Clinical trial NCT06307990: Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects
Official title: Advancing Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Resistance, Thyroid Hormone
Lead sponsor: Istituto Auxologico Italiano
Sponsor class: OTHER
Collaborators: name: ASST Fatebenefratelli Sacco
name: Federico II University
First posted: 2024-03-13
Enrollment: 150
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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

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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* none

Primary outcomes:
measure: to define the frequency and improve early diagnosis for RTH syndromes.
timeFrame: two years
measure: to demonstrate that zebrafish zygotes are useful for screening of the pathogenicity of new TR mutations
timeFrame: two years
measure: Direct differentiation of THRA mutant patients-derived human induced pluripotent stem cells (hiPSCs) to neural progenitors (hiPSc-CNeu) and cardiomyocyte (hiPSC-CMs)
timeFrame: two years
measure: To identify TH-target genes involved in determining stemness, proliferation potential and differentiation of hiPSC
timeFrame: two years
Secondary outcomes:
measure: to define the prevalence of RTH syndromes in specific cohorts of patients with unexplained phenotypes
timeFrame: two years
measure: Generation of a comprehensive RTH database
timeFrame: two years
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Istituto Auxologico Italiano IRCCS
city: Milan
country: Italy
facility: Department of Endocrine & Metabolic Diseases, San Luca Hospital
Study officials:
References: