Behavioural side effects of inhaled corticosteroids among children and adolescents with asthma.

BACKGROUND: Inhalation corticosteroids (ICS) are prescribed for treatment of asthma in approximately 3% of all children in Denmark. Despite limited evidence, case reports suggest that ICS-related behavioural adverse drug events (ADEs) may be frequent. In general, underreporting of ADEs to official databases is common, and little is known about doctor's clinical experiences with behavioural ADEs when prescribing ICS for children with asthma. The objective was to investigate the extent of behavioural ADEs in children with asthma treated with ICS by comparing database findings to experiences of specialist doctors. METHODS: First, databases of the European Medicines Agency (EMA) and the Danish Medicines Agency (DKMA) were searched for reports made by healthcare professionals about behavioural ADEs in children from 2009 to 2018. Second, questionnaire data on behavioural ADEs were collected from eight of the 11 specialist doctors responsible for treating children with asthma at the six paediatric departments in Central Denmark Region and North Denmark Region. RESULTS: EMA and DKMA had registered 104 and 3 reports, respectively, on behavioural ADEs during the 10-year study period. In contrast, five of the eight specialist doctors (45.5%) had experienced patients who had developed behavioural changes during ICS treatment. However, none of the five specialist doctors had filed reports on these events to DKMA. CONCLUSION: Behaviour-related ADEs to ICS in children with asthma are likely to be highly underreported in official databases and doctors treating children with ICS should be aware of potential ADEs and consider submitting ADE reports whenever appropriate.

Blood pressure, sympathovagal tone, exercise capacity and metabolic status are linked in Turner syndrome.

OBJECTIVES: We studied cardiac autonomic changes in relation to metabolic factors, body composition and 24-hour ambulatory blood pressure measurements in Turner syndrome patients without known hypertension. DESIGN: Cross sectional. PATIENTS: Participants were 48 TS women and 24 healthy female controls aged over 18 years. METHODS: Short-term power spectral analysis was obtained in supine-standing-supine position. Bedside tests included three conventional cardiovascular reflex tests of heart rate response to standing up, heart rate response to deep breathing and blood pressure response to standing up. Mean heart rate during the last 2 minutes of work was used to calculate the maximal aerobic power (VO2max ). RESULTS: We found a significantly higher mean reciprocal of the heart rate per second (RR) in TS. Testing for interaction between position and status (TS or control), there were highly significant differences between TS and controls in high-frequency (HF) power, the coefficient of component variation (square root of HF power/mean RR) and low-frequency (LF): HF ratio, with a dampened decline in vagal activity among TS during standing. Bedside test showed TS had a significantly higher diastolic BP in the supine position compared to controls, and the adaptive rise in BP, when changing to upright position was reduced. VO2max and self-reported level of physical activity were significantly correlated to systolic ambulatory blood pressure both 24-hour and night diastolic ambulatory blood pressure. CONCLUSION: Vagal tone and modulation of the sympathovagal balance during alteration in body position are impaired in TS. These changes can be risk factors for cardiovascular disease.

Clinical care of adult Turner syndrome--new aspects.

Turner syndrome (TS) is characterized by numerous medical challenges during adolescence and adulthood. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) should continue during adult years. These issues are normally dealt with by the paediatrician, but once a TS female enters adulthood it is less clear who should be the primary care giver. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular diseases, as well as the risk of type 2 diabetes, hypertension, osteoporosis, thyroid disease and other diseases. The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. The transition period from paediatric to adult care seems to be especially vulnerable and the proper framework for transition has not yet been established. Likewise, no framework is in place for continuous follow-up during adult years in many countries. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as growth hormone and oxandrolone treatment for increasing height, are becoming well founded. Osteoporosis, diabetes, both type 1 and 2, hypothyroidism, obesity and a host of other endocrine diseases and conditions are seen more frequently in TS. Prevention, intervention and proper treatment is only just being recognized. Hypertension is frequent and can be a forerunner of cardiovascular disease. The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. Proper care during adulthood should be studied and a framework for care should be in place, since most morbidity potentially is amenable to intervention. In summary, TS is a condition associated with a number of diseases and conditions which need the attention of a multi-disciplinary team during adulthood.

Carotid intima-media thickness is increased in Turner syndrome: multifactorial pathogenesis depending on age, blood pressure, cholesterol and oestrogen treatment.

OBJECTIVE: Carotid intima-media thickness (IMT) may potentially supplement cardiovascular risk assessment in Turner syndrome (TS), where cardiovascular risk is high and appropriate risk stratification difficult. Knowledge of IMT in TS is scarce, and this study aimed to enhance insight into the cardiovascular risk marker. DESIGN, PATIENTS AND MEASUREMENTS: IMT was cross-sectionally assessed by ultrasonography of the common carotid artery (cIMT) and carotid bulb (bIMT) in TS (n = 69, age 40 ± 10 years) and age-matched, healthy female controls (n = 67). Additional prospective IMT assessment was performed in TS over 2·4 ± 0·3 years. Metabolic biomarkers and 24-h ambulatory blood pressure were also assessed. RESULTS: cIMT and bIMT (body surface area indexed) were increased in TS (P < 0·05) with 17-18% having IMTs that exceeded the 95th percentile of the controls (P < 0·05). Blood pressure, heart rate, glycosylated haemoglobin A1c and high-density lipoprotein cholesterol were increased in TS, where 43% received antihypertensive treatment. cIMT decreased during follow-up, coinciding with intensified cardiovascular risk prophylaxis, whereas bIMT was unchanged. In multiple regression analyses (R = 0·52-0·69, P < 0·05), baseline IMT in TS increased with age, blood pressure and cholesterol as well as in the presence of diabetes whilst IMT was inversely associated with duration of oestrogen replacement. In an analogue analysis, the prospective changes in cIMT (R = 0·37, P < 0·05) were beneficially influenced by antihypertensive treatment and oestrogen therapy and adversely by the presence of diabetes. CONCLUSION: Carotid IMT was abnormal in TS and negatively influenced by age, metabolic biomarkers, blood pressure and short duration of oestrogen treatment. Attention to common cardiovascular and endocrine risk markers over more than 2 years appeared to influence IMT beneficially.

Coagulation and fibrinolytic disturbances are related to carotid intima thickness and arterial blood pressure in Turner syndrome.

OBJECTIVE: Turner syndrome (TS) is characterized by growth retardation, hypogonadism and a high risk of cardiovascular complications and atherosclerosis; case reports suggest that thrombo-embolic complications may be present. DESIGN: Cross-sectional study. PATIENTS: Sixty women with TS. MEASUREMENTS: We characterized the activities of the haemostatic system, elucidated by the assessment of a panel of clotting factors and thrombosis risk factors and related these findings to carotid intima thickness (CIMT) and blood pressure. RESULTS: Most (81%) received hormone replacement therapy. The medians of all measured factors and inflammatory parameters were not different from normative data, but many cases displayed values of C-reactive protein (CRP) (40%), fibrinogen (15%), fibrin D-dimer (15%), factor VIII (25%), von Willebrand factor (vWF) (15%), cholesterol and liver parameters that were greater than normative limits. CRP, fibrinogen, vWF, factor VIII and liver parameters were highly and positively correlated. Haemostatic variables were positively related to both CIMT and blood pressure. The Factor V Leiden G1691A gene polymorphism heterozygosity was detected in 12·5%. CONCLUSION: We describe a significant proportion of individual TS females having high levels of vWF, factor VIII, fibrinogen and CRP (15-40%) and an increased frequency of the Leiden mutation, with important associations with CIMT and blood pressure, suggesting that a subset of TS may have an unfavourable haemostatic balance, which may contribute to the increased risk of premature ischaemic heart disease and possibly increase the risk of deep venous and portal vein thrombosis.

Dilation of the ascending aorta in Turner syndrome - a prospective cardiovascular magnetic resonance study.

BACKGROUND: The risk of aortic dissection is 100-fold increased in Turner syndrome (TS). Unfortunately, risk stratification is inadequate due to a lack of insight into the natural course of the syndrome-associated aortopathy. Therefore, this study aimed to prospectively assess aortic dimensions in TS. METHODS: Eighty adult TS patients were examined twice with a mean follow-up of 2.4 ± 0.4 years, and 67 healthy age and gender-matched controls were examined once. Aortic dimensions were measured at nine predefined positions using 3D, non-contrast and free-breathing cardiovascular magnetic resonance. Transthoracic echocardiography and 24-hour ambulatory blood pressure were also performed. RESULTS: At baseline, aortic diameters (body surface area indexed) were larger at all positions in TS. Aortic dilation was more prevalent at all positions excluding the distal transverse aortic arch. Aortic diameter increased in the aortic sinus, at the sinotubular junction and in the mid-ascending aorta with growth rates of 0.1 - 0.4 mm/year. Aortic diameters at all other positions were unchanged. The bicuspid aortic valve conferred higher aortic sinus growth rates (p < 0.05). No other predictors of aortic growth were identified. CONCLUSION: A general aortopathy is present in TS with enlargement of the ascending aorta, which is accelerated in the presence of a bicuspid aortic valve.

Delayed ß-cell response and glucose intolerance in young women with Turner syndrome.

BACKGROUND: To investigate glucose homeostasis in detail in Turner syndrome (TS), where impaired glucose tolerance (IGT) and type 2 diabetes are frequent. METHODS: Cross sectional study of women with Turner syndrome (TS)(n = 13) and age and body mass index matched controls (C) (n = 13), evaluated by glucose tolerance (oral and intravenous glucose tolerance test (OGTT and IVGTT)), insulin sensitivity (hyperinsulinemic, euglycemic clamp), beta-cell function (hyperglycaemic clamp, arginine and GLP-1 stimulation) and insulin pulsatility. RESULTS: Fasting glucose and insulin levels were similar. Higher glucose responses was seen in TS during OGTT and IVGTT, persisting after correction for body weight or muscle mass, while insulin responses were similar in TS and C, despite the higher glucose level in TS, leading to an insufficient increase in insulin response during dynamic testing. Insulin sensitivity was comparable in the two groups (TS vs. control: 8.6 ± 1.8 vs. 8.9 ± 1.8 mg/kg*30 min; p = 0.6), and the insulin responses to dynamic ß-cell function tests were similar. Insulin secretion patterns examined by deconvolution analysis, approximate entropy, spectral analysis and autocorrelation analysis were similar. In addition we found low IGF-I, higher levels of cortisol and norepinephrine and an increased waist-hip ratio in TS. CONCLUSIONS: Young normal weight TS women show significant glucose intolerance in spite of normal insulin secretion during hyperglycaemic clamping and normal insulin sensitivity. We recommend regularly testing for diabetes in TS. TRIAL REGISTRATION: Registered with http://clinicaltrials.com, ID nr: NCT00419107.

Thoracic aortopathy in Turner syndrome and the influence of bicuspid aortic valves and blood pressure: a CMR study.

BACKGROUND: To investigate aortic dimensions in women with Turner syndrome (TS) in relation to aortic valve morphology, blood pressure, karyotype, and clinical characteristics. METHODS AND RESULTS: A cross sectional study of 102 women with TS (mean age 37.7; 18-62 years) examined by cardiovascular magnetic resonance (CMR- successful in 95), echocardiography, and 24-hour ambulatory blood pressure. Aortic diameters were measured by CMR at 8 positions along the thoracic aorta. Twenty-four healthy females were recruited as controls. In TS, aortic dilatation was present at one or more positions in 22 (23%). Aortic diameter in women with TS and bicuspid aortic valve was significantly larger than in TS with tricuspid valves in both the ascending (32.4 +/- 6.7 vs. 26.0 +/- 4.4 mm; p < 0.001) and descending (21.4 +/- 3.5 vs. 18.8 +/- 2.4 mm; p < 0.001) aorta. Aortic diameter correlated to age (R = 0.2 - 0.5; p < 0.01), blood pressure (R = 0.4; p < 0.05), a history of coarctation (R = 0.3; p = 0.01) and bicuspid aortic valve (R = 0.2-0.5; p < 0.05). Body surface area only correlated with descending aortic diameter (R = 0.23; p = 0.024). CONCLUSIONS: Aortic dilatation was present in 23% of adult TS women, where aortic valve morphology, age and blood pressure were major determinants of the aortic diameter.

Long-term hormone replacement therapy preserves bone mineral density in Turner syndrome.

CONTEXT: Reduced bone mineral density (BMD) and increased risk of fractures are present in many women with Turner syndrome (TS). OBJECTIVE: Examine longitudinal changes in BMD in TS and relate changes to biochemical parameters. DESIGN: Prospective, pragmatic, and observational study. Examinations at baseline and follow-up (5.9+/-0.7 years). SETTING: Tertiary hospital. PARTICIPANTS: Fifty-four women with TS (43.0+/-9.95 years). Interventions Hormone replacement therapy (HRT) and calcium and vitamin D supplementation. Main outcome measures BMD (g/cm(2)) measured at lumbar spine, hip, and the non-dominant forearm. Bone formation and resorption markers, sex hormones, IGF1, and maximal oxygen uptake. RESULTS: At follow-up, forearm BMD, radius ultradistal BMD, and hip BMD remained unchanged, radius 1/3 BMD declined (0.601+/-0.059 vs 0.592+/-0.059, P=0.03), while spine BMD increased (0.972+/-0.139 vs 1.010+/-0.144, P<0.0005). Bone formation markers did not change over time in TS. Bone resorption markers decreased over time in TS. Testosterone, IGF1, and maximal oxygen uptake was significantly reduced in TS. CONCLUSION: Longitudinal changes in BMD in TS were slight. BMD can be maintained at most sites in well-informed women with TS, being encouraged to maintain a healthy lifestyle, including HRT and intake of calcium and vitamin D.

Turner syndrome and clinical treatment.

BACKGROUND: Turner syndrome (TS) is a genetic disorder associated with abnormalities of the X chromosome, occurring in about 50 per 100,000 liveborn girls. TS is usually associated with reduced adult height, gonadal dysgenesis and thus insufficient circulating levels of female sex steroids leading to premature ovarian failure and infertility. The average intellectual performance is within the normal range. New insight into genetics, epidemiology, cardiology, endocrinology and metabolism from a number of recent studies will be included in this review. SOURCES OF DATA: For this review we concentrated on all papers published on TS with special emphasis on the most recent literature. Also papers relating to cardiology, especially aortic dissection, paediatrics and the effects of estradiol in other conditions were considered. The main source was PubMed and the major endocrinology and cardiology journals. AREAS OF AGREEMENT: Treatment with growth hormone (GH) during childhood and adolescence allows a considerable gain in adult height. SHOX deficiency explains some of the phenotypic characteristics in TS, principally short stature. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) is given during adult years. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular (CV) diseases, as well as the risk of type 2 diabetes, osteoporosis and thyroid disease. AREAS OF CONTROVERSY: The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. In most countries it seems that the transition period from paediatric to adult care is especially vulnerable and the proper framework for transition has not been established. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as GH treatment for increasing height, are well founded. GROWING POINTS: The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. AREAS TIMELY FOR DEVELOPING RESEARCH: Proper care during adulthood should be studied, since most morbidity potentially is amenable to proper care. Especially, interventional strategy and follow-up with respect to congenital CV malformations, as well as secondary CV disease, have to be developed and new treatment algorithms have to be studied. In summary, TS is a condition associated with a number of diseases and conditions, which need the attention of a multi-disciplinary team.