Thyroid hormone resistance in identical twins

Brooks, Augustin; Lockett, Helen; Vaidya, Bijay

doi:10.1093/qjmed/hcq174

Cited by 1 publication

(5 citation statements)

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“…In a study by Hayashi et al [8], there was a significant correlation between the extent of T3-binding loss (in a subset of TRβ gene mutations) and the free T4 level. Thus mutations affecting the TRβ ligand binding domain which caused moderate-severe impairment of T3 binding, including the A317T mutation, were associated with higher free T4 level [8]. Recent X-ray crystallography data of two different mutant TR β receptors complexes to TRIAC (3,5,3'-triiodothyroacetic acid) suggest the A317T mutation causes enlargement of the TRβ ligand binding pocket associated with an ~ 100-fold increase in the rate of the T3 binding off-reaction compared to that observed in the wildtype TRβ receptor [18].…”

Section: Discussionmentioning

confidence: 95%

“…Recent X-ray crystallography data of two different mutant TR β receptors complexes to TRIAC (3,5,3'-triiodothyroacetic acid) suggest the A317T mutation causes enlargement of the TRβ ligand binding pocket associated with an ~ 100-fold increase in the rate of the T3 binding off-reaction compared to that observed in the wildtype TRβ receptor [18]. The R316H mutation also caused 100fold loss in T3 binding, and impaired TRβ homodimerization [18], but was associated with lower free T4 levels (~ 140% of upper normal range) than the A317T mutation [8].…”

Section: Discussionmentioning

confidence: 97%

“…Ninety percent of RTH mutations occur in the TRβ gene, clustering in three regions involved in T3-ligand binding [1]. In a study by Hayashi et al [8], there was a significant correlation between the extent of T3-binding loss (in a subset of TRβ gene mutations) and the free T4 level. Thus mutations affecting the TRβ ligand binding domain which caused moderate-severe impairment of T3 binding, including the A317T mutation, were associated with higher free T4 level [8].…”

Section: Discussionmentioning

confidence: 99%

“…Our patient and her identical twin sister (harbored the A317T mutation) and both developed atrial fibrillation and refractory congestive heart failure in the sixth decade of life. A review of published literature in additional adult RTH patients harboring the same A317T mutation revealed that all three of three adults (age 50 or older) were reported to have suffered with atrial fibrillation [8,9]. For example, Brooks et.…”

Section: Discussionmentioning

confidence: 99%

“…[8] described a 62year-old man who presented with atrial fibrillation followed by cerebellar infarction. The patient's identical twin brother harbored the same Ala317Thr mutation in the TR-beta gene and also experienced a cerebellar infarction secondary to unrecognized atrial fibrillation [8]. Guo et.…”

Section: Discussionmentioning

confidence: 99%

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Thyroid Hormone Resistance in Identical Twin Sisters with Atrial Fibrillation: Case Report and Review of the Literature

Zimering¹

2018

JED

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Aim: To report identical twin sisters harboring the A317T mutation in the thyroid hormone beta receptor gene (TR β) who developed atrial fibrillation and refractory congestive heart failure in the sixth decade of life. To critically assess whether the A317T mutation may be responsible for increased cardiotoxicity compared to other thyroid hormone beta receptor gene mutations. Methods: A 59-year-old woman referred for evaluation of abnormal thyroid function tests had been experiencing frequent spells of tachycardia associated with dyspnea, and dizziness necessitating multiple hospitalizations. Elevation in free thyroxine (T4), total triiodothyronine (T3) and inappropriately normal thyroid stimulating hormone (TSH) was consistent with a clinical diagnosis of thyroid hormone resistance. Magnetic resonance imaging of the brain was negative for a TSH-secreting pituitary adenoma. A blood sample was sent for thyroid hormone receptor gene mutational analysis, but it would require eight weeks to complete processing. Results: A modified L-T3 suppression test was used to assess thyroid-pituitary axis feedback. After three weeks' of cytomel (L-T3) (25 micrograms daily) TSH decreased by 50%, and free T4 level decreased by 22% compared to baseline levels. Genetic testing revealed a heterozygous A317T mutation in the thyroid hormone beta receptor gene. Serial two-dimensional echocardiography demonstrated evolution to left atrial enlargement over a three-year period. Prior published literature suggests a less than 10% prevalence of atrial fibrillation in adults with thyroid hormone resistance harboring various TR-β gene mutations. Yet all five of five (100%) adults having the A317T mutation were reported to experience atrial fibrillation by age 50. Conclusions: A new kindred with resistance to thyroid hormone harboring the A317T disease-causative mutation is described in which identical twin sisters had a mid-life onset of atrial fibrillation and refractory congestive heart failure.

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Section: Discussionmentioning

confidence: 95%