Endocrine Abstracts

Background: Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome of reduced tissue responsiveness to thyroid hormones (THs). It is driven in 85% of cases by mutations in the thyroid hormone receptor beta (THRb). The estimated incidence is 1:40.000 to 1:19.000 live births. We report the clinical, laboratory, and genetic analysis of a patient with this disorder.

Case report: A 12-year-old boy with a history of Attention-Deficit/Hyperactivity Disorder was referred to endocrinological evaluation due to hyperactive, impulsive behavior, insomnia, palpitations, heat intolerance, and perspiration. Physical examination was unremarkable except for resting tachycardia and hypertension. Thyroid function tests (TFTs) showed normal thyroid-stimulating hormone (TSH) of 2.38 uIU/ml (normal range: 0.4-4.0), elevated free thyroxine (fT4) of 2.48 ng/dl (0.7-1.3), free triiodothyronine (fT3) of 10.9 pg/ml (2.4-4.1) and reverse T3 (435 pg/ml; 90-215) levels. He was not taking any medications that could have affected thyroid labs. Repeat TFTs using a different assay showed a similar pattern. Antithyroid peroxidase and TSH receptor antibodies were not detected. Sex Hormone-Binding Globulin (SHBG), a peripheral marker of THs action, was in the euthyroid range. A diffuse cystic goiter was revealed on ultrasound. The magnetic resonance imaging identified a 5 mm hypointense area in a slightly hyperplasic pituitary. His father showed hormonal abnormalities consistent with RTHβ. T3 and Thyrotropin-releasing hormone (TRH) was not available for dynamic tests. A heterozygous missense mutation in the THRβ gene (c.1012C>T) was identified. Tiratricol was prescribed thereafter.

Discussions: Elevated serum THs accompanied by unsuppressed TSH are suggestive of RTHβ. However, alternative diagnoses (assay interferences, thyroxine-binding globulin abnormalities, and familial dysalbuminemic hyperthyroxinemia) should be excluded first by measuring free THs with equilibrium dialysis and T4-binding panel. First-degree relatives hormonal testing, a-subunit/TSH ratio, markers of THs action (SHBG, Type I Collagen C-Terminal Telopeptide), pituitary imaging, dynamic tests with T3 and TRH are used to discriminate between RTHβ and thyrotropinoma. As in our patient, a pituitary lesion mimicking thyrotropinoma may appear in RTHβ as an incidental finding; although it can result from thyrotropes enlargement after a longstanding absence of negative feedback. Genetic testing is regarded as the gold standard for definitive diagnosis. THRβ c.1012C>T affects a highly conserved amino acid (p.Arg338Trp) in the THRβ T3-binding domain and was classified as pathogenic.

Conclusions: In the setting of normal TSH and elevated THs, after ruling-out artifactual laboratory interference, there is a high suspicion for RTHβ. Alternative diagnoses should be excluded as they have completely different management approaches.