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      Resistance to Thyroid Hormone with Missense Mutation (V349M) in the Thyroid Hormone Receptor Beta Gene

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          Resistance to thyroid hormone (RTH) is a syndrome characterized by reduced sensitivity to the thyroid hormone. It is generally caused by mutations in the thyroid hormone receptor β (TRβ) gene. On the basis of its clinical features, two different forms of this syndrome have been described: generalized resistance and pituitary resistance. A total of 122 TRβ gene mutations have been identified thus far. A 38-year-old woman presented with intermittent palpitation. Thyroid function tests revealed elevated levels of free T 4 and TSH. TSH α-subunit levels were 0.41 mIU/mL, and magnetic resonance images of the sellar region evidenced no abnormal findings. The TSH response to TRH stimulation was found to be normal. The sequence analysis of the TRβ gene verified a missense mutation in exon 11, and the observed amino acid alteration was a substitution of a valine for a methionine at codon 349. We report the first case of a woman with RTH, which was found to be caused by a missense mutation (V349M) in the TRβ gene.

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          Most cited references 16

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          The syndromes of resistance to thyroid hormone.

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            Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study.

            To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution. Prospective, controlled study. National Institutes of Health. 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic backgrounds. Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance. Inheritance was autosomal dominant in 22 families, sporadic in 14 families, and unknown in 6 families. We found mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR beta gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart. This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.
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              The variable clinical phenotype in thyroid hormone resistance syndrome.

              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 responses to iodothyronine action. On the basis of clinical features, at least two different forms of RTH have been described: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs and pituitary resistance (PRTH) where patients present with some signs and symptoms associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of symptoms and signs exhibited by individuals with GRTH or PRTH. Assessments using biochemical and physiological indices of thyroid hormone action are useful, but limited by their lack of precision and also show an overlap between values recorded in GRTH and PRTH. In addition, we have observed significant temporal variations in clinical signs as well as in parameters of thyroid hormone action in the same individuals, with no correlation with their subjective symptoms. Recent genetic analyses indicate that patients with either GRTH or PRTH are heterozygous for mutations in the thyroid hormone receptor beta (TR beta) gene. Indeed, different clinical features have been observed in affected individuals within a kindred harboring the same Tr beta mutation, and identical mutations have been identified in unrelated kindreds classified as GRTH or PRTH. These data support the view that GRTH and PRTH are variable manifestations of a single genetic entity. Nevertheless, this clinical distinction will remain useful as a guide to the most appropriate treatment. The variable phenotypic spectrum of thyroid hormone resistance may be related to factors other than mutations in Tr beta that have yet to be elucidated.

                Author and article information

                [1 ]Department of Internal Medicine, Soonchunhyang University Medical College, Cheonan, Korea.
                [2 ]Department of Laboratory Medicine, Soonchunhyang University Medical, Bucheon, Korea.
                Author notes
                Correspondence to: Yeo Joo Kim, M.D., Division of Endocrinology College of Medicine, Soonchunhyang University, 23-20, Bong-myeong dong, Cheonan 330-721, Korea. Tel: 82-41-570-3685, Fax: 82-41-574-5762, yeojoo@
                Korean J Intern Med
                The Korean Journal of Internal Medicine
                The Korean Association of Internal Medicine
                March 2008
                20 March 2008
                : 23
                : 1
                : 45-48
                Copyright © 2008 The Korean Association of Internal Medicine
                Case Report


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