Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects (ADAM-THAD)

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:

• 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.

Study Overview

• Status: Recruiting
• Conditions: Resistance, Thyroid Hormone
• Intervention / Treatment: Genetic: NGS sequencing; Diagnostic test: serological tests

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.

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Luca Persani, Prof; Phone Number: 039 02619112738; Email: luca.persani@unimi.it

Study Locations

• Italy
  • Milan, Italy, 20145
    • Recruiting
    • Istituto Auxologico Italiano IRCCS
    • Contact: Irene Campi, MD, PhD
  • Milan, Italy
    • Recruiting
    • Department of Endocrine & Metabolic Diseases, San Luca Hospital
    • Contact: Luca Persani, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• 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

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
RTH Syndromes; Patients with THRA or THRB gene mutations	Genetic: 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; Diagnostic test: serological tests; assessment of T4, T3 and other TH metabolites (LC-MS) in serum and dried blood spots

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
to define the frequency and improve early diagnosis for RTH syndromes.	Thyroid hormone levels determinations in DBS of newborns	two years
to demonstrate that zebrafish zygotes are useful for screening of the pathogenicity of new TR mutations	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
to define the prevalence of 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.	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.	two years

Collaborators and Investigators

• Sponsor: Istituto Auxologico Italiano
• Collaborators: Federico II University; ASST Fatebenefratelli Sacco

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: March 6, 2024
• First Submitted That Met QC Criteria: March 6, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Hyperthyroxinemia; Thyroid Diseases; Thyroid Hormone Resistance Syndrome
• Other Study ID Numbers: 05M202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No