Homozygous thyroid hormone receptor β-gene mutations in resistance to thyroid hormone: three new cases and review of the literature

Abstract

Context: The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor β (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event.

Objective: In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRβ.

Methods: We conducted clinical studies and genetic analyses.

Results: The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRβ, but not in RTH due to THRB gene deletions.

Conclusion: We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRβ. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRβ interferes with the function of the TRα1 in humans.

Fig. 1.

Pedigrees showing the genotype and TFT results. Results are aligned with each symbol. Values represent the mean of two determinations on separate samples collected several months apart. In two instances (A, II-1 and IV-1), when samples were obtained almost 4 yr apart, both values are given. Ages represent those at the time of blood sampling. Tx, Thyroidectomy.

Fig. 2.

A and B, Proposita of family Mbyd. A, Facial features; B, visible goiter. C–H, Subjects from family Mozv, facial features and appearance of the thyroid gland. C and D, Subject IV-2; E and F, subject IV-3. Both show the dysmorphic features of birdlike facies with prominent nasal bridge. Affected subject IV-2 had thyroidectomy, whereas subject IV-3 has a visible goiter. G and H, Subject IV-1, the normal sister without the facial features of her affected siblings. Thyroid gland is visible due to autoimmune thyroid disease.

Fig. 3.

Bone age of affected patients in family Mozv. Note the severe delay in both siblings.