TSH Receptor Mutations Research Articles

Structural and morphologic characteristics of nodular goiter in chronic iodine deficiency status

OBJECTIVES. Diffuse and nodular goiter are the most common thyroid gland (thyroid) diseases in children and adults living in iodine-deficient regions. Thyroid hormone potentiates progressive hypertrophy and hyperplasia of thyrocytes, with uneven proliferation of thyroid cells leading to nodule formation. Iodine deficiency, which promotes replication of thyroid follicular cells, also increases the incidence of TSH Receptor mutations, leading to receptor activation and autonomous functioning of follicles.AIM. To evaluate and describe ultrasound and cytologic thyroid nodes in the regions in Russia with proven iodine deficiency.MATERIALS AND METHODS. The study was conducted in regions with proven iodine deficiency in the Central and North Caucasian Federal Districts. Population of conditionally healthy adult volunteers (mean age — 47.5 years) was recruited as part of visiting events to screen for the occurrence of thyroid nodes.RESULTS. The results obtained indicate a high prevalence of multinodular colloid goiter in adult patients living in conditions of chronic iodine deficiency. In the Chechen Republic, the prevalence of nodular thyroid pathology was found in 64.5% (205/318) of cases, and in the Tula region — in 40.6% (116/286). In the studied sample the results of cytologic examination confirmed the presence of colloid thyroid masses in 97% (60/62) — Bethesda category II; in 3% (2/62) of patients nodular masses had Bethesda IV. Diffuse goiter prevalence in the examined population was 20.8%.CONCLUSIONS. A study indicates a high prevalence of iodine-deficient thyroid disease — multinodular colloid goiter in regions with proven chronic iodine deficiency. The wide prevalence of goiter with colloid and cystic components is confirmed by the cytologic examination with different ultrasound characteristics according to the EU-TIRADS classification. The obtained data correspond to the official statistics demonstrating high prevalence of nontoxic goiter in adults in the examined regions, which is an important argument confirming the need for systemic iodine prophylaxis.

Unraveling the significance of TSHR mutations in indeterminate thyroid cytology specimens.

We investigated the clinical significance of thyroid-stimulating hormone receptor (TSHR) mutations detected in thyroid fine needle aspiration (FNA) specimens. The pathology archives at our institution were reviewed between 2018 and 2021 for indeterminate (Bethesda category III and IV) specimens with Thyroseq® analysis showing TSHR mutations. A total of 2184 cases diagnosed as atypia/follicular lesion of undetermined significance (AUS/FLUS), and 2625 diagnosed as follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) were identified. A total of 1735 AUS/FLUS and 2339 SFN/FN underwent Thyroseq® analysis; 69 showed TSHR mutations (1.6%, 59 female, 10 male, average age: 55 years). Ten cases showed oncocytic features. Twelve patients underwent radionuclide scans within 1 year of FNA:11 were hyperfunctioning. Nodule size and TSH levels were weakly correlated. Twenty-two different TSHR mutations were identified (most common: M453T). A second mutation was found in five cases (EZH1 n = 2, and EIF1AX n = 3). The expression of sodium-iodide transporter (NIS) mRNA was in the range of 0.01%-62.43% out of all sequencing reads, and was elevated in 49 (71%) cases. Surgical pathology follow-up was available in five cases (all benign except one). On follow-up available for 38 cases (mean: 24 months; range: 7-47 months), 34 (89.5%) nodules remained stable and 3 (8%) increased in size. TSHR mutations in thyroid FNA samples classified as indeterminate are rare, generally benign, and commonly associated with autonomy on scan if performed.

Structure of full-length TSH receptor in complex with antibody K1-70™.

Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.

Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations.

To evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma® Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category. ITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated. Five percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant. TSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.

Thyrotropin Receptor p.N432D Retained Variant Is Degraded Through an Alternative Lysosomal/Autophagosomal Pathway and Can Be Functionally Rescued by Chemical Chaperones.

Background: Loss-of-function mutations of thyrotropin receptor (TSHR) are one of the main causes of congenital hypothyroidism. As for many disease-associated G-protein coupled receptors (GPCRs), these mutations often affect the correct trafficking and maturation of the receptor, thus impairing the expression on the cell surface. Several retained GPCR mutants are able to effectively bind their ligands and to transduce signals when they are forced to the cell surface by degradation inhibition or by treatment with chaperones. Despite the large number of well-characterized retained TSHR mutants, no attempts have been made for rescue. Further, little is known about TSHR degradation pathways. We hypothesize that, similar to other GPCRs, TSHR retained mutants may be at least partially functional if their maturation and membrane expression is facilitated by chaperones or degradation inhibitors. Methods: We performed in silico predictions of the functionality of known TSHR variants and compared the results with available in vitro data. Western blot, confocal microscopy, enzyme-linked immunosorbent assays, and dual luciferase assays were used to investigate the effects of degradation pathways inhibition and of chemical chaperone treatments on TSHR variants' maturation and functionality. Results: We found a high discordance rate between in silico predictions and in vitro data for retained TSHR variants, a fact indicative of a conserved potential to initiate signal transduction if these mutants were expressed on the cell surface. We show experimentally that some maturation defective TSHR mutants are able to effectively transduce Gs/cAMP signaling if their maturation and expression are enhanced by using chemical chaperones. Further, through the characterization of the intracellular retained p.N432D variant, we provide new insights on the TSHR degradation mechanism, as our results suggest that aggregation-prone mutant can be directed toward the autophagosomal pathway instead of the canonical proteasome system. Conclusions: Our study reveals alternative pathways for TSHR degradation. Retained TSHR variants can be functional when expressed on the cell surface membrane, thus opening the possibility of further studies on the pharmacological modulation of TSHR expression and functionality in patients in whom TSHR signaling is disrupted.

SUN-LB78 Hyperfunctioning Papillary Thyroid Carcinoma With a BRAF Mutation

Background: Hyperfunctioning papillary thyroid carcinoma (PTC) is a rare tumor and accounts for less than 0.1% of all thyroid tumors. Information about its driver mutations is limited. Our literature search yielded 16 cases wherein a mutational analysis was conducted. Thyrotropin receptor (TSHR) mutations were identified in 11 of these cases. One case revealed a combination of TSHR and KRAS mutations. No mutations were identified in the other four cases. BRAFV600E is a prominent oncogene in PTC; however, hyperfunctioning PTC with this mutation has not yet been reported. Clinical Case: In a 48-year-old man, ultrasonography (US) during an annual medical checkup revealed a nodule at the right lobe of the thyroid gland. He visited the outpatient clinic for further evaluation. Thyroid function tests indicated that he was hyperthyroid with TSH level of 0.01 mIU/L (reference range: 0.05-5.00), free thyroxine level of 1.8 ng/dL (reference range: 0.9-1.7), and free triiodothyronine level of 4.3 pg/mL (reference range: 2.3-4.0). Serum thyroglobulin was 62.1 ng/mL (reference range: <33.7) and TSHR autoantibodies (TRAb) was <0.8 IU/L (reference range: <2.0 IU/L). B-mode US revealed a hypoechoic, heterogeneous nodule with largest diameter of 25 mm, and it had a jagged border and microcalcification. Color Doppler US revealed increased intranodular vascularity. The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with suppression in the remainder of the gland. These findings were consistent with an autonomously-functioning thyroid nodule. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignant cytological diagnosis. The histopathological diagnosis of the patient was PTC, tall cell variant, pT2, pEx0, pN1b, and M0. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 9 and 10), GNAS (exons 7-10), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) only identified a heterozygous point mutation in BRAFV600E in tissue samples. Conclusion: We report for the first time a case of hyperfunctioning papillary thyroid carcinoma with a BRAF mutation.

The Thyrotropin Receptor Mutation Database Update.

The thyrotropin receptor (TSHR) mutation database, consisting of all known TSHR mutations and their clinical characterizations, was established in 1999. The database contents are updated here with the same website (tsh-receptor-mutation-database.org). The new database contains 638 cases of TSHR mutations: 448 cases of gain of function mutations (7 novel mutations and 41 new cases for previously described mutations since its last update in 2012) and 190 cases of loss of function mutations (28 novel mutations and 31 new cases for previously described mutations since its last update in 2012). This database is continuously updated and allows for rapid validation of patient TSHR mutations causing hyper- or hypothyroidism or insensitivity to TSH.

Perspective Summary of Brief Report on Thyroid Disease of Post Glaciations Quaternary Is Endocrinology of Ecology System in Centre Marc Sankale Setting in Dakar

Reflexions about immunoradiometric Tsh and Trh test during on Optimal thyroid hormonal therapy (Optimal dosages and overdosages) as Pionnary Auto-immune Primary Hypothyroidism in Dakar [Senegal] gives us A Propose of Whitaker Syndrome Case Report and THYROID GLAND AND ITS PEPTIDES OR ACTUALITYOF GENERAL ENDOCRINOLOGY. Many peptides by their cell molecular metabolism in the thyroid gland are involved: mutations of TSH receptor is linked to hormone resistance with congenital hypothyroidism; a new oroxigenic peptide, Ghrelin is widespread in endocrine tissues; tachykinine is another novel peptide with endocrine paracrine effect. PTTG and FGF-2 are prognostic markers of differentiated cancers; CRIF1 is a novel protein of nucleus interacting with Gadd45 and could negatively regulate cycle cell progression and cell growth; mutations of RET protooncogene is now the best CMT biomarker in the place of calcitonin in addition with CGRP, CGRPβ and Amylin; regulating proteins of CAMP, protein G, Gi alpha 1, MAL proteolipid are identified near immunologic antigens involved in Grave’s disease, autoimmune polyendocrinopathies. These peptides by their diversity of function support the concept of general endocrinology equivalent of medical sciences. Bastenie P. A. classification is a bio-clinical semeiology that could be reviewed by doing the integration of obesity as the incipient stage of epigenetic thyroid turnover of deiodinase realizing an inactive TSH. Thus primary hypothyroidism in an historical-technically point of view can recognize since Bastenie: -1 Atrophic thyroid myxedema with: low T4 and low T3 and High TSH and TRH positive. -2 Mild hypothyroidism where only TSH is High and TRH Test positive. -3 Infra-clinic hypothyroidism where only TRH Test is positive. -4 Compensated thyroiditis where only auto-antibodies are positive. -5 Common obesity where deiodinase turnover is only disturbed. Iodine regulates nutritional metabolism probably via the microbiome. Thyro-diabetes has concerned clinicians. Endocrine disruptors have come to recall us if necessary that thyroid gland is a gate keeper of the environment which in our approach is the testimony of primordial role of mineral iodine in the majority of living beings. Here are the perspectives of General Practitioner of Endocrine Diseases and Clinical Medicine Department.

Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism

BackgroundDefects in the human thyroid stimulating hormone receptor (TSHR) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify mutations in Chinese patients with CH and analyze the relationships between TSHR phenotypes and clinical phenotypes. Methods220 patients with primary CH were screened for TSHR mutations by performing next-generation sequencing. All the exons and exon–intron boundaries of TSHR were analyzed. The function of 8 mutants in TSHR were further investigated in vitro. ResultsAmong 220 patients with CH, 15 distinct TSHR mutations were identified in 13 patients (5.91%, 13/220, including our previous reported 110 patients, carried with 10 mutations in 8 patients). We found five distinct mutations in the additional cohort of 110 CH patients and identified 7 mutations (including a novel mutation, p.S567R) were loss-of-function mutations. ConclusionOur study indicated that the prevalence of TSHR mutations was 5.91% among studied Chinese patients with CH. One novel TSHR variant was found and four genetic alterations revealed important role of the Ile216, Ala275, Asn372, Ser567 residues in signaling.

Utility of systematic TSHR gene testing in adults with hyperthyroidism lacking overt autoimmunity and diffuse uptake on thyroid scintigraphy.

SummaryObjectivePatients with hyperthyroidism lacking autoimmune features but showing diffuse uptake on thyroid scintigram can have either Graves’ disease or germline activating TSH receptor (TSHR) mutation. It is important to identify patients with activating TSHR mutation due to treatment implication, but the overlapping clinical features with Graves’ disease make it difficult to discriminate these two conditions without genetic testing. Our study aimed to assess the potential of systematic TSHR mutation screening in adults with hyperthyroidism, showing diffuse uptake on thyroid scintigraphy but absence of TSH receptor antibodies (TRAb) and clinical signs of autoimmunity.DesignA cross‐sectional study of Caucasian adults with hyperthyroidism, managed at three endocrine centres in the South West, UK, from January 2006 to April 2017.MethodsWe recruited 78 adult Caucasian patients with hyperthyroidism showing diffuse uptake on 99mTc‐pertechnetate thyroid scintigraphy but without TRAb and other autoimmune clinical features of Graves’ disease (such as thyroid‐associated ophthalmopathy or dermopathy). Genomic DNA of these patients was analysed for variants in the TSHR gene.ResultsGenetic analysis identified 11 patients with four variants in TSHR [p.(Glu34Lys), p.(Asp36His), p.(Pro52Thr) and p.(Ile334Thr)]. None of these variants were pathogenic according to the American College of Medical Genetics and Genomics guideline.ConclusionsActivating TSHR mutations are a rare cause of nonautoimmune adult hyperthyroidism. Our study does not support the routine genetic testing in adult patients with hyperthyroidism showing diffuse uptake on scintigraphy but negative TRAb and lacking extrathyroidal manifestations of Graves’ disease.

Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice.

Constitutively active thyrotropin receptor (TSHR) mutations are the most common etiology of non-autoimmune hyperthyroidism (NAH). Thus far, the functionality of these mutations has been tested in vitro, but the in vivo models are lacking. To understand the pathophysiology of NAH, the patient-derived constitutively active TSHR D633H mutation was introduced into the murine Tshr by homologous recombination. In this model, both subclinical and overt hyperthyroidism was observed, depending on the age, sex, and genotype. Homozygous mice presented hyperthyroidism at two months of age, while heterozygous animals showed only suppressed thyrotropin. Interestingly, at six months of age, thyroid hormone concentrations in all mutant mice were analogous to wild-type mice, and they showed colloid goiter with flattened thyrocytes. Strikingly, at one year of age, nearly all homozygous mice presented large papillary thyroid carcinomas. Mechanistically, this papillary thyroid carcinoma phenotype was associated with an overactive thyroid and strongly increased stainings of proliferation-, pERK-, and NKX2-1 markers, but no mutations in the "hot-spot" areas of common oncogenes (Braf, Nras, and Kras) were found. This is the first study to reveal the dynamic age-, sex-, and genotype-dependent development of NAH. Furthermore, the study shows that a constitutively active TSHR can trigger a malignant transformation of thyrocytes.

Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies.

Objectives: To examine the prevalence of genetic alterations of thyroid-stimulating hormone receptor (TSHR) gene and sodium-iodine symporter (NIS) in a series of thyroid fine needle biopsy (FNB) specimens with indeterminate cytology, and to assess the correlation of the type of genetic changes with clinical features and follow-up results in the target thyroid nodule.Methods: Between February 2015 and September 2017, 388 consecutive FNBs with indeterminate cytology were evaluated for TSHR mutations and NIS gene overexpression using ThyroSeqV.2 next-generation sequencing (NGS) panel. Medical records were reviewed for target nodules.Results: Among 388 indeterminate FNBs, TSHR mutations and/or NIS overexpression were detected in 25 (6.4%) nodules. Ten nodules (2.6%) harbored TSHR mutations only, 7 nodules (1.8%) over-expressed NIS gene only, and 8 nodules (2.1%) had both alterations. The TSHR mutations were located between codons 281 and 640, with codon 453 being the most frequently affected. The allelic frequency of the mutated TSHR ranged from 6 to 36%. One nodule with NIS overexpression was simultaneously detected EIF1AX mutation and GNAS mutation. Nodules with TSHR mutations and/or NIS overexpression presented hyperfunctioning (n = 4), hypofunctioning (n = 5), and isofunctioning (n = 3) on the available thyroid scintigraphies. Eight cases accompanied with hyperthyroidism in which only 1 was caused by the target nodule. Evidence of co-existing autoimmune thyroid disease (AITD) and multinodular goiter were found in 52% and 52% of cases, respectively. Seven nodules underwent surgeries and all were benign on final pathology. None of 9 nodules with follow-up by ultrasound (3~33 mon, median 12 mon) showed grow in size.Conclusions: TSHR mutations and/or NIS overexpression can be detected in pre-operative FNB specimens using the NGS approach. These genetic alterations occurred in 6.4% thyroid nodules in this consecutive series with indeterminate cytology. They present not only in hyperfunctioning nodules but also in hypo- or iso-functional nodules, indicating their prevalence may be higher than previously expected. Co-existing AITD was common in cases with these molecular alterations. None of our patients with TSHR mutations and/or NIS overexpression manifested malignant outcomes. How to use these two molecular markers in thyroid FNBs to guide our clinical practice warrants further investigation.

Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations.

Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.

Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor

Thyroid stimulating hormone receptor (TSHR), a G-protein-coupled receptor, is important for thyroid development and growth. In several cases, frameshift and/or nonsense mutations in TSHR were found in the patients with congenital hypothyroidism (CH), however they have not been functionally studied in an animal model. In the present work, we generated a unique TshrDf/Df rat model that recapitulates the phenotypes in TSHR Y444X patient by CRISPR/Cas genome editing technology. In this rat model, TSHR is truncated at the second transmembrane domain, leading to CH phenotypes as what was observed in the patients, including dwarf, thyroid aplasia, infertility, TSH resistant as well as low serum thyroid hormone levels. The phenotypes can be reversed, at least partially, by levothyroxine (L-T4) treatment after weaning. The thyroid development is severely impaired in the TshrDf/Df rats due to the suppression of the thyroid specific genes, i.e., thyroperoxidase (Tpo), thyroglobulin (Tg) and sodium iodide symporter (Nis), at both mRNA and protein levels. In conclusion, the TshrDf/Df rat serves as a brand new genetic model to study CH in human, and will greatly help to shed light into the development of terminal organs that are sensitive to thyroid hormones.

Identification of compound heterozygous TSHR mutations (R109Q and R450H) in a patient with nonclassic TSH resistance and functional characterization of the mutant receptors.

.Genetic defects of the TSH receptor (TSHR) signaling pathway cause a form of congenital hypothyroidism (CH) known as TSH resistance. Consistent with the physiological understanding that thyroidal iodine uptake is up-regulated by TSHR signaling, most patients with TSH resistance have low to normal thyroidal 123I uptake representing the classic TSH resistance. However, paradoxically high 123I uptake was reported in four molecularly-confirmed patients indicating nonclassic TSH resistance. Here, we report the fifth patient with the nonclassic phenotype. He was a 12-yr-old CH patient and treated with levothyroxine. At the age 11 yr, he showed slightly small thyroid gland and elevated thyroidal 123I uptake. Genetic analysis showed that he was compound heterozygous for two known missense mutations (Arg109Gln and Arg450His) in the TSHR gene. Further, the signal transduction of Arg109Gln-TSHR was defective in both Gs- and Gq-coupled pathways, while Arg450His-TSHR showed Gq-dominant defect. 123I uptake was evaluated earlier in 16 patients with TSH resistance, and a correlation between TSH levels and 123I uptake was shown in patients with specific genotypes (Arg450His or Leu653Val). Collectively, we have re-confirmed that the emergence of the nonclassic phenotype requires two factors: mutant TSHR with Gq-dominant coupling defect and relatively high levels of serum TSH.

Long-Term Follow-Up of a Patient with Sporadic Nonautoimmune Hyperthyroidism Due to a Thyrotropin-Receptor Mutation (D619G)

ABSTRACT Objective: Sporadic nonautoimmune hyperthyroidism caused by germline mutations of the thyrotropin receptor (TSHR) gene is a very rare disease that manifests as severe congenital hyperthyroidism. We describe a case presenting with sporadic nonautoimmune hyperthyroidism during adolescence. Methods: Laboratory data, imaging, histopathology, clinical follow-up, and DNA sequencing were evaluated. Results: The patient was born at term with a normal birth weight but showed increased growth velocity at approximately 7 months. He had no medical consultation before tachycardia was detected at a school physical examination at the age of 13 years. Thyroid function tests confirmed hyperthyroidism with negative anti-TSHR antibodies. After maintaining methimazole therapy for 12 years, he underwent total thyroidectomy, and the weight of the resected thyroid tissue was 131 g. The subsequent histopathologic findings showed an encapsulated follicular adenoma, adenomatous goiter, and hyperplastic changes of the foll...

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood.

Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. Observational, retrospective study. Thirty four children (age 7days to 11years) and 18 adult carriers of TSHR variants. The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15years). Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.

Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis

BackgroundThe abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. MethodsThe exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. ResultsSeven variants were detected in TSHR—p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. ConclusionsOur study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.

Thyroid Stimulating Hormone Receptor.

Thyroid stimulating hormone receptor (TSHR) plays a pivotal role in thyroid hormone metabolism. It is a major controller of thyroid cell function and growth. Mutations in TSHR may lead to several thyroid diseases, most commonly hyperthyroidism. Although its genetic and epigenetic alterations do not directly lead to carcinogenesis, it has a crucial role in tumor growth, which is initiated by several oncogenes. This article will provide a brief review of TSHR and related diseases.

Identification and functional characterization of a novel thyrotropin receptor mutation (V87L) in a Chinese woman with subclinical hypothyroidism.

The thyrotropin receptor (TSHR) gene has been defined as a highly mutable gene. Mutations in the TSHR gene result in either gain or loss of the receptor function. Subclinical hypothyroidism (SH) is a clinical condition defined as an elevated serum TSH level associated with normal free thyroxine and free triiodothyronine. Chronic autoimmune thyroiditis is the most frequent cause of subclinical hypothyroidism in adults. In rare cases, a loss-of-function mutation of TSHR is the cause of SH. In the present study, a novel TSHR mutation (V87L; confirmed to be a loss-of-function mutation) was identified in a 59-year-old Chinese woman, as the potential cause of the patient's subclinical hypothyroidism. The case may provide valuable insight into the etiology of SH.