Abstract

Background

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

Methods

We retrospectively evaluated 51 children (aged 1–18 years) diagnosed with idiopathic SH followed for a mean of 4.9 ± 2.6 years. 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.

Results

Heterozygous TSHR variants were identified in 18 patients (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 SDS 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.

Conclusion

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.