A novel familial variation of the thyroid hormone receptor beta gene (I276N) associated with resistance to thyroid hormone
S. Moia, A. Monzani, F. Prodam, A. Petri, G. Genoni, R. Ricotti, V. Agarla & G. Bona
Introduction: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome, first identified in 1967 by Refetoff, characterized by reduced organ responsiveness to thyroid hormone. The most typical pattern being an elevated serum free T4 (fT4) concentration in association with non-suppressed TSH, usually accompanied by high serum levels of free T3 (fT3), with a considerable inter-individual variation and heterogeneous phenotype. The most frequent defect which causes RTH involves the thyroid hormone receptor beta gene (THRB) located on chromosome 3.
Methods: Genomic DNA was isolated from peripheral blood. Molecular analysis of THRB gene was performed. Exons 7 through 10 and their flanking intronic regions were amplified by PCR and the products were analyzed by direct sequencing.
Results: Molecular analysis of THRB gene identified a novel missense variation in exon 8 in the heterozygous state (I276N). The patient was a 3-year-old girl referred to our Pediatric Endocrinology Unit for statural and ponderal growth retardation. She presented elevated thyroid hormone levels with unsuppressed TSH, in presence of an unusual positivity to anti-thyroperoxidase antibodies for age. The childs mother, a 42-year-old women, reported from 25-years of age a history of tachycardia, high stool frequency and goiter, elevated fT3 and fT4 with normal TSH, increased levels of anti-thyroperoxidase and anti-thyroglobulin antibodies and a thyroid ultrasound and cytological pattern suggestive for lymphocytic thyroiditis. The same THRB variation was identified also in the mother in the heterozygous state.
Conclusion: We described the case of a child and her mother affected by RTH presenting with different clinical phenotype even if they carried an identical novel THRB missense variation. In both of them RTH was associated with the presence of anti-thyroid antibodies. RTH should be suspected every time elevated thyroid hormones and unsuppressed TSH are found, independently of the clinical phenotype, even in association with an autoimmune thyroiditis.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector