We identified five patients with congenital
secondary hypothyroidism with isolated
thyrotropin (
TSH) deficiency originating from three and two unrelated Argentinean and Swiss families, respectively. The affected patients presented with both low TSH as well as low
thyroid hormone levels. Further, TSH-releasing
hormone (TRH) stimulation failed to increase serum TSH, whereas
prolactin increased adequately. These affected children were homozygous for a 1-bp deletion (822delT) in the
TSH-beta subunit gene leading to a
cysteine 105 to
valine conversion (C105V) and to a frameshift with a
premature stop codon at position 114 (C105Vfs114X). In a total of 22 families five different mutations located within the coding region of the
TSH-beta subunit gene responsible for congenital
secondary hypothyroidism have been reported so far (E12X; G29R; Q49X; IVS2 +5, G --> A; C105Vfs114X). Importantly, out of 13 families, including our five families, the C105Vfs114X mutation has been described in 12 unrelated and non-consanguineous families, whereas the remaining four
TSH-beta subunit gene mutations have been described in consanguineous families only. Therefore the C105Vfs114X mutation within the
TSH-beta subunit gene is the most frequent alteration causing congenital
secondary hypothyroidism (13 of 22; 59%) and occurs mainly in unrelated and non-consanguineous families (12 of 13; 92%). As we could exclude a common ancestry by microsatellite marker analysis in our five independent families we concluded that the
codon 105 in the
TSH-beta subunit gene might be a "hot spot," although a founder effect has been reported in certain cases clustered in a highly specific and restricted geographical area.