Retrospective Diagnosis of a Novel ACAN Pathogenic Variant in a Family With Short Stature: A Case Report and Review of the Literature.

Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.

Supplementation with Bifidobacterium breve BR03 and B632 strains improved insulin sensitivity in children and adolescents with obesity in a cross-over, randomized double-blind placebo-controlled trial.

BACKGROUND & AIMS: Variations in gut microbiota might impact metabolism leading to body weight excess. We assessed the impact of a probiotic supplementation in pediatric obesity on weight, metabolic alterations, selected gut microbial groups, and functionality. METHODS: Cross-over, double-blind, randomized control trial (BIFI-OBESE trial; NCT03261466). 101 youths (6-18 years, Tanner stage ≥2) with obesity and insulin-resistance on diet were randomized to 2 × 109 CFU/AFU/day of Bifidobacterium breve BR03 (DSM 16604) and B. breve B632 (DSM 24706) (51) or placebo (50) for 8 weeks with a 4-weeks wash-out period. RESULTS: All subjects (M/F 54/47) completed the first 8 weeks, and 82 (M/F 43/39) the last part without adverse events. Mixed-effects models revealed a carry-over effect on many variables in the entire study, narrowing the analysis to the first 8 weeks before the wash-out periods. All subjects improved metabolic parameters, and decreased weight and Escherichia coli counts. Probiotics improved insulin sensitivity at fasting (QUICKI, 0.013 CI95%0.0-0.03) and during OGTT (ISI, 0.654 CI95%-0.11-1.41). Cytokines, GLP1, and target microbial counts did not vary. Of 25 SCFAs, acetic acid and acetic acid pentyl-ester relative abundance remained stable in the probiotics, while increased in the placebo (p < 0.02). A signature of five butanoic esters identified three clusters, one of them had better glucose responses during probiotics. CONCLUSION: An 8 weeks treatment with B. breve BR03 and B632 had beneficial effects on insulin sensitivity in youths with obesity. Microbiota functionality could influence metabolic answers to probiotics. Long-term studies to confirm and enrich our findings are justified. Tailored probiotic treatments could be an additional strategy for obesity. TRIAL REGISTRATION: NCT03261466.

Linear growth and puberty in childhood obesity: what is new?

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.

Three-Month Feeding Integration With Bifidobacterium Strains Prevents Gastrointestinal Symptoms in Healthy Newborns.

Infantile functional gastrointestinal disorders are common in the first months of life. Their pathogenesis remains unknown although evidences suggest multiple independent causes, including gut microbiota modifications. Feeding type, influencing the composition of intestinal microbiota, could play a significant role in the pathogenesis. Previous studies supported probiotic supplementation success against colics, however mainly Lactobacillus spp. were tested. The aim of this study was to evaluate the effectiveness against functional gastrointestinal disorders of a Bifidobacterium breve based probiotic formulation including in the study both breast-fed and bottle-fed subjects. Two hundred and sixty-eight newborns were enrolled within 15 days from birth. One hundred and fifty-five of them effectively entered the study and were randomized in probiotic and placebo group, receiving the formulation for 90 days. The probiotic formulation consists of a 1:1 mixture of 2 strains of B. breve prepared in an oily suspension and administered in a daily dosage of 5 drops containing 108 CFU of each strain. Absolute quantification of selected microbial groups in the faeces was performed using qPCR. Anthropometric data, daily diary minutes of crying, number of regurgitations, vomits and evacuations, and colour and consistency of stools were evaluated before and after treatment. The study confirmed the positive role of breast milk in influencing the counts of target microbial groups, in particular the bifidobacteria community. No adverse events upon probiotic administration were reported, suggesting the safety of the product in this regimen. B. breve counts increased significantly in all administered newborns (p < 0.02). The study demonstrates that a 3 months treatment with B. breve strains in healthy breast-fed newborns helps to prevent functional gastrointestinal disorders, in particular reducing 56% of daily vomit frequency (p < 0.03), decreasing 46.5% of daily evacuation over time (p < 0.03), and improving the stool consistency (type 6 at the Bristol Stool chart instead of type 5) in those at term (p < 0.0001). Moreover, a significant reduction (8.65 vs. 7.98 LogCFU/g of feces, p < 0.03) of B. fragilis in the bottle-fed group receiving the probiotic formulation was observed.

High-normal estimated glomerular filtration rate and hyperuricemia positively correlate with metabolic impairment in pediatric obese patients.

BACKGROUND: Childhood obesity represents a major health concern worldwide due to its well established detrimental effect on cardiovascular and its potential negative effect on kidney functions. However, biomarkers that can help diagnose early stages of kidney damage in obese children represent an unmet clinical need. OBJECTIVES: In this study, we asked whether the prevalence of microalbuminuria, estimated glomerular filtration rate (eGFR) or hyperuricemia recorded in a wide cohort of obese children and adolescents would positively correlate with cardiometabolic dysfunction in these subjects. METHODS: We carried out a cross-sectional study on 360 obese children and adolescents between the ages of 3-18 years, enrolled in a tertiary care center. Clinical and biochemical evaluations including oral glucose tolerance tests (OGTTs) were performed on all patients. Microalbuminuria was defined as urinary albumin-to-creatinine ratio (u-ACR) of 30-300 mg/g. All data are expressed as mean ± standard deviation (SD), absolute values or percentages. Sex age-specific and eGFR SDs were used for statistical analyses. Serum uric acid ≥ 5.5 mg/dL was considered abnormal. RESULTS: The prevalence of microalbuminuria was 6.4%. Except for a lower insulinogenic-index, no correlations between microalbuminuria and cardiometabolic risk factors were detected. eGFR was < -1 SD and > 1 SD in 1.4% and 60.8% of subjects, respectively. Subjects with an eGFR > 1 SD had higher systolic blood pressure, liver enzymes, insulin resistance, glucose and insulin during OGTT, lower insulin sensitivity and a more prevalent microalbuminuria. Hyperuricemia (27.5%) increased the odds of hypertension, HDL ≤ 10th percentile and glucose ≥ 155.0 mg/dL after 60 minutes of OGTT. CONCLUSIONS: A worse cardiometabolic profile was observed in subjects with an eGFR > 1 SD compared to other subgroups. Therefore, pediatric obese patients with eGFR > 1 SD or hyperuricemia should be closely monitored for microalbuminuria and post-challenge glucose and insulin secretion, all potential indicators of renal dysfunction in these young patients.

The Association of Bifidobacterium breve BR03 and B632 is Effective to Prevent Colics in Bottle-fed Infants: A Pilot, Controlled, Randomized, and Double-Blind Study.

GOALS: To assess the effectiveness of Bifidobacterium breve B632 and BR03 association in the reduction of infants crying over time. The second endpoint was to observe the effect of the same strains on daily evacuations and on the number of regurgitations and vomits. BACKGROUND: Infant colics represent a clinical condition in childhood, characterized by an uncontrollable crying that occurs without any apparent organic cause. An altered intestinal microbiota composition in the very first months may induce intestinal colics in infants. Thus far, no treatment is really effective for this problem, but recent literature shows an increasing attention toward probiotics. STUDY: A total of 83 subjects were enrolled, 60 breastfed infants and 23 bottle-fed infants. Sixty of them carried out the study: 29 infants were given probiotics, whereas 31 placebo. During the 90 days of the study, parents were asked to give 5 drops of active product (10 viable cells/strain) or placebo and to daily take note of: minutes of crying, number, color, and consistency of evacuations, and number of regurgitations or vomits. RESULTS: No significant differences were detected in the infants treated with probiotics, compared with placebo group (P=0.75). The analysis of the 3 months of treatment demonstrated that during the third month, the probiotic group cried 12.14 minutes on average and the placebo cried 46.65 minutes. This difference is statistically significant (P=0.016). CONCLUSIONS: The evidence of the usefulness of some probiotic strains in the treatment and prevention of infant colics is growing, and therefore their use in clinical practice is spreading.

Vitamin D Deficiency and Glycemic Status in Children and Adolescents with Type 1 Diabetes Mellitus.

BACKGROUND: Vitamin D (25OHD) effects on glycemic control are unclear in children and adolescents with type 1 diabetes. Aims of this study were to investigate 25OHD status among children with T1DM and its relationship with insulin sensitivity and glycemic status. SUBJECTS AND METHODS: A cross sectional study was carried out between 2008-2014. A total of 141 patients had a T1DM >12 months diagnosis and were enrolled in the present study. Of these 35 (24.8%) were migrants and 106 (75.2%) Italians (T2). We retrospectively analyzed data at the onset of the disease (T0)(64 subjects) and 12-24 months before the last visit (T1,124 subjects). Fasting glucose, glycated hemoglobin (HbA1c), 25OHD levels and daily insulin requirement were evaluated and Cholecalciferol 1000 IU/day supplementation for the management of vitamin D insufficiency (<75 nmol/L) was systematically added. RESULTS: A generalized 25OHD insufficiency was found at each study time, particularly in migrants. At T0, the 25OHD levels were inversely related to diabetic keto-acidosis (DKA) severity (p<0.05). At T1 and T2, subjects with 25OHD ≤25nmol/L (10 ng/mL) showed higher daily insulin requirement (p<0.05) and HbA1c values (p<0.01) than others vitamin D status. The 25OHD levels were negatively related with HbA1c (p<0.001) and daily insulin dose (p<0.05) during follow up. There was a significant difference in 25OHD (p<0.01) between subjects with different metabolic control (HbA1c <7.5%,7.5-8%,>8%), both at T1 and T2. In supplemented subjects, we found a significant increase in 25OHD levels (p<0.0001) and decrease of HbA1c (p<0.001) between T1 and T2, but this was not significant in the migrants subgroup. Multivariate regression analysis showed a link between HbA1c and 25OHD levels (p<0.001). CONCLUSIONS: Children with T1DM show a generalized 25OHD deficiency that impact on metabolic status and glycemic homeostasis. Vitamin D supplementation improves glycemic control and should be considered as an additional therapy.

Influence of Ultraviolet Radiation on the Association between 25-Hydroxy Vitamin D Levels and Cardiovascular Risk Factors in Obesity.

OBJECTIVE: To establish if the correction with estimates of ultraviolet (UV) exposure influences the association between 25-OH-vitamin D (25OHD) levels and metabolic variables. STUDY DESIGN: A cross-sectional study was performed in 575 obese children and adolescents (>6 years of age) in a tertiary referral center. Cardiovascular risk factors were measured. The estimate of UV exposure was evaluated by 3 methods: (1) season; (2) mean of UV radiation (UVR); and (3) mean of UV index (UVI). UVR and UVI were considered at 1 (UVR 1 month prior to testing [UVR1], UVI 1 month prior to testing [UVI1]) or 3 (UVR 3 months prior to testing [UVR3], UVI 3 months prior to testing [UVI3]) months prior to testing. All analyses were corrected for confounders (sex, age, puberty, body mass index, waist circumference, the inclusion and exclusion of estimates of UV exposure). RESULTS: The 25OHD levels were associated with seasons, UVR1, UVR3, UVI1, and UVI3, and best associations with UVR3 and UVI3. In all models, total cholesterol, low-density lipoprotein cholesterol and triglycerides were negatively associated with 25OHD levels. The strength of the association increased with no correction, correction for seasons, UVR, and UVI. UVR3 and UVI3 performed better than UVR1 and UVI3. CONCLUSIONS: Higher lipid concentrations were associated with low 25OHD levels in obese children and adolescents with the power of the association dependent on the estimates of UVR. As the mean values 3 months prior to testing for both UVR and UVI determined the best associations, the interval of the steady state time of 25OHD levels could be preferentially used in the metabolic studies. Controlling for an estimate of UVR is important to decrease the heterogeneity of studies.

Adiponectin oligomers are similarly distributed in adequate-for-gestational-age obese children irrespective of feeding in their first year.

BACKGROUND: Nutrition and growth in early postnatal life have a role in future diseases. Our aim was to investigate adiponectin oligomers in adequate-for-gestational-age obese children with respect to type and duration of feeding in the first year of life. METHODS: Adiponectin oligomers and cardiometabolic risk factors were measured in 113 adequate-for-gestational-age obese children, divided into group A (prolonged breast feeding, >6 mo), group B (short breast feeding, 1-6 mo), and group C (formula feeding from birth). RESULTS: All the parameters were similar among the groups. Adiponectin oligomers did not correlate with gestational age, months of breast feeding, and time of weaning. Total and high-molecular weight adiponectin were differently distributed across gender and pubertal stages (P < 0.02), being lower in males from the start of puberty. Prepregnancy BMI and at the end of the pregnancy were negatively associated (P < 0.04) with total and medium-molecular weight adiponectin in female and male offspring, respectively. CONCLUSIONS: Adiponectin oligomers and metabolic characteristics are similarly distributed in adequate-for-gestational-age obese children, irrespective of the type and duration of the feeding in the first year of life. Gender and mother's BMI in pregnancy are contributors to adiponectin regulation. Further studies will explain whether breastfeeding protects against metabolic impairment later in life.

Obesity and infection: two sides of one coin.

The prevalence of obesity has exponentially risen worldwide. The etiology of obesity is multifactorial, and genetic inheritance and behavioral/environmental causes are considered the main etiological factors. Moreover, evidence that specific infections might promote the development of obesity has steadily accumulated. Only a few works investigate the impact of obesity on the immune response to infections and the risk of infections in the obese population. The aim of this paper was to review the available data regarding the various aspects of the association between obesity and infections and to highlight the possibility that infectious agents may have an etiological role in obesity, an idea known as "infectobesity". Several microbes have been considered as possible promoter of obesity, but most of the data concern adenovirus-36 that exerts an adipogenic action mainly via a direct effect on adipose tissue leading to weight gain, at least in animal models.Obesity affects the immune response leading to an increased susceptibility to infections. Obese adults and children show an increased incidence of both nosocomial and community-acquired infections. Furthermore, obesity may alter the pharmacokinetics of antimicrobial drugs and impact on vaccine response. However, the various aspects of the association of obesity infections remain poorly studied, and a call to research is necessary to better investigate the problem.In conclusion, obesity impacts millions globally, and greater understanding of its etiology and its effects on immunity, infections, and prevention and management strategies is a key public health concern.