Compound heterozygous and homozygous mutations of the TSHbeta gene as a cause of congenital central hypothyroidism in Europe.

BACKGROUND: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHbeta subunit gene have been identified as a cause of congenital TSH deficiency.
METHODS: We performed a genetic and clinical study in children from four European countries diagnosed with congenital isolated central hypothyroidism.
RESULTS: TSHbeta gene analysis revealed compound heterozygosity for 145C-->T (Q49X) and 313delT (C105Vfs114X) in 1 infant and homozygous mutation 313delT (C105Vfs114X) in 5 patients. Although all presented with typical symptoms of hypothyroidism, diagnosis and treatment was delayed until 3-5 months in 5 of 6 patients. In a longitudinal sibpair analysis, thyroxine substitution initiated immediately after birth was effective to prevent developmental delay and growth retardation.
CONCLUSION: Clinical awareness is required to detect hypothyroidism due to TSHbeta mutations, which is not identified by TSH-based newborn screening. TSHbeta variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state. 2004 S. Karger AG, Basel