Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children.

BACKGROUND: Short stature (SS) is defined as height more than 2 standard deviations below the mean for age and sex. Hypothyroidism, celiac disease, growth hormone deficiency, hormonal abnormalities, and genetic conditions are among its causes. A wide range of conditions often due to largely unknown genetic variants can elude conventional diagnostic workup. AIM: We used next-generation sequencing (NGS) to better understand the etiology of SS in a cohort of Italian children. PATIENTS AND METHODS: The study sample was 125 children with SS of unknown origin referred to our Institute between 2015 and 2021. All had undergone complete auxological and hormonal investigations to exclude common causes of SS. Genetic analysis was performed using a NGS panel of 104 genes. Clinical data were reviewed to clarify the pathogenicity of the variants detected. RESULTS: In this cohort, 43 potentially causing variants were identified in 38 children. A syndromic genetic condition was diagnosed in 7: Noonan syndrome in 3, Leri-Weill syndrome in 3, and hypochondroplasia in 1. Moreover, 8 benign variants and other 37 like benign variants were found. In 88 children, 179 variants of uncertain significance (VUS) were identified. No variant was found in 16 children. CONCLUSION: Genetic analysis is a useful tool in the diagnostic workup of patients with SS, in adapting management and treatment, and in identifying syndromes with mild atypical clinical features. The role of VUS should not be underestimated, particularly when multiple VUS with possible mutual worsening effects are present in the same child.

Predictors of blood pressure at 7-13 years: The "new millennium baby" study.

BACKGROUND AND AIMS: The purpose of this study is to evaluate the association between blood pressure (BP) at 7-13 years of age and body mass index (BMI), early feeding, lifestyle indicators, and parental characteristics. METHODS AND RESULTS: Retrospective plus cross-sectional cohort study was started in 1294 children born in 2000-2004, right from their birth in primary care settings. Early feeding was estimated by measuring breast-feeding (BF) duration, complementary feeding (CF) introduction time, and lifestyle indicators such as daily screen time and weekly extracurricular sports activity time. Parental education, smoking, and obesity-related diseases were also considered. Multivariable linear regression and mediation analysis were used. CF introduction at 5-6 months of age was a negative predictor of systolic and diastolic BP (mean systolic BP-standard deviation score (SDS) -0.38 [95% CI: -0.47, -0.29] (p < 0.001); mean diastolic BP-SDS -0.32 [95% CI: -0.40, -0.24]) (p < 0.001); BMI was a positive predictor of systolic and diastolic BP (p < 0.001); and parental hypertension was a positive predictor of diastolic BP (p < 0.05). Predictors of mean BMI-SDS at 7-13 years of age were birth weight, screen time, and parental obesity and smoking (p < 0.001). BF had no effect on BP or BMI. Mediation analysis showed virtually no indication of the effect of CF on BP mediated by BMI. CONCLUSIONS: CF introduction between 5 and 6 months of age could be associated with low BP at 7-13 years. The effect of CF on BP seems to be independent of BMI. Low screen time is associated with low BMI. CF time may play a role in the occurrence of surrogates of noncommunicable disorders in future.

US pediatric population-level associations of DXA-measured percentage of body fat with four BMI metrics with cutoffs.

OBJECTIVE: Four body mass index (BMI) metrics--BMI, BMI z-score, BMI percentile and BMI%--are commonly used as proxy measures for children's adiposity. We sought to determine a BMI metric that is most strongly associated with measured percentage of body fat (%BF) in the US pediatric population stratified by sex, age and race/ethnicity, and to determine cutoffs that maximize the association for each BMI metric. SUBJECTS, DESIGN AND METHODS: %BF was measured by dual-energy X-ray absorptiometry among N=6120 US boys and girls aged 8.0-17.9 years old from the National Health and Nutrition Examination Survey 1999-2004. We fit piecewise linear regression models with cutoffs to %BF data using each BMI metric as the predictor stratified by sex, race/ethnicity and age. The slopes were modeled differently before and after the cutoffs which were determined on the basis of grid searches. RESULTS: BMI z-score was in general most strongly associated with %BF for both boys and girls. The associations of the four BMI metrics were lowest for boys aged 12-13.9 years and girls aged 16-17.9 years, and strongest for Mexican-American boys and for non-Hispanic Black girls. Overall, the associations were stronger for girls than for boys. In boys, BMI had the lowest association with %BF (R(2)=0.39) for all ages combined. The fold changes in slopes before and after cutoffs were greatest in general for BMI percentiles regardless of age, sex and race/ethnicity. BMI z-score cutoffs were 0.4 for both boys and girls for all ages combined. Except for BMI, the slopes after the cutoffs were in general greater than those before. CONCLUSIONS: All BMI metrics were strongly associated with %BF when stratified by age and race/ethnicity except that BMI was the least associated with %BF in boys for all ages combined. Overall, BMI z-score was superior for evaluation of %BF, and its cutoff of 0.4 can also serve as a threshold for careful monitoring of weight status.

Interdisciplinary management of orofacial lesions in early childhood: paediatric alert system at University of Verona.

BACKGROUND: Orofacial trauma (OFT) occurs frequently in children and requires thorough evaluation not only by paediatric dentists but also by all specialists involved in emergency services, particularly in cases involving children under 3 years of age, given their inability to directly participate in clinical-anamnestic evaluations. Addressing early childhood orofacial trauma resulting from maltreatment, this study explores the key role played by various healthcare professionals, including paediatric dentists, general dentists, maxillofacial surgeons, dental hygienists, and paediatricians, in the optimal management of these cases. In the event of trauma due to suspected or confirmed mistreatment, it is essential that all healthcare workers involved have precise knowledge of the appropriate course of action from both a clinical and legal point of view, guaranteeing maximum protection for the young patient. This is particularly significant as cases of mistreatment with apparently minor consequences can degenerate into situations of irreparable severity. The latest guidelines from the International Association of Dental Traumatology (IADT) in 2020 continue to emphasise the potential correlation between OFT and cases of abuse or violence. Recent recommendations in the literature highlight the importance of facilitating mandatory reporting of incidents to relevant authorities and improving information sharing between dental healthcare professionals and child welfare services. A new flow diagram, called Paediatric Orofacial Trauma Alert (P.O.T.A.), has been proposed at the University of Verona. This tool is specifically designed to assist specialists dealing with early childhood orofacial trauma cases by assisting them in identifying potential cases of maltreatment. In this innovative approach, the collaborative efforts of general dentists, paediatric dentists, maxillofacial surgeons, dental hygienists and paediatricians play a vital role in cases of abuse. In addition to restoring the oral health of young patients, these professionals can activate a vast network of contacts, ensuring not only optimal oral health care but also providing comprehensive support to victims. The objective is to safeguard not only the physical but also the psychological well-being of these vulnerable subjects.

Waist circumference-to-height ratio predicts adiposity better than body mass index in children and adolescents.

OBJECTIVE: Body mass index (BMI) is the surrogate measure of adiposity most commonly employed in children and adults. Waist circumference (WC) and the waist circumference-to-height ratio (WCHt) have been proposed as markers of adiposity-related morbidity in children. However, no study to date has compared WCHt, WC, BMI and skinfolds thickness for their ability to detect body adiposity. AIM: To compare WCHt, WC, BMI and skinfolds for their accuracy in predicting percent body fat (PBF), percent trunk fat (PTF) and fat mass index (FMI) in a large sample of children and adolescents. DESIGN, SETTING AND PARTICIPANTS: We studied 2339 children and adolescents aged 8-18 years from the US National Health and Nutrition Examination Survey 2003/2004. Body fat was measured using dual-energy X-ray absorptiometry. Multivariable regression splines were used to model the association between PBF, PTF, FMI and the predictors of interest. RESULTS: WCHt alone explained 64% of PBF variance as compared with 31% for WC, 32% for BMI and 72% for the sum of triceps and subscapular skinfolds (SF2) (P<0.001 for all). When age and gender were added to the predictors, the explained variance increased to 80% for the WCHt model, 72% for the WC model, 68% for the BMI model and 84% for the SF2 model. There was no practical advantage to add the ethnic group as further predictor. Similar relationships were observed with PTF and FMI. CONCLUSIONS: WCHt is better than WC and BMI at predicting adiposity in children and adolescents. It can be a useful surrogate of body adiposity when skinfold measurements are not available.

Lifestyle and nutrition related to male longevity in Sardinia: an ecological study.

BACKGROUND AND AIMS: A demographic analysis in the Mediterranean island of Sardinia revealed marked differences in extreme longevity across the 377 municipalities and particularly identified a mountain inner area where the proportion of oldest subjects among male population has one of the highest validated value worldwide. The cause(s) of this unequal distribution of male longevity may be attributed to a concurrence of environmental, lifestyle and genetic factors. METHODS AND RESULTS: In this study we focussed on some lifestyle and nutrition variables recorded in the island's population in early decades of 20th century, when agricultural and pastoral economy was still prevalent, and try to verify through ecological spatial models if they may account for the variability in male longevity. By computing the Extreme Longevity Index (the proportion of newborns in a given municipality who reach age 100) the island's territory was divided in two areas with relatively higher and lower level of population longevity. Most nutritional variables do not show any significant difference between these two areas whereas a significant difference was found with respect to pastoralism (P = 0.0001), physical activity estimated by the average slope of the territory in each municipality (P = 0.0001), and average daily distance required by the active population to reach the usual workplace (P = 0.0001). CONCLUSION: Overall, these findings suggest that factors affecting the average energy expenditure of male population such as occupational activity and geographic characteristics of the area where the population mainly resides, are important in explaining the spatial variation of Sardinian extreme longevity.

[Epignathus, hypolastic left heart syndrome, and trisomy 18 in a small for gestational age female twin]. / Epignato, sindrome del cuore sinistro ipoplasico e trisomia 18 in una gemella piccola per età gestazionale.

We describe a rare association of hypoplastic left heart syndrome, trismony 18, and epignathus in a 970 g female twin born at 37 weeks of gestational age. She died at 24 hours of age. Neonatologists and obstetricians should be aware of this rare association for a thorough prenatal counselling.

Epoprostenol for very low birth weight (VLBW) infants: a novel dilution protocol.

Epoprostenol has been the first effective treatment for severe pulmonary arterial hypertension. Epoprostenol is provided in vials for adult therapy. To our knowledge there are no reports on specific dilution protocols for epoprostenol in VLBW infants, when very small infusion rates are required. We describe the dilution protocol we applied to a preterm infant who was born at 30 weeks of gestational age with a weight of 1.000 g. Our dilution protocol keeps the recommended dilution ratios, and the required solution pH, for very small dosages of epoprostenol, using the same diluent vial. Our method allows a correct and safe administration of epoprostenol in VLBW infants.

Effect of intrauterine growth retardation on liver and long-term metabolic risk.

Intrauterine growth retardation predisposes toward long-term morbidity from type 2 diabetes and cardiovascular disease. To explain this association, the concept of programming was introduced to indicate a process whereby a stimulus or insult at a critical period of development has lasting or lifelong consequences on key endocrine and metabolic pathways. Subtle changes in cell composition of tissues, induced by suboptimal conditions in utero, can influence postnatal physiological functions. There is increasing evidence, suggesting that liver may represent one of the candidate organs targeted by programming, undergoing structural, functional and epigenetic changes following exposure to an unfavorable intrauterine environment. The aim of this review is to provide insights into the molecular mechanisms underlying liver programming that contribute to increase the cardiometabolic risk in subjects with intrauterine growth restriction.

A twin study of self-regulatory eating in early childhood: estimates of genetic and environmental influence, and measurement considerations.

OBJECTIVE: Children differ greatly in their ability to self-regulate food intake for reasons that are poorly understood. This laboratory-based twin study tested the genetic and environmental contributions to self-regulatory eating and body fat in early childhood. METHODS: A total of 69 4-7 year-old same-sex twin pairs, including 40 monozygotic and 29 dizygotic pairs, were studied. Self-regulatory eating was operationalized as the percentage compensation index (COMPX%), assessed by a 'preload' challenge in which lunch intake was measured following a low- (3 kcal) or high-calorie (159 kcal) drink. Body fat indexes also were measured. The familial association for COMPX% was estimated by an intraclass correlation, and biometric analyses estimated heritability. RESULTS: Children ate more at lunch following the low- compared with high-energy preload (P<0.001), although variability in COMPX% was considerable. Compensation was significantly poorer among African American and Hispanic compared with European American children, and among girls compared with boys. There was a familial association for self-regulatory eating (ρ = 0.23, P = 0.03) but no significant genetic component. In all, 22% of the variance in COMPX% was due to shared environmental 'household' factors, with the remaining variance attributable to child-specific 'unique' or 'random' environments. Poorer self-regulatory eating was associated with greater percent body fat (r = -0.21, P = 0.04). CONCLUSIONS: Self-regulatory eating was influenced by environmental factors, especially those differing among siblings. The absence of a significant genetic effect may reflect the age of the sample or could be artifactual due to measurement issues that need to be considered in future studies.

Physical activity as the main therapeutic tool for metabolic syndrome in childhood.

Physical activity (PA) and diet directly influence obesity and metabolic syndrome (MS) as important determinants of body composition. Understanding how PA relates to MS in youth is of great importance, and could offer a common strategy for clinical and public health approaches to control this condition. The underlying disorder of MS is a condition of insulin resistance, and a strong relationship between PA level and insulin sensitivity is clearly ascertained. The type, duration, frequency and intensity of PA affect fuel metabolism, in particular carbohydrate and lipid oxidation. The possible modulation of metabolism because of increased fat oxidation by PA is the basis for both prevention and restoration of insulin resistance and MS in obese children. In daily clinical practice, diet followed by pharmacologic treatment are usually the approaches taken, whereas PA is often considered just a suggestion. Although diet and PA have different effects on body composition, with both contributing to fat loss, only PA increases muscle mass and thus has a direct effect on metabolic function, expressed by changes in cardiovascular risk factors. Therefore, it is important to remember their complementary but different targets in daily clinical practice, such as body weight control for diet and metabolic health for PA. In this review, we have summarized the literature on the relationship between PA and MS in pediatrics. Then, we have analyzed the possibility of using PA for MS treatment, as an alternative to drugs, by discussing the results of intervention studies, reasons for low compliance to PA, related benefits, adherence difficulties and costs. Finally, we have tried to suggest recommendations for a multiple-step PA strategy in children and adolescents at risk for MS, by considering PA as the 'key' player in treatment.

Asthma and obesity in childhood: on the road ahead.

Epidemiological data show a link between asthma and obesity, suggesting many different mechanisms that may underlie the association. However, diagnosis of asthma is often self-reported by patients or caregivers. Definition of asthma is crucial, particularly in childhood. Obesity can be associated with symptoms commonly attributed to asthma, such as wheezing, dyspnoea and sleep apnoea. Obese subjects are less fit and may have more frequent bouts of breathlessness on exertion accompanied by an exaggerated symptom perception. Therefore, the link between the two diseases should be analysed by focusing not only on reported diagnosis of asthma but also on objective markers that can better characterize the asthma phenotype. These markers should include lung function parameters, bronchial hyper-reactivity, atopic sensitization and indices of lung inflammation. As we look back and move forward, a multidisciplinary approach is increasingly necessary to understand the complexity of obesity and asthma, keeping in mind that diet and exercise could influence both diagnosis and treatment. In the meantime, in clinical settings, physicians should be cautious about diagnosing asthma in obese children on the basis of self-reported symptoms alone and should confirm the diagnosis by using objective measurements and marker evaluations that can better identify asthma phenotype and exclude overdiagnosis.

An unusual case of extra-abdominal desmoid tumour.

Desmoid tumour is relatively rare and generally non-metastatisizing lesion of mesenchymal origin composed of fibrous tissue and fitting in the group of aggressive fibromatosis; it is a locally aggressive proliferative soft-tissue lesion with controversial nature. This tumour accounts for 0.03% of all tumours and 3% of soft-tissue tumours with annual incidence of two to four cases per million. Although desmoid tumours are more common in persons aged 10-40 years than in others, they do occur in young children and older adults; in children the sex incidence is equal. This is a rare case of extra-abdominal desmoid tumour in a 14-year-old girl affected by spastic tetraparesis. To our knowledge no similar cases are present in literature to date.

Clinical research in adolescents: challenges and opportunities using obesity as a model.

Adolescent medicine is relatively young, compared to paediatric or adult medicine. Descriptive and observational studies have dominated the adolescent literature, including those studies published in the International Journal of Obesity. In addition, many studies have combined child and adolescent age groups, making it difficult to determine adolescent-specific outcomes. It is important that high quality intervention studies in adolescents occur. Adolescence is a time of extraordinary plasticity. Habits, attitudes and physical morbidity that develop during adolescence set up trajectories that have a profound influence on health and wellbeing for the long term. Overweight and obesity are an excellent example of the need for high quality intervention studies and yet in the last two decades there have been very few randomized, controlled trials of overweight and obesity management in adolescents. There are a number of complexities in adolescent research that create additional challenges to those that accompany any clinical research. These include recruitment and retention, issues around consent and confidentiality and the central role that parents play in supporting the research protocol. Pubertal stage is a potential confounder and needs to be accurately measured. This is certainly true for studies in overweight and obesity where excess adiposity influences pubertal and other hormones. The opportunities to undertake quality research in adolescents are likely to be enhanced by the use of novel approaches which acknowledge the unique features of adolescents and their world.

Body mass index as a phenotypic expression of adiposity: quantitative contribution of muscularity in a population-based sample.

OBJECTIVE: Although widely applied as a phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI) is also acknowledged to reflect muscularity even though relevant studies directly measuring skeletal muscle (SM) mass are lacking. The current study aimed to fill this important gap by applying advanced imaging methods to test the hypothesis that, after controlling first for adiposity, SM mass is also a significant determinant of BMI in a population-based sample. DESIGN: Whole-body magnetic resonance imaging scans were completed in Coronary Artery Risk Development in Young Adults study subjects aged 33-45 years. Physical activity (PA) levels, alcohol intake and adequacy of food intake were assessed by standardized questionnaires. SUBJECTS: The study included 58 African-American (AA) and 78 Caucasian (C) men; and 63 AA and 64 C women. MEASUREMENTS: Whole-body adipose tissue (AT) and SM volumes. RESULTS: AT was significantly predicted by not only BMI, but also PA and alcohol intake with total model R (2)'s of 0.68 (P<0.0001) for men and 0.89 (P<0.0001) for women. Men had more SM than AT at all levels of BMI whereas SM predominated in women at lower BMIs (C<26 kg/m(2); AA<28 kg/m(2)). In men, both AT and SM contributed a similar proportion of between-subject variation in BMI. In contrast, in women AT contributed approximately 30% more than SM to the variation in BMI. Developed allometric models indicated SM associations with AT, PA and race after adjusting for height. There was little association of age, lifestyle factors or race with BMI after controlling for both AT and SM. CONCLUSION: Variation in muscularity provides a mechanistic basis for the previously observed nonspecificity of BMI as a phenotypic expression of adiposity. These quantitative observations have important implications when choosing adiposity measures in population and gene-search studies.

Self-esteem in a clinical sample of morbidly obese children and adolescents.

AIM: To study self-esteem in clinical sample of obese children and adolescents. METHODS: Obese children and adolescents aged 8-19 years (n = 107, mean age 13.2 years, mean BMI 32.5 [range 22.3-50.6], mean BMI z-score 3.22 [range 2.19-4.79]; 50 boys and 57 girls) were referred for treatment of primary obesity. Self-esteem was measured with a validated psychological test with five subscales: physical characteristics, talents and skills, psychological well-being, relations with the family and relations with others. A linear mixed effect model used the factors gender and adolescence group, and the continuous covariates: BMI z-scores, and BMI for the parents as fixed effects and subjects as random effects. RESULTS: Age and gender, but neither the child's BMI z-score nor the BMI of the parents were significant covariates. Self-esteem decreased (p < 0.01) with age on the global scale as well as on the subscales, and was below the normal level in higher ages in both genders. Girls had significantly lower self-esteem on the global scale (p = 0.04) and on the two subscales physical characteristics (p < 0.01) and psychological well-being (p < 0.01). CONCLUSION: Self-esteem is lower in girls and decreases with age. In treatment settings special attention should be paid to adolescent girls.

A two-phase population study: relationships between overweight, body composition and risk of eating disorders.

BACKGROUND: Overweight and eating disorder (ED) are major public health problems in adolescents. AIMS: To assess the association of overweight, body composition and anthropometric characteristics with the probability being at risk of ED. METHODS: A two-phase study was used. 329 girls and 96 boys (aged 12-18 years) from an initial sample of 2967 adolescents were studied. The BMI, percentage of fat mass estimated by bioimpedance (FM(BIA)), waist circumference, waist-to-height ratio, and waist-to-hip ratio (WHipr) were calculated. The Eating Attitudes Test, Youth's Inventory-4 and a questionnaire to evaluate social influences were administered. RESULTS: A total of 34.7% of girls and 53.6% of boys at risk of ED were overweight (including obesity). For girls, overweight frequency was significantly higher in risk ED group than in control group. Increases of one point in the BMI or FM(BIA) increased the probability of being at risk of ED by 12% (3.0-19.0) and 4% (0.0-8.0), respectively. An increase in WHipr was negatively associated with ED risk. Smoking and symptoms of dysthymia and the genralized anxiety disorder also increase the probability of being at risk of ED in adolescent girls. In adolescent boys, these relations were not observed. CONCLUSIONS: The higher BMI and the percentage of FM(BIA) are associated with greater risk of ED in adolescent girls, when psychological factors are present. Increases in the WHipr, characteristic of childhood body is negatively associated with that risk.