Multigenerational thyroid hormone resistance due to THRβ mutation

Resistance to thyroid hormone (RTH) is a rare genetic disorder caused by mutations in the thyroid hormone receptors α or β (THRα, THRβ) genes, leading to impaired tissue responsiveness to thyroid hormones. While its systemic effects are well-documented, the cardiac manifestations of RTH, including hypertrophic and dilated cardiomyopathy (DCM), arrhythmias, and heart failure, are often underrecognized, particularly in cases of treatment refractory heart failure. This case report aims to highlight the importance of cardiological awareness in diagnosing and managing RTH-related cardiomyopathy.

We report the case of a 50-year-old Caucasian female with a confirmed variant c.1357C > A, p.P453T mutation in the THRβ gene, presenting with recurrent goitre, hypothyroidism, and progressive cardiovascular complications. Her clinical course was marked by episodes of angina-like symptoms, atrial fibrillation, left heart failure, and severe pulmonary oedema, eventually progressing to DCM with an ejection fraction below 30%. Despite optimal guideline-directed medical therapy, her cardiac condition deteriorated, necessitating orthotopic heart transplantation. Genetic testing confirmed the same mutation in her mother, brother, and two sons, highlighting the autosomal dominant inheritance of the disease. Thyroidectomy and lifelong levothyroxine therapy, combined with post-transplant immunosuppression, further complicated her management, underscoring the systemic interplay of RTH with cardiac function.

This case emphasizes the rarity and clinical significance of RTH as a potential aetiology in refractory cardiac failure. Cardiologists should maintain a high index of suspicion for thyroid dysfunction in unexplained or treatment-resistant cardiomyopathy, particularly when associated with familial thyroid disorders or arrhythmias. Early diagnosis and a multidisciplinary approach involving endocrinology and cardiology are essential for improving outcomes and tailored therapeutic strategies for patients with RTH-related cardiomyopathy.