The clinical and genetic diversity of thyroid hormone resistance: four clinical vignettes.

Introduction: Resistance to thyroid hormones (RTH) is a rare but an 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, THRB), while a few are caused by mutations in thyroid hormone receptor α (TRα, THRA). 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.

Case presentation: 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 THRA (NM_199334.3:c.-298+5G>A) missense mutation in the first intron in the 5' untranslated region (UTR) of THRA, with causal variant prediction with CADD 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 THRB mutations showcase the consequences of misdiagnosis, with two patients prescribed medications that could exacerbate symptoms and one child presenting with behavioral problems that might benefit from tailored management with hormone therapies.

Conclusion: 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.