Congenital central isolated hypothyroidism caused by a homozygous mutationin the TSH-beta subunit gene

We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) defic iency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T-4) at 0-3 mu g/dL (4 nmol/L; N[normal ]: 5.6-11.4 mu g/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 thy rotropin-releasing hormone (TRH) stimulation, whereas prolactin increased n ormally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy f or 6 weeks, TRH stimulation slightly increased serum TSH using two immunome tric 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 a ntibody and iodinated recombinant TSH. Sequencing of the TSH-beta subunit g ene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-beta with nonhomologous 9 ca rboxylterminal amino acids and a loss of the 5 terminal residues. This muta tion was previously reported in one Brazilian and two German families. The abnormal, and presumably biologically inactive, TSH can be detected in seru m using appropriate antibodies. Its relatively small amount in serum is due to either reduced secretion or rapid degradation. The occurrence of the sa me mutation in three families of different ethnic origin suggests that this mutation may be prevalent in the population. Common ancestry or de novo mu tations in a hot spot cannot be excluded. Finally, we must be aware that ne onatal screening of congential hypothyroidism based on blood spot TSH measu rement will not detect this rare but severe genetic defect.