Endocrine Abstracts

JOINT2692

Introduction: Resistance to thyroid hormone beta (RTHβ) is a rare, typically autosomal dominant genetic disorder, caused by mutations in the THRB gene, encoding thyroid hormone receptor beta (TRβ), leading to impaired responsiveness to thyroid hormone in tissues expressing TRβ. While affected individuals often present with elevated circulating free thyroxine (FT4) and free triiodothyronine (FT3) alongside non-suppressed thyroid-stimulating hormone (TSH), clinical manifestations, ranging from overt symptoms to asymptomatic presentations, complicate diagnosis. This case series highlights phenotypic variability and management of RTHβ in two sisters.

Case Report: The older sister, a 24-year-old woman, was referred to an endocrinologist during her first pregnancy at 26 weeks of gestation for elevated FT3: 4.19 pmol/mL (N 1.58–3.91) with other thyroid function tests normal. Thyroid ultrasound suggested possible autoimmune thyroiditis. She was started on L-thyroxine (50 mg daily), but follow-up two months later showed elevated FT4: 26.05 pmol/l (N 7.87–20.3) and FT3: 6.56 pmol/l (N 3.34–5.14) and non-suppressed TSH: 3.9 mU/l (N 0.4–3.6). Thyroid antibodies were negative. After delivering a healthy baby, L-thyroxine was discontinued. During her second pregnancy, she again had elevated FT4: 30.54 pmol/l and FT3: 6.65 pmol/l with a non-suppressed TSH: 3.52 mU/l. No treatment was initiated, thyroid hormone levels were monitored throughout pregnancy. Genetic testing confirmed a pathogenic heterozygous mutation in the THRB gene (c.1291A>T, p.Ile431Leu). She delivered another healthy, lower-birth-weight non-carrier baby. The younger sister, a 17-year-old female, underwent genetic testing after her sibling’s diagnosis. Asymptomatic with no thyroid dysfunction on examination, she showed elevated FT4: 30.19 pmol/l and FT3: 7.13 pmol/l, with a non-suppressed TSH: 2.80 mU/l and negative thyroid antibodies (antiTPO, antiTg, antiTSH). Genetic testing confirmed the same THRB (c.1291A>T, p.Ile431Leu) mutation. Clinical management focused on monitoring thyroid function without initiating thyroid hormone suppression or beta-blocker therapy due to the absence of symptoms. Functional testing using a luciferase reporter assay in Jeg-3 cells showed reduced affinity of TRβ2-I341L (EC0 I341L vs WT: 9.1 [7.8-10.6] vs 0.71 [0.69-0.74] nM, p<0.001). The T3-affinity of the mutant was significantly reduced, as evident from a ~13-fold higher EC50 for T3 compared to wild-type in the reporter assay.

Conclusion: This family case demonstrates the phenotypic variability of RTHβ, ranging from pregnancy-associated thyroid dysfunction to an asymptomatic carrier state. It underscores the importance of familial genetic screening in diagnosing RTHβ and highlights the need for individualized, symptom-based management strategies to avoid overtreatment while ensuring appropriate monitoring for potential complications.