Severe congenital hypothyroidism due to a homozygous mutation of the beta TSH gene

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condit ion, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case wi th an, autosomal recessive TSH defect caused by a homozygous mutation of th e beta TSH gene that was diagnosed in the early neonatal period. Hypothyroi dism in the first child of apparently unrelated parents was suspected becau se of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of Life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of ser um thyroid hormone levels revealed almost undetectable levels and thyroid h ormone substitution was immediately started. Because there was no indicatio n for other pituitary hormone deficiencies, sequence analysis of the beta T SH gene was initiated. A homozygous T deletion in codon 105 was found resul ting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. Thi s altered beta TSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppr esses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immedi ate comprehensive work-up of thyroid function including molecular genetic s tudies irrespective of the screening result.