Delayed age at menarche in chronic respiratory diseases.

OBJECTIVE: Age at menarche (AAM) is an important indicator of physiological development in women, and delayed AAM has been associated with chronic illnesses. We investigated predictive factors at diagnosis that influence AAM in adolescents with chronic respiratory diseases. STUDY DESIGN: AAM was assessed in 1207 northern Italian female aged 11-24 (1062 healthy, 98 with asthma and 47 with cystic fibrosis [CF]). AAM was defined by recall and status quo methods. We studied anthropometric data, metabolic status, diagnosis parameters, presence of irregular menses. Clinical data of subjects with chronic respiratory illness were compared with that of healthy adolescents. RESULTS: Mean AAM for healthy adolescents was 12.49 ± 1.2 years. Mother's AAM was positively associated with that of their daughters (P < .001). BMI was negatively correlated with AAM (P < .001). 69% of healthy adolescents referred regular menses. AAM in the different groups was 12.79 ± 3.0 years for patients with asthma (P < .05 vs healthy) and 13.24 ± 1.44 years for adolescents with CF (P < .0001 vs healthy). In the asthmatic group, 57% of the patients referred regular menses, and no significant differences were found between AAM and control of the disease (ACT test). In the CF group, no correlation was found between the type of CFTR mutation or FEV1% and AAM. 53% of the patients with CF referred regular menses. CONCLUSIONS: AAM in patients with CF and asthma was significantly higher than in healthy adolescents, and menses abnormalities were observed in the last two groups. Inflammation influences the reproductive function in chronic respiratory disease.

Fatty Acid Profile and Desaturase Activities in 7-10-Year-Old Children Attending Primary School in Verona South District: Association between Palmitoleic Acid, SCD-16, Indices of Adiposity, and Blood Pressure.

In previous studies, dietary and circulating fatty acids (FA) and desaturases activity (delta-5 desaturase [D5D], delta-6 desaturase [D6D], and stearoyl-CoA desaturase [SCD-16]) involved in their metabolism were associated with metabolic and cardiovascular disorders. The aim of the study was to assess the association between different FAs and desaturases activity (estimated as product:precursor ratios) with individual cardiovascular risk factors (in particular, anthropometric measurements and blood pressure [BP]) in children. The FA profile was determined on a whole-blood drop in 243 children (age: 8.6 ± 0.72 years) participating in a school-based cross-sectional study. Docosahexaenoic acid (DHA) inversely correlated with indices of adiposity, glucose, and triglycerides. Palmitoleic acid and SCD-16 were directly associated with markers of adiposity and BP, even after adjustment for main confounders. D6D correlated directly with the waist/height ratio. Children with excess weight (>85th percentile; that is overweight plus obese ones) showed higher palmitic acid, palmitoleic acid, and higher SCD-16 activity as compared to normal-weight children. Most of the associations were confirmed in the excess-weight group. Omega-3 FAs, particularly DHA, but not omega-6 FA, showed a potentially beneficial association with metabolic parameters, whereas palmitoleic acid and SCD-16 showed a potentially harmful association with indices of adiposity and BP, especially in obese children.

Individual fatty acids in erythrocyte membranes are associated with several features of the metabolic syndrome in obese children.

PURPOSE: Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children. METHODS: We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (rS) were calculated to evaluate associations between FA and features of the MetS. RESULTS: Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (rS = - 0.352), triglycerides (rS = - 0.379), fasting insulin (rS = - 0.337) and 24-h SBP (rS = - 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (rS = 0.354), triglycerides (rS = 0.400) and fasting insulin (rS = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (rS = 0.515) and inversely to AA (rS = - 0.472). CONCLUSIONS: Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.

Analysis of the d3-growth hormone receptor polymorphism in large cohorts of small, appropriate and large for gestational age newborns.

BACKGROUND: Several studies evidenced a possible role of the d3-Growth Hormone Receptor (GHR) polymorphism in fetal growth. The GHR genotype distribution was studied in small (SGA) and appropriate (AGA) for gestational age newborns but never in the large (LGA) for gestational age babies. The aim of this study was to evaluate the frequencies of this polymorphism in a large cohort of SGA, AGA and LGA newborns. METHODS: A total of 536 healthy newborns, randomly selected among the infants referred to the Italian North-Eastern centre for endocrinological and metabolic newborn screening, were enrolled: 192 SGA, 200 LGA and 144 AGA. Weight was recorded at birth. Isoforms of d3-GHR gene (fl/fl, d3/fl, and d3/d3) were analysed. RESULTS: The analysis of the GHR genotype evidenced a lower frequency of the d3/d3 genotype in SGA cohort compared to the AGA population (P=0.005), or to the total population (P=0.035). No differences were found in the genotypic distribution between LGA and AGA population (P=0.373), or between LGA and the whole population (P=0.292). CONCLUSIONS: d3/d3 GHR genotype was found twice as frequent in AGA and LGA cohorts compared to SGA subjects, whereas no significant differences in the frequency distribution of the GHR genotypes between LGA and AGA newborns were detected. The data leads to the exclusion of the GHR exon 3 deletion polymorphism as a possible genetic factor leading to LGA pregnancies.

Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.

BACKGROUND: Congenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband. METHODS: We screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband's family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant. RESULTS: A new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8. CONCLUSIONS: In vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.

Diagnostic pitfalls in the assessment of congenital hypopituitarism.

BACKGROUND: The diagnosis of congenital hypopituitarism is difficult and often delayed because its symptoms are nonspecific. AIM: To describe the different clinical presentations of children with congenital hypopituitarism to reduce the time for diagnosis and to begin a precocious and appropriate treatment. STUDY DESIGN: We analyzed a cohort of five children with congenital hypopituitarism, describing their clinical, biochemical and radiological characteristics from the birth to diagnosis. RESULTS: As first sign of the disease, all of five patients presented a neonatal hypoglycemia, associated in four cases with jaundice. In all these four cases, the clinicians hypothesized a metabolic disease delaying the diagnosis, which was performed in only two cases within the neonatal period. In the other three cases, the diagnosis was formulated at 2, 5 and 8 years of life because there was severe and precocious growth impairment. CONCLUSIONS: It is important to suspect congenital hypopituitarism in the presence of persistent neonatal hypoglycemia associated with jaundice and of a precocious and severe reduction of the growth velocity in childhood. In all these cases, it is necessary to undertake a hypothalamic-pituitary magnetic resonance imaging scan as soon as possible, and to start appropriate treatment.

Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE: To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease. METHODS: This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed. RESULTS: The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis. CONCLUSIONS: our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.

Comparison of Performance in the Six-Minute Walk Test (6MWT) between Overweight/Obese and Normal-Weight Children and Association with Haemodynamic Parameters: A Cross-Sectional Study in Four Primary Schools.

Physical activity plays a pivotal role in preventing obesity and cardiovascular risks. The six-minute walk test (6MWT) is a tool to assess functional capacity and predict cardiovascular events. The aim of this cross-sectional study was to compare the performance and haemodynamic parameters before and after a 6MWT between obese/overweight vs. normal-weight children (average age 8.7 ± 0.7 years) participating in a project involving four primary schools in South Verona (Italy). Validated questionnaires for physical activity and diet, as well as blood drops, were collected. Overweight or obese children (OW&OB; n = 100) covered a shorter 6MWT distance compared to normal-weight children (NW, n = 194). At the test's conclusion, the OW&OB group exhibited a higher Rate Pulse Product (RPP = Systolic Blood Pressure × Heart Rate) as compared to the NW. Body Mass Index, waist-to-height ratio, fat mass by electrical impedance, and trans fatty acids showed direct correlations with pre and post-test haemodynamic parameters, such as RPP, and inverse correlations with oxygen saturation. OW&OB children demonstrated lower performance in this low-intensity exercise test, along with an elevated haemodynamic response. Excess fat in childhood can be considered a risk factor for haemodynamic stress, with potential deleterious consequences later in life. Efforts should be initiated early to break this cycle.

Central Precocious Puberty in Italian Boys: Data From a Large Nationwide Cohort.

CONTEXT: There are only a few nationwide studies on boys with central precocious puberty (CPP) and the last Italian study is a case series of 45 boys that dates back to 2000. OBJECTIVE: We aimed to evaluate the causes of CPP in boys diagnosed during the last 2 decades in Italy and the relative frequency of forms with associated central nervous system (CNS) abnormalities on magnetic resonance imaging (MRI) compared to idiopathic ones. METHODS: We performed a national multicenter retrospective study collecting data from 193 otherwise normal healthy boys with a diagnosis of CPP. Based on MRI findings, the patients were divided into: Group 1, no CNS abnormalities; Group 2, mild abnormalities (incidental findings) unrelated to CPP; and Group 3, causal pathological CNS abnormalities. RESULTS: The MRI findings show normal findings in 86%, mild abnormalities (incidental findings) in 8.3%, and causal pathological CNS abnormalities in 5.7% of the cases. In Group 3, we found a higher proportion of patients with chronological age at diagnosis < 7 years (P = .00001) and body mass index greater than +2 SDS (P < .01). Gonadotropin-releasing hormone analogue therapy was started in 183/193 subjects. The final height appeared in the range of the target height in all groups and in 9 patients in whom the therapy was not started. CONCLUSION: In our study on a large nationwide cohort of boys referred for precocious puberty signs, the percentage of forms associated with CNS abnormalities was one of the lowest reported in the literature.

Autoimmune adrenal insufficiency in children: a hint for polyglandular syndrome type 2?

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

Complex relationship between growth hormone and sleep in children: insights, discrepancies, and implications.

Growth hormone (GH) is crucial to growth and development. GH secretion is regulated by a complex feedback system involving the pituitary gland, hypothalamus, and other organs, and predominantly occurs during deep sleep. Isolated and idiopathic growth hormone deficiency (GHD) is a condition characterized by GHD without any other signs or symptoms associated with a specific syndrome or disease. The aim of this narrative review was to evaluate the relationship between GH and sleep in children using published data. Various databases (Medline/PubMed, Scopus, and Web of Science) were systematically searched for relevant English language articles published up to April 2023. Search strategies included the terms 'children/pediatric', 'growth hormone', 'growth hormone deficiency' and 'sleep'. Data were extracted by two independent reviewers; 185 papers were identified of which 58 were duplicates and 118 were excluded (unrelated n=83, syndromic/genetic GHD n=17, non-English n=13, abstract n=1, case report n=1). Overall, nine studies (six clinical studies, two case series, and one survey) were included. GHD appears to have an adverse effect on sleep in children, and GH therapy has only been shown to have a beneficial effect on sleep parameters in some individuals. Notably, identified data were limited, old/poor quality, and heterogenous/inconsistent. Further research of GHD in pediatric populations is necessary to improve the understanding of GHD impact on sleep and its underlying mechanisms, and to determine the specific impacts of GH therapy on sleep in children.

Decreased vitamin D levels in the pediatric population after COVID-19 lockdown.

BACKGROUD: SARS-Cov2 infection began to spread worldwide since December 2019; on March 2020, the World Health Organization characterized its related disease, named COVID-19, as a pandemic. In Italy, to contain the spread of infection a severe lockdown in the spring 2020 was instituted. Other less severe restrictions were imposed in the winter 2020-2021 and in the spring 2021. The containment measures caused a series of consequences for the population and, in particular, for children and adolescents that presented psychophysical problems. The aim of this manuscript is to investigate the serum levels of vitamin D in children and adolescents before, during and after the lockdown consequent to COVID-19 pandemic. METHODS: This is a retrospective cross-sectional study, including all children and adolescents between 1 to 18 years referring to the Pediatric Endocrinology Service of the University Hospital of Verona, Italy, between January 2019 and December 2021. All patients affected by clinical conditions that involve vitamin D metabolism or assuming vitamin D supplementation were excluded. RESULTS: In total, 491 children (36.7% males and 63.3% females) were enrolled in this study. The vitamin D levels decreased over time: 28.3 ± 10.2 ng/mL in 2019; 28.2 ± 11.4 ng/mL in 2020 and 24.9 ± 10.1 ng/mL in 2021 (p < 0.05). The vitamin D levels are significant higher in summer and in autumn in comparison with the levels of winter and spring, regardless of the examined years. CONCLUSIONS: The measures adopted to contain the COVID-19 pandemic led to a reduction of serum levels of vitamin D in pediatric population, probably due to the reduced solar exposure. This may have severe consequences on the bone metabolism of those children who did not present optimal vitamin D levels even before the lockdown. Therefore, an adequate supplementation of vitamin D is necessary from the end of fall to the beginning of spring (November-April) in all children and adolescents living in Northern Italy.

The influence of growth hormone on pediatric body composition: A systematic review.

Background: Growth hormone (GH) affects metabolism and regulates growth in childhood. The most prominent feature of GH deficiency (GHD) in children is diminished height velocity that eventually leads to short stature. In adult-onset GHD, lean body mass (LBM) is reduced, and visceral fat mass (FM) increased. Beneficial effects of GH treatment on body composition in adults with GHD, including an increase in muscle mass and a decrease in FM, are well established. Relatively few studies have investigated the effects of GH treatment on the body composition of pediatric patients with idiopathic or hypothalamic-pituitary disease-associated GH deficiency. This systematic review aimed to summarize available evidence relating to the effects of GH treatment on body composition in children with GHD. Methods: The PubMed, Science Direct, Cochrane Trials, and Embase databases, were searched with keywords including "GH", "body composition", "children", and "growth hormone" for English-language articles, published between January 1999 and March 2021. Two reviewers independently evaluated the search results and identified studies for inclusion based on the following criteria: participants had a confirmed diagnosis of GHD (as defined in each study); participants were pediatric patients who were receiving GH or had stopped GH treatment, regardless of whether they were pre- or post-pubertal; the intervention was recombinant human GH (rhGH; somatropin); and outcomes included changes in body composition during or after stopping GH therapy. Data extracted from each study included study quality, study sample characteristics, study interventions, and body composition. Data on fat-free mass and LBM were combined into a single category of LBM. Results: Sixteen studies reporting changes in body composition (i.e., FM and LBM) associated with GH treatment in children with GHD were identified and included in the review. Collectively, these studies demonstrated that FM decreased, and LBM increased in response to GH replacement therapy. Conclusion: Despite study limitations (i.e., potential effects of diet and physical activity were not considered), we concluded that a periodic body composition assessment is required to ensure that a satisfactory body composition is achieved during GH replacement therapy in children with GHD.

Vitamin D and Osteogenesis Imperfecta in Pediatrics.

Osteogenesis Imperfecta (OI) is a heterogeneous group of inherited skeletal dysplasias characterized by bone fragility. The study of bone metabolism, in these disease, is problematic in terms of clinical and genetic variability. The aims of our study were to evaluate the importance of Vitamin D levels in OI bone metabolism, reviewing studies performed on this topic and providing advice reflecting our experience using vitamin D supplementation. A comprehensive review on all English-language articles was conducted in order to analyze the influence of vitamin D in OI bone metabolism in pediatric patients. Reviewing the studies, contradictory data were found on the relationship between 25OH vitamin D levels and bone parameters in OI, and in several studies the baseline levels of 25OH D were below the threshold value of 75 nmol/L. In conclusion, according to the literature and to our experience, we highlight the importance of adequate vitamin D supplementation in children with OI.

Children and adolescents treated with neridronate for osteogenesis imperfecta show no evidence of any osteonecrosis of the jaw.

Over recent years, several reports have been published on unusual cases of osteonecrosis of the jaw (ONJ) in adults using second- and third-generation nitrogen-containing bisphosphonates such as pamidronate, alendronate, risedronate and zoledronate, but no case has ever been reported either in children or in adult patients taking neridronate. Children and adolescents affected by osteogenesis imperfecta (OI) could belong to a high-risk group for ONJ because bone fragility in OI is associated with a connective tissue malfunction. The purpose of this study is to evaluate the incidence of ONJ in a pediatric population treated with neridronate for OI. A total of 102 pediatric patients with OI who received neridronate infusions for a mean of 6.81 years (SD ± 3.06 years) were clinically assessed for possible ONJ. Eligibility criteria for participation included patients between 1.2 and 24 years old who received cyclical neridronate infusions for at least 1 year. All the patients were reviewed to determine duration, dosage and cumulative dose of their bisphosphonate therapy and were examined clinically to assess their oral health status. We have not demonstrated any occurrence of ONJ in our patients. In conclusion, at the moment insufficient data are available to prove a greater risk of ONJ in children with OI than in children affected by other forms of bone fragility. However, cases may emerge in future because the risk of ONJ seems to be related to the cumulative dose and the duration of therapy.

A complex pheotype in a girl with a novel heterozygous missense variant (p.Ile56Phe) of the GNAS gene.

BACKGROUND: GNAS is a complex gene that encodes Gsα, a signaling protein that triggers a complex network of pathways. Heterozygous inactivating mutations in Gsα-coding GNAS exons cause hormonal resistance; on the contrary, activating mutations in Gsα result in constitutive cAMP stimulation. Recent research has described a clinical condition characterized by both gain and loss of Gsα function, due to a heterozygous de novo variant of the maternal GNAS allele. PATIENTS AND METHODS: We describe a girl with a complex combination of clinical signs and a new heterozygous GNAS variant. For the molecular analysis of GNAS gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples. In silico analysis was performed to predict the possible in vivo effect of the detected novel genetic variant. The activity of Gsα protein was in vitro analyzed from samples of erythrocyte membranes, recovered from heparinized blood samples. RESULTS: We found a new heterozygous missense c.166A > T-(p.Ile56Phe) GNAS variant in exon 2, inherited from the mother that determined a reduced activity of 50% of Gsα protein function. The analysis of her parents showed a 20-25% reduction in Gsα protein activity in the mother and a normal function in the father. Clinically our patient presented a multisystemic disorder characterized by hyponatremia compatible with a nephrogenic syndrome of inappropriate antidiuresis, subclinical hyperthyroidism, subclinical hypercortisolism, precocious thelarche and pubarche and congenital bone abnormalities. CONCLUSIONS: This is the first time that the new variant c.166A > T (p.Ile56Phe) on exon 2 of GNAS gene, originated on maternal allele, has been described as probable cause of a multisystemic disorder. Although the mutation is associated with a reduced activity of the function of Gsα protein, this unusual phenotype on the contrary suggests a mild functional gain.

Supportive treatment of vascular dysfunction in pediatric subjects with obesity: the OBELIX study.

INTRODUCTION: Overweight or obese children develop abnormal endothelial cell dysfunction and arterial intima-media thickening with increased vasomotor tone and inflammation. Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D have shown beneficial effects on endothelial function. We test, among overweight and obese pediatric subjects, the effects on the endothelium of a combination of curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D. METHODS: Forty-eight subjects (6-17 years) were randomized into two groups (placebo vs treatment) attended three visits at 0, 3, and 6 months (±15 days). Endothelial function was assessed by means of a post-occlusive release hyperemic (PORH) test for estimation of delta flow (DF) and hyperemic AUC index, and a heat provocation test (HPT) to measure DF HPT (DFHPT). RESULTS: Significant DF difference was noted at 6 months in both groups (p < 0.001). Overall time trend was significantly different between baseline, 3 months, and 6 months both in placebo (p < 0.05) and treatment (p < 0.001) groups and their comparison (p < 0.001). No differences were noted in hyperemic AUC index (3 and 6 months), whilst there were significant differences in time trends of rreatment (p < 0.001) and placebo (p < 0.05) groups and their comparison (p < 0.001). DFHPT difference between groups was significant at 3 and 6 months (p < 0.05). The overall time trend was significant exclusively in Treatment group between 3 and 6 months (p < 0.05). Correlation with anthropometrics was found for DF and body mass index (r = 0.677 6 months, p < 0.05), as well as for hyperemic AUC index and males (r = 0.348, p < 0.05), while DFHPT showed no correlation. CONCLUSION: Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D appear to be promising in enhancing endothelial function by improvement of both DF in the PORH test and DF in the HPT, lowering the risk of developing cardiovascular diseases in overweight and obese pediatric subjects.

Twenty Years of Neonatal Screening for Congenital Adrenal Hyperplasia in North-Eastern Italy: Role of Liquid Chromatography-Tandem Mass Spectrometry as a Second-Tier Test.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) based on 17-hydroxyprogesterone (17-OHP) concentration in dried blood spots has been taking place in North-Eastern Italy since 2001. Since 2017, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced, for the first time in Italy, as a second-tier test. AIMS: Our study aims to evaluate, on the one hand, the effectiveness of the newborn screening for CAH after 20 years of testing and, on the other, the impact that the introduction of the second-tier test had on the diagnostic accuracy of the screening program. METHODS: Since 2001 dried blood spots taken from newborns have been screened with a time-resolved fluoroimmunoassay for 17-OHP determination. Over the years, the cut-off levels of 17-OHP were adjusted according to gestational age. Since 2017, a second-tier test in LC-MS/MS was introduced for samples displaying fluoroimmunoassay 17-OHP exceeding the cut-off. RESULTS: In total, 862,521 newborns have been screened over a period of 20 years. The total incidence of 21-hydroxylase deficiency (21-OHD) was 1:25,368, moreover, a case of 11-ß-hydroxylase deficiency was identified. All these diagnoses were genetically confirmed. The sensitivity and specificity of the screening program were 97% and 99.4%, respectively. The use of LC-MS/MS as a second-tier test significantly reduced the recall rate and increased the positive predictive value. CONCLUSIONS: Screening for CAH is useful in the neonatal diagnosis of a classic form of 21-OHD, allowing a precocious treatment of affected children. The introduction of an LC-MS/MS second-tier reduced the recall rate, avoiding unnecessary blood withdrawal and medical evaluations and preventing stress to families. Furthermore, it helped identify rarer forms of CAH.

Benefits of rescreening newborns of mothers affected by autoimmune hypothyroidism.

Introduction: Infants of mothers with autoimmune hypothyroidism (AH) are at risk of developing late-onset hypothyroidism, often escaping at newborn screening. This condition might be caused both by the action of maternal antibodies and/or by maternal treatment. Objectives: The aim of this study is to evaluate the prevalence of AH in the mothers of children born in Veneto region, Italy, and to define what is the most appropriate management for these newborns. Methods: Newborns of six different hospitals with a mother suffering from AH and with negative neonatal screening for congenital hypothyroidism (CH) were included in the study. Between 15 and 20 days of life, we collected a serum sample for the evaluation of thyroid function (thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3)) and anti-thyroid antibodies. On the same occasion, a capillary blood sampling was performed for a second screening test. Results: Maternal AH has a prevalence of 3.5%. A total of 291 newborns were enrolled from November 2019 to May 2021. Whereas the 11.4% of infants had a slight elevated serum TSH (>6 mU/L) and required a follow-up, only 2 children presented an elevated TSH level at the second screening test. One of these, with the gland in situ, showed persistently elevated serum TSH levels and required treatment with levothyroxine. Conclusions: Maternal AH rarely caused neonatal thyroid dysfunction. We suggest to reassess newborns from mothers with AH 15 days after birth by means of a second neonatal screening test. This procedure avoids false negatives due to maternal thyroid status, is less invasive and cheaper than the serum TSH evaluation, and prevents a long follow-up.