{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:46Z","timestamp":1777630546221,"version":"3.51.4"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hyperthyroxinemia with non\u2010suppressed thyroid\u2010stimulating hormone (TSH) is a complex clinical entity that presents significant diagnostic challenges. Inherited causes include resistance to thyroid hormone beta (RTH\u03b2), characterised by highly variable clinical presentation, and familial dysalbuminemic hyperthyroxinemia (FDH), a form of assay interference caused by pathogenic variants in the\n                      <jats:italic>ALB<\/jats:italic>\n                      gene leading to pseudo elevation of free thyroxine (FT4). This study aimed to characterise the clinical, laboratory, and molecular features of a paediatric cohort presenting with hyperthyroxinemia and non\u2010suppressed TSH, and to identify clinical parameters that may aid in differential diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this retrospective observational study, 25 children from 19 unrelated families with elevated FT4 and non\u2010suppressed TSH were evaluated. Clinical history, anthropometric data, physical examination findings, vital signs, laboratory results, radiological imaging, and sequencing data of the\n                      <jats:italic>THRB<\/jats:italic>\n                      and\/or\n                      <jats:italic>ALB<\/jats:italic>\n                      genes were reviewed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>THRB<\/jats:italic>\n                      gene sequencing was performed in 21 children from 18 families, identifying pathogenic or likely pathogenic variants in six patients from six unrelated families, including a novel variant c.997\u2009G\u2009&gt;\u2009C, p.(Glu333Gln), consistent with a diagnosis of RTH\u03b2 in 33.3% of those tested. Among these patients, tachycardia was observed in three cases (50%).\n                      <jats:italic>ALB<\/jats:italic>\n                      gene sequencing was completed in 16 children from 13 families, revealing the hotspot variant c.725\u2009G\u2009&gt;\u2009A, p.(Arg242His) in 12 patients from six unrelated families, corresponding to FDH in 46.2% of those tested. None of the FDH\u2010confirmed patients exhibited tachycardia or other signs of thyroid dysfunction. FT4 and TSH levels were similar between RTH\u03b2 and FDH groups; however, FT3 levels tended to be lower in FDH, although FT3\/FT4 ratio did not differ significantly.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings highlight the critical role of molecular testing in accurately diagnosing the underlying cause of elevated FT4 with non\u2010suppressed TSH and in preventing unnecessary interventions. Hotspot analysis of the\n                      <jats:italic>ALB<\/jats:italic>\n                      gene is recommended as a first\u2010line test, particularly in asymptomatic individuals.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cen.70126","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:21:47Z","timestamp":1773051707000},"page":"693-701","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Utility of Genetic Testing in Hyperthyroxinemia With Non\u2010Suppressed TSH"],"prefix":"10.1111","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6482-870X","authenticated-orcid":false,"given":"Hilal","family":"Sekizkardes","sequence":"first","affiliation":[{"name":"Pediatric Endocrinology, Department of Pediatrics Sancaktepe Sehit Prof Dr Ilhan Varank Training and Research Hospital Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-9620","authenticated-orcid":false,"given":"Mehmet","family":"Eltan","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Department of Pediatrics Sancaktepe Sehit Prof Dr Ilhan Varank Training and Research Hospital Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8374-0359","authenticated-orcid":false,"given":"Senol","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Van Training and Research Hospital University of Health Sciences Van Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7660-4052","authenticated-orcid":false,"given":"Dilek","family":"Giray","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology, Department of Pediatrics Sancaktepe Sehit Prof Dr Ilhan Varank Training and Research Hospital Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-6181","authenticated-orcid":false,"given":"Zehra","family":"Yavas Abali","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology and Diabetes, Department of Pediatrics School of Medicine Marmara University Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6552-2801","authenticated-orcid":false,"given":"Saygin","family":"Abali","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology, Department of Pediatrics School of Medicine Acibadem Mehmet Ali Aydinlar University Istanbul Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","unstructured":"T.PappaandS.Refetoff \u201cResistance to Thyroid Hormone Beta: A Focused Review \u201d2021 https:\/\/doi.org\/10.3389\/fendo.2021.656551.","DOI":"10.3389\/fendo.2021.656551"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/THY.2013.3393.NOMEN"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01084-9"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1102777"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","unstructured":"G.Caridi F.Lugani A.Angeletti M.Campagnoli M.Galliano andL.Minchiotti \u201cVariations in the Human Serum Albumin Gene: Molecular and Functional Aspects \u201d2022 https:\/\/doi.org\/10.3390\/ijms23031159.","DOI":"10.3390\/ijms23031159"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BEEM.2013.10.003"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-017-0770-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.4274\/JCRPE.2183"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.4274\/JCRPE.GALENOS.2019.2019.0127"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/ER.2018-00119"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1530\/ETJ-24-0125"},{"key":"e_1_2_10_13_1","unstructured":"W. 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