Genetic Defects in Thyroid Hormone Supply

INTRODUCTION Congenital hypothyroidism (CH) is the most frequent endocrine-metabolic disease in infancy, with an incidence of about 1/2000-4000 newborns (1,2). 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 due to alterations occurring during the gland development (thyroid dysgenesis, TD) or distruptions in thyroid hormone biosynthesis (thyroid dysormonogenesis). Less common causes of CH are secondary or peripheral defects in TSH synthesis and/or action, defects in thyroid hormone transport, metabolism, or action (3). In the majority of cases (80-85%), primary permanent CH is due to alterations occurring during the gland organogenesis, resulting in a thyroid that is absent (athyreosis), hypoplastic (thyroid hypoplasia) or located in an unusual position (thyroid ectopy). All these entities are grouped under the term “thyroid dysgenesis” (TD)(4). TD occurs mostly as a sporadic disease, however a genetic cause of the disease has been demonstrated in about 5% of the reported cases (5). Genes associated with TD include several thyroid transcription factors expressed in the early phases of thyroid organogenesis (NKX2.1/TITF1, FOXE1/TITF2, PAX8, NKX2.5) as well as genes, like the thyrotropin receptor gene (TSHR) expressed later during gland morphogenesis.