Rare genetic disorders of thyroid hormone axis: A case series of IGSF1 deficiency syndrome and allan–herndon–dudley syndrome

Background

Rare genetic disorders involving the hypothalamic–pituitary–thyroid axis are an uncommon cause of congenital hypothyroidism and neurodevelopmental disability. Early recognition through characteristic biochemical patterns and genetic testing facilitates accurate diagnosis, appropriate management, and genetic counselling. We present two genetically confirmed cases with distinct thyroid hormone disorders. Case Series: The first case is a 17-year-old male diagnosed with congenital hypothyroidism during the neonatal period and treated with levothyroxine. He had global developmental delay, poor scholastic performance, memory impairment, hearing deficit, and seizures. Examination revealed short stature and pubertal development appropriate for age. Ultrasonography showed an atrophic thyroid gland, and genetic testing confirmed an IGSF1 mutation, consistent with IGSF1 deficiency syndrome. The second case is a 4-year-old boy with severe global developmental delay, hypotonia evolving to hypertonia, poor neck holding, and delayed motor milestones. Thyroid function tests demonstrated the characteristic pattern of low free T4 with elevated T3 and normal TSH, raising suspicion of impaired thyroid hormone transport. Genetic evaluation confirmed Allan–Herndon–Dudley syndrome (SLC16A2/MCT8 mutation).