Neonatal hyperthyroidism: Distinguishing transient antibody-mediated disease from permanent genetic forms

Background: Neonatal hyperthyroidism and thyrotoxicosis, though rare, represent critical endocrine emergencies associated with significant cardiovascular, metabolic, and neurodevelopmental risks. Most cases result from transplacental passage of thyroid-stimulating receptor antibodies (TRAb) in mothers with Graves’ disease, whereas a minority arise from activating TSHR or GNAS mutations. Early identification, correct etiological classification, and timely treatment are essential to prevent morbidity. Objectives: To synthesize current evidence on the prevalence, clinical characteristics, etiologic differentiation, and therapeutic strategies for neonatal hyperthyroidism, with emphasis on distinguishing transient from permanent disease and highlighting optimal treatment dosing, duration, and outcomes. Methods: A structured literature review (2000–2025) was performed using PubMed, Scopus, and Google Scholar. Inclusion criteria were neonatal hyperthyroidism cases with documented biochemical diagnosis, etiology (maternal TRAb or genetic), treatment details, and clinical outcomes. Case reports, case series, prospective cohorts, and reviews were included. Data extracted included prevalence, onset timing, hormone levels, TRAb status, TSHR/GNAS mutation status, methimazole and propranolol dosing, adjunctive therapies, treatment duration, and short- and long-term outcomes. Results: Across 35 eligible studies, neonatal hyperthyroidism occurred in approximately 1 in 50,000 births in the general population and 1–5% of infants born to mothers with Graves’ disease. Transient antibody-mediated hyperthyroidism predominated, typically presenting in the first 1–2 weeks of life. Clinical manifestations included tachycardia, irritability, feeding difficulty, poor weight gain, goiter, cholestasis, and, in severe cases, heart failure and craniosynostosis. Biochemical markers consistently demonstrated elevated FT4/T3 with suppressed TSH, with positive TRAb confirming autoimmune etiology. Permanent hyperthyroidism from TSHR/GNAS activation was rare but led to persistent hormone excess beyond antibody clearance. Methimazole (MMI) emerged as the preferred therapy, used at 0.25–1.0 mg/kg/day in divided doses, achieving biochemical control within days and typically continued for 2–10 weeks until TRAb clearance. Propranolol (~2 mg/kg/day) provided adrenergic symptom control, particularly tachycardia and irritability. In severe or unstable cases, iodine (Lugol/SSKI) and glucocorticoids were used to rapidly reduce hormone release and T4-to-T3 conversion. Importantly, transient hypothyroidism developed in some infants following treatment, necessitating dose adjustment or temporary levothyroxine. Most treated neonates achieved complete recovery with normal growth and neurodevelopment, whereas permanent cases required prolonged antithyroid therapy with potential progression to definitive treatment later in childhood. Conclusions: Neonatal hyperthyroidism requires proactive screening in at-risk infants, prompt initiation of methimazole-based therapy, and structured follow-up to monitor biochemical response, growth, and neurodevelopment. Differentiating transient antibody-mediated disease from genetic forms enables optimized treatment duration and long-term management planning.