FAMILIAL CONGENITAL HYPOTHYROIDISM CAUSED BY ABNORMAL AND BIOINACTIVETSH DUE TO MUTATIONS IN THE BETA-SUBUNIT GENE

Hereditary TSH deficiency is a rare autosomal recessive disease descri bed in inbred Japanese families and in Greek and Brazilian kindreds. T he TSH-beta-subunit gene has been shown to be the site of mutations th at will give rise to truncated proteins that cannot dimerize with the at subunit or; alternatively, will produce a mutated TSH that is prese nt in the circulation of the affected patients, but it is biologically inactive. Characteristically, the patients with TSH-beta-subunit-defe cts are bowl with congenital hypothyroidism, with very low levels of s erum thyroid hormones and serum thyroglobulin and paradoxically, with serum TSH levels that are consistently undetectable or at very low lev els. Goiter is not present at birth, but the low radioactive thyroid u ptake will increase after bovine TSH stimulation Other pituitary hormo nes responses to provocative tests are normal. The subunit levels are at high concentration and are significantly increased following TRH st imulation. In two kindreds, molecular biological studies have indicate d mutations in two different sites of exon 2, generating a peptide tha t would not dimerize with subunits to synthesize TSH molecules. In one kindred, a truncated TSH-beta protein was translated that generated a biologically inactive but detectable serum TSH molecule. (C) 1997, El sevier Science Inc.