Thyroid Function and Perchlorate in Drinking Water: An Evaluation among California Newborns, 1998

Perchlorate (ClO(4)(−)) has been detected in groundwater sources in numerous communities in California and other parts of the United States, raising concerns about potential impacts on health. For California communities where ClO(4)(−) was tested in 1997 and 1998, we evaluated the prevalence of primary congenital hypothyroidism (PCH) and high thyroid-stimulating hormone (TSH) levels among the 342,257 California newborns screened in 1998. We compared thyroid function results among newborns from 24 communities with average ClO(4)(−) concentrations in drinking water > 5 μg/L (n = 50,326) to newborns from 287 communities with average concentrations ≤5 μg/L (n = 291,931). ClO(4)(−) concentrations obtained from the California Drinking Water Program provided source-specific data for estimating weighted average concentrations in community water. Fifteen cases of PCH from communities with average concentration > 5 μg/L were observed, with 20.4 expected [adjusted prevalence odds ratio (POR) = 0.71; 95% confidence interval (CI), 0.40–1.19]. Although only 36% of all California newborns were screened before 24 hr of age in 1998, nearly 80% of newborns with high TSH were screened before 24 hr of age. Because of the physiologic postnatal surge of TSH, the results for newborns screened before 24 hr were uninformative for assessing an environmental impact. For newborns screened ≥24 hr, the adjusted POR for high TSH was 0.73 (95% CI, 0.40–1.23). All adjusted odds ratios (ORs) were controlled for sex, ethnicity, birth weight, and multiple birth status. Using an assessment of ClO(4)(−) in drinking water based on available data, we did not observe an association between estimated average ClO(4)(−) concentrations > 5 μg/L in drinking water supplies and the prevalence of clinically diagnosed PCH or high TSH concentrations

Models predicting the growth response to growth hormone treatment in short children independent of GH status, birth size and gestational age

<p>Abstract</p> <p>Background</p> <p>Mathematical models can be used to predict individual growth responses to growth hormone (GH) therapy. The aim of this study was to construct and validate high-precision models to predict the growth response to GH treatment of short children, independent of their GH status, birth size and gestational age. As the GH doses are included, these models can be used to individualize treatment.</p> <p>Methods</p> <p>Growth data from 415 short prepubertal children were used to construct models for predicting the growth response during the first years of GH therapy. The performance of the models was validated with data from a separate cohort of 112 children using the same inclusion criteria.</p> <p>Results</p> <p>Using only auxological data, the model had a standard error of the residuals (SD_res), of 0.23 SDS. The model was improved when endocrine data (GH_maxprofile, IGF-I and leptin) collected before starting GH treatment were included. Inclusion of these data resulted in a decrease of the SD_resto 0.15 SDS (corresponding to 1.1 cm in a 3-year-old child and 1.6 cm in a 7-year old). Validation of these models with a separate cohort, showed similar SD_resfor both types of models. Preterm children were not included in the Model group, but predictions for this group were within the expected range.</p> <p>Conclusion</p> <p>These prediction models can with high accuracy be used to identify short children who will benefit from GH treatment. They are clinically useful as they are constructed using data from short children with a broad range of GH secretory status, birth size and gestational age.</p

Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.M.A.M.C. was supported by a PhD studentship from the Cambridge Centre for Trophoblast Research. Research was supported by grants from the MRC (MR/J001597/1 and MR/L002345/1), the Medical College of Saint Bartholomew's Hospital Trust, a Wellcome Trust Investigator Award, EpigeneSys (FP7 Health-257082), EpiHealth (FP7 Health-278414), a Herchel Smith Fellowship (N.T.) and NIH grant RO1 DK89989. The contents are the authors' sole responsibility and do not necessarily represent official NIH views. We thank G. Burton for invaluable support, and M. Constância and I. Sandovici (University of Cambridge) for the Meox2-cre mice. We are extremely grateful to all of the participants in the Pregnancy Outcome Prediction study. This work was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme) and project grants from the MRC (G1100221) and Sands (Stillbirth and Neonatal Death Charity). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for this study) and by the NIHR Cambridge Clinical Research Facility, where all research visits took place.This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ng.369

Catch-up growth up to ten years of age in children born very preterm or with very low birth weight

BACKGROUND: Improved survival due to advances in neonatal care has brought issues such as postnatal growth and development more to the focus of our attention. Most studies report stunting in children born very preterm and/or small for gestational age. In this article we study the growth pattern of these children and aim to identify factors associated with postnatal catch-up growth. METHODS: 1338 children born with a gestational age <32 weeks and/or a birth weight of <1500 grams were followed during a Dutch nationwide prospective study (POPS). Subgroups were classified as appropriate for gestational age and <32 weeks (AGA) or small for gestational age (<32 wks SGA and ≥32 wks SGA). Data were collected at different intervals from birth until 10 years for the 962 survivors and compared to reference values. The correlation between several factors and growth was analysed. RESULTS: At 10 years the AGA children had attained normal height, whereas the SGA group demonstrated stunting, even after correction for target height (AGA: 0.0 SDS; SGA <32 wks: -0.29SDS and ≥32 wks: -0.13SDS). Catch-up growth was especially seen in the SGA children with a fast initial weight gain. BMI was approximately 1 SD below the population reference mean. CONCLUSION: At 10 years of age, children born very preterm AGA show no stunting. However, many children born SGA, especially the very preterm, show persistent stunting. Early weight gain seems an important prognostic factor in predicting childhood growth

Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

Pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene. PHP-Ib patients have isolated Parathormone (PTH) resistance and GNAS epigenetic defects while PHP-Ia cases present with hormone resistance and characteristic features jointly termed as Albright's Hereditary Osteodystrophy (AHO) due to maternally inherited GNAS mutations or similar epigenetic defects as found for PHP-Ib. Pseudopseudohypoparathyroidism (PPHP) patients with an AHO phenotype and no hormone resistance and progressive osseous heteroplasia (POH) cases have inactivating paternally inherited GNAS mutations.We here describe 17 subjects with an AHO-like phenotype that could be compatible with having PPHP but none of them carried Gsalpha mutations. Functional platelet studies however showed an obvious Gs hypofunction in the 13 patients that were available for testing. Methylation for the three differentially methylated GNAS regions was quantified via the Sequenom EpiTYPER. Patients showed significant hypermethylation of the XL amplicon compared to controls (36 ± 3 vs. 29 ± 3%; p<0.001); a pattern that is reversed to XL hypomethylation found in PHPIb. Interestingly, XL hypermethylation was associated with reduced XLalphaS protein levels in the patients' platelets. Methylation for NESP and ExonA/B was significantly different for some but not all patients, though most patients have site-specific CpG methylation abnormalities in these amplicons. Since some AHO features are present in other imprinting disorders, the methylation of IGF2, H19, SNURF and GRB10 was quantified. Surprisingly, significant IGF2 hypermethylation (20 ± 10 vs. 14 ± 7%; p<0.05) and SNURF hypomethylation (23 ± 6 vs. 32 6%; p<0.001) was found in patients vs. controls, while H19 and GRB10 methylation was normal.In conclusion, this is the first report of methylation defects including GNAS in patients with an AHO-like phenotype without endocrinological abnormalities. Additional studies are still needed to correlate the methylation defect with the clinical phenotype