Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects

NCT06307990 | Recruiting

• 1 other identifier: 05M202
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Resistance, Thyroid Hormone

Outcome Measures

Primary Outcomes (4)

• 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

  two years

• 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

  two years

• 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

  two years

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

  Transcriptome analysis of hiPSc-CNeu and hiPSC-CMs

  two years

Secondary Outcomes (2)

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

  two years

• Generation of a comprehensive RTH database

  two years

Study Arms (1)

RTH Syndromes

Patients with THRA or THRB gene mutations

Genetic: NGS sequencing; Diagnostic Test: serological tests

Interventions

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

RTH Syndromes

serological tests DIAGNOSTIC_TEST

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

RTH Syndromes

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study 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

You may qualify if:

• \- biochemical signature suggestive of RTHs syndromes at birth (a) or symptoms suggestive of RTHs syndromes (b) or known diagnosis of RTHs syndromes (c)

You may not qualify if:

• none

Sponsors & Collaborators

• Istituto Auxologico Italiano: lead
• ASST Fatebenefratelli Sacco: collaborator
• Federico II University: collaborator

Study Sites (2)

Istituto Auxologico Italiano IRCCS

Milan, 20145, Italy

RECRUITING

Department of Endocrine & Metabolic Diseases, San Luca Hospital

Milan, Italy

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

dried blood spots (DBS) peripheral blood cells extracted DNA

MeSH Terms

Conditions

Thyroid Hormone Resistance Syndrome

Interventions

Serologic Tests

Condition Hierarchy (Ancestors)

Hyperthyroxinemia; Thyroid Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Immunologic Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Immunologic Techniques

Central Study Contacts

Luca Persani, Prof

CONTACT

02619112738; luca.persani@unimi.it

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2024
• First Posted: March 13, 2024
• Study Start: January 1, 2023
• Primary Completion: October 31, 2025
• Study Completion: January 31, 2026
• Last Updated: September 2, 2025

Record last verified: 2025-08

Locations

IT (2)