Thyroid最新文献

{"title":"A Scholarly Dialog on Recent Trends in National Institutes of Health's Funding for the Thyroid Field.","authors":"Jorge Hidalgo-Álvarez, Antonio C Bianco","doi":"10.1089/thy.2024.0084","DOIUrl":"10.1089/thy.2024.0084","url":null,"abstract":"<p><p><b><i>Background:</i></b> The National Institutes of Health (NIH) is the major funding agency for biomedical research in the United States. To initiate a scholarly dialog about research and career development in the thyroid field, here we reviewed recent trends in NIH funding for this area. We used the Research Portfolio Online Reporting Tool database to estimate the level of NIH extramural support during 2013-2022 (number of active grants/year and $amount/year weighed by the total number of active grants/year and $amount/year), provided by the NIH to the thyroid field. We determined that in 2013, the NIH supported ∼140 grants/year, totaling almost $50 million/year, the majority in the form of R01 grants. Within the thyroid field, support was evenly split between thyroid cancer and thyroid hormone metabolism and action subareas. In the subsequent years (2014-2022), the total number of active grants peaked at 150/year ($55 million) in 2014 but progressively decreased to about 100 active grants/year ($30 million) in 2022. This trend occurred while the NIH budget increased from $29 to $46 billion/year. Globally, the number of thyroid-related publications increased by ∼70% during the study period, and the fractional contribution of several countries remained relatively stable, except for China which increased by ∼600%. Remarkably, the fraction of thyroid-related publications in the United States sponsored by the NIH decreased from 5.5% to 3.1% of the global number. <b><i>Conclusion:</i></b> These results constitute a very concerning scenario for research and education in the thyroid field. We appeal to the NIH, the professional societies in endocrinology and thyroidology, and all other relevant stakeholders such as thyroid-related professionals and thyroid patients to engage in further discussions to identify the root causes of this trend and implement an action plan to stabilize and eventually reverse this situation.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"962-968"},"PeriodicalIF":5.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140868744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.","authors":"Stefan Groeneweg, Chantal Zevenbergen, Elaine C Lima de Souza, Ferdy S van Geest, Barbara Kloeckener-Gruissem, Endre Laczko, Simone M R Camargo, Marcel E Meima, Robin P Peeters, W Edward Visser","doi":"10.1089/thy.2023.0551","DOIUrl":"10.1089/thy.2023.0551","url":null,"abstract":"<p><p><b><i>Background:</i></b> Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. <b><i>Methods:</i></b> In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing <i>Xenopus</i> oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. <b><i>Results:</i></b> Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [¹²⁵I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC₅₀: 2.5 ± 1.5 µM) or thyroxine (T4) (IC₅₀: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [¹²⁵I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [³H]-glutamate or [³H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. <b><i>Conclusions:</i></b> Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone <i>in vitro</i> and <i>vice versa</i>. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines <i>in vivo</i>.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"931-941"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140866378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials.","authors":"George J Kahaly, Prem S Subramanian, Elizabeth Conrad, Robert J Holt, Terry J Smith","doi":"10.1089/thy.2023.0656","DOIUrl":"10.1089/thy.2023.0656","url":null,"abstract":"<p><p><b><i>Introduction:</i></b> Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. <b><i>Methods:</i></b> A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. <b><i>Results:</i></b> At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, <i>n</i> = 56), mean GO-QoL improvement was 15.22 (SE 2.82, <i>n</i> = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. <b><i>Conclusion:</i></b> The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"880-889"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Thyroid Peroxidase Antibodies and Neurodevelopment of the Offspring: Innocent Bystander or Guilty Accomplice.","authors":"Jinrong Fu, Haixia Guan","doi":"10.1089/thy.2024.0340","DOIUrl":"10.1089/thy.2024.0340","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"812-814"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levothyroxine Treatment in Pregnant Women with Thyrotropin Levels Ranging Between 2.5 and 10 mIU/L: A Propensity Score Matched Analysis.","authors":"Shen Gao, Xueran Wang, Rong Zhao, Yuchen Cui, Shaofei Su, Enjie Zhang, Jianhui Liu, Shuanghua Xie, Yue Zhang, Yuxi Yang, Kaikun Huang, Minhui Hu, Wentao Yue, Ruixia Liu, Chenghong Yin","doi":"10.1089/thy.2023.0662","DOIUrl":"10.1089/thy.2023.0662","url":null,"abstract":"<p><p><b><i>Objective:</i></b> To clarify the association between levothyroxine (LT4) treatment and various adverse pregnancy outcomes in pregnant women with thyrotropin (TSH) levels ranging between 2.5 and 10.0 mIU/L in the first trimester, stratified according to thyroid peroxidase antibody (TPOAb) positivity and TSH level. <b><i>Methods:</i></b> This retrospective analysis of retrospectively and prospectively collected cohort data included Chinese pregnant women with TSH levels of 2.5-10 mIU/L and normal free thyroxine levels (11.8-18.4 pmol/L) in the first trimester. All participants were followed up until the completion of pregnancy, and information on LT4 treatment, pregnancy complications, and pregnancy outcomes was recorded. A 1:1 nearest-neighbor propensity score matching (PSM) between the LT4-treated and - untreated groups with a caliper distance of 0.02 was performed using a multivariable logistic regression model. Multivariable-adjusted modified Poisson regression was used to estimate the relative risk (RR) and 95% confidence interval (CI) of LT4 treatment for adverse pregnancy outcomes. Subgroup analyses were also performed in four subgroups simultaneously stratified by TPOAb status (negative or positive) and TSH levels (2.5-4.0 mIU/L as high-normal group and 4.0-10.0 mIU/L as SCH group). The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100047394). <b><i>Results:</i></b> Among the 4,370 pregnant women in the study, 1,342 received LT4 treatment and 3,028 did not. The 1:1 PSM yielded 668 pairs of individuals and revealed that LT4 treatment was significantly associated with a decreased risk of pregnancy loss (RR = 0.528, 95% CI: 0.344-0.812) and an increased risk of small-for-gestational-age infants (RR = 1.595, 95% CI: 1.023-2.485). Subgroup analyses suggested that the above effects of LT4 treatment were mainly from TPOAb-negative participants. LT4 treatment was associated with an increased risk of preterm birth (RR = 2.214, 95% CI: 1.016-4.825) in TPOAb-positive pregnant women with high-normal TSH levels. <b><i>Conclusion:</i></b> LT4 treatment was significantly associated with a lower risk of pregnancy loss and a higher risk of small-for-gestational-age infants in pregnant women with TSH levels of 2.5-10 mIU/L. An increased risk of preterm birth was observed in the LT4-treated group among TPOAb-positive participants with TSH levels of 2.5-4.0 mIU/L.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"912-919"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Growth Kinetics Based on Initial Tumor Volume Doubling Time in Active Surveillance of Low-Risk Papillary Thyroid Carcinoma.","authors":"Chae A Kim, Seung Hee Baek, Jungmin Yoo, Sae Rom Chung, Jung Hwan Baek, Ki-Wook Chung, Won Bae Kim, Min Ji Jeon, Won Gu Kim","doi":"10.1089/thy.2024.0054","DOIUrl":"10.1089/thy.2024.0054","url":null,"abstract":"<p><p><b><i>Background:</i></b> During active surveillance (AS) of low-risk papillary thyroid carcinomas (PTCs), the majority remain stable, while some exhibit either an increase or a decrease in tumor diameter or tumor volume (TV). We aimed to evaluate the clinical outcomes and relevant parameters influencing tumor growth kinetics of low-risk PTCs. <b><i>Methods:</i></b> This retrospective cohort study evaluated clinical parameters of 402 patients with low-risk PTC sized <2 cm, with a follow-up duration over 3 years. Changes in maximum tumor diameter, TV, and initial TV doubling time (i-TVDT) calculated within 3 years were assessed. A significant change in TV was defined as a change of 75% or more. <b><i>Results:</i></b> Of the 402 patients with low-risk PTC, 93.3% (375/402) were diagnosed with papillary thyroid microcarcinoma. During a median follow-up of 5 years, 3.4% (14/402) of patients developed new cervical lymph node (LN) metastasis, and 8.2% (33/402) experienced a maximal diameter increase of ≥3 mm. The i-TVDT of <5 years emerged as an independent risk factor for both maximal diameter growth and new LN metastasis (<i>p</i> < 0.001 and <i>p</i> = 0.04, respectively). Based on TV changes and i-TVDT during AS, we identified four statistically significant tumor kinetic patterns (<i>p</i> < 0.001): Stable (±75% change in TV), Rapid growth (TV increase >75% and i-TVDT <5 years), Slow growth (TV increase >75% and i-TVDT ≥5 years), and Shrinkage (TV decrease >75%). Most of the PTCs remained stable (67.7%), but 17.2% were rapidly growing, with a median onset of growth of 2.0 years. Slowly growing PTCs, comprising 10.9%, grew at a median of 4.3 years. A minority, 4.2%, exhibited shrinkage. In total, 115 (28.6%) patients underwent delayed surgery >12 months after initiating AS. The reasons for delayed surgery included patient preference (51/115, 44.3%), disease progression (31/115, 27.0%), and suspected disease progression, which was referred to as tumor growth not meeting the criteria of an increase of ≥3 mm in maximal tumor diameter (17/115, 14.8%). <b><i>Conclusion:</i></b> An i-TVDT of <5 years serves as an important prognostic indicator for disease progression, including tumor growth and new LN metastasis. The four tumor kinetic patterns based on TV changes and i-TVDT assist in guiding personalized decisions early in AS.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"846-855"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preview of the 93rd American Thyroid Association Annual Meeting.","authors":"Meredith D Hartley, Whitney S Goldner","doi":"10.1089/thy.2024.0185","DOIUrl":"https://doi.org/10.1089/thy.2024.0185","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":"34 7","pages":"807-809"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alginate/Carboxymethyl Chitosan Core-Shell Microspheres Coloaded with Doxorubicin/Docetaxel Reverse Chemotherapy Resistance in Anaplastic Thyroid Carcinoma.","authors":"Yili Zhou, Fan Yang, Hongzhong Zhou, Shixu Lv","doi":"10.1089/thy.2024.0023","DOIUrl":"10.1089/thy.2024.0023","url":null,"abstract":"","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"856-870"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Human TRIAC Transmembrane Transporters.","authors":"Paul Carlos Becker, Mandy Güth-Steffens, Katina Lazarow, Niklas Sonntag, Doreen Braun, Islam Masfaka, Kostja Renko, Lutz Schomburg, Josef Köhrle, Jens Peter von Kries, Ulrich Schweizer, Gerd Krause, Jonas Protze","doi":"10.1089/thy.2023.0592","DOIUrl":"10.1089/thy.2023.0592","url":null,"abstract":"<p><p><b><i>Background:</i></b> 3,5,3'-Triiodothyroacetic acid (TRIAC) is a T₃-receptor agonist pharmacologically used in patients to mitigate T₃ resistance. It is additionally explored to treat some symptoms of patients with inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8, <i>SLC16A2</i>). MCT8 is expressed along the blood-brain barrier, on neurons, astrocytes, and oligodendrocytes. Hence, pathogenic variants in <i>MCT8</i> limit the access of TH into and their functions within the brain. TRIAC was shown to enter the brain independently of MCT8 and to modulate expression of TH-dependent genes. The aim of the study was to identify transporters that facilitate TRIAC uptake into cells. <b><i>Methods:</i></b> We performed a whole-genome RNAi screen in HepG2 cells stably expressing a T₃-receptor-dependent luciferase reporter gene. Validation of hits from the primary and confirmatory secondary screen involved a counter screen with siRNAs and compared the cellular response to TRIAC to the effect of T₃, in order to exclude siRNAs targeting the gene expression machinery. MDCK1 cells were stably transfected with cDNA encoding C-terminally myc-tagged versions of the identified TRIAC-preferring transporters. Several individual clones were selected after immunocytochemical characterization for biochemical characterization of their ¹²⁵I-TRIAC transport activities. <b><i>Results:</i></b> We identified SLC22A9 and SLC29A2 as transporters mediating cellular uptake of TRIAC. <i>SLC22A9</i> encodes the organic anion transporter 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver, and other organs. Competition with the SLC22A9/OAT7 substrate estrone-3-sulfate reduced ¹²⁵I-TRIAC uptake. <i>SLC29A2</i> encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed, including pituitary and brain. Coincubation with the SLC29A2/ENT2 inhibitor nitrobenzyl-6-thioinosine reduced ¹²⁵I-TRIAC uptake. Moreover, ABCD1, an ATP-dependent peroxisomal pump, was identified as a ¹²⁵I-TRIAC exporter in transfected MDCK1 cells. <b><i>Conclusions:</i></b> Knowledge of TRIAC transporter expression patterns, also during brain development, may thus in the future help to interpret observations on TRIAC effects, as well as understand why TRIAC may not show a desirable effect on cells or organs not expressing appropriate transporters. The identification of <i>ABCD1</i> highlights the sensitivity of our established screening assay, but it may not hold significant relevance for patients undergoing TRIAC treatment.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"920-930"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and Clinical Features of Congenital Hypothyroidism Due to Multiple <i>DUOX2</i> Variants.","authors":"Erika Uehara, Kiyomi Abe, Kanako Tanase-Nakao, Koji Muroya, Atsushi Hattori, Keiko Matsubara, Maki Fukami, Satoshi Narumi","doi":"10.1089/thy.2024.0046","DOIUrl":"10.1089/thy.2024.0046","url":null,"abstract":"<p><p><b><i>Background:</i></b> <i>DUOX2</i> is one of the major causative genes of congenital hypothyroidism (CH). Still, the mutation spectrum and clinical outcomes of biallelic <i>DUOX2</i> variants are not fully understood. This study aimed to elucidate the molecular features and long-term clinical manifestations of CH caused by multiple pathogenic <i>DUOX2</i> variants. <b><i>Methods:</i></b> A total of 255 patients with CH were screened for rare variants of 11 known causative genes. <i>DUOX2</i> variants were classified according to their protein structure and residual activity. <i>In vitro</i> assays were performed for several variants of unknown functions. Clinical analyses were conducted for patients with multiple pathogenic variants of <i>DUOX2</i> but not of other genes. <b><i>Results:</i></b> We identified 24 pathogenic variants of <i>DUOX2</i>, together with two benign variants and seven variants of uncertain significance, in 63 patients. The pathogenic variants included three missense substitutions and one frameshift variant that have not yet been linked to CH. Twenty-one patients carried multiple pathogenic <i>DUOX2</i> variants without any other pathogenic gene variants. Three of the 21 patients harbored homozygous variants. Family analysis, long-read amplicon sequencing, and haplotype phasing confirmed compound heterozygosity of the <i>DUOX2</i> variants in 14 patients, whereas the allelic positions of the variants in the remaining four patients could not be determined. Of the 21 patients, 19 were treated with levothyroxine; their ages at drug withdrawal ranged from 9 months to 21.4 years. Three patients required retreatment after drug-free intervals of 6 months, 8 months, and 10 years. There were no differences in clinical severity among patients with <i>DUOX2</i> amorphic/amorphic, amorphic/hypomorphic, and hypomorphic/hypomorphic variants. <b><i>Conclusions:</i></b> These results broaden the mutational spectrum of <i>DUOX2</i>. Furthermore, our data imply that patients with multiple pathogenic <i>DUOX2</i> variants typically exhibit transient CH without significant genotype-phenotype correlations. Most importantly, this study demonstrated for the first time that these patients are at risk of developing recurrent hypothyroidism after a long drug-free interval.</p>","PeriodicalId":23016,"journal":{"name":"Thyroid","volume":" ","pages":"827-836"},"PeriodicalIF":5.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}