Spectrum of Human Foxe1/TTF2 Mutations

FOXE1 (or TTF-2) has been recognized as one of the thyroid dysgenesis (TD)-related genes based on its early expression at the thyroid bud stage and on the finding in Foxe1 knockout mice of a sublingual or absent thyroid gland. In humans, three homozygous loss-of-function missense mutations located within the forkhead domain have been reported in 5 patients with Bamforth syndrome. This syndrome is a rare inherited condition whose main features are congenital hypothyroidism (CH) due to TD (usually athyreosis), cleft palate, and spiky hair, with or without choanal atresia and bifid epiglottis. These FOXE1 mutations were typically inherited from heterozygous carrier parents who were usually consanguineous. Recently, a novel missense mutation was found in a patient with sporadic Bamforth syndrome, inherited via uniparental isodisomy. Altogether these observations strongly suggest that FOXE1 is involved in both familial and sporadic syndromic CH due to TD in association with cleft palate. Nevertheless, despite intensive research, FOXE1 mutations have been identified in only a minority of the affected patients. Recent data suggest that the transcription factor encoded by FOXE1 may act as a susceptibility factor for TD via variations in FOXE1 polyalanine tract length, which may modulate the risk of TD. Copyright (C) 2010 S. Karger AG, Basel