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Mels Sluyser - One of the best experts on this subject based on the ideXlab platform.
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Role of estrogen receptor variants in the development of Hormone Resistance in breast cancer.
Clinical biochemistry, 1992Co-Authors: Mels SluyserAbstract:Recent evidence suggests that the progression to Hormone Resistance in some breast tumors is due to mutations in the estrogen receptor (ER). Various types of ER variants have been found in breast cancer biopsies and breast cancer cell lines. The ER variants include dominant-positive receptors that are transcriptionally active in the absence of estrogen, and dominant-negative receptors that are themselves transcriptionally inactive but prevent the action of the normal receptor. The mechanisms by which these variants cause loss of hormonal control is becoming clear. ER variants may be prognostic factors for breast cancer. By modifying the action of ER variants, it should be possible to develop new strategies for treatment of malignant breast disease.
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Nuclear Hormone receptor variants: their role in malignancy and progression to Hormone Resistance in cancer.
European Journal of Endocrinology, 1991Co-Authors: Mels SluyserAbstract:Structural variants of nuclear Hormone receptors have been found in tumour tissues. Experimental evidence suggests two ways in which these variants may have oncogenic potential: 1. by suppressing the action of the normal Hormone receptor, thereby acting as dominant negative oncogenes; 2. by activating Hormone-responsive genes in a Hormone-independent manner. These mechanisms may not only contribute to oncogenesis but also to the development of Hormone Resistance in tumours, e.g. breast and prostate cancer.
Jp Berg - One of the best experts on this subject based on the ideXlab platform.
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Clues to a possible new variant of thyroid Hormone Resistance.
European Journal of Endocrinology, 1998Co-Authors: Jp BergAbstract:Patients with thyroid Hormone Resistance, first described by Refetoff et al. in 1967 (1), usually present with goitre, elevated thyroid Hormone levels and an inappropriately normal or elevated thyrotrophin (TSH) level (reviewed in 2, 3). Clinical effects of thyroid Hormone Resistance can include variable features of hypoand hyperthyroidism such as tachycardia, attention deficit/hyperactivity disorder, growth retardation and hearing defects. The syndrome is known to be caused by mutations in the thyroid Hormone receptor (TR) b gene, but the molecular basis of cases without mutations in this gene remains elusive, and no mutations have ever been found in the a gene of the receptor (TRa). A recent study by Wikstrom et al. (4) indicates that there may be another variant of Resistance to thyroid Hormones with a different clinical presentation caused by defects in TRa. TRs are ligand-modulated transcription factors and the products of two different genes (reviewed in 5, 6). The TRb gene in chromosome 3 encodes two receptor isoforms (TRb1 and TRb2), which are splice variants. Proteins encoded by the TRa gene in chromosome 17 include one receptor that binds thyroid Hormones (TRa1), two isoforms that bind thyroid Hormone responsive elements on DNA, but do not bind thyroid Hormones (TRa2 and TRa3), and one structurally related orphan receptor encoded by the opposite DNA strand (rev-erbAa). The first case of thyroid Hormone Resistance showed an autosomal recessive pattern of inheritance and lacked not only the TRb gene, but also adjacent sequences (7). In all other familial cases there is an autosomal dominant inheritance pattern. Mutations have been demonstrated in the TRb gene resulting in a receptor with a dominant negative effect of the mutated receptor protein on normal TR function. This has also been shown in sporadic cases of thyroid Hormone Resistance. It has been speculated that TRa gene mutations in humans would be incompatible with early foetal survival or give rise to clinical features not associated with the recognized form of thyroid Hormone Resistance. In mice, homozygous inactivation of the TRa gene, which abrogated the production of the TRa1 and TRa2 isoforms, led to hypothyroidism, growth arrest and death within 5 weeks after birth (8). Wikstrom et al. (4), at Bjorn Vennstroms laboratory at the Karolinska Institute in Stockholm, wanted to identify effects of thyroid Hormones specifically mediated by TRa1. A transgenic mouse, which lacked a functional TRa1, without losing TRa2 and rev-erbAa expression, was developed. They demonstrated that deletion of TRa1 did not affect viability of the mice, and there was a normal ratio between male and female offspring. Homozygous animals survived to at least 18 months of age, and both sexes were fertile with normal litter sizes. No overt abnormalities were discovered at autopsy, and no compensatory increase in the expression of the other thyroid Hormone receptors was detected in the brain. In contrast to the increase in thyroid Hormone levels observed in thyroid Hormone Resistance, TRa1 deficient mice had lower serum levels of free thyroxine (T4) than the controls, whereas the levels of free tri-iodothyronine (T3) were not statistically significantly different. In male TRa1 deficient mice, serum TSH levels were lower than in the control mice. Northern blot analyses of pituitaries from these animals revealed that the mRNA levels of the TSH a subunit were reduced in mice without TRa1, whereas the b subunit was increased. Although a reduction in the glycoprotein Hormone a subunit mRNA was associated with a reduction in the TSH level, there was no effect on luteinizing Hormone, chorionic gonadotrophin and follicle-stimulating Hormone function since sexual maturation and fertility were unaffected. However, mice lacking both TRa1 and TRa2, became severely hypothyroid, their pituitary mRNA level of the TSH b subunit was lower than in the control mice, and their thyroid glands were hypoplastic (8). Hypothyroidism seems to induce the expression of TSH a subunit mRNA in the pituitary not only by removing a passive repression induced by thyroid Hormones, but also by transcriptional activation through TRa1. Studies of TRb deficient mice indicate that TRb2, which is highly expressed in thyrotrophs of the pituitary, is essential for a normal inhibition of TSH production by thyroid Hormones (9, 10). However, a normal feed-back regulation of thyroid Hormones on TSH production also depends on a normal TRa gene. In the TRa gene knock-out mouse models a functional TRa2 is associated with a less severe hypothyroidism (4, 8), which indicates that TRa2 attenuates the inhibitory effects of TRb2 on TSH production. The syndrome of thyroid Hormone Resistance is often accompanied by tachycardia. In TRa1 deficient mice, heart rate was slower than in control mice even after prolonged treatment with T3 (4). Both TRa1 and TRb are expressed in mouse heart (11). To some degree the effects of thyroid Hormones on pacemaking functions in the heart are mediated by TRb in TRa1 deficient mice. The molecular basis of the bradycardia induced by TRa1 deficiency has not been revealed, but may be mediated by modulating the effects of b-adrenergic or muscarinic receptor activation in the cardiac sinoatrial node or the expression of ion channels and pumps. However, the levels of well-known myocardial target genes for thyroid Hormones, such as the sarcoplasmic H IG H L IG H T European Journal of Endocrinology (1998) 139 16–17 ISSN 0804-4643
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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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, Y. Y. Djuh, D. Nicholson, P. Rhooms, L. Wartofsky, H. G. Fein, 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 × 10^10 M^−1 compared to about 5 × 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. Further studies analyzing the mechanism by which a single point mutation in one allele results in the biochemical and clinical manifestations of generalized thyroid Hormone Resistance are warranted.
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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.
Canan Ersoy - One of the best experts on this subject based on the ideXlab platform.
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Atypical Thyroid Function Tests, Thyroid Hormone Resistance [Atipik Tiroid Fonksiyon Testleri: Tiroid Hormon Direnci]
Medicine Science | International Medical Journal, 2014Co-Authors: Soner Cander, Ozen Oz Gul, Canan ErsoyAbstract:Abstract The assessment of thyroid function tests for to the diagnose hyperthyroidism (thyrotoxicosis) or hypothyroidism does not constitute a nuisance when the clinical suspicion is strong. However, substantial proportion of discordant results with clinical findings or atypical results possible to come across in the thyroid function tests. In such cases, accurate diagnosis is very important for appropriate management to the patient, prevention of unnecessary tests and cost increases. For accurate diagnosis in these patients, a detailed clinical evaluation with specific laboratory studies are needed. Atypical hyperthyroxinemia (high thyroid Hormone levels are incompatible with TSH) is an atypical thyroid function test pattern can be seen in the rare cases of thyrotropin releasing pituitary adenoma or thyroid Hormone Resistance syndrome. However, in this case, assay interferences and euthyroid situations such as thyroxin replacement therapy with poor-compliance, euthyroid sick syndrome including acute psychiatric disorders, hyperthyroxinemia due to drugs like heparin, disorders with protein binding abnormalities (familial dysalbuminemic hyperthyroxinemia, transthyretin related hyperthyroxinemia) which are seen more common, should be excluded primarily. Then should be consulted further examinations for the differential diagnosis of thyrotropin-secreting pituitary adenomas and thyroid Hormone Resistance syndrome. The Refetoff Syndrome is developing due to a defect in the beta-receptor and is most common in thyroid Hormone Resistance syndromes. It includes a combination of findings of hyperthyroidism and hypothyroidism and suggests an autosomal dominant inheritance feature. Therefore, family screening should be done in patients diagnosed. Mostly, beta blockers is sufficient in the treatment. Other rare syndromes of thyroid Hormone Resistance that occurs due to alpha-receptor defects, thyroid Hormones membrane transport defect and thyroid Hormone metabolism defect related with deficiency of deiodinases. The clinical pictures of this rare syndromes are more severe compared to classic syndrome and often the choice of treatment is only supportive therapy. Keywords: Thyroid function tests, atypical TFT, thyroid Hormone Resistance Ozet Klinik suphenin kuvvetli olmasi durumunda tiroid fonksiyon testlerinin degerlendirilmesi ile hipertiroidi (tirotoksikoz) veya hipotiroidi tanisinin konmasi hekimler acisindan bir sikinti olusturmamaktadir. Ancak tiroid fonksiyon testlerinde azimsanmayacak oranda atipik sonuclara veya klinik bulgularla uyumsuz sonuclara rastlamak mumkundur. Boyle durumlarda dogru taniyi koyabilmek hasta icin uygun yaklasim ve gereksiz maliyet artisina yola acan tetkiklerin engellenmesi acisindan oldukca onemlidir. Dogru tani ve yaklasim icin bu hastalarda cok iyi bir klinik degerlendirme ile beraber, spesifik laboratuar calismasi gerekmektedir. Atipik hipertiroksinemi (TSH ile uyumsuz yuksek tiroid hormon duzeyleri) nadir rastlanan durumlar olarak tirotropin salgilayan hipofiz adenomu veya tiroid hormon direnci sendromlarinda gorulebilen bir atipik tiroid fonksiyon testi paternidir. Ancak bu durumda oncelikle daha sik rastlanan otiroid durumlarin (L-tiroksin kullanan hastalarda kompliyans sorunu, akut psikiyatrik tablolarla birlikte otiroid hasta sendromu, heparin gibi ilaclar nedeniyle olusan hipertiroksinemi, familyal disalbuminemik hipertiroksinemi ve transtiretin ile iliskili hipertiroksinemi gibi proteine baglanma ile ilgili hastaliklar) ve analitik hatalarin dislanmasi gerekmektedir. Daha sonra tirotropin salgilayan adenomu ve tiroid hormon direnci sendromunun ayirici tanisi icin gerekli ileri incelemelere gidilmelidir. Tiroid hormon direnci sendromlari icinde en sik goruleni beta reseptor defektine bagli olarak gelisen Refetoff Sendromudur. Hipertiroidi ve hipotiroidi bulgularini bir arada iceren sendrom otozomal dominant gecis ozelligi gostermektedir. Tani konan hastalarda bu yuzden aile taramasi yapilmalidir. Tedavisinde ise cogunlukla beta blokerler yeterli olmaktadir. Bunun disinda cok daha nadir gorulen diger tiroid hormon direnci sendromlari; alfa reseptor defektine bagli tiroid hormon direnci, tiroid hormon membran transport defekti ve deiyodinaz eksikligine bagli tiroid hormon metabolizmasi defekti sonucu olusur. Bu nadir sendromlarda klinik tablolar, klasik beta reseptor defektine bagli sendroma gore daha agirdir ve tedavileri cogunlukla destekleyici tedavi seklindedir. Anahtar kelimeler: Tiroid fonksiyon testleri, atipik TFT, tiroid hormon direnci
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Atypical Thyroid Function Tests, Thyroid Hormone Resistance [Atipik Tiroid Fonksiyon Testleri: Tiroid Hormon Direnci]
Society of TURAZ AKADEMI, 2014Co-Authors: Soner Cander, Ozen Oz Gul, Canan ErsoyAbstract:The assessment of thyroid function tests for to the diagnose hyperthyroidism (thyrotoxicosis) or hypothyroidism does not constitute a nuisance when the clinical suspicion is strong. However, substantial proportion of discordant results with clinical findings or atypical results possible to come across in the thyroid function tests. In such cases, accurate diagnosis is very important for appropriate management to the patient, prevention of unnecessary tests and cost increases. For accurate diagnosis in these patients, a detailed clinical evaluation with specific laboratory studies are needed. Atypical hyperthyroxinemia (high thyroid Hormone levels are incompatible with TSH) is an atypical thyroid function test pattern can be seen in the rare cases of thyrotropin releasing pituitary adenoma or thyroid Hormone Resistance syndrome. However, in this case, assay interferences and euthyroid situations such as thyroxin replacement therapy with poor-compliance, euthyroid sick syndrome including acute psychiatric disorders, hyperthyroxinemia due to drugs like heparin, disorders with protein binding abnormalities (familial dysalbuminemic hyperthyroxinemia, transthyretin related hyperthyroxinemia) which are seen more common, should be excluded primarily. Then should be consulted further examinations for the differential diagnosis of thyrotropin-secreting pituitary adenomas and thyroid Hormone Resistance syndrome. The Refetoff Syndrome is developing due to a defect in the beta-receptor and is most common in thyroid Hormone Resistance syndromes. It includes a combination of findings of hyperthyroidism and hypothyroidism and suggests an autosomal dominant inheritance feature. Therefore, family screening should be done in patients diagnosed. Mostly, beta blockers is sufficient in the treatment. Other rare syndromes of thyroid Hormone Resistance that occurs due to alpha-receptor defects, thyroid Hormones membrane transport defect and thyroid Hormone metabolism defect related with deficiency of deiodinases. The clinical pictures of this rare syndromes are more severe compared to classic syndrome and often the choice of treatment is only supportive therapy. [Med-Science 2014; 3(3.000): 1545-70
E. Chester Ridgway - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone Resistance syndromes.
The American Journal of Medicine, 1993Co-Authors: Michael T. Mcdermott, E. Chester RidgwayAbstract:Abstract The thyroid Hormone Resistance syndromes are disorders in which the body's tissues are resistant to the effects of thyroid Hormone. Generalized Resistance to thyroid Hormone (GRTH) is characterized by Resistance in the pituitary gland and in most or all of the peripheral tissues. Affected individuals have elevated serum thyroid Hormone levels and inappropriately normal or elevated thyroid-stimulating Hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary Resistance to thyroid Hormone (PRTH) is characterized by Resistance in the pituitary gland but not in peripheral tissues. Patients have elevated serum thyroid Hormone levels and normal or elevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, but current choices are not completely satisfactory. Selective peripheral Resistance to thyroid Hormone (PerRTH) is characterized by Resistance in peripheral tissues but not in the pituitary. The only patient thus far described had normal serum thyroid Hormone and TSH levels but was clinically hypothyroid and unproved with thyroid Hormone administration. All of these disorders are probably more common than is generally recognized and are often misdiagnosed and inappropriately treated. GRTH, in most cases studied, results from a mutation in the thyroid Hormone receptor β gene causing an amino acid substitution in or a partial or complete deletion of the thyroid Hormone-binding domain of the receptor. The causes of PRTH and PerRTH remain to be determined.
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Thyroid Hormone Resistance syndromes.
The American journal of medicine, 1993Co-Authors: Michael T. Mcdermott, E. Chester RidgwayAbstract:The thyroid Hormone Resistance syndromes are disorders in which the body's tissues are resistant to the effects of thyroid Hormone. Generalized Resistance to thyroid Hormone (GRTH) is characterized by Resistance in the pituitary gland and in most or all of the peripheral tissues. Affected individuals have elevated serum thyroid Hormone levels and inappropriately normal or elevated thyroid-stimulating Hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary Resistance to thyroid Hormone (PRTH) is characterized by Resistance in the pituitary gland but not in peripheral tissues. Patients have elevated serum thyroid Hormone levels and normal or elevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, but current choices are not completely satisfactory. Selective peripheral Resistance to thyroid Hormone (PerRTH) is characterized by Resistance in peripheral tissues but not in the pituitary. The only patient thus far described had normal serum thyroid Hormone and TSH levels but was clinically hypothyroid and improved with thyroid Hormone administration. All of these disorders are probably more common than is generally recognized and are often misdiagnosed and inappropriately treated. GRTH, in most cases studied, results from a mutation in the thyroid Hormone receptor beta gene causing an amino acid substitution in or a partial or complete deletion of the thyroid Hormone-binding domain of the receptor. The causes of PRTH and PerRTH remain to be determined.