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.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.

Context:Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis.Objective:We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD.Design:Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis.Setting:The study was conducted on patients from three pediatric centers in the United Kingdom.Patients:Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study.Interventions:There were no interventions.Main Outcome Measure:Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured.Results:A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line.Conclusion:In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

Type I diabetes mellitus (DM) has been associated with abnormalities of T cells. Our objective was to assess whether antibody responses to T-cell-dependent and -independent antigens in children with DM are lower than those of children without DM. We performed a case-control study matching children with DM to children without DM by age and by assessing antibody levels to pneumococcal serotypes, Haemophilus influenzae, and tetanus and diphtheria toxoids and reassessing antibody levels in patients with antibody levels below protective thresholds after booster immunization. We recruited 36 children with DM and 36 age-matched controls. The mean age was 10 years. There was no difference between groups in antibody levels against the antigens tested. Pneumococcal antibody levels below the protective threshold were found in 35.9% of DM patients after conjugate pneumococcal vaccination with no difference between groups. Booster immunization with unconjugated pneumococcal vaccine resulted in a median level against pneumococcal serotypes of 2.3 g/ml (range, 0.05 to 664.7 g/ml) in children with DM and 6.1 g/ml (0.12 to 203.36 g/ml) in children without DM (P ‫؍‬ 0.013). Over 85% of children had levels above the protective threshold after booster immunization with no difference between groups. There was no evidence for a reduced antibody response to T-cell-dependent antigens given during childhood immunizations in children with DM. There was a reduced antibody response to antigens of pneumococcal strains in children with DM given unconjugated pneumococcal polysaccharide vaccine compared to that of children without DM without being associated with a difference in percentage of antibody levels below the protective threshold between groups.T ype I diabetes mellitus (DM) has been associated with multiple abnormalities of T-cell function and quantities. In the first ground-breaking studies, decreased CD4/CD8 lymphocyte ratios, reduced lymphocyte blastogenesis, and acquired defects in interleukin-2 production were observed in people affected by DM (1, 2, 3). Subsequent research revealed reduced T-cell primary responses to protein antigens (4). Other investigations demonstrated features of a suppression of a T-helper cell 1 phenotype, with reduced expression of Th1-associated chemokine receptors and decreased secretion of Th1 cytokines (5).A previous study showed that compared to healthy controls, adult DM patients mounted a significantly impaired primary antibody response to T-cell-dependent primary protein antigens used for immunization, like hepatitis A vaccine and diphtheria toxoid, while the response to the T-cell-independent pneumococcal polysaccharide vaccine was not different. Patients with type II diabetes showed a normal response to immunization, illustrating that hyperglycemia is not involved in a change of the immune response (6).People with DM are susceptible to bacterial and particularly pneumococcal infection and are at increased risk of morbidity and mortality from bacteremia due to Streptococcus pneumoniae (7,8).Ther...

The percutaneous endoscopic gastrostomy (PEG) tube has become a widely used feeding tube for long-term delivery of fluids, liquid feed and medicines. PEG tube insertion can be considered a minimally invasive technique, associated with rapid recovery and early discharge from hospital but is not without risk (Vervloessem et al 2009; Naiditch et al 2010). A lack of nationally agreed, evidence-based clinical practice guidelines makes PEG exit site care a matter of local clinical practice and clinical judgement. In paediatric practice, children experience care shared across several healthcare settings, meeting clinical teams with varying levels of knowledge and experience of PEG care. This can lead to conflicting advice, which can have a negative effect on patient safety and experience. The case history in this article demonstrates how PEG tube insertion is never a minor procedure for a child and family (Vervloessem et al 2009; Khattak et al 1998). It highlights areas of potential conflict in clinical management of PEG exit sites, and it shows how application of wound care principles, along with a range of modern products can have a positive outcome.

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