Longitudinal Evaluation of Patients with a Homozygous R450H Mutation of the TSH Receptor Gene

Abstract

Background/Aim: The R450H mutation of the TSH receptor (TSHR) gene has been frequently observed in Japanese patients with resistance to TSH. The purpose of this study was to clarify the phenotype of patients with a homozygous R450H mutation of the TSHR gene; the mutant receptor has previously demonstrated moderately impaired function in vitro. Methods: We performed a clinical investigation of 5 Japanese patients who had hyperthyrotropinemia as neonates, in whom a homozygous R450H mutation of the TSHR gene had been demonstrated by genetic sequencing analysis. Results: The thyroid hormone levels of the patients were normal in early infancy, although their serum levels of TSH were mildly elevated. After supplemental treatment with levothyroxine sodium (L-T4) was started, we had to increase the dose to maintain the level of TSH within the normal range in all patients. Thyroid dysfunction became obvious in one patient at reexamination during adolescence when L-T4 treatment was stopped for 1 month. Four patients were examined for intelligence quotient and their scores were normal. Conclusions: Thyroid hormone replacement therapy should be considered based on biological data in patients with hyperthyrotropinemia who have a homozygous R450H mutation of the TSHR gene even if they do not exhibit obvious hypothyroidism in infancy.

Long-Term Outcome of Loss-of-Function Mutations in Thyrotropin Receptor Gene

“…Homozygotes had a more severe phenotype manifested by higher TSH levels at diagnosis and at last visit (mean TSH 53.6 vs. 9.24, p < 0.0001; 62.07 vs. 9.79, p = 0.0005, respectively). Despite the significantly higher serum TSH concentrations, mean serum fT4 levels did not differ between homozygotes and heterozygotes (13.96 vs. 16.27 at diagnosis, p = 0.175; 12.53 vs. 14.35 at last visit, p = 0.1006, respectively). Compound heterozygous subjects had one severe mutation and one very mild one (L653V/ P68S) presenting with a moderate phenotype, reflecting the weak functional effect of the P68S mutation (9,11).…”

“…There is only one longitudinal study of subjects with TSHR mutations, which describes five subjects homozygous for the R450H TSHR mutation who presented with congenital hyperthyrotropinemia. Of the five individuals, one developed frank hypothyroidism during adolescence (16), supporting the need for long-term follow-up, especially in homozygotes.…”

Frequent TSH Receptor Genetic Alterations with Variable Signaling Impairment in a Large Series of Children with Nonautoimmune Isolated Hyperthyrotropinemia

“…This controversy is also reflected by the variable use of L-T 4 therapy in this multicenter study. In partial TSH resistance, previous studies suggested that the presence of higher TSH concentrations may be sufficient to compensate for the diminished thyroid sensitivity and thus stimulate an adequate production of thyroid hormones (9,14). Here, despite that several patients did not receive replacement therapy, they had no obvious neurological or growth abnormalities.…”

Severe post-partum autoimmune hypothyroidism associated with a novel loss-of-function mutation in intracellular domain of human thyrotropin receptor

“…In contrast to subclinical hypothyroidism in the context of AITD, the thyroidal compensation in mild to moderate RTSH is expected to be clinically stable with no progression toward true hypothyroidism or spontaneous regression toward normal TSH levels. In contrast, development of overt hypothyroidism at the age of 15 years was shown in a patient homozygous for the R540H mutation presenting with compensated hypothyroidism in infancy, but not in an additional four subjects with the same genotype after long-term follow-up [21].…”