Genetic Defects in Thyroid Hormone Supply

Congenital hypothyroidism (CH) is the most frequent endocrine-metabolic disease in infancy, with an incidence of about 1/2500 newborns [1, 2]. In the last 20-30 years the incidence of congenital hypothyroidism in newborns has increased from 1:4000 to 1:2000 [3, 4]. This phenomenon could be explained by using a lower b-TSH cutoff, that allowed the detection of an unsuspected number of children with neonatal hypothyroidism [5]. With the exception of rare cases due to hypothalamic or pituitary defects, CH is characterized by elevated TSH in response to reduced thyroid hormone levels. In absence of an adequate treatment, CH determines growth retardation, delays in motor development, and permanent intellectual disability. Primary CH is determined by alterations occurring during the thyroid gland development (thyroid dysgenesis, TD [6]) or alterations in the thyroid hormone biosynthesis pathways (thyroid dyshormonogenesis). Less common causes of CH are secondary or peripheral defects in TSH synthesis and/or action, defects in thyroid hormone transport, metabolism, or action [7]. Table 1 shows a summary of the forms of CH with a genetic cause. In the majority of cases (80-85%), primary permanent CH is associated with TD. These forms include developmental disorders such as athyreosis, ectopy, hemiagenesis or hypoplasia. TD occurs mostly as sporadic disease, however a genetic cause has been demonstrated in about 2-5% of the reported cases [8]. Genes associated with TD include several thyroid transcription factors expressed in the early phases of thyroid organogenesis (, , , ) as well as genes, like the thyrotropin receptor gene () expressed later during gland morphogenesis. In the remaining 15-20% of cases, CH is caused by inborn errors in the molecular steps required for the biosynthesis of thyroid hormones, and generally it is characterized by enlargement of the gland (goiter), presumably due to elevated TSH levels [9]. Generally, thyroid dyshormonogenesis shows classical Mendelian recessive inheritance. Rarely CH has a central origin, as consequence of hypothalamic and/or pituitary diseases, with reduced production or function of thyrotropin releasing hormone (TRH) or thyrotropin hormone (TSH) [10]. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.