Thyroid dyshormonogenesis caused by iodotyrosine deiodinase pathogenic variant: three cases presenting in adolescence

We describe three patients from three unrelated consanguineous families, all homozygous for the c.301C>T (p.Arg101Trp) variant in the iodotyrosine deiodinase (IYD) gene. These patients presented in late childhood around puberty with diffuse goiter, primary hypothyroidism, and negative thyroid autoantibodies, consistent with thyroid dyshormonogenesis (DH). Initiation of levothyroxine therapy led to a significant reduction in goiter size and clinical improvement. Notably, all patients had normal thyroid function at neonatal screening, suggesting a delayed clinical manifestation of congenital hypothyroidism. These cases highlight the importance of considering genetic causes of hypothyroidism, particularly in consanguineous families. The ultrasound findings of a homogeneously enlarged, hypervascularized goiter without micronodularity in adolescent patients with non-autoimmune hypothyroidism should prompt consideration of DH, specifically IYD variants. Increased clinical awareness, combined with targeted molecular testing once an index patient is identified, can facilitate detection of the pathogenic variant, timely initiation of treatment, and screening of at-risk family members.