Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations

Context: Recently several patients with resistance to thyroid hormone (RTH)-alpha due to T-3 receptor-alpha (TR alpha) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests. Objective: The objective of the study was to describe the clinical phenotype of three new families with RTH alpha and thereby gain more detailed knowledge on this novel syndrome. Design, Setting, and Participants: RTH alpha was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TR alpha mutations were investigated in vitro. Results: We studied 22 individuals from three families and identified 10 patients with heterozygous TR alpha mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TR alpha, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T-3 ranged from high-normal to high and serum free T-4 and rT(3) from normal to low. TSH levels were normal in all patients. Conclusions: This large case series underlines the variation in the clinical phenotype of RTH alpha patients. RTH alpha should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T-3, low/normal free T-4, and normal TSH.