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Resistance to Thyrotropin (TSH) in Three Families Is not Associated with Mutations in the TSH Receptor or TSH¹

Departments of Medicine (J.X., S.P., J.Po., R.E.W., S.R.) and Pediatrics (J.Po., S.R.), The University of Chicago, Chicago, Illinois 60637; the Department of Pediatrics, Yale University (K.M.), New Haven, Connecticut 06512; Kinderkrankenhaus auf der Bult (M.M.), Hannover, Germany; Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Istituto Clinico Humanitas, and Centro Auxologico Italiano IRCCS (C.A., L.P., P.B.P.), Milan, Italy; and Institut de Recherche Interdisciplinaire, and Service de Génétique Médicale, Faculté de Médicine, Université Libre de Bruxelles, Campus Erasme (J.Pa., G.V.), 1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. Samuel Refetoff, University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.bsd.uchicago.edu

Resistance to TSH (RTSH) is a recently described syndrome of reduced sensitivity to TSH that manifests as euthyroid hyperthyrotropinemia. It is usually identified at birth during routine neonatal screening for congenital hypothyroidism. In less than 2 yr, 13 subjects with RTSH belonging to 8 families have been reported, and all were shown to harbor mutations in the TSH receptor (TSHR) gene. We now report the occurrence of RTSH in 3 unrelated families. Contrary to previous reports, the inheritance of RTSH in 2 of the families was dominant rather than recessive and was not associated with abnormalities in the TSHR gene. Abnormalities in the TSHR gene were excluded by sequencing all coding sequences, exon/intron junctions, and the promoter region of the gene. Furthermore, the involvement of the TSHR in the manifestation of the RTSH phenotype was excluded in 2 families by linkage analysis using intragenic polymorphic markers. We excluded defects in the TSH ß-subunit by sequencing its gene and by showing that the circulating TSH in affected subjects from all families had normal bioactivity. Also, no abnormalities were found in the G_s gene of one family analyzed by GC-clamped denaturing gradient gel electrophoresis. This study shows that RTSH may be a manifestation of several different genetic defects that requires the exploration of other candidate genes involved in the TSH-TSHR-G_s cascade and genes participating in its regulation.

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