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Stephen J. Usala - One of the best experts on this subject based on the ideXlab platform.
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Enhanced Levels of Wild-Type versus Mutant Thyroid Hormone Receptor βl Messenger RNA in Fibroblasts from Heterozygotes of Kindred S with Thyroid Hormone Resistance
Thyroid : official journal of the American Thyroid Association, 1996Co-Authors: Barry B. Bercu, Stephen J. Usala, Richard C. Klann, Allen W. Root, Uyen K. Nguyen, Betsaida Torres, C. Tate HolbrookAbstract:Thyroid Hormone Resistance syndromes, which result from heterozygous mutations in the βl Thyroid Hormone receptor gene, are sometimes associated with adult short stature, but more frequently with delayed bone age (BA). Primary fibroblasts from young children with both delayed BA and short stature from a kindred A have been reported to overexpress the mutant allele. However, in fibroblasts from affected members of two different kindreds with Thyroid Hormone Resistance, S and Mf, there were equal levels of mutant and wild-type β1 mRNA. We investigated the ontogeny of differential allelic expression using competitive reverse transcription with PCR (RT-PCR) to measure relative mRNA levels for β1 and S receptor in very young affected children of kindred S. Total RNA was prepared from fibroblasts of two patients (ages 3-0.5/12 and 1-4/12 years) with delayed BA but normal growth curves. Using PCR amplimers that create an Mlu-1 site in wild-type but not mutant cDNA products from the competitive RT, we quantitated...
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Competitive polymerase chain reaction quantitation of c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 messenger ribonucleic acid levels in normal, heterozygous, and homozygous fibroblasts of kindred S with Thyroid Hormone Resistance.
The Journal of clinical endocrinology and metabolism, 1993Co-Authors: R C Klann, Jay B. Menke, B Torres, C T Holbrook, B B Bercu, Stephen J. UsalaAbstract:Mutations in the T3-binding domain of the Thyroid Hormone receptor gene c-erbA beta result in dominant negative proteins and Thyroid Hormone Resistance syndromes. Variable clinical manifestations of Resistance to Thyroid Hormones have been reported, including short stature and neuropsychological abnormalities. The molecular bases for heterogeneity of phenotype among and within kindreds have not been fully elucidated. Recent investigations have considered differential expression of mutant and wild-type beta 1-receptor alleles and the regulation thereof as a mechanism to explain differential sensitivity to Thyroid Hormones. We used reverse transcription-competitive polymerase chain reaction (PCR) to measure c-erbA beta 1, c-erbA alpha 1, and c-erbA alpha 2 mRNAs in skin fibroblasts cultured from normal subjects, heterozygotes, and a severely affected homozygous mutant of kindred S. The homozygous mutant of kindred S had severe growth and mental retardation. After reverse transcription with primers specific ...
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Generalized Thyroid Hormone Resistance: identification of an arginine to cystine mutation in codon 315 of the c-erb A beta Thyroid Hormone receptor.
Journal of endocrinological investigation, 1992Co-Authors: Kenneth D. Burman, Stephen J. Usala, Henry G. Fein, Y. Y. Djuh, P. Rhooms, L. Wartofsky, E. -h. Hao, W. E. C. Bradley, J. BerardAbstract: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)
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Thyroid Hormone Resistance syndromes
Trends in Endocrinology & Metabolism, 1991Co-Authors: Stephen J. Usala, Bruce D. WeintraubAbstract:Abstract The gene for generalized Thyroid Hormone Resistance has been mapped to the c- erb Aβ Thyroid Hormone receptor on chromosome 3 in multiple kindreds. Different mutations have been identified in the triiodothyronine (T 3 )-binding domain of c- erb Aβ and result in variable changes in T 3 binding affinity. The variant phenotypes of Thyroid Hormone Resistance are likely due to different mutations in the c- erb Aβ receptor.
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Diverse Abnormalities of the c-erbAβ Thyroid Hormone Receptor Gene in Generalized Thyroid Hormone Resistance
Advances in experimental medicine and biology, 1991Co-Authors: Stephen J. Usala, Barry B. Bercu, Samuel RefetoffAbstract:The syndrome of generalized Thyroid Hormone Resistance (GTHR) was first described in 1967 in a kindred, G, with elevated free Thyroid Hormones and absence of the typical clinical features of hyperThyroidism (1). The proband, a 6-year-old girl, demonstrated stippled epiphyses, dysmorphic features (bird-like facies, pigeon breast, and winged scapulae) and deaf-mutism. The syndrome was transmitted as a recessive trait and affected members were the product of a consanguineous union. As children, affected members had intelligence quotients within the ranges normally seen in hearingimpaired individuals (1,2). Although minimal delay of bone age was observed in affected members, final adult height was above the parental mean. Interestingly, affected members showed a paradoxical increase of serum TSH in response to the administration of suppressive doses of T3 (3) and no significant effect of antiThyroid drugs on the level of TSH (2). This constellation of clinical findings in the original kindred--stippled epiphyses, somatic abnormalities, and deafmutism--has never been reported in other kindreds with GTHR. However, less severe hearing defects, learning disabilities and growth retardation are not uncommon.
Bruce D. Weintraub - One of the best experts on this subject based on the ideXlab platform.
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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.
Human mutation, 1996Co-Authors: Donald Seto, Bruce D. WeintraubAbstract: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.
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Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized Thyroid Hormone Resistance. Evidence for two "hot spot" regions of the ligand binding domain.
The Journal of clinical investigation, 1991Co-Authors: R Parrilla, A J Mixson, J A Mcpherson, John H. Mcclaskey, Bruce D. WeintraubAbstract:Genetic analysis in our laboratory of families with generalized Thyroid Hormone Resistance (GTHR) has demonstrated tight linkage with a locus, c-erbA beta, encoding a nuclear T3 receptor. Three point mutations and two deletions in this locus have previously been reported in affected individuals in unrelated families as potential molecular bases for this disorder. In the present study, we have used direct sequencing of polymerase chain reaction-amplified exons of the c-erbA beta gene to rapidly identify novel point mutations from seven previously uncharacterized kindreds with GTHR. Six single base substitutions and one single base insertion were identified and found to be clustered in two regions of exons 9 and 10 in the ligand binding domain of the receptor: in the distal ligand-binding subdomain L2 and across the juncture of the taui and dimerization subdomains. Reduction of T3-binding affinity in each of four mutations tested as well as segregation of all mutations to clinically affected individuals strongly supports the hypothesis that these changes are the cause of GTHR in these kindreds. In view of the diversity of clinical phenotypes manifested, the distinct topographic clustering of the mutations provides an invaluable genetic tool for the molecular dissection of Thyroid receptor function.
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Thyroid Hormone Resistance syndromes
Trends in Endocrinology & Metabolism, 1991Co-Authors: Stephen J. Usala, Bruce D. WeintraubAbstract:Abstract The gene for generalized Thyroid Hormone Resistance has been mapped to the c- erb Aβ Thyroid Hormone receptor on chromosome 3 in multiple kindreds. Different mutations have been identified in the triiodothyronine (T 3 )-binding domain of c- erb Aβ and result in variable changes in T 3 binding affinity. The variant phenotypes of Thyroid Hormone Resistance are likely due to different mutations in the c- erb Aβ receptor.
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A New Point Mutation in the 3,5,3′-Triiodothyronine-Binding Domain of the c-erbAβ Thyroid Hormone Receptor Is Tightly Linked to Generalized Thyroid Hormone Resistance
The Journal of clinical endocrinology and metabolism, 1991Co-Authors: Stephen J. Usala, Robert W. Lash, Tracey L. Watson, Jay B. Menke, Allen E. Bale, Jacques Bérard, W. Edward C. Bradley, Bruce D. WeintraubAbstract:Two different mutations in the c-erbAβ Thyroid Hormone receptor have recently been reported as genetic abnormalities responsible for the syndrome of generalized Thyroid Hormone Resistance (GTHR). We have now found in a third kindred, D, in which GTHR is inherited as a dominant disease, a new point mutation in the T3-binding domain of c-erbAβ. A guanine to cytosine base substitution at nucleotide position 1305, which altered codon-335 from glutamine (CAG) to histidine (CAC), was found in one allele of 10 affected members and was not found in 6 unaffected members. This C-1305 sequence was not present in 106 random alleles, indicating that it was a mutation in c-erbAβ, and it was tightly linked to GTHR in kindred D, with a maximum logarithm of the odds score of 4.19 at a recombination fraction of 0. The tight linkage result confirms that GTHR maps to the c-erbAβ locus in multiple kindreds. In view of the tight linkage between the C-1305 mutation and GTHR, and that this mutation is a nonconservative alteratio...
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Tight linkage of the human c-erbAβ gene with the syndrome of generalized Thyroid Hormone Resistance is present in multiple kindreds
Journal of endocrinological investigation, 1991Co-Authors: Henry G. Fein, Stephen J. Usala, Bruce D. Weintraub, Kenneth D. Burman, Allen E. Bale, Y. Y. Djuh, Robert C. SmallridgeAbstract:Generalized Thyroid Hormone Resistance recently was reported to map in a single kindred to the same chromosomal region as the c-erbAβ gene, which codes for a putative Thyroid Hormone receptor. Restriction fragment length polymorphisms (RFLPs) of c-erbAβ were linked with GTHR in three kindreds with variable neuropsychologic dysfunction; two unrelated kindreds have been reported to possess different single base mutations in the T3 binding domain of c-erbAβ. In order to ascertain if tight linkage with c-erbAβ could be generalized to other families with this syndrome, we performed RFLP analysis in a separate laboratory on an unrelated family with GTHR which lacks the neuropsychologic defects or short stature often associated with GTHR (Kindred WR). RFLPs were identified after Bam HI and Eco RV digestion of DNA from leukocytes from 14 family members. The Bam HI RFLPs were 2.8 and 5.3 kb bands, and the Eco RV RFLPs were 1.6 and 3.3 kb bands. These RFLPs cosegregated with the GTHR phenotype and 11 family members were informative when both RFLPs were employed. The logarithm of the odds ratio between GTHR and c-erbAβ was 3.67, and therefore GTHR mapped to the c-erbAβ locus in this kindred. Allelic-specific hybridization with a probe constructed to identify the C to A mutation at nucleotide position 1643 (previously identified in one other kindred) suggested that our family has a different c-erbAβ abnormality. Although GTHR appears to be commonly associated with alterations in the human c-erbAβ gene, different kindreds may inherit different genetic defects.
J L Jameson - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone receptor dimerization is required for dominant negative inhibition by mutations that cause Thyroid Hormone Resistance.
The Journal of biological chemistry, 1993Co-Authors: T Nagaya, J L JamesonAbstract:The syndrome of Thyroid Hormone Resistance (THR) is caused by multiple distinct mutations of the ligand-binding domain of the Thyroid Hormone beta receptor. Although the mutant receptors are transcriptionally inactive, they inhibit normal receptor function in a dominant negative manner to cause Hormone Resistance. Because most of the naturally occurring mutations are clustered within two areas that lie on either side of a putative dimerization region, we hypothesized that receptor dimerization was important for dominant negative inhibition. In gel mobility shift assays, two THR mutants (G345R and P453H) formed homodimers as well as heterodimers with the retinoic acid X receptor alpha. In contrast, an artificial mutation (L428R) in one of the hydrophobic heptad repeats of the putative receptor dimerization domain impaired heterodimerization with retoinoic acid X receptor alpha without altering the formation of homodimers. Double mutants containing either of the THR mutations along with the dimerization mutation formed homodimers but not heterodimers, reflecting the properties of the dimerization mutant alone. In transient expression assays using positively (TRETKLuc) or negatively (TSH alpha Luc) regulated reporter genes, the dominant negative activity of the THR mutants was eliminated by the addition of the dimerization mutation. These results support a mechanism for dominant negative activity by THR mutants in which functionally inactive heterodimers bind to DNA to inhibit access by normal receptors.
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Functional properties of a novel mutant Thyroid Hormone receptor in a family with generalized Thyroid Hormone Resistance syndrome.
Clinical endocrinology, 1992Co-Authors: M. Adams, Takashi Nagaya, Y. Tone, J L Jameson, V. Krishna ChatterjeeAbstract:SUMMARY objective We wished to ascertain whether a mutation in the Thyroid Hormone receptor β gene was present in a family with generalized Thyroid Hormone Resistance syndrome and to characterize the functional properties of this mutant receptor. design Blood samples were obtained from family members for Hormone assays and genomic DNA was isolated from leucocytes for genetic analyses patients Three members (B, C, E) of a family with possible Thyroid Hormone Resistance and two normal family members (A, D) were studied measurements Basal Thyroid function tests together with serum sex Hormone binding globulin (SHBG) levels were measured. The Thyroid Hormone receptor β 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. results 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 giycine to serine mutation at codon 340 (G340S) in the Hormone binding domain was identified in one of the two β 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 wlld type Thyroid Hormone receptor in a co-expression assay but differed In their inhibitory potential. conclusions We report a second type of mutation (Gly to Ser) in codon 340 of hTRβ in a family with generalized Thyroid Hormone Resistance. Mutations at thls slte ellminate T3 blndlng, causing a loss of Hormone-stimulated receptor functlon. However, the mutant receptors retain the abllity 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 generatlng the clinical phenotype of thls disorder.
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Thyroid Hormone Resistance syndrome. Inhibition of normal receptor function by mutant Thyroid Hormone receptors.
The Journal of clinical investigation, 1991Co-Authors: V. Krishna Chatterjee, Takashi Nagaya, Laird D. Madison, Shoumen Datta, Anne Rentoumis, J L JamesonAbstract:Thyroid Hormone (T3) Resistance is inherited in most cases in an autosomal dominant manner. The disorder is characterized by elevated free Thyroid Hormone levels and partial Resistance to Thyroid Hormone at the cellular level. Distinct single amino acid substitutions in the ligand binding domain of the beta form of the Thyroid Hormone receptor have been described in two kindreds with this disorder. We used transient expression assays to characterize the functional properties of these receptor mutants, one containing a Gly to Arg change at amino acid 340 (G340R) and the other a Pro to His change at amino acid 448 (P448H). A nine amino acid carboxy terminal deletion (delta 448-456), analogous to an alteration that occurs in v-erbA, was also studied for comparison with the mutations that occur in the T3 Resistance syndrome. None of the receptor mutants were able to mediate Thyroid Hormone dependent activation (TreTKCAT) or repression (TSH alpha CAT) of reporter genes when compared with the wild type receptor. In addition, the mutants inhibited the activity of normal alpha and beta receptor isoforms when examined in coexpression assays. This activity, referred to as dominant negative inhibition, was manifest with respect to both the positively and negatively regulated reporter genes. Although mutant receptor binding to DNA was unaffected, ligand binding studies showed that the G340R and delta 448-456 mutants failed to bind T3, whereas the P448H mutant bound Hormone with reduced affinity (approximately 10% of normal) compared to the wild type receptor. Consistent with this finding, the P448H mutant receptor was partially active at higher T3 concentrations. Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3. These findings indicate that mutant beta receptors in patients with Thyroid Hormone Resistance have reduced affinity for T3 and are functionally deficient, but impair the activity of normal receptors, thereby providing a mechanism for the dominant mode of inheritance in this disorder.
Paolo Beck-peccoz - One of the best experts on this subject based on the ideXlab platform.
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Syndromes of Thyroid Hormone Resistance.
Annales d'endocrinologie, 2005Co-Authors: Paolo Beck-peccoz, Deborah Mannavola, Luca PersaniAbstract:Thyroid Hormone Resistance (RTH) is a rare autosomal dominant disorder, characterized clinically by goiter and biochemically by elevated circulating free Thyroid Hormone levels in the presence of measurable serum TSH concentrations. About 85% of patients with RTH are harboring mutations in Thyroid Hormone receptor beta (TRB). These mutations cluster in three different "hot spot" in the T3 binding domain of the receptor. When mapped to their homologous residues in the TR crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TRB mutations impair the Hormone binding to the receptor and interfere with the mechanism(s) of corepressor release and the consequent recruitment of coactivators. Thus, the remodeling of chromatin structure throughout the process of histone acetylation is prevented and the transcriptional activity of the mutant receptor on both positively and negatively regulated genes, severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRB on the transcriptional activity of the normal receptor.
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Clinical and hormonal outcome after two years of triiodothyroacetic acid treatment in a child with Thyroid Hormone Resistance.
Thyroid : official journal of the American Thyroid Association, 1997Co-Authors: Giorgio Radetti, Deborah Mannavola, Luca Persani, G. Molinaro, D. Cortelazzi, V. K. K. Chatterjee, Paolo Beck-peccozAbstract:We report here a new family with Thyroid Hormone Resistance (RTH), with phenotypic variability among subjects. Particular emphasis is given to the clinical and hormonal outcome after 2 years of triiodothyroacetic acid (TRIAC) treatment in an affected child with peripheral thyrotoxic features (pituitary RTH [PRTH]). The genetic defect was a substitution in position 1642 (C to A) within the exon 10 of Thyroid Hormone receptor beta1 (TRbeta1) gene, resulting in the codon change P453T. The mutant receptor had a significantly reduced triiodothyronine (T3) binding affinity. Within this family, the child and the mother suffered from hyperThyroidism and were clinically classified as PRTH, while the maternal grandmother was clinically euThyroid, indicating a generalized form of the disease (GRTH). Rapid normalization of heart rate was initially obtained by the association of the cardioselective beta-blocker atenolol with TRIAC. Nevertheless, long-term TRIAC therapy, through its lowering action of serum thyrotropin (TSH) and Thyroid Hormone levels, maintained a normal heart rate after atenolol discontinuation and normalized the neurological disturbances and the clinical signs in the child, without any apparent side effect. In fact, growth velocity remained unchanged and no alteration of several parameters of Thyroid Hormone action at the tissue level was observed, whereas soluble interleukin-2 receptor levels improved significantly, confirming the safety and efficacy of long-term TRIAC therapy for PRTH also during childhood. We thus recommend testing the efficacy of TRIAC therapy in all RTH patients presenting with clinical features of hyperThyroidism.
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The Variable Clinical Phenotype in Thyroid Hormone Resistance Syndrome
Thyroid : official journal of the American Thyroid Association, 1994Co-Authors: Paolo Beck-peccoz, V. Krishna K. ChatterjeeAbstract:Thyroid Hormone Resistance syndrome (RTH) is a rare disorder characterized by elevated levels of circulating free Thyroid Hormones, inappropriate TSH secretion, and reduced peripheral tissue respon...
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2 Thyroid Hormone Resistance
Bailliere's clinical endocrinology and metabolism, 1994Co-Authors: V. Krishna, K Chatterjee, Paolo Beck-peccozAbstract:Summary The syndromes of Resistance to Thyroid Hormone (RTH) are rare disorders characterized by elevated levels of circulating free Thyroid Hormones, inappropriate TSH secretion and variably reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, two major forms of RTH are recognized: generalized Resistance (GRTH) in which patients are asymptomatic with few clinical signs, and pituitary Resistance (PRTH) where patients present with features associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of clinical and biochemical features between individuals with GRTH or PRTH. Genetic analysis shows that both disorders are associated with a number of different mutations in the Thyroid Hormone receptor β (TR-β) gene which localize to two regions in the Hormone-binding domain. The mutant proteins are transcriptionally impaired but preserve the ability to bind DNA, dimerize and inhibit the function of their wild-type counterparts in a dominant negative manner. Dominant negative effects of mutant receptors within the pituitary—Thyroid feedback axis generate abnormal Thyroid function test results characteristic of RTH. The variable peripheral Resistance may be related to differences in tissue distribution of TR-α versus TR-β receptor isoforms, variable dominant negative effects of mutant receptors on different target genes or other factors not related to the receptor mutation. Although GRTH and PRTH represent the variable phenotypic spectrum of a single genetic entity, this clinical distinction will remain useful as a guide to appropriate treatment.
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Pituitary Resistance to Thyroid Hormones
Hormone research, 1992Co-Authors: Paolo Beck-peccoz, Luca Persani, F. Forloni, D. Cortelazzi, C Asteria, M J Papandreou, Giovanni FagliaAbstract: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.
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone Resistance Syndromes
The Thyroid and Its Diseases, 2019Co-Authors: Roy E. Weiss, Samuel RefetoffAbstract:Syndromes with impaired sensitivity to Thyroid Hormone (TH) include three types of Resistance to Thyroid Hormone (RTH) syndromes (RTHβ, RTHα, and nonTR-RTH) and also include patients with defects in TH transport into cells (Thyroid Hormone cell membrane transport defect, THCMTD) and defects in TH metabolism (Thyroid Hormone metabolism defect, THMD). The overall goal of this chapter is to discuss the treatment options for patients with various syndromes of impaired sensitivity to TH. These are rare conditions with little or no evidence-based information for the “best” treatment of patients. The first step toward treatment of all of these syndromes is making an accurate diagnosis based on a combination of the clinical presentation and laboratory tests that ultimately requires genetic confirmation. Recognizing the etiology leads to a more logical approach to treatment.
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multiple genetic factors in the heterogeneity of Thyroid Hormone Resistance
The Journal of Clinical Endocrinology and Metabolism, 1993Co-Authors: Roy E. Weiss, C Marcocci, G Brunobossio, Samuel RefetoffAbstract:Generalized Resistance to Thyroid Hormone (GRTH), a syndrome of inherited tissue hyposensitivity to Thyroid Hormone, is linked to Thyroid Hormone receptor (TR) mutations. A typical feature of GRTH is variable severity of organ involvement among families that, surprisingly, does not correlate with the degree of T3-binding impairment of the corresponding in vitro synthesized mutant TRs. Furthermore, variations in the clinical severity among family members harboring identical TR beta mutations have been reported. We compared serum levels of Thyroid Hormones that maintained a normal TSH in members of a large family with GRTH divided in three groups: Group A, 8 affected subjects with a mutation replacing arginine-320 with a histidine in the T3-binding domain of TR beta; Group B, 11 first degree relatives (sibs and children of affected subjects) with no TR beta mutation; Group C, 16 controls related by marriage. TSH values were not different among the three groups. As expected, total and free T4 and T3, and rT3...
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Thyroid Hormone Resistance.
Annual Review of Medicine, 1992Co-Authors: Roy E. Weiss, Samuel RefetoffAbstract:: Generalized Resistance to Thyroid Hormone (GRTH) encompasses a heterogeneous group of conditions characterized by reduced responses of target tissues to Thyroid Hormone due to defects at the site of Hormone action. In the majority of patients, GRTH is inherited as a dominant trait associated with mutations in the Hormone-binding domain of the Thyroid Hormone receptor. GRTH serves as a prototype of other Resistance syndromes for Hormones that act via nuclear receptors.
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Diverse Abnormalities of the c-erbAβ Thyroid Hormone Receptor Gene in Generalized Thyroid Hormone Resistance
Advances in experimental medicine and biology, 1991Co-Authors: Stephen J. Usala, Barry B. Bercu, Samuel RefetoffAbstract:The syndrome of generalized Thyroid Hormone Resistance (GTHR) was first described in 1967 in a kindred, G, with elevated free Thyroid Hormones and absence of the typical clinical features of hyperThyroidism (1). The proband, a 6-year-old girl, demonstrated stippled epiphyses, dysmorphic features (bird-like facies, pigeon breast, and winged scapulae) and deaf-mutism. The syndrome was transmitted as a recessive trait and affected members were the product of a consanguineous union. As children, affected members had intelligence quotients within the ranges normally seen in hearingimpaired individuals (1,2). Although minimal delay of bone age was observed in affected members, final adult height was above the parental mean. Interestingly, affected members showed a paradoxical increase of serum TSH in response to the administration of suppressive doses of T3 (3) and no significant effect of antiThyroid drugs on the level of TSH (2). This constellation of clinical findings in the original kindred--stippled epiphyses, somatic abnormalities, and deafmutism--has never been reported in other kindreds with GTHR. However, less severe hearing defects, learning disabilities and growth retardation are not uncommon.