Endocrine, cardiac and neuropsychological aspects of adult congenital adrenal hyperplasia.

OBJECTIVE: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. DESIGN, PARTICIPANTS, MEASUREMENTS: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. RESULTS: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. CONCLUSION: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.

The TGFß system and TIMP1 and 3 genotypes in Turner syndrome-Relation with aortic congenital malformations.

OBJECTIVE: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk. DESIGN, PATIENTS, PARTICIPANTS AND MEASUREMENTS: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFß), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease. RESULTS: TS participants had lower TGFß1 and TGFß2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFß1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFß1 and TGFß2 levels in TS. CONCLUSION: TGFß and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

The comorbidity landscape of 47,XXX syndrome: A nationwide epidemiologic study.

PURPOSE: This study aimed to describe the comorbidity pattern in 47,XXX syndrome. METHODS: This was a registry-based study of hospital diagnoses and prescribed medication in a nationwide cohort of females with 47,XXX (n = 103) and 46,XX/47,XXX (n = 57) in which they were compared with 16,000 age-matched general population female controls. RESULTS: The overall occurrence of hospital diagnoses was significantly increased in females with 47,XXX when compared with controls (incidence rate ratio = 2.1, CI = 1.7-2.5), and when divided into 19 organ-specific groups, there was a significantly increased risk in the following 14 groups: infection, blood, endocrine and metabolism, mental, nervous system, eye, ear, respiratory, oral cavity and gastrointestinal, musculoskeletal, perinatal, congenital malformations, external factors, and "other." The risk of being prescribed any medication was not significantly increased in females with 47,XXX when compared with controls (hazard ratio = 1.2, CI = 0.9-1.4). However, when stratified according to medication groups, a significantly increased risk was detected in 4 of 13 groups. The overall occurrence of hospital diagnoses was also significantly increased when females with 46,XX/47,XXX were compared with controls (incidence risk ratio = 1.3, CI = 1.01-1.8), but generally, in comparison with controls, females with 46,XX/47,XXX were less severely affected than females with 47,XXX. CONCLUSION: The 47,XXX syndrome is associated with an increased occurrence of a wide variety of diseases. Increased awareness of this may contribute to improve counseling and clinical assessment of these patients.

What microRNAs could tell us about the human X chromosome.

MicroRNAs (miRNA) are small-non coding RNAs endowed with great regulatory power, thus playing key roles not only in almost all physiological pathways, but also in the pathogenesis of several diseases. Surprisingly, genomic distribution analysis revealed the highest density of miRNA sequences on the X chromosome; this evolutionary conserved mammalian feature equips females with a larger miRNA machinery than males. However, miRNAs contribution to some X-related conditions, properties or functions is still poorly explored. With the aim to support and focus research in the field, this review analyzes the literature and databases about X-linked miRNAs, trying to understand how miRNAs could contribute to emerging gender-biased functions and pathological mechanisms, such as immunity and cancer. A fine map of miRNA sequences on the X chromosome is reported, and their known functions are discussed; in addition, bioinformatics functional analyses of the whole X-linked miRNA targetome (predicted and validated) were performed. The emerging scenario points to different gaps in the knowledge that should be filled with future experimental investigations, also in terms of possible implications and pathological perspectives for X chromosome aneuploidy syndromes, such as Turner and Klinefelter syndromes.

The epidemiology of sex chromosome abnormalities.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females.

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X-chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome-wide DNA-methylation and RNA-expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA-methylation and RNA-expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome-wide DNA-methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X-chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

Morbidity in 47,XYY syndrome: a nationwide epidemiological study of hospital diagnoses and medication use.

PURPOSE: A systematic description of morbidity in 47,XYY syndrome based on nationwide registry data of hospital diagnoses and prescribed medication. METHODS: All males in Denmark diagnosed with 47,XYY syndrome during 1960-2014 were identified. Each was matched with 100 male controls from the general population. Diagnoses related to hospital encounters (1977-2014) and prescriptions (1996-2014) were analyzed by negative binominal regression and Cox regression, respectively. RESULTS: 47,XYY syndrome was associated with a significantly increased overall incidence of hospital diagnoses (incidence rate ratio = 2.30, confidence interval [CI]: 1.99-2.65), including a significantly increased incidence of diagnoses associated with congenital malformations and genetic disorders as well as with psychiatric, neurologic, respiratory, urogenital, endocrine, circulatory, gastrointestinal, and musculoskeletal system disorders. Diagnoses associated with infections, skin and eye disorders were significantly increased as well. 47,XYY syndrome was associated with a significantly increased occurrence of prescriptions overall (hazard ratio = 1.25, CI: 1.10-1.44), with sex hormones and medication related to the urogenital system, blood, and nervous system being most prominently increased. CONCLUSION: 47,XYY syndrome is associated with a significantly increased morbidity owing to a wide variety of diseases. Increased awareness of the diverse morbidity in 47,XYY syndrome may help guide clinicians assessing 47,XYY males, thereby improving long-term health outcomes.

Key metabolic parameters change significantly in early breast cancer survivors: an explorative PILOT study.

BACKGROUND: With increasing number of breast cancer survivors, more attention is drawn to long-term consequences of curative cancer treatment. Adjuvant treatment of breast cancer patients is associated with several unfavorable medical conditions, including dyslipidemia, insulin resistance, and obesity, potentially leading to cardiovascular disease and/or the metabolic syndrome. The aim of this explorative study is to investigate metabolic side effects of adjuvant treatment in breast cancer patients. METHODS: A cohort of 13 premenopausal and 20 postmenopausal women with early stage breast cancer were extensively examined prior to, immediately after and 1 year after ended adjuvant chemotherapy and compared with healthy controls (N = 36) matched by age and menopausal status. Repeated examinations included: anthropometric measures, DEXA scans, 24-h blood pressure measurements, and blood samples [high sensitivity CRP, lipid profile and glucose metabolism, including homeostatic model assessment (HOMA)]. RESULTS: At baseline, breast cancer patients were similar to healthy controls regarding all measures. From baseline to 1-year post-treatment specific components of the metabolic syndrome increased significantly in premenopausal breast cancer patients; body fat (P = 0.01), triglycerides (P = 0.03), waist circumference (P = 0.008) and diastolic blood pressure (P = 0.04). In postmenopausal patients, waist circumference also increased significantly (P = 0.03), and High density lipoprotein (HDL) cholesterol decreased significantly (P = 0.05). CONCLUSIONS: Specific components of the metabolic syndrome changed significantly during chemotherapy in early stage breast cancer patients. After 1 year, several key parameters remained pathologically changed. Premenopausal breast cancer patients seemed to be especially prone to develop these unfavorable changes. Trial registration ClinicalTrial.gov, registration number NCT02652975. Registered 15 December 2015-Retrospectively registered, https://clinicaltrials.gov/ .

Clinical and pathophysiological aspects of bicuspid aortic valve disease.

A bicuspid aortic valve is not only a common congenital heart defect but also an enigmatic condition that can cause a large spectrum of diseases, such as aortic valve stenosis and severe heart failure in newborns whereas aortic dissection in adults. On the contrary, a bicuspid aortic valve can also occur with normal function throughout life and never need treatment. Numerous genetic mechanisms are involved in the abnormal cellular functions that may cause abnormal development of the aortic valve during early foetal life. As several chromosomal disorders are also associated with a bicuspid valve, there does not appear to be an apparent common trigger to the abnormal development of the aortic valve. The clinical care of the bicuspid aortic valve patient has been changed by a significant body of evidence that has improved the understanding of the natural history of the disease, including when to best intervene with valve replacement and when to provide prophylactic aortic root surgery. Moreover, as bicuspid valve disease is also part of various syndromes, we can identify high-risk patients in whom a bicuspid valve is much more unfavourable than in the normal population. This review provides an overview of all aspects of the bicuspid aortic valve condition and gives an updated perspective on issues from pathophysiology to clinical care of bicuspid aortic valve disease and associated aortic disease in asymptomatic, symptomatic, and pregnant patients, as well as our viewpoint on population screening.

Growth hormone replacement does not increase mortality in patients with childhood-onset growth hormone deficiency.

CONTEXT: Long-term safety of growth hormone (GH) treatment is an area of much debate. Studies including children treated with GH not only due to GHD, but also due to non-GHD causes like idiopathic short stature or like short stature in children born small for gestational age have suggested that GH treatment is associated with increased mortality or stroke. OBJECTIVE: To study the impact of GH replacement on overall and cause-specific mortality in childhood-onset GHD (CO GHD) patients. DESIGN: A nationwide population-based registry study on patients with CO GHD and general population controls matched on age and gender. Mortality hazard ratios (HRs) were computed comparing patients and controls, and comparing GH-replaced patients and non-GH-replaced patients, using Cox regression. Comparing GH- and non-GH-replaced patients HRs were adjusted for birth year, year of diagnosis, gender, irradiation, ACTH insufficiency and primary disease. PATIENTS AND CONTROLS: A total of 494 patients with CO GHD each matched with 100 general population controls were included. RESULTS: Mortality was substantially increased comparing patients with CO GHD and general population controls, HR = 7·51 (95% CI = 6·06-9·31). Comparing GH-replaced patients with non-GH-replaced patients mortality was significantly decreased in total (HR = 0·27, CI = 0·17-0·43) and due to malignancy (HR = 0·14, CI = 0·07-0·28) in GH-replaced patients. Adjusting for relevant confounders, this decrease remained significant both in total (HR = 0·56, CI = 0·32-0·96) and due to malignancy (HR = 0·33, CI = 0·16-0·69). Overall and cause-specific mortality was increased in both GH-replaced and non-GH-replaced patients compared to general population controls, but mortality was generally highest in non-GH-replaced patients. CONCLUSION: The present data from a national cohort of patients with CO GHD do not support the suggestion that GH replacement is associated with increased mortality.

Osteoprotegerin in Turner syndrome - relationship to aortic diameter.

BACKGROUND: Cardiovascular disease is a cardinal trait of Turner syndrome (TS), causing half of the threefold excess mortality. As osteoprotegerin (OPG) is a potential biomarker of cardiovascular disease, this cross-sectional and prospective study aimed at elucidating OPG levels in TS and its relationship to aortic diameter as well as validated cardiovascular risk markers. METHODS: Adult women with TS (n = 99) were examined thrice (mean follow-up 4·7 ± 0·5 years), and 68 age-matched healthy female controls were examined once. Aortic diameter was assessed by cardiovascular magnetic resonance. Twenty-four-hours blood pressure monitoring and biochemical assessments were also performed. RESULTS: Osteoprotegerin levels (median with range) were lower in TS (777 [326-10 569] ng/l) compared with controls (979 [398-1987] ng/l; P < 0·05) and did not change during follow-up. The OPG concentration was higher among women with TS older than 50 years of age (996 [542-4996] vs 756 [326-10 569] ng/l; P < 0·05) with a trend towards a higher OPG in TS who were on antihypertensive medication (938 [490-2638] vs 752 [326-10 569] ng/l; P = 0·09). Contrary to controls, OPG levels correlated with BSA-indexed aortic diameter (r = 0·31-0·45; P < 0·05), age (r = 0·29; P < 0·05) and high-sensitivity C-reactive protein (r = 0·23; P = 0·02) and inversely with BSA (r = -0·20; P < 0·05), weight (r = -0·23; P < 0·05) and plasma oestradiol levels (r = -0·34; P < 0·05). CONCLUSION: Levels of OPG are lower in TS and correlate with aortic diameter, age, BSA, weight and oestradiol in TS, but not controls. Future studies are needed to assess whether OPG may serve as a biomarker of aortic or cardiovascular disease in TS.

Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.

BACKGROUND: An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. METHODS AND RESULTS: Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 µmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 µmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. CONCLUSION: MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.

Only a minority of sex chromosome abnormalities are detected by a national prenatal screening program for Down syndrome.

STUDY QUESTION: How does a national prenatal screening program for Down syndrome (DS) perform in detecting sex chromosome abnormalities (SCAs)-Turner syndrome (TS), Klinefelter syndrome, 47,XXX and 47,XYY syndromes. SUMMARY ANSWER: The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs. WHAT IS KNOWN ALREADY: The detection rates of SCAs are higher in countries with DS screening. TS is associated with greater nuchal translucency (NT) and lower pregnancy-associated plasma protein-A (PAPP-A). However, specific detection rates of SCAs using prenatal DS screening have not been determined. No clear trend in PAPP-A, free beta human chorionic gonadotropin (ß-hCG) and NT has been found in the remaining SCAs. Several lines of inquiry suggest that it would be advantageous for individuals with SCA to be detected early in life, leading to prevention or treatment of accompanying conditions. There is limited information about pre- and perinatal status that distinguishes SCA embryogenesis from normal fetal development. STUDY DESIGN, SIZE, DURATION: A register-based case-control study from the Danish Central Cytogenetic Register (DCCR), cross-linked with the Danish Fetal Medicine Database (DFMD), was performed from 2008 to 2012. Groups of SCAs were compared with DS and then matched with non-SCA controls to assess differences between these groups in prenatal markers and birth outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included cases with prenatal and post-natal SCA karyotypes (n = 213), DS (n = 802) and 168 056 controls. We screened 275 037 individuals examined prenatally. We retrieved information regarding maternal age, NT, ß-hCG and PAPP-A, as well as details regarding maternal and newborn characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The DS screening procedure detected 87 per 100 000 TS (42% of expected), 19 per 100 000 Klinefelter syndrome (13% of expected), 16 per 100 000 47,XXX (16% of cases) and 5 per 100 000 47,XYY (5% of expected) SCAs, with an overall detection rate of 27%. Compared with controls, all four SCA groups showed significantly higher NT and lower PAPP-A compared with controls (all P < 0.01) and similar to DS. The legal abortion rate was high for all four syndromes (47,XXX: 24%; 47,XYY: 29%; Klinefelter syndrome: 48%, TS: 84%). For SCA fetuses carried to term, only TS fetuses had consistently lower birthweights and placenta weights than non-SCA controls (both P = 0.0001). A few SCA cases localized in DCCR could not be found in DFMD (n = 16). LIMITATIONS, REASON FOR CAUTION: Controls were matched on sex of the fetus of cases, meaning that all electively aborted fetuses (before week 12) were excluded, possibly reducing the diversity in the control group. We were not able to localize all diagnosed cases of SCA and DS in DFMD. Although these cases were present in DCCR, we were not able to account for the discrepancy. In addition, we suspect that several SCA children have not been diagnosed yet and future post-natal diagnosis of these cases would reduce the diagnostic yield reported here even further. WIDER IMPLICATIONS OF THE FINDINGS: The prenatal detection rate is below 50% for all SCAs. The approach used for detecting DS cannot be extended to also include SCAs. In addition, all SCAs have low PAPP-A and increased NT, thus probably reflecting an abnormal embryogenesis. Growth retardation of TS fetuses is if anything more pronounced than previously reported, both when evaluating fetus and placenta. STUDY FUNDING/COMPETING INTERESTS: This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study.

Short QTc interval in males with klinefelter syndrome-influence of CAG repeat length, body composition, and testosterone replacement therapy.

BACKGROUND: Klinefelter syndrome (KS) is a sex chromosomal aneuploidy (47,XXY) affecting 1/660 males. Based on findings in Turner syndrome, we hypothesized that electrocardiogram (ECG) abnormalities would be present in males with KS. OBJECTIVE: To investigate ECGs in males with KS and compare with controls. METHODS: Case control study of 62 males with KS and 62 healthy males matched on age. The primary outcome parameter was a difference in the ECG presentation between the two groups. The ECGs were analyzed by one blinded examiner (intraobserver variability 0.2-2.1%). The QT-interval was measured using "teach-the-tangent" method excluding the U-wave. QTc was calculated using Bazett's equation, Hodges' equation, and a linear regression model. Body mass index, abdominal fat, and muscle mass as well as sex hormone levels were secondary parameters. The prevalence of mutations in genes related to short QT syndrome was determined in participants with a QTc < 330 ms. RESULTS: Compared to controls, the QTc-interval was shorter (P = 0.02-0.06) in males with KS depending on the applied correction method. QTc was shortest among testosterone (T)-treated males with KS, while untreated and thus hypogonadal KS had QTc interval comparable to controls. No mutations in genes related to short QT syndrome were found. CONCLUSION: We found short QTc interval in males with KS, with further shortening of the QTc interval by T. These results suggest that genes on the X chromosome could be involved in regulation of the QTc interval and that T treatment may aggravate this mechanism.

A Prospective Study of Lipids in Adult Women With Turner Syndrome.

Context: Turner syndrome (TS) is a rare genetic syndrome with an increased mortality, mainly attributed to cardiovascular disease. Objective: This work aimed to investigate and correlate the lipid profile in adult women with TS to clinical characteristics. Methods: A 12-year prospective cohort study, including 4 study visits, was conducted at a specialist hospital. A total of 102 women with TS qualified for inclusion. Excluding missing variables and participants lost to follow-up, 86 women (mean age 38.1 years; range, 18.4-62.1 years) were included in this study. Fifty-three women completed the study. Repeated-measurement analysis was performed, using total cholesterol (Total-C), low-density lipoprotein (LDL), triglycerides (TGs), and high-density lipoprotein (HDL) as outcome variables and age, karyotype, body mass index (BMI), treatment with statins, antidiabetics, and hormone replacement therapy as explanatory variables. Principal component analysis (PCA) and partial least squares (PLS) analysis were performed at the first study visit. Results: Hyperlipidemia was present in 30% of the TS cohort. Total-C increased with age (0.12 mmol/L/y; P = .016). LDL (P = .08), TGs (P = .14), and HDL (P = .24) were not associated with age. BMI significantly increased total-C (0.19 mmol/L/kg/m2; P = .006), LDL (0.63 mmol/L/kg/m2; P < .001), and TGs (0.80 mmol/L/kg/m2; P < .001) and decreased HDL (-0.59 mmol/L/kg/m2; P < .001). PCA and PLS analysis found correlations between weight and BMI and total-C, LDL, and TGs. Conclusion: Hyperlipidemia is more prevalent in adult women with TS across adulthood compared to the background population. Total-C, LDL, TGs, and HDL were significantly associated with BMI characterizing the atherogenic profile in adult women with TS.

Increased morbidity evaluated on hospital contacts and prescriptions among 100,834 Danish breast cancer survivors.

BACKGROUND: Cardiovascular disease competes with breast cancer (BC) as the leading cause of death for females diagnosed with breast cancer. Not much is known concerning morbidity and medicine use in the short and long term after a BC diagnosis. AIM: The aim of this study was to determine acute and long-term morbidity in Danish women treated for BC. METHOD: A nationwide registry-based cohort study of 100,834 BC patients identified in the clinical database of Danish Breast Cancer Cooperative Group (DBCG) and 1,100,320 (10 per patient) age-matched Danish women without BC, serving as controls. Morbidity was studied using complete data on hospital contacts and medicinal use. RESULTS: The risk of hospital contacts was significantly increased in BC survivors compared with controls evaluated both by means of Cox regression and negative binomial regression analysis both during and after cessation of breast cancer treatment. Young age at breast cancer diagnosis was associated with the most pronounced increase in risk of hospital contacts, both during and after cessation of BC treatment. Medicinal use was significantly increased among BC patients compared to controls, both during (HR 1.27 (1.26-1.28), p < 0.0001) and after BC treatment (HR 1.18 (1.17-1.19), p < 0.0001, and present for all subgroups of medicine. CONCLUSION: Overall, BC survivors have a pronounced increase in hospital contacts and medicinal use compared to women without BC. Premenopausal status at BC diagnosis was associated with an overall higher excess morbidity and a higher burden both during and after treatment.

Dosage of the pseudoautosomal gene SLC25A6 is implicated in QTc interval duration.

The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is incompletely understood. Only a minor part of the QT interval variation in the general population has been linked to autosomal variant loci. Altered X chromosome dosage in humans, as seen in sex chromosome aneuploidies such as Turner syndrome (TS) and Klinefelter syndrome (KS), is associated with altered QTc interval (heart rate corrected QT), indicating that genes, located in the pseudoautosomal region 1 of the X and Y chromosomes may contribute to QT interval variation. We investigate the dosage effect of the pseudoautosomal gene SLC25A6, encoding the membrane ADP/ATP translocase 3 in the inner mitochondrial membrane, on QTc interval duration. To this end we used human participants and in vivo zebrafish models. Analyses in humans, based on 44 patients with KS, 44 patients with TS, 59 male and 22 females, revealed a significant negative correlation between SLC25A6 expression level and QTc interval duration. Similarly, downregulation of slc25a6 in zebrafish increased QTc interval duration with pharmacological inhibition of KATP channels restoring the systolic duration, whereas overexpression of SLC25A6 shortened QTc, which was normalized by pharmacological activation of KATP channels. Our study demonstrate an inverse relationship between SLC25A6 dosage and QTc interval indicating that SLC25A6 contributes to QT interval variation.

Platelet aggregation in Klinefelter syndrome is not aggravated by testosterone replacement therapy: A longitudinal follow-up study.

BACKGROUND: Men with Klinefelter syndrome (KS) are routinely offered testosterone replacement therapy (TRT) suggested to potentially promote platelet aggregation and increase cardiovascular risk. OBJECTIVE: We investigated platelet aggregation in men with KS before and during TRT. MATERIALS AND METHODS: Forty-one adult men with KS participated, of which 20 had no history of TRT at baseline, with 15 completing follow-up after 18 months TRT. Further, we included 21 adult men with KS on long-term TRT (>10 years) and a male reference population. We assessed platelet impedance aggregometry using adenosine diphosphate (6.5 µM), thrombin-receptor-activating-peptide-6 (TRAP 32 µM), and arachidonic acid (ASPI 0.5 mM) as agonists in KS compared to a male reference population and stratified by route of TRT administration. RESULTS: Platelet aggregation among men with KS at baseline or during TRT was not increased compared with the male reference population. For all three agonist, no change was seen in platelet aggregation in KS at follow-up compared with baseline (p ≥ 0.2). Platelet aggregation was not associated with total testosterone and furthermore, platelet count was not affected by treatment with testosterone. Men with KS treated with testosterone gel showed slightly increased TRAP- and ASPI-induced platelet aggregation compared with those treated with testosterone injection (p = 0.02 and p = 0.04, respectively). DISCUSSION AND CONCLUSIONS: We observed normal platelet aggregation in men with KS before TRT and following both short and long term treatment. Our findings do not support an independent role of platelets in driving the cardiovascular risk in KS.