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Thyrotropin-Stimulating Hormone Receptor Gene Analysis in Pediatric Patients with Non-Autoimmune Subclinical Hypothyroidism

Department of Gynaecologic, Obstetric, and Paediatric Sciences (A.N., M.B., L.B., S.M., E.B., A.Ci., A.Ca.), S. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; and Department of Endocrinology and Metabolism (G.D.M., P.A., M.T.), Excellence Centre AmbiSEN, University of Pisa, 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Alessandra Cassio, Department of Gynaecologic, Obstetric, and Pediatric Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 11, 40138 Bologna, Italy. E-mail: alessandra.cassio{at}unibo.it.

Context: Mutations in TSH receptor (TSHR) are notoriously associated with congenital hypothyroidism as well as with non-autoimmune subclinical hypothyroidism, a mild form of TSH resistance that is not as well characterized by diagnostic procedures.

Objective: The genetic analysis of the TSHR gene was performed to determine the prevalence of TSHR gene mutations in non-autoimmune subclinical hypothyroidism during the pediatric age. The new mutations were studied for genotypic-phenotypic correlation.

Patients: Thirty-eight children (ages 0.5–18.0 yr) affected by non-autoimmune subclinical hypothyroidism diagnosed in our center (follow-up from 1 to 11.5 yr) and normal at neonatal screening were enrolled in the genetic study. In 11 cases, the relatives were included in the genetic analysis.

Results: Eleven different mutations of the TSHR gene were identified in 11 of the 38 patients. Two are new: the nonsense mutation C31X and the missense mutation P68S, which shows a decrease in TSH binding capacity but not in biological activity. In all cases the carrier parent was identified.

Conclusions: To date, this study demonstrates the highest prevalence (29%) of TSHR gene mutations in children and adolescents with non-autoimmune subclinical hypothyroidism not selected by neonatal screening. Functional studies show that some mutations cause a slight inactivation of the TSHR. This reveals a possible limit of the in vitro study or of the knowledge of mechanisms involving TSHR, or that other candidate genes must be considered.