ESPE Abstracts

Background: Resistance to thyroid hormone (RTHβ) is a rare disease caused by an inactivating mutation in the thyroid hormone receptor beta gene (THRB). This condition leads to elevated thyroid hormone levels with non-suppressed TSH levels. The clinical phenotype is highly variable, ranging from asymptomatic to signs of hyperthyroidism and/or hypothyroidism. This study analysed the genotype and phenotype of paediatric and adult patients followed in three Belgian referral centres and describe the long-term outcomes.

Methods: We conducted a retrospective multicentric cohort study involving patients diagnosed with RTHβ either genetically or biochemically at UZ Leuven, OLVZ Aalst and UZ Brussel. Patient records from January 2000 to September 2022 were reviewed for genotype, clinical presentation, biochemistry, imaging, therapy and potential long-term effects like learning difficulties, cardiovascular comorbidities and bone demineralisation.

Results: The study included 51 individuals with RTHβ (44 adults, 7 children), of whom 45 had a pathogenic variant. The most prevalent signs/symptoms were palpitations (54.1%), anxiety/nervousness (39.6%) and goiter (32.6%). Asymptomatic patients accounted for 20.4%. In paediatric patients 66.7% had learning difficulties. Among adults, 81.6% did not obtain higher education. Betablockers were prescribed to 56.9%, while only 5.8% used 3,5,3'-Triiodothyroacetic Acid (TRIAC). Cardiovascular problems were significant: 31.8% had atrial fibrillation, 29.5% had arterial hypertension, 9.1% experienced CVA/TIA and 6.1% had myocardial infarction. Cardiac ultrasound and ECG were performed in 59.1% and 63.6% of adults, respectively. Bone densitometry, conducted in 29.5%, revealed osteopenia or osteoporosis in 92.3% (12/13). Subgroup analysis of the most common pathogenic variants in THRB (NM_001354712.2) revealed distinct patterns. In Group 1 (c.727C>T, p.Arg243Trp) 40% presented asymptomatic, 40% with goiter and 40% with palpitations. Group 2 (c.959G>A, p.Arg320His) had no asymptomatic patients, 57.1% had palpitations, 42.9% goiter and 42.9% anxiety/nervousness. In group 3 (c.1378G>A, p.Glu460Lys) 16.7% presented asymptomatic, 50% with goiter, 50% with palpitations, 50% had anxiety/nervousness.

Conclusion: Patients with RTHβ exhibit very heterogeneous clinical presentation. Learning difficulties are prevalent in children, while adults often have atrial fibrillation. This study underscores the importance of a personalized approach in treating and monitoring RTHβ patients. Systematic screening for bone and cardiovascular problems is crucial. Establishing international registries and programs, such as EU Reference Network of Rare Endocrine Conditions (ENDO ERN), is essential for improving patient outcomes.