CONGENITAL CENTRAL HYPOTHYROIDISM DUE TO A HOMOZYGOUS MUTATION IN THETHYROTROPIN BETA-SUBUNIT GENE FOLLOWS AN AUTOSOMAL RECESSIVE INHERITANCE

A 5-month-old infant of nonconsanguineous parents had severe hypothyro idism. Undetectable serum levels of T-3 and T-4 in combination with an undetectable baseline TSH level led to the diagnosis of central hypot hyroidism. Administration of TRH failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. Measurement of the TSH in se rum with three different immunoassays that recognize different epitope s 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 cod on 114. The truncated TSH beta peptide lacks the terminal five amino a cids. Furthermore, the cysteine in codon 105 that is believed to be im portant for the interaction of the TSH beta-subunit with the alpha-sub unit, is replaced with a valine (C105V), supporting the theory of a co nformational change in the TSH molecule. Genotyping confirmed that the proposita was homozygous for this mutation, whereas her unaffected pa rents, the paternal grandmother, and the maternal grandfather were het erozygous. Thus, isolated TSH deficiency follows an autosomal recessiv e mode of inheritance in this kindred.