Ciliopathies in pediatric enodcrinology

Ciliopathies are a group of disorders that involve many organs and systems. In this review, we consider the role of the cilium in multiorgan pathology with a focus on endocrinological aspects. Identification of new genes and mutations is the major challenge in development of a tailored and appropriate therapy. It is expected that new mutations will be identified to characterize ciliopathies and promote new therapies.

Growth plate extracellular matrix defects and short stature in children

Many etiological factors causing short stature have already been identified in humans. In the last few years, the advent of new techniques for the detection of chromosomal and molecular abnormalities has made it possible to better identify patients with genetic causes of growth failure. Some of these factors directly affect the development and growth of the skeleton, since they damage the epiphyseal growth plate, where linear growth occurs, influencing chondrogenesis. In particular, defects in genes involved in the organization and function of the growth plate are responsible for several well-known conditions with short stature. These genes play a pivotal role in various mechanisms involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. In this review, we will discuss the genes involved in extracellular matrix disorders. The identification of genetic defects in linear growth failure is important for clinicians and researchers in order to improve the care of children affected by growth disorders.

Deciphering short stature in children

Short stature is a common reason for referral to pediatric endocrinologists. Multiple factors, including genetic, prenatal, postnatal, and local environmental factors, can impair growth. The majority of children with short stature, which can be defined as a height less than 2 standard deviation score below the mean, are healthy. However, in some cases, they may have an underlying relevant disease; thus, the aim of clinical evaluation is to identify the subset of children with pathologic conditions, for example growth hormone deficiency or other hormonal abnormalities, Turner syndrome, inflammatory bowel disease, or celiac disease. Prompt identification and management of these children can prevent excessive short stature in adulthood. In addition, a thorough clinical assessment may allow evaluation of the severity of short stature and likely growth trajectory to identify the most effective interventions. Consequently, appropriate diagnosis of short stature should be performed as early as possible and personalized treatment should be started in a timely manner. An increase in knowledge and widespread availability of genetic and epigenetic testing in clinical practice in recent years has empowered the diagnostic process and appropriate treatment for short stature. Furthermore, novel treatment approaches that can be used both as diagnostic tools and as therapeutic agents have been developed. This article reviews the diagnostic approach to children with short stature, discusses the main causes of short stature in children, and reports current therapeutic approaches and possible future treatments.

Insulin resistance and type 2 diabetes in children

Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.

Insulin resistance and type 2 diabetes in children

Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.

Usefulness of nBos d 4, 5 and nBos d 8 Specific IgE Antibodies in Cow's Milk Allergic Children

PURPOSE: The aim of study was to assess the value of recombinants in predicting the degree of symptoms in children with and without anaphylaxis to cow's milk. METHODS: The study included 79 children (70+/-40 months) referred to the Allergological Unit of the Pediatric Department between the years 2008-2012. Group A was composed of 17 children (78+/-49.6 months) with anaphylaxis after ingestion of milk. Group B was composed of 62 children (73.1+/-38.6 months) without a history of anaphylaxis, but with less severe symptoms (gastrointestinal and/or skin symptoms). All patients from Group B had a positive open challenge with cow's milk. All patients underwent an allergic evaluation and blood samples were collected to test for IgE to recombinans of milk (nBos d 4, 5, 8). RESULTS: A significant difference in nBos d 8 emerged with higher levels in Group A (median [IQR]=2.80 [0.91-16.1]) than B (0.65 [0.24-1.67]; P=0.006), whereas there were no statistically significant differences for nBos d 4 and 5. The recombinants' sum was higher in Group A than B: 8.39 [2.72-41.39] vs 3.04 [1.85-7.31] kUA/L; P=0.044. The recombinant nBos d 8 was superior to the other recombinants in identifying children at risk for anaphylaxis, with an area under the curve of 0.718 (95% CI, 0.57-0.86, P=0.006). Considering a cutoff of 1.8 kUA/L, nBos d 8 had the most favorable sensitivity and specificity ratio (sensitivity=0.65, specificity=0.77) with an odd ratio of 6.02 (95% C.I: 1.89-19.23). CONCLUSIONS: This study suggested 2 phenotypes of allergic children, "high-anaphylaxis-risk" and "milder-risk". These types can be differentiated through measuring the level of IgE to nBos d 8.

p53 Codon 72 Genetic Polymorphism in Asthmatic Children: Evidence of Interaction With Acid Phosphatase Locus 1

Several lines of evidence are implicating an increased persistence of apoptotic cells in patients with asthma. This is largely due to a combination of inhibition, or defects in the apoptotic process and/or impaired apoptotic cell removal mechanisms. Among apoptosis-inducing genes, an important role is played by p53. In the present study, we have investigated the possible relationship between p53 codon 72 polymorphism and asthma and the interaction with ACP1, a genetic polymorphism involved in the susceptibility to allergic asthma. We studied 125 asthmatic children and 123 healthy subjects from the Caucasian population of Central Italy. p53 codon 72 and ACP1 polymorphisms were evaluated using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method. There is a statistically significant association between p53 codon 72 polymorphism and allergic asthma: Arg/Arg genotype is more represented in asthmatic patients than in controls (P=0.018). This association, however, is present in subjects with low ACP1 activity A/A and A/B only (P=0.023). The proportion of children with A/A and A/B genotype carrying Arg/Arg genotype is significantly high in asthmatic children than in controls (OR=1.941, 95% C.I. 1.042-3.628). Our finding could have important clinical implications since the subjects with A/A and A/B genotypes of ACP1 carrying Arg/Arg genotype are more susceptible to allergic asthma than Pro/Pro genotype.