RESUMO
Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (Tnfsf14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- Tnfsf14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Reabsorção Óssea/metabolismo , Estrogênios/deficiência , Osteoblastos/patologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto , Animais , Linfócitos B/metabolismo , Células da Medula Óssea/metabolismo , Diferenciação Celular/fisiologia , Estrogênios/metabolismo , Humanos , Camundongos , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/fisiologia , Ligante RANK/metabolismo , Células Estromais/metabolismoRESUMO
Alkaptonuria (AKU) is a rare disorder characterized by the deficiency of the enzyme homogentisate 1,2-dioxygenase and consequent homogentisate accumulation, which leads to progressive and severe osteoarthopathy starting from the second decade of life. Thus, in AKU patients, bone involvement represents an important clinical issue, which we investigated. Serum levels of receptor activator of NF-κB ligand (RANKL), osteoprotegerin, sclerostin, Dickkopf-1, and bone remodeling markers were measured in nine AKU patients (two children and seven adults) and 22 controls, together with lumbar spine bone mineral density (LS-BMD) and femoral-BMD. In the two AKU children, the average of LS-BMD and femoral-BMD Z-scores were within the normal range, but reduced with respect to the controls. Otherwise, in the adult AKU patients, LS-BMD T-score was inside the normal range, but femoral-BMD T-score reached osteopenic levels. Consistently, in AKU adults, higher RANKL and C-terminal telopeptide of collagen type 1 and lower osteoprotegerin levels were observed than in controls. Otherwise, spontaneous osteoclastogenesis was already evident in peripheral blood mononuclear cell cultures from AKU children, together with a high percentage of circulating osteoclast precursors. Osteoclastogenesis was sustained by the high levels of tumor necrosis factor-α, RANK, RANKL, and LIGHT. In conclusion, the altered osteoclastogenesis was observed already in AKU children, despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease that appears in adult AKU.
Assuntos
Alcaptonúria/patologia , Osteoclastos/patologia , Osteogênese , Adolescente , Adulto , Alcaptonúria/sangue , Alcaptonúria/urina , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Calcitonina/urina , Cálcio/urina , Células Cultivadas , Criança , Creatinina/urina , Citocinas/metabolismo , Densitometria , Feminino , Taxa de Filtração Glomerular , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Osteoclastos/metabolismo , Ligante RANK/sangue , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Índice de Gravidade de Doença , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Irisin is a myokine secreted by skeletal muscle during physical activity. Irisin treatment increased cortical bone mineral density (BMD) in young healthy mice and restored bone and muscle mass loss in a mouse model of disuse-induced osteoporosis and muscular atrophy. In humans, Irisin was positively correlated with BMD in young athletes. Considering that the bone mass reached during childhood is one of the most important determinants of lifelong skeletal health, we sought to determine if Irisin levels were correlated with bone mineral status in children. METHODS: Irisin and bone metabolic markers were quantified in sera and bone mineral status was evaluated by quantitative ultrasound in a population of 34 healthy children (9.82 ± 3.2 years). RESULTS: We found that Irisin levels were positively correlated with the amplitude-dependent speed of sound Z-score (r = 0.305; p < 0.001), bone transmission time Z-score (r = 0.375; p < 0.001) and osteocalcin (r = 0.370; p < 0.001), and negatively with Dickkopf WNT Signaling Pathway Inhibitor 1 (r = -0.274; p < 0.001). CONCLUSION: In a regression analysis model, Irisin was one of the determinants of bone mineral status to a greater extent than bone alkaline phosphatase and parathyroid hormone, indicating that Irisin might be considered as one of the bone formation markers during childhood.
Assuntos
Densidade Óssea , Fibronectinas/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Feminino , Humanos , Masculino , Valores de ReferênciaRESUMO
Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.
Assuntos
Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteína SOS1/genética , Adolescente , Adulto , Criança , Éxons , Feminino , Estudos de Associação Genética , Comunicação Interatrial/genética , Comunicação Interventricular/genética , Humanos , Mutação INDEL/genética , Íntrons , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Mutação de Sentido Incorreto/genética , Conformação Proteica , Estenose da Valva Pulmonar/genética , Proteína SOS1/químicaRESUMO
Pediatric obesity is a growing and alarming global health problem and represents an important determinant of morbidity. Since nutrition plays an important role in regulating growth and development, the excess weight gain related to overnutrition can affect growth patterns, bone maturation and pubertal development. The purpose of this review was to summarize the current knowledge about the effect of primary obesity on linear growth and pubertal development in children and adolescents. Evidence about regulatory hormones and adipokines that may be involved in the physiology of childhood growth in the context of obesity were also discussed. The most recent literature confirms previous studies indicating that linear growth is accelerated (mainly due to longer trunks rather than longer legs) and bone age is advanced in prepubertal children with obesity, while there is a reduction of pubertal height gain and attainment of normal adult height. Conflicting results are reported on the timing of puberty, specifically in boys. Indeed, previous studies suggested earlier onset of puberty in obese girls and overweight boys, and a delayed puberty in obese boys. Conversely, the most recent studies show more consistently an earlier onset and completion of pubertal development also in boys with obesity. Considering the false belief of health associated with transient taller stature in children and the adverse outcomes related to early puberty, interventions on diet and physical activity are urgently needed to tackle the epidemics of childhood obesity in public health and clinical setting.
Assuntos
Obesidade Infantil , Adolescente , Adulto , Estatura , Peso Corporal , Criança , Feminino , Humanos , Masculino , Sobrepeso , PuberdadeRESUMO
BACKGROUND AND OBJECTIVE: Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood. The management of ITP in children is controversial, requiring personalized assessment of patients and therapeutic choices. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, have been shown to be safe and effective for the treatment of pediatric ITP. The aim of our research is to define the role of thrombopoietin receptor agonists in the management of pediatric ITP. METHODS: This review focuses on the use of TPO-RAs in pediatric ITP, in randomized trials and in clinical routine, highlighting their key role in the management of the disease. RESULTS: Eltrombopag and romiplostim appear effective treatment options for children with ITP. Several clinical studies have assessed that the use of TPO-RAs increases platelet count, decreases bleeding symptoms and improves health-related quality of life. Moreover, TPO-RAs are well tolerated with minor side effects. CONCLUSION: Although long term efficacy and safety of TPO-RAs still require further investigations, their use is gradually expanding in the clinical practice of children with ITP.
Assuntos
Benzoatos/uso terapêutico , Plaquetas/efeitos dos fármacos , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adolescente , Fatores Etários , Benzoatos/efeitos adversos , Plaquetas/imunologia , Plaquetas/metabolismo , Criança , Pré-Escolar , Medicina Baseada em Evidências , Feminino , Humanos , Hidrazinas/efeitos adversos , Lactente , Masculino , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Trombopoetina/metabolismo , Proteínas Recombinantes de Fusão/efeitos adversos , Transdução de Sinais , Trombopoetina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Preterm neonates are likely to require red blood cell (RBC) transfusion, and extremely low birth weight infants almost invariably receive multiple transfusions. Transfusion-reduction strategies can reduce transfusion rates, and might diminish certain adverse outcomes associated with transfusions. MATERIALS AND METHODS: In a single centre, we retrospectively evaluated RBC transfusion rates among preterm infants ≤32 weeks' gestational age (GA), over a 6-year period before and after adopting national transfusion-reduction strategies. We compared demographic data, adverse events, and outcomes between transfused vs not-transfused neonates. Univariate logistic regression was used to evaluate associations between dichotomous outcomes and number of transfusions, and day of first transfusion. Multivariate logistic regression evaluated the correlation between dichotomous outcomes and transfusion as an independent risk factor. RESULTS: During the 6 years studied, 181 infants born at ≤32 weeks' GA were admitted to our Neonatal Intensive Care Unit of whom 80 (44%) received at least one RBC transfusion. The transfusion rate tended downwards after adopting transfusion-reduction strategies, reaching 31% in 2018. The reduction was largely due to a marked fall in transfusions of neonates born at 29-32 weeks' GA (p<0.001). The number of transfusions received correlated with odds of having intraventricular haemorrhage (IVH) (OR=1.9; 95% CI: 1.3-2.7; p=0.0001) and the duration of oxygen supplementation (rho=0.51; 95% CI: 0.33-0.66; p≤0.0001). In multivariate logistic regression analysis, transfusion was an independent risk factor for IVH (adjusted OR=7.38; 95% CI: 2.24-24.30; p=0.0001). DISCUSSION: The application of national, standardised transfusion-reduction strategies was associated with a lower transfusion rate in neonates born at 29-32 weeks' GA, but was less effective among neonates ≤28 weeks, in whom transfusions appeared to be an independent risk factor for severe IVH.
Assuntos
Transfusão de Eritrócitos , Nascimento Prematuro/terapia , Transfusão de Eritrócitos/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Nascimento Prematuro/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Obese children have a great risk of hypertension and cardiovascular morbidity in adults. The insulin-like growth factor type II (IGF-II) regulates glucose homeostasis, cardiovascular functions, and lipid metabolism. IGF2 gene variants have shown a strong association with weight, body mass index (BMI), and metabolic profile in adults. We performed the molecular screening of two IGF2 polymorphisms (6815 A/T, 820 G/A), in 227 obese children to evaluate the potential association between IGF2 variants with either obesity or high blood pressure (assessed with a 24-h holter system) or both. A second cohort of age-, sex-, and BMI-matched children were enrolled to confirm any eventual association. We observed a significant association between the 6815 A/T IGF2 gene variant and high systolic blood pressure in obese children. Homozygote subjects for the T6815 allele showed, even in 24-h measurements, a higher risk to develop hypertension than those carrying the A6815 allele (OR = 3.7, 95% CI: 1.59-8.66). This result was confirmed in the second cohort (OR = 4.1, 95% CI: 1.41-6.50). Any statistically significant difference in terms of BMI between the genotype groups was observed. Our results suggest that IGF2 gene variants are involved in the blood pressure regulation in obese children.
Assuntos
Hipertensão/genética , Fator de Crescimento Insulin-Like II/genética , Obesidade/genética , Adolescente , Índice de Massa Corporal , Peso Corporal , Criança , Estudos de Coortes , Metabolismo Energético/fisiologia , Humanos , Hipertensão/etiologia , Itália , Modelos Logísticos , Obesidade/complicações , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients can develop autoantibodies such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. OBJECTIVE: The purpose of this article is to provide a review about: 1) the prevalence of positivity of anti-thyroid antibodies (TPO and TG) in pediatric patients with chronic ITP; 2) the role of autoimmune thyroiditis on the outcome of chronic ITP. METHODS: The authors individually completed a review of the literature for this article. Retrospective and prospective clinical studies with pediatric cohorts were considered. RESULTS: From the analysis of data, we found 4 papers which included studies only on pediatric population, and which corresponded to selected criteria. Pediatric ITP patients have been shown to have a statistically significant prevalence of anti-thyroid antibodies over healthy controls (11.6-36% versus 1.2-1.3%). No correlation has been found between the platelet count and the prevalence of positive anti-thyroid antibodies at any time of the follow up. CONCLUSION: The results of our bibliographic research demonstrated that: a) pediatric patients with chronic ITP tend to have a statistically significant prevalence of anti-thyroid antibodies positivity respect to general pediatric population; b) there are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age.
Assuntos
Autoanticorpos/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Glândula Tireoide/metabolismo , Autoanticorpos/imunologia , Criança , Pré-Escolar , Humanos , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/imunologia , Estudos Retrospectivos , Glândula Tireoide/imunologia , Tireoidite Autoimune/sangue , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/imunologiaRESUMO
Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-fragment crystallizable region (RANK-Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.
Assuntos
Neoplasias Ósseas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Linhagem Celular Tumoral , Humanos , Leucócitos Mononucleares , Camundongos , Osteoclastos , Ligante RANK , Microambiente Tumoral , Membro 14 da Superfamília de Ligantes de Fatores de Necrose TumoralRESUMO
NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.
RESUMO
CONTEXT: Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities include defects of the corpus callosum and hippocampus. OBJECTIVE: We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues. RESULTS: All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit beta-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathke's pouch, the developing anterior pituitary, and the eye. CONCLUSIONS: Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Olho/embriologia , Proteínas HMGB/fisiologia , Hipófise/embriologia , Prosencéfalo/embriologia , Fatores de Transcrição/fisiologia , Adolescente , Adulto , Criança , Proteínas de Ligação a DNA/genética , Anormalidades do Olho/etiologia , Anormalidades do Olho/genética , Feminino , Proteínas HMGB/genética , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/genética , Mutação , RNA Mensageiro/análise , Fatores de Transcrição SOXB1 , Transdução de Sinais , Fatores de Transcrição/genética , beta Catenina/fisiologiaRESUMO
AIMS: Growth hormone deficiency therapy is demanding for patients and caregivers. Teams engaged in the clinical management of growth hormone deficiency therapy need to know how families live with this condition, to provide an adequate support and prevent the risk of withdrawal from therapy. METHODS: Using Narrative Medicine, testimonies from patients, their parents and providers of care were collected from 11 Italian centers. Narrations were analyzed throughout an elaboration of recurring words and expressions. RESULTS: Although care management and outcomes were considered satisfying in the 182 collected narratives, recurring signals of intolerance among adolescents and the worry of not being well informed about side effects among parents are open issues. CONCLUSION: Narratives found that communication issues could decrease adherence and influence the physicians' clinical practice.
RESUMO
Paediatric obesity, like adulthood obesity, is associated with an increase of fibrinolysis inhibitors. No study, however, has evaluated the impact of these changes on plasma fibrinolytic capacity. We investigated plasma fibrinolysis and the role therein of the fibrinolytic changes associated with obesity in 59 obese children (body mass index > 95th percentile) and 40 matched controls. Fibrinolysis was investigated by measuring 1) the plasma levels of relevant fibrinolytic factors; 2) the in vitro fibrinolytic capacity under different conditions, using a microplate plasma clot lysis assay; 3) the circulating levels of markers of clotting and fibrinolysis activation. Plasminogen activator inhibitor 1 (PAI-1), total thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen levels were higher in obese children as compared to controls (p<0.01). Plasma clots from obese children lysed significantly slower than control clots when exposed to exogenous plasminogen activator, indicating a greater resistance to fibrinolysis. By the use of a selective inhibitor of activated TAFI and by regression analyses we found that fibrinolysis resistance in obese samples was attributable to PAI-1 increase and to enhanced TAFI activation. The ratio between the circulating levels of D-dimer and thrombin-antithrombin complex, a marker of in vivo fibrinolysis, was significantly lower in obese children, suggesting a reduced fibrinolytic efficiency. These data indicate that paediatric obesity is associated with a hypofibrinolytic state which might contribute to the increased thrombotic risk associated with this condition.
Assuntos
Fibrinólise/imunologia , Coagulação Sanguínea , Fatores de Coagulação Sanguínea , Testes de Coagulação Sanguínea , Índice de Massa Corporal , Carboxipeptidase B2/biossíntese , Estudos de Casos e Controles , Criança , Feminino , Fibrinogênio/biossíntese , Humanos , Masculino , Obesidade/complicações , Obesidade/terapia , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Análise de RegressãoRESUMO
The endothelial protein C receptor (EPCR) has a critical role in the regulation of anticoagulant and anti-inflammatory functions of activated protein C (APC). Abnormalities in EPCR might be associated with an increased risk of thrombosis. In this respect, a 23 bp insertion in the exon 3 of the EPCR gene predicts a truncated protein which cannot bind APC. High levels of C-reactive protein (CRP), a strong predictor of cardiovascular events, are found both in the obese and in subjects with Prader-Willi syndrome (PWS). Several cardiovascular risk factors are already present in prepubertal PWS children, but it is uncertain which mechanism contributes to the increased risk of cardiovascular disease in PWS. We analyzed the distribution of 23 bp insertion in the EPCR gene in 81 overweight and obese PWS subjects, 52 adults and 29 children, and in 58 overweight and obese children and adolescents (controls). We found that 1/58 (1.7%) of the controls was heterozygous for the 23 bp insertion, while this mutation was never found in PWS subjects. Furthermore, we evaluated CRP levels, glucose, insulin, and lipid profile, and we found higher CRP values in PWS adults with respect to children with PWS and controls, and a better insulin sensitivity in all PWS subjects than in the controls. This study suggests that in PWS subjects there is no predisposition to develop thrombotic events in association with EPCR gene alteration and demonstrates substantial differences regarding metabolic and inflammatory profile between PWS and non-PWS obese children, with further impairment in adults with PWS.