Mutational and bioinformatics analysis of the NKX2.1 gene in a cohort of Iranian pediatric patients with congenital hypothyroidism (CH)

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder in neonates and children with a global incidence of 1 in 3,000–4,000. Adequate thyroid hormone levels in the bloodstream are essential for the normal growth and development of the nervous system in children. Consequently, CH is associated with irreversible central nervous system and mental health problems, as well as poor growth of untreated children with CH. Girls are more likely to be affected than boys (female to male ratios are 2:1) [1–3]. Early diagnosis methods for CH are still necessary to establish more efficient treatments of CH, which is an important public health issue worldwide, including developed countries [4]. CH can be classified either as primary or as central hypothyroidism, and it is an autosomal recessive disorder. But in a significant percentage of patients, CH is sporadic and non-hereditary and caused by de novo developmental defects in the thyroid gland (primary congenital hypothyroidism). Hereditary forms of CH with decreased thyroid hormone synthesis are either due to a defective thyroid gland development (thyroid dysgenesis) present in 80% of patients or to a failure in thyroid hormone synthesis (thyroid dyshormonogenesis) present in 20% of the patients [5, 6]. Thyroid dysgenesis (TD; OMIM 218700), which refers to the most common cause of congenital hypothyroidism and abnormal structural malformations in the thyroid, is subcategorized into: (i) thyroid ectopy, an abnormally located and small thyroid gland; (ii) thyroid athyreosis, complete lack of the thyroid gland in imaging studies; and (iii) hypoplasia, a smaller gland of thyroid tissue but in a normal position. Dyshormonogenesis (OMIM 274400–274900) refers to the failure of thyroid hormone synthesis by a structurally normal thyroid gland [7]. In recent years, the overall incidence of CH has increased, including the transient form of CH in children, which is a consequence of thyroid hormone deficiency due to low thyroxine and elevated thyrotropin expression. Temporary CH may show symptoms of mild dyshormonogenesis during the first months of life due to insufficient production of thyroxine (T4) [8, 9]. Transient CH usually resolves itself in the first few months of infancy because of an increase in thyroxine production, but some of these children may also be treated for CH in infancy with levothyroxine (a manufactured form of the thyroid hormone thyroxine). However, after treatment endogenous hormonal levels are normalized, and by the age of 3, these children no longer need medication. info:eu-repo/semantics/publishedVersion