Variable clinical presentation and outcome in pediatric patients with resistance to thyroid hormone (RTH)

Abstract

Resistance to thyroid hormone (RTH) is characterized by elevated levels of thyroid hormones, normal or slightly increased TSH levels respondent to TRH, resistance to thyroid hormone administration, and variable clinical expression. To describe the diverse clinical and biochemical findings of six children from five unrelated families with molecular diagnosis of RTH (0.5–12.7 years) and their follow-up (3–20 years). All RTH patients and 4 affected parents’ harbored mutations in exons 9 or 10 of the thyroid receptor β gene: p.M313T (de novo), pN331D, p.L341P, p.L346F, and p.P453L. At consultation 5/6 had goiter, 4/6 tachycardia, and 3/5 learning disabilities. Median hormone levels were: T4 257.4 nmol/l (NR: 77.2–180.2); FreeT4 39.9 pmol/(NR:10.3–28.3); T3 4.28 nmol/l (NR:1.23–3.39) TSH 2.8 mUI/l (NR: 0.5–5) always responsive to TRH. TSH levels remained detectable after supraphysiologic T3 administration while SHBG levels showed a paradoxical decrease in 4/6. Thyroid antibodies, initially present in two subjects, became positive in other two during follow-up. All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression). Parent’s thyroid profile showed similar TSH and T3 levels but lower T4 and FT4 than their children. RTH has a distinctive biochemical profile with highly variable clinical manifestations and outcomes. Its recognition and molecular characterization avoid misleading diagnosis. Treatment has to be instituted according to each subject’s own clinical requirements.