A novel familial variation of the thyroid hormone receptor beta gene (I276N) associated with resistance to thyroid hormone

Background: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome characterized by reduced organ responsiveness to thyroid hormone, with elevated thyroid hormone levels and unsuppressed TSH concentrations, and a widely variable clinical phenotype. RTH is most frequently caused by point mutations in the thyroid hormone receptor beta gene (THRB). We report the case of a child and her mother with different clinical signs in presence of high thyroid hormone and normal TSH levels with positive anti-thyroid antibodies, both carrying a novel variation of THRB. Patient findings: A 3-year-old girl presented to our Pediatric Endocrinology Unit with statural and ponderal growth retardation since the first months of life and biochemical findings of elevated thyroid hormone levels with unsuppressed TSH, in presence of an unusual positivity to anti-thyroperoxidase antibodies for age. Molecular analysis of THRB gene identified a novel missense variation in exon 8 in the heterozygous state (I276N). The child's 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. Summary: 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. Conclusions: 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.