Frequent TSH Receptor Genetic Alterations with Variable Signaling Impairment in a Large Series of Children with Nonautoimmune Isolated Hyperthyrotropinemia

Calebiro, Davide; Gelmini, Giulia; Cordella, Daniela; Bonomi, Marco; Winkler, Franziska; Biebermann, Heike; Marco, Alessandro De; Marelli, Federica; Libri, Domenico; Antonica, Francesco; Vigone, Maria Cristina; Cappa, Marco; Mian, Caterina; Sartório, Alessandro; Beck‐Peccoz, Paolo; Radetti, Giorgio; Weber, Giovanna; Persani, Luca

doi:10.1210/jc.2011-1938

Cited by 52 publications

(34 citation statements)

References 22 publications

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“…These findings are in accordance with those reported by other authors in both adults [13] and children [10] with SH and confirm that baseline TSH concentration is the most powerful predictor of SH evolution over time. The stable and even worsening TSH elevation recorded in the present study in some children of both groups might be the expression of mild mutations of TSH receptor gene, which are known to be a possible cause of TSH resistance and apparently idiopathic SH [14,15,16,17]. Children with TSH receptor gene mutations and consequent TSH resistance are likely to need supranormal amounts of TSH to adequately stimulate the thyroid, and persistence over time of an SH condition is not surprising in these subjects.…”

Section: Discussionmentioning

confidence: 93%

Comparative Evaluation of Therapy with <i>L</i>-Thyroxine versus No Treatment in Children with Idiopathic and Mild Subclinical Hypothyroidism

et al. 2012

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Background: The question of whether children with subclinical hypothyroidism (SH) should be treated or not is controversial due to the lack of studies on outcomes of SH children treated with L-thyroxine (L-T₄) versus those receiving no therapy. Objectives: (a) To evaluate thyroid tests under L-T₄ and after therapy withdrawal in 69 SH children (group A) and (b) to compare our results with those recorded in 92 untreated children (group B). Design: Group A children were treated for 24 months and TSH and FT₄ levels 3 months after therapy withdrawal were compared with those measured in group B at the end of follow-up in order to investigate treatment effects. Results: The prevalence of children who had normalized TSH at the end of follow-up was higher in group A, but the prevalence of those who had normalized or maintained unchanged TSH was similar in the two groups, as was the prevalence of children who exhibited a TSH increase >10 mU/l. In group A, TSH values at 27 months were associated with baseline values. Conclusions: (a) Two-year treatment in SH children is unable to modify posttherapy outcome of hyperthyrotropinemia; (b) therapy is unable to prevent the risk of further TSH increase after treatment withdrawal, and (c) posttherapy TSH outcome is conditioned by baseline TSH.

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Section: Discussionmentioning

confidence: 93%

Comparative Evaluation of Therapy with <i>L</i>-Thyroxine versus No Treatment in Children with Idiopathic and Mild Subclinical Hypothyroidism

et al. 2012

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“…The defect may affect steps along the cascade after TSH binding to its receptor. Resistance to TSH because of either TSHR or G s alpha mutations (53) and the resulting TSH elevations does not necessarily indicate hypothyroidism (54). Compound heterozygotes or homozygotes for partially inactivating mutations of the TSHR may have an elevated TSH, but with normal peripheral hormones, and be euthyroid, while monoallelic mutations in the G s alpha subunit are associated with pseudohypoparathyroidism.…”

Section: Tsh Measurementsmentioning

confidence: 99%

Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Estrada

Soldin

Buckey

et al. 2014

Thyroid

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Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis. Thyrotropin SynthesisT hyrotropin (TSH) is a heterodimeric 28-kDa-glycoprotein hormone released from the anteromedial pituitary and is a regulator of thyroid function. Its synthesis is controlled by the hypothalamic neuropeptide TSH-releasing hormone (TRH). The two peptide subunits of TSH are noncovalently linked and cotranslationally glycosylated with mannose-rich oligosaccharides (1). Posttranslationally, the two subunits are combined and the attached oligosaccharides are further processed. Synthesis of a mature TSH molecule requires the excision of signal peptides from both TSH a-and b-subunits, followed by trimming of mannose and further addition of fucose, galactose, and sialic acids (2). Thus, mature TSH molecules are asparagine-(N)-linked [Asp(N)-linked] complex carbohydrate structures capped with sulfate and/or sialic acid molecules (3,4) (Fig. 1). TSH oligosaccharide structures vary according to the source of TSH: human pituitaryderived TSH comprises fucosylated biantennary glycans with terminal N-acetylgalactosamine sulfate and low sialic acid content (5-7), while recombinant human TSH (rhTSH), synthesized in Chinese hamster ovary cells, specifically terminates in a2,3-linked sialic acid (8-11) and rhTSH formed in yeast lacks sialic acid residues altogether (12). Glycosylation Patterns and TSH BioactivityAppropriate glycosylation is necessary to maintain normal TSH bioactivity (13). Indeed, both a-and b-subunits of TSH have functionally important domains associated with TSH receptor (TSHR) binding and activation. The a-subunit has two Asp(N)-linked oligosaccharide chains with a typical biantennary structure, while TSH b-subunit has only one chain (Fig. 2). The transcriptional and posttranscriptional mechanisms involved in TSH glycosylation result in folding of these subunits, leading to their heterodimerization. These mechanisms also qualitatively regulate TSH secretion, prevent intracellular degradation, and influence TSH clearance rate from the circulation (14,15). A three-dimensional TSH structure has been proposed in the 1990s based on crystallographic studies and comparisons with other glyco...

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“…Depending on the type of the mutation and on the number of alleles affected, LOF mutations can result in partial or complete TSH resistance (10,11). Partial resistance is usually monoallelic and is generally associated with nonautoimmune isolated hyperthyrotropinemia, where the dominant negative effect of the mutant receptor has been suggested (12).…”

mentioning

confidence: 99%

Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

Lábadi

Grassi

Gellén

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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Frequent TSH Receptor Genetic Alterations with Variable Signaling Impairment in a Large Series of Children with Nonautoimmune Isolated Hyperthyrotropinemia

Cited by 52 publications

References 22 publications

Comparative Evaluation of Therapy with <i>L</i>-Thyroxine versus No Treatment in Children with Idiopathic and Mild Subclinical Hypothyroidism

Comparative Evaluation of Therapy with <i>L</i>-Thyroxine versus No Treatment in Children with Idiopathic and Mild Subclinical Hypothyroidism

Thyrotropin Isoforms: Implications for Thyrotropin Analysis and Clinical Practice

Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

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