Pediatric Non Autoimmune Hyperthyrotropinemia and TSH Receptor Gene (TSHR) Variants

SCAGLIA, P.A; KESELMAN, ANA; GRUÑEIRO PAPENDIECK, L; PAPENDIECK P; BERGADÁ, I; DOMENÉ, HORACIO; CHIESA, A.

Congreso; XXIV Reuniòn de la Sociedad Latinoamericana de Endocrinología Pediátrica; 2014

Introduction: Mild TSH resistance characterized by non autoimmune hyperthyrotropinemia (NAH) has been described associated with heterozygous variants in TSHR gene. The prevalence of this condition varies in different reports and its occurrence is considered when subclinical hypothyroidism is assessed. Objective: To study the prevalence of TSHR gene variants in a pediatric population with NAH. Subjects and Methods: Thirty five non obese unrelated children with NAH (18 girls), aged 1 to 19 years, were enrolled. Eighteen patients were born small for gestational age (SGA). All presented at least two TSH measurements >5 mIU/L (median 8.8, range 5.7?14.0 mIU/L), with normal total (T4) and free thyroxine (FT4) and negative ATPO and ATG anti-thyroid antibodies. Serum levels of TSH, T4 and FT4 were measured by ECLIA method and ATPO and ATG antibodies by ICMA (Immulite). The whole coding sequence of TSHR gene (exons 1 to 10 and intronic flanking regions) was PCR amplified from genomic DNA and automatically sequenced. Polyphen 2, SIFT and Mutation Taster softwares were used for in silico prediction of gene variants effects. Results: Several known polymorphic variants were found (allelic frequency): p.Pro52Thr (4.3%), p.Asn187Asn (14.3%), p. Ala459Ala (1.4%), p.Asp727Glu (15.7%) and p.Asn744Lys (1.4%). In two patients, both non SGA, two uncommon heterozygous variants were found in exon 10. Both variants were predicted as pathogenic by three different prediction softwares. Patient 1 and his father carried the novel p.Pro407Leu (c.1220C>T) missense variant, present with very low allelic frequency (1/13005) only in Exome variant server database [1]. Patient 2, his father and brother carried the p.Ile583Thr (c.1748T>C) variant, absent in available population databases but already reported in one NAH patient and described as less responsive to TSH stimulation in vitro than the wild type receptor. In vitro expression of the novel p.Pro407Leu variant is required to establish its role in thyroid pathogenesis. Conclusions: In a relatively small cohort of pediatric patients with NAH we were able to find ~6% of potential pathogenic TSHR gene variants. Nevertheless, further investigation is needed to assess their deleterious effect on thyroid function and to apply this knowledge to the clinical management of pediatric subclinical hypothyroidism.