A novel de novo mutation in the thyroid hormone receptor-beta gene

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH). Patients with RTH are identified by persistent elevation of circulating free TH levels with non-suppressed serum TSH. The underlying genetic defect is usually, but not always, a mutation in the TRβ gene. The frequency of de novo mutations is estimated to 21%. The inheritance is autosomal dominant. The clinical presentation varies significantly among different patients. However, goiter and the absence of neuropsychological symptoms and metabolic sequences of TH excess belong to the common features of the syndrome.

A 20 year old Caucasian female was admitted to the emergency department with palpitations. Her initial ECG showed supraventricular tachycardia. After administration of 5 mg metoprolol iv a sinus rhythm with heart rate of 85 bpm was documented. Initial laboratory findings revealed secondary hyperthyroidism. Additional blood tests revealed hyperlipidemia. The pituitary MRI discovered a lesion of 4 mm in the adenohypophysis. Symptoms and signs of hypopituitarism or overproduction of pituitary hormones were absent. TRH stimulation test led to adequate TSH response. Moreover, SHBG and α-GSU/TSH molar ratio were within normal values, ruling out a TSH-producing adenoma. Genetic analysis of TRβ gene identified a novel mutation in the 1st mutational cluster in the T3-binding domain of TRβ gene (c.1355C>G (p.Pro452Arg)). Unlike certain polymorphisms of deiodinases, this mutation was not identified in the genetic analysis of the family members, demonstrating a sporadic, de novo mutation of TRβ gene. Therapy with TRIAC (initial dosis 0.35 mg/day, gradually increasing to 1.4 mg/day) led to normalization of TSH and cholesterol levels with simultaneous decrease in the fT4 levels. Furthermore, it could be documented a fall of the initially increased TTSI after administration of TRIAC.

In patients with TRβ gene mutations and pituitary incidentalomas the differential diagnosis of the secondary hyperthyroidism might be challenging.