This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tenenbaum-Rakover, Y. Articles by Refetoff, S. Search for Related Content PubMed PubMed Citation Articles by Tenenbaum-Rakover, Y. Articles by Refetoff, S. Related Collections Thyroid

Loss-of-Function Mutations in the Thyrotropin Receptor Gene as a Major Determinant of Hyperthyrotropinemia in a Consanguineous Community

Pediatric Endocrine Unit (Y.T.-R.), Ha'Emek Medical Center, and Technion Faculty of Medicine, 31096 Haifa, Israel; Departments of Medicine (H.G., S.M., U.R., M.S.B., S.R.), and Pediatrics and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Institute of Interdisciplinary Research (L.M.), Free University of Brussels, 1070 Brussels, Belgium; and Clalit Health Service (A.M.-H.D.), 30010 Um-El Fahem, Israel

Address all correspondence and requests for reprints to: Yardena Tenenbaum-Rakover, Director, Pediatric Endocrine Unit, Ha’ Emek Medical Center, Afula, Israel. E-mail: rakover_y{at}clalit.org.il.

Context: Resistance to TSH (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated serum TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland.

Objectives: The aim of the study was to evaluate the clinical course and the genotype-phenotype relationship of RTSH caused by two different TSH receptor (TSHR) gene mutations in a consanguineous population.

Patients and Methods: We conducted a clinical and genetic investigation of 46 members of an extended family and 163 individuals living in the same town. In vitro functional studies of the mutant TSHRs were also performed.

Results: Two TSHR gene mutations (P68S and L653V) were identified in 33 subjects occurring as homozygous L653V (five subjects), heterozygous L653V (20 subjects), heterozygous P68S (four subjects), and compound heterozygous L653V/P68S (four subjects). With the exception of one individual with concomitant autoimmune thyroid disease, all homozygotes and compound heterozygotes presented with compensated RTSH (high TSH with free T₄ and T₃ in the normal range). Only nine of 24 heterozygotes had mild hyperthyrotropinemia. The L653V mutation resulted in a higher serum TSH concentration and showed a more severe in vitro abnormality than P68S. Haplotype analysis predicted a founder of the L653V six to seven generations earlier, whereas the P68S is older. Cross-sectional and prospective longitudinal studies indicate that TSH and T₄ concentrations remain stable over time.

Conclusions: High frequency hyperthyrotropinemia in an Israeli Arab-Muslim consanguineous community is attributed to two inactivating TSHR gene mutations. Concordant genotype-phenotype was demonstrated clinically and by in vitro functional analysis. Retrospective and prospective studies indicate that in the absence of concomitant autoimmune thyroid disease, elevated TSH levels reflect stable compensated RTSH.

This article has been cited by other articles:

				A. Nicoletti, M. Bal, G. De Marco, L. Baldazzi, P. Agretti, S. Menabo, E. Ballarini, A. Cicognani, M. Tonacchera, and A. Cassio Thyrotropin-Stimulating Hormone Receptor Gene Analysis in Pediatric Patients with Non-Autoimmune Subclinical Hypothyroidism J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4187 - 4194. [Abstract] [Full Text] [PDF]