Recurrent Pathogenic THRB Variant p. Arg338Trp (c.1012C>T) in a New Family with Pituitary-Selective Resistance to Thyroid Hormone Beta: a case report

Background Resistance to thyroid hormone beta (RTH-β) is a rare autosomal dominant disorder caused by heterozygous loss-of-function mutations in THRB . It presents with elevated free thyroxine (FT4) and free triiodothyronine (FT3) with non-suppressed thyrotropin (TSH), constituting the syndrome of inappropriate TSH secretion. Distinguishing RTH-β from thyrotropin-secreting pituitary adenomas is essential because management differs fundamentally. Two phenotypes exist: generalized resistance (GRTH), involving both pituitary and peripheral tissues, and pituitary-selective resistance (PRTH), in which peripheral thyroid hormone sensitivity is preserved. Over 170 pathogenic THRB variants have been described, largely within the ligand-binding domain, with arginine 338 recognized as a recurrent mutational hotspot. Case Presentation A 49-year-old South Asian woman was evaluated for persistently abnormal thyroid function tests. Laboratory studies showed elevated FT4 and FT3 with non-suppressed TSH. Sex hormone-binding globulin (SHBG) was elevated, indicating preserved peripheral thyroid hormone responsiveness and supporting PRTH. The alpha-subunit and alpha-subunit/TSH molar ratio were normal. Pituitary MRI revealed a partial empty sella without adenoma. Whole exome sequencing identified a heterozygous THRB c.1012C>T (p.Arg338Trp; R338W) variant, a well-established pathogenic mutation. The same variant was detected in her daughter, who exhibited mild biochemical abnormalities, confirming autosomal dominant inheritance. Management consisted of beta-adrenergic blockade and clinical surveillance. Conclusion This report documents an independent occurrence of the recurrent THRB p.Arg338Trp variant in a South Asian family. Elevated SHBG supported pituitary-selective RTH-β, distinguishing it from GRTH and thyrotropinoma. The case reinforces arginine 338 as a critical mutational hotspot and highlights the indispensable role of genetic testing when pituitary imaging is non-diagnostic.