Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

The joint effect of congenital hypothyroidism and hypercaloric diet consumption as triggers of type 2 diabetes mellitus

Introduction Congenital hypothyroidism affects metabolic and thyroid programming, having a deleterious effect on bodyweight regulation promoting metabolic diseases. This work aimed to demonstrate the development of type 2 diabetes mellitus (T2D) in animals with congenital hypothyroidism, only by the consumption of a mild hypercaloric diet in the extrauterine stage. Methods Two groups of female Wistar rats (n = 9): euthyroid and hypothyroid were used. Hypothyroidism was induced by a thyroidectomy with parathyroid reimplantation. Male offsprings post-weaning were divided into four groups (n = 10): euthyroid, hypothyroid, euthyroid + hypercaloric diet, and hypothyroid + hypercaloric diet. The hypercaloric diet consisted of ground commercial feed plus 20% lard and was administered until postnatal week 40. Bodyweight and energy intake were monitored weekly. Also, metabolic and hormonal markers related to cardiovascular risk, insulin resistance, and glucose tolerance were analyzed at week 40. Then, animals were sacrificed to perform the morphometric analysis of the pancreas and adipose tissue. Results T2D was developed in animals fed a hypercaloric diet denoted by the presence of central obesity, hyperphagia, hyperglycemia, dyslipidemia, glucose tolerance, insulin resistance and hypertension, as well as changes in the cytoarchitecture of the pancreas and adipose tissue related to T2D. The results show that congenital hypothyroid animals had an increase in metabolic markers and an elevated cardiovascular risk. Conclusions Congenital hypothyroid animals develop T2D, having the highest metabolic disturbances and a worsened clinical prognosis than euthyroid animals.

Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism

BackgroundsAs a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH).MethodsMutations in the TPO gene were screened and identified in 219 patients with CH from northwest China by using high-throughput sequencing and bioinformatics analysis. The biological function of detected variants was studied by in vitro experiments and homology modeling.ResultsNineteen rare variants, including seven novel ones, were detected in 17 of 219 patients (7.8%). Most cases were detected with one single heterozygous variant, and only two patients were detected with multiple variants, i.e., compounds for (1) IVS7-1G>A, p.Ala443Val, and p.Arg769Trp and (2) p.Asn592Ser and p.Asn798Lys. The biological function of the four missense mutations (i.e., p.Ala443Val, p.Arg769Trp, p.Asn592Ser, and p.Asn798Lys) they carried were further studied. Experimental data showed that these four mutations did not affect the protein expression level of the TPO gene but remarkably reduced the peroxidase activity toward guaiacol oxidation, retaining 8–32% of activity of the wild-type protein. The comparison of the predicted 3-D structures of wild-type and mutant TPO proteins showed that these four amino acid substitutions changed the non-covalent interactions of studied residues that might alter the structure and function of the TPO protein.ConclusionThis study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO mutation was not a common reason to cause CH in China. The functional data may help to clarify the structure-function relationship of the TPO protein and provide further evidence for the elucidation of the genetic etiology of CH.

Overview on Neurological Manifestations of Thyroid Disease

Hypothyroidism and hyperthyroidism are both prevalent medical conditions that are frequently accompanied with neurologic and neuromuscular dysfunction. Triiodothyronine (T3) and thyroxine (T4) hormones are produced by the thyroid gland and play a crucial role in tissue formation and metabolism. Both of these hormones have a variety of impacts on the brain and neuromuscular system. Specially in children, because brain development can be effected by any disturbances in Thyroidal hormones level. And thus, conditions like Allan-Herndon-Dudley Syndrome & Benign Hereditary Chorea is considered genetic thyroidal diseases both will be discussed in this review. hypothyroidism can have serious consequences for neuropsychiatric function. The pathophysiological processes underlying the neurological symptoms of hypothyroidism and hyperthyroidism are likely to be multifactorial, in this review we will be looking at multiple neurological as well as psychiatric manifestations related to thyroidal hormones disorders. Methods: We used the phrases "hypothyroidism," "hyperthyroidism," "neurological problems," "neuropathy," "myopathy," "congenital hypothyroidism," and "encephalopathy" in a PubMed search, google scholar and google search engines. Case series, individual case reports, systematic reviews, retrospective analyses, and randomized controlled trials were among the papers examined. Classification of thyroidal dysfunction has been made depending on the thyroidal hormones level. The neurological consequences of congenital hypothyroidism were examined, as well as the clinical aspects of hypothyroidism and hyperthyroidism-related neuromuscular disorders, as well as other autoimmune illnesses. Hashimoto encephalopathy's evidence and pathophysiological issues were also examined. Conclusion: Thyroid is critical organ due to role of its thyroidal hormones, both hypothyroidism and hyperthyroidism induce some serious neurological and phycological disorders, some of which is genetic, hypothyroidism can impact the development of child and thus regular thyroidal hormones testing is recommended in children who demonstrates any signs of neurological psychiatric or cognitive disease.

Neonatal Screening for Hyperthyroidism proof of concept

Context Early treatment is essential to avoid the cardiac complication of Neonatal hyperthyroidism (NH). Our results have direct implications for clinical care. Objective NH can cause potentially fatal neonatal thyrotoxicosis. Here, we evaluated the feasibility of neonatal hyperthyroidism screening using the thyroid-stimulating hormone value in dried blood collected routinely on filter paper on the third postnatal day of life for congenital hypothyroidism screening. Design Retrospective case-control Methods Cases were identified using data from our previously published study of 280,000 infants born in ten maternity units in France in 2007-2014. Controls were identified among the 1,362,564 infants born in the Ile-de-France region during the same period. Results A screening thyroid-stimulating hormone level below 0.18 mIU/L on the third postnatal day had 71% (95% confidence interval [95%CI], 44%–90%) sensitivity, 99% (95%CI, 99%–100%) specificity, 81% (95%CI, 74%–86%) positive predictive value, and 98% (95%CI, 97%–99%) negative predictive value for detecting severe NH. By univariate regression analysis, the screening thyroid-stimulating hormone value was the strongest predictor of NH (p<0.00001), with an area under the receiver-operating characteristics curve of 0.98 (95%CI, 0.95–1.0). Expected frequencies were not significantly different from observed frequencies (Hosmer-Lemeshow test, p=0.99). Conclusions The screening thyroid-stimulating hormone test can be used to detect severe NH, the optimal cut-off being 0.18 mIU/L. The additional cost compared to screening for congenital hypothyroidism only would be small. Infants with neonatal hyperthyroidism would benefit from an earlier diagnosis with treatment initiation at the pre-symptomatic stage in many cases, ensuring optimal outcomes.

Congenital Hypothyroidism and Brain Development: Association With Other Psychiatric Disorders

Thyroid hormones play an important role in brain development, and thyroid hormone insufficiency during the perinatal period results in severe developmental delays. Perinatal thyroid hormone deficiency is clinically known as congenital hypothyroidism, which is caused by dysgenesis of the thyroid gland or low iodine intake. If the disorder is not diagnosed or not treated early, the neuronal architecture is perturbed by thyroid hormone insufficiency, and neuropathological findings, such as abnormal synapse formation, defects in neuronal migration, and impairment of myelination, are observed in the brains of such patients. Furthermore, the expression of psychiatric disorder-related molecules, especially parvalbumin, is significantly decreased by thyroid hormone insufficiency during the perinatal period. Animal experiments using hypothyroidism models display decreased parvalbumin expression and abnormal brain architecture, and these experimental results show reproducibility and stability. These basic studies reinforce the results of epidemiological studies, suggesting the relevance of thyroid dysfunction in psychiatric disorders. In this review, we discuss the disruption of brain function associated with congenital hypothyroidism from the perspective of basic and clinical research.

Targeted Secondary Screening for Congenital Hypothyroidism in High-Risk Neonates: A 9 Year Review in a Large California Health Care System

Secondary screening for missed congenital hypothyroidism (CH) has been introduced sporadically, but its necessity and optimal strategy have not been recognized. We hypothesized that a simple clinical protocol (performed by a medical group without a governmental mandate) targeting infants at high risk for missed CH can identify cases. We performed a 9-year retrospective review of 338,478 neonates within a California health plan following the introduction of thyrotropin (TSH) secondary screening for neonates at high risk for missed CH due to very-low-birthweight (VLBW), hospitalized congenital heart disease (CHD), and same-sex multiples (SSM). Screening performance by day 60 of life was 95% successful for VLBW and >50% for CHD and SSM, leading to an additional 35% CH treated cases despite re-testing only 1.7% of the cohort. Infants with VLBW or CHD were 33 times more likely (190 times more likely for CHD with Down Syndrome) to receive treatment for CH than random infants diagnosed by primary screening (p < 0.001), and 92% of these infants were not found by primary newborn screening. Currently, permanent disease has been documented in 84% of CH by primary screening compared to 27% by secondary screening (p < 0.001). This targeted secondary screening program identifies and treats additional CH cases after TSH-only newborn screening.