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1/54. prenatal diagnosis of thyroid hormone resistance.

    A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hormone receptor beta (TRbeta) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyroacetic acid (TRIAC) until the onset of pregnancy. This therapy was then discontinued in order to prevent TRIAC, a compound that crosses the placental barrier, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdrawal, we sought to verify, by means of genetic analysis and hormone measurements, whether the fetus was also affected by RTH, in order to rapidly reinstitute TRIAC therapy, which could potentially be beneficial to both the mother and fetus. At 17 weeks gestation, fetal dna was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TRbeta gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC treatment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The mother rapidly became euthyroid, and the fetus grew normally up to 24 weeks gestation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (287 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 /- 0.4 vs 12.7 /- 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal values in age-matched fetuses: 5-22 pmol/L). Fetal FT3 levels were raised (7.1 pmol/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the extremely high circulating TSH levels and fetal goiter, the dose of TRIAC was increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroidism, another cordocentesis was performed at 33 weeks gestation, showing that TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a simultaneous ultrasound examination revealed a clear reduction in fetal goiter. After this latter cordocentesis, acute complications occured, prompting delivery by cesarean section. The female neonate was critically ill, with multiple-organ failure and respiratory distress syndrome. In addition, a small goiter and biochemical features ofhypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical features of RTH. In summary, although further fetal studies in cases of RTH are necessary to determine whether elevated TSH levels with a markedly reduced bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate prenatal diagnosis of RTH and adequate treatment of the disease in case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy. ( info)

2/54. A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor beta gene.

    Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRbeta for triiodothyronine (T3). Formation of T329N mutant TR homodimers and heterodimers with RXRalpha on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T3 to interrupt T329N mutant TRbeta homodimerization was markedly reduced. The T329N mutant TRbeta was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRbeta1, the mutant TRbeta1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T3-binding domain of TRbeta is responsible for RTH in the proposita's family. ( info)

3/54. The thyroid hormone receptor-beta gene mutation R383H is associated with isolated central resistance to thyroid hormone.

    Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T4 and T3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received three escalating T3 doses over a 13-day period. indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-beta mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation. ( info)

4/54. Resistance to thyroid hormone caused by a new mutation (V336M) in the thyroid hormone receptor beta gene.

    Resistance to thyroid hormone (RTH), usually caused by an inherited defect of the thyroid hormone receptor, (TRbeta), results in a reduced responsiveness of target tissues to thyroid hormone. Until now, more than 600 cases with RTH have been identified. Although usually linked to the TRbeta gene, located on chromosome 3, RTH may also occur in the absence of mutations in the coding region of this gene. We report a 10-month-old boy who had laboratory findings typical of RTH. He was born prematurely on the 34th week of gestation and his thyrotropin (TSH) during neonatal screening was 121 microU/mL, a value very high for RTH or prematurity. Direct sequencing of the TRbeta gene from the patient's genomic dna revealed a heterozygous substitution of the normal valine with a mutant methionine in codon 336 (V336M) that has not been previously reported. in vitro expression studies showed that this mutant TRbeta has an impaired triiodothyronine (T3)-dependent transactivation that reduces the activity of the wild-type TRbeta (dominant negative effect). While the functional impairment of V336M is not unusual compared to other TRbeta gene mutations, the very high TSH value in this prematurely born infant suggests that fetuses with RTH have altered maturation of the hypothalamo-pituitary-thyroid axis or actually may suffer from hypothyroidism. ( info)

5/54. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene.

    Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hyposensitivity to TH. In 191 families, the RTH phenotype has been linked to mutations located in the ligand-binding or hinge domains of the TH receptor (TR) beta gene. The defective TRbeta molecules interfere with the function of the normal TRs to produce dominantly inherited RTH. Of the 65 families with RTH studied in our laboratory, 59 had mutations in the mutagenic region of the TRbeta gene that encompasses exons 7-10. Isolation of a TRbeta PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TRbeta gene from genomic dna. Not a single nucleotide substitution, deletion, or insertion was found in all coding and noncoding TRbeta1- and TRbeta2-specific and common exons of the five families with RTH reported herein. Furthermore, linkage analysis using polymorphic markers excluded involvement of the TRbeta and TRalpha genes in two and three of the five families, respectively. The phenotype of RTH in patients without TRbeta gene defects was not different from that in patients with RTH due to TRbeta gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TRbetas that have more than 50-fold reduction of T3 binding affinity and strong dominant negative effect. In these five families and another with non-TRalpha/non-TRbeta RTH, previously identified in our laboratory, evidence for dominant inheritance was secured in two families, and the appearance of a new defect or recessive inheritance was found in the remaining four families. RTH without a structural TRbeta defect occurs in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TRbeta and TRalpha gene involvement has been excluded in 5%. We postulate that a cofactor that interacts with TR is potentially responsible for the manifestation of RTH in these families. As affected subjects are not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of RTH may be due to reduced survival of embryos harboring the defect. ( info)

6/54. Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index.

    Previous studies have shown that, in patients with primary alterations in thyroid hormone secretion, the level of the natural logarithm of serum TSH (lnTSH) is negatively related to the level of free T4. Because such patients can generally be assumed to exhibit normal tissue responsivity to thyroid hormone, we were interested in determining whether the lnTSH/free T4 index (FTI) relationship in patients with established thyroid hormone resistance (THR) exhibit a lower slope than patients with normal tissue sensitivity to thyroid hormone. We have therefore analyzed the relationship between the lnTSH and the FTI in members of three families with documented THR. In these patients, a given dose of T4 was maintained for a 1- to 2-month period, to achieve hormonal equilibration. Two of the families, though not related, exhibited the same mutation, E460K. The third was identified as A317T. As anticipated, the slope of the lnTSH/FTI ratio was significantly lower in the patients with THR than in T4-treated patients who were presumed to have normal sensitivity to thyroid hormone. The slope of the lnTSH/FTI relationship seemed to be characteristic of the specific mutation involved in the three genotypes (wild-type and two mutations) examined. Further, the in vivo slope of the lnTSH/FTI relationship seemed to be linearly related to the T3 association constant of the in vitro translated receptor. These findings support the potential usefulness of measuring the slope of lnTSH, as a function of the FTI, in quantitating pituitary THR. ( info)

7/54. Resistance to thyroid hormone in a family with no TRbeta gene anomaly: pathogenic hypotheses.

    Syndromes of resistance to thyroid hormone (RTH) are almost always linked to a defective triiodothyronine-receptor B gene (TRB). Only six families with RTH exhibiting a normal TRB gene have been reported so far. We report another and discuss possible mechanisms. patients AND methods: We studied a kindred expressing a typical RTH phenotype. dna was amplified and the TRB gene was sequenced. Linkage analysis assessed linkage between the TRB gene and RTH phenotype. RESULTS: Direct sequencing of the TRB gene failed to identify any anomaly in the coding exons. Linkage analysis demonstrated that the RTH phenotype was not linked to the TRB gene in this family. CONCLUSION: TRB1 and TRB2 genes were not defective in this family. Multiple mechanisms might account for this situation at the pre-receptor, receptor and post-receptor levels. The most likely hypothesis is the involvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action. ( info)

8/54. A case of familial euthyroid hyperthyroxinemia--thyroid hormone resistance syndrome?

    We describe a case of euthyroid hyperthyroxinemia in whom clinical and laboratory investigations strongly supported the diagnosis of generalised thyroid hormone resistance. ( info)

9/54. A novel mutation (M310L) in the thyroid hormone receptor beta causing resistance to thyroid hormone in a Brazilian kindred and a neonate.

    Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone (T3) caused by mutations in the thyroid hormone receptor beta (TRbeta). The index patient of the family reported here, a 17-year-old woman, came to medical attention because of a diffuse goiter, short stature, and learning disabilities. Biochemical tests revealed an elevated free T4 of 5.2 ng/dl (0.8-2.1), a T3 of 270 ng/dl (80-220), and a nonsuppressed TSH of 1.79 mU/l (0.4-4). Administration of exogenous T4 or T3 did not result in the usual TSH suppression, prompting the clinical diagnosis of RTH. Her father and one of her brothers also had clinical and biochemical findings consistent with RTH. Direct sequence analysis of the TRbeta gene revealed a heterozygous transition 928A>G in exon 9 resulting in substitution of methionine 310 by leucine (M310L). This novel receptor mutant has a reduced affinity for T3 ( approximately 10% of normal) and dominant negative properties that are similar in comparison to other RTH mutations. The index patient had a normal pregnancy and delivery. At birth, the female neonate had no goiter, a significantly elevated T4, and increased TSH. The diagnosis of RTH was confirmed by sequencing the TRbeta gene. She was underweight at birth and her length was between the 5th and 10th percentile. At 26 months, her height remained at the 10th percentile but her bone age was 18 months, suggesting mild hypothyroidism at the level of the bone. In contrast, increased heart rate and restlessness are consistent with hyperthyroidism in other tissues, such as the heart and possibly the brain. ( info)

10/54. Generalized resistance to thyroid hormone associated with possible selective cardiac nonresistance.

    OBJECTIVE: To review the condition of generalized resistance to thyroid hormone and to report a case of generalized thyroid hormone resistance associated with atrial fibrillation. methods: A case report is presented of a 52-year-old man with atrial fibrillation who was referred by a cardiologist for thyroid ablation because of "hyperthyroidism," when his free thyroxine was found to be 4.35 ng/dL (normal, 0.55 to 2.46) and his free triiodothyronine was 6.5 pg/mL (normal, 1.4 to 4.4). RESULTS: This clinically euthyroid man with no signs or symptoms of hyperthyroidism except for the possibly related atrial fibrillation had a thyrotropin level of 3.45 mIU/L (normal, 0.46 to 4.7) in conjunction with the aforementioned increased levels of thyroid hormones. Further evaluation revealed normal 6-hour (11.7%) and 24-hour (27.6%) (123)I uptakes. magnetic resonance imaging of the pituitary revealed a normal-sized gland with no masses. CONCLUSION: This is a rare case of generalized resistance to thyroid hormone in a patient with only atrial fibrillation. Whether the heart was selectively nonresistant to thyroid hormone as the cause of his atrial fibrillation or whether his atrial fibrillation was due to his mitral valve prolapse documented on echocardiography could not be determined with certainty. His ventricular rate of 83 per minute and laboratory evaluation suggest that thyroid hormone was not the cause of the atrial fibrillation. ( info)
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