Abstract
BACKGROUND: Hashimoto's thyroiditis (HT) is the commonest cause of acquired hypothyroidism in children and adolescents in iodine non-endemic areas. The genetic analysis in HT shows two types of susceptibility genes-immune regulatory and thyroid specific genes. The exact genotype-phenotypic correlations and risk categorization of hypothyroid phenotypes resulting from these known mutations are largely speculative. The genetic studies in pediatric HT are very sparse from Indian sub-continent. In this context, we analysed the prevalence of TPO, NIS and DUOX2 gene mutations along with genotype-phenotype correlations in hypothyroid children with HT. METHODS: This is inter-disciplinary study conducted by collaboration between a tertiary care endocrinology hospital, biochemistry department of a teaching medical institute and genetics lab. In this prospective study, we employed 8 sets of primers and screened for 142 known single nucleotide polymorphisms in TPO, NIS, DUOX2 genes. The subjects were children and adolescents with hypothyroidism due to HT. Congenital hypothyroidism, iodine deficiency and dyshormonogenetic hypothyroidism cases were excluded. RESULTS: We detected 8 mutations in 7/20 (35%) children in the entire cohort (6 in NIS and 2 in TPO genes. No mutations were observed in DUOX2 gene. All our mutations were localized in introns and we found none in exons. Except for bi-allelic, synonymous polymorphism of TPO gene in child No. 18, all other mutations were heterozygous in nature. Genotype-phenotype correlations show that our mutations significantly expressed the presence of associated autoimmune manifestations and existence of family history. Clinical phenotypes of painful thyroiditis, severity of hypothyroidism and absence of goiter were statistically significant in the presence of these mutations. But, they could not reach significance on multivariate analysis. CONCLUSIONS: NIS gene followed by TPO mutations appears to be most prevalent mutations in HT amongst South Indian children and these mutations significantly influenced phenotypic expressions such as severity of hypothyroidism, goiter, auto-immune manifestations and family history.