Genetics of primary congenital hypothyroidism—a review

Purpose Congenital primary hypothyroidism (CH) is a state of inadequate thyroid hormone production detected at birth, caused either by absent, underdeveloped or ectopic thyroid gland (dysgenesis), or by defected thyroid hormone biosynthesis (dyshormonogenesis). A genetic component has been identified in many cases of CH. This review summarizes the clinical and biochemical features of the genetic causes of primary CH. Methods A literature review was conducted of gene defects causing congenital hypothyroidism. Results Mutations in five genes have predominantly been implicated in thyroid dysgenesis ( TSHR , FOXE1 , NKX2-1 , PAX8 , and NKX2-5 ), the primary cause of CH (85%), and mutations in seven genes in thyroid dyshormonogenesis ( SLC5A5 , TPO , DUOX2 , DUOXA2 , SLC6A4 , Tg , and DEHAL1 ). These genes encode for proteins that regulate genes expressed during the differentiation of the thyroid, such as TPO and Tg genes, or genes that regulate iodide organification, thyroglobulin synthesis, iodide transport, and iodotyrosine deiodination. Besides thyroid dysgenesis and dyshormonogenesis, additional causes of congenital hypothyroidism, such as iodothyronine transporter defects and resistance to thyroid hormones, have also been associated with genetic mutations. Conclusion The identification of the underlying genetic defects of CH is important for genetic counseling of families with an affected member, for identifying additional clinical characteristics or the risk for thyroid neoplasia and for diagnostic and management purposes.