Subclinical hypothyroidism caused by a mutation of the thyrotropin receptor gene

Abstract

Key wordssubclinical hypothyroidism, thyrotropin receptor mutation.Subclinical hypothyroidism is defined as an elevated serum TSH concentration, and normal serum free thyroxine (T 4 ) and 3,5,3 ′ -triiodothyronine (T 3 ) concentrations associated with few or no symptoms or signs of hypothyroidism. 1,2 Recently, not only infants with overt hypothyroidism but also those with subclinical or mild hypothyroidism have been found by neonatal screening for congenital hypothyroidism.We identified a missense mutation in the thyrotropin receptor (TSHR) gene in a patient with subclinical hypothyroidism found by neonatal screening. Case reportThe propositus (a girl) was the first child of non-consanguineous Japanese parents. She was born at 39 weeks of gestation following an uncomplicated pregnancy and delivery, with a weight of 2682 g. She was referred because of a TSH level of 15 mU/L on neonatal screening at day 5 of life. The family history revealed no thyroid disease. At recall examination at day 46 of life, a serum TSH concentration of 12.0 mU/L in conjunction with normal serum concentrations of T 4 (10.4 µ g/dL) and T 3 (181 ng/dL) were detected. She did not have a goiter nor abnormal physical findings. Though her serum thyroid hormone levels were within normal limits, she was followed up for hyperthyrotropinemia. At the age of 3 years, an excessive TSH response to intravenous administration of thyrotropin releasing hormone (TRH) was considered diagnostic of congenital primary hypothyroidism, and subsequently, she was treated with levothyroxine (L-T 4 ). Figure 1 shows the clinical course of the propositus until 13 years of age. Before treatment with L-T 4 , the serum TSH level fluctuated between 10 and 30 mU/L. It declined to within normal limits after treatment with L-T 4 . The serum T 3 and T 4 levels were almost within normal limits throughout the course. At the age of 8 years, she underwent 123 I scintigraphy and TRH testing after the discontinuation of L-T 4 treatment. 123 I scintigraphy showed a normal-sized eutopic thyroid gland. Her 24 h 123 I uptake value was 17%. The perchlorate discharge test was negative. After the intravenous administration of 300 µ g/m 2 of TRH, her serum TSH concentration increased from 18.8 mU/L to a peak of 93.7 mU/L, while serum T 3 did not increase from the basal level of 111 ng/dL to 100 ng/dL at 120 min.

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

“…123 I scintigraphy showed a normal-sized eutopic thyroid gland. Her basal serum TSH level (18.8 mU/l) remained elevated, but the report did not mention serum T4 or FT4 level at that time [19]. So the thyroid function in older children with a homozygous R450H mutation of TSHR remains unclear.…”

“…In the Japanese population, five different loss of function mutations (R450H, G498G, V473I, R519C, R519G) have been found [12, 17, 19, 20]. The R450H mutation affects the first cytoplasmic loop of the TSHR, and all patients with TSH resistance resulting from TSH receptor mutations identified in Japan possessed R450H mutation at least in one allele [12, 17, 19, 20].…”

“…Only one report mentioned a Japanese patient with a homozygous R450H mutation of the TSHR gene [19]. The patient was hospitalized because of hyperthyrotropinemia on neonatal screening.…”

“…The R450H mutation affects the first cytoplasmic loop of the TSHR, and all patients with TSH resistance resulting from TSH receptor mutations identified in Japan possessed R450H mutation at least in one allele [12, 17, 19, 20]. In a previous study, COS-7 cells transfected with the R450H mutant demonstrated a 30–60% decrease in TSH binding activity and a 20–40% decrease in cAMP response to TSH, as well as expression in the cell surface as wild type [12].…”

Hypothyroidism: diagnosis and screening, genetic influences, and treatment options

“…Alternatively, it may occur following a subacute, postpartum, painless thyroiditis, or after a partial thyroidectomy (19; 37) Shibayama and colleagues used neonatal screening to identify a mutation in the thyrotropin receptor (TSHR) gene in a patient with subclinical hypothyroidism. In their study, they found a mild dysfunction of the R450H mutant on the TSHR gene, and it correlated it with mild clinical and biochemical manifestations (121).…”