Clinical phenotypes and molecular analysis of the THRB gene in children with thyroid hormone resistance

Purpose: Resistance to thyroid hormone (RTH) is an autosomal dominant disorder characterized by hyposensitivity to T3, with persistent elevation of free T3 (FT3) and free thyroxine (FT4) levels associated with non-suppressed serum thyroid stimulating hormone (TSH). Two forms of RTH are generalized type involving both peripheral target tissues and the pituitary, and pituitary RTH. Only a few cases of RTH harboring THRB mutations have been reported in Korea. This study described the phenotypic spectrum of RTH patients and analyzed mutations in THRB. Methods: A total of 5 unrelated patients (1 male and 4 females) with RTH were included. Clinical manifestation such as goiter, sinus tachycardia, mental retardation, and thyroid function tests were reviewed retrospectively. All coding exons of THRB were amplified by PCR and directly sequenced in all patients. Results: The age at diagnosis was 9.5 ± 10.2 years (range, 2 month to 26 years). The most common presenting sign was goiter (n = 4, 80%), followed by sinus tachycardia (n = 3, 60%), and palpitation (n = 2, 40%). Two patients (40%) were considered to have generalized RTH because of language developmental delay and cognitive function deficit. Three subjects had attention deficit hyperactivity disorder, one of them has been treated with methylphenidate. Initial TSH and FT4 levels at diagnosis were 37.3 ± 36.5 μIU/ml (range, 5.8-76.8 μIU/ml) and 2.41 ± 1.55 ng/dL (range, 1.5-2.5 ng/dL), respectively. Two patient was initially misdiagnosed with Graves disease and goiter had been getting worsen during medication of methimazole, afterwards showed high free thyroxine with non-suppressed TSH. Goiter was improved after stopping the methimazole. Four novel heterozygous mutations in THRB were identified in 5 patients; most were missense mutations (n = 4; p.H435Y, p.L456S, p.T327I), and one patient harbored frameshift mutation (n = 1; c.1352dup(T) [p.F451fs∗14]). Two patients were detected by familial screening. All mutations are located in the ligand-binding domain. Thyroid hormone analogue was given in most patient, and two patients needed β-blocker to control symptoms of thyrotoxicosis. Conclusions: This study described clinical, endocrinological, and molecular characteristics patients with RTH. Most patients displayed high FT4 level with non-suppressed TSH. Clinical features were variable according from generalized to pituitary RTH, resulting from genetic heterogeneity of target tissues.