The C105fs114X Is the Prevalent Thyrotropin Beta-Subunit Gene Mutation in Argentinean Patients with Congenital Central Hypothyroidism

Abstract

Background: Congenital isolated thyrotropin (TSH) deficiency is an unusual condition characterized by low levels of thyroid hormones and TSH, usually presenting early typical signs of severe hypothyroidism. Five different β-TSH mutations have been described so far. While 4 of them affect only consanguineous families, a frameshift mutation in exon 3 (C105fs114X) has been found also in nonconsanguineous families. Objective: The aim of the present study was to characterize β-TSH mutations in Argentinean patients with congenital central hypothyroidism (CCH) and to emphasize the importance of early biochemical and molecular diagnosis of this disorder. Patients and Methods: We investigated 8 Argentinean children (3 boys, 5 girls) from 7 unrelated families with CCH based upon low levels of T₄ and T₃, and low basal and stimulated TSH levels. Mutation characterizations for the β-TSH gene were performed by PCR amplification followed by sequence and restriction enzyme analysis with SnaBI in the patients, 9 parents and in 100 newborn children. Results: All patients presented the same homozygous mutation in exon 3 of the β-TSH gene (C105fs114X), the 9 studied parents were heterozygous for the same mutation and 1 carrier was found in the 100 studied newborns. Conclusion: Our findings show that the C105fs114X mutation is prevalent in our population and may constitute a hot spot at codon 105 in the β-TSH gene. Since this mutation is easily demonstrable by a SnaBI digestion in DNA amplified from dried blood spots, its investigation would be indicated in patients in our milieu with clinical and biochemical features of CCH, allowing early L-thyroxine (LT₄) replacement and genetic counseling of the family.