10 September 2004
Background: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHβ 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: TSHβ 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 TSHβ mutations, which is not identified by TSH-based newborn screening. TSHβ 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.