Inborn Errors of Synthesis and Sensitivity to Thyroid Hormone

Inborn errors of thyroid hormone synthesis leading to insufficient amounts of hormone, commonly referred to as congenital hypothyroidism is the most frequent neonatal endocrine disorder. Thyroid hormones play an essential role in the maturation of the central nervous system. Untreated congenital hypothyroidism can result in neurodevelopmental impairment and hypothyroidism in infancy is the most common preventable cause of irreversible intellectual impairment worldwide. Because clinical signs of hypothyroidism are rarely apparent in the newborn period, newborn screening programs have been implemented in many regions to detect congenital hypothyroidism and permit early treatment with levothyroxine, which prevents severe intellectual disability.
Congenital hypothyroidism can be caused by defects occurring at any of two different levels: the hypothalamic-pituitary axis and the thyroid gland itself. In addition, inborn errors also impair sensitivity to thyroid hormone in peripheral tissues due to defects in thyroid hormones metabolism, transport of thyroid hormones into the cell, and genomic and non-genomic effects of thyroid hormones due to defective thyroid hormone receptor isoforms and nuclear receptor corepressors and coactivators. Although many cases of inborn error leading to hypothyroidism have no clear genetic etiology, a variety of monogenic defects have been reported in individuals with thyroid dysgenesis, thyroid dyshormonogenesis, central hypothyroidism, and sensitivity to thyroid hormone, highlighting the genetic heterogeneity of the disease. Moreover, next-generation sequencing technologies have illuminated the potential role of oligogenicity in the etiology of congenital hypothyroidism. Although genetic analysis may not necessarily affect the management of the patients, the results can aid genetic counseling and may guide treatment. Considering recent advances in preclinical stages of potential therapies for Allan Herndon Dudley syndrome, caused by defective triiodothyronine uptake in neurons, the importance of genetic diagnosis is gaining more momentum.

We welcome original research articles and review proposals, including the following themes:

· Newborn screening for neonatal hypothyroidism.

· Diagnosis and management of patients with defective synthesis and sensitivity to thyroid hormone.

· Clinical outcomes of patients with defective synthesis and sensitivity to thyroid hormone.

· Novel therapies for patients with impaired sensitivity to thyroid hormone.

· Molecular basis of congenital hypothyroidism and impaired sensitivity to thyroid hormone.

· Functional characterization of disease-causing pathogenic variants.

· Technological advances in molecular diagnosis.

· Technological advances in models to study the molecular basis of inborn errors of defective synthesis and sensitivity to thyroid hormone.

This research topic will explore the latest advances in the genetic basis of inborn errors of defective synthesis and sensitivity to thyroid hormone and novel strategies to uncover the molecular etiology of the disease. Moreover, the articles will present current knowledge and future perspectives on clinical management, the clinical relevance of the molecular diagnosis, and the development of novel therapies for patients with defective synthesis and sensitivity to thyroid hormone.