[Clinical characteristics of thyroid hormone resistance syndrome in two cases with different subtypes].

Objective: To analyze the clinical characteristics of children with two types of thyroid hormone resistance (RTH) syndrome, and to detect the variants of thyroid hormone receptor alpha(TRα) and TRß gene in children. Method: Two children with RTH were reported in regard to clinical manifestation, laboratory examination and genetic variants. Some related reports in literature were reviewed. Result: Case 1 was a girl, 10 years old, with thyroid enlargement for several days and without thyrotoxicosis. Laboratory work-up revealed that free thyroxine (FT(4)) was 65.77 pmol/L (reference 12-22) , free triiodothyronine (FT(3)) was 15.36 pmol/L (reference 3.1-6.8) and thyroid stimulating hormone (TSH) level was normal. There was a likely pathogenic missense variant detected in TRß gene and this patient was diagnosed with RTHß. Case 2 was a boy, 3 years old, with classic features of hypothyroidism(growth retardation, developmental retardation, skeletal dysplasia) but had only borderline-abnormal thyroid hormone levels. Targeted sequencing showed a de novo heterozygous nonsense variant in TRα gene which is a pathogenic variant and this patient been diagnosed with RTHα. Conclusion: Thyroid enlargement is a common clinical manifestation of RTHß, with laboratory work-up reveals elevated FT(4) and FT(3) levels but TSH level is normal. The clinical manifestations of RTHα are similar to those of hypothyroidism, but the thyroid hormone levels are almost normal. The gene sequence and the pathogenicity analysis for TRα and TRß will help to make a definitive diagnosis.

TRα receptor mutations extend the spectrum of syndromes of reduced sensitivity to thyroid hormone.

Since 2012, eight different abnormalities have been described in the THRA gene (encoding the TRα1 thyroid hormone receptor) of 14 patients from 9 families. These mutations induce a clinical phenotype (resistance to thyroid hormone type α) associating symptoms of untreated mild congenital hypothyroidism and a near-normal range of free and total thyroid hormones and TSH (the T4/T3 ratio is nevertheless usually low). The phenotype can diversely include short stature (due to growth retardation), dysmorphic syndrome (face and limb extremities), psychoneuromotor disorders, constipation and bradycardia. The identified genetic abnormalities are located within the ligand-binding domain and result in defective T3 binding, an abnormally strong interaction with corepressors and a dominant negative activity against still functional receptors. The identification of patients with consistent phenotypes and the underlying mutations are warranted to better delineate the spectrum of the syndromes of reduced sensitivity to thyroid hormone.

Resistance to thyroid hormone due to defective thyroid receptor alpha.

Thyroid hormones act via nuclear receptors (TRα1, TRß1, TRß2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated.

Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1).

Mutations in the ligand-binding domain of the thyroid hormone receptor ß (TRß) lead to resistance to thyroid hormone (RTH). These TRß mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRß mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed Thrb(PV) mice (a model of RTH) expressing a human TRß mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1(ΔID) mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1ΔID, the abnormally elevated thyroid-stimulating hormone and TH levels found in Thrb(PV) mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1ΔID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRß mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.

A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome / Uma nova mutação no TR beta (I431V) prejudica a liberação de correpressores e induz síndrome de resistência ao hormônio tireoideano

Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). We describe a large Brazilian family harboring a novel mutation affecting TRβ gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRβ gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRβ, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.

A resistência ao hormônio tireoideano (RHT) é uma doença rara, causada por variável hiporresponsividade dos tecidos aos hormônios tireoideanos, usualmente causada por mutações no receptor beta do hormônio tireoideano (TRβ). Descrevemos uma grande família brasileira portadora de uma nova mutação afetando o gene do TRβ, induzindo RHT. Uma paciente de 14 anos de idade apresentou concentrações plasmáticas elevadas de T4 e T3 livres, associadas a TSH não-suprimido e bócio questionável. O diagnóstico de RHT foi estabelecido pela identificação da mutação I431V no gene do TRβ. Dezesseis parentes assintomáticos da probanda também são afetados pela mutação. Estudos funcionais mostram que a mutação I431V exerce efeito dominante negativo sobre o TR selvagem, basicamente, por prejudicar a liberação do correpressor SMRT ligante-dependente. A presença desta mutação reduz a potência, mas não afeta a eficácia da ação do hormônio tireoideano, o que está de acordo com a apresentação clínica de eumetabolismo dos indivíduos afetados.

Pituitary resistance to thyroid hormone syndrome is associated with T3 receptor mutants that selectively impair beta2 isoform function.

Resistance to thyroid hormone (RTH) syndrome is an inherited inability to respond appropriately to T3 hormone. In generalized RTH, the T3 response of both the pituitary and periphery is disrupted. In pituitary (or central) RTH, the ability of the pituitary to sense (and down-regulate) elevated T3 is selectively impaired, whereas the periphery remains relatively T3 responsive, resulting in peripheral thyrotoxicity. Both forms of disease are linked to mutations in thyroid hormone receptor (TR)-beta. TRbeta is expressed by alternate mRNA splicing as two isoforms: TRbeta2, found primarily in the pituitary/hypothalamus, and TRbeta1, expressed broadly in many tissues. We report here that the wild-type TRbeta2 isoform displays an enhanced T3 response relative to the TRbeta1 isoform. Mutations associated with generalized RTH (P453S, G345S) impair both TRbeta2 and TRbeta1 function proportionally, whereas mutations associated with pituitary-specific RTH (R338L, R338W, R429Q) disproportionately disrupt TRbeta2 function. We propose that in the normal organism, and in generalized RTH, TRbeta2 in the pituitary can sense rising T3 levels in advance of TRbeta1 in the periphery, preventing thyrotoxicity. In contrast, the TRbeta mutations associated with pituitary RTH disproportionately disrupt the pituitary's ability to sense and suppress elevated T3 levels in advance of the periphery, producing symptoms of thyrotoxicity.

Thyroid hormone resistance and enlargement of the sella turcica during pregnancy.

CASE REPORT: A 26-year-old pregnant woman was admitted to our institution running her 30 weeks of gestation. The patient had a past history of total thyroidectomy cause of a thyroid papillary carcinoma and presented with increased supraphysiological TSH levels under 250 microg T4, while slightly hyperthyroid, from the clinical point of view. Partial resistance to thyroid replacement therapy or TSH-secreting tumour was evoked. Pituitary MRI revealed a pituitary enlargement without excluding a pituitary adenoma. To avoid further stress on pituitary a caesarean section was performed at 38 weeks of gestation. MRI 7 months later was normal, while the patient remained under high doses of T4 replacement therapy and TSH was found at the upper limits of normalcy, while T3, T4 and FTI were above normalcy. CONCLUSION: We conclude that, in the absence of thyroid gland, high TSH levels due to thyroid hormone resistance could be erroneously attributed to a pituitary TSH secreting tumour, when associated with a pregnancy-related pituitary enlargement.

Genetic analyses and evaluation of peripheral parameters of thyroid hormone action for the differential diagnosis of RTH. A novel heterozygous missense mutation (M334T) discovered.

Resistance to thyroid hormone (RTH) is a rare disease characterized by goiter and elevated free thyroid hormone (TH) levels in the presence of detectable concentrations of TSH. Most RTH patients harbor mutations in the ligand binding domain (LBD) of thyroid hormone receptor beta (TRbeta) gene, without a clear correlation between genotype and phenotype. Clinical, biochemical and genetic analyses were performed in several members of one family, because the index case presented with elevated free TH, measurable TSH and no hyperthyroid manifestations, but with a pituitary lesion at MRI. High free TH levels and TSH concentrations in the normal range were found also in 4 relatives. The presence of euthyroidism in all patients together with peripheral parameters of TH action in the normal range led to the diagnosis of generalized RTH (GRTH). In the five affected members, the genetic analysis revealed a novel heterozygous missense mutation at codon 334 (M334T). A different mutation at codon 334 was previously described in association with selective pituitary resistance to thyroid hormone (PRTH). Therefore, we confirm that substitutions at Methionine 334 are critical for the structural integrity of TRbeta LBD. The association of different phenotypes with substitutions affecting the same codon is another contribution confirming that RTH phenotype does not generally depend upon the site of the mutation in the LBD of TRbeta1.