Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism

J Clin Endocrinol Metab. 2009 Nov;94(11):4187-94. doi: 10.1210/jc.2009-0618. Epub 2009 Oct 9.


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.

MeSH terms

  • Adolescent
  • Amino Acid Substitution
  • Animals
  • COS Cells / metabolism
  • Child
  • Child, Preschool
  • Chlorocebus aethiops
  • Family
  • Humans
  • Hypothyroidism / genetics*
  • Infant
  • Mutation*
  • Receptors, Thyrotropin / genetics*
  • Thyrotropin / blood
  • Thyrotropin / metabolism
  • Transfection


  • Receptors, Thyrotropin
  • Thyrotropin