Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Design, synthesis, conformational analysis, and biological activity of Cα1-to-Cα6 1,4- and 4,1-disubstituted 1H-[1,2,3]triazol-1-yl-bridged oxytocin analogues.

Oxytocin (OT) is a neurohypophyseal peptide hormone containing a disulphide-bridged pseudocyclic conformation. The biomedical use of OT peptides is limited amongst others by disadvantageous pharmacokinetic parameters. To increase the stability of OT by replacing the disulphide bridge with the stable and more rigid [1,2,3]triazol-1-yl moiety, we employed the Cu2+-catalysed side chain-to-side chain azide-alkyne 1,3-cycloaddition. Here we report the design, synthesis, conformational analysis, and in vitro pharmacological activity of a homologous series of Cα1-to-Cα6 side chain-to-side chain [1,2,3]triazol-1-yl-containing OT analogues differing in the length of the bridge, location, and orientation of the linking moiety. Exploiting this macrocyclisation approach, it was possible to generate a systematic series of compounds providing interesting insight into the structure-conformation-function relationship of OT. Most analogues were able to adopt similar conformation to endogenous OT in water, namely, a type I ß-turn. This approach may in the future generate stabilised pharmacological peptide tools to advance understanding of OT physiology.

Current knowledge on the effects of environmental contaminants in early life nutrition.

Breast milk represents the optimal source of feeding for newborns, in terms of nutritional compounds and as it provides immunological, metabolic, organic, and neurological well-being. As a complex biological fluid, it consists not only of nutritional compounds but also contains environmental contaminants. Formulas through production, contact with bottles and cups, and complementary feeding can also be contaminated. The current review focuses on endocrine-disrupting chemicals, and made-man xenoestrogens present in the environment and both commonly present in food sources, agricultural practices, packaging, consumer products, industry, and medical care. These contaminants are transferred by passive diffusion to breast milk and are delivered during breastfeeding. They mainly act by activating or antagonizing hormonal receptors. We summarize the effects on the immune system, gut microbiota, and metabolism. Exposure to endocrine-disrupting chemicals and indirect food additives may induce tissue inflammation and polarize lymphocytes, increase proinflammatory cytokines, promote allergic sensitization, and microbial dysbiosis, activate nuclear receptors and increase the incidence of allergic, autoimmune, and metabolic diseases. Breast milk is the most important optimal source in early life. This mini-review summarizes current knowledge on environmental contaminants and paves the way for strategies to prevent milk contamination and limit maternal and infant exposure during pregnancy and the first months of life.

Current evidence on the impact of the COVID-19 pandemic on paediatric endocrine conditions.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) interacts with the host cells through its spike protein by binding to the membrane enzyme angiotensin-converting enzyme 2 (ACE2) and it can have a direct effect on endocrine function as ACE2 is expressed in many glands and organs with endocrine function. Furthermore, several endocrine conditions have features that might increase the risk of SARS-CoV-2 infection and the severity and course of the infection, as obesity for the underlying chronic increased inflammatory status and metabolic derangement, and for the possible changes in thyroid function. Vitamin D has immunomodulatory effects, and its deficiency has negative effects. Adrenal insufficiency and excess glucocorticoids affect immune conditions also besides metabolism. This review aims to analyze the rationale for the fear of direct effects of SARS-Cov-2 on endocrinological disorders, to study the influence of pre-existing endocrine disorders on the course of the infection, and the actual data in childhood. Currently, data concerning endocrine function during the pandemic are scarce in childhood and for many aspects definite conclusions cannot be drawn, however, data on properly managed patients with adrenal insufficiency at present are re-assuring. Too little attention has been paid to thyroid function and further studies may be helpful. The available data support a need for adequate vitamin D supplementation, caution in obese patients, monitoring of thyroid function in hospitalized patients, and confirm the need for an awareness campaign for the increased frequency of precocious puberty, rapidly progressive puberty and precocious menarche. The changes in lifestyle, the increased incidence of overweight and the change in the timing of puberty lead also to hypothesize that there might be an increase in ovarian dysfunction, as for example polycystic ovarian disease, and metabolic derangements in the next years, and in the future we might be facing fertility problems. This prompts to be cautious and maintain further surveillance.

A comparative study on the incidence of type 1 diabetes mellitus between children of North African migrants and Italian children in Emilia-Romagna region, Italy.

In the last few decades, many studies have reported an increasing global incidence of type 1 diabetes. Studies on migrant populations have underlined the importance of both environmental and genetic factors. AIMS: Evaluate the incidence of type 1 diabetes in North African vs Italian children aged 0-14 years from 1 January 2015, to 31st December 2018, in Emilia-Romagna region, Italy. METHODS: Clinical and epidemiological data about childhood onset type 1 diabetes in Emilia Romagna region were retrospectively collected by the regional centers of pediatric diabetology and matched using 3 different data sources. RESULTS: 365 new cases were diagnosed. Total cumulative incidence was 15.4/100,000/year. North African cases showed a cumulative incidence of 53.8/100,000/year, statistically significant compared to cumulative incidence of the Italian cases alone 13.1/100,000/year (p value < 0.001). The annual incidence did not differ in the 4 years for both groups.  Conclusion: The incidence of type 1 diabetes in the pediatric age (0 14 years) was significantly higher in the North African population than in the Italian one, suggesting that a mix of genetic and environmental factors may have caused the increase in newly diagnosed cases. WHAT IS KNOWN: • The incidence of type 1 diabetes largely varies worldwide. • Study on immigrants helped to better understand the interplay role between genetics and environment. WHAT IS NEW: • This is the first study focused on the incidence of children and adolescents of North African migrants in Italy. • The incidence of children and adolescents of North African migrants in Emilia Romagna region, Italy, seems to be higher than that reported in the host countries, and, above all, than that reported in highest-incidence countries in Europe and in the world.

Precocious Puberty and Covid-19 Into Perspective: Potential Increased Frequency, Possible Causes, and a Potential Emergency to Be Addressed.

A significant increase in precocious puberty, rapidly progressive puberty and precocious menarche has been reported in Italy since the initial lockdown because of the pandemic, and this could represent a new emergency to be addressed during this pandemic. There is a need, therefore, for further understanding and research. Many causes could account for this. Initially, it was thought that the changes in life-style, in screen time, and sleeping habits could be the cause but if considered individually these are insufficient to explain this phenomenon. Likely, changes in central nervous mediators, and an increase in catecholamines could contribute as a trigger, however, these aspects are poorly studied and understood as well as the real perceptions of these children. Finally, staying more indoors has certainly exposed these children to specific contaminants working as endocrine disruptors which could also have had an effect. It would be of utmost importance to compare this phenomenon worldwide with appropriate studies in order to verify what is happening, and gain a new insight into the consequences of the covid-19 pandemic and into precocious puberty and for future prevention.

GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer.

Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.

Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs.

Endocrine disrupting chemicals (EDCs) are exogenous chemicals which can disrupt any action of the endocrine system, and are an important class of substances which play a role in the Developmental Origins of Health and Disease (DOHaD) [...].

Clinical expression of endocrine disruptors in children.

PURPOSE OF REVIEW: Health status is the result of complex interaction between individual factors, general environmental factors and specific factors as nutrition or the presence of chemicals. Aim of this review is to point out the more recent knowledge covering the role of the endocrine disrupting chemical (EDC) on pediatric population wellbeing. RECENT FINDINGS: Prenatal, postnatal life and puberty are the three main temporal windows of susceptibility when EDCs may act. The mechanism is independent from dose or duration of exposition, sex, age or combination of chemicals and may also be transgenerational, affecting both growth and pubertal timing. A window of susceptibility for breast cancer has been detected. Thyroid gland is influenced by environmental chemicals, both in utero and during childhood. Alteration in Thyrotropin stimulating hormone (TSH) levels and neurodevelopmental impairment have been demonstrate. It has been detected a pro-obesogenic action of specific chemicals, impairing also glucose homeostasis during childhood. SUMMARY: With a multidisciplinary approach and the use of big data platforms, an attempt has to be made to verify biological variations related to a disease, and how much the risk is influenced by the presence of the endocrine disruptors. This may help the future generation to better interpret uncommunicable diseases.

Current treatment for polycystic ovary syndrome: focus on adolescence.

Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women and it is associated with an increased rate of infertility. Its etiology remains largely unknown, although both genetic and environmental factors play a role. PCOS is characterized by insulin resistance, metabolic disorders and low-grade chronic inflammation. To date, the treatment of PCOS is mainly symptomatic and aimed at reducing clinical signs of hyperandrogenism (hirsutism and acne), at improving menstrual cyclicity and at favoring ovulation. Since PCOS pathophysiology is still largely unknown, the therapeutic interventions currently in place are rarely cause-specific. In such cases, the therapy is mainly directed at improving hormonal and metabolic dysregulations typical of this condition. Diet and exercise represent the main environmental factors influencing PCOS. Thus, therapeutic lifestyle changes represent the first line of intervention, which, in combination with oral contraceptives, represent the customary treatment. Insulin resistance is becoming an increasingly studied target for therapy, most evidence stemming from the time-honored metformin use. Relatively novel strategies also include the use of thiazolidinediones and GLP1-receptor agonists. In recent years, a nutraceutical approach has been added to the therapeutic toolkit targeting insulin resistance. Indeed, emerging data support inositol and alpha-lipoic acid as alternative compounds, alone or in combination with the aforementioned strategies, with favorable effects on ovulation, insulin resistance and inflammation. Nevertheless, additional studies are required in adolescents, in order to assess the effectiveness of diet supplements in preventing negative impacts of PCOS on fertility in adult age. This review focuses on the main therapeutic options for PCOS to date.

HMGB1 is increased in adolescents with polycystic ovary syndrome (PCOS) and decreases after treatment with myo-inositol (MYO) in combination with alpha-lipoic acid (ALA).

PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml; p < .05) and normalized after treatment (2.27 ± 0.36 ng/ml, p < .05). Treatment significantly reduced insulin (24.0 ± 4.11 versus 12.13 ± 2.13 uU/ml), HOMA-IR (3.91 ± 0.41 versus 2.42 ± 0.45), and 17-hydroxyprogesterone (1.20 ± 0.15 versus 0.78 ± 0.11 ng/ml). Cholesterol, luteinizing hormone, 17-ß-estradiol, delta 4-androstenedione, and testosterone were unchanged. Circulating HMGB1 was increased in PCOS adolescents, and treatment was effective in normalizing HMGB1.

A review of current knowledge on Pollution, Cigarette Smoking and COVID-19 diffusion and their relationship with inflammation.

Coronavirus disease (COVID-19) is an infectious disease caused by the newly discovered coronavirus, Sars-Cov-2. This infection can cause mild to very severe respiratory and systemic illness mainly related with a cytokine storm. The epidemiology of COVID-19 is under continuous evolution, and studies are ongoing aiming at identifying the possible factors facilitating the diffusion of this infection. It is documented that air pollution and smoking are a leading cause of human morbidity and mortality globally, and can increase the risk of many diseases, including respiratory diseases. Overall, a linear relationship between exposure to atmospheric pollutants and diffusion of the Sars-Cov2 virus seems to exist. However, this correlation, cannot be regarded as a cause-effect relationship.  The available data show that air pollution is responsible for inflammation and hyper-activation of innate immunity that are associated with the worst outcomes of covid-19 but do not allow to conclude that atmospheric particulate is responsible for increased contagion. As to smoking, nicotine activation of nicotinic receptors leads to enhanced protease activation, apoptosis and inflammatory signaling through the same pathways (Renin-angiotensin system (RAS) and angiotensin-converting enzyme 2 (ACE2)) used by the virus increasing the inflammatory/destructive action of the virus itself. The increase in non-communicable diseases and of chronic inflammatory diseases is in line with environmental pollution, related climate changes, and with an augmented susceptibility to infectious diseases with increased contagiousness and morbidity. Restrictive measures to limit environmental pollution are needed worldwide as this represents a threat for human health.

CFTR and FOXO1 gene expression are reduced and high mobility group box 1 (HMGB1) is increased in the ovaries and serum of women with polycystic ovarian syndrome.

We previously described increased HMGB1 and reduced FOXO1 dependent on CFTR loss of function in cystic fibrosis (CF) and we showed in vitro that HMGB1 was lowered by insulin. Reduced CFTR gene expression has been described in granulosa cells (GC) from PCOS-induced rats. We aimed at studying CFTR and FOXO1 gene expression in GC, HMGB1 concentrations in serum and follicular fluids (FF), and insulin and IL-6 in FF in PCOS women. Thirty PCOS and 36 non-PCOS women (CTRL) undergoing in vitro fertilization were enrolled. CFTR and FOXO1 gene expression were downregulated in PCOS (p ≤ .05). HMGB1 was higher in PCOS both in FF (p ≤ .05) and in serum (p < .005) whereas insulin was lower, and IL-6 was unchanged with respect to controls. 17-ß estradiol was higher in PCOS than in CTRL (p ≤ .005). HMGB1 correlated negatively with insulin in FF (p ≤ .005). The increase in HMGB1 both in FF and in serum, likely reflects both low grade inflammation and insulin sensitivity. IL-6 was unchanged possibly reflecting functions other than inflammation.

Correction to: Parma consensus statement on metabolic disruptors.

CORRECTION: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Endocrinological Abnormalities Are a Main Feature of 17p13.1 Microduplication Syndrome: A New Case and Literature Review.

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.

miR-146a, miR-155, miR-370, and miR-708 Are CFTR-Dependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs.

CONTEXT: Cystic fibrosis-related diabetes (CFRD) is the most frequent and severe co-morbidity in cystic fibrosis (CF). Presentation and severity are quite variable. OBJECTIVE: To investigate changes in microRNAs (miRNAs) due to CF transmembrane conductance regulator malfunctioning in vitro, to study the circulating levels of selected miRNAs in serum samples from patients, and to assess their relationships in different age groups with genotype, glucose tolerance state, and at onset of CFRD. Design/Setting/Patients/Interventions: Transcriptional profiling of all known miRNAs in CFBE41o- cells, in their normal counterparts (16HBE14o- cells), and in IB3 cells was performed. A set of miRNAs was differentially expressed in the CF cells. By in silico analysis, four miRNAs (miR-146a, miR-155, miR-370, and miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and 50 healthy subjects whose glucose tolerance was characterized by an oral glucose tolerance test were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements/Results: A total of 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, and miR-708 were up-regulated and miR-146a was down-regulated in vitro, whereas in vivo, miR-146a, miR-155, and miR-370 were up-regulated, and miR-708 was down-regulated. These changes showed relationships with genotype, glucose tolerance state, and onset of CFRD. CONCLUSIONS: The data showed significant changes in miRNAs dependent on genotype and glucose tolerance state in CF patients and highlighted some miRNAs of importance in CFRD at onset. miRNAs could explain some of the variability observed in CF.

Data Mining of Determinants of Intrauterine Growth Retardation Revisited Using Novel Algorithms Generating Semantic Maps and Prototypical Discriminating Variable Profiles.

OBJECTIVES: Intra-uterine growth retardation is often of unknown origin, and is of great interest as a "Fetal Origin of Adult Disease" has been now well recognized. We built a benchmark based upon a previously analysed data set related to Intrauterine Growth Retardation with 46 subjects described by 14 variables, related with the insulin-like growth factor system and pro-inflammatory cytokines, namely interleukin-6 and tumor necrosis factor-α. DESIGN AND METHODS: We used new algorithms for optimal information sorting based on the combination of two neural network algorithms: Auto-contractive Map and Activation and Competition System. Auto-Contractive Map spatializes the relationships among variables or records by constructing a suitable embedding space where 'closeness' among variables or records reflects accurately their associations. The Activation and Competition System algorithm instead works as a dynamic non linear associative memory on the weight matrices of other algorithms, and is able to produce a prototypical variable profile of a given target. RESULTS: Classical statistical analysis, proved to be unable to distinguish intrauterine growth retardation from appropriate-for-gestational age (AGA) subjects due to the high non-linearity of underlying functions. Auto-contractive map succeeded in clustering and differentiating completely the conditions under study, while Activation and Competition System allowed to develop the profile of variables which discriminated the two conditions under study better than any other previous form of attempt. In particular, Activation and Competition System showed that ppropriateness for gestational age was explained by IGF-2 relative gene expression, and by IGFBP-2 and TNF-α placental contents. IUGR instead was explained by IGF-I, IGFBP-1, IGFBP-2 and IL-6 gene expression in placenta. CONCLUSION: This further analysis provided further insight into the placental key-players of fetal growth within the insulin-like growth factor and cytokine systems. Our previous published analysis could identify only which variables were predictive of fetal growth in general, and identified only some relationships.

Parma consensus statement on metabolic disruptors.

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Di-(2-ethylhexyl) phthalate metabolites in urine show age-related changes and associations with adiposity and parameters of insulin sensitivity in childhood.

OBJECTIVES: Phthalates might be implicated with obesity and insulin sensitivity. We evaluated the levels of primary and secondary metabolites of Di-(2-ethylhexyl) phthalate (DEHP) in urine in obese and normal-weight subjects both before and during puberty, and investigated their relationships with auxological parameters and indexes of insulin sensitivity. DESIGN AND METHODS: DEHP metabolites (MEHP, 6-OH-MEHP, 5-oxo-MEHP, 5-OH-MEHP, and 5-CX-MEHP), were measured in urine by RP-HPLC-ESI-MS. Traditional statistical analysis and a data mining analysis using the Auto-CM analysis were able to offer an insight into the complex biological connections between the studied variables. RESULTS: The data showed changes in DEHP metabolites in urine related with obesity, puberty, and presence of insulin resistance. Changes in urine metabolites were related with age, height and weight, waist circumference and waist to height ratio, thus to fat distribution. In addition, clear relationships in both obese and normal-weight subjects were detected among MEHP, its products of oxidation and measurements of insulin sensitivity. CONCLUSION: It remains to be elucidated whether exposure to phthalates per se is actually the risk factor or if the ability of the body to metabolize phthalates is actually the key point. Further studies that span from conception to elderly subjects besides further understanding of DEHP metabolism are warranted to clarify these aspects.