Nonautoimmune congenital hyperthyroidism due to p.Asp633Glu mutation in the TSHR gene.
ABSTRACT: Most cases of congenital hyperthyroidism are autoimmune forms caused by maternal thyroid stimulating antibodies. Nonautoimmune forms of congenital hyperthyroidism caused by activating mutations of the thyrotropin receptor (TSHR) gene are rare. A woman gave birth to a boy during an emergency cesarean section at 33 weeks of gestation due to fetal tachycardia. On the 24th day of life, thyroid function tests were performed due to persistent tachycardia, and hyperthyroidism was confirmed. Auto-antibodies to TSHR, thyroid peroxidase, and thyroglobulin were not found. The patient was treated with propylthiouracil and propranolol, but hyperthyroidism was not well controlled. At 3 months of age, the patient had craniosynostosis and hydrocephalus, and underwent a ventriculoperitoneal shunt operation. Direct sequencing of the TSHR gene showed a heterozygous mutation of c.1899C>A (p.Asp633Glu) in exon 10. No mutations were discovered in any of the parents in a familial genetic study. We have reported a case of sporadic nonautoimmune congenital hyperthyroidism, by a missense mutation of the TSHR gene, for the first time in South Korea.
Project description:OBJECTIVE:Patients 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. DESIGN:A cross-sectional study of Caucasian adults with hyperthyroidism, managed at three endocrine centres in the South West, UK, from January 2006 to April 2017. METHODS:We recruited 78 adult Caucasian patients with hyperthyroidism showing diffuse uptake on 99m Tc-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. RESULTS:Genetic 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. CONCLUSIONS:Activating 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.
Project description:We describe severe thyrotoxicosis in young members of a family with nonautoimmune hyperthyroidism caused by a C672W germline mutation in exon 10 of TSHR gene. In this family, lack of genotype-phenotype correlation and anticipation across generations could be linked to an increased iodine intake as recently observed in France.
Project description:Congenital hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormones. It occurs in 1:2000-4000 newborns. Common clinical features include decreased activity and increased sleep, feeding difficulty, constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment, congenital hypothyroidism leads to severe intellectual deficit and short stature. Congenital hyperthyroidism occurs when the thyroid gland produces too much of the hormone thyroxine, which can accelerate body metabolism, causing unintentional weight loss and a rapid or irregular heartbeat. Hyperthyroidism is very rare and its prevalence is unknown. Common clinical features include unintentional weight loss, tachycardia, arrhythmia, palpitations, anxiety, tremor and sweating. Here we summarize the genes involved in congenital hypo- and hyperthyroidism and the tests we use for genetic analysis.
Project description:BACKGROUND:Graves' disease is the most common form of autoimmune thyroid disorder, characterized by hyperthyroidism due to circulating autoantibodies. To address the pathological features and establish a therapeutic approach of this disease, an animal model carrying the phenotype of Graves' disease (GD) in concert with Graves' Ophthalmopathy (GO) will be very important. However, there are no ideal animal models that are currently available. The aim of the present study is to establish an animal model of GD and GO disease, and its pathological features were further characterized. METHODS:A recombinant plasmid pcDNA3.1- T289 was constructed by inserting the TSHR A-subunit gene into the expression vector pcDNA3.1, and genetic immunization was successfully performed by intramuscular injection of the plasmid pcDNA3.1-T289 on female 8-week-old BALB/c mice. Each injection was immediately followed by in vivo electroporation using ECM830 square wave electroporator. Morphological changes of the eyes were examined using 7.0T MRI scanner. Levels of serum T4 and TSHR antibodies (TRAb) were assessed by ELISA. The pathological changes of the thyroid and orbital tissues were examined by histological staining such as H&E staining and Alcian blue staining. RESULTS:More than 90% of the immunized mice spontaneously developed goiter, and about 80% of the immunized mice manifested increased serum T4 and TRAb levels, combined with hypertrophy and hyperplasia of thyroid follicles. A significantly increased synthesis of hyaluronic acid was detected in in the immunized mice compared with the control groups. CONCLUSION:We have successfully established an animal model manifesting Graves' hyperthyroidism and ophthalmopathy, which provides a useful tool for future study of the pathological features and the development of novel therapies of the diseases.
Project description:Graves' hyperthyroidism is characterized by the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments, including antithyroid medication, radioiodine, or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy, in the case of the latter 2 options. The demand for new therapeutic options, combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves' hyperthyroidism. The current therapies under investigation include biologics, small molecules, and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies present a new opportunity to supersede the inadequate treatments currently available for some Graves' patients, offering hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves' hyperthyroidism.
Project description:Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Methods: Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Results: Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones (r?=?0.85, p?=?0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism.
Project description:Graves'-like hyperthyroidism is induced by immunizing BALB/c mice with adenovirus expressing the thyrotropin receptor (TSHR) or its A-subunit. Nonantigen-specific immune strategies can block disease development and some reduce established hyperthyroidism, but these approaches may have unforeseen side effects. Without immune stimulation, antigens targeted to the mannose receptor induce tolerance. TSHR A-subunit protein generated in eukaryotic cells binds to the mannose receptor. We tested the hypothesis that eukaryotic A-subunit injected into BALB/c mice without immune stimulation would generate tolerance and protect against hyperthyroidism induced by subsequent immunization with A-subunit adenovirus. Indeed, one sc injection of eukaryotic, glycosylated A-subunit protein 1 wk before im A-subunit-adenovirus immunization reduced serum T(4) levels and the proportion of thyrotoxic mice decreased from 77 to 22%. Prokaryotic A-subunit and other thyroid proteins (thyroglobulin and thyroid peroxidase) were ineffective. A-subunit pretreatment reduced thyroid-stimulating and TSH-binding inhibiting antibodies, but, surprisingly, TSHR-ELISA antibodies were increased. Rather than inducing tolerance, A-subunit pretreatment likely expanded B cells that secrete nonfunctional antibodies. Follow-up studies supported this possibility and also showed that eukaryotic A-subunit administration could not reverse hyperthyroidism in mice with established disease. In conclusion, glycosylated TSHR A-subunit is a valuable immune modulator when used before immunization. It acts by deviating responses away from pathogenic toward nonfunctional antibodies, thereby attenuating induction of hyperthyroidism. However, this protein treatment does not reverse established hyperthyroidism. Our findings suggest that prophylactic TSHR A-subunit protein administration in genetically susceptible individuals may deviate the autoantibody response away from pathogenic epitopes and provide protection against future development of Graves' disease.
Project description:TSH receptor (TSHR) antibodies and hyperthyroidism are induced by immunizing mice with adenovirus encoding the TSHR or its A-subunit. Depleting regulatory T cells (Treg) exacerbates thyrotoxicosis in susceptible BALB/c mice and induces hyperthyroidism in normally resistant C57BL/6 mice. Vitamin D plays an important role in immunity; high dietary vitamin D intake suppresses (and low intake enhances) adaptive immune responses. Vitamin D-induced immunosuppression may enhance Treg. Therefore, we hypothesized that decreased vitamin D intake would mimic Treg depletion and enhance hyperthyroidism induced by A-subunit adenovirus immunization. BALB/c mice had a reduced ability vs. C57BL/6 mice to generate the active metabolite of vitamin D (1,25-dihydroxyvitamin D3). Vitamin D deficiency induced subtle immune changes in BALB/c (not C57BL/6) mice. Compared with mice fed regular chow, vitamin D-deprived BALB/c mice had fewer splenic B cells and decreased interferon-gamma responses to mitogen and lacked memory T-cell responses to A-subunit protein. However, vitamin D deficiency did not alter TSHR antibody responses measured by ELISA, TSH binding inhibition, or cAMP generation from TSHR-expressing cells. Unexpectedly, compared with vitamin D-sufficient mice, vitamin D-deficient BALB/c mice had lower preimmunization T(4) levels and developed persistent hyperthyroidism. This difference was unrelated to the immunological changes between vitamin D-deficient or -sufficient animals. Previously, we found that different chromosomes or loci confer susceptibility to TSHR antibody induction vs. thyroid function. Our present studies provide evidence that an environmental factor, vitamin D, has only minor effects on induced immunity to the TSHR but directly affects thyroid function in mice.
Project description:Graves' disease (GD) and thyroid-associated ophthalmopathy (TAO) are thought to result from actions of pathogenic antibodies mediated through the thyrotropin receptor (TSHR). This leads to the unregulated consequences of the antibody-mediated receptor activity in the thyroid and connective tissues of the orbit. Recent studies reveal antibodies that appear to be directed against the insulin-like growth factor-I receptor (IGF-IR). Areas covered: In this brief article, I attempt to review the fundamental characteristics of the TSHR, its role in GD and TAO, and its relationship to IGF-IR. Strong evidence supports the concept that the two receptors form a physical and functional complex and that IGF-IR activity is required for some of the down-stream signaling initiated through TSHR. Recently developed small molecules and monoclonal antibodies that block TSHR and IGF-IR signaling are also reviewed in the narrow context of their potential utility as therapeutics in GD and TAO. The Pubmed database was searched from its inception for relevant publications. Expert opinion: Those agents that can interrupt the TSHR and IGF-IR pathways possess the potential for offering more specific and better tolerated treatments of both hyperthyroidism and TAO. This would spare patients exposure to toxic drugs, ionizing radiation and potentially hazardous surgeries.
Project description:Graves' is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves' disease.We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients' progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients.When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism.We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients' data including loading and maintenance doses and describe the mechanism, hyperthyroidism?euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.