Advances and Perspectives in Genetics of Congenital Thyroid Disorders

Congenital hypothyroidism (CH) is the most frequent endocrine disease in infants, affects about 1 in 3,000 newborns and is characterized by elevated levels of thyroidstimulating hormone (TSH) as a consequence of reduced thyroid function. It is also one of the most common preventable causes of cognitive and motor deficits. Prevention of CH is based on carrier identification, genetic counseling and prenatal diagnosis. In neonates a complete diagnosis of CH should include clinical examination, biochemical thyroid tests, thyroid ultrasound, radioiodine or technetium scintigraphy and perchlorate discharge test (PDT). In the last two decades, considerable progress has been made in identifying the genetic and molecular causes of CH. Knowing the prevalence of mutations in each population will facilitate greatly the molecular genetic testing. The classification based on the genetic alterations divides CH into two main categories caused: (a) by disorders of thyroid gland development (dysembriogenesis or thyroid dysgenesis group) or (b) by defects in any of the steps of thyroid hormone synthesis (dyshormonogenesis group) [1]. The dysembryogenesis or thyroid dysgenesis group, which accounts for the 80-85% of the cases, results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [1]. In only 5% of the patients, the CH is associated with mutations in genes responsible for the development or growth of thyroid cells: NKX2.1 (also known as TTF1 or T/EBP), FOXE1 (also known as TTF2 or FKHL15), paired box transcription factor 8 (PAX-8), NKX2.5, and TSHR genes [1]. Consequently, the genetic mechanisms underlying the defects in thyroid organogenesis in the majority of the cases remain to be elucidated. Epigenetic mechanisms leading to stochastic variations in the expression of multiple loci could be responsible for the sporadic characteristic of thyroid dysgenesis. Dyshormonogenesis, which accounts for the remaining 15-20% of the cases, has been linked to mutations in the SLC5A (Na+/I_ symporter, NIS) [2], SLC26A4 (Pendrine, PDS) [3], thyroperoxidase (TPO) [4], dual oxidase2 (DUOX2), DUOX maturation factor 1 and 2 (DUOXA1 and DUOXA2) [5-7], iodotyrosine dehalogenase 1 (DEHAL1) [8] and thyroglobulin (TG) [1] 27 genes. These mutations produce a heterogeneous spectrum of congenital hypothyroidism, with an autosomal recessive inheritance. Thereafter, the patients are typically homozygous or compound heterozygous for the gene mutations and the parents, carriers of one mutation.