Clinical Consequences of Variable Results in the Measurement of Free Thyroid Hormones: Unusual Presentation of a Family with a Novel Variant in the <b><i>THRB</i></b> Gene Causing Resistance to Thyroid Hormone Syndrome

Abstract

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the &lt;i&gt;THRB&lt;/i&gt; gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. &lt;b&gt;&lt;i&gt;Case Presentation:&lt;/i&gt;&lt;/b&gt; A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of &lt;i&gt;THRB&lt;/i&gt; gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel &lt;i&gt;THRB&lt;/i&gt; variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of &lt;i&gt;THRB&lt;/i&gt; variants.

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant

“…RTHβ is characterized by inappropriate findings in the serum levels of free thyroid hormones (T3 and T4) with high circulating thyroid-stimulating hormone (TSH). Most RTHβ patients are considered clinically euthyroid and present a wide phenotypic variability, even among patients harboring the same variant in THRB (Campi et al, 2021). More than 190 truncating and missense variants have been associated with RTHβ (data from HGMD-pro, March 2023), most of which are located in the LBD (T3-binding) domain or in the contiguous hinge region (Figure 1).…”

Unusual causes of hyperthyrotropinemia and differential diagnosis of primary hypothyroidism: a revised diagnostic flowchart

“…A detailed discussion regarding the limitations of such a screening approach goes beyond the aims of this review; however, thyroidologists should be aware that the reflex TSH strategy can generate false-negative results in conditions such as central hypothyroidism, syndromes of reduced sensitivity to thyroid hormone, and TSH-secreting adenomas and that the biochemical tests need to be interpreted in light of a careful clinical assessment of the patients ( 13 , 14 ).…”