Resistance, Thyroid HormoneADAM-THADNCT06307990
Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects
An observational study of Resistance, Thyroid Hormone, run by Istituto Auxologico Italiano at 2 sites in Italy.
Trial 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). Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Resistance, Thyroid Hormone
- What is being tested?
- NGS sequencing and serological tests
- How many people
- 150 participants
- Where
- 2 sitesItaly
- Study dates
- 1 Jan 2023to 31 Jan 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
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
Who may be able to join
- biochemical signature suggestive of RTHs syndromes at birth (a) or symptoms suggestive of RTHs syndromes (b) or known diagnosis of RTHs syndromes (c)
Who cannot join
- none
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy2 sites, 2 recruiting
- Recruiting
Istituto Auxologico Italiano IRCCS
Milan, 20145
Irene Campi, MD, PhD
- Recruiting
Department of Endocrine & Metabolic Diseases, San Luca Hospital
Milan
Luca Persani, Prof
About this study
Official title: Advancing Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)
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:
Read more
- 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.
Read the 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:
- develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
- understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
- 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.
- Conditions
- Resistance, Thyroid Hormone
- Being tested
- NGS sequencing, serological tests
- Medical subject headings
- Thyroid Hormone Resistance Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NGS sequencingGenetic
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 testsDiagnostic test
assessment of T4, T3 and other TH metabolites (LC-MS) in serum and dried blood spots
| Study group | Role | What they receive |
|---|---|---|
| RTH Syndromes | Patients with THRA or THRB gene mutations Receives: Genetic: NGS sequencing; Diagnostic Test: serological tests |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: two years
Secondary outcomes (2)
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.
Measured: two years
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.
Measured: two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2024
- Study start1 Jan 2023
- Primary completion31 Oct 2025 (estimated)
- Study completion31 Jan 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Resistance, Thyroid HormoneStudies of the same condition, open and under way.
- More trials run by Istituto Auxologico ItalianoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Istituto Auxologico Italiano
- Sponsor type
- University, hospital or other
- Collaborators
- ASST Fatebenefratelli Sacco, Federico II University
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06307990
- Sponsor's protocol ID
- 05M202
- Acronym
- ADAM-THAD
- Status last verified
- Aug 2025
- First submitted
- 6 Mar 2024
- Last updated
- 2 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Advancing Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)
- ClinicalTrials.gov ID
- NCT06307990
- Acronym / sponsor ID
- ADAM-THAD / 05M202
- Conditions
- Resistance, Thyroid Hormone
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Istituto Auxologico ItalianoUniversity, hospital or other
- Collaborators
- ASST Fatebenefratelli Sacco, Federico II University
- Study start
- 1 Jan 2023 (actual)
- Primary completion
- 31 Oct 2025 (estimated)
- Study completion
- 31 Jan 2026 (estimated)
- First posted
- 13 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
- understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
- 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.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| RTH Syndromes | – | Genetic: NGS sequencing, Diagnostic Test: serological testsPatients with THRA or THRB gene mutations |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- 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
Key inclusion criteria (1 listed)
- biochemical signature suggestive of RTHs syndromes at birth (a) or symptoms suggestive of RTHs syndromes (b) or known diagnosis of RTHs syndromes (c)
Key exclusion criteria (1 listed)
- none
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NGS sequencinganalysis of candidate genes for RTHs syndromes, transporters defects or gene involved in thyroid hormone metabolism. Whole exome sequencing (WES) in a minority of cases | Genetic | RTH Syndromes |
| serological testsassessment of T4, T3 and other TH metabolites (LC-MS) in serum and dried blood spots | Diagnostic test | RTH Syndromes |
Primary outcome
Number of Newborns With Abnormal Thyroid Hormone Levels Suggestive of Resistance to Thyroid Hormone (RTH) Syndromes, as Measured in Dried Blood Spots (DBS).
Time frame: 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).
Time frame: 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)
Time frame: 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
Time frame: two years
Transcriptome analysis of hiPSc-CNeu and hiPSC-CMs
2 secondary outcomes
Prevalence of Resistance to Thyroid Hormone (RTH) Syndromes in Specific Cohorts of Patients with Unexplained Phenotypes
Time frame: two years
Generation of a comprehensive RTH database
Time frame: two years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Sep 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Resistance, Thyroid Hormone, run by Istituto Auxologico Italiano at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 2 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Luca Persani, Prof (02619112738 ext. 039, luca.persani@unimi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Newborns With Abnormal Thyroid Hormone Levels Suggestive of Resistance to Thyroid Hormone (RTH) Syndromes, as Measured in Dried Blood Spots (DBS). (time frame: two years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Sep 2025.