Clinically Symptomatic Resistance to Thyroid Hormone ß Syndrome Because of THRB Gene Mosaicism.

CONTEXT: Resistance to thyroid hormone ß syndrome (RTHß) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHß phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. CASE DESCRIPTION: The patient is a 52-year-old woman with clinical and biological signs of RTHß. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHß syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949G > A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. CONCLUSIONS: We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHß syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHß, thus avoiding patient mismanagement.

High birth weight and early postnatal weight gain protect obese children and adolescents from truncal adiposity and insulin resistance: metabolically healthy but obese subjects?

OBJECTIVE: Low birth weight (LBW), no early catch-up weight, and subsequent fat accumulation have been associated with increased risks of insulin resistance from childhood onward and later cardiovascular disease. We sought to clarify the effects of high birth weight (HBW) and postnatal weight gain on insulin resistance. RESEARCH DESIGN AND METHODS: A total of 117 obese children aged 10.4 +/- 2.4 years were divided into three groups according to fetal growth after exclusion of maternal diabetes. They were comparable for age, sex, puberty, and percent body fat. Customized French birth weight standards, adjusted for maternal characteristics and gestation number, identified subjects with true altered fetal growth: 32 had increased fetal growth according to customized standards (HBWcust), 52 were eutrophic, and 33 had restricted fetal growth according to customized standards (LBWcust). Fat distribution by dual-energy X-ray absorptiometry, insulin sensitivity indexes from an oral glucose tolerance test (OGTT), and leptin, adiponectin, and visfatin levels were compared between groups. RESULTS: The HBWcust subjects had a higher adiponectin level, higher whole-body insulin sensitivity index (WBISI), and lower hepatic insulin resistance index, lower insulin and free fatty acid concentrations during OGTT, and lower trunk fat percent than eutrophic (P < 0.05) and LBWcust subjects (P < 0.05). Besides birth weight, weight gain between 0 and 2 years was a positive predictor (P < 0.05) of WBISI, whereas weight gain after 4 years was a negative predictor (P < 0.05). CONCLUSIONS: HBW and early weight gain may program insulin sensitivity and adipose tissue metabolism and contribute to so-called metabolically healthy obesity.

Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta.

Maternal smoking during pregnancy is often associated with a decrease in placental function, which might lead to intrauterine growth retardation. Because tobacco is known to alter the mitochondrial respiratory function in cardiomyocytes and lung tissue, we hypothesized that placental mitochondrial function could be altered by maternal smoking. Placental mitochondria from 9 smoking and 19 nonsmoking mothers were isolated by differential centrifugation. Mitochondrial oxygen consumption was measured by polarography, and the enzymatic activity of each complex of the electron transport chain was assessed by spectrophotometry. In addition, the relative content in mitochondrial DNA (mtDNA) was determined by real-time quantitative PCR in placentas from seven smoking and seven nonsmoking mothers. We observed a 29% reduction in the enzymatic activity of complex III in the placental mitochondria from smokers compared with nonsmokers (P = 0.03). The relative content of mtDNA (with respect to the beta-globin gene) was reduced by 37% in the placental tissue from smokers compared with nonsmokers (P < 0.02). Both the enzymatic activity of complex III and mtDNA content were inversely related with the daily consumption of cigarettes, and mtDNA content was correlated with cord blood insulin-like growth factor-binding protein-3 (r = 0.74, P < 0.01), a marker of fetal growth. These results show that maternal smoking is associated with placental mitochondrial dysfunction, which might contribute to restricted fetal growth by limiting energy availability in cells.

Divergent effect of endogenous and exogenous sex steroids on the insulin-like growth factor I response to growth hormone in short normal adolescents.

The lower responsiveness to GH in women than in men is probably due to a divergent effect of gonadal steroids. It is unknown, however, how the progressive increase in sex steroid production that occurs during puberty affects this responsiveness. To compare the effects of puberty and sex steroid administration on responsiveness to GH, we used the IGF-I generation test, in which the peak IGF-I level 24 h after a single injection of GH (2 mg/m2) was studied in 117 healthy short subjects (56 females and 61 males). The subjects, aged 8-16 yr, were divided into four groups: prepuberty, early puberty, midpuberty, or pubertal delay. In the latter group, the IGF-I response was determined before and after priming with oral 17beta-estradiol in girls and im testosterone in boys. We also tested for an association between body composition (by dual energy x-ray absorptiometry) and the IGF-I response to GH. The IGF-I increment in response to GH (change in IGF-I from baseline) was correlated with the growth velocity sd score (P < 0.05). Progression throughout puberty was associated with an increase in both baseline IGF-I (P < 0.05) and the IGF-I increment in response to GH (P < 0.05), with no gender difference. Pubertal category (pre-, early, and midpuberty; P < 0.05) and fat percentage (P < 0.05) were the main positive predictors of the IGF-I increment in response to GH, expressed as micrograms per liter as well as sd score, independently of baseline IGF-I. After sex steroid priming, both the GH peak in response to insulin-induced hypoglycemia and baseline IGF-I were increased (P < 0.05, after vs. before sex steroid). However, the IGF-I increment in response to GH decreased after oral 17beta-estradiol (P < 0.05), whereas it was unchanged after testosterone administration. Endogenous gonadal steroid secretion appears to result in increased responsiveness to GH in peripubertal girls and boys. By contrast, exogenous estrogen and testosterone, respectively, produce a relative decrease and no change in responsiveness to GH in similar populations, possibly through the achievement of sex steroid concentrations exceeding physiological ranges for age. Fat percentage was a positive determinant of the responsiveness to GH, suggesting a link between the energy stores and the anabolic action of GH.