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Claus H Gravholt, Niels H Andersen, Gerard S Conway, Olaf M Dekkers, Mitchell E Geffner, Karen O Klein, Angela E Lin, Nelly Mauras, Charmian A Quigley, Karen Rubin, David E Sandberg, Theo C J Sas, Michael Silberbach, Viveca Söderström-Anttila, Kirstine Stochholm, Janielle A van Alfen-van derVelden, Joachim Woelfle, Philippe F Backeljauw, and On behalf of the International Turner Syndrome Consensus Group

Turner syndrome affects 25–50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society of Endocrinology and the Pediatric Endocrine Society, in collaboration with the European Society for Paediatric Endocrinology, the Endocrine Society, the European Society of Human Reproduction and Embryology, the American Heart Association, the Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society of Endocrinology, the Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

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L Martinerie, A Condat, A Bargiacchi, C Bremont-Weill, M C de Vries, and S E Hannema

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the ‘Dutch Approach’ initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-to-medium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences.

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Fiorella Galluzzi, Stefano Stagi, Roberto Salti, Sonia Toni, Elisabetta Piscitelli, Gabriele Simonini, Fernanda Falcini, and Francesco Chiarelli

Objective: Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption.

Design: We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications.

Methods: Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1–13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihy-droxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children.

Results: Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student’s t-test, P < 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student’s t-test, P < 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student’s t-test, r = −0.62; P = 0.001), and HbA1c (r = −0.59; P = 0.007). OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003).

Conclusions: Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.

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Angela Galler, Götz Gelbrich, Jürgen Kratzsch, Nicole Noack, Thomas Kapellen, and Wieland Kiess

Objective: Adiponectin plays an important role in pathophysiology of obesity, type 2 diabetes and cardiovascular disease. The aim of this study was to determine adiponectin concentrations in children and adolescents with type 1 diabetes in a longitudinal manner and to study the impact of age, gender, body mass index (BMI) and metabolic control.

Research design and methods: In this study, 88 children and adolescents with type 1 diabetes were followed longitudinally. At baseline and during follow-up, serum levels of adiponectin were measured by enzyme-linked immunoassay and correlated with clinical data, HbA1c and lipids. Healthy children (n = 259) were chosen as a control group.

Results: Serum adiponectin levels were significantly higher in children with type 1 diabetes compared with healthy children (13.1 vs 9.1 μg/ml at baseline, P < 0.001). Adiponectin concentrations inversely correlated with BMI s.d.s (P < 0.001). No significant difference of adiponectin levels regarding gender, diabetes duration or HbA1c was seen. Adiponectin concentrations decreased in males with type 1 diabetes during puberty (P = 0.03) while there was no significant change in females. In a subgroup of patients with new onset type 1 diabetes, adiponectin concentrations were not different from adiponectin levels in control subjects but increased during follow-up (P = 0.007). Stepwise multiple regression analysis showed that most important predictors of adiponectin levels in type 1 diabetes at the end of the study were adiponectin concentration at baseline (β = 0.574, P < 0.001) and BMI s.d.s (β = −0.302, P = 0.001, r 2 = 0.56).

Conclusions: Children and adolescents with type 1 diabetes have BMI-dependent elevated serum concentrations of adiponectin compared with healthy children.

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Clare A Whicher, Hermione C Price, and Richard I G Holt

Objective

There have been concerns about the effects of antipsychotics on weight gain and the development of type 2 diabetes (T2DM). This article aims to provide an up-to-date review on the evidence addressing this issue and the practical implications for the management of people taking antipsychotics in the context of T2DM.

Methods

We carried out searches on MEDLINE/PUBMED and the ClinicalTrials.gov website in August 2017 using the terms ‘antipsychotic’ and ‘diabetes’ or ‘glucose’ citing articles published after 2006 preferentially.

Results

Antipsychotics are associated with T2DM and are likely to exert a causal effect of uncertain magnitude. Children and adolescents appear especially vulnerable to these metabolic effects; as T2DM is not common in healthy younger people, the relative risk is more apparent. Antipsychotics act on glucose and insulin homeostasis in a variety of direct and indirect mechanisms. To reduce the increasing health inequalities among individuals with mental illness screening, monitoring and prevention of T2DM is important, as is improved diabetes care in this population.

Conclusion

It remains unclear whether these antipsychotic medications exacerbate an underlying predisposition to the development of T2DM or have a direct effect. Potential risks need to be weighed up and balanced between improved and lasting mental health benefits and any detrimental physical health side effects. Achieving parity of esteem between mental and physical health is a worldwide priority if we wish to improve life expectancy and quality of life in people with severe mental illness.

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Primoz Kotnik, Pamela Fischer-Posovszky, and Martin Wabitsch

Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.

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Rolf E Brenner, Bert Riemenschneider, Werner Blum, Martin Mörike, Walter M Teller, Wolfgang Pirsig, and Eberhard Heinze

We studied the influence of fasting serum from nine insulin-dependent diabetic children and adolescents under insufficient metabolic control on normal human bone cells in vitro compared with serum from eight sex- and age-matched controls. Cell number 24 h after plating was significantly less under diabetic serum, indicating impaired cell attachment, spreading and initiation of cell proliferation. Cell number after five days was reduced by 1% diabetic serum, while higher serum concentrations had diverging effects on osteoblast proliferation. Collagen synthesis of human osteoblasts was significantly reduced by 8% diabetic serum compared to 8% control serum, while synthesis of non-collagenous proteins was not affected. Duration of diabetes (several weeks up to 12 years) had no influence on these parameters. The serum from one patient, which was studied a second time under excellent metabolic control three months later, however, had lost its inhibitory influence on collagen synthesis of osteoblasts. The pattern of the interstitial collagen types I, III and V was not altered by diabetic serum. These results indicate that defective regulation of proliferation and collagen synthesis of osteoblasts by components present in human diabetic serum may be an important factor in the development of diabetic osteopenia. The negative influence might be explained in part by reduced levels of IGF-I and elevated levels of IGF binding protein-1 in the diabetic sera.

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D Hansen, FN Bennedbaek, M Hoier-Madsen, L Hegedus, and BB Jacobsen

OBJECTIVE: Thyroid autoantibodies (TA) and thyroid ultrasonography are widely used in the diagnosis of autoimmune thyroid disease (AITD). However, we know little of the significance of having ultrasonographic abnormalities (USabn) without having any other signs of AITD. In a previous population-based study of 105 young patients with type 1 diabetes (T1DM) we found a high prevalence (42%) of USabn. In the present study we evaluate the development of both USabn and TA in a 3-Year follow-up of this cohort. DESIGN: Of the 105 previously investigated children and adolescents with T1DM (aged 5-21 Years), 101 were re-examined. Serum concentrations of tri-iodothyronine (T(3)), thyroxine (T(4)), TSH, thyroid peroxidase antibodies (TPOab) and thyroglobulin antibodies (Tgab), as well as thyroid size and morphology were determined in all patients. RESULTS: During the 3 Years follow-up period, the prevalence of thyroid dysfunction increased from 5 to 8%, the prevalence of TPOab was unchanged at 13%, while the prevalence of Tgab decreased from 14 to 7%. The prevalence of USabn increased from 42 to 49%. Most patients presented USabn at both examinations. Patients with USabn had a higher prevalence of TA than those without USabn (P=0.038) and higher serum levels of TSH (P=0.027). All patients with thyroid dysfunction presented with USabn. However, many patients with USabn had no other signs of AITD. CONCLUSIONS: A high prevalence of thyroid dysfunction, TA and thyroid USabn were found in young patients with T1DM. Thyroid USabn was a sensitive but non-specific marker of AITD and is therefore unsuitable for screening purposes. Instead, we recommend regular screening using serum TSH in the follow-up of young diabetic patients.

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A Vatanen, M Wilhelmsson, B Borgström, B Gustafsson, M Taskinen, U M Saarinen-Pihkala, J Winiarski, and K Jahnukainen

Objective

The aim of the study was to evaluate long-term ovarian function after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence.

Subjects and methods

Predictive factors for ovarian function were evaluated among 92 adult or pubertal female survivors transplanted at Huddinge and Helsinki University Hospital during 1978–2000, at a mean age of 9±4.3 years (range 1–19). At the time of the study a mean±s.d. of 13±5.5 years (range 6–27) had elapsed since the HSCT and the mean age of the participants was 22±6.3 years (range 9–41).

Results

Spontaneous puberty based on breast development occurred in 40 and menarche in 30 of the 70 girls who were prepubertal at transplantation. Six out of 20 girls who received HSCT after initiation of pubertal development recovered their ovarian function. Younger age at HSCT, conditioning without total body irradiation (TBI), and a non-leukemia diagnosis predicted the spontaneous menarche. The incidence of menarche was higher after fractioned vs single fraction TBI (P<0.05), cyclophosphamide (Cy) vs busulfan (Bu)-based conditioning (P<0.05), and among leukemia patients transplanted at first remission vs later remissions (P<0.01) and with no cranial irradiation (cranial radiotherapy, CRT) vs given CRT (14–24 Gy) (P<0.01). The majority of recipients conditioned with only Cy vs TBI (P<0.001) or vs Bu-based regimens (P<0.01) showed preserved ovarian function and required no estrogen replacement at their latest follow-up visit at a mean age of 23±6.3 years (range 15–41). Ten women became pregnant.

Conclusions

Patients conditioned with TBI or Bu-based regimes are at high risk of ovarian failure. Intensive anti-leukemia therapy before HSCT including CRT especially among relapsed patients may further decrease the possibility of spontaneous menarche.

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T Arrigo, F De Luca, M Maghnie, A Blandino, F Lombardo, MF Messina, M Wasniewska, L Ghizzoni, and M Bozzola

In this study, perinatal history, postnatal auxological and clinical evolution and endocrine features were retrospectively evaluated in 49 children, adolescents and young adults with apparently idiopathic hypopituitarism. They were divided into two groups according to magnetic resonance images: 32 patients with isolated pituitary hypoplasia (group A) and 17 with pituitary stalk interruption syndrome (group B). The aim of the study was to assess whether these neuroradiological pictures are associated with specific endocrine and clinical patterns. No significant difference in terms of gestational age, intrauterine growth and rates of adverse perinatal events was found between the two groups. Clinical signs documenting the existence of pituitary dysfunction in utero or shortly after birth were either slightly (micropenis, cryptorchidism, cholestatic jaundice) or significantly (hypoglycemia) more frequent in patients in group B. Although diagnosis of hypopituitarism was made significantly earlier in patients in group B, height deficiency at diagnosis was similar in both groups. Endocrine investigations revealed a more severe and widespread impairment of pituitary function among those in group B. The main conclusion is that the postnatal clinical course is more severe when growth hormone deficiency is associated with pituitary stalk interruption syndrome than when the pituitary is only reduced in height, probably because of the more severe and widespread impairment of pituitary function in the former cases.