The Clinical Spectrum of Resistance to Thyroid Hormone Alpha in Children and Adults

Abstract

Resistance to thyroid hormone alpha occurs due to pathogenic, heterozygous variants in THRA. The entity was first described in 2012 and to date only a small number of patients with varying severity have been reported. In this review, we summarize and interpret the heterogeneous clinical and laboratory features of all published cases, including ours. Many symptoms and findings are similar to those seen in primary hypothyroidism. However, thyroid-stimulating hormone levels are normal. Free triiodothyronine (T3) levels are in the upper half of normal range or frankly high and free thyroxine (T4) levels are low or in the lower half of normal range. Alterations in free T3 and free T4 may not be remarkable, particularly in adults, possibly contributing to underdiagnosis. In such patients, low reverse T3 levels, normo- or macrocytic anemia or, particularly in children, mildly elevated creatine kinase levels would warrant THRA sequencing. Treatment with L-thyroxine results in improvement of some clinical findings.

Keywords: Constipation; LT4; autism spectrum disorder; central hypothyroidism; developmental delay; growth failure; impaired sensitivity to thyroid hormone.

Figure 1

Thyroid function test results in previously untreated children and adults [derived from all available data in Table 1 (Cases 1-10, 14, 17-20, 24, and 25) and Table 2 (Cases 1-5, 9, 11, and 13)]. All of the data (x) was expressed relative to the relevant reference range with the following formula: (x - lower limit of normal range) / (upper limit of normal range - lower limit of normal range). Grey shaded areas indicated the normal range LT4: L-thyroxine

Figure 2

Classification of thyroid hormone profiles and peripheral indicators of hypothyroidism belonging to previously untreated children and adults [derived from all available data in Table 1 (Cases 1-10, 14, 17-21, 24, and 25) and Table 2 (Cases 1-5, 9, and 11-13)] LT4: L-thyroxine, fT3: free T3, fT4: free T4, TSH: thyroid-stimulating hormone

Figure 3

Numerical values of creatine kinase levels obtained from previously untreated children and adults with resistance to thyroid hormone alpha [derived from all available data in Table 1 (Cases 3-7, 10, 17, and 20) and Table 2 (Cases 3-5, 9, and 11)]. All of the data (x) was expressed relative to the relevant reference range with the following formula: (x - lower limit of normal range) / (upper limit of normal range - lower limit of normal range). Grey shaded area indicated the normal range LT4: L-thyroxine

Figure 4

Algorithm for the differential diagnosis of hypothyroidism in previously untreated children and adults with particular emphasis on resistance to thyroid hormone alpha TSH: thyroid-stimulating hormone, RTHα: resistance to thyroid hormone alpha, CK: creatine kinase, rT3: reverse T3