The Clinical and Genetic Diversity of Thyroid Hormone Resistance: Four Clinical Vignettes.

<bold><italic>Introduction:</italic></bold> Resistance to thyroid hormones (RTH) is a rare but important genetic cause of decreased peripheral tissue responses to the actions of thyroxine. Most RTH cases are caused by mutations in thyroid hormone receptor β (TRβ, <italic>THRB</italic>), while a few are caused by mutations in thyroid hormone receptor α (TRα, <italic>THRA</italic>). RTH is clinically heterogeneous, and the biochemical features are often confusing, resulting in misdiagnoses, mismanagement, and life-long consequences for affected individuals. An awareness of the clinical and genetic spectrum of RTH is therefore essential to avoid misdiagnosis and to ensure timely referral for definitive management. <bold><italic>Case Presentation:</italic></bold> Here we present four clinical vignettes describing three children and one adult with RTH encountered in our “real-world” tertiary pediatric endocrinology practice. We describe a novel <italic>THRA</italic> (NM_199334.3:c.-298 + 5G>A) missense mutation in the first intron in the 5’ untranslated region (UTR) of <italic>THRA</italic>, with causal variant prediction with Combined Annotation Dependent Depletion placing the mutation in the top 1% most deleterious variants (scaled C-score 21.7). We speculate that this mutation causes an exon skipping event affecting the 5’UTR and protein-coding region, thereby resulting in abnormal or absent TRα1, although supporting clinical, genetic, and/or functional analyses are required to upgrade the pathogenicity classification from uncertain significance to pathogenic/likely pathogenic. The three cases describing “classical” RTH caused by <italic>THRB</italic> mutations showcase the consequences of misdiagnosis, with 2 patients prescribed medications that could exacerbate symptoms and one child presenting with behavioral problems that might benefit from tailored management with hormone therapies. <bold><italic>Conclusion:</italic></bold> This report not only highlights the importance of a high index of suspicion for RTH to prompt the genetic diagnosis but also contributes to a growing appreciation of the pathogenic role of non-coding variants in rare diseases. [ABSTRACT FROM AUTHOR]