Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene.

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. DNA was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (1568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.