4.4 Review

Genetic disorders of thyroid development, hormone biosynthesis and signalling

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Summary: Resistance to thyroid hormone alpha is caused by pathogenic variants in the THRA gene, with diverse clinical and laboratory features. Symptoms are similar to primary hypothyroidism, but with normal thyroid-stimulating hormone levels. Treatment with L-thyroxine can improve some clinical findings.

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Summary: Novel DIO1 pathogenic variants were identified and characterized in families with abnormal TH metabolism, demonstrating inherited D1 deficiency in humans for the first time. The mutant D1 proteins showed lower substrate affinity and slower enzyme velocity, leading to elevated serum reverse triiodothyronine levels and rT3/T3 ratios.

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Summary: Resistance to thyroid hormone is defined by impaired sensitivity to TH, mainly caused by mutations in the THRB gene, leading to elevated serum TH levels despite normal thyroid function. Management is tailored to individual symptoms as there is currently no therapy to fully correct the TR beta defect. Phenotypic variability exists among individuals with different mutations and tissue types.

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