IDENTIFICATION OF A NEW THYROTROPIN RECEPTOR GERMLINE MUTATION (LEU(629)PHE) IN A FAMILY WITH NEONATAL ONSET OF AUTOSOMAL-DOMINANT NONAUTOIMMUNE HYPERTHYROIDISM

Constitutively activating germline mutations in the TSH receptor (TSHR ) gene have been identified as a cause of autosomal dominant nonautoim mune hyperthyroidism and sporadic congenital hyperthyroidism. We repor t a 10-yr-old boy and his 31-yr-old mother, both presenting with a his tory of recurring toxic thyroid hyperplasia and no evidence for autoim mune thyroid disease. In the boy, onset of hyperthyroidism and goiter was neonatal. In the mother, onset of thyroid disease dates back to ea rly childhood. There was no history of thyroid disease in the rest of the family. Screening for germline mutations in exon 10 of the TSHR wa s performed by direct sequencing of genomic DNA extracted from periphe ral blood leukocytes of both patients. In the boy and his mother, an i dentical heterozygous TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629 of the TSHR (TTG-->TTT). Transient e xpression of the mutated TSHR construct in COS-7 cells confirmed the c onstitutive activity of the new TSHR germline mutation. This is the se cond family displaying congenital manifestation of hyperthyroidism in familial nonautoimmune hyperthyroidism.