The patient was a 36-year-old woman with RTHbeta due to a novel THRbeta gene mutation coexisting with AITD. After thyroid surgery, she was admitted to the Department of Endocrinology due to significantly elevated TSH, which was persistent despite the treatment with 150 microg of thyroxine and 15 microg triiodothyronine. Her history of thyroid-related problems started 25 years ago including a small goiter, palpitations, and at the same time cold intolerance and skin dryness. Clinical symptoms were accompanied by peculiar and disturbing laboratory results (elevated TH levels with normal/slightly elevated TSH). For many years, she received anti-thyroid drugs and/or different doses of thyroxine periodically; however, pharmacological treatment failed to normalize her thyroid hormone levels, and this resulted in patient's frustration. In 2000, she was disqualified from treatment with radioiodine with suspicion of the RTHbeta syndrome. Unfortunately, genetic testing was not performed at that time. Finally, in 2003, she underwent subtotal thyroidectomy for "suspicion of Graves-Basedow disease." Her laboratory results at that time were as follows: increased concentrations of THs accompanied by normal TSH levels [FT4: 45.7 pmol/L (N: 10-25), FT3: 22.3 pmol/L (N: 2.25-6), and TSH: 1.53 mIU/mL] and elevated levels of TgAb and TPOAb (TRAB was not available at that time). The results were obtained from patient's documentation; however, the assay type remains unknown. Before surgery, thyroid ultrasound showed the gland of a normal size (right lobe: 19 x 16 x 57 mm, and left lobe: 19 x 15 x 50 mm); in the right lobe, two hypoechogenic lesions with the diameter of 10 mm and 6 mm were found, with no pathological lymph nodes. Fine aspiration biopsy (FNAB) of these nodules revealed the presence of benign lesions (category no. 2:according to TBSRTC classification), confirmed by histopathology. After the surgery, she chronically felt weak and sleepy. Despite the treatment with 150 mug/d of thyroxine and 15 mug/d of triiodothyronine (Euthyrox N 75 1 x 1 and Novothyral 75 1 x 1), the levels of TSH exceeded 100 mIU/L (N: 0.27-4.2), but TH levels were normal; the other results are as follows: FT3: 3.38 pg/mL (N: 2.6-4.4), FT4: 1.78 ng/dL (N: 0.93-1.7), anti-Tg: 188.7 IU/mL (N:<115), anti-TPO: 180.3 (N:<34) IU/mL, and TRAb: <0.3 IU/L (N:<1.75). All results were determined by commercially available electrochemiluminescence one-step immunoassays (ECLIA Cobas e601, Roche). She had a history of recurrent ear infections and mitral valve prolapse. She delivered twice: the first healthy daughter was born before thyroid surgery and the second daughter with the diagnosis of hypoacusis was born after the surgery. Family history revealed Hashimoto's disease in mother and a benign non-toxic goiter in sister. The patient was admitted to the Department of Endocrinology for additional diagnostics. On admission, she presented normal mental and physical development without significant abnormalities in physical examination. Hormonal tests (TH and TSH) were repeated on different platforms, with similar results. Compliance problems, heterophilic antibody interference, and the presence of TSH-oma (normal results of MRI and normal concentrations of other pituitary hormones, alpha subunit, SHBG, and ferritin) as causes of observed abnormalities were excluded. Then, genetic testing in the patient and her family was suggested. The patient and all family members gave their informed consent to participate in this study, and the investigation was performed in accordance with the principles of the Declaration of Helsinki.
The coding region of THRbeta gene was sequenced using the ABI 3500 Genetic Analyzer (Life Technologies, Carlsbad, CA) and analyzed using Mutation Surveyor software v.5.0.1. The alignment to reference sequence NM_000461.4 was performed.
Sequence analysis revealed a novel heterozygous delins mutation c.1357_1358delinsAA in exon 10 (Figure 1). This variant is located in a highly conserved region encoding functionally important domains: nuclear hormone receptor and ligand-binding domain. The missense mutation created a substitution of proline to asparagine at codon 453 (p.Pro453Asn). This variant was not previously reported in any genetic databases (HGMD, ClinVar, ExAC, 1000 Genomes Project, and GnomAD). Moderate physicochemical differences between Pro and Asn were observed (Grantham dist.: 91 [0-215]). The variant was qualified as disease causing by SIFT (score: 0, median: 4.32) and as probably damaging by PolyPhen (score: 1). This mutation was absent in other family members.
After establishing the diagnosis of RTH, the dose of thyroxine was increased to 300 microg, which showed clinical improvement and normalization of TSH.