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Objectives: To study the cytogenetic patterns, congenital heart disease, and thyroid dysfunction in children with Down syndrome., Study Design: This was a retrospective observational study of children with Down syndrome over a period of 20 years, from a major referral institution in Kerala state, South India. The cytogenetic patterns, echocardiography reports, and thyroid profiles were analyzed using SPSS, version 20, software. The prevalence of heart disease and thyroid status in the various cytogenetic patterns also were analyzed., Results: The prevalence of translocation (9.45%) was high compared with the reported 4% in the literature. More of the younger mothers had translocation with a greater, but not statically significant, incidence of heart disease. Mosaic karotypes (3.04%) were also greater than reported (1%) in the literature, with female preponderance. Heart disease was seen in 58% of cases, with atrial septal defect being the most common lesion, compared with atrioventricular septal defect noted in literature. Hypothyroidism was noted in 31.2% with no difference among the cytogenetic groups. There was no case of hyperthyroidism., Conclusions: The high prevalence of translocation and mosaic Down syndrome stresses the need for routine karyotyping in children with Down syndrome. The need for routine screening and regular follow up of heart diseases and thyroid status should be emphasized., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Transcription factor FOXP3 is a crucial regulator in the development and function of regulatory T cells (Treg) that are essential for immunological tolerance and homeostasis. Numerous studies have indicated the correlation of tumor infiltrating FOXP3+ Treg upregulation with poor prognostic parameters in thyroid cancer, including lymph node metastases, extrathyroidal extension, and multifocality. Most immune-checkpoint molecules are expressed in Treg. The blockage of such signals with checkpoint inhibitors has been approved for several solid tumors, but not yet for thyroid cancer. Thyroid abnormalities may be induced by checkpoint inhibitors. For example, hypothyroidism, thyrotoxicosis, painless thyroiditis, or even thyroid storm are more frequently associated with anti-PD-1 antibodies (pembrolizumab and nivolumab). Therefore, Targeting FOXP3+ Treg may have impacts on checkpoint molecules and the growth of thyroid cancer. Several factors may impact the role and stability of FOXP3, such as alternative RNA splicing, mutations, and post-translational modification. In addition, the role of FOXP3+ Treg in the tumor microenvironment is also affected by the complex regulatory network formed by FOXP3 and its transcriptional partners. Here we discussed how the expression and function of FOXP3 were regulated and how FOXP3 interacted with its targets in Treg, aiming to help the development of FOXP3 as a potential therapeutic target for thyroid cancer., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD., Objectives: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci., Methods: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method., Results: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis., Conclusions: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Objective: To explore the association of ATG5 gene polymorphisms with autoimmune thyroid diseases (AITDs) including Hashimoto's thyroiditis (HT) and Graves' illness (GD) as well as their clinical features., Methods: rs6568431, rs548234, and rs6937876 were selected to investigate the correlation of single-nucleotide polymorphisms of ATG5 gene with AITDs. Their frequencies in 824 AITD patients, including 271 HT patients and 553 GD patients, and 764 healthy controls were tested using both ligase detection reaction and multiplex polymerase chain reaction., Results: Allele A frequency of rs6568431 in AITDs patients ( p = 0.016, OR = 1.201, 95% CI = 1.034 - 1.394) and allele G frequency of rs6937876 in AITDs patients ( p = 0.009, OR = 1.223, 95% CI = 1.052 - 1.422) and in GD patients ( p = 0.009, OR = 1.247, 95% CI = 1.056 - 1.473) were significantly higher than those in the healthy controls. The frequency of G allele ( p = 5.42E - 18, OR = 0.242, 95% CI = 0.173 - 0.339) of rs6937876 was significantly higher in GD patients with ophthalmopathy. However, no relationship was found between family history, age onset, and the three SNPs., Conclusion: The study is the first to reveal the association between AITDs and ATG5 polymorphisms, and ATG5 gene is considered as a predisposing gene to AITDs, especially GDs., Competing Interests: The authors declare no conflict of interest and are responsible for the content of this paper., (Copyright © 2022 Wen Wang et al.)

Consistent activation and functioning of thyroid hormones are essential to the human body as a whole, especially in controlling the metabolic rate of all organs and systems. Impaired sensitivity to thyroid hormones describes any process that interferes with the effectiveness of thyroid hormones. The genetic origin of inherited thyroid hormone defects and the investigation of genetic defects upon the processing of thyroid hormones are of utmost importance. Impaired sensitivity to thyroid hormone can be categorized into three conditions: thyroid hormone cell membrane transport defect (THCMTD), thyroid hormone metabolism defect (THMD), and thyroid hormone action defect (THAD). THMD is caused by defects in the synthesis and processing of deiodinases that convert the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). Deiodinase, a selenoprotein, requires unique translation machinery that is collectively composed of the selenocysteine (Sec) insertion sequence (SECIS) elements, Sec-insertion sequence-binding protein 2 (SECISBP2), Sec-specific eukaryotic elongation factor (EEFSEC), and Sec-specific tRNA (TRU-TCA1-1), which leads to the recognition of the UGA codon as a Sec codon for translation into the growing polypeptide. In addition, THMD could be expanded to the defects of enzymes that are involved in thyroid hormone conjugation, such as glucuronidation and sulphation. Paucity of inherited disorders in this category leaves them beyond the scope of this review. This review attempts to specifically explore the genomic causes and effects that result in a significant deficiency of T3 hormones due to inadequate function of deiodinases. Moreover, along with SECISBP2 , TRU-TCA1-1 , and deiodinase type-1 ( DIO1 ) mutations, this review describes the variants in DIO2 single nucleotide polymorphism (SNP) and thyroid stimulating hormone receptor ( TSHR ) that result in the reduced activity of DIO2 and subsequent abnormal conversion of T3 from T4. Finally, this review provides additional insight into the general functionality of selenium supplementation and T3/T4 combination treatment in patients with hypothyroidism, suggesting the steps that need to be taken in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Shin, Lee and Lee.)

Network pharmacology was used to illuminate the targets and pathways of polybrominated diphenyl ethers (PBDEs) causing thyroid dysfunction. A protein-protein interaction (PPI) network was constructed. Molecular docking was applied to analyze PBDEs and key targets according to the network pharmacology results. A total of 247 targets were found to be related to 16 PBDEs. Ten key targets with direct action were identified, including the top five PIK3R1, MAPK1, SRC, RXRA, and TP53. Gene Ontology (GO) functional enrichment analysis identified 75 biological items. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified 62 pathways mainly related to the regulation of the thyroid hormone signaling pathway, MAPK signaling pathway, PI3K-Akt signaling, pathways in cancer, proteoglycans in cancer, progesterone-mediated oocyte maturation, and others. The molecular docking results showed that BDE-99, BDE-153, 5-OH-BDE47, 5'-OH-BDE99, 5-BDE47 sulfate, and 5'-BDE99 sulfate have a good binding effect with the kernel targets. PBDEs could interfere with the thyroid hormone endocrine through multiple targets and biological pathways, and metabolites demonstrated stronger effects than the prototypes. This research provides a basis for further research on the toxicological effects and molecular mechanisms of PBDEs and their metabolites. Furthermore, the application of network pharmacology to the study of the toxicity mechanisms of environmental pollutants provides a new methodology for environmental toxicology., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Qiaoyu He et al.)

Cyclic neutropenia has been rarely associated with chronic inflammation and development of reactive AA amyloidosis. We report a family with cyclic neutropenia with associated renal and thyroid amyloid. A 12-year-old female presented with thyromegaly, recurrent aphthous ulcers, severe neutropenia, and renal failure. Renal and thyroid biopsies revealed abundant amyloid deposition. Presence of a heterozygous ELANE c.358 A>T gene mutation p.I120F variant with autosomal dominant inheritance confirmed the diagnosis of cyclic neutropenia. The patient's father also had neutropenia and amyloidosis with renal failure. We started filgrastim to attenuate neutropenia and thereby reduce chronic inflammation and minimize further amyloid deposition., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Context: Genetic risk factors play a major role in the pathoetiology of autoimmune thyroid diseases (AITD). So far, only common risk variants have been identified in AITD susceptibility genes. Recently, rare genetic variants have emerged as important contributors to complex diseases, and we hypothesized that rare variants play a key role in the genetic susceptibility to AITD., Objective: We aimed to identify new rare variants that are associated with familial AITD., Methods: We performed deep sequencing of 3 previously mapped AITD-linked loci (10q, 12q, and 14q) in a dataset of 34 families in which AITD clustered (familial AITD)., Results: We identified 13 rare variants, located in the inositol polyphosphate multikinase (IPMK) gene, that were associated with AITD (ie, both Graves' disease [GD] and Hashimoto's thyroiditis [HT]); 2 rare variants, within the dihydrolipoamide S-succinyltransferase (DLST) and zinc-finger FYVE domain-containing protein (ZFYVE1) genes, that were associated with GD only; and 3 rare variants, within the phosphoglycerate mutase 1 pseudogene 5 (PGAM1P5), LOC105369879, and methionine aminopeptidase 2 (METAP2) genes, that were associated with HT only., Conclusion: Our study demonstrates that, in addition to common variants, rare variants also contribute to the genetic susceptibility to AITD. We identified new rare variants in 6 AITD susceptibility genes that predispose to familial AITD. Of these, 3 genes, IPMK, ZFYVE1, and METAP2, are mechanistically involved in immune pathways and have been previously shown to be associated with autoimmunity. These genes predispose to thyroid autoimmunity and may serve as potential therapeutic targets in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Women with thyroid diseases at the beginning of pregnancy may have suboptimal thyroid hormone levels because of potential difficulties in compensating for the physiological thyroid hormone changes occurring in pregnancy. Our objective was to study the association between preexisting thyroid diseases, pregnancy complications, and neonatal anthropometry. In total, 16,395 women from the ELFE French longitudinal birth cohort were included, and 273 declared pre-pregnancy thyroid diseases. Associations were investigated with multivariable regression models, with adjustment for relevant potential confounders. Body mass index (BMI) was additionally adjusted for in a second stage. As compared with other women, women with pre-pregnancy thyroid diseases were more frequently obese (19.6% vs. 9.8%) and had greater odds of gestational diabetes development (odds ratio [OR] = 1.58 [95% confidence interval [CI] 1.08, 2.30]) or had undergone treatment for infertility (OR = 1.57 [95% CI 1.07, 2.31]). After adjustment for BMI, the association with gestational diabetes was no longer significant (OR = 1.27 [95% CI 0.86, 1.88]). After excluding women with another medical history, those with pre-pregnancy thyroid diseases had increased odds of premature rupture of membranes (OR = 1.51 [95% CI 1.01, 2.25]). Children born from mothers with hypothyroidism before conception due to a disease or as a potential side effect of treatment had a smaller head circumference at birth than other children (β = -0.23 [95% CI -0.44, -0.01] cm). In conclusion, pre-pregnancy thyroid diseases were associated with risk of infertility treatment, gestational diabetes, and premature rupture of membranes. The association between history of hypothyroidism and moderate adverse effects on fetal head circumference growth needs replication.

Context: Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment., Objectives: To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity., Design, Participants and Methods: A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale, Fourth Edition, and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance imaging., Results: Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71 and 84 was found in 28.6% of permanent CH and of <70 (P = 0.06) in 10.7%. The Processing Speed Index (PSI; P = 0.004), sustained visual attention (P = 0.02), reading speed (P = 0.0001), written calculations (P = 0.002), and numerical knowledge (P = 0.0001) were significantly lower than controls. Children born to mothers with Hashimoto's thyroiditis have significantly lower IQ values (P = 0.02), Working Memory Index (P = 0.03), and PSI (P = 0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (P = 0.004 and P = 0.009, respectively). In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical, and cognitive measures were documented., Conclusions: These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of which polymorphisms can alter their function, leading to pathologic conditions, including autoimmune diseases. We examined whether miR-499 rs3746444 polymorphism is associated with susceptibility to HT in an Iranian subpopulation. Furthermore, we investigated the potential interacting regulatory network of the miR-499. This case-control study included 150 HT patients and 152 healthy subjects. Genotyping of rs3746444 was performed by the PCR-RFLP method. Also, target genomic sites of the polymorphism were predicted using bioinformatics. Our results showed that miR-499 rs3746444 was positively associated with HT risk in heterozygous (OR = 3.32, 95%CI = 2.00-5.53, p < 0.001, CT vs. TT), homozygous (OR = 2.81, 95%CI = 1.30-6.10, p = 0.014, CC vs. TT), dominant (OR = 3.22, 95%CI = 1.97-5.25, p < 0.001, CT + CC vs. TT), overdominant (OR = 2.57, 95%CI = 1.62-4.09, p < 0.001, CC + TT vs. CT), and allelic (OR = 1.92, 95%CI = 1.37-2.69, p < 0.001, C vs. T) models. Mapping predicted target genes of miR-499 on tissue-specific-, co-expression-, and miR-TF networks indicated that main hub-driver nodes are implicated in regulating immune system functions, including immunorecognition and complement activity. We demonstrated that miR-499 rs3746444 is linked to HT susceptibility in our population. However, predicted regulatory networks revealed that this polymorphism is contributing to the regulation of immune system pathways.

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE)., Experimental Design: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI., Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit., Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response., (©2021 American Association for Cancer Research.)

Cellular thyroid hormone homeostasis requires adequate function of: (1) thyroid hormone transporter proteins at the plasma membrane, (2) deiodinating enzymes and (3) nuclear thyroid hormone receptors (TRs). Defects in any of these processes give rise to distinct disease entities, collectively called thyroid hormone signaling disorders. Thyroid hormone analogues hold therapeutic potential in thyroid hormone signaling disorders by bypassing defective transporters or binding to mutant TRs. This review will focus on the application of analogues in thyroid hormone signaling disorders, particularly monocarboxylate transporter (MCT)8 deficiency, and resistance to thyroid hormone due to mutations in TRβ (RTHβ)., (Copyright © 2020. Published by Elsevier Masson SAS.)

The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs ( THRA and THRB ), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA , differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM&#95;199334 | p.(E173G), NP&#95;955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor.

Context: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited., Objective: To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts., Method: We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed., Results: We identified 2 DMPs with epigenome-wide significant (P < 2.4E-7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E-10) and cg04173586 in DOT1L (P = 2.09E-16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH., Conclusions: This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD)., Design and Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder., Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4)., Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

This issue is the second volume of the previous Special Issue, " Cell and Molecular Biology of Thyroid Disorders " [...].

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort., Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment., Design, Setting, and Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018., Main Outcomes and Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry., Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype., Conclusions and Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Introduction: Family history of thyroid disease (FHTD) constitutes a possible risk factor for congenital hypothyroidism (CH) in the general population; however, FHTD possible relationship with CH in subjects with Down syndrome (DS) has not yet been explored., Objective: To determine whether FHTD is associated with an increased incidence of CH in neonates with DS., Method: Hospital-based case-control study in 220 neonates with DS. Thyroid function tests of 37 infants with DS and positive FHTD (cases) were compared with those of 183 newborns with DS without FHTD (control group). Data were analyzed using multivariate logistic regression analysis and adjusted odds ratios (aORs) with their respective 95 % confidence intervals (CI) were calculated., Results: Nine newborns with DS in our sample had CH (4.1 %). In the multivariate analysis, FHTD showed an association with CH in neonates with DS (aOR = 8.3, 95 % CI: 2.0-34.3), particularly in males (aOR = 9.0, 95 % CI: 1.6-49.6). In contrast, newborns with DS without FHTD were less likely to suffer from CH (aOR = 0.4, 95 % CI: 0.1-0.8)., Conclusions: Newborns with DS and FHTD have an eight-fold higher risk for CH, particularly when the index case is male. FHTD detailed evaluation can be an easy and accessible strategy to identify those newborns with DS at higher risk for CH., (Copyright: © 2021 Permanyer.)

Autoimmune thyroid disease (AITD) is a complex disorder with both genetic and environmental risk factors. A number of genetic factors such as HLA and CTLA-4 loci have been associated with risk of this disorder. In addition to these factors, recent studies have shown contribution of non-coding RNAs in the pathogenesis of this condition. Several microRNAs (miRNAs) and a number of long noncoding RNAs (lncRNAs) such as IFNG-AS1, Heg, NR&#95;038461, NR&#95;038462, T204821 and NR&#95;104125 have been dysregulated in peripheral blood of patients with AITD. These transcripts are mostly enriched in pathways that modulate humoral and cellular immune responses such as those associated with antigen presentation and differentiation of Th1, Th2 and Th17 cells. Functional studies verified the role of a number of lncRNAs and miRNAs in regulation of critical immune-related pathways in AITD. Thus, they participate in the pathophysiology of AITD. In the current review, we summarize the results of studies that assessed participation of non-coding RNAs in the pathophysiology of AITD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Thyroid hormone plays a pivotal role in human metabolism. In epidemiologic studies, adequate registration of thyroid disorders is warranted. We examined the prevalence of thyroid disorders, reported thyroid medication use, thyroid hormone levels, and validity of thyroid data obtained from questionnaires in the Lifelines Cohort Study., Methods: We evaluated baseline data of all 152180 subjects (aged 18-93 years) of the Lifelines Cohort Study. At baseline, participants were asked about previous thyroid surgery and current and previous thyroid hormone use. At follow-up (n = 136776, after median 43 months), incident thyroid disorders could be reported in an open, non-structured question. Data on baseline thyroid hormone measurements (TSH, FT4 and FT3) were available in a subset of 39935 participants., Results: Of the 152180 participants, mean (±SD) age was 44.6±13.1 years and 58.5% were female. Thyroid medication was used by 4790 participants (3.1%); the majority (98.2%) used levothyroxine, and 88% were females. 59.3% of levothyroxine users had normal TSH levels. The prevalence of abnormal TSH levels in those not using thyroid medication was 10.8%; 9.4% had a mildly elevated (4.01-10.0 mIU/L), 0.7% had suppressed (<0.40 mIU/L), while 0.7% had elevated (>10.0 mIU/L) TSH levels. Over 98% of subjects with TSH between 4 and 10 mIU/L had normal FT4. Open text questions allowing to report previous thyroid surgery and incident thyroid disorders proved not to be reliable and severely underestimated the true incidence and prevalence of thyroid disorders., Conclusions: Undetected thyroid disorders were prevalent in the general population, whereas the prevalence of thyroid medication use was 3.1%. Less than 60% of individuals using levothyroxine had a normal TSH level. The large group of individuals with subclinical hypothyroidism (9.4%) offers an excellent possibility to prospectively follow the natural course of this disorder. Both structured questions as well as linking to G.P.'s and pharmacists' data are necessary to improve the completeness and reliability of Lifelines' data on thyroid disorders., Competing Interests: The authors have declared that no competing interests exist.

The new era of immune and reconstitution therapy of autoimmune disorders is ongoing. However, endocrine autoimmune diseases comprise a group of elaborating pathologies where the development of new treatment strategies remains slow. Substitution of the missing hormones is still standard practice, taking care of the devastating symptoms but not the cause of disease. As our knowledge of the genetic contribution to the aetiology of endocrine disorders increases and early diagnostic tools are available, it is now possible to identify persons at risk before they acquire full-blown disease. This review summarizes current knowledge and treatment of endocrine autoimmune disorders, focusing on type 1 diabetes, Addison's disease, autoimmune thyroid diseases and primary ovarian insufficiency. We explore which new therapies might be used in the different stages of the disease, focus on legalized therapy and elaborate on the ongoing clinical studies for these diseases and the research front, before hypothesizing on the way ahead., (© 2020 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: SHORT syndrome is a rare genetic disease named with the acronyms of short stature, hyper-extensibility of joints, ocular depression, Rieger anomaly and teething delay. It is inherited in an autosomal dominant manner confirmed by the identification of heterozygous mutations in PIK3R1. This study hereby presents a 15-year-old female with intrauterine growth restriction, short stature, teething delay, characteristic facial gestalts who was identified a novel de novo nonsense mutation in PIK3R1., Case Presentation: The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*)., Conclusions: This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*). The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.

Introduction: The pathogenesis of autoimmune thyroid diseases is complicated and not completely known. Among the causes of thyroid autoimmunity, we distinguish genetic predisposition and environmental factors. Graves' disease and Hashimoto's thyroiditis are associated with a disturbance of immune tolerance of thyroid antigen molecules. The IL2RA gene is located on chromosome 10 and encodes the interleukin 2 receptor (IL2RA), which is expressed by the regulatory T-cells (Tregs) responsible for suppression. It has been shown that this gene and its polymorphism occur in people with various autoimmune diseases ( e.g. type 1 diabetes mellitus, rheumatoid arthritis, Graves' disease, or multiple sclerosis). The FAIM2 gene is located on chromosome 12 and encodes the molecule involved in the apoptosis inhibition process. The PADI4 gene is located on chromosome 1, and its expression is associated with activation of T-cells, differentiation of macrophages, which leads to increased inflammation., Aim: The aim of the study was to analyze the polymorphisms of the IL-2RA (rs7093069), FAIM2 (rs7138803) and PADI4 (rs1748033) genes and their correlation to thyroid hormones and anti-thyroid antibodies in pediatric patients with Graves' disease and Hashimoto's thyroiditis compared to the control group., Material and Methods: The study was performed in 180 patients with GD (mean age 16.5 ± 2), 80 with HT (mean age, 15.2 ± 2.2), and 114 children without any autoimmune diseases (mean age 16.3 ± 3) recruited from the endocrinology outpatient clinic. Three single nucleotide polymorphisms (SNPs): rs7138803-FAIM2, rs7093069-IL-2RA, and rs1748033 PADI4 were determined by TaqMan SNP QuanStudio 12K Flex-OpenArray genotyping with PCR and correlated to thyroid hormones and anti-thyroid antibodies., Results: Rs7090369-IL-2RA allele T was more frequent in patients with AITDs (33.7% in GD vs 28.7% in HT, p = 0.077, OR = 1.52) compared with healthy children (25%). Allele T of that gene predisposes to the occurrence of autoimmune thyroid diseases, especially GD and TT genotype gives a statistically significant 5.2 times higher risk of GD (p = 0.03, OR = 5.26) and increased risk of HT (p = 0.109, OR = 4.46). Allele A rs7138803-FAIM2 is more frequent in patients with GD (p = 0.071, OR = 1.45) and HT (p = 0.028, OR = 1.8). In our data the presence of GG genotype of that gene significantly reduces the risk of autoimmune thyroid diseases (p = 0.05, OR = 0.42). Allele C rs1748033PADI4 and its CC genotype were more frequent in patients with autoimmune thyroid diseases, but it was not statistically significant. The occurrence of CT genotype significantly reduces the risk of HT (p = 0.03, OR = 0.4)., Conclusions: 1). Polymorphisms rs7138803-FAIM2 and rs1748033-PADI4 are more frequent in patients with autoimmune thyroid diseases, more frequent in patients with Hashimoto' thyroiditis, but the occurrence of GG rs7138803-FAIM2 genotype could reduce the risk of thyrocyte apoptosis inhibition. 2). The TT rs7093069-IL2RA genotype may increase the risk of autoimmune thyroid diseases. 3). Analysis of polymorphisms of given genes in clinical practice will allow to determine predisposition to autoimmune thyroid disease development, to find symptoms of thyroid gland dysfunction earlier and to use appropriate treatment., (Copyright © 2020 Sawicka, Borysewicz-Sańczyk, Wawrusiewicz-Kurylonek, Aversa, Corica, Gościk, Krętowski, Waśniewska and Bossowski.)

Background: Many studies have shown that NLRC4 inflammasome polymorphisms are associated with a variety of autoimmune diseases, but the associations between NLRC4 polymorphisms and autoimmune thyroid diseases (AITDs) are unclear. Our research was aimed at identifying the correlations between NLRC4 polymorphisms and AITDs., Methods: Hi-SNP high-throughput genotyping technology was used for detecting four single-nucleotide polymorphisms (SNPs) of NLRC4 in 1005 AITDs patients (including 629 Graves' disease and 376 Hashimoto's thyroiditis) and 781 healthy controls., Results: Compared with healthy controls, the allele frequencies and genotype distribution of rs385076 were statistically related to AITDs ( P = 0.016 and P = 0.048, respectively) and Hashimoto's thyroiditis ( P = 0.022 and P = 0.046, respectively). Before adjusting for age and gender, rs385076 and AITDs had a significant association in three models of allele model, dominant model, and homozygous model. After adjusting for age and gender, in the above three models, there is still a clear relationship between them. Before adjusting for age and gender, there were prominent discrepancy between rs385076 and Hashimoto's thyroiditis in the allele model (OR = 0.81, 95% CI 0.67-0.97; P = 0.021) and the dominant model (OR = 0.73, 95% CI 0.57-0.94; P = 0.014), after adjusting for age and gender, rs385076 and Hashimoto's thyroiditis were significantly related to allele model, dominant model, and homozygous model. However, rs455060, rs212704, and rs675712 were not related to AITDs in our study., Conclusion: NLRC4 rs385076 was found to have a significant association with Hashimoto's thyroiditis for the first time. It laid a foundation for the disclosure of the pathogenesis of AITDs, and provided a possible treatment prospect for HT., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Xuerong Liu et al.)

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.

Context: Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels., Evidence Acquisition: This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease., Evidence Synthesis: Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint., Conclusions: Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Background Thyroid cancer (TC) is known to be the most common endocrine malignancy with an incidence rate which has increased by 2.3-fold over the past 30 years. Approximately, 30% of the thyroid fine-needle aspiration biopsy (FNAB) outcomes are indecisive. Moreover, researchers recognized multiple differentially expressed microRNAs (miRNAs) as candidate diagnostic markers for thyroid nodules. The purpose of this study was to identify thyroid tumor-associated miRNAs in FNAB with the capacity to be developed as unique biomarkers. Materials and methods According to the study design, a quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) was applied to evaluate the expression levels of nine miRNAs (Let7, miR-34a, miR-146b, miR-221, miR-151, miR-155, miR-181b, miR-222 and miR-375) among 224 FNA samples as the training set. Results The findings of this study revealed that miR-181b and miR-146b are the best predictors to diagnose benign thyroid FNA samples from malignant samples. However, the remaining miRNAs were co-expressed and had no significant effect on the predictor model. On the other hand, sensitivity and specificity of miR-181b and miR-146b were reported at 83.0%-83.0% and 83.0%-66.0%, respectively. Conclusions According to the results of this study, miR-146b and miR-181b might be considered as adjunct markers contributing to thyroid FNAB in tumor types. In addition, miR-146b and miR-181b were recognized as biomarkers for discriminating benign thyroid nodules from malignant ones. It is suggested that further prospective clinical trials be conducted to evaluate the accuracy of such findings in a larger cohort and determine the clinical uses.

Context: Selenocysteine insertion sequence binding protein 2 (SECISBP2, SBP2) is an essential factor for selenoprotein synthesis. Individuals with SBP2 defects have characteristic thyroid function test (TFT) abnormalities resulting from deficiencies in the selenoenzymes deiodinases. Eight families with recessive SBP2 gene mutations have been reported to date. We report 2 families with inherited defect in thyroid hormone metabolism caused by 4 novel compound heterozygous mutations in the SBP2 gene., Case Descriptions: Probands 1 and 2 presented with growth and developmental delay. Both had characteristic TFT with high T4, low T3, high reverse T3, and normal or slightly elevated TSH. The coding region of the SBP2 gene was sequenced and analysis of in vitro translated wild-type and mutant SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel compound heterozygous mutations resulting in mutant SBP2 proteins E679D and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In vitro translation of the missense E679D demonstrated all four isoforms, whereas R197* had only 2 shorter isoforms translated from downstream ATGs, and Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction in serum glutathione peroxidase enzymatic activity was also demonstrated in both probands., Conclusions: We report 2 additional families with mutations in the SBP2 gene, a rare inherited condition manifesting global selenoprotein deficiencies. Report of additional families with SBP2 deficiency and their evaluation over time is needed to determine the full spectrum of clinical manifestations in SBP2 deficiency and increase our understanding of the role played by SBP2 and selenoproteins in health and disease., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Developing insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. In this study, we apply the principles of Mendelian randomization to systematically evaluate transcriptome-wide associations between gene expression (across 48 different tissue types) and 395 complex traits. Our findings indicate that variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. Moreover, detailed investigations of our results highlight tissue-specific associations, drug validation opportunities, insight into the likely causal pathways for trait-associated variants and also implicate putative associations at loci yet to be implicated in disease susceptibility. Similar evaluations can be conducted at http://mrcieu.mrsoftware.org/Tissue&#95;MR&#95;atlas/.

The past half century has seen a number of advances in pathology of thyroid diseases, especially neoplastic lesions. These include the description of new entities, the definition of prognostically important lesions, the incorporation of fine needle aspiration biopsy and its functional risk stratification of diagnoses into the clinical evaluation and therapeutic recommendations of the patient with thyroid nodules and the understanding of thyroid neoplastic development, diagnostic and prognostic parameters by use of molecular analysis so that such techniques are becoming standard of care for patients with thyroid tumors. The histopathologist and cytopathologist have been and continue to be at the forefront in the definition and understanding of these areas of thyroid disease. This review describes many of the most important advances in this area in an attempt bring the practicing pathologist up to date in these developments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There are three important thyroid hormone-binding proteins in human serum, thyroxine-binding globulin, transthyretin, and albumin. Genetic variation in these proteins can lead to altered thyroid hormone binding and abnormalities in serum tests of thyroid hormone. Importantly, patients harboring these mutations are euthyroid; thus, the recognition of these conditions is crucial to prevent unnecessary repeated testing and treatment. This article provides an updated overview of serum thyroid hormone transport biology and reviews the underlying genetic alterations, clinical presentation, and appropriate evaluation of patients with suspected mutations in serum thyroid hormone-binding proteins.

Thyroid peroxidase (TPO) is an enzyme that participates in thyroid hormone biosynthesis. TPO is also a major autoantigen in autoimmune thyroid diseases (AITD). In this review, we summarize the latest developments in the field of TPO research. We present the current understanding of immunodominant serologic determinants, frequency of TPO-specific autoantibodies in the population, as well as genetic and environmental factors contributing to their development. Moreover, we report recent progress in the clinical utilities of TPO autoantibody testing, including thyroid dysfunctions and extra-thyroidal disorders., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Interferon (IFN)-α treatment predisposes patients to the occurrence of autoimmune thyroid disease (AITD)., Methods: We investigated associations of single nucleotide polymorphisms (SNPs) of molecules participating in the IFN-α signature, including rs2304204 and rs2304206 of IFN regulatory factor 3 (IRF3), rs1061501 of IRF7, and rs7708392 of TNFA1P3-interacting protein 1 with serum IFN-α levels and AITD in an ethnic Chinese (ie Taiwanese) population. Totally, 319 patients with Graves' disease (GD), 83 patients with Hashimoto's thyroiditis (HT) and 351 healthy controls were recruited., Results: There were increased percentages of the C allele, and CC and TC + CC genotypes of rs1061501 in GD patients compared to the controls. HT patients had higher serum IFN-α levels compared to the controls, while there was no difference in serum IFN-α levels between patients with GD and controls. However, patients with GD in a remission status had lower serum IFN-α levels than those without remission. On the other hand, the C allele of rs1061501 was only associated with serum IFN-α levels in patients with HT., Conclusions: The SNP rs1061501 of IRF7 was associated with the development of GD. Serum IFN-α levels were associated with HT, while they might modify the disease status of GD. Moreover, a genetic effect of rs1061501 on regulating serum IFN-α production was observed in HT., (© 2019 John Wiley & Sons Ltd.)

Increasing evidence has found that long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) play an important role in the progress of autoimmune thyroid diseases (AITD). So, in this study, the different expressed of lncRNA and mRNA was screened by microarray analysis and quantitative real-time polymerase chain reaction (PCR). To further investigate the relationship among the differentially expressed genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene ontology (GO) were used for biofunctions and signaling pathways analysis, respectively. Finally, the interaction relationship between lncRNA and mRNAs was analysis with lncRNA-mRNA coexpression network. The result found that the abnormal expression of lncRNAs and mRNAs were 1615 and 1913, respectively. The altered genes included CD40LG, IFNG, CTLA4, FAS, STAT1, STAT3, and STAT4. These were enriched in presentation and antigen processing, Th1 and Th2 cell differentiation, natural killer cell-mediated cytotoxicity, B cell receptor signaling pathway, Th17 cell differentiation, and cell adhesion molecules (CAMs), all of which had been suggested to be associated with immunopathogenic mechanisms and AITD-induced pathophysiologic changes. A coexpression network profile was contained with 126 network nodes and 477 connections which were based on seven mRNAs and 119 interacted lncRNAs. The outcomes of differentially expressed lncRNAs and their coreralated mRNAs in our study revealed that lncRNAs involved in immunopathogenic mechanisms may play a crital role in the pathogenesis of AITD., (© 2019 Wiley Periodicals, Inc.)

Purpose: Radioiodine (I 131 ) therapy is the treatment mainstay for several benign and malignant thyroid disorders, however I 131 is known to cause DNA damage and liberation of thyroidal self-antigens inducing secondary immunoreactivity. The exact mechanisms underpinning cellular death and subsequent induction of autoimmune thyroid disease following I 131 treatment have not yet been fully elucidated. This manuscript aims to review the literature concerning the effects of I 131 on the thyroid gland. Conclusion: The effects of I 131 on malignant thyroid cells appears to depend on absorbed dose with the literature demonstrating a clear initial delay in the triggering of apoptosis in response to I 131 -mediated cellular damage. Some studies also observed necrotic cellular death following high-dose I 131 treatment. Liberation of thyroidal self-antigen following I 131 treatment helps to explain phenomena such as the subsequent induction of autoimmune thyroid disease. The clinical utility of cytokines and autoantibodies for prognostication of hypothyroidism and treatment failure following I 131 remains uncertain and further appropriately-powered studies are required to clarify their role. The potential role of other cell death mechanisms activated after treatment with I 131 should also be explored in order to fully delineate the thyroidal response.

Purpose: Thyroid hormones are essential for the normal function of almost all human tissues, and have critical roles in metabolism, differentiation and growth. Free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels are under strong genetic influence; however, most of the heritability is yet unexplained., Methods: In order to identify novel loci associated with fT3, fT4 and TSH serum levels we performed a genome-wide meta-analysis of 7 411 206 polymorphisms in up to 1731 euthyroid individuals from three Croatian cohorts from Dalmatia region: two genetically isolated island populations and one mainland population. Additionally, we also performed a bivariate analysis of fT3 and fT4 levels., Results: The EPHB2 gene variant rs67142165 reached genome-wide significance for association with fT3 plasma levels (P = 9.27 × 10 -9 ) and its significance was confirmed in bivariate analysis (P = 9.72 × 10 -9 ). We also found a genome-wide significant association for variant rs13037502 upstream of the PTPN1 gene and TSH plasma levels (P = 1.67 × 10 -8 )., Conclusion: We identified a first genome-wide significant variant associated with fT3 plasma levels, as well as a novel locus associated with TSH plasma levels. These findings are biologically relevant and enrich our knowledge about the genetic basis of pituitary-thyroid axis function.

Aim: Patients with celiac disease (CeD) are prone to develop other autoimmune diseases such as autoimmune thyroid disease and type 1 diabetes. While 7.5% of first-degree relatives (FDRs) of patients with CeD develop CeD, it is not clear whether FDRs of patients with CeD are at higher risk of developing autoimmune thyroid disease., Methods: In this prospective case-control study, we recruited 194 FDRs (males 53.1%) of 91 patients with CeD and 140 age-matched healthy controls (males 76.4%). They were screened for CeD using anti-tissue transglutaminase antibodies (anti-tTG Ab) and thyroid disease using a symptom questionnaire, anti-thyroid peroxidase antibodies (anti-TPO) and serum thyroid-stimulating hormone (TSH). Subjects having positive anti-TPO but a normal TSH were classified as having thyroid autoimmunity and those with elevated TSH with or without positive anti-TPO Ab were classified as having autoimmune thyroid dysfunction., Results: The prevalence of thyroid autoimmunity and autoimmune thyroid dysfunction in FDRs was significantly higher than that in healthy controls (17.5% vs. 5.0%, p < 0.01; 11.8% vs. 3.5%, p < 0.01), respectively. A significantly higher number of FDRs had a positive anti-tTG Ab in comparison with controls (13.9% vs. 2.2%, p < 0.001). Amongst FDRs having thyroid autoimmunity, 44.1%, 47.0% and 8.8% were siblings, parents and children of patients with CeD, respectively. Familial clustering was seen only in 1 family., Conclusion: FDRs of patients with CeD have 3-fold higher risk of developing autoimmune thyroid disorders and associated thyroid dysfunction. Therefore, it is advisable for early screening of FDRs for CeD and associated thyroid autoimmune through screening measures.

The thyroid is a hormone gland involved in metabolism, regulatory functions, growth, and development of the human organism [...].

Background: Thyroid diseases are the most common endocrine pathologies second to diabetes. They have been shown to have high genetic impact, and variants in any of the genes involved in the metabolism of thyroid hormones have marked influence on the development of these diseases., Aim: To identify the genes that have been most involved in the development of thyroid pathologies by reviewing the literature with recent relevant articles., Materials and Methods: We performed a literature search on the NCBI (National Center for Biotechnology Information) databases, and that of the European Bioinformatics Institute (EMBL-EBI) using keywords related to the topic of interest)., Results: Activation of oncogenes such as RAS, BRAF, RET/PTC and the overstimulation of the PI3K/AKT pathway plays an important role in thyroid tumorigenesis. SLC5A5, SLC26A4, TG, TPO, DUOX2, DUOXA2 are related to hypothyroidism. Risk factors for Graves' disease are associated with the presence of HLA-DR3, CTLA4, PTPN22, CD40, IL2RA (CD25), FCRL3, and IL23R. FOXE1 can be associated to hypothyroidism and papillary thyroid cancer., Conclusions: Thyroid diseases are polygenetic, and while there are sufficient pathways affected by genetic changes, and there is, to our knowledge, no gene that has been found to be specifically causal, and the pathology has been the result of the interaction of many genetic variables such as polymorphisms or mutations.

Objective: To investigate the karyotype, clinical manifestations and natural and therapeutic outcome of Turner syndrome (TS) in China., Method: A total of 124 TS patients with definite diagnosis were included. Karyotype, main clinical signs, sexual development and therapeutic outcome were analyzed., Results: TS karyotype was classified in 4 types: monosomy (32.7%), mosaic (15.9%), variant (23.9%) and mosaic with variant (27.4%). All patients showed short stature, with mean adult height<145cm. Sixteen percent of adolescent patients showed spontaneous breast development and 8% spontaneous menstruation. The rate of spontaneous sexual development was lowest in the monosomy karyotype. Common signs included cubitus valgus and wide breast space in about 50% of patients, epicanthus and skin nevus in 30% and webbed neck and shield chest in 10-20%. More than 10% of patients had associated heart, kidney or thyroid abnormalities. The rate of kidney malformation was highest in the monosomy karyotype. Growth hormone (GH) therapy can accelerate growth, with 7.6cm and 6.7cm increase in height in the first and second years of therapy respectively, slowing to 5.7cm and 4.1cm in the third and fourth years. Treated patients who reached nearly adult height were 10.2cm taller than untreated patients. Therapeutic effect correlated with GH therapy duration., Conclusion: TS patients showed a variety of karyotypes, related to the diversity of clinical manifestations and outcomes. Sexual development and adult height were poorer in monosomy karyotypes than in other types., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Autoimmune thyroid disease (AITD) mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT), and its pathogenesis is not clearly defined. This study was designed to explore risk loci for AITD. Genome-wide genetic data were analyzed to identify important risk loci for GD, and a case-control study with 845 AITD patients and 694 healthy controls was also conducted. The functional role of possible risk loci for GD was explored by analyzing the correlations of Centrosomal protein 128 (CEP128) expression level with intrathyroidal immune cells and key genes for candidate immune cells in GD thyroid tissues. CEP128 was identified as an important risk locus for GD in the genome-wide genetic analysis, and it was located near TSHR without obvious linkage disequilibrium with TSHR. Two tag single-nucleotide variants in CEP128 including a missense variant rs327463 were substantially related to genetic predisposition to GD and HT in the case-control study. CEP128 rs327463 was substantially related to GD under the allele model (OR = 1.31, 95%CI 1.08-1.59, P = 0.006) and the dominant model (OR = 1.37, 95%CI 1.09-1.72, P = 0.008), and it was related to HT under the recessive model (OR = 1.85, P = 0.031) and the homozygous model (OR = 1.91, P = 0.025). Moreover, CEP128 was substantially correlated with the frequencies of T-follicular helper (Tfh) cell and M1 macrophages in GD tissues. Gene set enrichment analysis suggested that CEP128 was related to several common immune pathways involved in GD pathogenesis, such as interferon-γ mediated signaling pathway and toll-like receptor signaling pathway. This study highlight the crucial role of CEP128 in the pathogenesis of GD, and polymorphisms in CEP128 contribute to genetic predisposition to both GD and HT., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Skewed X chromosome inactivation (XCI) was associated with female predominance in adult autoimmune thyroid disease (ATD). In normal females, skewed XCI is increased with age. Whether early-onset skewed XCI is associated with childhood ATD remains unknown. This study aimed to determine XCI skewing in paediatric ATD., Design, Patients and Measurements: Ninety-one female ATD patients, aged 3-20 years and 57 age-matched, female controls were enrolled. XCI was analysed by enzymatic digestion of DNA with methylation-sensitive enzymes followed by PCR of the polymorphic CAG repeat in the androgen receptor gene. Skewed XCI was defined as having 80% or greater of the cells preferentially inactivated on the same X chromosome. XCI pattern of the enrolled patients and parental origin of the skewed XCI were determined., Results: After exclusion of samples with homozygous CAG repeats, skewed XCI was analysed in 83 patients (57 Graves' disease and 26 Hashimoto thyroiditis) and 52 controls. There was an increased frequency of skewed XCI in ATD patients as compared with the controls (23% vs 8%, P = 0.022). Patients with Hashimoto thyroiditis had greater frequency of skewed XCI than patients with Graves' disease (38% vs 16%, P = 0.023). There were no differences in clinical parameters between patients with skewed and random XCI. Analysis of 7 patients with skewed XCI showed a preferential inactivation of paternal X chromosome in 6 patients (86%)., Conclusions: Frequency of skewed XCI was increased in childhood ATD. This observation suggests a possible association of skewed XCI in the development of paediatric ATD., (© 2018 John Wiley & Sons Ltd.)

Bipolar disorder (BD) is a mental disorder characterized by alternating periods of depression and mania. Individuals with BD have higher levels of early mortality than the general population, and a substantial proportion of this is due to increased risk for comorbid diseases. To identify the molecular events that underlie BD and related medical comorbidities, we generated imputed whole-genome sequence data using a population-specific reference panel for an extended multigenerational Old Order Amish pedigree (n = 394), segregating BD and related disorders. First, we investigated all putative disease-causing variants at known Mendelian disease loci present in this pedigree. Second, we performed genomic profiling using polygenic risk scores (PRS) to establish each individual's risk for several complex diseases. We identified a set of Mendelian variants that co-occur in individuals with BD more frequently than their unaffected family members, including the R3527Q mutation in APOB associated with hypercholesterolemia. Using PRS, we demonstrated that BD individuals from this pedigree were enriched for the same common risk alleles for BD as the general population (β = 0.416, p = 6 × 10 -4 ). Furthermore, we find evidence for a common genetic etiology between BD risk and polygenic risk for clinical autoimmune thyroid disease (p = 1 × 10 -4 ), diabetes (p = 1 × 10 -3 ), and lipid traits such as triglyceride levels (p = 3 × 10 -4 ) in the pedigree. We identify genomic regions that contribute to the differences between BD individuals and unaffected family members by calculating local genetic risk for independent LD blocks. Our findings provide evidence for the extensive genetic pleiotropy that can drive epidemiological findings of comorbidities between diseases and other complex traits.

Objective: Gitelman syndrome (GS) is an autosomal recessive disorder characterized by salt wasting and hypokalemia resulting from mutations in the SLC12A3 (solute carrier family 12 member 3) gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. To date, more than 488 mutations of the SLC12A3 gene have been discovered in patients with GS. In this study, we reported a GS pedigree complicated by thyroid diseases or thyroid dysfunction., Methods: Sanger sequencing and next-generation sequencing analysis were performed to determine the SLC12A3 gene mutations in a GS pedigree including the 16-year old male patient with GS and his family members within 3 generations. Chemiluminescence immunoassays were used to detect thyroid hormone and antibody concentrations., Results: Genetic analysis of the SLC12A3 gene identified 2 mutations in the 16-year old male patient with GS concomitant with Graves disease (GD) and his younger sister accompanied by abnormal thyroid function. Additionally, one mutation site (c.1456G>A) in SLC12A3 gene was found in his father, paternal uncle and elder female cousin, who were complicated by subclinical hypothyroidism or autoantibody against thyroid. The other mutation site (c.2102&#95;2107 delACAAGA) in SLC12A3 gene, a novel mutated variant of SLC12A3 gene, was carried by his mother and maternal grandfather., Conclusion: Two mutation sites were documented in the pedigree with GS, and one has not been reported before. Moreover, we found a mutation at nucleotide c.1456 G>A in the SLC12A3 gene that may affect thyroid function. However, further studies are needed to explore the underlying molecular mechanisms., Abbreviations: FT3 = free triiodothyronine; FT4 = free tetraiodothyronine; GD = Graves disease; GS = Gitelman syndrome; SLC12A3 = solute carrier family 12 member 3; TGAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hormone; TT3 = total triiodothyronine; TT4 = total tetraiodothyronine.

Deiodinase 2 (DIO2) plays an important role in thyroid hormone metabolism and its regulation. However, molecular mechanism that regulates DIO2 activity remains unclear; only mutaions in selenocysteine insertion sequence binding protein 2 and selenocysteine tranfer RNA (tRNA [Ser]Sec ) are reported to result in decreased DIO2 activity. Two patients with clinical evidence of abnormal thyroid hormone metabolism were identified and found to have TSHR mutations as well as DIO2 T92A single nucleotide polymorphism (SNP). Primary-cultured fibroblasts from one patient present a high level of basal DIO2 enzymatic activity, possibly due to compensation by augmented DIO2 expression. However, this high enzymatic active state yet fails to respond to accelerating TSH. Consequently, TSHR mutations along with DIO2 T92A SNP ("double hit") may lead to a significant reduction in DIO2 activity stimulated by TSH, and thereby may have clinical relevance in a select population of hypothyroidism patients who might benefit from a T3/T4 combination therapy.