CONTEXT: Recently the first patients with inactivating mutations in T₃ receptor 
(TR)-α1 have been identified. These patients have low free T₄, low T₄, high T₃, 
low rT₃, 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 To evaluate the effect of LT4 treatment, LT4 was withdrawn for 35 days 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 T₄ 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.