Correlation of Genotype-Phenotype of Congenital Hypothyroidism Cohort Diagnosed by Newborn Screening: A Long-Term Observational Study

This long-term observational study aimed to define the spectrum of genetic variation in a congenital hypothyroidism (CH) cohort and investigate the correlations between specific genotypes and clinical phenotypes, including treatment requirements and outcomes. We analyzed the maintenance dose of L-thyroxine (L-T4) at 6, 12, 18, and 24 months, alongside clinical outcomes after 3 years. Data were collected from the Neonatal Disease Screening Center at our hospital between January 2011 and March 2024. Of 247 patients with confirmed CH, 119 had available genetic testing and complete clinical information. The genetic positivity rate was 56.3% (67/119). <i>DUOX2</i> was the most frequently mutated gene (28.57%), followed by <i>TPO</i>, <i>TG</i>, and <i>TSHR</i>. Phenotypic correlation analysis revealed that patients with <i>DUOX2</i> variants had significantly lower initial screening TSH levels and required lower L-T4 maintenance doses at 12 months compared to those with <i>TPO</i> or <i>TSHR</i> variants. Patients with <i>TPO</i> and <i>TSHR</i> variants exhibited more severe clinical phenotypes and a higher prevalence of thyroid enlargement on ultrasound. Notably, no significant differences in biochemical data, L-T4 doses, or clinical outcomes were observed between patients with monoallelic and biallelic <i>DUOX2</i> variations, or among the negative, monogenic, and oligogenic variation groups. This study establishes a high genetic diagnostic yield for CH in the studied cohort, with <i>DUOX2</i> as the predominant genetic etiology. The findings demonstrate significant genotype-phenotype correlations, where variations in different genes are associated with distinct biochemical severities and treatment demands. Crucially, the lack of correlation between the number of affected <i>DUOX2</i> alleles and disease severity highlights the complex genetic and phenotypic heterogeneity of CH. These results provide valuable insights for the precise management and prognostic counseling of patients with CH.