scholarly journals Genetic Manipulation on Zebrafish duox Recapitulate the Clinical Manifestations of Congenital Hypothyroidism

Endocrinology ◽  
2021 ◽  
Author(s):  
Feng Sun ◽  
Ya Fang ◽  
Man-Man Zhang ◽  
Rui-Jia Zhang ◽  
Feng-Yao Wu ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Congenital Hypothyroidism ◽  
Growth Retardation ◽  
Genetic Manipulation ◽  
Clinical Manifestations ◽  
Primary Sources ◽  
H2o2 Production ◽  
Endocrine Disorder ◽  
Thyroid Dyshormonogenesis

Abstract Congenital hypothyroidism (CH) is a highly prevalent but treatable neonatal endocrine disorder. Thyroid dyshormonogenesis is the main cause of congenital hypothyroidism in Chinese CH patients and DUOX2 is the most frequent mutated gene involved in H2O2 production. In human, the primary sources for H2O2 production are DUOX1 and DUOX2, while in zebrafish, there is only a single orthologue for DUOX1 and DUOX2. In this study, duox mutant zebrafish were generated through knockdown duox by morpholino or knockout duox by CRISPR Cas9. The associated phenotypes were investigated and rescued by thyroxine (T4) treatment. Mutant zebrafish displayed hypothyroid phenotypes including growth retardation and goiter and infertility. Homozygous mutants in adults also displayed extra-thyroidal abnormal phenotypes including lacking barbels, pigmentation defects, erythema in the opercular region, ragged fins and delayed scales. All these abnormal phenotypes can be rescued by 10 nM T4 treatment. Strikingly, the fertility of zebrafish was dependent on thyroid hormone, T4 treatment should be continued and cannot be stopped over two weeks in hypothyroid zebrafish in order to achieve fertility. Thyroid hormones played a role in the developing and maturing of reproductive cells. Our work indicated that duox mutant zebrafish may provide a model for human congenital hypothyroidism.

scholarly journals Zebrafishduoxmutations provide a model for human congenital hypothyroidism

2018 ◽  
Author(s):  
Kunal Chopra ◽  
Shoko Ishibashi ◽  
Enrique Amaya
Keyword(s):  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Primary Sources ◽  
Oxygen Species ◽  
Hormone Synthesis ◽  
Larval Stages ◽  
Thyroid Hormone Synthesis ◽  
Thyroid Dyshormonogenesis ◽  
Thyroid Hyperplasia ◽  
Treatable Condition

ABSTRACTThyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidase, DUOX1 and DUOX2. Indeed mutations inDUOX1andDUOX2have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue forDUOX1andDUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles of the singleduoxgene in zebrafish,sa9892andsa13017. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine the external and internal phenotypes, we discovered a strong correlation between TH synthesis andduoxfunction, beginning from the early larval stage, when T4levels are already noticeably absent in the mutants. Loss of T4production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia / external goiter, and infertility. Remarkably all of these defects associated with chronic congenital hypothyroidism could be rescued with T4treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafishduoxmutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advance stages of development.

scholarly journals Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria C. Opazo ◽  
Juan Carlos Rivera ◽  
Pablo A. Gonzalez ◽  
Susan M. Bueno ◽  
Alexis M. Kalergis ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Congenital Hypothyroidism ◽  
Gene Mutations ◽  
Genetic Variations ◽  
Hormone Deficiency ◽  
Iodide Transport ◽  
Transport Defect ◽  
Pregnancy And Lactation ◽  
Transient Congenital Hypothyroidism

Fetus and infants require appropriate thyroid hormone levels and iodine during pregnancy and lactation. Nature endorses the mother to supply thyroid hormones to the fetus and iodine to the lactating infant. Genetic variations on thyroid proteins that cause dyshormonogenic congenital hypothyroidism could in pregnant and breastfeeding women impair the delivery of thyroid hormones and iodine to the offspring. The review discusses maternal genetic variations in thyroid proteins that, in the context of pregnancy and/or breastfeeding, could trigger thyroid hormone deficiency or iodide transport defect that will affect the proper development of the offspring.

scholarly journals Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis

2018 ◽  
Vol 103 (5) ◽  
pp. 1889-1898 ◽  
Author(s):  
Minjing Zou ◽  
Ali S Alzahrani ◽  
Ali Al-Odaib ◽  
Mohammad A Alqahtani ◽  
Omer Babiker ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Congenital Hypothyroidism ◽  
Screening Program ◽  
Genetic Defects ◽  
Newborn Screening Program ◽  
Endocrine Disorder ◽  
Thyroid Dysgenesis ◽  
Thyroid Dyshormonogenesis ◽  
Biallelic Mutations ◽  
Saudi Patients

Abstract Context Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. Objective To identify the mutation spectrum of CH-causing genes. Methods Fifty-five patients from 47 families were studied by next-generation exome sequencing. Results Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. Conclusions TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

Causes and laboratory investigation of hypothyroidism

2011 ◽  
pp. 530-537 ◽  
Author(s):  
Ferruccio Santini ◽  
Aldo Pinchera
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Thyroid Hormone Receptor ◽  
Hormone Secretion ◽  
Thyroid Tissue ◽  
Clinical Manifestations ◽  
Primary Hypothyroidism ◽  
Central Hypothyroidism ◽  
Resistance To Thyroid Hormones

Hypothyroidism is the clinical state that develops as a result of the lack of action of thyroid hormones on target tissues (1). Hypothyroidism is usually due to impaired hormone secretion by the thyroid, resulting in reduced concentrations of serum thyroxine (T4) and triiodothyronine (T3). The term primary hypothyroidism is applied to define the thyroid failure deriving from inherited or acquired causes that act directly on the thyroid gland by reducing the amount of functioning thyroid tissue or by inhibiting thyroid hormone production. The term central hypothyroidism is used when pituitary or hypothalamic abnormalities result in an insufficient stimulation of an otherwise normal thyroid gland. Both primary and central hypothyroidism may be transient, depending on the nature and the extent of the causal agent. Hypothyroidism following a minor loss of thyroid tissue can be recovered by compensatory hyperplasia of the residual gland. Similarly, hypothyroidism subsides when an exogenous inhibitor of thyroid function is removed. Peripheral hypothyroidism may also arise as a consequence of tissue resistance to thyroid hormones due to a mutation in the thyroid hormone receptor. Resistance to thyroid hormones is a heterogeneous clinical entity with most patients appearing to be clinically euthyroid while some of them have symptoms of thyrotoxicosis and others display selected signs of hypothyroidism. The common feature is represented by pituitary resistance to thyroid hormones, leading to increased secretion of thyrotropin that in turn stimulates thyroid growth and function. The variability in clinical manifestations depends on the severity of the hormonal resistance, the relative degree of tissue hyposensitivity, and the coexistence of associated genetic defects (see Chapter 3.4.8).

scholarly journals Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction

2021 ◽  
Vol 12 ◽  
Author(s):  
Stephen H. LaFranchi
Keyword(s):  
Thyroid Hormone ◽  
Preterm Infants ◽  
Thyroid Function ◽  
Congenital Hypothyroidism ◽  
Clinical Manifestations ◽  
Thyroid Function Tests ◽  
Term Infants ◽  
Serum T4 ◽  
Preterm Babies ◽  
Hpt Axis

Maternal thyroid hormone crosses the placenta to the fetus beginning in the first trimester, likely playing an important role in fetal development. The fetal thyroid gland begins to produce thyroid hormone in the second trimester, with fetal serum T4 levels gradually rising to term. Full maturation of the hypothalamic-pituitary-thyroid (HPT) axis does not occur until term gestation or the early neonatal period. Postnatal thyroid function in preterm babies is qualitatively similar to term infants, but the TSH surge is reduced, with a corresponding decrease in the rise in T4 and T3 levels. Serum T4 levels are reduced in proportion to the degree of prematurity, representing both loss of the maternal contribution and immaturity of the HPT axis. Other factors, such as neonatal drugs, e.g., dopamine, and non-thyroidal illness syndrome (NTIS) related to co-morbidities contribute to the “hypothyroxinemia of prematurity”. Iodine, both deficiency and excess, may impact thyroid function in infants born preterm. Overall, the incidence of permanent congenital hypothyroidism in preterm infants appears to be similar to term infants. However, in newborn screening (NBS) that employ a total T4-reflex TSH test approach, a higher proportion of preterm babies will have a T4 below the cutoff, associated with a non-elevated TSH level. In NBS programs with a primary TSH test combined with serial testing, there is a relatively high incidence of “delayed TSH elevation” in preterm neonates. On follow-up, the majority of these cases have transient hypothyroidism. Preterm/LBW infants have many clinical manifestations that might be ascribed to hypothyroidism. The question then arises whether the hypothyroxinemia of prematurity, with thyroid function tests compatible with either non-thyroidal illness syndrome or central hypothyroidism, is a physiologic or pathologic process. In particular, does hypothyroxinemia contribute to the neurodevelopmental impairment common to preterm infants? Results from multiple studies are mixed, with some randomized controlled trials in the most preterm infants born <28 weeks gestation appearing to show benefit. This review will summarize fetal and neonatal thyroid physiology, thyroid disorders specific to preterm/LBW infants and their impact on NBS for congenital hypothyroidism, examine treatment studies, and finish with comments on unresolved questions and areas of controversy.

Phenotypic Variability of Patients With PAX8 Variants Presenting With Congenital Hypothyroidism and Eutopic Thyroid

2020 ◽  
Vol 106 (1) ◽  
pp. e152-e170
Author(s):  
Núria Camats ◽  
Noelia Baz-Redón ◽  
Mónica Fernández-Cancio ◽  
María Clemente ◽  
Ariadna Campos-Martorell ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Phenotypic Variability ◽  
Hereditary Diseases ◽  
Hormone Synthesis ◽  
Functional Studies ◽  
Thyroid Hormone Synthesis ◽  
Thyroid Dyshormonogenesis

Abstract Purpose Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Patients and Methods Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. Results We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Conclusions Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.

Clinical assessment and systemic manifestations of thyrotoxicosis

2011 ◽  
pp. 441-452
Author(s):  
Claudio Marcocci ◽  
Filomena Cetani ◽  
Aldo Pinchera
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Clinical Manifestations ◽  
Clinical Syndrome ◽  
Graves Disease ◽  
Free Triiodothyronine ◽  
Excessive Secretion ◽  
Almost All ◽  
Symptoms And Signs

The term thyrotoxicosis refers to the clinical syndrome that results when the serum concentrations of free thyroxine, free triiodothyronine, or both, are high. The term hyperthyroidism is used to mean sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland; Graves’ disease is the most common example of this. Occasionally, thyrotoxicosis may be due to other causes such as destructive thyroiditis, excessive ingestion of thyroid hormones, or excessive secretion of thyroid hormones from ectopic sites; in these cases there is no overproduction of hormone by thyrocytes and, strictly speaking, no hyperthyroidism. The various causes of thyrotoxicosis are listed in Chapter 3.3.5. The clinical features depend on the severity and the duration of the disease, the age of the patient, the presence or absence of extrathyroidal manifestations, and the specific disorder producing the thyrotoxicosis. Older patients have fewer symptoms and signs of sympathetic activation, such as tremor, hyperactivity, and anxiety, and more symptoms and signs of cardiovascular dysfunction, such as atrial fibrillation and dyspnoea. Rarely a patient with ‘apathetic’ hyperthyroidism will lack almost all of the usual clinical manifestations of thyrotoxicosis (1). Almost all organ systems in the body are affected by thyroid hormone excess, and the high levels of circulating thyroid hormones are responsible for most of the systemic effects observed in these patients (Table 3.3.1.1). However, some of the signs and symptoms prominent in Graves’ disease reflect extrathyroidal immunological processes rather than the excessive levels of thyroid hormones produced by the thyroid gland (Table 3.3.1.2).

Deficiência na Globulina de Ligação de Tiroxina: uma Revisão de Literatura

2019 ◽  
Vol 22 (2) ◽  
pp. 104
Author(s):  
Kledson Lopes Barbosa ◽  
Christiani Lozany Ferreira de Lima Araújo
Keyword(s):  
Mental Retardation ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Subclinical Hypothyroidism ◽  
Genetic Disease ◽  
Clinical Manifestations ◽  
Carrier Protein ◽  
Intellectual Deficiency ◽  
Review Of The Literature ◽  
Health Related

O hipotireoidismo congênito é classificado como a falta de hormônios tireoidianos após o nascimento, e que quando não tratado inicialmente,contribui para o atraso acentuado do desenvolvimento e retardo mental. A ingestão adequada de iodo é necessária para a produção de hormônios tireoidianos. Visto que sua deficiência pode levar ao hipotireoidismo congênito em neonato, uma condição caracterizada, geralmente, por deficiência intelectual e nanismo, podendo ainda afetar a audição. O presente estudo teve como objetivo realizar uma revisão de literatura acerca da Hipotebegenemia e seus agravos relacionados à saúde. Hipotebegenemia doença genética, ligada ao cromossomo X e que acomete, principalmente, meninos. Ocorre por uma deficiência na proteína transportadora dos hormônios tireodianos - TBG. Para isto, realizaram-se buscas bibliográficas em bases eletrônicas, tais como: Bireme, Lilacs, SciELO, Pubmed e Periódicos Capes. Conclui-se que o hipotireoidismo subclínico na infância parece ser reversível na maioria dos casos. Contudo, os riscos de progressão desta condição não devem ser afastados, uma vez que as manifestações clínicas irão depender de determinadas condições, tal como as formas autoimunes.Palavras chaves: Hipotireoidismo. Tireoglobulina Ligadora. Doença Genética.AbstractCongenital hypothyroidism is classified as the lack of thyroid hormones after birth, and when not treated initially, it contributes to markeddevelopmental delay and mental retardation. The ingestion of iodide it is necessary for the thyroid hormones production. Its deficiency can leadto congenital hypothyroidism in the neonate, a condition usually characterized by intellectual deficiency and dwarfism, and may even affect hearing. The objective of the present study was to carry out a review of the literature on Hypothembemia and its health related diseases. It is a Hipotebegenemia genetic disease, linked to the X chromosome and affects mainly boys. It occurs due to a deficiency in thyroid hormone carrier protein - TBG. For this, bibliographic searches were carried out in electronic databases, such as: Bireme, Lilacs, SciELO, Pubmed and Periodicals CAPES. It is concluded that subclinical hypothyroidism in childhood seems to be reversible in most cases. However, the risks of progress by category are not required, since that the clinical manifestations will depend on conditions, such as autoimmune forms.Keywords: Hypothyroidism. Binding Thyroglobulin. Genetic Disease.

Establishment of Early Pregnancy Related Thyroid Hormone Models and Reference Intervals for Pregnant Women in China Based on Real World Data

2021 ◽  
Vol 53 (04) ◽  
pp. 272-279
Author(s):  
Chaochao Ma ◽  
Xiaoqi Li ◽  
Lixin Liu ◽  
Xinqi Cheng ◽  
Fang Xue ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Pregnant Women ◽  
Early Pregnancy ◽  
Gestational Age ◽  
Dynamic Change ◽  
Reference Intervals ◽  
Thyroid Stimulating Hormone ◽  
Free Thyroxine ◽  
Stimulating Hormone

AbstractThyroid hormone reference intervals are crucial for diagnosing and monitoring thyroid dysfunction during early pregnancy, and the dynamic change trend of thyroid hormones during pregnancy can assist clinicians to assess the thyroid function of pregnant women. This study aims to establish early pregnancy related thyroid hormones models and reference intervals for pregnant women. We established two derived databases: derived database* and derived database#. Reference individuals in database* were used to establish gestational age-specific reference intervals for thyroid hormones and early pregnancy related thyroid hormones models for pregnant women. Individuals in database# were apparently healthy non-pregnant women. The thyroid hormones levels of individuals in database# were compared with that of individuals in database* using nonparametric methods and the comparative confidence interval method. The differences in thyroid stimulating hormone and free thyroxine between early pregnant and non-pregnant women were statistically significant (p<0.0001). The reference intervals of thyroid stimulating hormone, free thyroxine and free triiodothyronine for early pregnant women were 0.052–3.393 μIU/ml, 1.01–1.54 ng/dl, and 2.51–3.66 pg/ml, respectively. Results concerning thyroid stimulating hormone and free thyroxine reference intervals of early pregnancy are comparable with those from other studies using the same detection platform. Early pregnancy related thyroid hormones models showed various change patterns with gestational age for thyroid hormones. Early pregnancy related thyroid hormones models and reference intervals for pregnant women were established, so as to provide accurate and reliable reference basis for the diagnosing and monitoring of maternal thyroid disfunction in early pregnancy.

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