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Giorgio Radetti Marienklinik, Bolzano, Italy

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Franco Rigon Department of Paediatrics, University of Padua, Padua, Italy

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Alessandro Salvatoni Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Irene Campi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Tiziana De Filippis Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Valentina Cirello Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Silvia Longhi Department of Paediatrics, Regional Hospital of Bolzano, Bolzano, Italy

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Fabiana Guizzardi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy

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Marco Bonomi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Luca Persani Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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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, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment.

Methods

Nine patients with CH followed in three Academic Centre who developed over time 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 congenital hypothyroidism (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 thyroid hormone (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 free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH 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 TH action.

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Tiziana de Filippis Laboratory of Endocrine and Metabolic Research, Milan, Italy
Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Federica Marelli Laboratory of Endocrine and Metabolic Research, Milan, Italy
Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Maria Cristina Vigone Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy

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Marianna Di Frenna Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy

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Giovanna Weber Department of Pediatrics, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy

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Luca Persani Laboratory of Endocrine and Metabolic Research, Milan, Italy
Division of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

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Objectives: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset. Methods: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay. Results: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c.177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter. Conclusions: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations.

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Irene Campi Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Maura Agostini Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Federica Marelli Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Tiziana de Filippis Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Beatriz Romartinez-Alonso Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom

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Odelia Rajanayagam Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Giuditta Rurale Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

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Ilaria Gentile Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Federica Spagnolo Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy

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Massimiliano Andreasi Laboratorio Analisi Cliniche, Centro di Ricerche e Tecnologie Biomediche, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Italy

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Francesco Ferraù Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy
Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

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Salvatore Cannavò Unit of Endocrinology, University Hospital “G. Martino”, Messina, Italy
Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

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Laura Fugazzola Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Krishna V. Chatterjee Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Luca Persani Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Introduction: Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. Case Presentation: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. Conclusion: Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.

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