Identification of Resistance to Exogenous Thyroxine in Humans

Lacámara, Nerea; Lecumberri, Beatriz; Barquiel, Beatriz; Escribano, Arancha; González‐Casado, Isabel; Álvarez-Escolá, Cristina; Aleixandre-Blanquer, F.; Morales, Francisco J.; Alfayate, Rocı́o; Bernal-Soriano, Mari Carmen; Miralles, Raquel; Şimşir, Ilgın Yıldırım; Özgen, A. Gökhan; Bernal, Juan; Berbel, Pere; Moreno, J.C.

doi:10.1089/thy.2019.0825

Cited by 10 publications

(13 citation statements)

References 59 publications

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“…Our patient had non-suppressed TSH levels with high FT3 and FT4 values. Compared to RTHβ, patients with RETH usually have elevated TSH levels, normal FT3 values with significantly reduced T3/T4 ratios suggesting the presence of FT4 defects of deiodination ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

Prete

Campi

et al. 2021

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter. Learning points Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH). Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test. RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.

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Section: Discussionmentioning

confidence: 99%

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

Prete

Campi

et al. 2021

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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“…with a prompt normalization of TSH. She grew regularly along the 50th centile (see figure), but at 3.5 years of age a raised TSH was observed (7.22 mU/l) together with a normal fT4 serum level (20.9 pg/ml; nv [12][13][14][15][16][17][18][19][20][21][22]. During the follow-up, TSH remained elevated (>8 mU/l) with a fT4 always at or above the upper limit.…”

Section: Genetic Analysis Showed a Heterozygous Point Variant Of Uncertain Significance (Vus) In Glis3mentioning

confidence: 93%

“…During the follow-up, TSH remained elevated (>8 mU/l) with a fT4 always at or above the upper limit. At the last monitoring at the age of 4.8 years, while receiving 25 µg/daily, her TSH value was 11.3 mU/l (nv 0.7-6 mU/l) and fT4 21.3 pmol/l (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Thyroid ultrasound at the last visit showed a thyroid of normal size with a normal echographic pattern.…”

Section: Genetic Analysis Showed a Heterozygous Point Variant Of Uncertain Significance (Vus) In Glis3mentioning

confidence: 97%

“…Subsequently, on several occasions, high TSH levels and fT4 levels in the upper part of the reference range were simultaneously detected. At the last monitoring at the age of 8.8 years, while receiving 64 µg/daily (2.6 µg/kg/day), her TSH value was 15.1 mU/l (0.27-4.2 mU/l) and fT4 21.11 pmol/l (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). She grows regularly 25 th -10 th centile and doesn't show either neurological or cognitive deficits.…”

Section: Genetic Analysis Showed a Heterozygous Point Variant Of Uncertain Significance (Vus) In Glis3mentioning

confidence: 98%

“…Recently, Lacámara et al reported resistance to exogenous thyroxine (RETH) ( 18 ) in patients with different causes of hypothyroidism, including total thyroidectomy. Differently from RTHβ patients, RETH patients had a decreased T3/T4 ratio, suggesting that D2 functional deficiency underlies RETH but not RTHβ.…”

Section: Introductionmentioning

confidence: 99%

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Tissue sensitivity to thyroid hormones may change over time

Radetti

Rigon

Salvatoni

et al. 2022

European Thyroid Journal

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Introduction: Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals TSH fails to normalize despite adequate LT4 treatment. Methods: Nine patients with CH followed in three Academic Centre who developed over time a resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted Next Generation Sequencing technique including a panel of candidate genes involved in thyroid hormone actions and CH: THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2.5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. Results: All patients displayed a normal sensitivity to TH in the first years of life, but developed variable degrees of resistance to LT4 treatment at later stages. In all cases TSH normalized only in the presence of high FT4 levels. T3 suppression test followed by TRH stimulation was performed in two cases and was compatible with central resistance to thyroid hormones. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (N=2) or an eutopic gland (N=3) or in case of agenesis (N=1). None of the patients had genetic variants in genes involved in the regulation of thyroid hormone actions, while in two cases we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. Conclusions: We report CH patients who showed an acquired and unexplainable pituitary refractoriness to thyroid hormone action.

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Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism

Gentilini

Muzza

Filippis

et al. 2022

J Endocrinol Invest

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Purpose The elevated frequency of discordance for congenital hypothyroidism (CH) phenotype between monozygotic twins suggests the involvement of non-mendelian mechanisms. The aim of the study was to investigate the role of epigenetics in CH pathogenesis. Methods A genome-wide DNA methylation analysis was performed on the peripheral blood of 23 twin pairs (10 monozygotic and 13 dizygotic), 4 concordant and 19 discordant pairs for CH at birth. Results Differential methylation analysis did not show significant differences in methylation levels between CH cases and controls, but a different methylation status of several genes may explain the CH discordance of a monozygotic twin couple carrying a monoallelic nonsense mutation of DUOX2. In addition, the median number of hypo-methylated Stochastic Epigenetic Mutations (SEMs) resulted significantly increased in cases compared to controls. The prioritization analysis for CH performed on the genes epimutated exclusively in the cases identified SLC26A4, FOXI1, NKX2-5 and TSHB as the genes with the highest score. The analysis of significantly SEMs-enriched regions led to the identification of two genes (FAM50B and MEG8) that resulted epigenetically dysregulated in cases. Conclusion Epigenetic modifications may potentially account for CH pathogenesis and explain discordance among monozygotic twins.

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Identification of Resistance to Exogenous Thyroxine in Humans

Cited by 10 publications

References 59 publications

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome

Tissue sensitivity to thyroid hormones may change over time

Stochastic epigenetic mutations as possible explanation for phenotypical discordance among twins with congenital hypothyroidism

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