Unusual Manifestation of Extraosseous Ewing Sarcoma: Report of 3 Cases.

Ewing sarcoma (ES), described as a diffuse endothelioma of the bone, is divided into two categories: osseous and extraosseous, which mainly affects adolescents. Extraosseous Ewing Sarcomas (EES) are rare tumors originating from soft tissues. Their clinical presentation depends mainly on the primary location of the tumor and are highly chemosensitive and radiosensitive. The purpose of this study was to describe the clinical characteristics and outcomes of 3 children with EES and uncommon presentation treated in our Unit. The diagnosis of EES was confirmed by biopsy and cytogenetic analysis with fluorescence in situ hybridization (FISH). Surgical excision was planned as primary treatment, followed by adjuvant chemotherapy according to EURO-E.W.I.N.G protocol. To date, all patients are alive, 1, 3 and 4 years after completion of treatment, with no signs of recurrence or metastasis.

Association of Genetic Polymorphisms in Kawasaki Disease with the Response to Intravenous Immunoglobulin Therapy.

Kawasaki disease (KD) is an acute febrile and systemic vasculitis disease mainly affecting children < 5 years old. Although the first case of KD was reported in 1967 and despite extensive research on KD since then, the cause of the disease remains largely unknown. The most common complications of KD are coronary artery lesions (CAL), which significantly increase the risk of coronary heart disease. The standard treatment for KD is high-dose intravenous immunoglobulin (IVIG) plus aspirin within 10 days from symptoms' appearance, which has been shown to decrease the incidence of CAL to 5-7%. Despite the benefits of IVIG, about 25% of the patients treated with IVIG develop resistance or are unresponsive to the therapy, which represents an important risk factor for CAL development. The cause of IVIG unresponsiveness has not been fully elucidated. However, the role of gene polymorphisms in IVIG response has been suggested. Herein, we comprehensively review genetic polymorphisms in KD that have been associated with IVIG resistance/unresponsiveness and further discuss available models to predict IVIG unresponsiveness.Kindly check and confirm inserted city in affiliation [1] is correctly identified.confirm.

DNA hypermethylation of PTPN22 gene promoter in children and adolescents with Hashimoto thyroiditis.

PURPOSE: Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is an inhibitor of T-cell activation, regulating intracellular signal transduction and thereby being implicated in the pathogenesis of autoimmune thyroid disease (AITD). The exact molecular mechanisms have not been fully elucidated. The aim of the present study was to quantitate DNA methylation within the PTPN22 gene promoter in children and adolescents with AITD and healthy controls. METHODS: 60 Patients with Hashimoto thyroiditis (HT), 25 patients with HT and type 1 diabetes (HT + T1D), 9 patients with Graves' disease (GD) and 55 healthy controls without any individual or family history of autoimmune disease were enrolled. Whole blood DNA extraction, DNA modification using sodium bisulfate and quantification of DNA methylation in the PTPN22 gene promoter, based on melting curve analysis of the selected DNA fragment using a Real-Time PCR assay, were implemented. RESULTS: DNA methylation in the PTPN22 gene promoter was found to be significantly higher in HT patients (39.9 ± 3.1%) in comparison with other study groups (20.3 ± 2.4% for HT + T1D, 32.6 ± 7.8% for GD, 27.1 ± 2.4% for controls, p < 0.001). PTPN22 gene promoter DNA methylation was also associated marginally with thyroid autoimmunity in general (p = 0.059), as well as considerably with thyroid volume (p = 0.004) and the presence of goiter (p = 0.001) but not thyroid function tests. CONCLUSIONS: This study demonstrates for the first time that a relationship between autoimmune thyroiditis and PTPN22 gene promoter DNA methylation state is present, thus proposing another possible etiological association between thyroiditis and abnormalities of PTPN22 function. Further expression studies are required to confirm these findings.

Could vitamin D deficiency influence left heart ventricular geometry in youngsters with type 1 diabetes mellitus?

BACKGROUND: Experimental and clinical studies have shown the cardio-protective, anti-inflammatory, and anti-atherosclerotic actions of vitamin D. MATERIAL AND METHODS: We aimed to investigate a possible correlation between vitamin D status and heart geometry using echocardiographic parameters of the left ventricle in youngsters with type 1 diabetes mellitus (T1D). Seventy-eight pediatric patients (aged 13.47 ± 2.86 years) with T1D of more than two years duration and 74 healthy controls (aged 12.04 ± 2.79 years) were enrolled in this case-control study. Anthropometric parameters were recorded, vitamin D and parathormone serum levels were measured, and trans-thoracic echocardiographic study was performed. RESULTS: Vitamin D deficiency was found in 74 % T1D patients and in 72 % of the controls, while parathormone levels were normal in both groups. T1D patients presented significantly higher values of interventricular septal thickness at diastole (IVSD) compared to controls (0.76 ± 0.16 cm vs 0.71 ± 0.14 cm, p =0.043). All other echocardiographic parameters did not exhibit significant differences between patients and controls. The diastolic function of the left ventricle (LV) was normal in both groups. After sub-grouping, the participants according to the deficiency or not of vitamin D, only patients with T1D and low vitamin D levels had increased values of IVSD compared to controls (0.78 ± 0.17 vs 0.71 ± 0.14, p =0.008). Patients with T1D and normal vitamin D levels presented similar values of IVSD compared to controls (0.71 ± 0.12 vs 0.73 ± 0.15, p =NS). CONCLUSIONS: Children and adolescents with T1D and normal vitamin D levels do not exhibit changes in LV dimensions or diastolic function, except for increased IVSD, compared to controls. Larger and longitudinal studies are required to confirm and consolidate this finding. HIPPOKRATIA 2019, 23(1): 9-14.

Exercise testing and adipokine levels for the evaluation of overweight and obesity in children.

BACKGROUND: Childhood obesity poses a global health threat. We investigated the association of the cardiopulmonary exercise testing indexes with adipokines levels and insulin resistance along with the beneficial effect of physical exercise on insulin resistance in children. MATERIAL AND METHODS: Thirty-two obese, 21 overweight, and 30 normal-weight children participated in the current study, with mean age 11.98 (±1.95), 10.91 (±1.72), and 11.35 (±2.21) years, respectively. All children were clinically healthy. The children and their parents provided data on physical activity, while spirometry and maximal cardiopulmonary exercise testing were performed for the functional evaluation of the respiratory status of the study population. RESULTS: Leptin levels were significantly lower in normal-weight children compared to the obese ones (p <0.001). Maximum quantity of oxygen (VO2max) differences were statistically significant between the three groups (p =0.025 for normal weight vs overweight, and p =0.001 for normal vs obese children). Leptin levels were inversely related to VO2max in obese children (p =0.009, r =-0.491). Homeostatic model assessment of insulin resistance (HOMA-IR) was statistically significantly lower among children that were more physically active (p =0.042). Leptin was significantly related to body mass index among obese children (r =-0.582, p <0.001). CONCLUSIONS: Leptin is significantly inversely related to VO2max in obese children. This study, however, allows further assumptions for adipokines and childhood obesity, along with the possible role of leptin as an additional obesity index in relation with cardiopulmonary function. HIPPOKRATIA 2017, 21(3): 124-129.

Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis.

UNLABELLED: Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis. INTRODUCTION: Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss. METHODS: We evaluated 40 children and adolescents with T1DM (mean ± SD age 13.04 ± 3.53 years, T1DM duration 5.15 ± 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 ± 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference. RESULTS: Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD. CONCLUSIONS: T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis.

Common VDR polymorphisms and idiopathic short stature in children from northern Greece.

BACKGROUND: A Vitamin D Receptor gene (VDR) polymorphism, rs10735810 (Fok1), has been associated in the past with idiopathic short stature (ISS) in a linkage study. We have investigated the association of the same, as well as a different polymorphism in the same gene [rs731236 (Taq1)] with ISS, in an independent study in Greek children. METHODS: The VDR rs10735810 (Fok1) and rs731236 (Taq1) polymorphisms were genotyped in a group of ISS children (n= 47) and an age and sex-matched group of normal height children (n= 60) from northern Greece. Genotyping was accomplished through established PCR-RFLP methods. RESULTS: An association trend of rs10735810 with ISS was observed, with the TT (ff) genotype being apparently underrepresented among ISS children compared to controls (p= 0.076; OR= 0.165, 95% CI= 0.025-1.094). CONCLUSIONS: The above results, together with recent evidence related to the functionality of the rs10735810 polymorphism, cannot exclude an involvement of VDR in the pathogenesis of ISS. Hippokratia 2015, 19 (1): 25-29.

Apelin and G212A apelin receptor gene polymorphism in obese and diabese youth.

OBJECTIVE: The apelinergic system has been previously described to participate in fluid homeostasis, cardiac contractility, blood pressure and neo-vascularization. The role of apelin in obesity and glucose metabolism has also lately gained interest; however, it still remains obscure. This study aimed to assess serum apelin levels in obese youngsters and to investigate any possible association with the G212A polymorphism of the apelin receptor (APLNR) gene. METHODS: Ninety obese individuals and 90 matched for age and gender lean controls were included. Anthropometric measurements, data of glucose metabolism, including an oral glucose tolerance test, and serum apelin levels were obtained. The presence of the G212A polymorphism of the APLNR gene was also analyzed in the obese group. RESULTS: Obese participants had significantly lower serum apelin levels as compared with controls (P = 0.011). After being grouped according to their status of glucose metabolism, only obese subjects with impaired glucose metabolism (diabese) exhibited lower apelin levels as compared with controls. The presence of the G212A polymorphism did not differ from the HapMap-reported frequencies in Caucasians (GG = 53.3%/GA = 38.9%/ΑΑ = 7.8% vs. GG = 46.9%/GA = 39.8%/ΑΑ = 13.3%, P = 0.232). The GG and GA obese subgroups had significantly lower apelin levels as compared with the AA group (P = 0.013 and P = 0.016, respectively). CONCLUSION: Obese (especially diabese) youngsters demonstrated lower serum apelin levels; the G212A polymorphism of the APLNR gene was found to exert a favourable effect on circulating apelin levels in childhood obesity.

Insulin analogues for type 1 diabetes in children and adolescents.

Since insulin is the unique and life-long therapy in type 1 diabetes and classical insulin preparations have certain limitations due to their pharmacokinetic and pharmacodynamic properties, the new insulin analogues aim to eliminate these limitations. Five insulin analogues are commercially available and approved for individuals with type 1 diabetes: three rapid-acting (insulin lispro, insulin aspart and insulin glulisine) and two long-acting insulin analogues (insulin glargine and insulin detemir). According to several studies conducted in children with type 1 diabetes, insulin analogues, due to their structural alterations, offer flexibility, reduction of nocturnal hypoglycemic episodes and decrease in postprandial hyperglycemic events, resulting in improved quality of life for diabetic children and their families. However, diabetes control measured with glycosylated hemoglobin A1c has been reported to be similar to conventional insulin preparations. Evidence-based medical reports indicate that insulin analogues are safe and effective, and therefore approved for children even from the age of 2 years. Moreover, suspicions and reports on the association of insulin analogues with carcinogenesis have not been established, requiring further investigation. This review reports the properties and characteristics of insulin analogues, as well as the results of current studies concerning pediatric patients with type 1 diabetes.

Two-year cyclic infusion of pamidronate improves bone mass density and eliminates risk of fractures in a girl with osteoporosis due to Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome (HCS) is a rare disorder principally characterized by acro-osteolysis, distinctive craniofacial and skull changes, dental anomalies and short stature. A common finding in HCS patients is secondary osteoporosis that progresses over time and contributes to various skeletal problems, especially fractures. Although autosomal dominant inheritance has been documented in several families, sporadic (non-familial) cases have also been reported. Here, a case of a 9-year-old girl with familial HCS and multiple spinal fractures, who has been effectively treated with pamidronate, is presented. This is the first report of a beneficial effect of intravenous bisphosphonate administration on a child with HCS-related osteoporosis.

Gitelman syndrome: first report of genetically established diagnosis in Greece.

Gitelman syndrome is an inherited renal tubular disorder characterized by hypokalemic metabolic alkalosis. It is distinguished from other hypokalemic tubulopathies, such as Bartter syndrome, by the presence of both hypomagnesemia and hypocalciuria. We report a case of Gitelman syndrome in a 10-year-old girl who presented for examination of persistent unexplained hypokalemia. She had no severe clinical symptoms but she had typical laboratory findings including hypokalemia, hypomagnesemia and normocalcemic hypocalciuria. Molecular analysis revealed a mutation in the exon 21 of the SLC12A3 gene which encodes the thiazide-sensitive sodium-chloride co-transporter expressed in the distal convoluted tubule (a guanine to adenosine substitution at nucleotide 2538). She was treated with oral potassium and magnesium supplements. This is the first report of genetically established diagnosis in Greece. Gitelman syndrome should be considered as a cause of persistent hypokalemia and genetic analysis might be a useful tool to confirm the diagnosis.

Diabese youngsters have 3.7 more chances in developing metabolic syndrome compared with the obese.

BACKGROUND AND AIMS: Diabesity, the coexistence of diabetes and obesity, is a new health epidemic. The present case-control study aimed in assessing the prevalence of metabolic syndrome (MS) between diabese and obese children and adolescents. METHODS AND RESULTS: One-hundred and fifty-four obese children and adolescents aged 4-16 yr were recruited and divided in 2 groups: the diabese (no.=85) who were diagnosed with obesity and impaired glucose tolerance (IGT) and the obese (no.=69), who formed the controls group and did not demonstrate IGT. Von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), and uric-acid levels were measured. Being diabese increased the odds ratio (OR) for developing MS (OR: 3.714), demonstrating increased serum triglycerides (TG) (OR: 9.067) and low HDL-cholesterol (HDL-C) (OR: 1.405), developing hypertension (OR: 0.750) and acanthosis nigricans (OR: 2.882). In the total sample, low HDL-C was the most common MS criterion, diagnosed in 68% of the diabese and 62% of the obese subjects. Age and weight-adjustment of the continuous data demonstrated that the diabese subjects had higher fat mass index, blood pressure, and TG levels, however the obese exhibited lower HDLC concentrations. Principal component analysis demonstrated that among the inflammatory biomarkers PAI-1 and vWF contributed to the prevalence of MS. CONCLUSION: The present study is the first to demonstrate that the diabese youngsters have 3.7 times more chances in developing MS compared with the obese. From the examined atherosclerotic biomarkers, PAI-1 and vWF contributed to the prevalence of the syndrome and both indicate the initiation of endothelial dysfunction.

Quality of life of children and adolescents with diabetes of Northern Greek origin.

AIM: To culturally adapt the diabetes- specific quality of life (QOL) instrument PedsQL 3.0 Diabetes Module (DM) and the generic QOL instrument PedsQL 4.0 Generic Core Scales (GCS) to the population of Greek diabetic children. Also, to evaluate QOL in youths with type 1 diabetes, compare it with that of healthy youths, and identify relationships between QOL and metabolic control and intensity of treatment. PATIENTS AND METHODS: Eighty nine (89) children and adolescents with type I diabetes and 89 without diabetes, all with their parents (2-18 years of age, diabetes duration>6 months) completed the Greek GCS. Those with diabetes also completed the Greek DM. RESULTS: Cronbach alpha coefficient of child and parent report of both instruments, in general approached 0.70, indicating their internal consistency reliability. Both instruments demonstrated positive intercorrelations with their total scores and subscales of DM demonstrated positive intercorrelations with total score of the generic instrument, supporting the validity of both instruments for the evaluation of QOL of Greek diabetic children. No statistically important differences were found among patient and parent report of diabetes and control group in both instruments. Exception was "Social functioning" in which children with diabetes reported better QOL. Growing age, female gender, large BMI, poor metabolic control and intensity of treatment did not influence QOL of children with diabetes. CONCLUSIONS: Greek PedsQL GCS and DM have sufficient acceptability, reliability and validity so as to be used for the purposes of a comparative study. Youth with diabetes reported similar QOL with non-diabetic youth of the same age and socioeconomic status.

Effect of exocrine pancreatic function on resting energy expenditure in cystic fibrosis.

AIM: To prove the hypothesis that exocrine pancreatic function determines resting energy expenditure (REE) in cystic fibrosis (CF). METHOD: Thirty-eight CF individuals, 9-34 (19.98 +/- 1.0) years, were divided into three groups: Six pancreatic sufficient patients (PS; group A), 21 pancreatic insufficient patients (PI), whose pulmonary function was comparable to that of group A (group B1) and 11 PI patients, whose pulmonary function was significantly worse than that of group A (group B2). REE was estimated by indirect calorimetry. Predicted REE was based on Schofield equations. Measured REE was expressed as % of the predicted. BMI, BMI z-scores, serum albumin, cholesterol and triglycerides levels were related to REE. Results were expressed as mean +/- standard error. RESULTS: Groups B1 and B2 had significantly higher REE% (111.7 +/- 2.75% and 119.94 +/- 3.8, respectively) as opposed to group A (98.9 +/- 3.81%; p = 0.022 and 0.035, respectively) whose REE% was similar to that predicted. REE% between group B1 and B2 was not statistically significant. In groups A, B1 and B, mean FEV1% was 86.33 +/- 10.1%, 90.24 +/- 4.39%, 44.54 +/- 3.47%, respectively, mean BMI was 25.6 +/- 2.06, 19.48 +/- 0.64 and 20.09 +/- 8.8, respectively, BMI z-scores were 0.75 +/- 0.51, -0.52 +/- 0.24 and -1.07 +/- 0.37, respectively. Significant correlation was demonstrated between REE%, BMI z-scores and cholesterol levels in group A. CONCLUSION: Clinically stable CF patients, who had comparable pulmonary function, exhibited increased REE% only in the presence of exocrine pancreatic insufficiency. REE% strongly correlated with BMI z-scores in pancreatic sufficiency. These findings support the hypothesis that pancreatic rather than pulmonary function may determine nutritional status as well as REE in CF.

Acquired von Willebrand's syndrome resulting from untreated hypothyroidism in two prepubertal girls.

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder associated with a number of different diseases, including hypothyroidism. We describe two prepubertal girls with AvWS and undiagnosed hypothyroidism due to thyroiditis Hashimoto. The patients had neither family history nor symptoms of bleeding disorders. Substitution therapy with levothyroxine led to normalization of the coagulation parameters. We report these cases in order to raise awareness among paediatricians so that the AvWS should be suspected and searched for with the appropriate laboratary tests in all cases of hypothyroidism. Moreover, patients with bleeding diathesis of unknown origin should also be investigated for hypothyroidism.

Familial polythelia over three generations with polymastia in the youngest girl.

UNLABELLED: Supernumerary nipples or polythelia are developmental abnormalities located along the embryonic mammary lines. It is the most common form of accessory breast tissue malformation and usually occurs sporadically but familial aggregation has been reported. Polythelia has been reported in association with congenital malformations, in particular with renal anomalies. Polymastia in female patients has been reported to manifest usually during pregnancy or lactation. We report on a pedigree with six cases of polythelia over three generations and one case of polythelia and polymastia in the youngest member of this family. The girl (11 years old ) had in addition to six supernumerary nipples, an accessory breast gland located under the normal left breast. No other congenital malformations could be detected. This girl will remain under follow-up until the end of puberty when the accessory breast gland will be removed. Manifestation of polymastia during puberty rarely has been reported. CONCLUSION: Polymastia may appear with familial polythelia even without renal anomalies.

Insulin improves clinical status of patients with cystic-fibrosis-related diabetes mellitus.

UNLABELLED: Cystic-fibrosis-related diabetes mellitus is frequently underdiagnosed and associated with deterioration of overall clinical status. The purpose of this prospective study was to investigate the influence of insulin on nutrition, lung function and clinical status of cystic fibrosis patients. For a period of 5 y, and at 6-mo intervals, body mass index, forced expiratory volume in 1 sec, Shwachman score, intravenous glucose tolerance test and first-phase insulin response were determined in 30 cystic fibrosis patients (age range 10-35 y) with exocrine pancreatic insufficiency. During the study period, six patients (3M and 3F; age range 15-22 y) developed diabetes and required insulin therapy. The decrease of first-phase insulin response coincided with deterioration of nutritional and clinical status, which improved significantly 6 mo after the institution of insulin. CONCLUSION: Insulin, as an anabolic hormone, could have an influence on body mass, which may affect pulmonary function and clinical condition in cystic fibrosis. It is important to identify cystic fibrosis individuals at risk of developing diabetes so that early insulin therapy is instituted.

Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease.

GOALS: To evaluate the efficacy of UDCA in arresting the progression of the early multifocal hepatic lesion to overt CF-related NBC. BACKGROUND: Focal biliary cirrhosis is an early hepatic pathologic change related to the ion transport defect in cystic fibrosis. The factors involved in the progression of focal to nodular biliary cirrhosis are not clear. Ursodeoxycholic--a hydrophilic, nontoxic, choleretic, and hepatoprotective exogenous bile acid--has been reported to be effective in the management of cholestatic liver disease. STUDY: For 10 years at 6-month intervals, 70 individuals with cystic fibrosis (38 men and 32 women; age range, 2--29 years) were examined using hepatosplenomegaly, liver function tests, and ultrasound liver scan. Patients demonstrating evidence of liver involvement at the onset or during the study received ursodeoxycholic acid 20 mg/kg body weight. RESULTS: After the administration of ursodeoxycholic acid, the progression of nodular biliary cirrhosis ultrasound changes was arrested, hepatic function was preserved, and no variceal bleeding was observed. No case of focal biliary cirrhosis progressed to nodular biliary cirrhosis. Furthermore, the multifocal, multilobular changes suggestive of focal biliary cirrhosis on ultrasound scan were reversed to normal. CONCLUSION: Ursodeoxycholic acid is effective in improving cholestasis and hepatic dysfunction in nodular biliary cirrhosis and, also, in reversing the early sonography findings suggestive of focal biliary cirrhosis. It is speculated that ursodeoxycholic acid may prove to affect the natural history of cystic fibrosis-related liver disease.