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      Severe thyrotoxicosis in an infant revealing familial nonautoimmune hyperthyroidism with a novel (C672W) stimulating thyrotropin receptor germline mutation

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          Key Clinical Message

          We describe severe thyrotoxicosis in young members of a family with nonautoimmune hyperthyroidism caused by a C672W germline mutation in exon 10 of TSHR gene. In this family, lack of genotype‐phenotype correlation and anticipation across generations could be linked to an increased iodine intake as recently observed in France.

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          Most cited references21

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          Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism.

          The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.
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            Evidence for the presence of functional thyrotropin receptor in cardiac muscle.

            There is increasing evidence that the membrane-bound thyrotropin receptor (TSHR) may be mediating clinically important direct effects of thyrotropin (TSH) and of TSHR antibodies (TSHRab) in extra-thyroidal tissues. TSHR mRNA has formerly been detected in thyroid, retroorbital muscle and fibroblasts, peripheral lymphocytes and rodent fat. It is well known that thyroid disease may aggravate or induce heart disease, but the pathophysiological role of TSH and TSHRab is not clear. The aim of this study was to investigate if TSHR is present in cardiac muscle. Reverse transcriptase polymerase chain reactions revealed TSHR in human heart and Northern blot on extracted RNA showed a RNA species of 4.4 kb. TSH stimulation of cultured mouse AT-1 cardiomyocytes elevated the levels of intracellular second messenger 3',5'-cyclic AMP. This effect of TSH could be inhibited by TSHR antibodies. In solution hybridization levels of TSHR mRNA in AT-1 cells were 50% of mRNA in crude mouse heart. In conclusion functional TSHR is present in cardiomyocytes.
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              Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations.

              Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.
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                Author and article information

                Contributors
                caron.p@chu-toulouse.fr
                Journal
                Clin Case Rep
                Clin Case Rep
                10.1002/(ISSN)2050-0904
                CCR3
                Clinical Case Reports
                John Wiley and Sons Inc. (Hoboken )
                2050-0904
                25 October 2017
                December 2017
                : 5
                : 12 ( doiID: 10.1002/ccr3.2017.5.issue-12 )
                : 1980-1987
                Affiliations
                [ 1 ] Endocrine, Genetics, Bone Diseases, and Paediatric Gynecology Unit Children's Hospital CHU Toulouse Toulouse France
                [ 2 ] Biochemistry and Genetic laboratory Federative institute of biology CHU Purpan Toulouse Toulouse France
                [ 3 ] Department of Endocrinology and Metabolic Diseases Cardio‐Vascular and Metabolic Unit CHU Larrey Toulouse France
                Author notes
                [*] [* ] Correspondence

                Philippe Caron, Department of Endocrinology and Metabolic Diseases, Cardio‐Vascular and Metabolic Unit, CHU Larrey, 24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex, France. Tel: +33 (0)5 67 77 17 01; Fax: +33 (0)5 67 77 16 72; E‐mail: caron.p@ 123456chu-toulouse.fr

                Author information
                http://orcid.org/0000-0001-5391-7582
                Article
                CCR31178
                10.1002/ccr3.1178
                5715599
                d6ec0ad0-44a4-4cfa-974c-7e659eb76472
                © 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 April 2017
                : 21 June 2017
                : 13 August 2017
                Page count
                Figures: 5, Tables: 1, Pages: 8, Words: 4123
                Categories
                Case Report
                Case Reports
                Custom metadata
                2.0
                ccr31178
                December 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.7 mode:remove_FC converted:05.12.2017

                familial nonautoimmune hyperthyroidism,iodine intake,mitral valve prolapse,proptosis,stimulating tsh receptor gene mutation

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