Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB, causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β.

In patients with pituitary thyroid hormone resistance, the ability of the pituitary gland to detect (and down-regulate) the increase of triiodothyronine is selectively impaired, while the periphery remains sensitive to triiodothyronine levels, producing symptoms of peripheral thyrotoxicity. Subsequently, there is no feedback of pituitary production of thyroid-stimulating hormone (TSH), which is responsible for this hyperthyroidism. We report a case of a 46-year-old Chinese woman diagnosed with a thyroid nodule, with normal thyroid function. She underwent conventional subtotal thyroidectomy, and replacement therapy (levothyroxine) was used for as convention. However, it was later proven that she had pituitary resistance to thyroid hormone, as supra-physiological doses of levothyroxine were required to normalize TSH levels, which resulted in peripheral thyrotoxicity. Based on the patient's symptoms, laboratory tests results, imaging examinations, and genetic analysis (which noted a gene mutation), a diagnosis of pituitary resistance to thyroid hormones was confirmed. The dose of levothyroxine was adjusted periodically and β-adrenergic blocker was used as symptomatic treatment. The outcome in the reported case has been satisfactory despite the persistence of non-suppressed TSH. An inappropriate level of TSH should always be evaluated. We found a new mutation (H435A) of the thyroid hormone receptor beta gene, which allowed for the establishment of a definitive diagnosis.

Ectopic thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare. To date, there are only 6 cases reported. Here, we describe an even rarer ectopic TSH-secreting pituitary adenoma (TSH-oma) concomitant with papillary thyroid carcinoma. A 27-year-old female was admitted to the hospital in 2002 for neck enlargement and palpitation. Thyroid function test showed increased thyroid hormones and unrepressed TSH. Thyroid ultrasound examination displayed diffuse goiter. The patient was presumptively diagnosed as primary hyperthyroidism and treated with anti-thyroid drugs. Her condition was then improved, but the serum TSH was persistently unrepressed. Therefore, central hyperthyroidism due to TSH-oma or pituitary resistance to thyroid hormone (PRTH) was suspected. Pituitary magnetic resonance imaging (MRI) examination was deservedly performed to rule out TSH-oma, which turned out to be normal. In addition, T3 suppression test was negative. Thus, PRTH, as an uncommon cause of inappropriate TSH secretion, was regarded as the working diagnosis. Triiodothyroacetic acid, which was reported to be effective for PRTH, was then administrated. But it did not work well. To control the symptoms completely and normalize the level of thyroid hormones, radioiodine therapy was carried out in 2007, followed by levothyroxine replacement therapy. Consequently, the symptoms were relieved, whereas serum TSH remained at high levels even with adequate levothyroxine. Unexpected, thyroid papillary carcinoma and a neoplasm in her nasopharynx were successively detected in 2012, which were then removed by surgery. Somewhat interestingly, the serum TSH declined to normal after the operation. The patient was ultimately diagnosed as an ectopic TSH-secreting pituitary adenoma concomitant with papillary thyroid carcinoma. Thyroidectomy and removal of the ectopic TSH-secreting pituitary adenoma by surgery were carried out, followed by levothyroxine replacement therapy. Three years after the surgery, the patient felt well with levothyroxine 125ug daily. Serum thyroid hormones and TSH kept in normal and no signs of neoplasm recurrence. Although extremely rare, ectopic TSH-secreting pituitary adenoma, as an uncommon cause of thyrotoxicosis, should be taken into consideration among those who have a longstanding hyperthyroidism with unsuppressed TSH.

Thyroid hormone resistance syndrome (THRS) is a rare disorder with increased concentrations of free thyroxine (FT4) and triiodothyronine (FT3), but normal or slightly increased thyroid-stimulating hormone (TSH). The mutations in the thyroid hormone receptor β (THRβ) gene are thought to be the main pathogenesis. The aims of this study were to present 1 pedigree of Chinese THRS, summarize their clinical characteristics, and analyze the gene mutation. The clinical characteristics and thyroid function of the proband and his family members were collected. Gene mutations were analyzed by DNA sequencing. The proband and his mother exhibited symptoms of hyperthyroidism, such as palpitations, heat intolerance, and perspiration. The mother also had atrial fibrillation. The rest of the kindred did not display clinical manifestations of hyper- or hypothyroidism. DNA sequencing revealed a heterozygous G>A missense mutation at position 949 in Exon 9 of THRβ both in the patient and his mother, which led to the transition from alanine to threonine at position 317 of THRβ protein (A317T), whereas the rest of the kindred did not share this mutation. The proband and his mother were diagnosed with pituitary resistance to thyroid hormone. Oral administration of methimazole was stopped and β-receptor blockers were administrated. We present 1 pedigree of THRS with heterozygous A317T mutation in THRβ gene in the proband and his mother, which is the first reported mutation in Chinese and provides a comprehensive review of available literature.