1/53. Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na /I- symporter.iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na /I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. sequence analysis of the complementary dna (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.- - - - - - - - - - ranking = 1keywords = family, member (Clic here for more details about this article) |
2/53. An identical neo-mutation in the thyroid hormone receptor beta gene (A317T) in 2 unrelated Thai families with resistance to thyroid hormone.We reported two unrelated Thai girls with resistance to thyroid hormone. The affected patients presented with goiter and no other stigmata of hyperthyroidism. Their serum T4, T3, free T4 and free T3 concentrations were high and they had normal levels of TSH. The affected girl in family 1 was treated with an antithyroid drug for 1-9/12 years. The affected girl in family 2 was only observed her thyroid function tests. TRH test showed normal TSH response in both girls. Analysis of the thyroid hormone receptor beta gene of both affected girls revealed the same missense mutation, changing the guanine in nucleotide 1234 to an adenine which results in the replacement of the normal alanine (GCT) with a threonine (ACT) at codon 317. Two proposita were heterozygous, and this mutation was not present in their parents compatible with a neo-mutation.- - - - - - - - - - ranking = 0.66310746328626keywords = family (Clic here for more details about this article) |
3/53. Efficacy of oral iodide therapy on neonatal hyperthyroidism caused by maternal Graves' disease.OBJECTIVE: To verify the efficacy of oral iodide therapy in treating a case of early neonatal hyperthyroidism due to maternal Graves' disease. methods: We report a case of neonatal hyperthyroidism which occurred in a 2,650-gram, female baby, born at 39 weeks' gestational age (GA) to a 30-year-old mother affected by Graves' disease and treated with thionamides (propylthiouracil) from the 20th week of gestation. A fetal goiter, due to maternal therapy, had been observed by ultrasound scan at 31 and 35 weeks of gestation, with contemporary low cord thyroid hormone levels. Two intra-amniotic injections of levothyroxine were then performed at 34 and 36 weeks of gestation, which led to a significant reduction of fetal goiter and to normalization of cord thyroid hormone levels. The neonatal clinical course was characterized by symptoms of hyperthyroidism from the 2nd to 3rd days of life (irritability, tachycardia, tachypnea, hyperphagia), mostly during feeding. Oral treatment with potassium iodide (KI, 8 mg x 3 times a day) was started at 23 days of life. RESULTS: Treatment with KI led to a significant reduction of neonatal clinical symptoms and to a normalization of hormone levels within 4 days of therapy. The treatment was discontinued in 13th week of life because of neonatal well-being and normal hormone levels. CONCLUSIONS: We believe that KI therapy is effective in treating neonatal hyperthyroidism and does not cause suppression of neonatal thyroid activity, which is possible using antithyroid drugs like thionamides.- - - - - - - - - - ranking = 0.0012280092517244keywords = life (Clic here for more details about this article) |
4/53. Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome.Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The netherlands, indicating that the 1558T-->G mutation may be a common mutation.- - - - - - - - - - ranking = 1.9893223898588keywords = family (Clic here for more details about this article) |
5/53. Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene.The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. dna was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (1568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.- - - - - - - - - - ranking = 0.00040933641724147keywords = life (Clic here for more details about this article) |
6/53. Clinical and molecular analysis of three Mexican families with Pendred's syndrome.BACKGROUND: The autosomal recessive Pendred's syndrome is defined by congenital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes pendrin, a chloride/iodide transporter expressed in the thyroid, the inner ear, and the kidney. OBJECTIVE: To perform a detailed clinical and molecular analysis of patients with Pendred's syndrome from four patients from three unrelated Mexican families. methods: thyroid function tests, perchlorate test, thyroid scintigraphy, audiometry, computer tomography and magnetic resonance imaging were performed in all affected individuals. Haplotype analyses were performed using microsatellite markers flanking the PDS locus, and the PDS gene was submitted to direct sequence analysis. RESULTS: All patients presented with sensorineural deafness, Mondini malformations of the cochlea, an enlarged vestibular aqueduct, goiter, and a positive perchlorate test. Two patients were hypothyroid, two individuals were euthyroid. sequence analysis revealed a complex homozygous deletion/insertion mutation at the end of exon 4 in the index patient of family 1 resulting in a premature stop codon at position 138. In family 2, the affected individuals were compound heterozygous for a splice acceptor mutation (IVS2 -1G>A) and a 1231G>C transversion substituting alanine 411 by proline (A411P). In family 3, the index patient was found to be homozygous for a transversion 412G>T in exon 4 replacing valine 138 by phenylalanine (V138F). CONCLUSIONS: All patients included in this study presented with the classic Pendred syndrome triad and molecular analysis revealed pendrin mutations as the underlying cause. The identification of three novel mutations, one of them of complex structure, expands the spectrum of mutations in the PDS gene and emphasizes that they display marked allelic heterogeneity.- - - - - - - - - - ranking = 0.99466119492939keywords = family (Clic here for more details about this article) |
7/53. malignant hyperthermia in a patient with Graves' disease during subtotal thyroidectomy.We report the case of a 31-year-old man with Graves' disease who manifested malignant hyperthermia during subtotal thyroidectomy. His past medical history and family history were unremarkable. Before surgery, his condition was well controlled with propylthiouracil, beta-adrenergic blocker and iodine. During the operation, anesthesia was induced by intravenous injection of vecuronium and thiopental, followed by suxamethonium for endotracheal intubation. anesthesia was maintained with nitrous oxide and sevoflurane. One hour after induction of anesthesia, his end tidal carbon dioxide concentration (ET(CO2)) increased from 40 to 50 mmHg, heart rate increased from 90 to 100 beats per min and body temperature began to rise at a rate of 0.3 degrees C per 15 min. Suspecting thyroid storm, propranolol 0.4 mg and methylprednisolone 1,500 mg were administered, which, however, had little effect. Despite the lack of muscular rigidity, the diagnosis of malignant hyperthermia was made based on respiratory acidosis. Sevoflurane was discontinued and dantrolene was given by intravenous bolus. Soon after the treatment, ET(CO2), heart rate and body temperature started to fall to normal levels. His laboratory findings showed abnormally elevated serum creatine phosphokinase and myoglobin but normal thyroid hormone levels. Since dantrolene is efficacious in thyrotoxic crisis and malignant hyperthermia, an immediate intravenous administration of dantrolene should be considered when a hypermetabolic state occurs during anesthesia in surgical treatment for a patient with Graves' disease.- - - - - - - - - - ranking = 0.33155373164313keywords = family (Clic here for more details about this article) |
8/53. Congenital goiter with hypothyroidism caused by a 5' splice site mutation in the thyroglobulin gene.In this work we have extended our initial molecular studies of a consanguineous family with two affected goitrous siblings (H.S.N. and Ac.S.N.) with defective thyroglobulin (Tg) synthesis and secretion because of a homozygotic deletion of a fragment of 138 nucleotides (nt) in the central region of the Tg mRNA, identified previously in H.S.N. In order to identify the intron/exon boundaries and to analyze the regions responsible for pre-mRNA processing corresponding to a 138 nt deletion, we performed a screening of a human genomic library. The intron/exon junction sequences were determined from one positive clone by sequencing both strands of the dna template. The results showed that the deletion mapped between positions 5549 and 5686 of the Tg mRNA and corresponded to exon 30. The positions of the exon limits differed by three nucleotides from the previously reported data obtained from direct sequencing of the deleted reverse transcriptase-polymerase chain reaction fragment from H.S.N. These variations are because the intron/exon junctions in this region were not available at the time when the deletion was first described. The deletion does not affect the reading frame of the resulting mRNA and is potentially fully translatable into a Tg polypeptide chain that is shortened by 46 residues. The same 138 nt deletion was observed in reverse transcriptase-polymerase chain reaction studies performed in the thyroid tissues from Ac.S.N. Genomic dna analysis showed that a G to T transversion was observed at position 1 in the donor site of intron 30. Both affected patients (H.S.N. and Ac.S.N.) are homozygous for the mutation whereas the normal sister (At.S.N.) had a normal allele pattern. The functional consequences of the deletion are related to structural changes in the protein molecule that either could modify the normal routing of the translation product through the membrane system of the cell or could impair the coupling reaction. Probably the mutant Tg polypeptide might be functionally active in the production of thyroid hormone, because in the presence of a normal iodine ingestion (approximately 150 microg/day), Ac.S.N. was able to maintain normal serum levels of total triiodothyronine (T3) associated with relatively low serum total thyroxine (T4) with normal somatic development without signs of brain damage.- - - - - - - - - - ranking = 0.33155373164313keywords = family (Clic here for more details about this article) |
9/53. Two Chinese families with Pendred's syndrome--radiological imaging of the ear and molecular analysis of the pendrin gene.We report two families in whom the index cases satisfied the classical diagnostic criteria of Pendred's syndrome. In family I, two siblings were deaf, and one was normal. In family II, both parents and two offspring were deaf. Computed tomography scans performed in five of six of these deaf individuals showed enlarged vestibular aqueducts in all cases, and Mondini cochlea only in family II. Affected members in family I were compound heterozygotes inheriting the paternal allele with a novel mutation S398del in exon 10 and a maternal allele with two mutations IVS13 9C-->G in intron 13, in addition to H723R. In family II, the mother and one child carried both the novel intronic IVS8-2A-->G and H723R mutations, whereas the father and index case were homozygous for the IVS8-2A-->G mutation. A perchlorate discharge test was positive in 50% of cases tested. In conclusion, we concur that radiological and molecular studies should be performed for confirmation of Pendred's syndrome. We report, for the first time, a Pendred's syndrome family in which affected members had three mutations, as well as a second family in whom the intermarriage of two Pendred's syndrome patients resulted in Pendred's syndrome offspring.- - - - - - - - - - ranking = 2.3315537316431keywords = family, member (Clic here for more details about this article) |
10/53. Neonatal goiter caused by expectorant usage.A female newborn was admitted with the symptoms of mild respiratory distress, protruding tongue, hypotonicity, cutis marmorata, sclerema, myxedema, abdominal distension, and feeding problems on the first day of life. She had a huge neck mass, a large anterior and posterior fontanel, and hoarse cry. She had no umbilical hernia or jaundice. A history of maternal potassium iodine (expectorant) usage without doctor's advice was obtained; the mother had not attended a clinic throughout the pregnancy. On ultrasonographic examination, the thyroid right lobe was 53 x 31 mm and the left lobe was 34 x 31 mm. The results of thyroid hormone tests on the first day were as follows: T3 20 ng/dl (normal: 32-216 ng/dl), T4 0.9 microg/dl (11.8-22.6 microg/dl), TSH 120 mIU/l (2.5-13.3 mIU/l). This patient is presented to emphasize the role of hypothyroidism in drug-induced neonatal goiter and to discuss the possibility of a life-threatening effect of congenital goiter, i.e. respiratory tract obstruction.- - - - - - - - - - ranking = 0.00081867283448293keywords = life (Clic here for more details about this article) |
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