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Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects

ConditionResistance, Thyroid Hormone
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
AgeNot listed
SponsorIstituto Auxologico Italiano

About this trial

The goal of this observational study is to learn about the neurological and cardiological phenotype of patients with resistance to thyroid hormone (RTH) syndromes beta and alpha (RTHß and RTHa) due to dominant negative variants in the genes encoding the thyroid hormone receptors alpha (THRA) and beta (THRB).

The main question\[s\] it aims to answer are:

* Define frequency and improve early diagnosis for RTH syndromes * Developing tools to accelerate diagnosis of RTH syndromes * Development and validation of monitoring tools

Participants, recruited at neonatal screening or from cohorts of patients with unexplained specific neuro-cognitive or cardiovascular phenotypes will be submitted to biochemical and genetic investigations. In addition pluripotent stem cells will be generated from peripheral blood cells of RTHs patients and studied in vitro to understand the molecular mechanisms underlying neurological and cardiovascular consequences. In vitro and clinical data, will be correlated to identify biomarkers for monitoring treatment.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

None

Disqualifiers

none

Trial population

Newborn patients (a) with normal TSH, but T3 and other TH metabolites suggestive of RTH syndromes, we will be submitted to genetic analysis Cohorts of patients (b) with unexplained: i) mental retardation and delayed development or epilepsy (ii) autism spectrum disorders (iii) growth maturation defects (iv) early onset cardiovascular diseases (v) with inappropriate tachycardia (vi) with ADHD or learning disorders (vii) early onset tachyarrhythmias, will be submitted to genetic analysis Patients with RTH syndromes already diagnosed and followed in the collaborating centers

Trial design

Design model

Case-only

Time perspective

Prospective

Treatments tested in this trial

  • NGS sequencing

    Genetic

    analysis of candidate genes for RTHs syndromes, transporters defects or gene involved in thyroid hormone metabolism. Whole exome sequencing (WES) in a minority of cases

  • serological tests

    Diagnostic test

    assessment of T4, T3 and other TH metabolites (LC-MS) in serum and dried blood spots

Treatment groups

150 Participants
are divided into 1 treatment group
Group A: RTH Syndromes2 interventions

Trial outcomes

Primary outcomes

1

Number of Newborns With Abnormal Thyroid Hormone Levels Suggestive of Resistance to Thyroid Hormone (RTH) Syndromes, as Measured in Dried Blood Spots (DBS).

Thyroid hormone levels determinations in DBS of newborns

Time frame
two years
2

Frequency of Phenotypic Changes in Zebrafish Zygotes Microinjected with Human TR Variants, as a Measure of the Functional Impact of THRA and THRB Variants of Uncertain Significance (VUS).

Functional impact of THRA and THRB variant of uncertain significance (VUS) in the zebrafish model microinjected with different human TR variants

Time frame
two years
3

Direct differentiation of THRA mutant patients-derived human induced pluripotent stem cells (hiPSCs) to neural progenitors (hiPSc-CNeu) and cardiomyocyte (hiPSC-CMs)

Molecular characterization and electrophysiological characterization of hiPSc-CNeu and hiPSC-CMs carrying THRA and THRB variants and comparison with matched controls

Time frame
two years
4

To identify TH-target genes involved in determining stemness, proliferation potential and differentiation of hiPSC

Transcriptome analysis of hiPSc-CNeu and hiPSC-CMs

Time frame
two years

Secondary outcomes

1

Prevalence of Resistance to Thyroid Hormone (RTH) Syndromes in Specific Cohorts of Patients with Unexplained Phenotypes

To search novel RTHa cases in cohorts of patients with unexplained: i) mental retardation and delayed development or epilepsy (ii) autism spectrum disorders (iii) growth maturation defects (iv) early onset cardiovascular diseases. For RTHß, we aim to screen patients (i) with inappropriate tachycardia (ii) with ADHD or learning disorders (iii) early onset tachyarrhythmias.

Time frame
two years
2

Generation of a comprehensive RTH database

To establish a comprehensive RTH database including whole clinical/genetic/biochemical data of RTH patients, in view of the generation of a disease registry.

Time frame
two years

Other outcomes

Sponsors and contacts

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Istituto Auxologico Italiano

Lead sponsor

ASST Fatebenefratelli Sacco

Collaborator

Federico II University

Collaborator

Source ClinicalTrials.gov
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