The biochemical signature that defines resistance to thyroid hormone beta—a simultaneous rise in free thyroxine and free triiodothyronine with a thyroid-stimulating hormone level that fails to suppress—represents a fundamental paradox for clinicians trained to interpret thyroid function tests through a simple feedback model. In healthy physiology, rising circulating thyroid hormones act on pituitary thyrotrophs to shut down TSH secretion, so the combination of high hormone levels and detectable TSH immediately signals that something is wrong with the feedback loop itself rather than with the thyroid gland. In RTHβ, the defect sits squarely at the level of the receptor: mutant THRβ molecules in the pituitary and hypothalamus respond poorly to circulating hormone, so the axis reads the hormonal milieu as insufficient and keeps secreting TSH, which in turn drives the thyroid to produce more hormone. The result is a chronic, often lifelong elevation of thyroid hormone levels that the body has, in a sense, chosen for itself.

The tissue-specific distribution of the two thyroid hormone receptor isoforms explains much of the clinical picture observed in the Polish cohort. Because THRβ is concentrated in the liver, hypothalamus, and pituitary, tissues governed by this isoform display relative resistance, whereas tissues dominated by THRα—the myocardium, skeletal muscle, central nervous system, and adipose tissue—remain fully sensitive to the elevated hormone levels circulating in these patients. This mosaic of sensitivity and resistance produces the characteristic tension in the phenotype: the heart, driven by THRα-expressing tissue, races as if the patient were hyperthyroid, while the pituitary behaves as if the patient were hypothyroid. Tachycardia, documented in nearly three quarters of the children in this series, is the most direct clinical expression of this discordance, and it is also the symptom most likely to mislead clinicians toward an incorrect diagnosis of thyrotoxicosis.

The lean phenotype observed in more than half of the cohort deserves particular attention in the context of pediatric growth and metabolism. Adipose tissue is rich in THRα, which remains responsive to the elevated thyroid hormone levels, promoting increased lipolysis and energy expenditure. Children with RTHβ therefore often struggle to gain weight despite adequate intake, and a body mass index below the tenth percentile was recorded in 53 percent of the patients studied. This growth pattern can be mistaken for the weight loss of genuine hyperthyroidism, but it can also be confused with other causes of failure to thrive, prompting extensive and unnecessary gastrointestinal, endocrine, or nutritional work-ups. Height, by contrast, showed remarkable variability in the series, with height standard deviation scores ranging from well below the mean to well above it, including one child with tall stature defined as a height SDS above plus two. This variability underscores that linear growth in RTHβ is not reliably accelerated, contrary to what might be expected if the disorder were simply equated with thyroid hormone excess.

Neurodevelopmental disturbances, present in 60 percent of the children, represent perhaps the most consequential dimension of the syndrome for families and long-term outcomes. The spectrum observed in this cohort ranged from psychomotor hyperactivity and attention deficit-hyperactivity disorder to autism spectrum disorder, psychomotor delay, and speech delay. The overlap between RTHβ and common neurodevelopmental diagnoses creates a substantial risk that the underlying endocrine disorder will be missed entirely, with the child receiving treatment for ADHD or an autism spectrum condition while the thyroid abnormality goes unrecognized or, worse, is treated inappropriately. The central nervous system expresses both receptor isoforms, and the relative contribution of THRα-mediated thyroid hormone excess versus THRβ-mediated resistance to the neurobehavioral phenotype remains an area of active investigation. What is clear from clinical experience is that the neurodevelopmental burden in RTHβ is real, heterogeneous, and frequently the presenting concern that brings a child to medical attention.

The finding that 20 percent of the children in this series had been misdiagnosed with primary hyperthyroidism before the correct diagnosis was established illustrates a persistent and dangerous diagnostic trap. In primary hyperthyroidism, such as Graves disease in children, elevated thyroid hormones suppress TSH, and treatment with antithyroid drugs aims to reduce hormone production. Applying this logic to a child with RTHβ is physiologically backwards: the elevated hormones in RTHβ are the pituitary’s compensatory response to receptor resistance, and suppressing the thyroid gland pushes hormone levels toward the low range in tissues that are already receiving adequate or excessive stimulation. Children misdiagnosed in this way may receive antithyroid medication, radioiodine, or even surgical consideration for a disorder that in most cases requires no pharmacological intervention at all. The less common alternative misdiagnosis, a TSH-secreting pituitary adenoma, carries its own hazards, potentially triggering pituitary imaging, invasive testing, and neurosurgical consultation for a condition that is genetic and peripheral rather than tumoral.

Distinguishing RTHβ from a TSH-secreting adenoma has traditionally relied on a combination of clinical clues and biochemical patterns. The adenoma typically presents with a mass effect, elevated TSH that does not respond normally to thyrotropin-releasing hormone stimulation, and a molar ratio of alpha subunit to TSH that is elevated, whereas RTHβ shows a preserved alpha subunit ratio and, crucially, a family history of similar biochemical abnormalities in the absence of pituitary pathology. The identification of a heterozygous THRB variant by Sanger sequencing or targeted next-generation sequencing panels, as performed in this multicenter series, provides definitive confirmation. Variant classification followed the American College of Medical Genetics and Genomics and Association for Molecular Pathology 2015 guidelines, with interpretation supported by databases such as ClinVar and HGMD, and all variants annotated according to the MANE Select transcript for THRB. This rigorous, standardized approach to variant interpretation is essential in a disorder where the clinical presentation alone is insufficient to establish the diagnosis.

The genetic architecture of RTHβ adds an important dimension to family counseling. Because the disorder is typically inherited in an autosomal dominant fashion, the identification of an affected child should prompt evaluation of parents and siblings, both for the biochemical pattern and, where indicated, for the familial variant. Many adults with RTHβ have never been diagnosed, having lived with elevated thyroid hormone levels and nonsuppressed TSH that were dismissed as laboratory error or attributed to assay interference. Documenting the familial pattern not only clarifies inheritance for the family but also protects relatives from the same cascade of inappropriate treatment that affected the proband. In the present series, family medical history was collected as part of the retrospective data gathering, reflecting the recognition that RTHβ is a familial condition in the majority of cases, even when the family history appears negative because of under-recognition in previous generations.

The management conclusions drawn from this cohort are strikingly conservative and represent an important corrective to the interventional reflex that thyroid hormone excess usually provokes. Most of the fifteen children required no pharmacological treatment whatsoever, and those who did were managed with beta-blockers alone for symptomatic control of tachycardia. This approach acknowledges the physiological reality of the disorder: the elevated hormone levels are not pathological in the usual sense but represent the set point at which the pituitary achieves feedback equilibrium given the receptor defect. Beta-blockade addresses the THRα-mediated cardiac sensitivity directly, slowing the heart rate without disturbing the thyroid axis. Antithyroid drugs, by contrast, risk inducing a state of relative tissue hypothyroidism in THRβ-dominant tissues such as the liver, where hormone action is already impaired, potentially worsening metabolic parameters without providing meaningful symptomatic benefit.

The multicenter design of this study, drawing patients from nine pediatric endocrinology centers across Poland through the collaborative initiative of the Young Members Club of the Polish Society for Pediatric Endocrinology and Diabetology, offers a methodological advantage over single-center reports in a disorder this rare. Case ascertainment relied on clinicians consulting colleagues and reviewing records over approximately two years, collated in a shared spreadsheet rather than a formal registry. While this approach may miss undiagnosed cases in the community, it captures the real-world diagnostic experience of children who came to specialist attention, which is precisely the population in whom clinical awareness matters most. The retrospective design, with data drawn from routine clinical records and interpreted using age- and laboratory-specific reference ranges, mirrors the conditions under which most clinicians will encounter these patients, enhancing the practical relevance of the findings.

Certain limitations inherent to the study design warrant consideration when generalizing its conclusions. The cohort of fifteen children, while substantial for a disorder of this rarity, remains small, and no inferential statistical analyses were performed, meaning that the reported frequencies describe this particular group rather than establishing population-level estimates. Growth data were interpreted using WHO standards for children under five and Polish national reference charts for older children, which is appropriate for a Polish cohort but requires caution when applying the percentile findings to populations with different anthropometric baselines. The assessment of neurodevelopmental disorders depended on the availability of neurological, psychological, or psychiatric consultation records, introducing the possibility that milder disturbances were undercounted in children who had never undergone formal evaluation. These constraints do not undermine the central message of the study but do counsel against treating the reported percentages as definitive prevalence figures for the broader RTHβ population.

The age range at diagnosis in this series, spanning from one year to twelve and a half years with a median of 7.42 years, illustrates the variable routes by which children with RTHβ come to clinical attention. Some are identified in infancy, perhaps during evaluation of tachycardia, failure to thrive, or early developmental concerns, while others reach school age before the combination of hyperactivity, lean body habitus, and an abnormal thyroid function panel prompts definitive testing. The delay between the onset of symptoms and diagnosis is a recurring theme in rare endocrine disorders, and RTHβ is no exception. Every year spent under an incorrect diagnosis of hyperthyroidism, ADHD alone, or an unexplained metabolic state represents a year of potentially inappropriate treatment and missed opportunities for appropriate surveillance of growth, cardiac function, and neurodevelopment.

For the practicing pediatrician or pediatric endocrinologist, the practical lessons from this series can be distilled into a few principles grounded in the evidence presented. When a child presents with elevated free thyroxine and free triiodothyronine alongside a detectable, non-suppressed TSH, the first interpretive step should be to consider resistance to thyroid hormone rather than primary hyperthyroidism, and the second should be to obtain a family history and, where feasible, parental thyroid function tests. Measurement of thyroid antibodies, careful neck examination for goitre, and assessment of resting heart rate against age-specific norms all contribute to the clinical picture. Genetic confirmation through THRB sequencing, classified according to ACMG/AMP guidelines, remains the diagnostic gold standard and should be pursued before any decision to treat is made. Once the diagnosis is established, the default posture should be watchful waiting, reserving beta-blockade for children whose tachycardia is symptomatic, and avoiding antithyroid medication unless compelling evidence of genuine tissue thyrotoxicosis emerges.

The broader significance of this Polish multicenter series lies in its demonstration that pediatric RTHβ, while biochemically uniform, is clinically heterogeneous enough to defeat pattern recognition in most non-specialist settings. The consistent finding of elevated thyroid hormones with non-suppressed TSH across all fifteen patients confirms the reliability of this biochemical signature as a screening trigger, while the wide variation in growth parameters, cardiac findings, goitre status, and neurodevelopmental outcomes confirms that no single clinical presentation defines the syndrome. Raising awareness among clinicians who encounter children with thyroid function test anomalies, behavioral concerns, or unexplained leanness is the most effective available strategy for shortening the diagnostic odyssey, preventing iatrogenic harm from inappropriate antithyroid therapy, and ensuring that affected children and their families receive accurate genetic counseling and appropriately conservative long-term management.

Subject of Research: …

Article Title: Clinical manifestations of resistance to thyroid hormone beta (RTHβ) syndrome in children – multicenter case series

Article References: Fedorczak, A., Sokół, M., Beń-Skowronek, I., Mierzwa, M., Zachurzok, A., Bogusz-Wójcik, A., Przybylak-Ortega, J., Moszczyńska, E., Berezowiec, P., Bossowski, A., Dąbek, N., Mazur, A., Dyrka, K., Niedziela, M., Makowiecka-Wołek, M., Śmigiel, R., Ulenberg, A., Myśliwiec, M., & Stawerska, R. (2026). Clinical manifestations of resistance to thyroid hormone beta (RTHβ) syndrome in children – multicenter case series. Frontiers in Endocrinology, 17, Article 1972541. https://doi.org/10.3389/fendo.2026.1972541

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1972541

Keywords: resistance to thyroid hormone beta, RTHβ, THRB gene, pediatric endocrinology, thyroid hormone receptors, genetic diagnosis, TRIAC, bromocriptine, misdiagnosis, rare disease, Clinical, manifestations