Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects

Condition(s) studied

Investigational drug(s) / intervention(s)

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

Study summary

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

Primary outcome measure(s)

• Number of Newborns With Abnormal Thyroid Hormone Levels Suggestive of Resistance to Thyroid Hormone (RTH) Syndromes, as Measured in Dried Blood Spots (DBS). — two years
  Thyroid hormone levels determinations in DBS of newborns
• 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). — two years
  Functional impact of THRA and THRB variant of uncertain significance (VUS) in the zebrafish model microinjected with different human TR variants
• Direct differentiation of THRA mutant patients-derived human induced pluripotent stem cells (hiPSCs) to neural progenitors (hiPSc-CNeu) and cardiomyocyte (hiPSC-CMs) — two years
  Molecular characterization and electrophysiological characterization of hiPSc-CNeu and hiPSC-CMs carrying THRA and THRB variants and comparison with matched controls
• To identify TH-target genes involved in determining stemness, proliferation potential and differentiation of hiPSC — two years
  Transcriptome analysis of hiPSc-CNeu and hiPSC-CMs

Trial sites (2)

More Istituto Auxologico Italiano trials in Italy