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

Inpatient paediatric medication errors - what can be learned from enquiries made to the National Poisons Information Service (Cardiff Unit)?

Introduction Medication errors are one of the more common types of medical error. Much of the research into medication errors and their prevention has been carried out in the adult population. Fewer data exist on medication errors in paediatrics. Children may be more affected than adults by adverse medication events because of their lower body weight, altered pharmacology and their dependency on adult carers. The National Patient Safety Agency (NPSA) strongly advocates an open reporting culture. Review of reported errors can generate learning points enabling improvements in patient safety. We wished to explore the incidence, nature and severity of reported adverse medication events occurring in paediatric hospital settings which resulted in telephone enquiries to the National Poisons Information Service (Cardiff Unit). Aim To identify and analyse in-hospital paediatric medication errors which resulted in advice being sought from the National Poisons Information Service (Cardiff Unit). Methods Information concerning enquiries to the National Poisons Information Service (NPIS) is recorded in a structured fashion using the United Kingdom Poisons Information Database (UKPID). This database was interrogated for enquiries to the Cardiff Unit over a 3½ year period between 2004 and 2007 to ascertain those medication errors occurring in hospital for children aged 16 years or less. Results There were 82 enquiries involving suspected childhood medication errors occurring in hospital during this period. These included 16 children aged <1month, 36 aged 1month to 5 years, 19 aged 6 to 11 years and 11 children aged 12 to 16 years. Calls were received from throughout the British Isles. The routes of drug delivery involved included oral (n=46), intravenous (n=30), intramuscular (n=3) and intrathecal or epidural (n=3). Follow-up data were not available for all enquiries; however 59 cases needed specific treatment or a prolonged inpatient stay. There were no reported deaths. Conclusion Most enquiries to NPIS (Cardiff Unit) concerning suspected in-patient childhood medication errors involved children under the age of five years and were associated with a prolonged hospital stay. Poisons information data may be used as a source of information about medication errors and their consequences. A culture of open reporting of medication errors should be encouraged so that lessons can be learnt and safer systems for administering medicines developed