Patient 1, a 4-year-old boy, presented with delayed language development. Persistently elevated free triiodothyronine (FT3) and free thyroxine (FT4) were found, with normal or elevated thyroid-stimulating hormone (TSH). A de novo heterozygous mutation in the THRB gene (c.1373T>C, p.Val458Ala) was identified, and resistance to thyroid hormone syndrome (RTH) was diagnosed. No specific medication was administered, and regular follow-up was arranged. Patient 2, a 2-year-old boy, had elevated TSH detected on neonatal screening. Thyroid dysfunction persisted for 1 year and 10 months and was accompanied by growth delay and tachycardia. Genetic testing revealed a de novo heterozygous mutation in the THRB gene (c.959G>A, p.Arg320His), and pituitary-type RTH was diagnosed. Propranolol was administered for heart rate control. RTH shows marked clinical heterogeneity and is prone to misdiagnosis or missed diagnosis. For children with unexplained thyroid dysfunction and developmental disorders, early THRB gene testing helps achieve precise diagnosis and guide treatment decisions.