Neonatal hyperthyroidism (NH) is usually caused by Graves disease in the mother. These infants become euthyroid within several months as the maternal antibodies are cleared. Rarely, NH persists and, in some families, the condition appears to be inherited in an autosomal dominant manner. Following the demonstration of somatic mutations in the TSH receptor in toxic adenomas, germline mutations were found in two families with non-autoimmune familial hyperthyroidism and in a sporadic case with NH.
We report a second case with non-autoimmune NH due to a different germline mutation in the TSH receptor gene. In this child, a heterozygous C to T transversion was found in codon 632 resulting in the substitution of isoleucine (ACC) by threonine ATC) in the sixth transmembrane domain of the thyroid and functional analysis revealed a strong, constitutive activation of the cAMP pathway while TSH-binding was unaffected. Activation of the cAMP pathway leads to enhanced growth and function of thyroid follicular cells.
Our patient was born prematurely, as was the previously reported patient. There is no family history of thyroid disease. She had subtotal thyroidectomy during infancy and required thyroid hormone replacement during childhood. At age 14 years she again became hyperthyroid. Radioiodine uptake was elevated in the remaining tissue, serum TSH was suppressed and stimulating anti-TSH receptor and anti-thyroid antibodies were negative. Surgically removed thyroid tissue showed hyperplasia but no lymphocytic infiltration. Presently (age 17), she is mildly hyperthyroid and moderately impaired intellectually.
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Roe, T., Jameson, J. & Kopp, P. NON-AUTOIMMUNE NEONATAL HYPERTHYROIDISM DUE TO AN ACTIVATING MUTATION IN THE TSH RECEPTOR GENE † 565. Pediatr Res 39, 97 (1996). https://doi.org/10.1203/00006450-199604001-00586