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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?¹

Department of Pediatrics, Hôpital Sainte-Justine, Université de Montréal (N.G., C.D., G.V.V.), Québec, Canada H3T 1C5; and Department of Medical Genetics (J.P., G.V.) and Institut de Recherche Interdisciplinaire (G.V.), Université Libre de Bruxelles, 1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Guy Van Vliet, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. E-mail: vanvlieg{at}ere.umontreal.ca

Loss-of-function mutations in the TSH receptor gene (TSH-R), usually leading to asymptomatic hyperthyrotropinemia, have been reported since 1995 in a total of eight pedigrees, with a pattern of transmission suggesting autosomal recessive inheritance. Although normal TSH secretion and action are not necessary for normal migration of the thyroid anlage, they are essential for normal thyroid growth and function. In keeping with this concept, we report a severely hypothyroid boy with a normally located but very hypoplastic and hypofunctional thyroid caused by TSH-R loss-of-function mutations. The propositus’ maternal great aunt also had apparent athyreosis. The propositus had undetectable uptake on ^99mpertechnetate 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 exon 10). The great aunt’s TSH-R was normal. We also report the sex ratio of hypothyroid newborns referred to our center since 1989 with apparent athyreosis (5 girls, 7 boys) and with ectopic thyroid tissue (41 girls, 15 boys). We conclude that different genetic and nongenetic mechanisms for athyreosis and ectopic thyroid are likely, and that these two 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.

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