Thyroid hormone resistance beta and autoimmune thyroid disease - a family case study highlighting diagnostic and therapeutic challenges

Abstract Background Resistance to thyroid hormone (RTH) is a rare endocrine disorder, most commonly caused by mutations in the thyroid hormone receptor β (TRβ) gene, resulting in the RTH beta (RTHβ) subtype. In contrast, autoimmune thyroid disease (AITD) is common. The coexistence of RTHβ with AITD has not been fully clarified. Here, we describe a family in which RTHβ coexists with AITD, highlighting the complex interplay between these disorders. Case presentation A 45-year-old woman, previously for years treated for hyperthyroidism, presented after a decade-long gap in follow-up, reporting palpitations and fatigue. Laboratory evaluation revealed elevated free thyroxine (fT4 34 pmol/L) and free triiodothyronine (fT3 11.8 pmol/L) with inappropriately normal thyroid-stimulating hormone (TSH 1.87 µIU/mL). Thyroid antibodies, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) were positive, while TSH receptor antibodies (TRAb) was negative. Thyroid ultrasound demonstrated a mildly enlarged gland with clinically insignificant nodules, and Tc-99 m scintigraphy showed normally functioning tissue. Pituitary MRI was normal. The thyrotropin-releasing hormone (TRH) stimulation test demonstrated an exaggerated TSH response, consistent with RTHβ. Genetic testing confirmed a heterozygous pathogenic thyroid hormone receptor β THRB variant. Further evaluation of the patient’s family and genetic testing confirmed RTHβ in her daughter and sister, both of whom also had coexisting AITD. Conclusions The clinical phenotype of RTHβ is highly variable, ranging from asymptomatic individuals to features of hypo- or hyperthyroidism. Variable tissue responsiveness underlies the overlapping features of thyroid hormone excess and deficiency seen in RTHβ. Coexisting primary hypothyroidism due to AITD can further complicate the clinical course, creating diagnostic and therapeutic challenges. This overlap presents unique challenges in diagnosis and management, often leading to diagnostic uncertainty and therapeutic difficulties. Management should be patient-centred, emphasising individual assessment, multidisciplinary collaboration, and long-term follow-up to optimise outcomes and quality of life.