Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin β-subunit gene follows an autosomal recessive inheritance

A 5-month-old infant of nonconsanguineous parents had severe hypothyroidism. Undetectable serum levels of T-3 and T-4 in combination with an undetectable baseline TSH level led to the diagnosis of central hypothyroidism. Administration of TRH failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. Measurement of the TSH in serum with three different immunoassays that recognize different epitopes of the TSH molecule failed to detect TSH, suggesting an aberrant or absent TSH. Direct sequencing of the entire coding region of the human TSH beta-subunit gene revealed a homozygous single base pair deletion in codon 105, resulting in a frame shift with a premature stop at codon 114. The truncated TSH beta peptide lacks the terminal five amino acids. Furthermore, the cysteine in codon 105 that is believed to be important for the interaction of the TSH beta-subunit with the alpha-subunit, is replaced with a valine (C105V), supporting the theory of a conformational change in the TSH molecule. Genotyping confirmed that the proposita was homozygous for this mutation, whereas her unaffected parents, the paternal grandmother, and the maternal grandfather were heterozygous. Thus, isolated TSH deficiency follows an autosomal recessive mode of inheritance in this kindred.