SAT-434 Phenotype and Genotype Analysis of Patients with Resistance to Thyroid Hormone β: A Single-Center Experience
Authors: Wejaphikul Karn , Dejkhamron Prapai , Groeneweg Stefan , Visser W Edward , Unachak Kevalee , Meima Marcel E , Peeters Robin P 
Published: May 2020

Introduction Resistance to thyroid hormone β (RTHβ) is caused by mutations in THRB, the gene that encodes thyroid hormone receptor β. The clinical phenotype is variable and may include goiter, tachycardia, and learning disability with or without hyperactive behavior. The biochemical hallmark of RTHβ is elevated T4 and T3 with non-suppressed TSH concentrations. We here describe the phenotype and genotype of three Thai patients diagnosed with RTHβ in a pediatric referral center. Patients had previously been misdiagnosed and inappropriately treated with antithyroid drugs (ATDs). Methods Clinical features and thyroid function tests (TFTs) of three unrelated RTHβ patients were retrospectively reviewed. Genomic DNA of the RTHβ patients and affected family members was amplified for exon 7-10 of the THRB gene and sequenced to identify mutation by Sanger sequencing. The impact of the p.L341V novel mutation on the affinity for T3 and T3-induced transcriptional activity was previously determined in vitro. Results Three female patients were diagnosed with RTHβ. All of them had been misdiagnosed with hyperthyroidism and treated with ATDs prior to referral. The mean age at diagnosis was 8 years. The main presenting symptoms were diffuse goiter and tachycardia. The mean duration of ATD treatment was 3 years. During the treatment, patients had fluctuating thyroid hormone and increased TSH levels. An older sister and mother of one patient also had similar TFTs abnormalities, for which the mother had undergone a subtotal thyroidectomy. RTHβ was diagnosed based on the high FT3 and FT4 with normal (non-suppressed) TSH concentrations and confirmed by mutation analysis. Anti-thyroid peroxidase, anti-thyroglobulin, and TSH receptor antibody (TRAb) were negative, excluding autoimmune thyroid disease. Heterozygous missense mutations of the THRB gene were identified in all patients and affected family members. Two mutations had been previously reported (p.R243W and p.L456F), and one mutation was novel (p.L341V). In vitro studies confirmed an important role of Leu341 in T3 binding of the TRβ and functional impairment of the p.L341V novel mutation and were reported separately. According to available literature, only nine Thai RTHβ patients (in three families) carrying three different mutations (p.G251V, p.M313T, and p.A317T) had been previously reported. Goiter was the most common clinical finding, and almost all patients had a history of receiving unnecessary treatment with ATDs. Conclusion We report a series of RTHβ patients carrying THRB gene mutations, including one novel mutation (p.L341V). Clinicians should be alert that RTHβ can be found in patients with goiter and tachycardia. Elevated T4 and T3 with non-suppressed TSH concentration is the main diagnostic clue for this disease. Mutation analysis allows definitive diagnosis of RTHβ and may help to avoid potential misdiagnosis and improper treatment.