Abstract

Ashraf Soliman*, Nada Alaaraj, Fawzia Alyafei, Noora Al Humaidi, Noor Hamed, Shayma Ahmed, Nada Soliman, Ahmed Khalil, Ahmed Elawwa

ABSTRACT

Background Goitrous hypothyroidism in infants and children is a heterogeneous endocrine disorder characterized by thyroid enlargement and impaired hormone production. While iodine deficiency remains a leading cause globally, emerging evidence highlights the increasing role of genetic mutations, especially in iodine-sufficient regions. Objectives: This review aimed to comprehensively analyze the genetic and clinical spectrum of goitrous hypothyroidism in children, highlighting genotype-phenotype associations, syndromic presentations, and advances in diagnostic and therapeutic approaches. Methods: A structured review of 60 peer-reviewed studies was conducted. Data were extracted on genetic mutations (monogenic and oligogenic), clinical manifestations, diagnostic tools, and therapeutic outcomes. Studies were assessed for quality, population diversity, and relevance to pediatric populations. Results: Monogenic mutations in TG, TPO, DUOX2, SLC5A5, and PAX8 were most frequently implicated, with geographic variability influenced by founder effects and consanguinity. Oligogenic inheritance, involving multiple interacting gene variants, was associated with more severe, variable phenotypes and treatment resistance. Syndromic forms such as Pendred and Bamforth–Lazarus syndromes revealed pleiotropic gene effects, with the latter syndrome associated with thyroid agenesis or hypoplasia. Diagnostic delays correlated with poor neurodevelopmental outcomes. While levothyroxine remains the mainstay of treatment, emerging therapies—including combination T3/T4 regimens and intra- amniotic thyroxine—offer promise in select cases. Gene-based therapies and small-molecule interventions are under investigation. Conclusion: Goitrous hypothyroidism in children is increasingly recognized as a genetically complex condition with variable clinical presentations. Ear1ly diagnosis through newborn screening and molecular testing is critical for optimizing outcomes. The presence of oligogenic or syndromic forms necessitates comprehensive genetic evaluation and personalized management strategies. Future directions should integrate precision medicine approaches to address diagnostic gaps and therapeutic challenges across diverse populations.