Clinical Phenotype of a New Type of Thyroid Hormone Resistance Caused by a Mutation of the TRα1 Receptor: Consequences of LT4 Treatment

Mullem, Alies A. van; Chrysis, Dionisios; Eythimiadou, Alexandra; Chroni, Elizabeth; Tsatsoulis, Agathocles; Rijke, Yolanda B. de; Visser, Willy; Visser, Theo J.; Peeters, Robin P.

doi:10.1210/jc.2013-1050

Cited by 92 publications

(117 citation statements)

References 38 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…However, we did not find any mutations in the THRβ, THRα, TSHR and GNAS1 genes. According to previous reports, nearly 10% of the patients with RTH had no mutations in the coding region of THRβ and 5% of the patients did not have mutations in both the THRβ and THRα genes (3,15). There are multiple factors, including cofactors, transporters, deiodinases, and binding proteins, that may affect the actions of thyroid hormone (16).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up

Guo

Zheng

Yang

et al. 2016

Arch. Endocrinol. Metab.

View full text Add to dashboard Cite

SUMMARYResistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) β, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid. Arch Endocrinol Metab. 2016;60(6):601-4

show abstract

Section: Discussionmentioning

confidence: 99%

“…Most of RTH cases are caused by a mutation in the thyroid hormone receptor (THR) β gene (2). Recently, several reports described the RTH patients due to heterozygous truncating mutations in THRα (3). The clinical presentation of RTH is highly variable including hyperthyroidism, hypothyroidism and asymptomatic.…”

Section: Introductionmentioning

confidence: 99%

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up

Guo

Zheng

Yang

et al. 2016

Arch. Endocrinol. Metab.

View full text Add to dashboard Cite

show abstract

“…Sufficient levels of both TH and trace elements are important for normal development of the brain (8). Abnormalities in TH signaling can give rise to neurocognitive impairment, as illustrated by subjects with mutations in the gene encoding the TH transporter monocarboxylate transporter 8 (MCT8) (9,10) or in the TR THRA (encoding TRa) (11,12,13,14). Adequate levels of Cu are also important for normal development of the brain, as Cu is important in energy metabolism, antioxidative defense, and the production of neurotransmitters (15).…”

Section: Introductionmentioning

confidence: 99%

Association of antiepileptic drug usage, trace elements and thyroid hormone status

Zevenbergen

Korevaar

Schuette

et al. 2016

European Journal of Endocrinology

View full text Add to dashboard Cite

Background: Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions. Method: In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT 4 ), tri-iodothyronine (T 3 ), reverse T 3 , T 4 , and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models. Results: Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT 4 levels, and positively with T 3 levels. Cu was positively associated with T 4 , T 3 , and rT 3 , which was largely dependent on TBG levels. Conclusion: The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted.

show abstract

“…Heterozygous mutations of THRA were finally reported in three families in 2012 and 2013 (7,8,9,10). Affected individuals all had grossly delayed skeletal development and constipation but variable motor and cognitive abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…By analogy, it is likely that individuals with a spectrum of THRA mutations will be identified in the future. Significantly, the THRA mutations described so far result in a severe phenotype due to the expression of truncated TRa proteins with no T 3 -binding capability but potent dominant-negative activity (7,8, 9,10). Recognition of individuals with milder mutations and phenotypes will be much more difficult because disruption of THRA does not affect the HPT axis significantly and alteration of circulating thyroid status is likely to be subtle.…”

mentioning

confidence: 99%

THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women

Gogakos

Logan

Waung

et al. 2014

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: A new autosomal dominant disorder due to mutation of THRA, which encodes thyroid hormone receptor a, is characterised by severely delayed skeletal development but only slightly abnormal thyroid status. Adult mice with disrupted thyroid hormone action in bone due to a mutation of Thra or deletion of Dio2, encoding the type 2 deiodinase, have high bone mass and mineralisation despite essentially euthyroid status. No individuals with DIO2 mutations have been described and the adult phenotype of patients with THRA mutations is largely unknown. We hypothesised that screening euthyroid adults with high bone mineral density (BMD) could be used to identify individuals with mutations of THRA or DIO2. Design: The Osteoporosis and Ultrasound Study (OPUS) is a 6-year prospective study of fracture-related factors from five European centres. Methods: A cohort of 100 healthy euthyroid post-menopausal women with the highest BMD was selected from the OPUS population. We sequenced the intron-exon boundaries and critical exons of THRA and DIO2 in these subjects. TSH, free 3,5,3 0 -L-triiodothyronine, free thyroxine, vitamin D, parathyroid hormone and bone turnover marker concentrations, and BMD measurements were available in all OPUS participants. Results: No coding sequence or splice site mutations affecting THRA or DIO2 were identified. Conclusions: Mutations affecting THRA or DIO2 are not a common cause of high BMD in healthy euthyroid post-menopausal women.European Journal of Endocrinology (2014) 170, 637-644 IntroductionThyroid hormones (thyroxine (T 4 ) and 3,5,3 0 -L-triiodothyronine (T 3 )) are essential for skeletal development, post-natal growth, and bone maturation. In adults, thyroid hormones regulate bone turnover, and normal euthyroid status is required to maintain optimal bone mass and mineralisation (1). Accordingly, thyrotoxicosis is a well-established cause of osteoporosis, and hypothyroidism is associated with an increased risk of fracture (2).The thyroid gland secretes T 4 and T 3 in a ratio of about 15:1, but T 4 is a pro-hormone and must be converted to T 3 in the peripheral tissues (3). Conversion of T 4 to T 3 in target cells is catalysed by type 2 iodothyronine deiodinase (DIO2), and the activity of this enzyme regulates intracellular availability of T 3 . Two nuclear receptors, TRa and TRb, mediate T 3 action in the target cells, and their relative levels of expression vary between tissues. European Journal of Endocrinology Clinical StudyA Gogakos and others THRA and DIO2 in women with high bone density For example, TRa is expressed at high levels in bone and cartilage, whereas TRb predominates in the hypothalamus and pituitary, where it mediates feedback control of the hypothalamic-pituitary-thyroid (HPT) axis (4). The syndrome of resistance to thyroid hormone (RTH) was described in 1967 (5) and the first THRB mutations affecting TRb were identified in 1989 (6). Heterozygous mutations of THRA were finally reported in three families in 2012 and 2013 (7, 8, 9, 10). Affected individuals a...

show abstract

Clinical Phenotype of a New Type of Thyroid Hormone Resistance Caused by a Mutation of the TRα1 Receptor: Consequences of LT4 Treatment

Abstract: This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRα1. LT4 therapy leads to an improvement of certain but not all features of the clinical phenotype.

Cited by 92 publications

References 38 publications

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up

Association of antiepileptic drug usage, trace elements and thyroid hormone status

THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women

Contact Info

Product

Resources

About