Context: Recently the first patients with inactivating mutations in T 3 receptor (TR)-α1 have been identified. These patients have low free T4, low T4, high T3, low rT 3, and normal TSH serum levels, in combination with growth retardation, delayed bone development, and constipation. Objective: The aim of the current study was to report the effects of levothyroxine (LT4) treatment on the clinical phenotype of 2 patients (father and daughter) with a heterozygous inactivating mutation in TRα1. Setting and Participants: Both patients were treated with LT4 for the last 5 years. To evaluate the effect of LT4 treatment, LT4 was withdrawn for 35 days and subsequently reinitiated. Data were collected from medical records, by reanalysis of serum collected over the last 6 years, and by a detailed clinical evaluation. Results: Treatment with LT4 resulted in a suppression of serum TSH and normalization of serum free T 4 and rT3, whereas T3 levels remained elevated in both patients. In addition, there was a normalization of the dyslipidemia as well as a response in serum IGF-I, SHBG, and creatine kinase in the index patient. All these parameters returned to pretreatment values when LT4 was briefly stopped. LT4 also resulted in an improvement of certain clinical features, such as constipation and nerve conductance. However, cognitive and fine motor skill defects remained. Conclusion: This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRα1. LT4 therapy leads to an improvement of certain but not all features of the clinical phenotype. Copyright,
Journal of Clinical Endocrinology and Metabolism
Department of Clinical Chemistry

van Mol-van Mullem, A., Chrysis, D., Eythimiadou, A., Chroni, E., Tsatsoulis, A., de Rijke, Y., … Peeters, R. (2013). Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: Consequences of LT4 treatment. Journal of Clinical Endocrinology and Metabolism, 98(7), 3029–3038. doi:10.1210/jc.2013-1050