Endocrine Abstracts

JOINT496

We present a 24-year-old male who was referred to endocrinology team for evaluation of discordant thyroid function tests (TFTs). TFTs were first sent when he presented to Primary Care with intermittent palpitations. He was otherwise fit and healthy, with no comorbidities. Results showed elevated free T4 of 31pmol/l (Reference range 10-22 pmol/l) with a normal TSH of 0.91 miu/l (reference range 0.3 – 5.5 miu/l). On review in the endocrine clinic, his detailed history and systemic examination were unremarkable. He was not on any prescribed or over-the-counter medications. TSH-receptor antibodies were negative, and assay interference was ruled out by counter-checking TFTs on Roche & Beckman testing separately. There was no known family history of thyroid dysfunction. Given the patient’s young age and symptoms, we undertook genetic testing to look for possible de novo thyroid hormone resistance. The genetics laboratory undertook analysis of all the coding regions and exon/intron boundaries of the hyperthyroidism gene panel (ALB, SECISBP2, SLC16A2, THRA, THRB, TSHR and TTR). The initial report showed that a genetic cause for the hyperthyroidism had not been identified. After several months, we received further correspondence from the genetics team re-reporting his results as they had identified a rare cause of discordant TFTs consistent with a genetic diagnosis of TTR-related dystransthyretinaemic hyperthyroxinaemia. At the time of initial report, this gene mutation was labelled as “likely benign” with no correlation with isolated hyperthyroxinaemia. However, in the following months, similar variants were identified in more cases with similar findings and therefore labelled as “likely pathogenic” in context of isolated hyperthyroxinaemia. This functional genetic polymorphism is counter checked by Exeter and Cambridge genomic laboratories. In these cases, offspring would be at 50% risk of inheriting this variant and being predisposed to hyperthyroxinaemia. Hence, testing is recommended for family members affected with hyperthyroxinaemia. Variants in THRB are found in ~86% patients with Resistance to Thyroid Hormone beta. GWAS studies have shown a statistically significant positive association between this variant and FT4 levels.

Conclusion: Isolated hyperthyroxinaemia with normal TSH could be related to underlying genetic mutation involving transthyrenin receptors and therefore should be looked for. This does not require any treatment but testing for symptomatic family members is recommended. We feel this case highlights the importance of investigating discordant thyroid function tests to help the identification of previously unknown genetic variants.

References: 1. uk-practice-guidelines-for-variant-classification-v4-01-2020.pdf.

2. Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism, and Action - PubMed.