Thyroid Hormone Receptor Beta Gene Research Articles

Pituitary Hyperplasia and Overt Hypothyroidism Induced by Methimazole in an Adolescent Girl with Resistance to Thyroid Hormone Accompanying Hashimoto’s Thyroiditis: A Case Report

We describe a 13-year-old girl who presented at her local hospital with a diffuse goiter and had discrepant thyroid function test (TFT) of elevated free T4 (FT4), free T3 (FT3) levels with mildly elevated thyroid-stimulating hormone (TSH) and a pituitary magnetic resonance imaging (MRI) report of a pituitary hyperplasia. She was referred to our hospital where a repeat TFT found low FT4 and high TSH levels, and high levels of antithyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies, leading to the diagnosis of Hashimoto’s thyroiditis (HT) with overt primary hypothyroidism. The girl had a good response after daily 100 µg levothyroxine treatment for 8 months with decreased goiter size along with disappearance of the pituitary mass. However, her FT4 and FT3 levels were elevated while the TSH was in the high normal range, although at this time there were no signs of hyperthyroidism. A genetic study confirmed our provisional diagnosis that the patient had a p.Pro453Thr monoallelic loss-of-function mutation of the thyroid hormone receptor beta (THRB) gene, suggesting the diagnosis of coexisting resistance to thyroid hormone-β (RTHβ) and HT in this patient.

OR14-06 Serum Thyroid Hormones Increase At The Onset Of Lactation And Promote Metabolic Pathways Required For Human Milk Synthesis

Abstract Disclosure: H. Rostom: None. X. Meng: None. R. Humphrey: None. A. Fry: None. T. Elajnaf: None. F. Hannan: None. An increase in mammary metabolism is critical for initiating lactation during postpartum days 1-4. We utilised clinical and cellular approaches to investigate whether thyroid hormones, which promote lactation in rodents, are involved in initiating human lactation and regulating mammary metabolism. We recruited n=35 healthy pregnant women intending to breastfeed following informed consent and measured serum thyroid hormones (TSH and free T4) at 36 weeks’ gestation and on postpartum days 1-4 (1). Serum TSH significantly increased at post-partum day 1 compared with 36 weeks’ gestation (2.5±0.3 vs. 1.6±0.1 mU/L, p=0.001). This early postpartum rise in TSH was followed by a significant increase in free T4 on post-partum days 3 and 4 (11.7±0.2 vs. 10.5±0.2pmol/L at 36 weeks’ gestation, p<0.01). We hypothesised that thyroid hormones increase mammary metabolism to promote breast milk production. Reverse transcription-quantitative PCR (RT-qPCR) of genes encoding deiodinase enzymes (DIO1-3), which regulate intracellular thyroid hormone activity, was undertaken in lactating human mammary epithelial cells (HMECs) isolated from breast milk. This showed that DIO1, which converts T4 to T3, was expressed in lactating HMECs, whereas DIO2 and DIO3 were not detected. Moreover, RT-qPCR of the thyroid hormone receptor alpha and beta (THRA and THRB) genes in lactating HMECs showed that THRB has ∼4-fold greater expression than THRA (p<0.05, n=4). THRB phosphorylates Akt, which is required for initiating lactation. Consistent with this, cultured HMECs stimulated with 10nM T3, the most potent thyroid hormone, for 15min showed an ∼2-fold increase in Akt phosphorylation (p<0.0001, n=4). Akt regulates oxidative phosphorylation, which we assessed by measuring oxygen consumption rate (OCR) and ATP synthesis. HMECs treated with 10nM T3 for ≤8hrs showed a 2-fold increase in OCR (p<0.05, n=4) without any change in cellular ATP. These findings suggested that T3 uncoupled mitochondrial respiration from ATP synthesis. In support of this, RT-qPCR of cultured HMECs stimulated with 10nM T3 showed increased expression of genes encoding uncoupling proteins 2 and 3 (≥2-fold, p<0.01, n=4), which also function to divert substrates away from mitochondrial catabolism; and >20-fold increased expression of PPARGC1A (p<0.0001, n=4), which promotes mitochondrial biogenesis. In summary, these findings demonstrate that serum TSH and free T4 are increased at the onset of lactation. Moreover, our cellular studies indicate that thyroid hormones promote mammary mitochondrial biogenesis and may divert substrates used for ATP generation towards the synthesis of breast milk. Reference: (1) Rostom, H. et al. Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study. BMJ Open 12, e062478. Presentation: Friday, June 16, 2023

FRI479 Resistance To Thyroid Hormone Due To Thyroid Hormone Receptor Alpha (THRA) Gene Mutation

Abstract Disclosure: J.O. Abdelkarim: None. S. Parveen: None. M.G. Jakoby: None. J. Fleischer: None. Introduction: Resistance to thyroid hormone (RTH) is a heritable disorder characterized by diminished response to triiodothyronine (T3). Most cases of RTH are due to mutations in the thyroid hormone receptor beta (THRB) gene (“RTH-beta”). Mutations in thyroid hormone receptor alpha (THRA) gene appear to be a rare cause of RTH (“RTH-alpha”), with the first case reported in 2012. We present a case of RTH-alpha in a patient confirmed to have a pathogenic THRA mutation. Clinical Case: A 38-year-old Caucasian male was referred to genetic clinic due to mild developmental delay, dyscalculia and mild autism spectrum disorder. He was born at term by uncomplicated spontaneous vaginal delivery. Parents first noticed developmental delays at age 5 y, though no evaluation occurred during childhood. As an adult, the patient completed seminary studies and was employed as a Catholic priest. An intellectual disability gene panel revealed a pathogenic variant of the THRA gene (c.1151G>A p.R384H). Both parents tested negative for the mutation. Examination was notable for obesity (183 cm, 186 kg, BMI 55.5), macrocephaly, hypertelorism, pectus excavatum and small hands with short digits. No thyroid anatomic thyroid abnormalities were appreciated on neck examination or ultrasonography. TSH was 1.860 mIU/L (0.358-3.740), free T4 0.71 ng/dL (0.76-1.46), and free T3 3.2 pg/mL (2.2-4.0). The patient had no symptoms of hypothyroidism, and supplemental thyroid hormone was deferred. Discussion: There are 29 reported THRA gene mutations and 32 cases of RTH-alpha reported in the peer reviewed literature. Common clinical features include mild-to-moderate intellectual impairment, low basal metabolic rate (BMR), mild skeletal dysplasia, normocytic anemia, bradycardia, consistent with high expression of THRA in brain, heart, gastrointestinal tract, skeletal muscle, and bone. TSH is normal to slightly increased, free T4 is low to low normal, and free T3 is normal to modestly elevated. This is the third reported case of the c.1151G>A missense mutation resulting in an arginine to histidine substitution at codon 384. Thyroid function tests conform to the pattern described for other cases of RTH-alpha. Like the other two patients with the R384H mutation, developmental delays occurred, though intellectual manifestations mitigated with time and the patient completed seminary studies without difficulty. Mitigation of phenotype with age has been reported in RTH-alpha mice with the R384C missense mutation. Short stature did not occur in this patient or the other R384H cases. Unlike other patients, this patient did not experience anemia or constipation. Macrocephaly is a common feature of the three R384H cases, but the patient’s other skeletal manifestations (e.g. pectus excavatum) were not reported. This case demonstrates the difficulty of recognizing THR-alpha and extends our understanding of the R384H phenotype. Presentation: Friday, June 16, 2023

Diagnosis ofResistance to Thyroid Hormone due toa Rare Mutation inthe Thyroid Hormone Receptor Beta Gene ina Patient Previously Presumed to Have Graves' Disease.

Clinicians may confuse an impaired sensitivity to thyroid hormone with hyperthyroidism and offer an inappropriate treatment. We report a diagnosis of resistance to thyroid hormone (RTH) caused by a rare mutation in the thyroid hormone receptor beta gene in a patient previously presumed to have Graves' disease. We have found only one published case of a novel point mutation, c.749T>C (p.Ile250Thr variant) associated with 50% reduction in thyroid hormone receptor binding affinity for triiodothyronine in the I250T mutant; it was found in this patient. A 66-year-old male veteran, with a history of non-ischemic cardiomyopathy and arrhythmias, was referred by a cardiologist with concerns for a possible thyrotropin (TSH) adenoma on account of elevated TSH and free thyroxine (FT4) levels. Pituitary imaging was negative. He was previously treated with radioiodine for presumptive Graves' disease in the civilian sector. Examination revealed a goiter with no nodules. Repeat TSH and FT4 levels were elevated and also free triiodothyronine (FT3) and reverse triiodothyronine. These findings and other test results were consistent with RTH, which was confirmed by genetic testing. Mutation analysis showed the patient to be heterozygous for the p.Ile250Thr variant. He later developed hypothyroidism. Resistance to thyroid hormone can be misdiagnosed as hyperthyroidism with consequent inappropriate treatment. Treatment is not needed in most RTH-beta patients. Thyroid ablation should generally be avoided. Clinicians must be cautious whenever they encounter concurrent elevation of TSH, FT4, and FT3. This RTH-beta patient has a rare I250T mutant of the thyroid hormone receptor beta gene, the second reported case in the literature.

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.

Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3' (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5'-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.

Effect of the Fetal THRB Genotype on the Placenta.

Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high TH levels shown to be detrimental to a normal fetus (NlFe) but not to an affected (AfFe) fetus. However, no information is available about differences in placental TH regulators. To investigate whether there are differences in placentas associated with a NlFe compared to an AfFe, we had the unique opportunity to study placentas from two pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. Sections of placentas were collected and frozen at -80°C after term delivery of NlFe and AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. The following genes expression was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the thyroid hormone transporters MCT10, LAT1 and LAT2 and the THRA. Here, we present the first study of the effect of fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of thyroid hormone regulators in the placenta.

Thyroid Hormone Resistance Syndrome in an Adolescent Girl: A Case Report

Introduction: Resistance to Thyroid Hormones (RTH) is a rare, hereditary disease characterized by diminished sensitivity of target tissues to thyroid hormones. Most cases (~85%) are caused by mutations in the thyroid hormone receptor beta (THRβ) gene (RTHβ). The clinical spectrum of RTHβ is quite broad and highly heterogeneous, and the hallmark of the condition is a paucity of signs and symptoms of thyroid dysfunction despite elevated levels of T4 and T3, with a concomitant non-suppressed TSH. Case Report: Here, we describe a rare case of RTHβ in a female adolescent who was initially misdiagnosed and treated for Graves’ disease, but whose unusual evolution motivated her transference to a tertiary center. The patient exhibited mild manifestations, presenting with a goiter without compressive symptoms and some degree of cognitive impairment with learning disability. Misdiagnosis of RTHβ as Graves’ disease can lead to unnecessary treatments such as anti-thyroid medication, thyroidectomy or radioiodine, but treatment is generally not necessary for most patients with RTHβ. Discussion and Conclusion: Establishing the diagnosis of RTHβ can be challenging. It must be considered in patients who present with a goiter and increased thyroid hormone levels with an unsuppressed TSH, to potentially avoid an incorrect diagnosis of primary hyperthyroidism and the implementation of unnecessary and harmful treatments. Most patients with RTHβ are asymptomatic, and in children, particular attention must be paid to growth, bone maturation, and mental development.

PSUN346 TSHoma: A Rare Cause of Pituitary Adenoma

Abstract Introduction The TSH-producing adenoma (TSHoma) prevalence in the general population is 1 to 2 cases per million, accounting for less than 2% of all pituitary adenomas. Plurihormonal tumors account for about 30% of these cases, with the most common co-secreted hormone being GH. We present the case of a patient diagnosed with TSH adenoma many years after presentation. Case Presentation A 58 year old male with a history of incidentally diagnosed pituitary microadenoma on MRI in 2007, presented in 2014 following abnormal thyroid function testing (TFT), only reported symptoms being occasional headaches. TFT was significant for elevated TSH and FT4 (TSH 4.87—Ref range: 0.27-4.2. Free T4: 1.98–Ref range 0.7-1.7). Pituitary hormone profile was remarkable for a low IGF-1 and a borderline high Alpha subunit of glycoprotein hormone. A sellar MRI confirmed a 12mm pituitary macroadenoma. He was managed conservatively on beta blockers and low dose Methimazole, owing to a stable adenoma size and poor surgical candidacy with multiple comorbidities (e. g. Atrial fibrillation). Repeat labs in 2018 showed increasing TSH (12.85), with persistent elevations of FT3, FT4 and Thyroglobulin. He had follow up TFT monitoring and surveillance MRIs until 2021 when his lesion progressed to 14 mm with mass effect on right pre chiasmatic optic nerve and adjacent internal carotid artery. The patient underwent trans sphenoidal biopsy with debulking in 2021. The biopsy showed a plurihormonal adenoma (prolactin, GH and TSH secreting). Interestingly, prolactin, GH or IGF-1 were never elevated. Following surgery, MRI showed residual 13.2×9.7 mm tumor with no mass effect. His most recent labs showed a TSH: 2.5 and FT4: 1.7. Discussion The diagnosis of a TSHoma should be considered in all centrally hyperthyroid patients, to avoid complications and undue thyroid ablation. A TSHoma must be differentiated from Resistance to Thyroid Hormone (RTH)-beta, which occurs due to mutations in the Thyroid Hormone Receptor Beta gene. Serum a-subunit concentration and Sex Hormone Binding Globulin (SHBG) concentrations are normal in RTH-beta with no TSH suppression following somatostatin analog administration. The presence of a high TSH, FT3 and FT4, in the setting of an elevated a-subunit and pituitary macroadenoma on MRI is strongly suggestive of a TSHoma. Beta blockers are recommended for symptomatic individuals however anti thyroid drug therapy is not advisable for there is risk of thyroid hormone suppression with concomitant tumor overgrowth. Definitive therapy includes trans sphenoidal tumor resection with somatostatin analog therapy to achieve euthyroidism prior to surgery. Patients should be followed up with frequent monitoring of TFT's, along with MRIs every 2-3 years. For patients with residual disease following surgery, treatment with somatostatin analogs such as Octreotide or Lanreotide is favorable as opposed to pituitary irradiation. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Alterations of DNA methylation and expression of genes related to thyroid hormone metabolism in colon epithelium of obese patients

BackgroundColorectal cancer is common among obese individuals. The purpose of the current study was to determine changes in DNA methylation status and mRNA expression of thyroid hormone receptor beta (THRB), as a tumor suppressor, and thyroid hormone inactivating enzyme, type 3 deiodinase (DIO3) genes, in human epithelial colon tissues of healthy obese individuals.MethodsColon biopsies were analyzed by methylation sensitive-high resolution melting (MS-HRM) to investigate promoter methylation of DIO3 and THRB, and by quantitative real-time polymerase chain reaction to assay expression of DIO3 and THRB mRNA on eighteen obese and twenty-one normal-weight healthy men.ResultsThere was no significant difference in mean methylation levels at the THRB promoter region between the two groups. Nevertheless, obesity decreased THRB expression levels, significantly (P < 0.05; fold change: 0.19). Furthermore, obesity attenuated DNA methylation (P < 0.001) and enhanced mRNA expression of DIO3 (P < 0.05; fold change: 3).ConclusionsOur findings suggest that obesity may alter expression of THRB and DIO3 genes through epigenetic mechanism. Alterations of THRB and DIO3 expressions may predispose colon epithelium of obese patients to neoplastic transformation.

DIAGNOSING A PROBABLE CASE OF THYROID HORMONE RESISTANCE IN A RESOURCE-POOR SETTING

Resistance to Thyroid Hormone (RTH) is a rare inherited condition usually caused by mutations of the thyroid hormone receptor beta (THRB), thyroid hormone cell membrane transporters, or thyroid hormone metabolism which can present as asymptomatic, hypothyroidism, or hyperthyroidism. The objective is to report a probable case of RTH presenting with hypothyroidism and to demonstrate the resilience in the diagnosis of endocrine disorders in resource-poor settings. A 23-year old University undergraduate presented with clinical features of hypothyroidism but elevated thyroid hormones and thyroid stimulating hormone (TSH): free T4=38 [normal range 10-24] pmol/L, free T3=11 [normal range 3-8] pmol/L, TSH=3.8 [normal range 0.5-5.0] mU/L; and normal brain MRI. A working diagnosis of RTH was made. Though there was no facility to test for THRB gene mutation, the positive family history of a similar pattern of thyroid function tests, made for a probable diagnosis of RTH, and she was empirically placed on a gradually increased dose of levothyroxine from 50 µg till resolution of symptoms was achieved and maintained 6 months later at 600 µg daily. At 10 months follow-up, the patient felt well with the resolution of symptoms and improved academic performance despite elevated thyroid hormones and unsuppressed TSH. The diagnosis of RTH requires a high index of suspicion, to enable early diagnosis, and prevent unnecessary invasive treatments. The treatment target should be the resolution of symptoms and signs and not normalization of thyroid hormone levels. This report also underscores the resilience that can be adopted in diagnosing and treating endocrine cases in resource-poor settings.

Thyroid hormone resistance syndrome due to a novel heterozygous mutation and concomitant Hashimoto's Thyroiditis: A pedigree report.

Thyroid hormone resistance syndrome (THRS) is a rare disease characterized by reduced sensitivity to thyroid hormones. Mutations in the thyroid hormone receptor beta (THRB) gene are considered as contributing to the pathogenesis. This report describes a Chinese pedigree with THRS and Hashimoto’s thyroiditis (HT) due to novel point mutation in the 11th exon of the THRB gene (c. 1378 G > A). The proband complained of goitre with increased thyroid hormone and normal thyroid stimulating hormone levels. Gene sequencing was performed to confirm the diagnosis. HT was also diagnosed based on positive thyroid autoantibodies and diffuse, grid-like changes in the thyroid on ultrasound examination. Additionally, a comprehensive examination of the proband’s pedigree was conducted. The patient’s father exhibited the same gene mutation site and was diagnosed with THRS and HT. No mutation site was detected in three patients with HT only and three healthy volunteers. Thus, gene sequencing should be considered the gold standard for diagnosing THRS. Furthermore, treatment should be individualized to control the patient’s symptoms rather than normalizing thyroid hormone levels. Further studies that determine the relationship between THRS and TH are warranted.

Abstract #1174960: Thyroid Hormone Resistance: A Diagnostic Dilemma

Resistance to thyroid hormone (RTH) is a rare condition presenting with discrepant thyroid function tests (TFTs) posing a diagnostic challenge. RTH is defined by reduced tissue responsiveness to thyroid hormone and characteristic biochemical profile of elevated serum levels of free thyroxine (FT4) and free triiodothyronine (FT3) and non-suppressed levels of thyrotropin (TSH). It is an autosomal dominant inherited syndrome most commonly due to a mutation in the thyroid hormone receptor beta (THRB) gene.

Selective Pituitary Resistance to Thyroid Hormone: Clinical Hyperthyroidism with High TSH on Levothyroxine Administration in I-131 Ablated “Graves Disease”

Resistance to Thyroid Hormone (RTH) is a rare form of hormone resistance secondary to changes in the genes encoding thyroid hormone receptors. The two subtypes, Pituitary RTH (PRTH) and Generalized RTH (GRTH), cause clinically distinguishable patient presentations. In PRTH, typically only the pituitary gland is resistant to thyroid hormone (TH) while the rest of the body maintains sensitivity. Selective pituitary resistance to thyroid hormone results in dysregulation of thyroid hormone homeostasis with clinical presentation as either euthyroid or hyperthyroidism. PRTH is characterized by elevated thyroid hormone levels with an elevated or inappropriately normal TSH concentration. Herein we describe a case report of a 70-year-old woman who complained of weight loss of over 35 lbs., palpitations, jitters, hair loss, diarrhea, fatigue, muscle weakness, etc. over 6 months, thus, indicating the presence of iatrogenic hyperthyroidism while receiving levothyroxine 175 ug daily prescribed by her primary care provider because of a reported history of “Graves disease” treated by radioactive iodine ablation of the thyroid several years ago. The daily dose of levothyroxine had been increased gradually at an interval of 3 months over a year because of persistent elevation of serum TSH level. Laboratory tests revealed markedly elevated Free T4, Free T3 and TSH levels, along with low concentrations of all lipid fractions, serum creatinine and urea nitrogen levels, indicating TSH induced hyperthyroidism or PRTH. Further testing documented a mutation of thyroid hormone receptor beta gene 2 confirming presence of PRTH. We believe that the initial diagnosis of Graves Disease was erroneous and I-131 ablation further confounded and missed the diagnosis of PRTH. Thus, the purpose of this report is to report a patient with PRTH and describe potential pitfalls in diagnosis and management of this rare disorder.

A rare variant of thyroid hormone receptor beta (THR [beta]) gene mutation in a pre-school child

A rare variant of thyroid hormone receptor beta (THR [beta]) gene mutation in a pre-school child

Identification of a Long Non-Coding RNA Derived From the Antisense Strand of the Thyroid Hormone Receptor Beta Gene

Background: Long non-coding RNAs (lncRNAs) have various functions. Here, we describe a novel lncRNA which is induced from the antisense strand of the thyroid hormone receptor beta (THRB) gene. Methods: We sequenced RNA from leukocytes and identified a novel lncRNA derived from the antisense strand of the THRB gene. The lncRNA was named THRB antisense RNA 2 (THRB-AS2). Transcriptional regulation by THRB-AS2 was assessed by reporter assays. The putative translation initiation codons of THRB-AS2 were mutated to assess potential THRB-AS2 protein function. Results: THRB-AS2 stimulated the activities of multiple promoters irrespective of thyroid hormone response elements. Thyroid hormone treatment did not affect the function of THRB-AS2. These data suggest that THRB-AS2 is a potential general transcriptional activator and has broad specificity on target genes. Mutations in putative translation initiation codons of THRB-AS2 did not affect function, suggesting that THRB-AS2 acts as an RNA molecule. Conclusions: Although a small number of lncRNAs derived from antisense strand of the THRB gene, such as THRB-AS1, has been already reported, their functions remain largely unknown. To our knowledge, this is the first report of the functions of a lncRNA derived from the antisense strand of the THRB gene.

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome.

SummaryResistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.Learning pointsResistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH).Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test.RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

Resistance to Thyroid Hormone Beta: A Focused Review.

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHβ. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRβ protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRβ defect. This focused review aims to provide a concise update on RTHβ, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and “foggy brain”. Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance.

MON-472 A Case of Resistance to Thyroid Hormone with Concurrent Hashimoto’s Thyroiditis and Post-Surgical Hypothyroidism

Introduction: Resistance to thyroid hormone (RTH) is a rare defect that results in impaired sensitivity to thyroid hormone. While most commonly caused by mutations in the thyroid hormone receptor beta (THRβ) gene, in 15% of patients with the RTH phenotype, no mutation is identified.1 This entity is known as non-thyroid hormone receptor RTH (nonTR-RTH). Patients with RTH have an increased risk of autoimmune thyroid disease with a reported odds ratio of 2.36.2 Hashimoto’s thyroiditis or other etiologies of hypothyroidism add a layer of complexity to RTH as such individuals may require high doses of levothyroxine to overcome hormone resistance.Clinical Case: A 36-year-old male was referred for abnormal thyroid function tests. He denied symptoms of thyroid dysfunction. Physical examination was notable for a goiter. Weight was 83 kg. Initial labs revealed TSH 6.8 mcIU/mL (0.3-4.7 mcIU/mL), free T4 2.0 ng/dL (0.8-1.7 ng/dL), free T3 491 pg/dL (222-383 pg/dL), and thyroid peroxidase antibody >600 IU/mL (≤20 IU/mL). Additional work-up demonstrated elevated free T4 by equilibrium dialysis 2.5ng/dL (0.9-2.2 ng/dL) and elevated TSH with HAMA treatment 5.96 mIU/L (0.40-4.50 mIU/L), thereby ruling out familial dysalbuminemic hyperthyroxinemia and HAMA interference. Alpha-subunit of 0.30 ng/mL (<0.55 ng/mL) and normal pituitary MRI did not support a TSH-secreting adenoma. Quest Diagnostics RTH Gene Sequencing was negative for a mutation in the THRβ gene. The patient was subsequently diagnosed with nonTR-RTH. Thyroid ultrasound showed multiple thyroid nodules, including a 1.8 cm hypoechoic, complex nodule in the left inferior gland and a 1.7 cm isoechoic nodule in the right inferior gland. Fine needle aspiration of the left nodule was suspicious for papillary thyroid carcinoma and the right nodule showed lymphocytic thyroiditis. The patient underwent total thyroidectomy and pathology demonstrated a benign left nodule and an incidental 0.3 cm right papillary thyroid carcinoma. The patient started levothyroxine 150 mcg daily (1.8 mcg/kg) post-operatively with subsequent TSH of 18.1 mcIU/mL. His dose was increased to 200 mcg daily (2.4 mcg/kg) and TSH was still elevated at 11.7 mcIU/mL. His levothyroxine dose was subsequently increased to 250 mcg daily (3 mcg/kg) and TSH is outstanding.Conclusions: This case highlights the diagnostic challenge in nonTR-RTH. It also demonstrates the complex management of patients with RTH and concurrent hypothyroidism. Such patients need close monitoring and aggressive titration of levothyroxine to achieve desired hormone levels.1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830:3987-4003.2. Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010;95:3189-93.

Structural insights revealed by two novel THRB mutations.

Among the inheritable forms of impaired sensitivity to thyroid hormone, resistance to thyroid hormone (RTH) due to mutations in the thyroid hormone receptor beta gene (THRB) is the first and best known described defect, revealing a wide phenotypic variability with an incompletely understood physiopathology. The objective of this study was to evaluate two novel mutations in THRB, N331H and L346R, in an attempt to provide a rational understanding of the harmful effects caused by them. The mutations of two patients with RTHβ were reproduced for analysis of gene transactivation by dual-luciferase reporter assay, and for molecular modeling for crystallography-based structural assessment. Serum measurements of TSH and FT4 were performed to compare the thyrotrophic resistance to thyroid hormone between RTHβ patients and controls. Both mutants showed impaired gene transactivation, with greater damage in L346R. Molecular modeling suggested that the damage occurring in N331H is primarily due to reduced strength of the hydrogen bonds that stabilize T3 in its ligand-binding cavity (LBC), whereas in L346R, the damage is more marked and is mainly due to changes in hydrophobicity and molecular volume inside the LBC. Hormonal dosages indicated that the L346R mutant exhibited greater thyrotrophic resistance than N331H. This study provides a rational understanding of the effects of mutations, indicating deleterious structural changes in the LBC in both THR, and discloses that not only the position of the mutation but, notably, the nature of the amino acid exchange, has a cardinal role in the functional damage of the receptor.