Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects
- Conditions
- Resistance, Thyroid Hormone
- Interventions
- Genetic: NGS sequencingDiagnostic Test: serological tests
- Registration Number
- NCT06307990
- Lead Sponsor
- Istituto Auxologico Italiano
- 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.
- Detailed Description
TH action defects (THAD) are a group of rare syndromes characterized by abnormal thyroid hormone (TH) cell signaling due to defective transport, metabolism or action of TH via binding with nuclear receptors (TRs): there are two TRs, the alpha (TRa) and beta (TRß) receptors. Among them, mutations of THRA or THRB genes cause two distinct syndromes with Resistance to Thyroid Hormone (RTH) action whose incidence was estimated 1:20,000-50,000 newborns, likely representing the most frequent THAD forms. RTHa is due to dominant negative (DN) heterozygous mutations in THRA and characterized by dramatic manifestations in TRa-expressing tissues resembling untreated congenital hypothyroidism (CH).
RTHß is due to DN heterozygous THRB mutations, which cause variable TH resistance in TRß-expressing tissues (hypothalamus, pituitary, liver), resulting in distinctive biochemical signature (high free TH and unsuppressed TSH) together with additional features like deafness, impaired color vision and thyrotoxic-related symptoms (goiter, tachyarrhythmias, osteoporosis, anxiety and Attention-Deficit/Hyperactivity Disorder, ADHD).
Outstandingly, early treatment with TH or its analogues is expected to reduce most of the adverse consequences of RTHs but early/neonatal diagnosis is presently not feasible due to the lack of accurate biomarkers. Indeed, uniform characterization is essential for a rare disease, and establishment of clear-cut endocrine fingerprints for RTHa and RTHß are essential for a timely diagnosis.
In addition, the wide application of next generation sequencing (NGS) has yielded an unprecedented wealth of genetic information, calling for proper instruments to distinguish benign from pathogenic variants.
Finally, biomarkers for monitoring treatment of these conditions have not been established or validated.
This study aim to:
1. develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
2. understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
3. generate induced pluripotent stem cells from RTH patients to understand the molecular mechanisms underlying neurological and cardiovascular consequences and correlate in vitro and clinical data, with the final goal to identify potential biomarkers for monitoring treatment of these rare diseases.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 150
- biochemical signature suggestive of RTHs syndromes at birth (a) or symptoms suggestive of RTHs syndromes (b) or known diagnosis of RTHs syndromes (c)
- none
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description RTH Syndromes serological tests Patients with THRA or THRB gene mutations RTH Syndromes NGS sequencing Patients with THRA or THRB gene mutations
- Primary Outcome Measures
Name Time Method to define the frequency and improve early diagnosis for RTH syndromes. two years Thyroid hormone levels determinations in DBS of newborns
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
to demonstrate that zebrafish zygotes are useful for screening of the pathogenicity of new TR mutations 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
- Secondary Outcome Measures
Name Time Method to define the prevalence of RTH syndromes in specific cohorts of patients with unexplained phenotypes two years 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.
Generation of a comprehensive RTH database two years To establish a comprehensive RTH database including whole clinical/genetic/biochemical data of RTH patients, in view of the generation of a disease registry.
Trial Locations
- Locations (2)
Istituto Auxologico Italiano IRCCS
🇮🇹Milan, Italy
Department of Endocrine & Metabolic Diseases, San Luca Hospital
🇮🇹Milan, Italy