Associationj of TSHR Gene Single Neucleotide Intronic Polymorphism with the Risk of Hypothyroid and Hyperthyroid Disorders in Yazd Province.

The present study was carried, for the first time, out to evaluate the association of rs2268458 polymorphism, biochemical and environmental factors on hypothyroid and hyperthyroid disorders in thyroid patients and healthy individuals in Yazd province, Iran. In this study, blood samples were collected from a total of 100 cases, including 60 hypothyroid, 20 hyperthyroidism individual cases and 20 normal individuals. DNA was extracted from blood samples and the rs2268458 single neucleotide intronic polymorphism was evaluated using RFLP-PCR. The results have shown that 59 cases were homozygote (TT), 40 cases heterozygote (TC) with one homozygote (CC) case, as follows; A total of 25 (TT) homozygote cases were observed to be hypothyroid females, 20 (TC) heterozygote cases of hypothyroid females, 7 (TT) homozygote male hypothyroid cases and 7 (TC) heterozygote male hypothyroid cases and 1 (CC) homozygote male hypothyroid patient. While, 7 (TT) homozygote hyperthyroid female cases, 8 (TC) heterozygote hyperthyroid female cases,were also observed. According to our study, heterozygote cases (TC) showed less severe symptoms, while homozygote cases (TT) showed no serious symptoms and the (CC) homozygote case (CC) showed severe thyroid abnormality symptoms. So, it can be concluded that the TSHR-related rs2268458 polymorphism is associated with hypothyroidism and hyperthyroidism in the male and female polulations of Yazd Province, Iran and C allele can be a risk factor for some physio-biochemical and hormonal imbalance in the thyroid disorder patients.

A Case of Definitive Therapy in Persistent Congenital Hyperthyroidism Secondary to an Activating Variant of the TSHR Gene

Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH. Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G->A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three. Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism. 1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.

Central TSH Dysregulation in a Patient with Familial Non-Autoimmune Autosomal Dominant Hyperthyroidism Due to a Novel Thyroid-Stimulating Hormone Receptor Disease-Causing Variant

Background and Objectives. Familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) is a rare cause of childhood hyperthyroidism. It is caused by the thyroid-stimulating hormone receptor (TSHR) gene variants. So far, only around 40 families with FNAH have been reported. Patients with activating TSHR variants demonstrated the same classical signs and symptoms of hyperthyroidism as seen in patients with Graves’ disease. Since 2012, ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences. Case Presentation. We presented a young adult male patient with a novel heterozygous TSHR disease-causing variant p.Arg418Lys (c.1253G>A) in the exon 10, who presented with a mild but progressive FNAH, with a follow-up since infancy. Discussion. Constantly suppressed TSH, including during the euthyreosis in childhood and hypothyreosis after iodine ablation therapy, suggested central dysregulation of the TSH secretion.

Congenital Hypothyroidism Patients With Thyroid Hormone Receptor Variants Are Not Rare: A Systematic Review

Background Primary congenital hypothyroidism (CH) is a common endocrine and metabolic disease. Various genetic factors, including the thyroid hormone receptor (TSHR), play an important role in CH. Aim To explore the occurrence of pathogenic TSHR variants in CH. Methods We searched published articles in PubMed, Web of Science, and Cochrane Library databases, from the establishment of the database to September 26, 2021. Studies with sequencing partial or full exons of TSHR in CH patients were included. Gene polymorphism was excluded. Results A total of 66 articles (44 case-control studies and 22 case reports) were selected from the database. Though case-control studies, we found the incidence of pathogenic TSHR variants were not rare (range from 0% to 30.6%) and varied greatly in different countries and race. The pathogenic genotypes varied in different regions. All the variants were “loss-of-function” mutations, in which the p.(Arg450His) variant was the most common variant. In addition, we analyzed the case reports and found that CH patients with a family genetic background expressed homozygous genotypes. Homozygotes had more obvious symptoms of hypothyroidism and higher risk of comorbidities than heterozygotes. Conclusion Pathogenic TSHR variants are not uncommon cause of the CH, especially in the Arabs. The role of TSHR gene detection in the treatment of children with CH needs to be further studied.

Familial neonatal nonautoimmune hyperthyroidism due to a gain-of-function (D619G) thyrotropin-receptor mutation

ObjectivesActivating germline mutations of the thyroid-stimulating hormone receptor (TSHR) are responsible for a rare form of neonatal nonautoimmune hyperthyroidism (NAH). We report the first case of familial neonatal neonatal nonautoimmune associated with c.1856A>G (p.Asp619Gly) variant in the TSHR gene.Case presentationWe describe an eight-year-old African-American female presenting with neonatal NAH associated with an inherited heterozygous c.1856A>G (p.Asp619Gly) variant in the TSHR gene. This variant was previously described in one patient presenting with sporadic NAH in adolescence. Our patient was diagnosed with hyperthyroidism in the neonatal period. The mother had a history of hyperthyroidism and had thyroidectomy at the age of 4 years. The patient had goiter and elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels that normalized with methimazole treatment; however, TSH level remained suppressed. Thyroid antibodies were negative. The patient also had bilateral exotropia, a trait shared by the mother and may represent a new association.ConclusionsFamilial neonatal NAH is associated with heterozygous c.1856A>G (p.Asp619Gly) variant of the TSHR gene.