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 3,3',5-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, e.g. 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 MCT8/THRα-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 fT3/fT4 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.
