Familial unresponsiveness to thyrotropin by autosomal recessive inheritance

Unresponsiveness to TSH has been identified and sufficiently studied in only three patients. We report siblings with this defect as the first documentation of familial occurrence. A 26-yr-old woman was diagnosed with congenital hypothyroidism during infancy. The thyroid was atrophic, and thyroid function tests without T4 replacement showed serum free T4 levels below 3 pmol/L, serum TSH of 125 mU/L, and serum thyroglobulin below 5 mg/L. 123I scintigram showed decreased uptake (5% at 24 h), but normal shape at the correct position in the neck. Autoantibodies against thyroglobulin, thyroid peroxidase, and TSH receptor in serum were not detected. The amount of cAMP released into FRTL-5 cell culture in the presence of TSH from the patient was not different from that released by the same amount of TSH from normal subjects, suggesting that TSH bioactivity in our patient was normal. The brother of the patient also had congenital hypothyroidism, and the data on his thyroid function was similar to that for his sister. There was a consanguineous marriage in the parents of the siblings, and the mother of the patients had a normal serum free T4 level, but slightly increased serum TSH and thyroglobulin levels, indicating subclinical hypothyroidism. The possible pathogenesis of TSH unresponsiveness in our patients includes a mutation in the TSH receptor gene, abnormality in transcription-regulating factor, abnormality in GTP-binding protein, and/or inhibition of the action of cAMP. The family history of the patients suggests that the mode of inheritance in TSH unresponsiveness is autosomal recessive.