Anders Bojesen

Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone

SummaryKlinefelter syndrome (KS) patients have lower bone mineral density (BMD) at the spine, hip and forearm compared to healthy subjects, but frank osteoporosis is not common. Muscle strength and bone markers predicted BMD but KS itself and serum testosterone did not. Low vitamin D and high PTH were frequent among KS.IntroductionThe long-term consequence of KS on bone health is not well described. The objective of this study is to investigate the regional BMD and its determinants in KS.MethodsThis is a cross-sectional study. BMD at the spine, hip and forearm are measured by DXA and correlated to biochemical markers of bone turnover, vitamin D metabolites, PTH, sex hormones, growth factors as well as muscle strength and anthropometric measures. The setting is at a university clinical research centre. The study involves 70 adult KS patients and 71 age-matched healthy subjects.ResultsIn KS, BMD was universally lowered in all regions. Markers of bone formation or bone resorption were not altered in KS, but 25-OH-Dvitamin was lower (55 vs. 82xa0nmol/L, pu2009<u20090.0001) than in healthy subjects. Significantly more KS patients had low BMD (Z-scores below −2) at the forearm (15 KS vs. two healthy subjects, pu2009=u20090.001) but not at the spine or hip. Muscle strength (bicep and quadriceps) was lower among KS patients. Multivariate analysis revealed that muscle strength, treatment with testosterone (ever/never), age at diagnosis, SHBG, bone-specific alkaline phosphatase and 1CTP were all independent predictors of BMD, but androgens was not.ConclusionsKS patients had lower BMD at the spine, hip and forearm compared to age-matched healthy subjects, but frank osteoporosis was not common. Muscle strength, previous history of testosterone treatment, age at diagnosis and bone markers were predictors of BMD, but testosterone was not. Signs of secondary hyperparathyroidism were present among KS. Dietary intake of vitamin D or sun exposure may be lower in KS patients.

Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism

Objectiveu2002 Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels.

Effect of sex hormone treatment on circulating adiponectin and subforms in Turner and Klinefelter syndrome

Eur J Clin Invest 2010; 40 (3): 211–219

Hypothyroidism Secondary to Hypothalamic-Pituitary Dysfunction May Be Part of the Phenotype in Klinefelter Syndrome: A Case-Control Study

CONTEXTnKlinefelter syndrome (KS) may involve a number of abnormalities besides the characteristic testicular insufficiency. Some studies have suggested that thyroid abnormalities may be common, but this has not been clarified.nnnDESIGNnA case-control study of men with KS (n = 75) compared with age-matched men from the general population (n = 75) was organized, and thyroid function, thyroid volume by ultrasonography, and thyroid antibodies were examined.nnnRESULTSnMen with KS were on average taller and heavier and tended to have a higher body mass index than the men in the control group. Serum free T(4) (fT4) was lower in men with KS than controls [mean (sd): 16.3 (2.35) vs. 17.6 (1.75) pmol/liter; P < 0.001], with clustering in or just below the lower part of the reference range for the assay. The ratio fT4 to free T(3) was low in KS (P < 0.001), whereas no differences between groups were observed in TSH, free T(3), TSH to fT4 ratio, thyroid volume, or the prevalence of thyroid antibodies. No difference in any of the variables were observed between testosterone-treated and untreated KS men. Adjustment for differences in height, weight, and concomitant disease in multivariate models did not alter the results.nnnCONCLUSIONSnMen with KS had a general shift toward lower values in distribution of serum fT4 with no compensatory increase in serum TSH. The most likely mechanism is a decrease or change in set point of thyrotroph control of thyroid function.

The macrophage low-grade inflammation marker sCD163 is modulated by exogenous sex steroids

Soluble CD163 (sCD163) is a novel marker linked to states of low-grade inflammation such as diabetes, obesity, liver disease, and atherosclerosis, all prevalent in subjects with Turner syndrome (TS) and Klinefelter syndrome (KS). We aimed to assess the levels of sCD163 and the regulation of sCD163 in regards to treatment with sex hormone therapy in males with and without KS and females with and without TS. Males with KS (n=70) and age-matched controls (n=71) participating in a cross-sectional study and 12 healthy males from an experimental hypogonadism study. Females with TS (n=8) and healthy age-matched controls (n=8) participating in a randomized crossover trial. The intervention comprised of treatment with sex steroids. Males with KS had higher levels of sCD163 compared with controls (1.75 (0.47–6.90) and 1.36 (0.77–3.11) respectively, P<0.001) and the levels correlated to plasma testosterone (r=−0.31, P<0.01), BMI (r=0.42, P<0.001), and homeostasis model of assessment insulin resistance (r=0.46, P<0.001). Treatment with testosterone did not significantly lower sCD163. Females with TS not receiving hormone replacement therapy (HRT) had higher levels of sCD163 than those of their age-matched healthy controls (1.38±0.44 vs 0.91±0.40, P=0.04). HRT and oral contraceptive therapy decreased sCD163 in TS by 22% (1.07±0.30) and in controls by 39% (0.55±0.36), with significance in both groups (P=0.01 and P=0.04). We conclude that levels of sCD163 correlate with endogenous testosterone in KS and are higher in KS subjects compared with controls, but treatment did not significantly lower levels. Both endogenous and exogenous estradiol in TS was associated with lower levels of sCD163.

DNA hypermethylation and differential gene expression associated with Klinefelter syndrome

Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000xa0newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.