{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:45:26Z","timestamp":1792010726119,"version":"4.4.0"},"reference-count":26,"publisher":"Bioscientifica","issue":"6","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":1578,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Introduction: Resistance to thyroid hormone \u03b2 (RTH\u03b2) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTH\u03b2 is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives\u2019 thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTH\u03b2 in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly\u201a the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTH\u03b2. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTH\u03b2 diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTH\u03b2. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.<\/jats:p>","DOI":"10.1159\/000519748","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T17:01:40Z","timestamp":1634922100000},"page":"533-541","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-17","source":"Crossref","is-referenced-by-count":4,"title":["Clinical Consequences of Variable Results in the Measurement of Free Thyroid Hormones: Unusual Presentation of a Family with a Novel Variant in the\n                    <b>\n                      <i>THRB<\/i>\n                    <\/b>\n                    Gene Causing Resistance to Thyroid Hormone Syndrome"],"prefix":"10.1530","volume":"10","author":[{"given":"Irene","family":"Campi","sequence":"first","affiliation":[{"name":"1Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Agostini","sequence":"additional","affiliation":[{"name":"2Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Marelli","sequence":"additional","affiliation":[{"name":"1Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"de Filippis","sequence":"additional","affiliation":[{"name":"1Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-6696","authenticated-orcid":false,"given":"Beatriz","family":"Romartinez-Alonso","sequence":"additional","affiliation":[{"name":"3Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odelia","family":"Rajanayagam","sequence":"additional","affiliation":[{"name":"2Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuditta","family":"Rurale","sequence":"additional","affiliation":[{"name":"1Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Gentile","sequence":"additional","affiliation":[{"name":"4Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"5Unit of Endocrinology, University Hospital \u201cG. Martino\u201d, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Andreasi","sequence":"additional","affiliation":[{"name":"6Laboratorio Analisi Cliniche, Centro di Ricerche e Tecnologie Biomediche, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ferra\u00f9","sequence":"additional","affiliation":[{"name":"5Unit of Endocrinology, University Hospital \u201cG. Martino\u201d, Messina, Italy"},{"name":"7Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8779-7283","authenticated-orcid":false,"given":"Salvatore","family":"Cannav\u00f2","sequence":"additional","affiliation":[{"name":"5Unit of Endocrinology, University Hospital \u201cG. Martino\u201d, Messina, Italy"},{"name":"7Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fugazzola","sequence":"additional","affiliation":[{"name":"1Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy"},{"name":"8Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna V.","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"2Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United 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