Generalized Thyroid Hormone Resistance Research Articles

SUN-594 Skeletal Dysplasia and Growth Failure in Congenital Hypothyroidism Due to a Novel Form of Generalized Thyroid Hormone Resistance

Background: Thyroid hormone exerts systemic actions mediated by its specific receptors. These actions encompass a wide array of functions, including energy homeostasis, skeletal growth, neural development, cardiac function, and gastrointestinal function. There are two thyroid hormone receptors, thyroid hormone receptor alpha (THRA) and thyroid hormone receptor beta (THRB) which are encoded by genes on two different chromosomes and with differing tissue distributions. Only mutations in THRB were known until recently with a reported incidence of 1 in ~40,000. Mutations in thyroid receptor THRA have recently been discovered and are exceedingly rare, with 14 cases documented in the past five years. We report a case of a patient with generalized thyroid hormone resistance due to THRA mutation. Clinical Case: Patient was born to non-consanguineous parents at term and was appropriate for gestational age. Prenatal ultrasound was suspect for shortened long bones. Congenital heart disease (ASD and VSD) were detected at birth. Genetics consultation confirmed ultrasound concern with finding of mild rhizomelia. Patient had coarse facial features, macroglossia, and dysmorphic appearance. Initial genetics work-up showed normal chromosomes, normal newborn screening, and normal metabolic studies. Genetics was concerned for possible mucopolysaccharidosis, but further testing ordered did not confirm this diagnosis. Patient exhibited post-natal growth failure after birth with length well below 3rd percentile by 18 months old. Delayed developmental milestones (verbal > motor) were noted. Thyroid function tests between birth and 11 months old were normal. Thyroid function testing at 11 months old were suspect for central hypothyroidism with free T4 0.6 ng/dl (0.6-1.3) and TSH 1.07 uIU/ml (0.71-5.81). Cranial MRI scan showed no abnormalities in hypothalamic-pituitary area. Levothyroxine 37.5 mcg was started, and thyroid function tests normalized. However, little change was seen clinically in patient’s growth pattern or development. Whole exome screening performed in 2013 demonstrated a heterozygous mutation in the THRA gene consistent with generalized thyroid hormone resistance from this mutation. Liothyronine treatment was added in 2014. Growth has continued to be extremely slow with current height standard deviation score of -4.2. Patient is developmentally delayed and non-verbal. Conclusions: A constellation of findings including post-natal growth failure, skeletal findings, and prominent verbal developmental delays are seen in generalized thyroid hormone resistance due to THRA mutation. The subtle presentation of this condition is different from congenital hypothyroidism or generalized thyroid hormone resistance due to THRB mutation. Presentation of this case will hopefully help pediatric specialist to recognize and test for this condition more promptly.

A Newly Identified Insertion Mutation in the Thyroid Hormone Receptor-β Gene in a Korean Family with Generalized Thyroid Hormone Resistance

Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-β (THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.

Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR-coupled automated direct sequencing of genomic DNA: detection of two novel mutations.

Generalized thyroid hormone resistance (GTHR) is a syndrome characterized by tissue nonresponsiveness to thyroid hormones and by variable clinical phenotype manifestations. This syndrome has also been implicated as a predisposing factor in some cases of attention deficit-hyperactivity disorder (ADHD). GTHR results from single mutations in the gene encoding the thyroid hormone receptor. These mutations are clustered in two major sites surrounding the ligand-binding domain. Mutations in 10 previously described patients as well as in five new THR cases have been identified using PCR amplification of genomic DNA coupled with automated direct sequencing with commercially available "universal" fluorescent dye-labeled primers. This strategy allows for the accurate and automated base-calling of normal and mutated nucleotides at the same position in a heterozygote. The rapid molecular diagnostic protocol, from whole blood to DNA sequence data, takes approximately 15 hr, allowing for rapid, efficient, and unambiguous direct detection of the mutant alleles.

Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR‐coupled automated direct sequencing of genomic DNA: Detection of two novel mutations

Rapid molecular diagnosis of mutations associated with generalized thyroid hormone resistance by PCR‐coupled automated direct sequencing of genomic DNA: Detection of two novel mutations

Thyroid hormone receptor homodimers can function as ligand-sensitive repressors.

Unlike the steroid hormone receptors that bind their response elements as homodimers, thyroid hormone receptor (TRs) as well as retinoic acid receptors and several other receptors have been shown to require heterodimerization with retinoid X receptors (RXR) for efficient binding to most response elements. In this article we have compared in detail TR DNA binding and its gene-regulatory characteristics in the presence and absence of RXR. We observe that in the absence of RXR, TRs are able to bind with high affinity as homodimers to a subset of thyroid hormone response elements consisting of two AGGTCA motifs arranged as inverted palindromes. This binding is inhibited by T3, which prevents TR homodimers from functioning as ligand-dependent transcriptional activators. We demonstrate that TR homodimers can act as potent ligand-responsive repressors, in particular when binding to sites 3' of the TATA box. Thus, TRs appear to have important regulatory functions in the absence of RXRs. This is strongly supported by our observations that some naturally occurring TR beta mutants that have been associated with generalized thyroid hormone resistance as well as the v-erbA oncogene are defective in this activity. Thus ligand-sensitive repression by TRs is an important regulatory mechanism.

Analysis of the binding of 3,3',5-triiodo-L-thyronine and its analogues to mutant human beta 1 thyroid hormone receptors: a model of the hormone binding site.

To understand the nature of the thyroid hormone binding site, we characterized the binding of 3,3',5-triiodo-L-thyronine (T3) and its analogues to eight naturally occurring mutated human beta 1 thyroid hormone receptors (h-TR beta 1). The mutant receptors were derived from patients with the syndrome of generalized thyroid hormone resistance, and each has a point mutation in the hormone binding domain (KT, R338W; TP, L450H; IR, D322H; NN, G347E; AH, P453H; OK, M442V; RL, F459C; and ED, A317T). Compared to the wild-type h-TR beta 1, binding of T3 was reduced by as much as 97% for the mutants. The order of binding affinity of wild-type h-TR beta 1 to the analogues is T3 > D-T3 > L-thyroxine > 3,5-diiodo-L-thyronine > 3,3',5'-triiodo-L-thyronine. The mutant receptors showed essentially the same order of reduced affinities for the analogues, but the amounts of the reductions varied in each case. These results suggest specific local interactions (interplay) of analogues with the mutated residues in the receptors. On the basis of these data and a putative structure of the hormone binding domains as an eight-stranded alpha/beta barrel, we propose the location of the hormone in the binding site of h-TR beta 1. Ionic bonds anchor the hormone's alanine side chain to loop 4 of the 8-fold alpha/beta barrel. The phenyl ring lies across the amino-terminal face of the domain with the phenoxy ring pointing downward into the barrel interacting with beta-strand 8 on the opposite side.(ABSTRACT TRUNCATED AT 250 WORDS)

Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA β receptor

Generalized resistance to thyroid hormone (GRTH) is a disorder of thyroid hormone action which has been linked to the β thyroid hormone receptor (TRβ) gene. A diverse array of TRβ mutations have been characterized, and these distinct genotypes have been associated with characteristic patterns of severity and tissue distribution of clinical thyroid resistance. In this report, we describe a patient with GRTH caused by a single C → A base mutation (nucleotide 1623) in one allele of TRβ (exon 10). The mutation produces a premature translation termination signal (UGA) at codon 446 and predicts expression of a mutant TRβ3 which is truncated by 16 carboxylerminal amino acids (TRβ ▴446–461). This sequence was absent in both parents, indicative of a de novo mutation in the proband. To our knowledge, this case represents the first description of a mutation producing premature translation termination of TRβ in association with the syndrome GRTH, and emphasizes the critical role of the carboxyl terminal region of TRβ in mediating both positive and negative regulation of thyroid-responsive target genes in many tissues.

Developmental regulation of the thyroid hormone receptor alpha 1 mRNA expression in the rat testis.

The multiplicity of thyroid hormone (TH) effects appears to be mediated by two TH receptors (THRs) encoded by two genes, alpha and beta, and, perhaps, by their various isoforms. The expression of THR beta is correlated with the presence of high affinity binding sites for TH, and all the mutations which cause the syndrome of generalized thyroid hormone resistance occur in THR beta. The function of THR alpha has not been clearly defined as yet. Another enigma in TH action is the effect on the testis. It has been shown that the testis of the adult rat does not respond to TH as measured by an increase in oxygen consumption. Furthermore, it has not been possible to demonstrate the presence of a nuclear high affinity binding site for TH in adult testis. To resolve these problems were measured the levels of THR alpha, its nonhormone binding variant, and THR beta mRNA in the testis at various stages of development. We discovered that the beta-message is absent at all times, whereas the alpha-message is expressed only from fetal through prepubertal stages and is absent in adult testis. THR alpha, but not the beta-mRNA, was detected in immature Sertoli cells in culture, and neither was found in adult Sertoli cell-enriched cultures. Furthermore, THR alpha and its variant mRNA was found, using in situ hybridization, in the seminiferous cords and seminiferous tubules of fetal and prepubertal testis.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between phenotype and intra‐cellular thyroid hormone effect in patients with altered peripheral thyroid hormone sensitivity

We wished to ascertain whether different phenotypic appearances in patients with altered cellular sensitivity to thyroid hormones were related to the type of altered intra-cellular thyroid hormone effect. Blood samples were obtained from two members of a family suffering from generalized thyroid hormone resistance (GTHR) for hormone assays and examination of the cellular thyroid hormone effect, and the results compared with results from other families with signs of altered peripheral thyroid hormone sensitivity. Two members of a family with thyroid hormone resistance and nine normal persons were studied. Basal thyroid hormone function tests were measured. The thyroid hormone effect on mononuclear blood cells was determined by measuring the thyroid hormone stimulated oxygen consumption and glucose uptake. The two family members appeared phenotypically normal except for nodular goitre. Thyroid hormone stimulated glucose uptake was depressed whereas thyroid hormone stimulated oxygen consumption was normal. Comparison of the present results of the cellular examination in two patients with GTHR, with the results obtained in other families with altered peripheral thyroid hormone sensitivity, suggest that the classic GTHR (phenotype: normal or with goitre) is linked to impaired thyroid hormone stimulated glucose uptake, whereas in patients with osteopetrosis, the thyroid hormone insensitivity seems located at the mitochondrial level (impaired thyroid hormone stimulated oxygen consumption.

Identification of a novel mutation in the gene encoding the β‐triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone

We investigated whether the first patient (L-F3) reported as having selective pituitary resistance had a mutation in the hTR beta gene. We compared the clinical parameters of this case with those of patients with generalized resistance to thyroid hormone. The patient, L-F3, was part of a study at the NIH to identify mutations by sequencing the hTR beta gene in kindreds with thyroid hormone resistance. The clinical data of L-F3 as well as patients with generalized resistance to thyroid hormone were compared and analysed retrospectively. We amplified by the polymerase chain reaction and then sequenced exons 5 to 10 of the hTR beta gene in L-F3 and a normal control. Upon finding the mutation in L-F3, we measured the affinity constant of this mutated hTR beta receptor. Criteria developed previously were used to assess tissue responsiveness to thyroid hormone of L-F3. We identified a C to T transition at base 1297 in codon 333 of the hTR beta gene in the first patient (L-F3) reported as having apparent selective pituitary resistance. This base substitution resulted in more than a four-fold decrease in T3-binding affinity for the hTR beta 1 receptor. The mutation of L-F3 occurred in the dimerization domain of exon 9, a region where the majority of mutations of kindreds with generalized thyroid hormone resistance have been found. Furthermore, the nucleotide substitution at base 1297 found in the apparent selective pituitary resistant case, L-F3, was the same as in an unrelated patient (K-T3) with generalized resistance to thyroid hormone. As a result, we compared the clinical parameters of both patients and found that they had similar patterns of resistance in several tissues. Besides the bone resistance present in both kindreds, the apparent selective pituitary resistance case also had liver and neuromuscular resistance. These findings suggest that apparent selective pituitary resistance and generalized resistance to thyroid hormone are not qualitatively different syndromes. Nevertheless, identification of selective pituitary resistance is a useful clinical distinction since such patients with clinical and biochemical features of hyperthyroidism appear to benefit from reduction in serum thyroid hormone concentrations. In contrast, patients with more conventional forms of thyroid hormone resistance require no treatment or may benefit from increased concentrations of thyroid hormone.

Urinary Cortisol Metabolites in the Assessment of Peripheral Thyroid Hormone Action: Application for Diagnosis of Resistance to Thyroid Hormone

Urinary cortisol metabolites are altered both quantitatively and qualitatively in thyroid dysfunction. This study was conducted to elucidate the usefulness of urinary cortisol metabolites in the assessment of peripheral thyroid hormone action, particularly in the patients with inappropriate thyrotropin secretion. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) level and gas chromatographical steroid profile were studied in 25 hyperthyroid, 18 hypothyroid, and 24 euthyroid control subjects. Five patients with generalized thyroid hormone resistance and two patients with thyrotropin secreting pituitary tumor were also studied. The ratio of urinary tetrahydrocortisone to tetrahydrocortisol (THE/THF) was significantly elevated in hyperthyroidism (4.58 +/- 1.49) and depressed in hypothyroidism (1.31 +/- 0.55) compared to control (1.93 +/- 0.35). There were good correlations between THE/THF and serum thyroid hormone levels, especially in hypothyroidism. THE/THF can be a good biochemical indicator for deficiency of peripheral thyroid hormone action. Two patients with thyrotropin-secreting tumor showed high THE/THF, which reflected thyroid hormone excess. In contrast, THE/THF in the patients with generalized thyroid hormone resistance was low as compared to high serum thyroid hormone levels. Similar findings were demonstrated with 17-OHCS but discrimination of thyroid hormone resistance was insufficient. Thus, the ratio of the urinary concentrations of cortisol metabolites, THE/THF, appears to be a good marker for peripheral thyroid hormone resistance.

Spectrum of Serum Thyroglobulin Elevation in Congenital Thyroid Disorders

Serum thyroglobulin (Tg) data are presented for 47 infants with congenital thyroid disorders. Abnormal elevation of serum Tg (> 250 micrograms/L) occurred in 17% of the population studied, whereas values in excess of 1,000 micrograms/L were demonstrated in 11% of infants. The latter group includes the first report of supraphysiologic Tg elevation in an infant with thyroid gland ectopia, and the highest reported thyroglobulin level in the syndrome of generalized thyroid hormone resistance in an infant homozygous for a novel deletion in the c-erbA beta receptor. Mechanisms involved in the pathogenesis of Tg elevation are discussed. We conclude that Tg elevation in congenital thyroid disorders is more common than previously recognized, and values > 1,000 micrograms/L identify infants with a spectrum of anatomic and biochemical abnormalities.

Kindred S thyroid hormone receptor is an active and constitutive silencer and a repressor for thyroid hormone and retinoic acid responses.

Mutations in the gene encoding the human thyroid hormone receptor beta (hTR beta) have been associated with generalized thyroid hormone resistance (GTHR). However, the molecular basis by which the receptor mutants cause the clinical symptoms is largely unknown. We show here that the beta form of the human receptor possesses, in addition to hormone-dependent activation, the ability to repress basal-level activity of a target promoter. This silencing function is localized in the carboxyl-terminal part of the receptor and can be transferred to a heterologous DNA binding domain. This mode of silencing is therefore distinct from inhibition by competition with activator proteins on DNA. We show that two receptor mutants isolated from patients with GTHR are impaired in transcriptional activation but fully retain the silencing function, which enforces dominant negative regulation by the receptor. Interestingly, the kindred S receptor (hTR delta 332) acts as a constitutive repressor with a strong silencing ability similar to that of the v-erbA oncogene product. We also provide evidence for distinct transcriptional regulatory properties of both proteins. Finally, we show that both thyroid hormone- and retinoic acid-responsive genes are potentially repressed to generate the clinical manifestations of the GTHR syndrome. Our findings suggest that silencing plays an important role in the phenotypic expression of the symptoms in patients with GTHR.

Generalized thyroid hormone resistance: identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor.

The present report studies a large kindred (WR) with generalized thyroid hormone resistance that has varying degrees of neuropsychological dysfunction, hyperactivity, poor attention span, decreased IQ and/or abnormalities in spatial perception. In this kindred, there has been found tight linkage of the syndrome with the c-erb A beta gene. The present study was performed to identify the presence of a possible gene mutation as a cause for this syndrome. DNA from peripheral leukocytes was isolated from 15 unaffected and 8 affected individuals from the kindred. Primers encompassing exons 9 (nucleotides 1171-1429) and 10 (nucleotides 1430-1698) were synthesized and used in PCR reactions to amplify these exons. Direct sequencing revealed a consistent substitution in each affected subject, but in none of the unaffected individuals, of a C to T change in one allele from nucleotide 1243, resulting in an arg to cys change in codon 315. The mutant and wild-type human beta 1 receptors were prepared and their translated proteins were analyzed for T3 binding. The WR T3 receptor from affected patients had reduced T3 binding affinity, with values approximately 2.5 x 10(10) M-1 compared to about 5 x 10(10) M-1 in normals. In summary, we have: i) identified a consistent and reproducible mutation of a C to T change in nucleotide 1243 in each of the affected but in none of the unaffected individuals of a large well characterized kindred with generalized thyroid hormone resistance; and ii) noted that the WR allele causes an approximate 50% decrease in the T3 binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance.

Various point mutations in the c-erbA thyroid hormone receptor (TR) beta gene of unrelated kindreds have been reported to be responsible for different phenotypes of generalized thyroid hormone resistance. We now report a new point mutation, Td, in one of two TR beta alleles of three affected members of one family, designated family T. In contrast to the previously described point mutations, all located in the T3-binding domain of the TR beta gene, mutation Td was identified in the carboxy-terminal part of the hinge domain. Direct sequencing of the polymerase chain reaction-amplified whole coding region of the patients' fibroblast TR beta genes displayed a single guanine to adenine transition at cDNA nucleotide position 985. This altered alanine (GCC) to threonine (ACC) in codon 229. Garnier prediction of the consequence of the mutation indicated an altered secondary structure. The G----A nucleotide substitution was not present in 80 random TR beta alleles, suggesting that this point mutation is responsible for generalized thyroid hormone resistance in family T. The in vitro expressed mutant TR beta was shown to bind with high affinity to various thyroid hormone response elements. However, the affinity of the TR beta to bind to T3 was reduced 3-fold, indicating that the hinge domain of the TR beta is important for full ligand-binding activity. Moreover, it seems that multiple subdomains of the TR beta interact cooperatively to achieve optimal T3 activity.

A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance

A point mutation (Ala229 to Thr) in the hinge domain of the c-erbA beta thyroid hormone receptor gene in a family with generalized thyroid hormone resistance

Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome.

We wished to ascertain whether a mutation in the thyroid hormone receptor beta gene was present in a family with generalized thyroid hormone resistance syndrome and to characterize the functional properties of this mutant receptor. Blood samples were obtained from family members for hormone assays and genomic DNA was isolated from leucocytes for genetic analyses. Three members (B,C,E) of a family with possible thyroid hormone resistance and two normal family members (A,D) were studied. Basal thyroid function tests together with serum sex hormone binding globulin (SHBG) levels were measured. The thyroid hormone receptor beta gene was amplified using the polymerase chain reaction and the receptor mutation identified by sequence analysis. The ability of mutant receptor to bind T3, interact with a specific DNA sequence and to modulate target gene expression was tested. The effects of mutant receptor on co-expressed wild type receptor action were determined. Patients with resistance had raised levels of T4 and T3 together with inappropriately normal serum TSH and SHBG whereas unaffected individuals had a normal hormone profile. A single nucleotide substitution corresponding to a glycine to serine mutation at codon 340 (G340S) in the hormone binding domain was identified in one of the two beta receptor gene alleles in patients with resistance, but not in the normal family members. When expressed in vitro, this receptor protein (G340S), as well as a related (G340R) mutant identified in another family, retained the ability to bind to a specific DNA sequence but were unable to bind ligand or to activate or repress target gene expression. In addition both receptor mutants were capable of inhibiting the function of wild type thyroid hormone receptor in a co-expression assay but differed in their inhibitory potential. We report a second type of mutation (Gly to Ser) in codon 340 of hTR beta in a family with generalized thyroid hormone resistance. Mutations at this site eliminate T3 binding, causing a loss of hormone-stimulated receptor function. However, the mutant receptors retain the ability to block normal receptor action. The occurrence of different mutations at the same site suggests that alterations in this region of the receptor may be important for generating the clinical phenotype of this disorder.

The thyroid hormone receptors: molecular basis of thyroid hormone resistance.

Major progress has been achieved in the mechanism of action of thyroid hormones thanks to the identification of the T3 receptor as the product of the proto-oncogene c-erbA. Recognition of subsets of receptors with and without T3-binding properties and of the interaction of different receptors with each other leads to new insights in cell regulation and development. In thyroid hormone resistance, distinct mutations in the T3-binding domain of thyroid hormone receptor (TR)beta have been identified in unrelated families. No correlation between the type of mutation and tissue resistance has been established. Mutant TRs bind to thyroid hormone response elements (TREs) on both negative or positive T3-controlled genes. Subjects with heterozygous TR beta gene deletion are not affected, supporting the hypothesis that mutant TRs act through a dominant negative effect. In generalized thyroid hormone resistance, mutated TR beta may interfere through competition for TREs and/or formation of inactive dimers. Finally, deficiency in T3 receptor auxiliary protein or other accessory proteins or competition between mutant and normal TRs for these factors is not excluded.

Thyroid hormone generalized resistance.

The syndromes of thyroid hormone resistance may affect overall or only some tissues. The generalized resistance is an inherited disease which involves a familial eumetabolic or hypometabolic goiter, increased free thyroid hormones with normal or elevated plasma TSH levels; children may present mental retardation, deafness, short stature and delayed bone age. The disease is frequently misdiagnosed. In vivo and in vitro tests may be used to assess the diagnosis. The defect of increment of sex hormone-binding globulin after administration of T3 may be useful in the demonstration of the disease. Therapy uses high T4 or T3 doses in hypometabolic patients. The generalized thyroid hormone resistance could be linked to abnormalities at the T3 receptor and c-erb A gene level, as a consequence of different point mutations or deletions involving the hormone-binding domain.

Pituitary resistance to thyroid hormones.

Pituitary thyroid hormone resistance (PRTH) refers to a particular form of thyroid hormone refractoriness that is accompanied by peripheral hyperthyroidism, as only the TSH-secreting pituitary cells appear to be resistant to the effects of thyroid hormones. The presence of PRTH is suspected and diagnosed on the basis of the finding of high free thyroid hormone levels along with unsuppressed TSH, clinical signs and symptoms of hyperthyroidism and values of at least one of the parameters evaluating peripheral thyroid hormone action in the hyperthyroid range. However, most patients with PRTH present with clinical signs and symptoms of thyroid dysfunction, particularly goiter and tachycardia, overlapping those recorded in patients with generalized thyroid hormone resistance (GRTH), i.e. refractoriness to thyroid hormones at both pituitary and peripheral tissue level. Moreover, most of them display normal values of other parameters evaluating the peripheral effects of thyroid hormones and bear mutations in the gene encoding for T3 nuclear receptors similar to those found in patients with GRTH. These findings are questioning the existence of PRTH as a separate clinical entity and support the view that the various forms of thyroid hormone resistance may be part of a spectrum of disease with variable expression in different issues.