Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.This study made use of data generated by the UK10K Project and we acknowledge the contribution of the UK10K Consortium. This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.) and the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310

Adverse effects of antiepileptic drugs on bone mineral density

The aim of this study is to determine the frequency of changes in biochemical markers of bone metabolism in children who are receiving valproic acid, carbamazepine, and oxcarbazepine. Thirty healthy children and 68 children with idiopathic epilepsy treated with either carbamazepine (n = 23), valproic acid (n = 31), or oxcarbazepine (n = 14) for more than 1 year were enrolled into the study. Blood samples were obtained in order to determine biochemical parameters (calcium, phosphorus, alkaline phosphates, parathormone, and 25-hydroxyvitamin D). Bone mineral density was measured with the dual-energy x-ray absorptiometry method. There were no significant differences in the serum concentrations of calcium, phosphorus, aspartate aminotransferase, alanine aminotransferase, and albumin levels between the four groups. However, serum alkaline phosphatase concentrations were higher in the patient group as compared with the control subjects. In patients receiving antiepileptic drugs, bone mineral density values were significantly lower than the healthy control group. In conclusion, long-term antiepileptic drug treatment either with valproic acid, carbamazepine, or with oxcarbazepine which has unknown effects on skeletal mineralization, induces a state of decreased bone mineral density. (c) 2006 by Elsevier Inc. All rights reserved

The frequency of vitamin D insufficiency in healthy female adolescents

Aim: To establish the frequency and causes of vitamin D insufficiency in healthy female adolescents in Izmir, Turkey. Methods: 64 adolescents from alow-(Ikinci Inonu) and a high- (Ilica) socio-economic settlement were included. Parents' monthly income was classified as low, middle and high. The blood samples were drawn at the end of the summer and winter periods. Results: Vitamin D insufficiency percentages for the end-of-winter period were 59.4% in Ikinci Inonu and 15.6% in Ilica, and for the end of summer 25% and 15.6%, respectively. Calcidiol levels of cases from Ikinci Inonu were found to be lower compared with the levels of cases from Ilica (349/15 vs 599/24 nmol/l for end of winter, p = 0.000; 519/22 vs 659/28 nmol/l for end of summer, p = 0.03). Calcidiol levels of cases whose parental monthly income was low and whose mothers were illiterate were significantly lower than the others (489/18 vs 659/29 nmol/l for end of summer, p = 0.01; 339/16 vs 56 +/- 23 nmol/l for end of winter, p = 0.000; 45 +/- 13 vs 64 +/- 29 nmol/l for end of summer, p = 0.007; 36 +/- 17 vs 51 +/- 25 nmol/l for end of winter, p = 0.02; respectively)

Subclinical hypothyroidism in childhood and adolescense

WOS: 000345022900005PubMed ID: 25153584Subclinical hypothyroidism (SH) is defined as a serum thyroid-stimulating hormone (TSH) level above the reference range with normal serum free thyroxin (sT4) and free triiodothyronine (sT3) levels. The prevalence of SH in children and adolescents is reported between 1.7% and 9.5%. Hashimoto's thyroiditis is the most prevalent cause of SH in children. Although it has been suggested that SH is entirely an asymptomatic laboratory diagnosis, typical hypothyroid symptoms as well have been reported in some patients. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); neuromuscular system; and cognitive functions in the long term. The number of studies investigating the effect of childhood SH on growth, bone maturation, lipid parameters, carbohydrate metabolism, neuromuscular system, and cognitive and cardiac function is limited. Knowledge about the natural history of SH is unclear even though there are numerous studies upon this subject. In children and adults, treatment of SH with L-T-4 is still a matter of debate, and there is no consensus on this issue yet

Clinical and diagnostic characteristics of hyperprolactinemia in childhood and adolescence

WOS: 000316895000001PubMed ID: 23327784Pituitary adenoma is the most common cause of hyperprolactinemia, which is a rare endocrine disorder encountered in pediatric patient care. Epidemiological and clinical information about hyperprolactinemia in childhood and adolescence is limited. Clinical signs of hyperprolactinemia are very heterogeneous. In girls, disturbances in menstrual function and galactorrhea may be seen, whereas in boys, headache, visual disturbances, delayed pubertal development and hypogonadism are often present. Owing to the ease of ordering a serum prolactin measurement, an evidence-based, cost-effective approach to the management of this endocrine disorder is required. Before a diagnosis of hyperprolactinemia is made, drug use, renal insufficiency, hypothyroidism, and parasellar tumors should be excluded. The main objectives of treatment are normalization of prolactin level, adenoma shrinkage, and recovery from clinical signs related to hyperprolactinemia. In patients with microadenoma, invasive or non-invasive macroadenoma, and even in patients with visual field defects, dopamine agonists are the first-line treatment. Surgical treatment is indicated in patients who are unresponsive or intolerant to medical treatment or who have persistent neurological signs. Radio therapy should be considered as a supportive treatment for patients in whom surgery fails or medical response is not achieved

Efficacy and safety of oral alendronate treatment in children and adolescents with osteoporosis

Objectives: To evaluate the efficacy and safety of oral alendronate on bone mineral density (BMD) in children and adolescents with osteoporosis

Monitoring and prognostic evaluation of patients with congenital hypothyroidism treated in a pediatric endocrinology unit

WOS: 000341414800005PubMed ID: 24292031In this study, the etiological factors, diagnostic approaches, dose, and duration of treatment were compared between cases with transient and permanent congenital hypothyroidism (CH) with respect to prognosis. One hundred and twenty-two patients who received treatments with the diagnosis of CH in the last 10 years were included in the study. The records of the patients were reviewed retrospectively. Serum thyroid-stimulating hormone (TSH) levels at the time of diagnosis were found to be significantly higher, and total thyroxine (TT4) levels were found to be significantly lower in the permanent CH group in comparison to the transient CH group. A statistically significant difference was present between the groups regarding treatment doses, the time needed for TSH decrease to <5 mIU/ml and the TSH and free thyroxine (FT4) levels obtained one month after discontinuation of the treatment. The association between age at the time of initiation of treatment and results of Denver Developmental Test was noted to be statistically significant. The high frequency of transient CH in our region leads to the result that some of the patients had to be unnecessarily treated with L-thyroxine for a long time

Prevalence of anticardiolipin antibodies in type 1 diabetes and autoimmune thyroiditis

WOS: 000279614400003PubMed ID: 20332712INTRODUCTION High levels of anticardiolipin (aCL) antibodies may predict vascular complications that could develop in type 1 diabetes and auto-immune thyroiditis (AIT). However, the clinical relevance of these antibodies in subjects with type 1 diabetes and AIT is unclear. OBJECTIVES The aim of the study was to determine the prevalence and significance of aCL antibodies in patients with type 1 diabetes and AIT. PATIENTS AND METHODS The study involved 74 patients with type 1 diabetes (mean age 12.9 +/- 4.2 years), 64 patients with AIT (mean age 14.1 +/- 3.7 years), and 35 healthy control subjects (mean age 12.8 +/- 3.3 years). The levels of aCL immunoglobulin (Ig) G and aCL IgM antibodies were measured by enzyme-linked immunosorbent assays. Low-positive and medium/high-positive cut-off values were selected for aCL antibody positivity. RESULTS The prevalence of aCL antibodies was higher in AIT patients compared with diabetic and healthy subjects with low positive levels (P < 0.05), while the frequency of medium/high aCL positive levels in AIT and diabetic subjects was not statistically different from that observed in healthy subjects. CONCLUSIONS Our study showed an increased prevalence of aCL antibody positivity in patients with AIT at a low-positive aCL cut-off level, while the frequency of aCL antibody positivity at a moderate/high aCL cut-off level was not significantly different between the groups. We believe that routine investigation of aCL levels may not have clinical relevance in children with type 1 diabetes or AIT