Thyroxine binding globulin deficiency due to a novel HNF1B gene variant in a young girl with high thyroxine requirement.

Primary hypothyroidism is managed with oral levothyroxine (LT4) using a daily dose of 1.5 to 2 µg per kg. Elevated thyroid-stimulating hormone (TSH) despite a high dose of LT4 is a common problem and could be due to multiple etiologies, including poor drug compliance, thyroxine (T4) malabsorption, celiac disease, and consumptive hypothyroidism. A 12-year-old girl was referred with persistently elevated TSH despite using daily 100 µg LT4. Detailed evaluation, including the LT4 absorption test, was normal, and she achieved euthyroidism with a daily LT4 dose of 5.5 µg per kg. Her T4 levels were consistently normal despite a high LT4 dose, and evaluation revealed an undetectable thyroxine-binding globulin (TBG) level. Whole-exome sequencing for the TBG gene revealed a heterozygous missense variant in the HNF1B gene c.1007A>G p.His336Arg, usually described in renal cysts and diabetes syndrome. Our patient did not have dysglycemia or renal abnormalities. Previous reports suggest that mutations in the HNF1B gene could disrupt transcriptional regulation of the TBG gene. In this case, we report an HNF1B pathogenic variant that leads to TBG deficiency, underscoring the importance of genetic screening in unusual thyroid disorders.