Congenital Central Isolated Hypothyroidism Caused by a Homozygous Mutation in the TSH-β Subunit Gene

We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) deficiency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T4) at 0.3 μg/dL (4 nmol/L; N[normal]: 5.6-11.4 μg/dL). Basal TSH, only moderately elevated at 14.8 mU/L (N: 0-5.3; competitive radioimmunoassay, RIA), increased to 18.2 mU/L after thyrotropin-releasing hormone (TRH) stimulation, whereas prolactin increased normally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy for 6 weeks, TRH stimulation slightly increased serum TSH using two immunometric assays, from less than 0.03 to 0.07 and from 0.2 to 0.3 (a monoclonal and polyclonal antibody), and from 1.9 to 4.1 mU/L using a polyclonal TSH antibody and iodinated recombinant TSH. Sequencing of the TSH-β subunit gene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-β with nonhomologous 9 carboxylterminal amino acids and a loss of the 5 terminal ...