Background: Maternal thyroid function is essential for a healthy pregnancy, and elevated thyrotropin (TSH) is the hallmark of subclinical hypothyroidism (SCH). Previous studies have shown that both genetic factors, particularly the PDE8B rs4704397 polymorphism, and iodine intake influence TSH levels. However, whether iodine-related changes in TSH vary by genetic background remains unclear. This study aimed to investigate the association between iodine status and TSH levels across different genetic backgrounds in early pregnancy. Methods: We performed a retrospective analysis of prospectively collected data from the subclinical hypothyroid in early pregnancy (SHEP) prospective cohort, using a nested case-control design. The analysis included 728 pregnant women with SCH and 968 age- and body mass index-matched euthyroid controls. Participants were genotyped for PDE8B rs4704397 using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry. The urinary iodine-to-creatinine ratio (UIC/Cr) was used to assess iodine status. Restricted cubic spline (RCS), linear, and logistic regression models were applied to evaluate the associations of UIC/Cr with TSH, free thyroxine (fT4), and SCH, stratified by PDE8B genotype. Results: The distribution of the AA genotype did not differ between case and control groups. In the overall population, the AA genotype accounted for 70% of participants. RCS analyses showed a positive linear association between UIC/Cr and serum TSH concentrations in both the overall population and individuals with the AA genotype, but not in those with the GA + GG genotypes. A nonlinear inverse association between UIC/Cr and fT4 levels was observed across all genotypes. Among individuals with the AA genotype, each standard deviation increase in UIC/Cr was associated with higher serum TSH levels (adjusted β = 0.16, confidence interval [CI]: 0.08–0.24) and an increased risk of SCH (OR = 1.22, CI: 1.08–1.39), but not among those with the GA + GG genotypes ( p for genotype × UIC/Cr interaction = 0.09 for both outcomes). In contrast, fT4 levels decreased with increasing UIC/Cr across all genotypes (p for genotype × UIC/Cr interaction = 0.48). Conclusions: Higher iodine status was associated with higher TSH levels and an increased risk of SCH only among pregnant women with the PDE8B rs4704397 AA genotype, suggesting that the effect of iodine on thyroid function is modified by genotype.
Background: DIO3 encodes type 3 iodothyronine deiodinase, the major thyroid hormone-inactivating enzyme, and is an imprinted gene with preferential paternal-allele expression demonstrated in human neonatal skin. Dio3 -deficient mice develop neonatal thyrotoxicosis followed by central hypothyroidism, but human evidence has been lacking. Patient Findings: On newborn screening, thyrotropin (TSH) and free thyroxine (fT4) did not meet repeat-testing criteria, while T-cell lymphopenia was detected neonatally. From 5 months onward, fT4 progressively declined without compensatory TSH elevation. Chromosomal microarray identified a derivative chromosome 14 with a 14q32.31–q32.33 deletion encompassing DIO3 and TRAF3 . The deletion originated from a paternal balanced 4p/14q translocation. Summary: In this patient, delayed-onset central hypothyroidism was most consistent with paternal DIO3 loss, whereas the accompanying T-cell lymphopenia was consistent with TRAF3 haploinsufficiency. Conclusions: This case provides the first human evidence linking paternal DIO3 loss to delayed-onset central hypothyroidism, supporting a novel developmental mechanism that may alter hypothalamic–pituitary–thyroid axis programming.
Background: Postoperative thyrotropin (TSH)-directed levothyroxine is used to reduce recurrence risk in selected patients with differentiated thyroid cancer (DTC), but treatment-related adverse effects may vary based on patient susceptibility and treatment exposure. Contemporary guidelines increasingly require balancing anticipated oncologic benefit against potential harm. This scoping review synthesizes patient-, treatment-, and disease-related factors associated with adverse effects of postoperative TSH-directed levothyroxine therapy in adults with DTC. Methods: This scoping review was reported following PRISMA-ScR guidelines and prospectively registered on the Open Science Framework. MEDLINE, Embase, and Cochrane CENTRAL were searched from January 1, 2011, to February 24, 2026. Eligible studies reported associations between patient-, treatment-, or disease-related factors and adverse effects among adults with DTC receiving postoperative TSH-directed levothyroxine therapy. Data were summarized descriptively and synthesized narratively, with stratification according to TSH exposure definition. Results: Of 7361 records screened, 35 studies including 11,819 patients were included. Skeletal outcomes were most frequently reported (51.4%), followed by cardiometabolic (40.0%), neuropsychological (11.4%), reproductive (2.9%), and muscular outcomes (2.9%). TSH exposure definitions varied substantially: 18 studies evaluated subnormal TSH, 2 low-normal TSH, 8 mixed categories spanning subnormal and low-normal TSH, 4 continuous biochemical/treatment measures, and 3 unclear exposures. Greater suppression intensity was the most consistently reported treatment-related factor associated with adverse skeletal outcomes, particularly in studies evaluating subnormal TSH. Longer treatment duration was associated with skeletal harm in selected studies. Postmenopausal status emerged as a relatively consistent patient-level factor, whereas associations with age and body mass index were variable. Evidence for cardiometabolic, neuropsychological, reproductive, and muscular outcomes was less extensive and less consistent, and disease-related factors were infrequently examined. Only two studies conducted prediction/discrimination analyses, both involving skeletal outcomes. Conclusions: Evidence on adverse effects associated with TSH-directed levothyroxine therapy in DTC is most consistent for skeletal outcomes and predominantly derives from studies evaluating subnormal TSH exposure. The available literature provides limited evidence for clinically applicable prediction of toxicity or cumulative treatment burden. Future longitudinal studies should better characterize the intensity and persistence of biochemical exposure and develop outcome-specific prediction models integrating baseline susceptibility, organ vulnerability, and longitudinal treatment exposure to support individualized TSH management.
Background: Most thyroid malignancies harbor a limited set of well-characterized mutations driving tumor initiation and determining phenotype. This relatively direct genotype–phenotype association, bringing insights into molecular mechanisms of progression and drug resistance, makes advanced thyroid cancers suitable for genetic-based therapies. Personalized cancer treatment by targeting actionable tumor mutations represents one of the most innovative frontiers in oncology. Summary: The present narrative review focuses on actionable mutations occurring in thyroid cancers and provides a state-of-the-art overview of genetic-based treatments that have received regulatory approval worldwide. These include two selective RET inhibitors (sRET-Is) (selpercatinib and pralsetinib), three NTRK inhibitors (NTRK-Is) (larotrectinib, entrectinib, and repotrectinib), and two dual BRAF/MEK inhibitor regimens (dabrafenib plus trametinib and encorafenib plus binimetinib). The most significant impact has been observed in the management of RET -mutant medullary thyroid cancer. Selpercatinib, available in many countries, demonstrated superiority over standard multikinase inhibitors (MKIs) in a head-to-head comparison. It currently represents the best first-line treatment option. In BRAF V600E -positive anaplastic thyroid cancer, both dabrafenib plus trametinib and encorafenib plus binimetinib showed efficacy that appeared to exceed that historically observed with standard approaches. However, their approval is currently limited to a few countries. In radioiodine-refractory differentiated thyroid cancer (DTC), sRET-Is and NTRK-Is are effective in molecularly selected patients and are approved in many countries. However, their applicability is limited by the low prevalence of the corresponding actionable alterations. In BRAF V600E -positive radioiodine-refractory DTC, dabrafenib plus trametinib has emerged as a useful option after MKI failure, although a tumor-specific approval has been granted only in Europe. Conclusions: Precision oncology is increasingly being integrated into the management of advanced thyroid cancer. However, its impact varies widely across different tumor settings, and its real-world use is strongly influenced by country-specific drug regulations.
