Coffin-Siris syndrome: Clinical description of two cases.

Coffin-Siris syndrome is a rare disorder, which can be difficult to recognize. A broad spectrum of nonspecific clinical features is associated with Coffin-Siris syndrome, and the expression of these features is diverse. We describe two cases with Coffin-Siris syndrome with mutations in the ARID1A gene, with dissimilar presentation and clinical course.

Immuno-Hormonal, Genetic and Metabolic Profiling of Newborns as a Basis for the Life-Long OneHealth Medical Record: A Scoping Review.

Holistic and life-long medical surveillance is the core of personalised medicine and supports an optimal implementation of both preventive and curative healthcare. Personal medical records are only partially unified by hospital or general practitioner informatics systems, but only for citizens with long-term permanent residence. Otherwise, insight into the medical history of patients greatly depends on their medical archive and memory. Additionally, occupational exposure records are not combined with clinical or general practitioner records. Environmental exposure starts preconceptionally and continues during pregnancy by transplacental exposure. Antenatal exposure is partially dependent on parental lifestyle, residence and occupation. Newborn screening (NBS) is currently being performed in developed countries and includes testing for rare genetic, hormone-related, and metabolic conditions. Transplacental exposure to substances such as endocrine disruptors, air pollutants and drugs may have life-long health consequences. However, despite the recognised impact of transplacental exposure on the increased risk of metabolic syndrome, neurobehavioral disorders as well as immunodisturbances including allergy and infertility, not a single test within NBS is geared toward detecting biomarkers of exposure (xenobiotics or their metabolites, nutrients) or effect such as oestradiol, testosterone and cytokines, known for being associated with various health risks and disturbed by transplacental xenobiotic exposures. The outcomes of ongoing exposome projects might be exploited to this purpose. Developing and using a OneHealth Medical Record (OneHealthMR) may allow the incorporated chip to harvest information from different sources, with high integration added value for health prevention and care: environmental exposures, occupational health records as well as diagnostics of chronic diseases, allergies and medication usages, from birth and throughout life. Such a concept may present legal and ethical issues pertaining to personal data protection, requiring no significant investments and exploits available technologies and algorithms, putting emphasis on the prevention and integration of environmental exposure and health data.

Multicentre study found that adherence to national antibiotic recommendations for neonatal early-onset sepsis was low.

AIM: Our aim was to evaluate adherence to the Dutch neonatal early-onset sepsis (EOS) guidelines, adapted from UK guidance. We also looked at the effect on antibiotic recommendations and duration. METHOD: This was a multicentre, prospective observational cross-sectional study carried out in seven hospitals in the Netherlands between 1 September 2018 and 1 November 2019. We enrolled 1024 neonates born at 32 weeks of gestation or later if they demonstrated at least one EOS risk factor or clinical signs of infection. RESULTS: The Dutch guidelines recommended antibiotic treatment for 438/1024 (42.8%) of the neonates designated at risk, but only 186/438 (42.5%) received antibiotics. The guidelines advised withholding antibiotics for 586/1024 (57.2%) of neonates and in 570/586 (97.3%) cases the clinicians adhered to this recommendation. Blood cultures were obtained for 182/186 (97.8%) infants who started antibiotics and only four were positive, for group B streptococci. Antibiotic treatment was continued for more than 3 days in 56/178 (31.5%) neonates, despite a negative blood culture. CONCLUSION: Low adherence to the Dutch guidelines meant that the majority of neonates did not receive the antibiotic treatment that was recommended, while some antibiotic use was prolonged despite negative blood cultures. The guidelines need to be revised.

Scapula alata as presenting symptom of Fanconi anemia: A case for serendipity.

Fanconi anemia is a recessive genetic disorder with a wide range of presenting symptoms, from multiple congenital defects to exclusively (pan) cytopenia. Scapula alata may be a rare symptom of FA.

Multi-centre study found that strict adherence to guidelines led to computed tomography scans being overused in children with minor head injuries.

AIM: Our primary aim was to calculate the head computed tomography (CT) scan rate in children with a minor head injury (MHI) when the Dutch National guidelines were followed in clinical practice. The secondary aim was to determine the incidence of CT abnormalities and the guideline predictors associated with traumatic abnormalities. METHODS: We performed a multi-centre, prospective observational cross-sectional study in the emergency departments of six hospitals in The Netherlands between 1 April 2015 and 31 December 2016. RESULTS: Data on 1002 patients were studied and 69% of cases complied with the guidelines. The overall CT rate was 44% and the incidence of traumatic abnormal CT findings was 13%. CT scans were performed in 19% of children under two years of age, 48% of children between two and five years and 63% of children aged six years or more. Multivariate regression analysis for all age categories showed that CT abnormalities were predicted by a Glasgow Coma Scale of less than 15, suspicion of a basal skull fracture, vomiting and scalp haematomas or external lesions of the skull. CONCLUSION: Strict adherence to the Dutch national guidelines resulted in CT overuse. New guidelines are needed to safely reduce CT scan indications.

Exposure to Environmental Contaminants and Lung Function in Adolescents-Is There a Link?

Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDF)), polychlorinated biphenyls (PCBs), and brominated flame retardants (BDEs) are well known toxic environmental contaminants. Their possible role in the incidence of respiratory disease is not yet well understood. Previous studies showed a negative effect on lung function in relation to prenatal and lactational dioxin exposure in pre-pubertal children. Effects of BDE exposure on the lung function have not previously been evaluated. As part of a longitudinal cohort study, the effects of perinatal dioxin (PCDD/F) exposure and serum PCDD/F, dl-PCB, and BDE levels on lung function in adolescents were assessed using spirometry, a body box, and diffusion measurements. Thirty-three children (born between 1986 and 1991) consented to the current follow-up study. Prenatal, lactational, and current dioxin, PCB, and BDE concentrations were determined using GC-MS. No relationship was seen between prenatal and lactational dioxin exposure, nor with current PCB body burden, and lung function. Indications of increasing airway obstruction were seen in relation to increasing current BDE exposure. This is a novel finding and certainly warrants further research.

Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs.

OBJECTIVES: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life. STUDY DESIGN: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS. RESULTS: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI. DISCUSSION/CONCLUSION: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

Were the wrong cells studied?

Peripheral blood lymphocytes (PBL) studying the effects of dioxins and dioxin-like compounds in vitro is not correct. Peripheral lymphocytes in general (Th1, Th2) do not have an Ah-receptor. Polymorphonuclear leucocytes (PMN's) are more logical to use.

Thyroid hormone metabolism and environmental chemical exposure.

BACKGROUND: Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort. METHODS: Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels. RESULTS: The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group. CONCLUSION: Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Effects of dioxins, PCBs, and PBDEs on immunology and hematology in adolescents.

Dioxins and PCBs are environmental pollutants, proven to be immunotoxic. In the period 1987-1991 a cohort of mother-baby pairs was initiated to detect abnormalities in relation to dioxin levels in the mother's milk. At birth and at follow-up at 8-12 years, immunological and hematological effects were seen, prompting us to perform a new follow-up during adolescence. In addition, we assessed the immunological and hematological parameters in relation to current levels of PBDEs and PCBs. In the Netherlands, the pre- and postnatal exposure to dioxins have been studied prospectively since 1987. Venapuncture was performed to assess hematological (Hemoglobin, thrombocytes, thrombopoietin) and immunological (leukocytes, leukocyte differentiation) parameters and the current serum levels of dioxin, dioxinlike (dl)-PCBs and PBDEs. A decrease in the number of polymorphic neutrophils was found in adolescents with higher dl-PCBs in their serum (p = 0.021). No relation with total leukocytes, thrombocytes, hemoglobin, or thrombopoietin levels was seen. Similarly, we found no relation between prenatal, nor current dioxin levels and the hematological and the immunological parameters determined. The SigmaPBDEs were negatively associated with the number of lymphocytes (p = 0.01) and positively associated with the hemoglobin concentration (p = 0.003). These effects on the innate immunity by current levels of dl-PCBs and on the adaptive immunity by PBDEs are disconcerting, especially as the dl-PCB (0.04-7.8 WHOTEQ pg/g lipid, mean: 2.2 WHOTEQ pg/g lipid) and SigmaPBDE levels (mean 14.0 ng/g lipid, including one outlier with a sum of 73.6 ng/g lipid) were not high.

Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study.

OBJECTIVES: While many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed. STUDY DESIGN: Prenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearman's correlation coefficient. RESULTS: A delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds. DISCUSSION AND CONCLUSION: A relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems.

Perinatal dioxin exposure, cytochrome P-450 activity, liver functions and thyroid hormones at follow-up after 7-12 years.

OBJECTIVES: Prenatal and lactational exposure to Dutch "background" dioxin levels may cause health effects spanning many years. In addition, perinatal studies have shown a relationship between dioxin exposure and thyroid disturbance. To assess the later health effects of prenatal and lactational dioxin exposure on liver function we measured plasma ALAT and ASAT levels amongst our longitudinal cohort, as was done perinatally and at 2(1/2) years. The children underwent a caffeine loading test to determine CYP1A2 activity. To assess the later effects on thyroid function we measured plasma TSH and FT4. STUDY DESIGN: A longitudinal cohort of 37 healthy children (age 7-12, mean 8.2 years), with documented prenatal and lactational dioxin exposure, ingested 3mg caffeine/kg BW 6h prior to blood withdrawal. Paraxanthine/caffeine molar ratio, ALAT, ASAT, TSH and FT4 were determined in venous blood. RESULTS: Linear regression of ASAT and ALAT revealed no relation with prenatal and lactational dioxin exposure. No correlation was found between the paraxanthine/caffeine molar ratio and prenatal and lactational dioxin exposure. Linear regression of TSH and FT4 revealed no relation with prenatal and lactational dioxin exposure. CONCLUSION: This follow-up has shown a normalisation of previously abnormal ALAT and ASAT levels, indicating a transient effect. CYP1A2 activity, measured by means of a caffeine-loading test, revealed no correlation with the prenatal and lactational exposures. A normalisation of previously abnormal thyroid hormone homeostasis was seen, also possibly indicating a transient effect. This study provides new data on long-term follow-up after perinatal dioxin exposure to background levels of dioxins.

Paediatric environmental health history taking: why bother?

Environmental health history taking is often not part of standard medical history taking for clinical physicians. During recent years attention has been placed on home environments and asthma and allergies, high caloric intake and obesity and type 2 diabetes mellitus, yet environmental health history taking still remains relatively uncharted terrain for the clinical physicians of today. While the reasons for this are certainly varied, ignorance of environmental influences, ignorance of environmental pollutants, politics and prejudices will certainly play a role. We suggest a simple manner of environmental health history taking, and discuss the importance of the subject in our modern-day clinical practice.

Today's epidemics in children: possible relations to environmental pollution and suggested preventive measures.

BACKGROUND: Facts and hypotheses on the relationship between some children's diseases or disorders and external stressors during the developmental stage of a child, both prenatally and postnatally are described in literature. In this paper the following changes in patterns and causes of the main childhood illnesses are summarized and recommendations for actions are made. Prematurity. Intra-uterine growth restriction. Testicular dysgenesis syndrome. Type I and Type II diabetes. Asthma, atopy and hay fever. Autism. Attention deficit hyperactivity disorder (ADHD). Learning disabilities. Cancer. Obesity. Hearing problems. RESULTS: Literature provides a growing amount of information on changing patterns in childhood diseases. CONCLUSIONS: The following recommendations for action are formulated: Immediate research on endocrine disrupters in relation to prematurity. Diabetes: avoid Maillard Compounds in liquid baby food and in food in general: promote breastfeeding. Asthma: avoid exposure to smoking, the use of chemical household products, dioxin and dioxin-like chemicals, and avoid air pollution with high levels of particulate matter, especially around conception, during pregnancy and in the first years of life. Autism: more research on incidence and causes. ADHD and learning disabilities: more research on prevalence and causes. Preventions: 1) preconception counselling to avoid potentially harmful substances; 2) controlling and further lowering levels of polychlorinated biphenyls, lead and methyl mercury. Cancer: promote breastfeeding, carry out research into effects of foetal exposure to internal fission-product radionuclides. Obesity: stop smoking in pregnancy, avoid parental obesity, longer night sleep. Hearing problems: lower noise levels in discothèques, promote the day-evening-night level to avoid noise (longer night sleep).

The effects of PCBs and dioxins on child health.

BACKGROUND/EXPOSURE: Dioxins and PCBs are highly persistent and highly toxic environmental pollutants which at present are derived mainly from waste incineration and food contamination. They are widespread in nature and pollute human food, including breast milk so that basically all children in Europe are exposed to measurable levels. RESULTS/TOXICITY IN CHILDREN: The toxicity of dioxins and PCBs are well described both from animal studies and from a number of human epidemiological studies including several large cohort studies. Especially developmental exposure has been shown to affect endocrine and cognitive systems negatively. Measurable outcomes include reduced IQ and changed behaviour. Foetotoxic effects with reduced birth weight and increased congenital anomalies such as cleft lip have also been described. Exposure to PCBs and dioxins must be considered also in the context of multiple exposure to several toxins simultaneously or sequentially. CONCLUSION/SUGGESTED ACTION: Some measures aimed at reducing exposure to dioxins have been partly successful in that the dioxin content of breast milk is going down. However, further steps to reduce exposure must be taken. We suggest legislative measures for reducing the re-entry of especially PCBs from waste into the environment. Individual pre-conception counselling is recommended in order to reduce developmental exposure and its consequences. Biomonitoring of the substances themselves in breast milk and foods is recommended as well as monitoring possible endocrine effects.

Children's exposure to polybrominated diphenyl ethers.

BACKGROUND: Polybrominated biphenyl ethers (PBDEs), a class of brominated flame retardants, are frequently used in consumer products. PBDEs levels in environmental and human samples have increased in recent decades. Children are exposed to PBDEs through diet, mainly through fish, meat and milk. Total dietary exposure of children in Europe was calculated to be 2-3 ng/kg b.w./day. For nursing infants the main source of PBDE exposure is breast milk; exposure levels are around 15 ng/kg b.w./day. PBDE exposure levels in North America are 10 to a 100 times higher. Because of their persistence and their similarity to polychlorinated biphenyls (PCBs), concern has been raised about the effects of PBDEs on human health. Exposure to penta- and octa-BDE led to learning impairment and impaired motor behaviour in rodents. Exposure to penta-, octa- and also deca-BDE caused effects on thyroid homeostasis in animals. CONCLUSIONS: The EU has banned the production and use of penta- and octa-BDE since 2004; however, exposure will continue during the coming decades. Based upon current toxicological evidence, human exposure to deca-BDEs is not expected to lead to health effects, but data on exposure to deca-BDE and data on toxicity of deca-BDE are scarce. Therefore, monitoring studies and toxicity studies on deca-BDEs and other BDEs should continue.

Policy and science in children's health and environment: recommendations from the PINCHE project.

BACKGROUND: Policy recommendations result from the discussions and analysis of the present situation in environment and health. Such analysis was performed in PINCHE. This led to recommendations based on the scientific literature. In the field of children's environmental health the policy process will follow more or less fixed rules, but this process is still at an early level of development. The link between science and policy still faces many challenges. Scientific assessment of environmental risk must recognize and tackle the problems of data sets, variability of human and environmental systems, the range, spatial and temporal diffusion of potential health effects and many biases and confounding factors. RESULTS: The PINCHE network recommends a general improvement of the supporting scientific fields in environment and health. Assessments from epidemiology or toxicology should play a key role in influencing science-policy decisions in programmes that are intended to inform the public policy process. Scientific committees at a local level could play a role. The relation between health and environment needs to be better incorporated in training and education. There is a need for harmonization of data production and use. The priorities in PINCHE focus on the most important issues. A classification of low, medium or high priority for action was used to describe a range of different environmental stressors. CONCLUSIONS: PINCHE provided recommendations to reduce exposure for children. Exposure reduction is not always linked to improved health in the short term, but it will reduce the body burden of accumulating chemicals in children. A strategic choice is reduction of exposure of children to compounds by changing production techniques or by increasing the distance of child specific settings to sources. The contribution of all players in the production, distribution and use of scientific knowledge in the field of children's environmental health is necessary.

Exposure to multiple environmental agents and their effect.

INTRODUCTION: All children are exposed to multiple physical, chemical and biological challenges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single-chemical approach as used in classical toxicology. AIM: To open up a 'negotiation space' for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation? METHODS: A discussion of two general approaches is taken: 1) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor. RESULTS: Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low-dose insult can, in some circumstances, be more toxic than a single high-dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology, . These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress-susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more 'permissive' liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B). CONCLUSIONS: It is necessary to define and study groups of multiple stressors as in US EPA's Framework for Cumulative Risk Assessment (U.S. EPA 2003). Recent increased knowledge of the greater sensitivity of the unborn baby, the infant and the child, has led to general recognition that a higher degree of precaution is now needed in regulating for multiple stressors on the young. The more liberal permissive approach proceeding from established effects of the individual exposures is becoming less acceptable now that we know that there is much we do not understand about chronic effects of stressors during the early development phases. Conflicts over which approach to take may have to be resolved through engagement and negotiation with a wide community of stakeholders. This "community of interest" may include fundamental research scientists, practicing clinical paediatricians, patient groups, and others concerned with the health and wellbeing of infants and children.