Clinical Outcomes of Congenital Hypothyroidism Due to DUOX2 Biallelic Mutations after Levothyroxine Withdrawal

Background: DUOX2 is a major cause of congenital hypothyroidism (CH) in Chinese patients, but clinical outcomes for those with biallelic DUOX2 mutations remain unclear. This study aimed to describe the clinical manifestations of CH due to DUOX2 defect. Methods: One hundred eighty-one patients with primary CH were recruited initially and were subjected to genetic screening. Patients with DUOX2 biallelic mutations were chosen. After 3 years of age, 28 patients underwent a prospective clinical reevaluation after levothyroxine (LT4) withdrawal. Subsequent periodic evaluation of thyroid function was executed to evaluate the necessity of LT4 retreatment. The medical histories of all patients before the age of three years were collected and analyzed. DUOX2 residual enzymatic activity was also calculated relative to clinical outcomes. Results: Twenty-eight patients who were reevaluated were divided into three groups: patients with permanent CH (PCH; 7/28 [25%]), patients with transient CH (TCH; 6/28 [21.4%]), and patients with hyperthyrotropinemia (15/28 [53.6%]). The median duration of follow-up was 17.5 months (interquartile range: 8.5, 29.25). The correlation between DUOX2 residual enzymatic activity and the clinical outcome of patients with CH with DUOX2 biallelic mutations was not clear in this study. No significant differences in laboratory findings at diagnosis were observed among the three groups. LT4 dose decreased with age in TCH but remained stable in PCH. Doses at ages 2, 3, and pre-withdrawal were significantly higher in PCH versus TCH ( p = 0.027; p = 0.003; p = 0.025). After LT4 withdrawal, serum thyroglobulin levels and thyroid size increased in most patients (especially hyperthyrotropinemia group) and often persisted for months. Moreover, thyrotropin levels normalized in 44.4% of patients with hyperthyrotropinemia after more than one year off LT4. Conclusions: Some patients with CH and DUOX2 biallelic mutations may have TCH or hyperthyrotropinemia. These patients should undergo long-term follow-up to prevent excessive compensatory thyroid hyperplasia.