Valeria Calcaterra

Prevalence of metabolic syndrome (MS) in children and adolescents with varying degrees of obesity

Objective  Childhood obesity is increasingly common and is associated with health problems; in particular, obesity plays a central role in the metabolic syndrome (MS). We estimated the prevalence of MS in Caucasian children and adolescents with varying degrees of obesity.

Autoimmune stigmata in Turner syndrome: when lacks an X chromosome.

An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in patients with Turner syndrome; the most common autoimmune diseases appear to be thyroid autoimmune disease and inflammatory bowel diseases. Turner patients evolve towards autoimmunity much more frequently than people with normal karyotype without any relevant excess of the putative immunogenetic risk markers. That underscores the great influence of X-chromosome abnormalities in the development of autoimmune disorders and suggests an epistatic interaction of X genes with immune response genes. Interestingly, one of the human MHC-paralogues is located in the long arm of the X chromosome, so that who is defective in this region might be less efficient to control the pathogenic repertoire during the lifespan. Medical care for patients with TS should routinely include screening for the autoimmune disorders in order to assure early detection and appropriate treatment.

Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2

The inherited osteolysis syndromes are a heterogeneous group of skeletal disorders whose classification is still uncertain. Three osteolysis syndromes show autosomal recessive inheritance and multicentric involvement: Torg syndrome (OMIM 259600), Winchester syndrome (OMIM 277950) and Nodulosis–Arthropathy–Osteolysis syndrome (NAO; OMIM 605156). The 2001 Nosology of the International Skeletal Dysplasia Society (Hall CM, Am J Med Genet 2002: 113: 65) classifies NAO as a variant of Torg syndrome, while Winchester syndrome is considered as a separate disorder. Recently, mutations in the matrix metalloproteinase 2 (MMP2) gene were identified in affected individuals with a clinical diagnosis of NAO in two Arab families. We report a homozygous missense mutation (E404K) in the active site of MMP2 in a 21‐year‐old woman with a severe form of osteolysis best compatible with a diagnosis of Winchester syndrome. The clinical and molecular findings suggest that Torg, NAO and Winchester syndromes are allelic disorders that form a clinical spectrum.

Major childhood infectious diseases and other determinants associated with type 1 diabetes: A case-control study

The objective of the study was to evaluate the association between infectious diseases and other events pertaining to childhood medical history and type 1 diabetes. A case-control study was carried out, taking as cases 159 type 1 diabetic patients (0–29 years) recorded from 1988 to 2000 within the population registry of the Pavia province (North Italy). As controls 318 non-diabetic subjects were matched by age and sex. A questionnaire was administered by standardised interviewers. Data were analysed by conditional logistic regression. Viral childhood diseases (OR 4.29; 95%CI 1.57–11.74) and bottle feeding (OR 1.83; 95%CI 1.08–3.09) were directly correlated to type 1 diabetes; an inverse correlation was found for vitamin D administration during lactation (0–14 years) (OR 0.31; 95%CI 0.11–0.86) and for history of scarlet fever in both sexes and age groups (OR 0.19; 95%CI 0.08–0.46). Most associations of the studied variables confirm already known findings. The significant inverse correlation of type 1 diabetes with scarlet fever history is a peculiar finding, the meaning of which is still obscure, although it has been recently described that streptococcal A infections are regulated by HLA class II alleles.

Serum liver enzymes in Turner syndrome.

Abstract Increased serum concentrations of liver enzymes are sometimes observed, in the absence of clinical symptoms of liver disease, in patients with Turner syndrome. The purpose of this study was to evaluate, in our Turner patients, serum liver enzyme levels and to find a cause for their increase. In 70 Turner patients, serum AST, ALT, GGT levels were evaluated every 6 months during a period of 0.8–21.9 years. In patients in whom increased values of liver enzymes were found, serological markers for infectious hepatitis, serum hepatitis C virus RNA and virus genotype, IgG and IgA antibodies to gliadin and endomysium, coeruloplasmin, copper, α1-antitrypsin, total proteins and electrophoresis, IgG, IgA, IgM, fibrinogen, prothrombin, alkaline phosphatase, creatine kinase and total and direct bilirubin were also determined. Antinuclear, anti-smooth muscle and anti-liver-kidney microsome antibodies together with antithyroglobulin and anti-thyroid peroxidase antibodies were determined in all patients and in 166 age-matched female controls. In 22 patients, increased liver enzymes were observed, not related to karyotype. Follow-up showed that the hepatic disorder did not worsen with the time. Serological markers of hepatitis C virus were positive in three patients. When the serum liver enzyme increase was first observed in the other 19 patients with high enzyme levels (group A), 14 patients had never been submitted to hormonal treatment, 4 were on oestrogen/gestagen treatment and 1 was being treated with both growth hormone and oestrogen. Coeliac disease, α1-antitrypsin deficiency and Wilson disease were ruled out by appropriate investigations. In 8/19 group A patients, antinuclear and/or anti-smooth muscle antibodies were present versus 6/48 of patients with normal liver enzymes (group B). Thyroid antibodies were found in 8/19 patients in group A and in 13/48 in group B. Weight excess SDS was significantly higher in Turner girls with liver enzyme increase. Ultrasonography, performed in 17 patients of group A, showed mild hepatomegaly in 4 and increased echogenicity with fatty infiltration in 6. Conclusion Hepatic abnormalities in Turner syndrome are not progressive. Oestrogen should not be considered the main cause of increased liver enzymes in Turner syndrome since most of our patients with this finding had not been previously treated with oestrogens. An auto-immune pathogenesis might be considered in some cases, whereas the association with weight excess seems the most frequent cause of liver disorder in Turner syndrome.

Variations of the Perforin Gene in Patients With Type 1 Diabetes

OBJECTIVE—Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes. RESEARCH DESIGN AND METHODS—We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects. RESULTS—In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 6.68 [95% CI 1.83–7.48]). Sequencing of the entire coding region detected one novel mutation in one patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes–predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A. CONCLUSIONS—These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.

Post-Operative Benefits of Animal-Assisted Therapy in Pediatric Surgery: A Randomised Study

Background Interest in animal-assisted therapy has been fuelled by studies supporting the many health benefits. The purpose of this study was to better understand the impact of an animal-assisted therapy program on children response to stress and pain in the immediate post-surgical period. Patients and Methods Forty children (3–17 years) were enrolled in the randomised open-label, controlled, pilot study. Patients were randomly assigned to the animal-assisted therapy-group (n = 20, who underwent a 20 min session with an animal-assisted therapy dog, after surgery) or the standard-group (n = 20, standard postoperative care). The study variables were determined in each patient, independently of the assigned group, by a researcher unblinded to the patient’s group. The outcomes of the study were to define the neurological, cardiovascular and endocrinological impact of animal-assisted therapy in response to stress and pain. Electroencephalogram activity, heart rate, blood pressure, oxygen saturation, cerebral prefrontal oxygenation, salivary cortisol levels and the faces pain scale were considered as outcome measures. Results After entrance of the dog faster electroencephalogram diffuse beta-activity (> 14 Hz) was reported in all children of the animal-assisted therapy group; in the standard-group no beta-activity was recorded (100% vs 0%, p<0.001). During observation, some differences in the time profile between groups were observed for heart rate (test for interaction p = 0.018), oxygen saturation (test for interaction p = 0.06) and cerebral oxygenation (test for interaction p = 0.09). Systolic and diastolic blood pressure were influenced by animal-assisted therapy, though a higher variability in diastolic pressure was observed. Salivary cortisol levels did not show different behaviours over time between groups (p=0.70). Lower pain perception was noted in the animal-assisted group in comparison with the standard-group (p = 0.01). Conclusion Animal-assisted therapy facilitated rapid recovery in vigilance and activity after anaesthesia, modified pain perception and induced emotional prefrontal responses. An adaptative cardiovascular response was also present. Trial Registration ClinicalTrials.gov NCT02284100

Improved metabolic and cardiorespiratory fitness during a recreational training program in obese children

Abstract Physical activity may protect from the adverse effects of obesity. In obese children, an increased adherence and a decreased drop-out rate during exercise could be achieved with adaptated activities. We studied a recreational 12-week controlled training program for sedentary obese children, including interactive video games. We enrolled 22 obese subjects (13.23±1.76 years) in an exercise program, implemented twice a week for a 12-week period. The program consisted of a combination of circuit-based aerobics, strength and resistance exercises; specifically soccer, rugby, volleyball and basketball and interactive video game exercises. Outcome measurements included body composition, metabolic profile and cardiorespiratory fitness. During the 12-week training program there was a significant decrease in body mass index (BMI) (p=0.002), SDS-BMI (p=0.003), waist circumference (p=0.004), waist circumference/height ratio (p=0.001),% fat mass (p=0.001), blood glucose (p=0.001), homeostasis model assessment for insulin resistance (HOMA-IR) (p=0.04), triglycerides (p=0.03) and systolic pressure (p=0.04) before and after exercise. Improvement in estimated maximum oxygen consumption (VO2max) (p<0.001) correlated with a decrease in fat mass (p=0.01), triglycerides (p=0.04) and insulin resistance (p=0.02). Exercise improved metabolic and cardiorespiratory fitness in obese children. Exercise training does not necessarily need to be vigorous, recreational programs are also effective and may encourage children to participate in physical activity and limit initial drop-out.

Aortic dimensions in Turner's syndrome: Two-dimensional echocardiography versus magnetic resonance imaging

Background Patients with Turners syndrome have an increased risk of cardiac death caused by aortic disease. Consensus has not been reached about the best method to image the aorta in this syndrome. Aim This present study aimed: (i) to evaluate thoracic and abdominal aortic dimensions by two-dimensional echo (2-DE) and magnetic resonance imaging (MRI) and (ii) to assess agreement between 2-DE and MRI measurements. Material and methods Among 75 kariotypically proven Turners syndrome patients, 59 (79%) (mean age: 22 ± 7 years) underwent a 2-DE and an MRI study of the thoracic and proximal abdominal aorta. The aortic root (AR), the sino-tubular aortic junction (STJ), the first part of the ascending thoracic aorta (AscTA), the aortic arch (AArch), the descending thoracic aorta (DTAp) a few centimetres below the isthmus and the abdominal aorta (AbA) were analysed. The Bland and Altman method and Lins concordance correlation coefficient were utilized to compare 2-DE and MRI aortic dimensions. Results Compared to MRI, feasibility of aortic imaging by 2-DE was identical at AR level, but lower when measuring distal aorta (88% at DTAp and 91.5% at AbA level versus 100%). The 2-DE and MRI showed a very slight difference between measurements and a high concordance correlation coefficient at the level of AR and AscTA; correlations were weaker at the other aortic levels. Absolute differences calculated at each measurement level showed that concordance (defined as differences within 1 mm between 2-DE and MRI absolute measures) was highest at AR (45.6%) and AscTA (28%) level and lowest at STJ (12.2%) level. The 2-DE overestimated aortic arch diameters in approximately 70% of cases, whereas at the remaining aortic levels MRI measurements were usually 1 mm higher compared to the corresponding 2-DE values. Conclusions Concordance between 2-DE and MRI was found to be very good at the AR and AscTA levels. Because the risk of aortic complication is higher when AR and proximal thoracic aorta are dilated, 2-DE may be considered a useful method to screen for aortic disease and a good choice to follow proximal aortic dimensions over time in Turners syndrome patients.

Common immunogenetic profile in children with multiple autoimmune diseases: the signature of HLA-DQ pleiotropic genes

Type 1 diabetes mellitus (T1DM), celiac disease (CD) and autoimmune thyroid disease (ATD) are autoimmune conditions relatively common in paediatric age and frequently occur in association in the same subject. This event is not by chance and requires an explanation. Here, we studied the distribution of HLA-DQ αβ heterodimers in 334 Italian children with T1DM, ATD and CD alone or in association and in 224 Italian healthy controls. In particular, 164 patients had T1DM (133 alone, 20+ATD, 7+CD and 4+CD+ATD), 118 had ATD (110 alone, 8+CD) and 52 had CD (40 alone, 11+ATD and 1+T1DM). 51 patients suffered from multiple autoimmune diseases. The risk for multiple autoimmune diseases was significantly associated with the increased number of HLA-DQ markers of susceptibility for both T1DM (p = 0.003) and CD (p = 0.006). The presence of one or more diabetogenic DQ molecules significantly increased the probability of developing not only T1DM (p < 0.001) but also CD (p < 0.001) and ATD (p = 0.001). Similarly, the presence of one or more celiac HLA-DQ heterodimers significantly increased the likelihood of developing not only CD (p < 0.001), but also T1DM (p < 0.001) and ATD (p < 0.001). We confirm that the sharing of the immunogenetic background is responsible for the development of multiple autoimmune diseases although with a different risk according to the number and type of susceptible HLA-DQ heterodimers as reported in the algorithm proposed here. It is likely that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and HLA-DQ genomic typing will improve the capability to predict associated autoimmune diseases in infancy.