ESPE Abstracts (2014) 82 P-D-1-1-233

TSH Receptor Gene Variants in Pediatric Patients with Non Autoimmune Hyperthyrotropinemia

Paula Scaglia, Ana Keselman, Laura Gruñeiro Papendieck, Patricia Papendieck, Ignacio Bergadá, Horacio Domené & Ana Chiesa


Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina


Context: Heterozygous mutations in TSH recepter (TSHR) have been described associated with mild TSH resistance characterized by non autoimmune hyperthyrotropinemia (NAH). The prevalence of this condition varies in different reports.

Objective: To determine the prevalence of TSHR variants in pediatric NAH.

Subjects and methods: Thirty-five non obese unrelated children with NAH (18 girls, aged 1–19 years) were enrolled. All presented at least two TSH >5mIU/l (median 8.8 mIU/l) with normal total and free thyroxine and negative thyroid antibodies. 18 patients were born small for gestational age (SGA). The coding sequence of TSHR (exons 1–10 and their intronic flanking regions) was PCR amplified from genomic DNA and automatically sequenced. Polyphen 2, SIFT, and Mutation Taster sotwares were used for in silico prediction of gene variants effects.

Results: Several polymorphic variants were found (allelic frequency, AF): p.P52T (4.3%), p.N187N (14.3%), p.A459A (1.4%), p.D727E (15.7%), and p.N744K (1.4%). Uncommon heterozygous variants were found in exon 10 in two patients, both non SGA. Patient 1 carried a novel missense variant, p.P407L (c.1220C>T), while patient 2 carried the p.I583T (c.1748T>C) variant, already reported in one NAH patient. This variant was less responsive to TSH stimulation in vitro than the WT receptor (1). Both variants were predicted as pathogenic by three different prediction software and were absent (p.I583T) or present with very low AF in public databases (1/13 005 for p.P407L). Nevertheless, in vitro expression of the novel p.P407L variant is required to establish its role in thyroid pathogenesis.

Conclusions: The occurrence of ~6% of potential pathogenic variants of TSHR in a relative small cohort of pediatric NAH, confirms previous reports. Their deleterious effect on thyroid function needs further investigation but their identification might represent a useful tool in the clinical management of pediatric subclinical hypothyroidism.

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