Heterozygous TSHR Variants in Pediatric Idiopathic Subclinical Hypothyroidism: Association with a Variable and...

Subclinical hypothyroidism (SH) in childhood is frequently idiopathic and usually follows a benign course. Heterozygous loss-off-unction variants in the thyrotropin receptor (TSHR) gene have emerged as a genetic cause of isolated hyperthyrotropinemia but data regarding long-term outcomes and management are limited.

We retrospectively evaluated children (aged 1-18 years) diagnosed with idiopathic SH. TSHR gene analysis was performed using targeted next-generation sequencing in patients selected based on neonatal TSH elevation, family history of SH, thyroid gland in situ, or persistence of SH after levothyroxine withdrawal. Clinical, biochemical, ultrasonographic, and treatment outcomes were compared between patients with and without TSHR variants.

The cohort consisted of 51 patients followed for a mean of 4.9±2.6 years. Heterozygous TSHR variants were identified in 18 (35.2%), including one novel missense variant. Variant-positive patients generally showed a stable, compensated thyroid phenotype without progression to overt hypothyroidism. Levothyroxine therapy was discontinued in 6 of 11 initially treated patients after genetic diagnosis, with sustained biochemical stability. However, five patients required re-initiation of therapy due to rising TSH levels (15.7-27.8 mIU/L) or clinical symptoms. Lower thyroid volume standard deviation scores and the presence of additional clinical risk factors, such as small-for-gestational-age birth or developmental delay, were associated with treatment requirement. No patient developed overt hypothyroidism.

Heterozygous TSHR variants appear to contribute to the pathogenesis of pediatric idiopathic SH and are frequently associated with a stable, compensated thyroid phenotype. These findings support a conservative, individualized management strategy rather than routine levothyroxine therapy.