SUN-405 - Resistance to Thyroid Hormone Beta: Diagnostic Challenges and Therapeutic Approaches-A Five-Case Series

Introduction: Resistance to thyroid hormone beta (RTHβ) is a rare, genetically heterogeneous syndrome characterized by reduced tissue responsiveness to thyroid hormone, due to mutations in the thyroid hormone receptor β (THRβ) gene. Biochemically, RTHβ is characterized by elevated thyroid hormone with elevated thyrotropin (TSH). Clinical manifestations are highly variable, frequently leading to diagnostic confusion and inappropriate, potentially harmful interventions.

Methods: A retrospective chart review was conducted on five patients with genetically confirmed RTHβ, to illustrate the diagnostic challenges and management strategies.

Results: All five patients demonstrated the characteristic pattern of elevated free thyroxine (FT4) and TSH elevation. One diagnostic challenge was distinguishing RTHβ from TSH-secreting adenoma in two patients with pituitary microadenomas. A normal alpha subunit to TSH molar ratio, as well as specific tumor characteristics, supported the diagnosis of THRβ. One patient was misdiagnosed with Graves’ disease 22 years earlier and underwent inappropriate radioiodine ablation, ultimately presenting with atrial fibrillation, heart failure, and myocardial infarction while prescribed supraphysiologic doses of levothyroxine. Management focused on levothyroxine adjustment guided by peripheral tissue responses, rather than TSH normalization, plus beta-blocker therapy for cardiovascular symptoms. Autoimmune thyroid disease was also diagnosed in two patients (40%), consistent with reported 37.9-42.1% prevalence in RTHβ. One patient demonstrated elevated radioiodine uptake (46%) despite exogenous thyroid hormone, a key diagnostic finding. Prenatal genetic testing was required in two pregnancies in the same patient; methimazole was administered when carrying a wild-type fetus to prevent fetal thyrotoxicosis, while the affected fetus required no intervention. One patient with both papillary and follicular thyroid carcinoma achieved excellent oncologic outcome (suppressed thyroglobulin, no structural recurrence) despite persistent TSH elevation (max 75.23 mIU/L) following surgical resection and radioiodine ablation.

Conclusions: RTHβ is a diagnostically and therapeutically complex condition with significant potential for misdiagnosis. The primary value of genetic confirmation is distinguishing RTHβ from its critical differential diagnoses to prevent inappropriate interventions, particularly in atypical presentations. Management must be individualized based on comorbidities and other patient circumstances.

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