protocolSection identificationModule nctId: NCT06307990, orgStudyIdInfo id: 05M202, briefTitle: Understanding, Diagnosis and Monitoring of Thyroid Hormone Action Defects, acronym: ADAM-THAD, statusModule overallStatus: RECRUITING, startDateStruct date: 2023-01-01, primaryCompletionDateStruct date: 2024-12-31, completionDateStruct date: 2025-04-30, studyFirstPostDateStruct date: 2024-03-13, lastUpdatePostDateStruct date: 2024-03-13, sponsorCollaboratorsModule leadSponsor name: Istituto Auxologico Italiano, class: OTHER, collaborators name: ASST Fatebenefratelli Sacco, collaborators name: Federico II University, descriptionModule briefSummary: 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 toolsParticipants, 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., conditionsModule conditions: Resistance, Thyroid Hormone, designModule studyType: OBSERVATIONAL, designInfo observationalModel: CASE_ONLY, timePerspective: PROSPECTIVE, enrollmentInfo count: 150, type: ESTIMATED, armsInterventionsModule interventions name: NGS sequencing, interventions name: serological tests, outcomesModule primaryOutcomes measure: to define the frequency and improve early diagnosis for RTH syndromes., primaryOutcomes measure: to demonstrate that zebrafish zygotes are useful for screening of the pathogenicity of new TR mutations, primaryOutcomes measure: Direct differentiation of THRA mutant patients-derived human induced pluripotent stem cells (hiPSCs) to neural progenitors (hiPSc-CNeu) and cardiomyocyte (hiPSC-CMs), primaryOutcomes measure: To identify TH-target genes involved in determining stemness, proliferation potential and differentiation of hiPSC, secondaryOutcomes measure: to define the prevalence of RTH syndromes in specific cohorts of patients with unexplained phenotypes, secondaryOutcomes measure: Generation of a comprehensive RTH database, eligibilityModule sex: ALL, stdAges: CHILD, stdAges: ADULT, stdAges: OLDER_ADULT, contactsLocationsModule locations facility: Istituto Auxologico Italiano IRCCS, status: RECRUITING, city: Milan, zip: 20145, country: Italy, contacts name: Irene Campi, MD, PhD, role: CONTACT, geoPoint lat: 45.46427, lon: 9.18951, locations facility: Department of Endocrine & Metabolic Diseases, San Luca Hospital, status: RECRUITING, city: Milan, country: Italy, contacts name: Luca Persani, Prof, role: CONTACT, geoPoint lat: 45.46427, lon: 9.18951, hasResults: False