Long-term outcome of loss-of-function mutations in thyrotropin receptor gene.

BACKGROUND: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations. METHODS: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH. RESULTS: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time. CONCLUSION: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.

A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis.

CONTEXT: In the human thyroid gland, TSH activates both the cAMP and inositol phosphates (IP) signaling cascades via binding to the TSH receptor (TSHR). Biallelic TSHR loss-of-function mutations cause resistance to TSH, clinically characterized by hyperthyrotropinemia, and normal or reduced thyroid gland volume, thyroid hormone output, and iodine uptake. OBJECTIVE: We report and study a novel familial TSHR mutation (L653V). RESULTS: Homozygous individuals expressing L653V had euthyroid hyperthyrotropinemia. Paradoxically, patients had significantly higher 2-h radioiodide uptake and 2- to 24-h radioiodide uptake ratios compared with heterozygous, unaffected family members, suggesting an imbalance between iodide trapping and organification. In transfected COS-7 cells, the mutant TSHR had normal surface expression, basal activity, and TSH-binding affinity, equally (2.2-fold) increased EC50 values for TSH-induced cAMP and IP accumulation, and normal maximum cAMP generation. In contrast, the efficacy of TSH for generating IP was more than 7-fold lower with the mutant compared with wild-type TSHR. CONCLUSIONS: We identified and characterized a TSHR defect, preferentially affecting the IP pathway, with a phenotype distinct from previously reported loss-of-function mutations. Results provide the first in vivo evidence for the physiological role of the TSHR/IP/Ca2+ cascade in regulating iodination. According to systematic in vitro mutagenesis studies, other TSHR mutations can result in even complete loss of IP signaling with retained cAMP induction. We hypothesize that such TSHR mutations could be the cause in unexplained partial organification defects.

Infertility and celiac disease: do we need more than one serological marker?

OBJECTIVES: Celiac disease (CD) prevalence is higher in women with infertility. Our study aims were to evaluate the prevalence of undiagnosed CD in Arab infertile women and to explore the usefulness of using more than one serological marker in the diagnostic screening for CD in this population. METHODS: Women with unexplained infertility (n = 192) and age-matched healthy controls (n = 210) were prospectively enrolled. Serum was tested for human tissue transglutaminase antibodies (TTG), antiendomysial antibodies (EMA), and immunoglobulin A. Intestinal biopsy was offered to women with positive serology or immunoglobulin A (IgA) deficiency. RESULTS: CD was diagnosed in five infertile women (2.65%) and in one control (0.5%) (p = 0.11). Gastrointestinal complaints were present in 60% (three of five) of women with CD and 11.8% (22 of 187) of women without CD (p = 0.017). Anemia was reported in 80% of infertile women with CD and 4.8% of infertile women without CD (p = 0.0001). CONCLUSIONS: Undiagnosed CD is prevalent in Arab infertile women as well as in Arab women in general. CD in Arab infertile women is frequently associated with gastrointestinal complaints and anemia. EMA testing is sufficient in suspected cases.