Cortical gray matter structure in boys with Klinefelter syndrome.
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ABSTRACT:
SUBMITTER: Foland-Ross LC
PROVIDER: S-EPMC8321133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.
| S-EPMC6644684 | biostudies-literature
Project description:ContextKlinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and, as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood.ObjectiveTo determine the effects of androgen treatment on bone mass in children with KS.MethodsRandomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n = 38) versus placebo (PL; n = 40) for 2 years in boys with KS (ages 4-12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation score (SDS).ResultsBHI SDS was similar between groups at baseline (-0.46 ± 1.1 vs -0.34 ± 1.0 OX vs PL, P > .05) and higher in the OX group at 2 years (-0.1 ± 1.3 vs -0.53 ± 0.9, OX vs PL, P < .01). At baseline, BHI SDS values of all subjects were not normally distributed with 25.7% of subjects plotted below -1 SDS (P < .001), suggesting a deficit in bone mass. In total, 13.5% of subjects had sustained a fracture and their BHI SDS was lower than those with no fractures (-1.6 ± 1.3 vs -0.3 ± 1.0, P = .004).ConclusionBone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.
| S-EPMC7947965 | biostudies-literature
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: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
Project description:ContextKlinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown.ObjectiveTo compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl).DesignDouble-blind, randomized, controlled trial.SettingSingle tertiary care referral center.ParticipantsEighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12).InterventionsOx 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years.Outcome measuresOnset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations.ResultsOx-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups.ConclusionsTwo years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.
| S-EPMC6126887 | biostudies-literature
Project description:A new Q555X mutation on the SYN1 gene was recently found in several members of a family segregating dyslexia, epilepsy, and autism spectrum disorder. To describe the effects of this mutation on cortical gray matter microstructure, we performed a surface-based group study using novel diffusion and quantitative multiparametric imaging on 13 SYN1Q555X mutation carriers and 13 age- and sex-matched controls. Specifically, diffusion kurtosis imaging (DKI) and neurite orientation and dispersion and density imaging (NODDI) were used to analyze multi-shell diffusion data and obtain parametric maps sensitive to tissue structure, while quantitative metrics sensitive to tissue composition (T1, T2* and relative proton density [PD]) were obtained from a multi-echo variable flip angle FLASH acquisition. Results showed significant microstructural alterations in several regions usually involved in oral and written language as well as dyslexia. The most significant changes in these regions were lowered mean diffusivity and increased fractional anisotropy. This study is, to our knowledge, the first to successfully use diffusion imaging and multiparametric mapping to detect cortical anomalies in a group of subjects with a well-defined genotype linked to language impairments, epilepsy and autism spectrum disorder (ASD).
| S-EPMC6866302 | biostudies-literature
Project description:IntroductionWe performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging.MethodsTranscriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 ?m) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability.ResultsTranscripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT.ConclusionExpression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.
| S-EPMC3759649 | biostudies-literature
Project description:Cortical atrophy has been documented in both Parkinson's disease (PD) and healthy aging, but its relationship to changes in subcortical white matter is unknown. This was investigated by obtaining T1- and diffusion-weighted images from 76 PD and 70 controls at baseline and 18 and 36 months, from which cortical volumes and underlying subcortical white matter axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) were determined. Twelve of 69 cortical subregions had significant group differences, and for these, underlying subcortical white matter was explored. At baseline, higher cortical volumes were significantly correlated with lower underlying subcortical white matter AD, RD, and higher FA (ps ≤ 0.017) in PD. Longitudinally, higher rates of cortical atrophy in PD were associated with increased rates of change in AD RD, and FA values (ps ≤ 0.0013) in 2 subregions explored. The significant gray-white matter associations were not found in controls. Thus, unlike healthy aging, cortical atrophy and subcortical white matter changes may not be independent events in PD.
| S-EPMC5154847 | biostudies-literature
Project description:Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype, including tall stature, obesity, and hypergonadotropic hypogonadism, as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study, reproductive hormones and whole-body dual-energy x-ray absorptiometry-derived body composition and bone mineral content were standardized to age-related standard deviation scores in 62 patients with KS aged 5.9-20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas luteinizing hormone and follicle-stimulating hormone were high in patients before TRT. Despite normal body mass index, body fat percentage and the ratio between android fat percentage and gynoid fat percentage were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT, a tendency toward a more beneficial body composition with a significant reduction in the ratio between android fat percentage and gynoid fat percentage during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.
| S-EPMC10305500 | biostudies-literature