Genotype-phenotype correlation of biallelic DUOX2 mutations in transient and permanent congenital hypothyroidism

Congenital hypothyroidism (CH) due to DUOX2 mutations shows marked clinical heterogeneity. While some patients recover thyroid function during early childhood, others require long-term levothyroxine (LT4) therapy. The determinants of this variability remain unclear.

To determine whether baseline biochemical severity, thyroid morphology, bone maturation, and biallelic DUOX2 variant severity are associated with thyroid function recovery in DUOX2-related CH.

We retrospectively studied 71 patients with biallelic pathogenic DUOX2 variants, classified into 3 outcome groups: LT4 discontinued by age 4 years (n = 19), LT4 discontinued after age 4 years (n = 25), and continued LT4 with biochemical worsening requiring dose increase (n = 27). Baseline thyroid function tests, thyroid volume, and bone maturation were compared among groups. Bone maturation was assessed by distal femoral epiphyseal area (DFEA) and categorized as normal (DFEA ≥0.22 cm²) or delayed. Genotype-phenotype associations were examined, including variability among patients with identical biallelic genotypes.

Baseline thyroid function did not differ across groups (TSH P = .222; T3 P = .314; T4 P = .422; free T4 P = .505; thyroglobulin P = .363). Thyroid volume (P = .246) and bone maturation (P = .238) were not significantly different. The distribution of putative severe DUOX2 alleles did not differ (P = .862). Identical genotypes were observed across different outcome groups, indicating divergent clinical courses.

Baseline biochemical severity, thyroid volume, bone maturation, and DUOX2 variant severity did not reliably predict recovery in DUOX2-related CH. Substantial within-genotype heterogeneity suggests contributions from compensatory H₂O₂-generating pathways and/or other modifying factors.