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.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Real-life long-term efficacy and safety of recombinant human growth hormone therapy in children with short stature homeobox-containing deficiency.

Objective: This Italian survey aims to evaluate real-life long-term efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy. Design and methods: This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when available. Results: One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (ß = -0.31, P = 0.030) and the GV during the first year of rhGH treatment (ß = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported. Conclusions: Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype. Significance Statement: Among children with idiopathic short stature, the prevalence of SHOX-D is near to 1/1000-2000 (1.1-15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-term data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH therapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of treatment and the age when rhGH was started significantly impact the height gain.

The impact of BMI on long-term anthropometric and metabolic outcomes in girls with idiopathic central precocious puberty treated with GnRHas.

Background: Gonadotropin-releasing hormone analogs (GnRHas) are effective in increasing the final height of children with idiopathic central precocious puberty (ICPP). However, in previous years, some transient metabolic complications have been described during this treatment, for which there are no long-term outcome data. Our study aimed to evaluate the efficacy of GnRHas and clarify if body mass index (BMI) at diagnosis of ICPP could influence long-term outcomes. Methods: This was an observational, retrospective study that recruited a cohort of girls with ICPP. Data for anthropometric measures, fasting lipid profile, and glucose metabolism were collected at baseline [when GnRHas treatment started (T1)], at the end of the treatment (T2), and near-final height (nFH) or final height (FH) (T3). Predicted adult height (PAH) was calculated at T1 following Bayley and Pinneau's method. Analysis was carried out using BMI standard deviation score (SDS) categories at T1 (group A, normal weight, vs. group B, overweight/obese). Results: Fifty-seven girls with ICPP who were treated with GnRHas were enrolled in the study (group A vs. group B: 33 vs. 24 patients, aged 7.86 ± 0.81 vs. 7.06 ± 1.61 years, respectively; p < 0.05). In the study population, nFH/FH was in line with the target height (TH) (p = 0.54), with a mean absolute height gain of 11.82 ± 5.35 cm compared with PAH. Even if the length of therapy was shorter (group A vs. group B: 1.84 ± 2.15 vs. 2.10 ± 0.81 years, respectively; p < 0.05) and the age at menarche was younger (group A vs. group B: 10.56 ± 1.01 vs. 11.44 ± 0.85 years, respectively; p < 0.05) in group B than in group A, the nFH/FH gain was still comparable between the two groups (p = 0.95). At nFH/FH, BMI SDS was still greater in group B than in group A (p = 0.012), despite the fact that BMI SDS significantly increased in group A only (p < 0.05). Glucose metabolism got worst during GnRHa with a complete restoring after it, independently from pre-treatment BMI. The ratio of low-density to high-density lipoprotein cholesterol transiently deteriorated during treatment with GnRHas in group A only (p = 0.030). Conclusions: Our results confirm the effectiveness of treatment with GnRHas on growth and do not support the concern that being overweight and obese can impair the long-term outcomes of GnRHas therapy. However, the observed transient impairment of metabolic parameters during treatment suggests that clinicians should encourage ICPP girls treated with GnRHas to have a healthy lifestyle, regardless of their pretreatment BMI.

A comparative study on the incidence of type 1 diabetes mellitus between children of North African migrants and Italian children in Emilia-Romagna region, Italy.

In the last few decades, many studies have reported an increasing global incidence of type 1 diabetes. Studies on migrant populations have underlined the importance of both environmental and genetic factors. AIMS: Evaluate the incidence of type 1 diabetes in North African vs Italian children aged 0-14 years from 1 January 2015, to 31st December 2018, in Emilia-Romagna region, Italy. METHODS: Clinical and epidemiological data about childhood onset type 1 diabetes in Emilia Romagna region were retrospectively collected by the regional centers of pediatric diabetology and matched using 3 different data sources. RESULTS: 365 new cases were diagnosed. Total cumulative incidence was 15.4/100,000/year. North African cases showed a cumulative incidence of 53.8/100,000/year, statistically significant compared to cumulative incidence of the Italian cases alone 13.1/100,000/year (p value < 0.001). The annual incidence did not differ in the 4 years for both groups.  Conclusion: The incidence of type 1 diabetes in the pediatric age (0 14 years) was significantly higher in the North African population than in the Italian one, suggesting that a mix of genetic and environmental factors may have caused the increase in newly diagnosed cases. WHAT IS KNOWN: • The incidence of type 1 diabetes largely varies worldwide. • Study on immigrants helped to better understand the interplay role between genetics and environment. WHAT IS NEW: • This is the first study focused on the incidence of children and adolescents of North African migrants in Italy. • The incidence of children and adolescents of North African migrants in Emilia Romagna region, Italy, seems to be higher than that reported in the host countries, and, above all, than that reported in highest-incidence countries in Europe and in the world.

Longitudinal evaluation of endothelial markers in children and adolescents with familial hypercholesterolemia.

BACKGROUND AND AIM: Children with heterozygous familial hypercholesterolemia (heFH) are at risk of premature atherosclerosis. Aims of this study were: (a) to longitudinally evaluate the endothelial dysfunction, estimated through brachial flow mediated dilation (FMD), as first sign of subclinical atherogenesis in a group of children and adolescents affected by heFH in comparison to normo-lipidemic controls, and (b) to identify predictive factors influencing the endothelial function and its development in the same cohort of patients. METHODS: This is a prospective, longitudinal and cross-sectional study. Physical examination, plasma lipid profile and brachial artery FMD were measured at baseline and after follow-up. RESULTS: At baseline, FMD did not differ between heFH children (n.24, median age 9.71) and controls (n. 24, median age 10.29) (7.67 ± 9.26 vs. 11.18 ± 7.28 %, p 0.09). Nevertheless, during follow-up (median length of lipid-lowering diet 4.52 years), FMD got worse in 54% of heFH subjects and its worsening correlated to the increasing of low-density lipoprotein cholesterol (r -0.21, p < 0.05). Moreover, being male (ß -0.46, p 0.03), undergoing puberty (ß -0.61, p 0.03) and increasing of body mass index standard deviation score (ß -0.39, p 0.03) were identified as main independent predictor factors of FMD drop. CONCLUSIONS: During the first decades of life, not only hypercholesterolemia, but also clusters of pro-atherogenic conditions and their persistence, could affect the endothelial function and its trend. (www.actabiomedica.it).

Copy Number Variation Analysis Increases the Number of Candidate Loci Associated with Pediatric Obesity.

BACKGROUND/AIMS: Obesity is a multifactorial disease caused by the interaction of genetic, environmental, and behavioral factors. Currently, only a small number of obese children undergo genetic analysis, usually when obesity is associated with dysmorphic features. The aim of this study was to identify genomic rearrangement causing obesity. METHODS: We analyzed the DNA of children and adolescents by single-nucleotide polymorphism-array (platform CytoScan HD, Affymetrix). Patients included in this study were obese with dysmorphic features and/or intellectual disabilities and/or neuropsychomotor signs. RESULTS: Ninety-four children and adolescents with obesity (9.25 ± 4.04 years old, 60 males) were enrolled in the study. Dysmorphic features were found in 64 out of 94 subjects (68.1%), intellectual disability was found in 23 subjects (24.5%), and other neuropsychomotor signs in 31 (32.9%). Copy number variations (CNVs) were identified in 43 out of 94 patients (45.7%): among these 14 subjects showed at least 1 deletion, 22 duplication, whereas 7 patients showed both deletion and duplication. In 20 subjects (13 males), CNVs were linked or possibly related with obesity; in 23 subjects, this correlation cannot be inferred. CONCLUSION: A genetic origin of obesity was detected in about half of our obese children and adolescents with associated dysmorphic features and/or intellectual disability and/or neuropsychomotor signs. In these children, array-CGH analysis can be useful to identify causative genetic mutations, with consequent advantage in therapeutic management and follow-up of these patients.

Markers of Inflammation and Endothelial Dysfunction in Young Survivors from Acute Lymphoblastic Leukemia.

Purpose: To assess subclinical markers of endothelial inflammation in young survivors from acute lymphoblastic leukemia (ALL) treated with chemotherapy without cranial irradiation. Methods: Anthropometric parameters [height (H), body mass index (BMI), waist circumference (WC), hip circumference (HC), WC/H, and WC/HC ratio], blood pressure, lipid profile, serum markers of inflammation and endothelial dysfunction [Interleukin 6 (IL-6), vascular cell adhesion molecule, intercellular adhesion molecule, tumor necrosis factor-alfa (TNF-α), Endogenous secretory Receptor for Advanced Glycation Endproducts (Es-RAGE)], and carotid intima-media thickness (c-IMT) were assessed in a group of young ALL survivors and in matched controls. Local Ethics Committee approved the study (code 56/13) on June 24, 2013. Results: 28 ALL survivors (71% male, 18% prepubertal, aged 15.98 ± 4.41 years, mean follow-up 8.57 ± 3.14 years) exhibited lower levels of Es-RAGE than controls (0.18 ± 0.07 vs. 0.27 ± 0.08 ng/mL, p < 0.001). Among survivors, Es-RAGE values significantly correlated with BMI-SD off-therapy (R2 -0.42), WC/H ratio (R2 -0.41), WC/HC ratio (R2 -0.38), and low-density-lipoprotein cholesterol (LDL-C; R2 -0.43). Most of the ALL survivors (78%) presented c-IMT above the 95th centile if compared with gender and age standard. Mean c-IMT value correlated with blood pressure (R2 0.56) and with LDL-C levels (R2 0.56). Metabolic syndrome (MetS) was fully detected only in one ALL survivor. Nevertheless, 18% ALL survivors presented more than one MetS diagnostic criteria: 14% insulin resistance, 25% dyslipidemia, and 17.8% hypertension. Conclusion: We demonstrated an initial functional vascular alteration in young ALL survivors even when treated with standard risk protocols. Our data already support the activation at endothelial level of glycosylation and oxidation processes that are persistent long after the end of the treatment.

COVID-19 and Type 1 Diabetes: Concerns and Challenges.

Due to the current COVID-19 pandemic, worldwide population's lifestyle has changed dramatically, causing psychosocial consequences.  Patients presenting a preexisting chronic condition, as Type 1 Diabetes (T1D), are the ones suffering the most from this situation. Moreover, people affected by diabetes are the ones with the worst prognosis, if infected by SARS-CoV-2.  We analyzed why patients with T1D were poorly represented between the subjects hospitalized for COVID-19 and why the cases of diabetic ketoacidosis (DKA) were fewer and more severe compared with the past years. Furthermore, literature has showed how patients of all ages with T1D did not experience a deterioration in their glucose control throughout the lockdown. Among other causes, this is also due to the surging use of telemedicine. Finally, we tried to understand how the coronavirus tropism for endocrine tissues could influence the future epidemiology of T1D, focusing on the effects they have on pancreatic ß-cells.

Health-related quality of life and metabolic control in immigrant and Italian children and adolescents with type 1 diabetes and in their parents.

OBJECTIVE: To determine if the diabetes-specific health-related quality of life (D-HRQOL) of young people with type 1 diabetes (T1D) and their parents is influenced by migrant status. SUBJECTS AND METHODS: One hundred and twenty-five patients (12.4 ± 3.55 years, males 53.6%) with T1D and their parents (102 mothers, 37 fathers) were enrolled and categorized into: group A (both foreign parents) and group B (both native Italian parents). The Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 3.0 DM) was used to evaluate the D-HRQOL. Data on diabetic ketoacidosis (DKA) at T1D onset, insulin therapy, and glycosylate hemoglobin (HbA1c) were also collected. RESULTS: Group A (n = 40), compared to group B (n = 85), had higher frequency of DKA at T1D onset (P < .001) and a lower use of sensor augmented insulin pump (P = .015). HbA1c values were higher in group A than in group B (P < .001). Patients' "Diabetes symptoms" (P = .004), "Treatment barriers" (P = .001), and "Worry" (P = .009) scales scores were lower in group A than in group B. Mothers of group A had lower scores in "Diabetes symptoms" (P = .030), "Treatment barriers" (P < .001), "Treatment adherence" (P = .018), "Communication" (P = .009) scales, and total score (P = .011) compared to the group B ones. High PedsQL™ 3.0 DM was significantly associated with being Italian, being prepubertal, and having lower HbA1c mean levels. CONCLUSIONS: Being a migrant confers disadvantages in terms of D-HRQOL and metabolic control in children and adolescents with T1D. Specific educational interventions should be considered in the clinical care of patients with migration background, to improve D-HRQOL and health status.

Endocrine Disrupting Chemicals and Type 1 Diabetes.

Type 1 diabetes (T1D) is the most common chronic metabolic disease in children and adolescents. The etiology of T1D is not fully understood but it seems multifactorial. The genetic background determines the predisposition to develop T1D, while the autoimmune process against ß-cells seems to be also determined by environmental triggers, such as endocrine disrupting chemicals (EDCs). Environmental EDCs may act throughout different temporal windows as single chemical agent or as chemical mixtures. They could affect the development and the function of the immune system or of the ß-cells function, promoting autoimmunity and increasing the susceptibility to autoimmune attack. Human studies evaluating the potential role of exposure to EDCs on the pathogenesis of T1D are few and demonstrated contradictory results. The aim of this narrative review is to summarize experimental and epidemiological studies on the potential role of exposure to EDCs in the development of T1D. We highlight what we know by animals about EDCs' effects on mechanisms leading to T1D development and progression. Studies evaluating the EDC levels in patients with T1D were also reported. Moreover, we discussed why further studies are needed and how they should be designed to better understand the causal mechanisms and the next prevention interventions.

Glycemic Control Improvement in Italian Children and Adolescents With Type 1 Diabetes Followed Through Telemedicine During Lockdown Due to the COVID-19 Pandemic.

Background/Objective: To minimize the wide spread of coronavirus disease (COVID-19) pandemic, Italy was placed in an almost complete lockdown state that forced people to "stay at home". Aim of this study was to evaluate the effects of lockdown on glycemic control in children and adolescents with type 1 diabetes (T1D) followed through telemedicine. Subjects/Methods: This observational study involved patients with T1D using the real-time continuous glucose monitoring (CGM) Dexcom G6®. Ambulatory glucose profile data from the 3-months before schools closure (November 26, 2019-February 23, 2020; T0) and from the 3-months of consecutive lockdown (February 24-May 18, 2020; T1) were compared. Results: Sixty-two children and adolescents (11.1 ± 4.37 years, 50% males) with T1D (median time disease 3.67 years) were enrolled in the study. Insulin total daily dose was unchanged, while time spent on physical activities was decreased (p<0.0001). Despite the lack of statistical significance, median value of the glucose management indicator decreased from 7.4% to 7.25%. Glucose standard deviation (p<0.0001) and coefficient of variation (p=0.001) improved across the study. Median time in range increased from 60.5% to 63.5% (p=0.008), time above range decreased from 37.3% to 34.1% (p=0.048), and time below range decreased from 1.85% to 1.45% (p=0.001). Conclusions: Overall, in our children and adolescents with T1D glycemic control improved during lockdown. Despite patients were confined to their homes and limited to exercise, our data suggest that the use of real-time CGM, the continuous parental management, and the telemedicine can display beneficial effects on T1D care.

Isolated hypoaldosteronism as first sign of X-linked adrenal hypoplasia congenita caused by a novel mutation in NR0B1/DAX-1 gene: a case report.

BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

Long-term effects on growth, development, and metabolism of ALL treatment in childhood.

INTRODUCTION: One aim of the long-term care in survivors from acute lymphoblastic leukemia (ALL) during childhood is to avoid or limit complications caused by aggressive therapeutic strategies. AREAS COVERED: ALL survivors are a heterogeneous group according to therapeutic protocols. In the last decades, cranial radiotherapy (cRT) has been largely replaced by intrathecal chemotherapy (CT) with a reduction of endocrine sequelae. Published studies are generally difficult to be interpreted because patients were treated according to different risk-adapted protocols and results are conflicting. We perform this review on endocrine long-term effects in childhood ALL survivors focusing on studies published in the last decades. Articles were selected using the following terms (Mesh terms): 'acute lymphoblastic leukemia' AND 'survivors' AND 'childhood' AND 'growth/puberty/fertility/obesity/metabolic syndrome/bone'. EXPERT COMMENTARY: Most childhood ALL survivors treated with CT alone attain normal height and have adequate pubertal development. Despite recent protocols improvements, ALL survivors still develop long-term metabolic complications (overweight, obesity, and cardiovascular disease) especially the female gender and patients with an increased body mass index (BMI) at diagnosis. The aim of this review is to describe the state of the art on these topics. We should be able to anticipate, prevent, and treat endocrine long-term morbidities through a well-established follow-up strategy.

Switching From Glargine to Degludec: The Effect on Metabolic Control and Safety During 1-Year of Real Clinical Practice in Children and Adolescents With Type 1 Diabetes.

Background/Objective: Insulin degludec (IDeg) is an ultra-long-acting analog with less daily variability compared to other basal insulins. In this retrospective study we examined 1-year efficacy and safety of IDeg in youth with type 1 diabetes (T1D). Subjects/Methods: Thirty-seven patients [11.7 ± 4.22 years; T1D duration 4.97 ± 3.63 years; once-daily glargine (IGlar) by at least 1 year] were switched to once-daily IDeg because of glycosylated hemoglobin (HbA1c) >7.5% and/or reported physical pain at IGlar injection. Changes in HbA1c, 30-day mean fasting plasma glucose (mean FPG), daily insulin dose, and severe hypoglycemia rates were collected at basal insulin switch (T0), 3-months (T1), 6-months (T2), and 12-months (T3) after IDeg was started. Results: In patients with HbA1c >7.5% at T0 we found a decrease in HbA1c values (%) from 8.46 ± 0.53 to 7.89 ± 0.72 at T1 (p = 0.008) and 7.97 ± 0.89 at T2 (p = 0.035). At T3, 38.9% of patients had HbA1c ≤ 7.5%. Mean FPG levels significantly decreased at T2 (p = 0.043). In the overall study population, we documented an increase in IDeg dose (+12.5% at T3; p < 0.001) and a decrease in mealtime insulin dose (-11.6% at T3; p = 0.001) after switch. HbA1c levels were unchanged. No episode of severe hypoglycemia was reported. Conclusions: Our data in children and adolescents with T1D suggest that IDeg dose should be increased by 12% and mealtime insulin doses should be lowered by 11% for patients who previously received IGlar. IDeg might be considered useful and well tolerated and it seems to improve the glycemic control compared to IGlar, mainly in patients with poor glycemic control.

Adjusting insulin doses in patients with type 1 diabetes who use insulin pump and continuous glucose monitoring: Variations among countries and physicians.

AIMS: To evaluate physicians' adjustments of insulin pump settings based on continuous glucose monitoring (CGM) for patients with type 1 diabetes and to compare these to automated insulin dose adjustments. METHODS: A total of 26 physicians from 16 centres in Europe, Israel and South America participated in the study. All were asked to adjust insulin dosing based on insulin pump, CGM and glucometer downloads of 15 patients (mean age 16.2 ± 4.3 years, six female, mean glycated haemoglobin 8.3 ± 0.9% [66.8 ± 7.3 mmol/mol]) gathered over a 3-week period. Recommendations were compared for the relative changes in the basal, carbohydrate to insulin ratio (CR) and correction factor (CF) plans among physicians and among centres and also between the physicians and an automated algorithm, the Advisor Pro (DreaMed Diabetes Ltd, Petah Tikva, Israel). Study endpoints were the percentage of comparison points for which there was full agreement on the trend of insulin dose adjustments (same trend), partial agreement (increase/decrease vs no change) and full disagreement (opposite trend). RESULTS: The percentages for full agreement between physicians on the trend of insulin adjustments of the basal, CR and CF plans were 41 ± 9%, 45 ± 11% and 45.5 ± 13%, and for complete disagreement they were 12 ± 7%, 9.5 ± 7% and 10 ± 8%, respectively. Significantly similar results were found between the physicians and the automated algorithm. The algorithm magnitude of insulin dose change was at least equal to or less than that proposed by the physicians. CONCLUSIONS: Physicians provide different insulin dose recommendations based on the same datasets. The automated advice of the Advisor Pro did not differ significantly from the advice given by the physicians in the direction or magnitude of the insulin dosing.

Central Precocious Puberty and Response to GnRHa Therapy in Children with Cerebral Palsy and Moderate to Severe Motor Impairment: Data from a Longitudinal, Case-Control, Multicentre, Italian Study.

BACKGROUND: Children affected by neurodevelopmental disability could experience early pubertal changes at least 20 times more than the general population. Limited data about central precocious puberty (CPP) among children affected by cerebral palsy (CP) are available. METHODS: This is a longitudinal, observational, retrospective, case-control study involving 22 children affected by CPP and CP (group A), 22 paired with CP but without CPP (group B), and 22 children with CPP without CP. Auxological, biochemical, and instrumental data were collected at diagnosis of CPP and at 2 follow-up visits. RESULTS: No differences were detected between groups A (at baseline) and B. At diagnosis of CPP, height SDS adjusted for target height (H-TH SDS) was significantly reduced in A than in C (-0.63 ± 1.94 versus 1.56 ± 1.38), while basal LH and oestradiol levels were significantly elevated in A than in C. During follow-up, despite an effective treatment, growth impairment deteriorated in A than in C (Δ H-SDS from diagnosis of CPP to last follow-up: -0.49 ± 0.91 versus 0.21 ± 0.33, p = 0.023). CONCLUSIONS: Diagnosis of CPP could be partially mislead in CP due to growth failure that got worse during follow-up despite therapy. CPP in CP seems to progress rapidly along time supporting the hypothesis of a more intense activation of hypothalamic-pituitary-gonadal-axis in these patients.

Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia.

BACKGROUND AND AIMS: Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene, leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8. METHODS: We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia. RESULTS: Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol levels. For the molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*)] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized. CONCLUSIONS: Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.

Unusual presentation of Rosai-Dorfman disease in a 14-month-old Italian child: a case report and review of the literature.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare form of histiocytosis characterized by histiocyte proliferation within lymph nodes and extranodal tissue. Here we report an unusual presentation of RDD in an Italian toddler. Moreover, we reviewed the pediatric case reports published between 2004 and 2014, focusing in particular on medical therapy. CASE PRESENTATION: We report the case of a 14-month-old child who developed a progressive swelling of the right parotid, associated with systemic symptoms and abnormal blood tests. During diagnostic work-up, cervical, intraparotid, and unilateral hilar lymphadenopathies were found. Histopathological and immunohistochemistry studies of a cervical lymph node biopsy established the diagnosis of RDD, with positive PCR for Epstein - Barr virus on the biopsy specimen. Oral steroid therapy was started with progressive reduction in size of all lesions, resolution of systemic symptoms, and normalization of blood tests. CONCLUSION: RDD is generally considered a benign and self-limiting form of histiocytosis, usually associated with favorable prognosis. However, complications are not infrequent and fatal cases were reported even in children. Efforts should be made to establish the best therapeutic strategy for this disease, as no well-defined guidelines exist. Finally, RDD should be included in differential diagnosis of lymphadenopathy and parotid swelling even in very young children.

Reversible Growth Hormone Excess in Two Girls with Neurofibromatosis Type 1 and Optic Pathway Glioma.

BACKGROUND: A total of 12 children with neurofibromatosis type 1 (NF-1) with optic pathway glioma (OPG) and growth hormone (GH) excess are reported to date, but no data exist on the long-term outcome. We describe 2 girls with NF-1 with OPG and GH excess treated with somatostatin analogue (SSa) who maintained a normal GH axis after stopping SSa therapy. METHODS: The diagnosis of GH excess was established from auxological data, persistently high levels of insulin-like growth factor 1 (IGF-1) and a lack of GH suppression during an oral glucose tolerance test. RESULTS: Both patients were started on SSa treatment. During treatment, growth deceleration and normal IGF-1 levels were documented. The first case stopped treatment following the development of SSa side effects. The second case interrupted SSa when, closed to her final height, a normal IGF-1 level was documented. While off treatment, both cases maintained normal IGF-1 levels and appropriate growth velocity for their age and development, with normal GH secretion on biochemical testing. Both cases received treatment for central precocious puberty. CONCLUSION: GH excess in NF-1 children with OPG can be reversed and only short-term SSa therapy may be required. The aetiology remains undetermined, but the course suggests a hypothalamic dysfunction.