Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06566066
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-08-11
Brief Title:
Register for Patients With Thyroid Hormone Resistance
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Deep Geno- and Phenotyping of Patients With Thyroid Hormone Resistance a Register Study
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DEEPTYPE
Brief Summary:
Thyroid hormones TH play a pivotal role in the development and function of the mammalian brain Patients with impaired thyroid hormone transport into the brain tissue or in the case of defective local thyroid hormone receptor collectively referred to as thyroid hormone resistance subsequently experience psychomotor disabilities
The DEEPTYPE registry has been established with the objective of intensifying the genotyping and in particular the neurological phenotyping of patients exhibiting deficiencies in either the thyroid hormone transporter MCT8 or the thyroid hormone receptor alpha THRα The objective of this registry-based study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3fT4 ratio as a more sophisticated screening parameter Furthermore the investigators will study the genomic regulation of both genes and attempt to identify further coding and non-coding mutations that result in TH resistance The patient registry DEEPTYPE will document the retrospective and prospective clinical data of identified children in a comprehensive manner This will enable the identification of three key groups i patients with non-coding mutations ii patients with milder phenotypes presenting only with a subset of symptoms seen in both classic conditions and iii patients who are ready for clinical trials
The DEEPTYPE registry has been established with the objective of intensifying the genotyping and in particular the neurological phenotyping of patients exhibiting deficiencies in either the thyroid hormone transporter MCT8 or the thyroid hormone receptor alpha THRα The objective of this registry-based study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3fT4 ratio as a more sophisticated screening parameter Furthermore the investigators will study the genomic regulation of both genes and attempt to identify further coding and non-coding mutations that result in TH resistance The patient registry DEEPTYPE will document the retrospective and prospective clinical data of identified children in a comprehensive manner This will enable the identification of three key groups i patients with non-coding mutations ii patients with milder phenotypes presenting only with a subset of symptoms seen in both classic conditions and iii patients who are ready for clinical trials
Detailed Description:
Thyroid hormones TH are of vital importance in the development and functioning of the brain A deficiency in fetal thyroid hormone TH supply has been linked to significant psychomotor retardation in children born in regions with inadequate iodine supply Insufficient postnatal production of thyroid hormones TH can result in intellectual and motor disabilities These can be prevented by L-thyroxine T4 supplementation in children with congenital hypothyroidism immediately after birth
However in the event of impaired transport of thyroid hormones into the brain tissue or in the case of defective local thyroid hormone receptors the cerebral action of these hormones is impeded despite the presence of a sufficient thyroid hormone production Such conditions may result from mutations in either SLC16A2 which encodes the monocarboxylate transporter 8 MCT8 or THRA which codes for the thyroid hormone receptor alpha THRα THRα is widely expressed in the central nervous system CNS In both instances the absence of local TH action results in severe intellectual disability developmental delay movement disorders and decreased brain volumes In contrast to the outcomes observed in cases of congenital hypothyroidism treatment trials involving the substitution of TH were ineffective in preventing the neurological phenotype in these children
The full genotypic and phenotypic spectrum of these children has yet to be explored It is anticipated that both conditions will be significantly underdiagnosed given that awareness of these differential diagnoses within the pediatric community remains limited As the standard screening parameters such as thyroid-stimulating hormone TSH are not altered the condition is frequently overlooked and is most often only accidentally diagnosed through next-generation sequencing
The sole endocrine irregularity is a relative elevation of 335-triiodothyronine T3 in comparison to T4 However this is not a parameter that is routinely measured More often the concentrations of the free plasma concentrations of these hormones eg fT3 and fT4 are measured
To date only patients with mutations in the coding regions of the respective loci have been described It can be reasonably assumed that mutations in the non-coding regulatory regions will result in disruption of the tissue-specific TH action in the MCT8THRα-deficient brain Similarly disruptions in gene expression resulting from mutant regulatory enhancer sequences have recently been identified in other endocrine disorders including congenital diabetes and brain developmental disorders
The objective of this study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3fT4 ratio as a potentially more sophisticated screening parameter Furthermore the investigators will study the genomic regulation of both genes The patient registry DEEPTYPE will be used to comprehensively document retrospective and prospective clinical data of identified children with coding or non-coding mutations This will enable the investigators to identify patients with non-coding mutations and discover patients with milder phenotypes presenting only with a subset of symptoms seen in both classic conditions
However in the event of impaired transport of thyroid hormones into the brain tissue or in the case of defective local thyroid hormone receptors the cerebral action of these hormones is impeded despite the presence of a sufficient thyroid hormone production Such conditions may result from mutations in either SLC16A2 which encodes the monocarboxylate transporter 8 MCT8 or THRA which codes for the thyroid hormone receptor alpha THRα THRα is widely expressed in the central nervous system CNS In both instances the absence of local TH action results in severe intellectual disability developmental delay movement disorders and decreased brain volumes In contrast to the outcomes observed in cases of congenital hypothyroidism treatment trials involving the substitution of TH were ineffective in preventing the neurological phenotype in these children
The full genotypic and phenotypic spectrum of these children has yet to be explored It is anticipated that both conditions will be significantly underdiagnosed given that awareness of these differential diagnoses within the pediatric community remains limited As the standard screening parameters such as thyroid-stimulating hormone TSH are not altered the condition is frequently overlooked and is most often only accidentally diagnosed through next-generation sequencing
The sole endocrine irregularity is a relative elevation of 335-triiodothyronine T3 in comparison to T4 However this is not a parameter that is routinely measured More often the concentrations of the free plasma concentrations of these hormones eg fT3 and fT4 are measured
To date only patients with mutations in the coding regions of the respective loci have been described It can be reasonably assumed that mutations in the non-coding regulatory regions will result in disruption of the tissue-specific TH action in the MCT8THRα-deficient brain Similarly disruptions in gene expression resulting from mutant regulatory enhancer sequences have recently been identified in other endocrine disorders including congenital diabetes and brain developmental disorders
The objective of this study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3fT4 ratio as a potentially more sophisticated screening parameter Furthermore the investigators will study the genomic regulation of both genes The patient registry DEEPTYPE will be used to comprehensively document retrospective and prospective clinical data of identified children with coding or non-coding mutations This will enable the investigators to identify patients with non-coding mutations and discover patients with milder phenotypes presenting only with a subset of symptoms seen in both classic conditions
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None