Neonatal Hyperthyroidism Due to TSHR p.Thr632Ile Variant With a Suggestive Familial Pattern

Congenital nonimmune hyperthyroidism due to activating mutations in the thyroid-stimulating hormone receptor (TSHR) is rare and often presents diagnostic and management challenges. We report a case of the TSHR p.Thr632Ile variant, with a maternal clinical history highly suggestive of the same underlying disorder, highlighting diagnostic challenges and clinical variability associated with this mutation.

A 2-month-old female presented with severe thyrotoxicosis, feeding intolerance, tachycardia, and failure to thrive. Thyroid receptor antibodies were negative, and genetic testing confirmed a heterozygous pathogenic TSHR p.Thr632Ile variant. Her mother had a history of profound infantile hyperthyroidism, early thyroidectomy with regrowth, and recurrence during adolescence requiring radioactive iodine, features consistent with an activating TSHR mutation. Both the mother and infant demonstrated neurodevelopmental delays.

This report provides detailed phenotyping of a TSHR p.Thr632Ile variant, demonstrating persistent severe disease activity, partial resistance to medical therapy, requirement for definitive intervention, and neurodevelopmental impact.

Activating TSHR mutations should be considered in infants with persistent hyperthyroidism. Early genetic diagnosis guides management decisions and genetic counseling.