE than in those with a negative TESE (AMH: P = 0.001, Inhibin B: P = 0.036). The other factors did not differ between age groups or according to TESE outcome. AMH had a better predictive value than inhibin B. SRRs were significantly higher in the upper quartile of AMH plasma levels than in the lower quartile (or in cases with AMH plasma level below the quantification limit): 67.7% versus 28.9% in the whole population (P = 0.001), 60% versus 20% in the Young group (P = 0.025) and 71.4% versus 33.3% in the Adult group (P = 0.018).Limitations, reasons for cautionc-TESE was performed in the whole study; we cannot rule out the possibility of different results if microsurgical TESE had been performed. Because of the limited sensitivity of inhibin B and AMH assays, a large number of patients had values lower than the quantification limits, preventing the definition a threshold below which negative TESE can be predicted.Wider implications of the findingsIn contrast to some studies, age did not appear as a pejorative factor when comparing patients 15-22 and 23-44 years of age. Improved accuracy of inhibin B and AMH assays in the future might still allow discrimination of patients with persistent foci of spermatogenesis and guide clinician decision-making and patient information.Study funding/competing interest(s)The study was supported by a grant from the French Ministry of Health D50621 (Programme Hospitalier de Recherche Clinical Régional 2008). The authors have no conflicts of interest to disclose.Trial registration numberNCT01918280.
| S-EPMC9627253 | biostudies-literature
Project description:ContextBoys with XXY have greater adiposity and a higher risk of cardiovascular disease. Infants with XXY have lower testosterone concentrations than typical boys, but no studies have evaluated adiposity in infants with XXY or the physiologic effects of giving testosterone replacement.ObjectiveTo determine the effect of testosterone on body composition in infants with XXY.DesignProspective, randomized trial.SettingTertiary care pediatric referral center.Participants20 infants 6 to 15 weeks of age with 47,XXY.InterventionTestosterone cypionate 25 mg intramuscularly monthly for three doses vs no treatment.Main outcome measuresDifference in change in adiposity (percent fat mass z scores); other body composition measures, penile length, and safety outcomes between treated and untreated infants; and comparison with typical infants.ResultsThe increase in percent fat mass (%FM) z scores was greater in the untreated group than in the treated group (+0.92 ± 0.62 vs -0.12 ± 0.65, P = 0.004). Increases in secondary outcomes were greater in the testosterone-treated group for total mass, fat-free mass, length z score, stretched penile length, and growth velocity (P < 0.002 for all). At 5 months of age, adiposity in untreated infants with XXY was 26.7% compared with 23.2% in healthy male infants of the same age (P = 0.0037); there was no difference in %FM between the treated XXY boys and controls. Reported side effects were minimal and self-limited; no serious adverse events occurred.ConclusionsAdiposity of untreated infants was 15% greater than that of male controls by 5 months of age. Testosterone treatment for infants with XXY resulted in positive changes in body composition.
| S-EPMC6846330 | biostudies-literature
Project description:Background: The existing risk of procedure-related miscarriage following invasive sampling for prenatal diagnosis is higher for twin pregnancies and some women are reluctant to test these typically difficultly obtained pregnancies invasively. Therefore, there is a need for noninvasive testing options that can test twin pregnancies at an early gestational age and ideally test the twins individually. Case presentation: A pregnant woman opted for cell-based NIPT at GA 10 + 5. As cell-based NIPT is not established for use in twins, the test was provided in a research setting only, when an ultrasound scan showed that she carried dichorionic twins. Materials and Methods: Fifty mL of peripheral blood was sampled, and circulating fetal cells were enriched and isolated. Individual cells were subject to whole-genome amplification and STR analysis. Three fetal cells were analyzed by chromosomal microarray (aCGH). Results: We identified 20 fetal cells all sharing the same genetic profile, which increased the likelihood of monozygotic twins. aCGH of three fetal cells showed the presence of two X chromosomes and a gain of chromosome Y. CVS from both placentae confirmed the sex chromosomal anomaly, 47,XXY and that both fetuses were affected. Conclusion: NIPT options can provide valuable genetic information to twin pregnancies that help the couples in their decision-making on prenatal testing. Little has been published about the use of cell-based NIPT in twin pregnancies, but the method may offer the possibility to obtain individual cell-based NIPT results in dizygotic twins.
| S-EPMC8963804 | biostudies-literature
Project description:The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS) features. To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones [gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)], and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 pre-pubertal boys with KS age 4-12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. A total of 80% of this pre-pubertal cohort had ?1 feature of metabolic syndrome (MetS) and 11% had ?3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, LDL, and lower HDL (p < 0.05). An INHB <50 ng/dL yielded a sensitivity of 83% and a specificity of 79% for having ?3 features of MetS. INHB and AMH positively correlated with each other (p < 0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dL vs. 4.9 ng/dL, p < 0.0001), however, no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in pre-pubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well-known, this study is the first to report an association between impaired Sertoli cell function and cardiometabolic risk.
| S-EPMC5233646 | biostudies-literature
Project description:Context:Klinefelter syndrome (KS) is a common condition in males, resulting in androgen deficiency and cardiometabolic diseases. These interrelated conditions may be present in prepubertal boys with KS. Objective:To determine whether supplemental low-dose androgen has a beneficial effect on body composition in prepubertal boys with KS. Design, Setting, and Participants:We conducted a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial in 93 boys with KS aged 4 to 12 years. Interventions:Oral oxandrolone (Ox) 0.06 mg/kg/d or placebo for 2 years. Outcome Measures:The primary outcome was percent body fat standard deviation score (%BF SDS) at 2 years. Secondary outcomes included additional measures of cardiometabolic health and safety. Results:The %BF SDS at 2 years was significantly lower in the treatment (0.29 ± 0.76 SDS) compared with placebo group (0.81 ± 0.72 SDS) after adjusting for age and baseline %BF SDS (95% confidence interval for the difference between means -0.86 to -0.19 SDS, P = 0.009). Ox resulted in lower triglycerides (P = 0.043), but also lower high-density lipoprotein (HDL) cholesterol (P < 0.001) and a more rapid advancement in bone age (P = 0.011). Conclusions:Ox has positive effects on measures of cardiometabolic health in prepubertal boys with KS; however, it does lower HDL cholesterol and advance bone age.
| S-EPMC5413098 | biostudies-literature