APPARENT CONGENITAL ATHYREOSIS CONTRASTING WITH NORMAL PLASMA THYROGLOBULIN LEVELS AND ASSOCIATED WITH INACTIVATING MUTATIONS IN THE THYROTROPIN RECEPTOR GENE - ARE ATHYREOSIS AND ECTOPIC THYROID DISTINCT ENTITIES

Loss-of-function mutations in the TSH receptor gene (TSH-R), usually l eading to asymptomatic hyperthyrotropinemia, have been reported since 1995 in a total of eight pedigrees, with a pattern of transmission sug gesting autosomal recessive inheritance. Although normal TSH secretion and action are not necessary for normal migration of the thyroid anla ge, they are essential for normal thyroid growth and function. In keep ing with this concept, we report a severely hypothyroid boy with a nor mally located but very hypoplastic and hypofunctional thyroid caused b y TSH-R loss-of-function mutations. The propositus' maternal great aun t also had apparent athyreosis. The propositus had undetectable uptake on (99m)pertechnetate scintigraphy but normal plasma thyroglobulin at 15 days of age. He was found to be a compound heterozygote for TSH-R mutations, with the maternal allele carrying a splicing mutation (G to C transversion at position +3 of the donor site of intron 6) and the other allele a deletion of two nucleotides (2 bases of codon 655 in ex on 10). The great aunt's TSH-R was normal. We also report the sex rati o of hypothyroid newborns referred to our center since 1989 with appar ent athyreosis (5 girls, 7 boys) and with ectopic thyroid tissue (41 g irls, 15 boys). We conclude that different genetic and nongenetic mech anisms for athyreosis and ectopic thyroid are likely, and that these t wo distinct entities are themselves heterogeneous. Our results further show that inactivating mutations in TSH-R may account for some cases of apparent congenital athyreosis and should be suspected, especially if plasma thyroglobulin levels are normal.