Assessing external exposome by implementing an Environmental Data Management System using Open Data.

Due to the increasing importance of exposome in environmental epidemiology, feasibility and usefulness of an Environmental Data Management System (EDMS) using Open Data was evaluated. The EDMS includes data from 10 European cities (Celje (Slovenia), Lódz (Poland), Manchester (UK), Palermo (Italy), Paris (France), Porto (Portugal), Regensburg (Germany), Reus (Spain), Rijeka (Croatia), Thessaloniki (Greece)) about external non-specific and specific exposome factors at the city or country level (2017-2020). Findings showed that the highest values of life expectancy were in Reus females (86 years) and Palermo males (81 years). UK had the highest obesity rate (28%), Croatia the highest prescribed drug consumption (62%), Greece and Portugal the highest smoking rates (37%, 42%) and daily alcohol consumption (21%), respectively. The most polluted cities were Thessaloniki for PM10 (38 µg/m3), Lódz for PM2.5 (25 µg/m3), Porto for NO2 (62 µg/m3) and Rijeka for O3 (92 µg/m3). Thessaloniki had the highest grey space (98%) and Lódz the highest cumulative amount of pollen (39,041 p/m3). The highest daily noise levels ≥ 55 dB was in Reus (81% to traffic) and Regensburg (21% to railway). In drinking water, arsenic had the highest value in Thessaloniki (6.4 µg/L), boron in Celje (24 mg/L) and lead in Paris (46.7 µg/L). Portugal and Greece showed the highest pesticide residues in food (7%). In conclusion, utilizing open-access databases enables the translation of research findings into actionable strategies for public health interventions.

Approach to the Patient With Short Stature: Genetic Testing.

The first step in the evaluation of the short child is to decide whether growth parameters in the context of the history are abnormal or a variant of normal. If growth is considered abnormal, system and hormonal tests are likely to be required, followed by more directed testing, such as skeletal survey and/or genetic screening with karyotype or microarray. In a small percentage of short children in whom a diagnosis has not been reached, this will need to be followed by detailed genetic analysis; currently, exome sequencing using targeted panels relevant to the phenotype is the commonly used test. Clinical scenarios are presented that illustrate how such genetic testing can be used to establish a molecular diagnosis, and how that diagnosis contributes to the management of the short child. New genetic causes for short stature are being recognized on a frequent basis, while the clinical spectrum for known genes is being extended. We recommend that an international repository for short stature conditions is established for new findings to aid dissemination of knowledge, but also to help in the definition of the clinical spectrum both for new and established conditions.

Maternal Factors in Pregnancy and Ethnicity Influence Childhood Adiposity, Cardiac Structure, and Function.

Importance: The links between maternal and offspring adiposity and metabolic status are well established. There is much less evidence for the impact of these relationships combined with ethnic background on cardiac structure and function in childhood. Objective: To test the hypothesis that ethnicity, maternal adiposity and glycemic status, and child adiposity affect cardiac structure and function. Design: A prospective cohort study. Setting: A single-center mother-child cohort study. The cohort is a subset of the international multi-center Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. Participants: This study included 101 healthy pre-pubertal British-born children [56 White Europeans (WEs) and 45 South Asians (SAs)] with a median age of 9.1 years, range 6.0-12.2 years, at the time of the investigation. Main Outcomes and Measures: Anthropometric and echocardiographic measurements were made on the cohort. Maternal pregnancy and birth data were available. Relationships between maternal parameters (BMI and glucose status), child adiposity, and echo measures were assessed. Results: Despite no ethnic difference in BMI SDS at a median age of 9.1 years, SA children exhibited higher levels of body fat than WE children (whole body, right arm, and truncal fat all p < 0.001). SA children also exhibited greater changes in weight and height SDS but not BMI SDS from birth than WE children. As expected, maternal BMI correlated with child BMI (r = 0.28; p = 0.006), and body fat measures (e.g., whole body fat r = 0.25; p = 0.03). Maternal fasting glucose levels were associated with child body fat measures (r = 0.22-0.28; p = 0.02-0.05). Left ventricular (LV) indices were not different between SA and WE children, but E/A and E'/A' (measures of diastolic function) were lower in SA when compared with WE children. LV indices correlated positively to BMI SDS and body fat markers only in SA children. Maternal fasting and 2-h glucose were negatively correlated with E'/A' in SA children (r = -0.53, p = 0.015, and r = -0.49, p = 0.023, respectively) but not in WE children. Conclusion and Relevance: SA and WE children exhibit differences in adiposity and diastolic function at a median age of 9.1 years. Novel relationships between maternal glycemia, child adiposity, and cardiac structure and function, present only in SA children, were identified.

Pharmacogenomics applied to recombinant human growth hormone responses in children with short stature.

We present current knowledge concerning the pharmacogenomics of growth hormone therapy in children with short stature. We consider the evidence now emerging for the polygenic nature of response to recombinant human growth hormone (r-hGH). These data are related predominantly to the use of transcriptomic data for prediction. The impact of the complex interactions of developmental phenotype over childhood on response to r-hGH are discussed. Finally, the issues that need to be addressed in order to develop a clinical test are described.

Novel Mutations and Genes That Impact on Growth in Short Stature of Undefined Aetiology: The EPIGROW Study.

BACKGROUND: Children with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions. PURPOSE: To identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study. METHODS: First, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF) < 2%, whose carriage fitted the mode of inheritance. Known mutations were identified using Ensembl and gene-specific databases. Variants were classified as pathogenic, likely pathogenic, or variant of uncertain significance using criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. If predicted by ≥ 5/10 algorithms (eg, Polyphen2) to be deleterious, this was considered supporting evidence of pathogenicity. Second, gene-based burden testing determined the difference in SNP frequencies between cases and controls across all and then rare SNPs. For genotype/phenotype relationships, we used PLINK, based on haplotype, MAF > 2%, genotype present in > 75%, and Hardy Weinberg equilibrium P > 10-4. RESULTS: First, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ACAN) and a further 25 likely pathogenic mutations, including previously known missense mutations in FANCB, IGFIR, MMP13, NPR2, OBSL1, and PTPN11. Second, genes related to SS: all methods identified PEX2. Another 7 genes (BUB1B, FANCM, CUL7, FANCA, PTCH1, TEAD3, BCAS3) were identified by both gene-based approaches and 6 (A2M, EFEMP1, PRKCH, SOS2, RNF135, ZBTB38) were identified by gene-based testing for all SNPs and PLINK. CONCLUSIONS: Such panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets.

Effects of parental mental illness on children's physical health: systematic review and meta-analysis.

BACKGROUND: Children of parents with mental disorder face multiple challenges. AIMS: To summarise evidence about parental mental disorder and child physical health. METHOD: We searched seven databases for cohort or case-control studies quantifying associations between parental mental disorders (substance use, psychotic, mood, anxiety, obsessive-compulsive, post-traumatic stress and eating) and offspring physical health. Studies were excluded if: they reported perinatal outcomes only (<28 days) or outcomes after age 18; they measured outcome prior to exposure; or the sample was drawn from diseased children. A meta-analysis was conducted. The protocol was registered on the PROSPERO database (CRD42017072620). RESULTS: Searches revealed 15 945 non-duplicated studies. Forty-one studies met our inclusion criteria: ten investigated accidents/injuries; eight asthma; three other atopic diseases; ten overweight/obesity; ten studied other illnesses (eight from low-and middle-income countries (LMICs)). Half of the studies investigated maternal perinatal mental health, 17% investigated paternal mental disorder and 87% examined maternal depression. Meta-analysis revealed significantly higher rates of injuries (OR = 1.15, 95% CI 1.04-1.26), asthma (OR = 1.26, 95% CI 1.12-1.41) and outcomes recorded in LMICs (malnutrition: OR = 2.55, 95% CI 1.74-3.73; diarrhoea: OR = 2.16, 95% CI 1.65-2.84). Evidence was inconclusive for obesity and other atopic disorders. CONCLUSIONS: Children of parents with mental disorder have health disadvantages; however, the evidence base is limited to risks for offspring following postnatal depression in mothers and there is little focus on fathers in the literature. Understanding the physical health risks of these vulnerable children is vital to improving lives. Future work should focus on discovering mechanisms linking physical and mental health across generations. DECLARATION OF INTEREST: None.

Ghrelin and Growth.

Ghrelin is a pleiotropic hormone, whose effect on growth hormone secretion, through the growth hormone secretagogue (GHS) receptor, is one of its many actions. Relationships between GHS receptor gene variants and human height, both in healthy individuals and in patients with growth disorders have been identified. These include constitutional delay in growth and puberty, idiopathic short stature, and isolated growth hormone deficiency. In this review, we provide an overview of the role of ghrelin in growth.

Metabolites involved in glycolysis and amino acid metabolism are altered in short children born small for gestational age.

BACKGROUND: Later life metabolic dysfunction is a well-recognized consequence of being born small for gestational age (SGA). This study has applied metabolomics to identify whether there are changes in these pathways in prepubertal short SGA children and aimed to compare the intracellular and extracellular metabolome in fibroblasts derived from healthy children and SGA children with postnatal growth impairment. METHODS: Skin fibroblast cell lines were established from eight SGA children (age 1.8-10.3 y) with failure of catch-up growth and from three healthy control children. Confluent cells were incubated in serum-free media and the spent growth medium (metabolic footprint), and intracellular metabolome (metabolic fingerprint) were analyzed by gas-chromatography mass spectrometry. RESULTS: Nineteen metabolites were significantly altered between SGA and control cell lines. The greatest fold difference (FD) was seen for alanine (fingerprint FD, SGA: control 0.3, P = 0.01 and footprint FD = 0.19, P = 0.01), aspartic acid (fingerprint FD = 5.21, P = 0.01), and cystine (footprint FD = 1.66, P = 0.02). Network analysis of the differentially expressed metabolites predicted inhibition of insulin as well as growth (ERK) signaling in SGA cells. CONCLUSION: This study indicates that changes in cellular metabolism associated with both growth failure and insulin insensitivity are present in prepubertal short children born SGA.

Use of continuous glucose monitoring to identify glucose dysregulation in growth hormone insensitivity syndrome.

BACKGROUND/AIMS: Monogenic forms of growth hormone insensitivity (GHI) and its treatment with recombinant insulin-like growth factor-1 (rIGF-1) are both associated with glucose dysregulation. We used the information provided by continuous glucose monitoring systems (CGMS) for the clinical management of two children with monogenic GHI prior to the commencement of therapy as well as during the years when they received rIGF-1 treatment and continued to do so after the cessation of therapy. METHODS: We evaluated the extent of hyper- and hypoglycaemia with CGMS. RESULTS: In one patient, before treatment CGMS identified self-limiting nocturnal hypoglycaemia. Initiation of rIGF-1 treatment resulted in severe and persistent hypoglycaemia with an absence of spontaneous recovery. Corrective dietary measures were instituted. In a second patient, who had a poor growth response to rIGF-1 therapy, CGMS identified significant fluctuations in daytime glucose levels whilst on treatment with evidence of postprandial hyperglycaemia and both rebound and nocturnal hypoglycaemia. Given the lack of improved growth and the documented glucose dysregulation, treatment was stopped and repeat measurements with CGMS 1 month afterwards showed complete resolution. CONCLUSIONS: We have demonstrated that CGMS is an effective tool to assess glucose dysregulation in patients with GHI and alters clinical management.