Central hyperthyroidism, characterized by elevated thyroid hormone levels with a nonsuppressed thyroid-stimulating hormone (TSH), presents a diagnostic challenge in distinguishing thyroid hormone resistance (RTH) from a TSH-secreting pituitary adenoma (TSHoma). We report a 56-year-old man with a history of atrial fibrillation, obesity, and obstructive sleep apnea who was referred to our center with a prior diagnosis of RTH made elsewhere. Laboratory testing revealed elevated free T4 (2.2 ng/dL) and total T3 (234 ng/dL) with an inappropriately normal TSH (3.1 μIU/mL). Thyrotropin receptor antibody was negative, and radioactive iodine uptake was diffusely elevated. Pituitary magnetic resonance imaging demonstrated a 6 × 9 × 9 mm pituitary microadenoma, initially raising suspicion for TSHoma. However, a preserved TSH response to thyrotropin-releasing hormone stimulation, partial TSH suppression with high-dose T3, normal TSH α-subunit and sex hormone-binding globulin levels, and a pathogenic thyroid hormone receptor beta gene mutation all supported the diagnosis of RTH. Despite these findings, the patient underwent transsphenoidal pituitary surgery, and histopathology confirmed a plurihormonal PIT-1 lineage adenoma positive for TSH, growth hormone, and prolactin. Postoperatively, the patient recovered well and was discharged home. With postoperative normalization of TSH and free T4, it is conceivable that the pituitary tumor contributed to the TSH elevation, suggesting the possibility of dual pathology-concomitant TSHoma and RTH. This case highlights the diagnostic dilemmas and overlapping features of RTH and TSHoma, emphasizing the need for comprehensive hormonal testing and genetic confirmation to avoid unnecessary surgery.

Thyroid hormones (THs, namely T3 and T4) regulate intestinal development and homeostasis via thyroid hormone nuclear receptors (TRs), which are T3-modulated transcription factors. Previous work has highlighted the importance of THs and the TRα1 receptor in intestinal stem cell biology and tumor formation, through actions on WNT, NOTCH, and BMP signaling pathways, which mediate epithelial-stromal cell interactions. Recent findings underscore the critical role of stromal cells in maintaining homeostasis and interacting with colonic stem cells. Stromal cells, especially cancer-associated fibroblasts (CAFs), are also essential in colorectal cancer (CRC). While the TH/TR signaling on gut epithelia-stromal interactions is well characterized in amphibians during the TH-dependent metamorphosis process, its function in the normal mammalian colon is still poorly defined, and in CRCs, it remains underexplored. In addition, it is worth underlining that TRα1 mutations in patients are responsible for Resistance to Thyroid Hormone-α (RTH-α) syndrome. This syndrome is a complex pathology that recapitulates typical traits of hypothyroidism, including gut malfunction. Up to now, very little is known about the cellular alterations in the gut of RTH-α patients. This review summarizes recent studies on the roles of T3 and TRα1 in colon physiopathology, with an emphasis on epithelial/stromal or tumor/stromal interactions via cell-cell signaling.

Resistance to thyroid hormone (RTH) is a rare genetic disorder caused by mutations in the thyroid hormone receptors α or β (THRα, THRβ) genes, leading to impaired tissue responsiveness to thyroid hormones. While its systemic effects are well-documented, the cardiac manifestations of RTH, including hypertrophic and dilated cardiomyopathy (DCM), arrhythmias, and heart failure, are often underrecognized, particularly in cases of treatment refractory heart failure. This case report aims to highlight the importance of cardiological awareness in diagnosing and managing RTH-related cardiomyopathy. We report the case of a 50-year-old Caucasian female with a confirmed variant c.1357C > A, p.P453T mutation in the THRβ gene, presenting with recurrent goitre, hypothyroidism, and progressive cardiovascular complications. Her clinical course was marked by episodes of angina-like symptoms, atrial fibrillation, left heart failure, and severe pulmonary oedema, eventually progressing to DCM with an ejection fraction below 30%. Despite optimal guideline-directed medical therapy, her cardiac condition deteriorated, necessitating orthotopic heart transplantation. Genetic testing confirmed the same mutation in her mother, brother, and two sons, highlighting the autosomal dominant inheritance of the disease. Thyroidectomy and lifelong levothyroxine therapy, combined with post-transplant immunosuppression, further complicated her management, underscoring the systemic interplay of RTH with cardiac function. This case emphasizes the rarity and clinical significance of RTH as a potential aetiology in refractory cardiac failure. Cardiologists should maintain a high index of suspicion for thyroid dysfunction in unexplained or treatment-resistant cardiomyopathy, particularly when associated with familial thyroid disorders or arrhythmias. Early diagnosis and a multidisciplinary approach involving endocrinology and cardiology are essential for improving outcomes and tailored therapeutic strategies for patients with RTH-related cardiomyopathy.

Background: A finely tuned balance between excitation and inhibition is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders. Understanding GABAergic neuron maturation processes is thus currently a major challenge in basic neuroscience. Thyroid hormones (THs) are required for the proper maturation of parvalbumin (PV)-expressing GABAergic interneurons in the mouse neocortex. However, the timeline of this TH action has yet to be elucidated. The aim of the present study was to define better the time window during which THs promote the postnatal maturation of PV neurons in the mouse neocortex. Methods: We used genetically engineered mouse models expressing dominant-negative mutations of the TH nuclear receptor α1 (TRα1). The consequences of blocking TH signaling at different times in development were assessed in PV neurons of the somatosensory cortex, in terms of histology and gene expression. Results: Histological observations in mice revealed that the action of THs during the first three postnatal weeks was necessary to initiate the expression of PV and the elaboration of a specialized extracellular matrix called the perineuronal net (PNN). By contrast, after the third postnatal week, TH action on PV neuron maturation appeared to be somewhat dispensable. Transcriptome analysis of neocortical GABAergic neurons two weeks after birth identified a small set of putative target genes for TRα1. Several of these genes are involved in the postnatal remodeling of the repertoire of ion channels within PV neurons and in the elaboration of PNNs. Conclusions: These data suggest that THs act as a timer to define the temporal boundaries of the critical period of heightened cortical plasticity, which plays a fundamental role in the development of neuronal circuits. Unveiling the molecular underpinnings of TH action in PV neurons may help understand better neurological disorders associated with alterations of TH signaling, such as hypothyroidism, resistance to THs, or Allan-Herndon-Dudley syndrome, but also more widely, neurological disorders associated with an imbalance in the excitation/inhibition ratio in the brain, including attention-deficit/hyperactivity disorder, autism, and epilepsy.

Thyroid hormone resistance (THR) syndrome is characterized by decreased sensitivity of peripheral tissues to active forms of thyroid hormones. We present a clinical case of a patient, demonstrating symptoms of hypothyroidism while having subnormal FT4 and normal TSH and total T3 levels. Massive parallel sequencing allowed us to identify a previously undescribed heterozygous THRA c.1198C>G (p.Leu400Val) variant that arose de novo. The results of genetic testing corresponded well with the patient's phenotype that made it possible to verify the diagnosis of THR. Levothyroxine replacement therapy did not resulted in a significant clinical improvement; the use of supraphysiological doses led to refinement of the lipid profile but was accompanied by the appearance of some symptoms of thyrotoxicosis. Синдром резистентности к тиреоидным гормонам (СРТГ) характеризуется пониженной чувствительностью периферических тканей к активным формам тиреоидных гормонов. В данной статье описан клинический случай пациента с симптомами гипотиреоза, но с низконормальным уровнем свТ4 при нормальных ТТГ и общего Т3. Использование метода массового параллельного секвенирования позволило выявить ранее не описанный гетерозиготный вариант в гене THRA c.1198C>G (p.Leu400Val). Сопоставление результатов молекулярно-генетического исследования и фенотипа пациента позволило верифицировать диагноз: «СРТГ типа α». Данный клинический случай является первым описанием этой патологии в России. Заместительная терапия левотироксином не сопровождалась значимым улучшением клинической картины, а использование супрафизиологических доз привело к улучшению липидограммы, однако сопровождалось появлением некоторых симптомов тиреотоксикоза.