Endocrine Abstracts

Thyroid dyshormonogenesis (TDH) is an uncommon cause of congenital or persistent goitre, due to defects in thyroid hormone biosynthesis. Mutations in the thyroid peroxidase (TPO) gene are most frequently identified, and may predispose to goitrous enlargement with paradoxical thyroid function tests (TFTs). Coexistence of TDH with autoimmune thyroid disease, especially Graves’ disease may lead to complex biochemical and clinical presentations. A 57-year-old man with a ‘multinodular goitre’ diagnosed in 1994 underwent right hemithyroidectomy in 2013 for compressive symptoms, maintaining euthyroidism on levothyroxine. In 2020, he developed palpitations and was found to be thyrotoxic (FT4 62 pmol/l, suppressed TSH), despite dose reduction and cessation of levothyroxine. TFTs showed disproportionately elevated FT3 compared to FT4 and he was referred to the endocrine team. The remnant left thyroid lobe was soft and ‘boggy’ to touch, unlike a typical nodular goitre. Thyroid ultrasound revealed thyroiditis, and blood tests showed elevated TPO antibodies (687 IU/mL) and TRAb (73 IU/l), consistent with autoimmune thyroid disease. He was started on block and replace regimen to optimise thyroid function. The combination of an unusual goitre with atypical thyroid function suggested dyshormonogenesis. In 2024, extended genetic testing with R145 panel confirmed compound heterozygosity for a pathogenic nonsense variant in the TPO gene, diagnostic of TDH type 2A. This explained impaired FT4 synthesis with compensatory FT3 excess, complicated by coexistent autoimmune thyrotoxicosis.He is managed with carbimazole 40 mg and levothyroxine 100 µg daily, with consideration for completion thyroidectomy due to residual goitre and malignancy risk. This case underscores the importance of considering dual pathology in paradoxical or refractory TFTs. TPO-related dyshormonogenesis may coexist with autoimmune thyroid disease, resulting in labile biochemistry and therapeutic challenges. Genetic testing clarifies diagnosis, guides management, and informs long-term surveillance.

Reference: 1. Cangül H, et al. Clin Endocrinol (Oxf). 2013;79(2):275–281. doi: 10.1111/cen.12127