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.

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 Endogenous thyroid hormones modulate pituitary somatotroph differentiation during chicken embryonic development

2004 ◽  
Vol 180 (1) ◽  
pp. 45-53 ◽  
Author(s):  
L Liu ◽  
TE Porter
Keyword(s):  
Thyroid Hormone ◽  
Embryonic Development ◽  
Thyroid Hormones ◽  
Synthesis Inhibitor ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis ◽  
Growth Hormone Cell ◽  
Thyroid Hormone Levels

Growth hormone cell differentiation normally occurs between day 14 and day 16 of chicken embryonic development. We reported previously that corticosterone (CORT) could induce somatotroph differentiation in vitro and in vivo and that thyroid hormones could act in combination with CORT to further augment the abundance of somatotrophs in vitro. The objective of the present study was to test our hypothesis that endogenous thyroid hormones regulate the abundance of somatotrophs during chicken embryonic development. Plasma samples were collected on embryonic day (e) 9-14. We found that plasma CORT and thyroid hormone levels increased progressively in mid-embryogenesis to e 13 or e 14, immediately before normal somatotroph differentiation. Administration of thyroxine (T4) and triiodothyronine (T3) into the albumen of fertile eggs on e 11 increased somatotroph proportions prematurely on e 13 in the developing chick embryos in vivo. Furthermore, administration of methimazole, the thyroid hormone synthesis inhibitor, on e 9 inhibited somatotroph differentiation in vivo, as assessed on e 14; this suppression was completely reversed by T3 replacement on e 11. Since we reported that T3 alone was ineffective in vitro, we interpret these findings to indicate that the effects of treatments in vivo were due to interactions with endogenous glucocorticoids. These results indicate that treatment with exogenous thyroid hormones can modulate somatotroph abundance and that endogenous thyroid hormone synthesis likely contributes to normal somatotroph differentiation.

Effects of a selenium deficient diet on thyroid function of normal and perchlorate treated rats

1988 ◽  
Vol 118 (4) ◽  
pp. 495-502 ◽  
Author(s):  
J. Golstein ◽  
B. Corvilain ◽  
F. Lamy ◽  
D. Paquer ◽  
J. E. Dumont
Keyword(s):  
Thyroid Hormone ◽  
Tap Water ◽  
Selenium Deficiency ◽  
Thyroid Peroxidase ◽  
Deficient Diet ◽  
Adult Rats ◽  
Pregnant Rats ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis

Abstract. Pregnant rats were submitted to a selenium-deficient diet immediately after mating; it was continued for 4 weeks after delivery. The pups were sacrificed at 3 and 4 weeks of age. Perchlorate, an antithyroid agent inhibiting iodide trapping in the thyroid, was administered via the drinking water to half of the rats. Rats submitted to a normal laboratory diet and to the experimental diet supplemented with selenium were used as controls. The effects of selenium deficiency were an increase in the number of growth abnormalities, growth retardation, and decreased seleno-dependent glutathione peroxidase (GSH-Px) activity in plasma and in various organs. These effects were relieved by selenium supplementation in the diet. Perchlorate treatment induced the classic picture of primary hypothyroidism. Selenium deficiency increased thyroid hormone levels in perchlorate-treated rats and in controls drinking tap water. In the latter group, it also decreased TSH plasma concentration and thyroid weight. These effects were partially reversed by Se supplementation. In vitro experiments, performed on adult rats, revealed increased radioiodide uptake and organification in glands from the rats submitted to the selenium-free diet. Plasma T3 half-life was similar in control and Se-deficient rats. These data suggest a higher efficiency of thyroid hormone synthesis in the thyroids of selenium-deficient rats, despite a lower thyroid stimulation as evaluated by serum TSH. They are compatible with the hypothesis that decreased selenium supply, leading to a decreased GSH-Px in the thyroid, increases hydrogen peroxide steady state level and thus thyroid peroxidase activity and thyroid hormone synthesis.

scholarly journals Extrathyroidal thyroid hormone synthesis?

2011 ◽  
Vol 210 (1) ◽  
pp. 3-4 ◽  
Author(s):  
Marian Ludgate
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis

A paper published in this issue of the Journal of Endocrinology has revisited the hypothesis that thyroid hormones may be generated by tissues outside the thyroid gland in higher organisms including mammals. This commentary appraises the strengths and weaknesses of the study, the alternative explanations for the findings and possible future measures to investigate further. The concept of extrathyroidal thyroxine and triiodothyronine synthesis has previously been proposed; by assuming that Nagao et al. and earlier authors are correct, the plausibility and possible mechanisms underlying the hypothesis are discussed.

scholarly journals N-Glycans Modulate in Vivo and in Vitro Thyroid Hormone Synthesis

1995 ◽  
Vol 270 (50) ◽  
pp. 29881-29888 ◽  
Author(s):  
Bernard Mallet ◽  
Pierre-Jean Lejeune ◽  
Nathalie Baudry ◽  
Patricia Niccoli ◽  
Pierre Carayon ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis

scholarly journals Primary congenital hypothyroidism: defects in iodine pathways

2003 ◽  
pp. 247-256 ◽  
Author(s):  
JJ de Vijlder
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Congenital Hypothyroidism ◽  
Primary Hypothyroidism ◽  
Special Importance ◽  
Hormone Production ◽  
Central Hypothyroidism ◽  
Hormone Synthesis ◽  
Diagnosis And Classification ◽  
The Central Nervous System

The thyroid gland is the only source of thyroid hormone production. Thyroid hormone is essential for growth and development, and is of special importance for the development of the central nervous system. It was for that reason that neonatal screening on congenital hypothyroidism was introduced and is now performed in many countries. Defects in thyroid hormone production are caused by several disorders in hormone synthesis and in the development of the thyroid gland (primary hypothyroidism) or of the pituitary gland and hypothalamus (central hypothyroidism).This paper describes defects in the synthesis of thyroid hormone caused by disorders in the synthesis or iodination of thyroglobulin, leakage of iodinated proteins by a stimulated thyroid gland and the presence of abnormal iodoproteins, mainly iodinated albumin, in the thyroid gland and blood circulation. Circulating thyroglobulin and abnormal iodoproteins, as well as the breakdown products of these iodoproteins excreted in urine, are used for etiological diagnosis and classification. Moreover, our finding of an enzyme that catalyses the dehalogenation of iodotyrosines, which is important for iodine recycling and required for economical use of iodine, is also referred to.

scholarly journals Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Isabelle Oliver-Petit ◽  
Thomas Edouard ◽  
Virginie Jacques ◽  
Marie Bournez ◽  
Audrey Cartault ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Diagnostic Tools ◽  
World Population ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Hormone Synthesis ◽  
Thyroid Hormone Synthesis ◽  
Generation Sequencing

ContextCongenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.ObjectiveWe explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.Patients, Design and SettingUsing the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity.ResultsAmong the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.ConclusionThe systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.

Cognitive and Behavioral Complications of Congenital Hypothyroidism

2010 ◽  
Author(s):  
Ruth D. Nass
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Brain Development ◽  
Congenital Hypothyroidism ◽  
Behavioral Problems ◽  
Thyroid Stimulating Hormone ◽  
Primary Hypothyroidism ◽  
Normal Brain ◽  
Gene Encoding ◽  
Hormone Synthesis

Congenital hypothyroidism (CH) affects approximately 1 in 3,500 newborns. There is a female preponderance. In areas of iodine insufficiency, the incidence is higher, since iodine is a key element in the synthesis of thyroid hormone. Approximately 85% of CH cases are sporadic, whereas 15% are hereditary. Thyroid hormone is essential for normal pre- and postnatal brain development. The importance of in utero thyroid hormone status is demonstrated by the fact that maternal hypothyroidism during pregnancy is known to result in cognitive and motor deficits in the offspring (Forrest 2004; Zoeller and Rovet 2004). Congenital hypothyroidism is already expressed in fetal life; maternal T4, transferred via the placenta, is not sufficient for normal brain development (Forrest 2004; Haddow et al. 1999; Opazo et al. 2008; Pop and Vulsma 2005). Prior to newborn screening, CH that went undiagnosed and untreated for more than 3 months was associated with permanent and significant mental retardation, as well as behavioral problems. Outcome is now significantly better. Children with CH have normal intelligence, although subtle and specific cognitive and behavioral problems occur. Congenital hypothyroidism can be caused by primary hypothyroidism, due to a defect of the thyroid gland, or by central hypothyroidism secondary to defective hypothalamic or pituitary regulation of thyroid hormone. Several types of primary thyroid abnormalities may occur. Thyroid dysgenesis is the result of a missing, ectopic, or hypoplastic gland. Proteins that are crucial for normal thyroid gland development include the thyroid transcription factors PAX8, TTF1, TTF2, FOXE1 and the thyroid stimulating hormone (TSH) receptor gene. Thyroid dyshormonogenesis is generally due to an autosomal recessive genetic defect in any of many stages of thyroid hormone synthesis, secretion and transport (Moreno and Visser 2007). One in 50,000 children has autosomal dominant thyroid hormone resistance (RTH) due to a mutation in the gene encoding for the TRb thyroid receptors (Hauser et al. 1993; Weiss et al. 1993). Iodine deficiency can also cause CH (endemic cretinism) (DeLange et al. 2000). Gaudino and colleagues (2005) determined the etiology of CH in 49 non-athyroid cases.

H9c2 cardiomyoblasts produce thyroid hormone

2008 ◽  
Vol 294 (5) ◽  
pp. C1227-C1233 ◽  
Author(s):  
Christof Meischl ◽  
Henk P. Buermans ◽  
Thierry Hazes ◽  
Marian J. Zuidwijk ◽  
René J. P. Musters ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Peroxidase ◽  
Sodium Iodide Symporter ◽  
Hormone Synthesis ◽  
Cardiovascular Hemodynamics ◽  
Wide Range ◽  
Vitro Model

Thyroid hormone acts on a wide range of tissues. In the cardiovascular system, thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Although some early reports in the literature suggested an unknown extrathyroidal source of thyroid hormone, it is currently thought to be produced exclusively in the thyroid gland, a highly specialized organ with the sole function of generating, storing, and secreting thyroid hormone. Whereas most of the proteins necessary for thyroid hormone synthesis are thought to be expressed exclusively in the thyroid gland, we now have found evidence that all of these proteins, i.e., thyroglobulin, DUOX1, DUOX2, the sodium-iodide symporter, pendrin, thyroid peroxidase, and thyroid-stimulating hormone receptor, are also expressed in cardiomyocytes. Furthermore, we found thyroglobulin to be transiently upregulated in an in vitro model of ischemia. When performing these experiments in the presence of 125I, we found that 125I was integrated into thyroglobulin and that under ischemia-like conditions the radioactive signal in thyroglobulin was reduced. Concomitantly we observed an increase of intracellularly produced, 125I-labeled thyroid hormone. In conclusion, our findings demonstrate for the first time that cardiomyocytes produce thyroid hormone in a manner adapted to the cell's environment.

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