Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma.

Elevated concentrations of T3 and T4 concomitant with nonsuppressed TSH are found in both TSH-producing tumors and resistance to thyroid hormone beta (RTHß), posing a diagnostic challenge. We demonstrate here a 54-year-old female who presented with palpitations, goiter, and elevated free T4 with nonsuppressed TSH concentrations (TSH 2.2 mIU/L [normal range, NR 0.27-4.2 mIU/L] and FT4 59.08 pmol/L [NR 12.0-22.0 pmol/L]). Because magnetic resonance imaging revealed a pituitary microadenoma (4 mm), she was diagnosed with TSH-secreting pituitary adenoma and underwent transsphenoidal surgery. Pathological reports showed no tumor cells. Subsequent genetic testing revealed a pathogenic variant in the THRB gene resulting in a His435Arg amino acid substitution in the T3 receptor isoform beta 1 (TRß1), suggestive of RTHß. In vitro and ex vivo studies revealed that the His435Arg mutated TRß1 (TRß1-H435R) completely abolishes the T3-induced transcriptional activation, nuclear receptor corepressor 1 release, steroid receptor coactivator 1 recruitment, and T3-induced thyroid hormone target gene expression, confirming the pathogenicity of this variant. The identification of a pituitary microadenoma in a patient with RTHß led to a misdiagnosis of a TSH-producing tumor and unnecessary surgery. Genetic testing proved pivotal for an accurate diagnosis, suggesting earlier consideration in similar clinical scenarios.

Impaired Sensitivity to Thyroid Hormone and Risk of Carotid Plaque Development in a Chinese Health Check-Up Population: A Large Sample Cross-Sectional Study.

Objective: Previous research on the correlation between thyroid function and carotid plaque has revealed conflicting results, possibly attributable to the sensitivity of thyroid hormone indices. In this study, we aimed to analyze the association between thyroid hormone sensitivity indices and the risk of carotid plaque development in a Chinese health check-up population. Methods: A total of 19,388 health check-up subjects were included in this study (mean age: 50.78±10.17 years). Central sensitivity to thyroid hormone was evaluated using the thyroid feedback quantile-based index (TFQI), the Chinese-referenced parametric TFQI (PTFQI), the TSH index (TSHI), and the thyrotropin thyroxine resistance index (TT4RI), while peripheral sensitivity to thyroid hormone was assessed by free triiodothyronine/free thyroxine (FT3/FT4) ratio. Multivariable logistic regression analyses were performed to detect the association between thyroid hormone sensitivity indices and carotid plaque risk, and subgroup analysis was also conducted to explore this association stratified by sex, age, obesity, and the status of smoking, drinking, diabetes, hypertension and dyslipidemia. Results: Among the 19,388 participants, 3753 (19.4%) had carotid plaque. In multivariable adjustment models, the risk of carotid plaque was positively associated with TSHI (odds ratio [OR]: 1.23; 95% confidence interval [CI]: 1.18~1.28), TT4RI (OR: 1.28; 95% CI: 1.23~1.33), TFQI (OR: 1.06; 95% CI: 1.02~1.10), and PTFQI (OR: 1.11; 95% CI: 1.07~1.16), respectively. Conversely, the risk of carotid plaque was negatively correlated with FT3/FT4 (OR: 0.94; 95% CI: 0.90~0.98). In stratified analyses, all thyroid hormone sensitivity indices significantly increased the risk of carotid plaque especially in females, subjects<65 years, non-obese individuals, and those without current smoking, drinking, diabetes, hypertension and dyslipidemia. Conclusion: In Chinese health check-up populations, a considerable connection between reduced sensitivity to thyroid hormones and carotid plaque has been observed, especially in females, those younger than 65 years, non-obese individuals, and those without any current smoking, drinking, diabetes, hypertension, or dyslipidemia.

Central hyperthyroidism combined with Graves' disease: case series and review of the literature.

Background: Central hyperthyroidism is characterized by elevated free thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), and this laboratory feature includes TSH-secreting pituitary adenoma (TSHoma) and resistance to thyroid hormone ß (RTHß). Central hyperthyroidism combined with Graves' disease (GD) has been rarely reported. Case Report: We describe three patients with TSHoma combined with GD and one patient with GD combined with RTHß and pituitary adenoma. These three patients with TSHoma combined with GD showed elevated thyroid hormone, while TSH level was normal or elevated, and TSH receptor antibodies were positive. After thyrotoxicosis was controlled, they all underwent transsphenoidal surgery. We also describe a patient with an initial presentation of GD who developed hypothyroidism after anti-hyperthyroidism treatment and TSH was inappropriately significantly increased. His head magnetic resonance imaging revealed a pituitary adenoma. Genetic testing confirmed a heterozygous mutation in the thyroid hormone receptor ß gene c.1148G>A (p.R383H). After levothyroxine and desiccated thyroid tablet treatment, the TSH level decreased to normal. Conclusion: These four cases highlight the need to consider the diagnosis of GD combined with central hyperthyroidism when faced with inconsistent thyroid function test results, illuminating the specific diagnostic and therapeutic challenges of coexisting primary and central hyperthyroidism. Finally, we propose clinical management for central hyperthyroidism combined with GD.

Can a novel drug dose be used for T3 suppression test?

PURPOSE: This study aimed to investigate whether 25 µg/day dose of triiodothyronine (T3) can also suppress thyroid stimulating hormone (TSH) level, as well as the routine dose of 50-100 µg/day in T3 suppression test, which is used to the distinguish between resistance to thyroid hormone (RTH) and TSH secreting pituitary adenoma. METHODS: In this prospective study, 26 patients with genetically proven RTH were randomly divided into two groups: Group 1 comprised 13 patients who were administered 50-100 µg/day T3 for 3-9 days, while Group 2 also comprised 13 patients who were administered 25 µg/day T3 for 7 days for T3 suppression test. The two groups' responses to T3 suppression tests were compared. RESULTS: The comparison of the mean percentage changes in TSH values by the T3 suppression tests showed no significant differences between the groups, and a ≥80% decrease was detected in all patients. Nine patients in Group 1 and one patient in Group 2 reported that they had to use propranolol due to tachycardia developed during the test. CONCLUSION: As higher doses of T3 can increase the risk of severe tachycardia during T3 suppression test, a low dose with 25 mcg/day for a week appears to be safer and more useful.

Effect of the Fetal THRB Genotype on the Placenta.

CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

Resistance to thyroid hormone due to a novel mutation in the thyroid beta receptor (THRß) gene coexisting with autoimmune thyroid disease-A case report.

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired responsiveness of target tissues to thyroid hormones. The relationship between RTHß and thyroid autoimmunity has been under research. In this study, we demonstrate a case report of a woman with a novel mutation in THRß gene coexisting with autoimmune thyroid disease (AITD). The 36-year-old woman has been treated since childhood for a thyroid disease. Based on high levels of thyroid hormones (THs) and elevated concentrations of thyroperoxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively), she received unnecessary long-term treatment with methimazole and finally underwent subtotal thyroidectomy. After the surgery, her TSH level remained significantly elevated, despite the treatment with 150 + 15 µg of thyroxine and triiodothyronine. A sequence analysis of the THRß gene revealed a novel dinucleotide substitution affecting codon 453, resulting in the replacement of the normal proline with an asparagine (c.1357_1358delinsAA, p.(Pro453Asn)). The mutation has not been described in the literature yet; however, THRß codon 453 represents a mutational hot spot, frequently altered in the TH receptor ß gene. After establishing the diagnosis of RTH, the patient was treated with 300 µg of thyroxine, which showed clinical improvement and normalization of TSH. The coexistence of RTHß and AITD may additionally impede establishment of a proper diagnosis, leading to unnecessary therapy and delayed correct treatment. The presented case encourages a closer cooperation between clinical endocrinologists and geneticists.

Resistance to thyroid hormone beta coexisting with papillary thyroid carcinoma-two case reports of a thyroid hormone receptor beta gene mutation and a literature review.

Resistance to thyroid hormone beta (RTHß) is an autosomal dominant hereditary disorder that is difficult to diagnose because of its rarity and variable clinical features, which are caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies have indicated a close association between THRB mutations and human cancers, but the mechanistic role of THRB mutations in carcinogenesis is unknown. Herein, we report two cases of RTHß coexisting with papillary thyroid carcinoma (PTC) and their follow-up results. Two female patients presented with elevated serum thyroid hormone levels and nonsuppressed thyrotropin (TSH). Genetic analysis showed that each patient had a THRB gene mutation (p.P453T and p. R320H). Based on the results of ultrasound-guided fine-needle aspiration biopsy, the thyroid nodules were suspected to be PTC. Intraoperative pathology confirmed that the two patients had PTC with multifocal carcinoma of both lobes. One patient underwent total thyroidectomy and central lymph node dissection, and the other underwent total thyroidectomy alone. Following surgery, large doses of levothyroxine were administered to suppress TSH levels and prevent recurrent or persistent disease. However, it is difficult to continually suppress TSH levels below the upper limit of the normal range. To date, the two patients have experienced no recurrence of PTC on ultrasound.

Resistance to Thyroid Hormones: A Case-Series Study.

The aim of the study is to describe the clinical features of two unrelated patients with resistance to thyroid hormones (RTH), the first, a total thyroidectomized patient, and the second, a pregnant woman. We report the features found in her newborn who also showed RTH. Patient 1 is a 38-year-old man with total thyroidectomy managed for excessive thyroid stimulating hormone (TSH) production, which poorly responded to the replacement therapy. He was found with a THRß c.1378G>A p.(Glu460Lys) heterozygous mutation, which was also present in other members of his family (son, brother, and father). Interestingly, Patient 1 had hypertension, dyslipidemia, and hepatic steatosis, which have been recently suggested as RTH-related comorbidities. Patient 2 is a 32-year-old pregnant woman with multinodular goiter, and the THRß heterozygous variant c.959G>C, that, to the best of our knowledge, has been reported in literature only once. Her newborn had tachycardia and increased thyroid hormone levels, and showed the same mutation. After delivery, high parathyroid hormone (PTH) and calcium serum levels were found in Patient 2 and the scintigraphy showed the presence of adenoma of a parathyroid gland. This case-series study provides a practical example of the management of RTH in a thyroidectomized patient, a pregnant woman, and a newborn. A novel RTH pathogenic mutation is described for the second time in literature. Furthermore, the importance of metabolic assessment in patients with RTHß has been highlighted and the possible correlation between RTH and primary hyperparathyroidism is discussed.

Impaired sensitivity to thyroid hormones and carotid plaque in patients with coronary heart disease: A RCSCD-TCM study in China.

Context: Previous studies on the association between thyroid function and carotid plaque have shown contradictory results, which may be attributable to the sensitivity to thyroid hormone indices. This study aimed to analyze the association between thyroid hormone sensitivity and risk of carotid plaque in patients with coronary heart disease (CHD) and further explore this association according to sex, age, smoking, and drinking status. Methods: This large-scale, multi-center, retrospective, cross-sectional study included 6679 patients with CHD (age 35-75). Central sensitivity to thyroid hormone was evaluated by the thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyroid-stimulating hormone index (TSHI), and thyrotroph thyroxine resistance index (TT4RI). Peripheral sensitivity to thyroid hormone was assessed by free triiodothyronine/free thyroxine (FT3/FT4) ratio. Taking no carotid plaque as a reference, this study used logistic regression to analyze the association between central and peripheral thyroid hormone sensitivity and carotid plaque in patients with CHD. Results: Of the 6679 patients with CHD, 4843 (72.50%) had carotid plaque. In the multi-adjusted models, the TFQI (odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.26-1.78; P < 0.001), PTFQI (OR: 1.76; 95% CI: 1.46-2.12; P < 0.001), TSHI (OR: 1.21; 95% CI: 1.10-1.33; P < 0.001), and TT4RI (OR: 1.00; 95% CI: 1.00-1.01; P = 0.003) were positively associated with the risk of carotid plaque. Compared with that in females and people > 60 years, the OR value for carotid plaque was higher in males and people ≤ 60 years. Similarly, smokers and drinkers had higher OR values for carotid plaque than non-smokers and non-drinkers. Conversely, FT3/FT4 ratio (OR: 0.75; 95% CI: 0.70-0.81; P < 0.001) was negatively associated with carotid plaque, and the OR value for carotid plaque was lower in males, patients ≤ 60 years, smokers, and drinkers. Conclusion: This study showed that thyroid hormone sensitivity is significantly associated with carotid plaque in patients with CHD. This association is more significant in males, patients ≤ 60 years, smokers, and drinkers.

Resistance to thyroid hormone in a child with thyroid agenesis: A case report with review of the literature.

Introduction: The coexistence of thyroid dysgenesis and resistance to thyroid hormone (RTH) is a very rare occurrence. The current study aims to report a unique case of thyroid agenesis with RTH in a pediatric patient. Case report: A 5-year-old male patient presented with poor feeding, excessive somnolence, and a noticeable umbilical hernia since the age of 2 months. He was initially diagnosed as a case of congenital hypothyroidism, and since then, he had been placed on thyroid replacement therapy. No further investigations were conducted until the age of 5 years. Recent laboratory findings revealed an elevated TSH level (42.41 µIU/mL). X-ray examination showed delayed bone age (30 months). Ultrasound (US) examination demonstrated the complete absence of thyroid lobes, isthmus, and ectopic thyroid tissue, but small 2.7 x 2.5-mm non-echoic, cystic, and hypo-vascular nodules were seen in the bed of the right thyroid lobe. The patient was kept on thyroid replacement therapy (levothyroxine) and under close follow-up. On follow-up, the patient's thyroid function status revealed resistance to exogenous thyroid hormone. Discussion: Thyroid agenesis is the complete absence of the thyroid gland. Meanwhile, RTH is a hereditary disease characterized by decreased sensitivity of body tissues to thyroid hormone. Most cases of RTH are due to mutations in the gene encoding for THRß. However, recently RTH due to THRα mutations has also been reported. The presentations of RTH cases in general and with thyroid dysgenesis are quite heterogenous. Conclusion: Although the combination is exceedingly rare, thyroid agenesis can coexist with RTH.

Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone α (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function unexpectedly retain the ability to bind thyroid hormone. Visualization of the ligand T3 within the crystal structure of a prototypic TRα mutant validates this notion. This finding prompted the synthesis of different thyroid hormone analogues, identifying a lead compound, ES08, which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex for treatment of RTHα.

Clinical outcomes of 34 patients with resistance to thyroid hormone beta: a twenty-year experience in Japan.

Resistance to thyroid hormone beta (RTHß) caused by germline mutations in genes encoding thyroid hormone receptor beta (TRß) is a rare disorder. Little information is available regarding the clinical experience of this syndrome in Japan. We retrospectively reviewed the records of 34 patients with RTHß (21 adult females and 13 adult males) with positive TRß mutations identified at our division between 2000 and 2020. Of the 24 patients with available clinical history, 10 (41.7%) received inappropriate treatments such as antithyroid drugs, thyroidectomy, or radioactive iodine. Diagnostic delay and inappropriate management of RTHß are still present in Japan. Every patient except one demonstrated thyroid hormone profiles indicative of syndrome of inappropriate secretion of thyrotropin (SITSH), characterized by a hormonal profile of hyperthyroxinemia with a non-suppressed TSH concentration. Since the most common forms of hyperthyroidism including Graves' disease feature elevated thyroid hormone levels with suppressed TSH concentrations, early diagnosis of SITSH is critical for preventing inappropriate management. One patient positive for anti-thyroglobulin antibody (Tg-Ab) and anti-thyroperoxidase antibody (TPO-Ab) showed remarkably elevated TSH (>200 µIU/mL) despite thyroid hormone concentrations within the reference ranges. At least one thyroid autoantibody (Tg-Ab, TPO-Ab, or thyrotropin receptor antibodies) was identified in 37.9% (11/29) of the patients tested. One patient developed overt Graves' disease nine years after RTHß diagnosis. These findings suggest that RTHß is frequently comorbid with additional autoimmune thyroid disorders. Further research is required to identify the most appropriate treatments for RTHß patients who develop a second thyroid disorder.

Graves' disease coexisted with resistance to thyroid hormone: a case report.

BACKGROUND: Resistance to thyroid hormone is a rare autosomal dominant disorder characterized by reduced responsiveness to thyroid hormone and can cause syndrome of inappropriate secretion of thyroid stimulating hormone. Although Graves' disease is a common autoimmune thyroid disorder, the coexistence of these two diseases is extremely rare and makes the diagnosis and treatment complicated, leading to the delayed diagnosis of resistance to thyroid hormone. We describe the case of a Japanese man with resistance to thyroid hormone coexisting with Graves' disease, in which the correct diagnosis of resistance to thyroid hormone was delayed by masking of the signs of syndrome of inappropriate secretion of thyroid stimulating hormone, with final diagnosis 30 years after the initial treatment for Graves' disease. CASE PRESENTATION: A 30-year-old Japanese man presented with diffuse goiter and thyrotoxicosis. Anti-thyroid stimulating hormone receptor antibody was positive. He was diagnosed with Graves' disease. Anti-thyroid medication was chosen as the initial treatment for Graves' disease. However, this treatment failed to normalize the free triiodothyronine, free thyroxine, and thyroid stimulating hormone levels. His thyroid hormone levels indicated syndrome of inappropriate secretion of thyroid stimulating hormone. After cessation of methimazole treatment by remission of Graves' disease, his state of syndrome of inappropriate secretion of thyroid stimulating hormone persisted. Magnetic resonance imaging revealed no pituitary tumor lesions. The results of thyroid stimulating hormone-releasing hormone stimulation test showed a normal response of thyroid stimulating hormone. He was suspected to have resistance to thyroid hormone. Direct sequencing analysis of the thyroid hormone receptor ß gene identified a heterozygous missense mutation, R282S. Coexistence of resistance to thyroid hormone with Graves' disease was confirmed. He has no signs of thyrotoxic symptoms, and is capable in activities of daily living at the present time. CONCLUSION: We described a rare case of resistance to thyroid hormone simultaneously existing with Graves' disease. This case demonstrated that these diseases can coexist, and indicated some of the difficulties in diagnosis of resistance to thyroid hormone with coexisting Graves' disease. The diagnosis of resistance to thyroid hormone did not become apparent until after anti-hyperthyroidism treatment. Although rare, careful follow-up after the initial treatment of Graves' disease is necessary. The coexistence of these two diseases should be considered in patients showing occasional syndrome of inappropriate secretion of thyroid stimulating hormone.

An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.

Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of ß type of resistance to thyroid hormone (RTHß). The differential diagnoses of RTHß include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHß, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHß and TSHoma. The FT3/FT4 values in RTHß were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.

Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi.

Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and ß [TRα and TRß]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.

Early Diagnosis and Treatment of an Infant with a Novel Thyroid Hormone Receptor α Gene (pC380SfsX9) Mutation.

Resistance to thyroid hormone alpha (RTHα) is caused by mutations in thyroid hormone receptor α (THRA). Little is known about the natural history and treatment of RTHα, and diagnosis before the age of 1 year has not been previously reported. A de novo heterozygous THRA mutation (pC380SfsX9) was identified in a 10-month-old female investigated for developmental delay, hypotonia, macrocephaly, and severe constipation. Treatment with levothyroxine was accompanied by an appropriate rise in thyroxine (T4), triiodothyronine (T3), as well as decrease in thyrotropin levels and in the T3/T4 ratio with a trend toward normalization of peripheral markers of thyroid hormone action. THRA pC380SfsX9 results in extreme RTHα.

The Differential Diagnosis of Discrepant Thyroid Function Tests: Insistent Pitfalls and Updated Flow-Chart Based on a Long-Standing Experience.

Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHß) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis. Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging. Results: 88 patients were correctly diagnosed as RTHß with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHß (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHß (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHß a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHß showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 µUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHß patients had small pituitary lesions, leading to unnecessary surgery in one case. Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.

Resistance to thyroid hormone due to a novel THRB p.Val349Ala mutation in a Taiwanese boy.

Resistance to thyroid hormone (RTH) is a rare congenital disorder characterized by impaired sensitivity of target tissues to thyroid hormone. The disease is mostly caused by heterozygous mutations of thyroid hormone receptor ß (THRB) gene. We present a ten-year-old Taiwanese boy with goiter, mood disturbances and attention deficit hyperactivity disorder (ADHD). Blood tests showed elevated serum thyroxine (T4) and triiodothyronine (T3) levels with nonsuppressed thyrotropin (TSH) levels. Sella MRI failed to detect any pituitary adenoma. Initial treatment with anti-thyroid drugs resulted in increased TSH levels and goiter size. His medication was discontinued after his visit to our hospital for a second opinion. A thyrotropin-releasing hormone (TRH) stimulation test showed a normal TSH response to TRH stimulation. Molecular analysis identified a novel heterozygous THRB p.Val349Ala mutation. The patient attained normal growth and a paucity of symptoms without any medication during the follow-up period. We hope that the presentation of this case can make the early diagnosis of RTH possible so that inappropriate management of these patients can be avoided in the future.

Hyperthyroxinemia with a non-suppressed TSH: how to confidently reach a diagnosis in this clinical conundrum.

Disorders of thyroid function are among the commonest referrals to endocrinology. While interpretation of thyroid function testing is usually straightforward, accurate interpretation becomes significantly more challenging when the parameters do not behave as would be expected in normal negative feedback. In such cases, uncertainty regarding further investigation and management arises. An important abnormal pattern encountered in clinical practice is that of high normal or raised free thyroxine (fT4) with inappropriately non-suppressed or elevated thyroid-stimulating hormone (TSH). In this short review using two clinical vignettes, we examine the diagnostic approach in such cases. A diagnostic algorithm is proposed to ensure that a definitive diagnosis is reached in these challenging cases.

Diagnosing Thyrotropin-Secreting Pituitary Adenomas by Short-Term Somatostatin Analogue Test.

Background: Diagnosis of thyrotropin (TSH)-secreting pituitary adenomas (TSHoma) before surgery remains a challenge, especially for microadenomas. We aimed to establish a short-term somatostatin analogue (SSA) test to differentiate TSHomas from other causes of syndromes of inappropriate secretion of TSH (IST), mainly resistance to thyroid hormone ß (RTHß). Materials and Methods: We first evaluated the sensitivity and specificity of SSA test in a training cohort (TSHoma, n = 32; RTHß, n = 20). The test was then validated in an independent cohort (TSHoma, n = 9; RTHß, n = 2). We finally applied the SSA test in 12 perceptively enrolled IST cases with negative imaging findings and absent thyroid hormone receptor beta (THRB) mutations or mixed hormone imbalances. Results: Both TSHoma and RTHß patients showed a decrease of TSH at the start of the SSA test, but the velocity of the TSH suppression slowly decreased in RTHß patients after 2 hours. The suppression ratio of TSH at 24 hours versus 2 and 0 hours was significantly greater in TSHoma patients compared with RTHß patients (70.58% ± 18.6% vs. 6.01% ± 25.41%, p < 0.0001, 79.83% ± 12.79% vs. 51.16% ± 13.62%, p < 0.0001, respectively). The 24- versus 2-hour suppression ratio showed the best diagnostic accuracy at a cut point of 44.46% in the training cohort, with a sensitivity of 95.00%, a specificity of 93.75%, and a positive predictive value (PPV) of 88.89%. The accuracy was confirmed in the validation cohort. Three out of 12 patients in the prospective cohort showed a TSH suppression ratio greater than 44.46% and all developed microadenomas during follow-up. Conclusions: A short-term SSA test provides an alternative diagnostic approach for TSHomas. A positive SSA test result is suggestive for a TSHoma even before positive findings become apparent on pituitary imaging. However, studies including larger number of patients, especially those with RTHß, are needed to confirm our findings.