ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2012) 30 S4

Genetic disorders of thyroid physiology and development

Nadia Schoenmakers


University of Cambridge, Cambridge, UK.


Congenital Hypothyroidism (CH) is the commonest inborn endocrine disorder (prevalence 1 in 3000), and occurs either due to failure of normal gland development (thyroid dysgenesis), or due to defective thyroid hormone synthesis in a structurally normal gland (dyshormonogenesis). Mutations in known thyroid transcription factors, and in genes encoding components of the thyroid hormone biosynthetic machinery, have been implicated in CH, attesting to the role of these genes in human thyroid physiology and development. Dyshormonogenetic CH accounts for 15% of primary CH and usually demonstrates autosomal recessive inheritance; genetically ascertained cases harbour mutations in TPO, TG, SLC5A5 (NIS), SLC26A4 (Pendrin), DUOX2, DUOXA2, or IYD. Thyroid dysgenesis is more common, comprising 85% of CH, but its genetic basis remains largely unknown, with mutations in the transcription factors PAX8, Nkx2.1, Nkx2.5 and FOXE1, or biallelic TSHR mutations, underlying less than 5% of cases.

Thyroid hormone action is mediated by receptors encoded by the THRA and THRB genes generating receptor subtypes (TRa1, TRb1, TRb2) with differing, tissue-specific expression. Dominant negative THRB defects are well-recognized causes of resistance to thyroid hormone in TRb-expressing tissues, (e.g. hypothalamus and pituitary), manifesting as impaired negative feedback in the HPT axis (elevated fT4 and fT3, unsuppressed TSH), and variable hyperthyroidism in TRa-expressing tissues, (e.g. myocardium) which retain thyroid hormone sensitivity. Conversely, the first reported cases of human TRa-mediated thyroid hormone resistance due to dominant negative THRA mutations exhibit only borderline abnormal thyroid hormone levels (low-normal fT4, high-normal fT3, low rT3) associated with tissue-specific hypothyroidism (skeletal dysplasia, constipation, bradycardia), reflecting preserved hormone responsiveness in TRb-expressing tissues (hypothalamus, and pituitary) but resistance in TRa-expressing tissues (skeleton, gastrointestinal tract and myocardium). Clinical features of these two syndromes will be reviewed.

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