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Abstract Despite the implementation of preventive measures to counteract the obesity epidemics, the prevalence of childhood obesity is still alarming all over the world. Childhood obesity is the most common risk factor for both cardiovascular and metabolic diseases. In fact, an earlier onset of obesity can cause a greater risk of adiposity tracking across the lifespan and consequently a longer exposure to cardiometabolic risk factors. Accumulating evidence provided by prospective and intervention studies demonstrated the link between pediatric obesity and selected subclinical signs of cardiovascular damage (atherosclerosis and left ventricular hypertrophy), or fatal and not fatal cardiovascular events as early as 40 years of age. The numerous guidelines and scientific documents published in the last years demonstrate the relevance of assessing cardiometabolic risk factors in children and adolescents with OB. This Position paper, released by experts of the “Childhood Obesity study group” within the Italian Society for Pediatric Endocrinology and Diabetology, aims to review the assessment of cardiometabolic risk factors and comorbidities in children and adolescents with OW/OB on the light of the most recent scientific evidence. The main recommendations are: (a) early detection of comorbidities, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, inactivity, obstructive sleep apnea and decline in kidney function; (b) weight loss treatment, which is associated with a reduction of all cardiometabolic risk factors; (c) specific treatment of comorbidities, through lifestyle modifications or pharmacological treatment added to lifestyle for suitable individuals; d). monitoring comorbidities for mitigating future morbidity and mortality.

BackgroundRett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that involves mainly girls and is the second most frequent cause of genetic intellectual disability. RTT leads to neurological regression between 6 and 18 months of life and could be associated with a variable neurological impairment. However, RTT affects not only neurological function but also wide aspects of non-neurological organs. Recent data showed that the endocrine system is often involved in RTT patients, including disorders of growth, bone health, thyroid, puberty onset, and weight abnormalities However, systematic data on endocrinopathies in RTT are scarce and limited.ObjectiveThis review aims to analyze the prevalence and type of endocrine comorbidities in RTT population, to allow a precocious diagnosis and appropriate endocrinological management.MethodsSystematic research was carried out from January 2000 to March 2024 through MEDLINE via PubMed, Scopus, and the Cochrane Library.ResultsAfter the selection phase, a total of 22 studies (1090 screened) met the inclusion criteria and were reported in the present review. Five studies were observational-retrospective, four were cross-sectional and case report or series, three were survey, prospective, and case-control, and finally one study for descriptive-transversal and longitudinal population-based study. The sample population consisted of multiethnic groups or single ethnic groups. The main endocrinopathies reported were malnutrition, bone alterations, and alterations of puberty onset.ConclusionsOur analysis shows that endocrinopathies are not rare in RTT patients. Therefore, in the context of a multidisciplinary approach, accurate screening and monitoring for endocrinopathies should be recommended in all RTT patients, to improve clinical practice, healthcare management, and, finally, patients’ quality of life.

Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype–phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible.

Abstract Adiposity rebound (AR) refers to the second rise of the body mass index (BMI) curve that usually occurs between six and eight years of age. AR timing has a significant impact on patients’ health: early AR (EAR), usually before the age of five, is considered to be the earliest indicator of obesity and its related health conditions later in life. Many studies have evaluated factors that can be predictors of EAR, and identified low birth weight and gestational weight gain as novel predictors of EAR, highlighting the role of the intrauterine environment in the kinetics of adiposity. Furthermore, children with breastfeeding longer than 4 months have been found to be less likely to have an EAR, whereas children born to advanced-age mothers, high maternal BMI had a higher risk of having an EAR. Some differences were found in the timing of AR in boys and girls, with girls being more likely to have EAR. The aim of this review is to answer the following three questions: 1) Which are the prenatal and perinatal factors associated with increased risk of EAR? Is gender one of these? 2) Which are the outcomes of EAR in childhood and in adulthood? 3) Which measures can be taken in order to prevent premature AR?

Abstract Purpose ACTION Teens (NCT05013359) was conducted in 10 countries to identify perceptions, attitudes, behaviors, and barriers to effective obesity care among adolescents living with obesity (ALwO), caregivers of ALwO, and healthcare professionals (HCPs). Here, we report data from participants in Italy. Methods The ACTION Teens cross-sectional online survey was completed by 649 ALwO (aged 12–

Abstract Background Atrophic autoimmune thyroiditis (AAT) is a rare phenotype of autoimmune thyroiditis (AT) in pediatric age. AAT occurs without thyroid enlargement leading to a delay in its diagnosis. Growth impairment is infrequent in autoimmune thyroiditis, if timely diagnosed. Prolonged severe hypothyroidism is a rare cause of pituitary hyperplasia (PH) in childhood. Loss of thyroxine negative feedback causes a TRH-dependent hyperplasia of pituitary thyrotroph cells resulting in adenohypophysis enlargement. A transdifferentiation of pituitary somatotroph cells into thyrotroph cells could explain growth failure in those patients. Methods Twelve patients were retrospectively evaluated at five Italian and Polish Centres of Pediatric Endocrinology for height growth impairment. In all Centres, patients underwent routine clinical, biochemical and radiological evaluations. Results At the time of first assessment, the 75% of patients presented height growth arrest, while the remaining ones showed growth impairment. The study of thyroid function documented a condition of hypothyroidism, due to AT, in the entire cohort, although all patients had no thyroid enlargement. Thyroid ultrasound showed frankly atrophic or normal gland without goiter. Cerebral MRI documented symmetrical enlargement of the adenohypophysis in all patients and a homogeneous enhancement of the gland after the administration of Gadolinium-DPTA. Replacement therapy with levothyroxine was started and patients underwent close follow-up every 3 months. During the 12 months of follow-up, an improvement in terms of height growth has been observed in 88% of patients who continued the follow-up. Laboratory findings showed normalization of thyroid function and the control brain MRI documented complete regression of PH to a volume within the normal range for age and sex. Conclusions This is the largest pediatric cohort with severe autoimmune primary hypothyroidism without goiter, but with pituitary hyperplasia in which significant growth impairment was the most evident presenting sign. AAT phenotype might be correlated with this specific clinical presentation. In youths with growth impairment, hypothyroidism should always be excluded even in the absence of clear clinical signs of dysthyroidism.

Abstract Background Pseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation. Case presentation We describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A. Conclusions This study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype–phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.

Abstract Background In response to the imperative need for standardized support for adolescent Gender Dysphoria (GD), the Italian Academy of Pediatrics, in collaboration with the Italian Society of Pediatrics, the Italian Society for Pediatric Endocrinology and Diabetes, Italian Society of Adolescent Medicine and Italian Society of Child and Adolescent Neuropsychiatry is drafting a position paper. The purpose of this paper is to convey the author's opinion on the topic, offering foundational information on potential aspects of gender-affirming care and emphasizing the care and protection of children and adolescents with GD. Main body Recognizing that adolescents may choose interventions based on their unique needs and goals and understanding that every individual within this group has a distinct trajectory, it is crucial to ensure that each one is welcomed and supported. The approach to managing individuals with GD is a multi-stage process involving a multidisciplinary team throughout all phases. Decisions regarding treatment should be reached collaboratively by healthcare professionals and the family, while considering the unique needs and circumstances of the individual and be guided by scientific evidence rather than biases or ideologies. Politicians and high court judges should address discrimination based on gender identity in legislation and support service development that aligns with the needs of young people. It is essential to establish accredited multidisciplinary centers equipped with the requisite skills and experience to effectively manage adolescents with GD, thereby ensuring the delivery of high-quality care. Conclusion Maintaining an evidence-based approach is essential to safeguard the well-being of transgender and gender diverse adolescents.

Thyroid nodules in children are less common than in adults but they are approximately two- to three-fold more likely to be malignant in children. Among thyroid nodular diseases, Plummer's adenoma occurs very rarely in pediatrics, and currently, there is no literature providing evidence of this diagnosis in patients with Prader–Willi syndrome (PWS). We report the case of a 9-year-old Caucasian boy affected by PWS presenting with a rapidly growing palpable mass in the thyroid lodge associated with subclinical hyperthyroidism. Laboratory and other examinations (thyroid ultrasound, fine-needle aspiration of the nodule, and scintigraphy) were strongly suggestive for Plummer's adenoma; therefore, the patient underwent left hemithyroidectomy surgery, and anatomo-pathological examination confirmed the diagnosis. Our case describes the first evidence of an isolated follicular adenoma in children with PWS. Surgery is the only therapeutic option in younger children. Further evidence is needed to assess the possible correlation between these two conditions and the existence of potential risk factors.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Kawasaki disease (KD) is a vasculitis of the middle and little caliber arteries that specifically affects the coronary arteries. It represents the main cause of acquired cardiopathy in the pediatric population of western countries and in 25% of cases it leads to coronary artery aneurism (1). Atypical KD is nowadays considered a challenge for pediatrics, due to all of its possible clinical manifestations: it is characterized by a long-lasting fever (5 or more days) associated with some of the typical signs and symptoms and other unusual clinical manifestations (as neurological, nephrological, respiratory, gastrointestinal, rheumatological manifestations), variably associated with coronary arteries aneurism. Early diagnosis and treatment are essential to reduce the risk of coronary artery aneurysms (2,3). We report the case of a 5-year-old boy who came to our attention for skin rash, abdominal pain, increased liver enzymes, and hydrops of the gallbladder. He presented a fever for less than 5 days. 2 weeks later, the appearance of peeling on the fingers and the toes confirmed the diagnosis of an atypical, incomplete KD.

Familial male-limited precocious puberty (FMPP), or testotoxicosis, is a rare cause of precocious puberty in males. It is caused by an activating mutation in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene. This causes excessive production of testosterone, with LH and FSH levels suppressed. Generally, boys present with signs of puberty, with age of onset between 2-5 years essentially with penis and testes growth, linear growth acceleration and progressive bone age advancement. Differential diagnosis is often a challenge with others causes of peripheral puberty. The goal of treatment is to decrease the effect of testosterone as well as reduce the conversion of testosterone to estrogen. The long-term aims are to prevent precocious virilization and to delay closure of the epiphyseal plates to maintain adult height potential. Little is known about the long-term effects of treatment because the disorder is so rare. However recent studies using bicalutamide and anastrozole have been promising. In this report, we present a boy with FMPP with a classic mutation in the LHCGR gene, who has been challenging to manage with off-label drugs.

Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality affecting thehypothalamic pituitary complex. It is characterized by a peculiar radiological triad which includes thin or interruptedpituitary stalk, hypoplasia or aplasia of the adenohypophysis and absent or ectopic neurohypophysis seen on magnetic resonance imaging (MRI). Patients affected by PSIS may show a wide range of clinical manifestations depending on the variable involvement of pituitary specialized cells, ranging from isolated to multiple pituitary hormone deficiency. The exact aetiology of PSIS is still uncertain, even if genetic causes arelikely to be involved in some cases, especially mutations in genes implicated in pituitary and neuronal development. Prognosis may vary according to several factors, the most relevant of which is diagnostical-timing, being strictly related to the start of hormonal replacement therapy.This report describes an emblematic PSIS case diagnosed in a 15-year-old girl with primary amenorrhoea and short stature. Her past medical history was not significant. Accurate diagnostic investigation including bone age examination, basal hormonal evaluation and growth hormone stimulation dynamic tests were performed, revealingcombined pituitary hormone deficiency (CPHD). MRI findings confirmed a picture of PSIS. The case highlights the importance of accurate history taking and careful monitoring of growth and pubertal development, which is crucial to avoid diagnostic delay and to allow promptly hormonal replacement therapy.

Objective: This Italian survey aims to evaluate real-life long-term efficac y and safety of recombinant human growth hormone (rhGH) therapy in children wit h short stature homeobox-containing gene deficiency disorders (SHOX-D) and to id entify potential predictive factors influencing response to rhGH therapy. Design and methods: This is a national retrospective observational study collectin g anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhG H. 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 availab le. 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) SD S 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) a nd ones with regulatory region defects (group B) experienced a similar beneficial therap eutic effect. The multiple regression analysis identified the age at the start of rhGH trea tment (β = −0.31, P = 0.030) and the GV during the first year of rhGH treatment ( β = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH thera py, 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 o f 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-te rm 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 the rapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of trea tment and the age when rhGH was started significantly impact the height gain.

Abstract This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

Childhood obesity is rapidly increasing worldwide and there is an urgent need to implement treatment and prevention programs. Over the last decade, in addition to increasing rates of childhood obesity, we have also observed rapid technological and digital development. The Covid-19 pandemic has largely contributed to both expansions but has also allowed an opening towards a broader vision of medicine, through new therapeutic opportunities such as mobile healthcare. The digital and technological delivery of obesity prevention and treatment programs can represent an innovative tool to support children and families to overcome some limitations and barriers such as the accessibility of programs that prevent them from adopting healthy lifestyle changes. This review aimed to summarize the impact of different digital interventions for children and adolescent affected by obesity.

IntroductionZonulin recently emerged as a valuable biological marker to assess the integrity of the intestinal mucosal barrier. Nevertheless, data about zonulin in pediatric age are extremely scarce. Aim of this study was to investigate the relationship between serum zonulin levels, both fasting and postprandial, with body mass index (BMI) and biochemical markers of insulin resistance (IR), insulin sensitivity, b-cell function and cardio-metabolic risk in obese non-diabetic youths.MethodsOne hundred and four children and adolescents with obesity (BMI ≥ 2.0 SDS) were enrolled (mean age 11.43 ± 2.66). All the patients underwent clinical and biochemical assessment, including oral glucose tolerance test (OGTT) and liver ultrasonography. Zonulin serum levels were measured at fasting state, at 60-minute and 120-minute OGTT timepoint.ResultsImpaired fasting glycaemia and impaired glucose tolerance were documented in 27.9% and 11.5% of patients, respectively. IR was documented in 69.2% of cases. Liver steatosis was diagnosed in 39.4%. Zonulin serum levels significantly increased from baseline to 60-minute and 120-minute OGTT timepoint (p positive correlation between BMI SDS and serum zonulin levels at 120-minute OGTT timepoint (p highlighted a positive association of zonulin fasting levels with IR and glutamicoxalacetic transaminase levels (GOT, p zonulin levels were demonstrated for age, sex, pubertal status, glucose, lipid profile and the other obesity-related parameters.DiscussionOur results show, for the first time in a pediatric cohort, the meal-related pattern of secretion of serum zonulin, which tends to significantly increase during and at 2-hours postprandial assessment. Even if the underlying mechanisms associating intestinal permeability and obesity have not been fully elucidated yet, our data confirm a close relationship between zonulin concentration and obesity in pediatric population. IR seems to significantly influence zonulin serum levels, thus a central role of IR in this pathway is conceivable.

Summary: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with

ObjectiveDifferentiated thyroid cancer (DTC) is rare in childhood and adolescence although it represents the most frequent endocrine malignancy in this population. DTC includes both papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Most pediatric DTCs are PTCs, while FTCs are rare. To date, no systematic reviews on the global epidemiology of pediatric and adolescent DTC have been published. This systematic review and meta-analysis aims to estimate the overall incidence and prevalence of DTCs in patients aged 0–19 years.MethodsThe systematic research was conducted from January 2000 to December 2021 through MEDLINE via PubMed, Cochrane Library, and Embase databases. Two separate meta-analyses were performed for PTC and FTC.ResultsAfter the selection phase, a total of 15 studies (3,332 screened) met the inclusion criteria and are reported in the present systematic review. Five studies were conducted in Europe, five in North America, two in South America, one in Asia, one reported data for 49 countries and territories across the five continents, and one from both the USA and Africa. Most of the studies (n = 14) reported data obtained from national registries, and only one provided information collected from hospital medical records. Beyond the actual trend over time, our study reported a pooled global incidence rate (IR) of PTC and FTC in the pediatric age of 0.46 (95% CI: 0.33–0.59) and 0.07 (95% CI: 0.02–0.12) per 100,000 person-years, respectively. The highest IRs were recorded among Caucasian girls, and the lowest in black or other races/ethnicities.ConclusionOur data confirm that DTC in the pediatric population is a rare condition. The pooled IRs of the studies included in this meta-analysis are ~0.5 for PTC, which is the most common histological type when both genders and all age groups are considered. The implementation of a prospective international registry on pediatric DTC, as part of the wider European Registries for Rare Endocrine Conditions, has been recently proposed. In addition to providing relevant information on the clinical behavior of this rare disease, standardization of data collection will be pivotal to fill current gaps and allow an accurate estimation of the real incidence and risk factors of DTC.

Abstract Background Prader–Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients’ care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. Materials and methods The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. Results A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019–2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. Conclusions The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

Background: Possible therapeutic failure of pediatric obesity is influenced by the high dropout rate. The aim of this study was to evaluate the rate of dropout and the rate of weight loss over the 24 months of follow-up. Methods: The retrospective, single-center study, involved 489 patients followed for obesity in the period 2016–2020. Patients’ auxological data and blood samples were collected during the first (V1) and last visit (V2). Dropout was defined as a follow-up of less than 12 months and/or including less than one visit every 6 months. Patients were divided into two groups and compared: Group A of dropout (297 patients) and Group B of non-dropout (192 patients). Results: In the follow-up period, which had a mean duration of 24 months, the dropout rate was 60.7%. In Group A, the percentage of patients with BMI ≥ 3 SD at V2 was significantly higher than that in Group B. In Group B, the percentage of patients with pathological HOMA-IR and with fasting glucose >100 mg/dL was higher than group A. The probability of dropout was positively associated with pubertal stage and negatively with impaired fasting glycemia and pathological insulinemia at V1. Conclusion: The study demonstrated a high dropout rate during follow-up, mainly among adolescents and patients with no glucometabolic alterations.

BackgroundThyroid hormones (TH) play multiple effects on glucose metabolism. Some recent studies carried out in adult patients suggested an association between altered sensitivity to TH and type 2 diabetes, obesity, and metabolic syndrome. No studies are currently available on the presence of altered sensitivity to the action of TH in youths with prediabetes.ObjectiveTo evaluate the relationship between sensitivity to TH and impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or glycosylated hemoglobin (HbA1c) ≥ 5.7% in youths with overweight/obesity (OW/OB).Materials and methodsThis cross-sectional study included 805 Caucasian youths with OW or OB (aged 6-18 years) recruited at seven Italian centers for the care of OW/OB. Individuals with TH out of the normal range of TH in each center were excluded. The fT3/fT4 ratio was evaluated to assess peripheral sensitivity, while TSH index (TSHI), Thyrotroph T4 Resistance Index (TT4RI), Thyroid Feedback Quantile-based Index (TFQI) and Parametric TFQI were calculated to assess central sensitivity.ResultsYouths with IGT (n =72) showed higher levels of TSH (3.08 ± 0.98 vs 2.68 ± 0.98 mIU/L, P =0.001), TSHI (3.06 ± 0.51 vs 2.85 ± 0.53, P =0.001), TT4RI (46.00 ± 17.87 vs 38.65 ± 16.27, P

NR5A1 gene mutations are associated principally to 46,XY DSD (Disorders of Sex Development), with an extensive range of phenotypic variability in patients, comprising gonadal dysgenesis and male infertility. NR5A1 gene plays a crucial role in reproduction, steroidogenesis, and sexual differentiation. The present case describes an Italian male adolescent with ambiguous genitalia at birth and a 46,XY karyotype who was investigated for DSD genetic panel conditions due to slow pubertal progression. A heterozygous variant in NR5A1 (NM_004959.4: c.937CT, p.Arg313Cys) was identified in this patient and in his father. The same variant was previously described in other studies showing the wide heterogeneity of genotype-phenotype correlation in DSD patients.

Tricho-rhino-phalangeal syndrome (TRPS) is a genetic disease characterized by craniofacial and skeletal malformations including short stature, brachydactyly, with ulnar or radial deviation of the fingers, clinodactyly and early joint dysplasia, especially of the hips. The most remarkable craniofacial features are slow growing, sparse and brittle hair, pear-shaped nose with a bulbous tip, flat philtrum with thin upper lip, micrognatia and large low-set ears. The radiological hallmarks include cone-shaped phalangeal epiphyses, typical of all TRPS patients, but usually not present until 2 years of age, while bone exostoses appear only in TRPS II individuals. Management is primarily supportive. We describe a case of a male child with disharmonious short stature, affected by TRPS I. The diagnosis was established on the basis of clinical features and genetic testing

Pseudohypoparathyroidism (PHP) is a heterogeneous group of hereditary disorders characterized by clinical and biological characteristics of resistance to parathyroid hormone (PTH) caused by impaired hormonal signalling via receptors that are coupled, through the α- subunit of the stimulatory G protein (Gsα). In some cases, resistance to other hormones (such as TSH, gonadotropins, GHRH and calcitonin) that have receptors coupled via Gsα is observed. A subset of patients with PHP are characterized by the variable expression of a collection of physical features, termed Albright hereditary osteodystrophy (AHO), which includes brachydactyly, rounded face, short stature, central obesity, subcutaneous ossifications, and variable degrees of mental retardation. These patients face a wide range of problems from early childhood to adulthood, which include potentially severe alterations in mineral metabolism, which could be associated with seizures; other endocrine deficiencies due to hormone resistance that lead to hypothyroidism, hypogonadism and GH deficiency; growth impairment independently of hormonal status; ectopic ossifications with potential severe limitation of mobility; skeletal issues and cognitive and psychomotor impairment. Here we report three sisters affected by pseudohypoparathyroidism but with remarkably differences from each other in terms of phenotypic and clinical-auxological characteristics, a demonstration of how this disease is characterized by a very heterogeneous phenotype, even among patients carrying the same genetic alteration.

The Covid-19 pandemic drastically modified social life and lifestyle, in particular, among children and adolescents, promoting sedentary behaviors and unhealthy eating habits. The aims of this study were to assess the rate and the factors associated with outpatient drop-out in childhood obesity management, and to evaluate how the Covid-19 pandemic influenced weight status and lifestyle of children and adolescents with obesity. One hundred and forty-five children and adolescents with obesity were identified, including 80 subjects evaluated before the Covid-19 pandemic (group A) and 65 subjects in the period straddling the Covid-19 pandemic (group B). Anamnestic (family history of obesity, dietary habits, physical activity, screen time), socio-cultural (economic status, employment and schooling of parents, household composition, place of living) and clinical (weight, height, BMI, waist circumference) data were retrospectively analyzed for each subject in both groups at baseline (V0) and 12-months (V1) at in-person assessment. Glycemic and lipid profiles were assessed at V0. Drop-out rate did not differ significantly between the two groups. BMI SDS at V0 (OR=2.52; p=0.004), female sex (OR=0.41; p=0.035), and the presence of a single parent in the household (OR=5.74; p=0.033) significantly influenced drop-out in both groups. Weight loss between V0 and V1 was significantly greater among group A patients compared to group B (p=0.031). In group B, hours spent in physical activity significantly decreased from V0 to V1, being significantly lower than group A at V1; on the contrary, screen time significantly increased in the same period. The consumption of sugary drinks and snacks was significantly greater in group B than group A at V1. Our study documented that the Covid-19 pandemic, although not affecting the drop-out rate of obese children in a follow-up program, negatively influenced lifestyle and reduced the effectiveness of outpatient counseling in childhood obesity treatment.

Abstract Background Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies. Methods Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice. Results In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism. Conclusions The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.

Metabolic syndrome (MetS) is defined by a cluster of several cardio-metabolic risk factors, specifically visceral obesity, hypertension, dyslipidemia, and impaired glucose metabolism, which together increase risks of developing future cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). This article is a narrative review of the literature and a summary of the main observations, conclusions, and perspectives raised in the literature and the study projects of the Working Group of Childhood Obesity (WGChO) of the Italian Society of Paediatric Endocrinology and Diabetology (ISPED) on MetS in childhood obesity. Although there is an agreement on the distinctive features of MetS, no international diagnostic criteria in a pediatric population exist. Moreover, to date, the prevalence of MetS in childhood is not certain and thus the true value of diagnosis of MetS in youth as well as its clinical implications, is unclear. The aim of this narrative review is to summarize the pathogenesis and current role of MetS in children and adolescents with particular reference to applicability in clinical practice in childhood obesity.

Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive multi-organ autoimmunity syndrome usually defined by high serum titers of type I Interferon Autoantibodies (Type 1 IFN-Abs). These antibodies have recently been found in individuals in the general population who develop life-threatening Coronavirus Disease 2019 (COVID-19), but the significance of pre-existing Type 1 IFN-Abs in APECED patients with COVID-19 remains unclear. Previous reports of COVID-19 outcomes in APECED patients have been divergent, and protective roles have been proposed for female sex, age

Asprosin physiologically increases in fasting conditions and decreases with refeeding and has been implicated in glucose homeostasis. An alteration of meal-related circadian oscillation of asprosin has been suggested in adults affected by type 2 diabetes mellitus.Aims of this study were to test the hypothesis of an alteration in the meal-related variation of asprosin levels in non-diabetic children and adolescents with obesity and to assess which metabolic variables condition this variation in non-diabetic children and adolescents with obesity. This is a cross-sectional study which included 79 children and adolescents with obesity. Children underwent clinical and biochemical assessments, including oral glucose tolerance test (OGTT), and liver ultrasound evaluation. Asprosin serum levels were measured by an enzyme-linked immunosorbent assay at a fasting state and at the 120-minute OGTT timepoint (2h-postprandial asprosin). Fasting and 2h-postprandial asprosin serum levels did not significantly differ in the entire study population (374.28 ± 77.23 vs 375.27 ± 81.26;p=0.837). 55.7% of patients had a significant increase in 2h-postprandial asprosin compared with fasting levels. The asprosin level increase condition was significantly associated with HOMA-IR (OR,1.41; 95%CI,1.005-1.977; p=0.047), fasting glycaemia (OR,1.073; 95%CI,1.009-1.141;p=0.024) and HOMA-B (OR,0.99; 95%CI,0.984-0.999; p=0.035). Moreover, the IFG condition was associated with the increase in asprosin levels (OR, 3.040; 95%CI, 1.095-8.436; p=0.033), even after adjustment for HOMA-IR, BMI SDS, sex and pubertal stage. Insulin resistance and IFG influence meal-related changes of asprosin serum levels in our study population of obese, non-diabetic, children. Alteration of asprosin circadian secretion might be an early biomarker of impaired glucose regulation in obese children with insulin resistance.

The definition of metabolic syndrome (MetS) in childhood is controversial. Recently, a modified version of the International Diabetes Federation (IDF) definition was proposed using reference data from an international population for high waist circumference (WC) and blood pressure (BP), while the fixed cutoffs for lipids and glucose were not changed. We analyzed MetS prevalence using this modified definition (MetS-IDFm) and its association with non-alcoholic fatty liver disease (NAFLD) in 1057 youths (age 6–17 years) with overweight/obesity (OW/OB). A comparison with another modified definition of MetS according to the Adult Treatment Panel III (MetS-ATPIIIm) was performed. The prevalence of MetS-IDFm was 27.8% and 28.9% by MetS-ATPIIIm. The Odds (95% Confidence Intervals) of NAFLD was 2.70 (1.30–5.60) (p = 0.008) for high WC, 1.68 (1.25–2.26)(p = 0.001) for MetS, 1.54 (1.12–2.11)(p = 0.007) for low HDL-Cholesterol, 1.49 (1.04–2.13)(p = 0.032) for high triglycerides and 1.37 (1.03–1.82)(p = 0.033) for high BP. No substantial difference was found in the prevalence of MetS-IDFm and frequency of NAFLD compared to Mets-ATPIIIm definition. Our data demonstrate that one third of youths with OW/OB have MetS, whichever was the criterion. Neither definition was superior to some of their components in identifying youths with OW/OB at risk for NAFLD.

Food allergy (FA) is a significant health issue which considerably influences the quality of life of both children and their family. The increasing prevalence of FA, documented in the last 3 decades, has led to the reassessment of FA prevention strategies and particularly to giving up the approach based on delaying the introduction of potential food allergens. Several observational and interventional studies demonstrated a potential effectiveness of the early food introduction strategy in FA prevention, although strong evidence from randomized controlled trials are lacking and, sometimes, contrasting. The current approach to FA is mainly based on avoidance diet and the use of rescue medications in case of allergic reaction, although active allergen immunotherapy has recently become an increasingly important therapeutic strategy to approach IgE-mediated FA, potentially able to induce improvement through desensitization to a specific food. This review provides an overview on the historical evolution of recommendations about FA and on evidence published in the last 15 years on nutritional intervention strategy, i.e., early introduction of allergen or avoidance diet, in the prevention and management of IgE-mediated and non-IgE-mediated FA in children.

Objectives Prader-Willi syndrome (PWS) significantly impacts health-related quality of life; however, its relational and existential aspects remain unknown in Italian clinical and social debate. The project aimed to investigate the impact of PWS on illness experience through narrative medicine (NM) to understand the daily life, needs and resources of patients with PWS and their caregivers, and to furnish insights for clinical practice.Design and setting The project involved 10 medical centres of the Italian Network for Rare Diseases and PWS family associations and targeted underage and adult patients with PWS and their caregivers. Written interviews, composed by a sociodemographic survey and a narrative, were collected through the project’s website. Three dedicated illness plots employed evocative and open words to facilitate individual expression and to encourage reflection. Narratives were analysed through NVivo software. Researchers discussed the results with the project’s steering committee.Participants Twenty-one children and adolescents and 34 adults with PWS joined the project, as well as 138 caregivers. A PWS diagnosis or the caregiving of a patient with PWS older than 5 years represented the eligibility criteria, as well as the willingness to share their illness experience by writing and the ability to communicate in Italian.Results The analysis of narratives led to understanding the PWS social and relational issues concerning diagnosis and current management, PWS daily experiences and social contexts, PWS implications in the working sphere and participants’ future perspectives. Narratives demonstrated that PWS management affects relationships and work-life balance and that social stigma remains present.Conclusion The project represented the first effort to investigate the impact of PWS on illness experience in Italy through NM while considering the perspectives of patients with PWS and their caregivers. The findings indicated that a multiprofessional approach is fundamental to ensure adequate treatment and provided elements for its improvement.

Background: About 85–90% of children born small for gestational age (SGA) experience a catch-up growth that occurs mostly during the first year of life and results in a full stature recovery by the age of 2.Objective: To investigate the relation between bone maturation (BM) and catch-up growth during the first year of life in SGA infants.Method: Newborns whose weight and/or length was

Background: Childhood obesity is related to a wide spectrum of cardiovascular and metabolic comorbidities.Objectives: (1) To identify precocious, preclinical, cardiovascular sonographic modifications, in a cohort of overweight (OW) and obese (OB) children and adolescents compared to lean controls; (2) to investigate the association between clinical and metabolic variables and cardiovascular sonographic parameters; (3) to evaluate their relation with two different phenotypes of obesity: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO).Materials and Methods: Fifty-nine OW and OB children and adolescents (9.8 ± 2.9 years) and 20 matched lean controls underwent anthropometric, biochemical, echocardiography assessment, and sonographic evaluation of carotid artery and ascending aorta (AA). OW and OB subjects were divided in MHO and MUO, according to the Camhi et al. definition.Results: OW and OB children showed significantly higher left ventricular (LV) dimensions and mass, carotid artery intima–media thickness (CIMT), carotid stiffness [β-index, pulse wave velocity (PWV)], significantly lower mitral peak early (E) and late (A) velocity ratio (E/A ratio), and significantly impaired global longitudinal strain (GLS) compared to controls. BMI SD and HOMA-IR were positively significantly related to LV dimensions, LA volume and epicardial adipose tissue (EAT), and negative to E/A ratio. Waist circumference (WC) was positively correlated to LV dimensions, LA volume, CIMT, PWV, AA diameter, and EAT. Furthermore, WC was a strong predictor of LV dimensions, LA volume and strain, AA stiffness and diameter; BMI SD was significantly associated with EAT, LVM index, and E/A ratio; HOMA-IR and triglycerides were significant predictors of GLS. MUO patients showed higher BMI SD (p = 0.02), WC (p = 0.001), WHtR (p = 0.001), HOMA-IR (p = 0.004), triglycerides (p = 0.01), SBP (p = 0.001), as well as LV dimensions, EAT (p = 0.03), CIMT (p = 0.01), AA diameter (p = 0.02), β-index (p = 0.03) and PWV (p = 0.002), AA stiffness (p = 0.006), and significantly impaired GLS (p = 0.042) compared to MHO.Conclusions: Severity of overweight, abdominal obesity, insulin resistance, and MUO phenotype negatively affect cardiovascular remodeling and subclinical myocardial dysfunction in OW and OB children. MUO phenotype is likely to increase the risk of developing cardiometabolic complications since the pediatric age. Distinction between MHO and MUO phenotypes might be useful in planning a personalized follow-up approach in obese children.

Abstract Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune-Albright syndrome (MAS). On the basis of such analysis, we concluded that: 1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP.

Abstract Aim of this commentary is to analyze the relationships between genotypic bases and phenotypic expression of congenital “multiple pituitary hormone deficiency” (MPHD) syndrome and to indicate some reliable criteria for selecting the patients who should undergo genetic analyses in order to clarify the etiology of their disorder. On the basis of the most recent reports on this topic, it is possible to infer that: 1) in only few patients with congenital MPHD it is possible to detect a causative gene mutation; 2) therefore, it is fundamental to define some criteria for selecting the patients who should undergo genetic analyses; 3) such inclusion criteria should be based on the overall evaluation of hormonal clinical and neuroradiological phenotype; 4) it is crucial to consider whether the cases are sporadic or familial, since the probability of finding a causative gene mutation is distinctly higher in familial cases; 5) for PROP1 gene it is also important to consider the geographical origin of the patients, because this mutation is much more frequent in some ethnic groups.

Abstract ᅟ Aim of this commentary is to summarize the salient literature views on the relationships between presentation and evolution patterns of thyroid function in children with Hashimoto’s thyroiditis (HT). According to the most recent reports, children with HT and subclinical hypothyroidism (SH) are more prone to the risk of developing severe thyroid dysfunctions over time, if compared to those presenting with euthyroidism. In contrast, children presenting with HT and either overt or subclinical hyperthyroidism are incline to exhibit a definitive resolution of the hyperthyroid phase within some months, although there is a wide variability between the different individuals. The natural history of frank hypothyroidism in the children with HT has never been investigated so far, since in these cases an immediate onset of replacement treatment is mandatory. Conclusions 1) a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2) a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.

Abstract Background The available studies concerning the influence of age on the phenotypical expression of differentiated thyroid carcinoma (DTC) have hitherto compared DTC presentation either between pre-pubertal and pubertal children or between pediatric patients and aged adults; aim of this study was to ascertain for the first time whether presentation of DTC may significantly vary according to age, even within a peculiar study population covering only young patients aged less than 30 years. Methods The main clinical, biochemical and pathologic data at DTC diagnosis were retrospectively recorded in 2 selected cohorts including, respectively, 18 children and adolescents aged less than 18 years (Group A) or 45 young adults aged between 20 and 29.8 years (Group B). Results The statistical distribution of DTC cases in the different age ranges was found to progressively increase with increasing age; furthermore, the patients of Group A exhibited at diagnosis a more severe clinical involvement and a higher rate of extra-regional metastases; finally, also the association with both autoimmune thyroid diseases (AITDs) and a biochemical hypothyroid pattern was more common in Group A patients. Conclusions In a study population younger than 30 years: a) the risk of developing DTC increases with age, achieving its zenith during the 3rd decade of life; b) clinical presentation is more severe in children and adolescents younger than 18 years than in the patients aged between 20 and 30; c) in the cohort of children and adolescents DTC is more often associated with AITDs, which might play some role in conditioning the more aggressive phenotypical presentation of DTC in this patient group.

Prader–Willi syndrome (PWS) is a rare disease determined by the loss of the paternal copy of the 15q11-q13 region, and it is characterized by hypotonia, hyperphagia, obesity, short stature, hypogonadism, craniofacial dysmorphisms, and cognitive and behavioral disturbances. The aims of this retrospective study were to analyze interictal EEG findings in a group of PWS patients and to correlate them with genetic, clinical, and neuroimaging data. The demographic, clinical, genetic, EEG, and neuroimaging data of seventy-four patients were collected. Associations among the presence of paroxysmal EEG abnormalities, genotype, and clinical and neuroimaging features were investigated. Four patients (5.4%) presented drug-sensitive epilepsy. Interictal paroxysmal EEG abnormalities—focal or multifocal—were present in 25.7% of the cases, and the normalization of the EEG occurred in about 25% of the cases. In 63.2% of the cases, the paroxysmal abnormalities were bilaterally localized over the middle–posterior regions. Brain magnetic resonance imaging (MRI) was performed on 39 patients (abnormal in 59%). No relevant associations were found between paroxysmal EEG abnormalities and all of the other variables considered. Interictal paroxysmal EEG abnormalities—in particular, with a bilateral middle–posterior localization—could represent an important neurological feature of PWS that is not associated with genotype, cognitive or behavioral endophenotypes, MRI anomalies, or prognosis.

Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), tend to aggregate with other non-thyroidal autoimmune diseases (NTADs). Aim of this Mini-review is to report the most recent insights concerning the clustering of NTADs in pediatric patients with either HT or GD, the pathophysiology of AITDs and the metamorphic thyroid autoimmunity. A systematic literature research of the last 15 years, according to EQUATOR statement, was carried out through MEDLINE via PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) Embase, CINAHL, Cochrane Library, based on the following keywords: (autoimmune thyroid disease OR Hashimoto thyroiditis OR Grave's disease) AND (autoimmune comorbidities OR extra-thyroidal autoimmune disorders) AND (children OR adolescents OR pediatrics) AND (celiac disease OR type 1 diabetes mellitus OR arthropathies OR cutaneous diseases) AND (Turner syndrome OR Down syndrome). One-hundred and twenty-eight manuscripts were extrapolated but only seventeen were eligible. On the basis of the available reports it may be inferred that clustering of NTADs can be significantly modified by both patients' age at AITDs presentation and association with Down's syndrome (DS). Particularly, the association of AITDs with celiac disease and type 1 diabetes was most commonly reported in children than in adults. A sequential shifting from HT to GD has been described in children with AITDs, and it seems to be more frequent in children with DS than in those without DS. Coexistence of autoimmune diseases might be the result of a complex interaction among genetics, environment and epigenetic modifications that are able to affect gene expression, immune system response and, finally, the pathogenesis of autoimmune diseases.

Background: Advanced glycation end-products (AGEs) and their cell receptor (RAGE) are involved in the pathophysiology of cardio-metabolic diseases. Interaction of AGEs with RAGE results in increased generation of oxygen radicals and pro-inflammatory cytokines. Circulating soluble RAGE (sRAGE) interacts with AGEs in order to counterbalance the negative effects of AGEs-RAGE interaction.Objectives: To define factors influencing AGEs, sRAGE, AGEs/sRAGE-ratio, and advanced oxidation-protein products (AOPPs) levels and to investigate changes in oxidative balance among overweight/obese children.Materials and methods: Cross-sectional, one Center, case-control study included 41 overweight and obese children aged between 5 and 16 years and 36 lean matched controls. Inclusion criteria were: BMI ≥ 1 SD; term birth; no genetic or endocrine causes of obesity; no associated chronic diseases neither chronic therapies. All patients underwent clinical and biochemical investigations (lipid and glucose profiles, liver, renal and thyroid function tests, uric acid, C-reactive protein (CRP), AGEs, sRAGE, and AOPPs serum concentrations). Significance was established at 0.050.Results: AOPPs, AGEs/sRAGE-ratio, HOMA-IR, triglycerides, triglycerides/HDL-ratio, total cholesterol (TC)/HDL-ratio, atherogenic-index of plasma (AIP), uric acid, CRP were significantly higher, whereas sRAGE and HDL were significantly lower in overweight/obese children than controls. sRAGE was significantly negatively correlated with BMI SD, TC/HDL-ratio, CRP, AOPPs, and positively with HDL. AGE/sRAGE-ratio and AOPPs were significantly positively correlated with BMI SD, TC/HDL-ratio, AIP, CRP, and negatively with HDL. BMI SD was independently associated with AGEs/sRAGE-ratio (B = 0.06; p = 0.008), AOPPs (B = 0.13; p = 0.02), and sRAGE (B = −73.18; p = 0.000).Conclusions: We demonstrated, for the first time in a pediatric cohort, a significant higher value of AGEs/sRAGE-ratio among overweight/obese children, expression of a relative shift to oxidant from anti-oxidant factors, suggesting an AGE/RAGE-related oxidative homeostasis dysregulation that could enhance susceptibility to oxidative/inflammatory tissues damage. Severity of overweight, influencing the increase of oxidative stress in human organism and even in children, may contribute to the pathogenesis of long-term cardiovascular and metabolic alterations.

We describe a 13 years old girl with severe hypothyroidism due to Hashimoto’s Thyroiditis (HT) with an unusual clinical presentation, characterized only by growth arrest in absence of goiter and other clinical signs of overt hypothyroidism, like fatigue, bradycardia or worsening of school performance. The immediate start of Levotiroxine treatment resolved growth arrest and promoted pubertal development. This case confirmed that HT with overt hypothyroidism should be considered in the differential diagnosis of severe short stature in pediatric age

Aim of this mini review was to analyze the main variables which should be taken into account when the decision regarding a possible treatment with L-T4 has to be considered for a child with subclinical hypothyroidism (SH). The indications of periodical monitoring and vigilance have been also discussed. It was inferred that therapy should be recommended for children with underlying Hashimoto's thyroiditis and progressive deterioration of thyroid status over time, particularly in the cases with goiter and hypothyroid symptoms and in those with associated Turner syndrome or Down's syndrome and/or other autoimmune diseases. Treatment might also be recommended for children with proatherogenic metabolic abnormalities. Treatment is not advisable in children with idiopathic and mild SH, no goiter, no hypothyroid symptoms and negative anti-thyroid autoantibodies. In the absence of any therapeutic intervention, clinical status and thyroid function tests should be periodically monitored, in order to individuate the children who might benefit from treatment. It has been suggested that children with a persistent mild elevation of TSH, who are not treated with L-T4, should undergo biochemical monitoring of thyroid function and re-assessment of clinical status every 6 months. After 2 years with stable thyroid function tests, the interval between monitoring can be extended.

McCune-Albright Syndrome (MAS; OMIM # 174800) is a rare, sporadic disease caused by a post-zygotic, activating mutation in the guanine-nucleotide binding protein α-subunit (GNAS1) gene. MAS is characterized by the clinical triad of polyostotic fibrous dysplasia of bone, café-au-lait skin pigmentation and peripheral precocious puberty. However, clinical presentation is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Precocious puberty is the most common endocrine manifestation of MAS and is often the presenting, and sometimes the only, clinical sign of MAS. Due to the very low prevalence of MAS, data on course of precocious puberty, effectiveness of treatments and gonadal function during post-pubertal period are lacking. Our knowledge on this issue derives essentially from case reports and small cohorts of patients. The aim of this review is to report all available literature data on clinical aspects, therapeutic management and outcomes of precocious puberty in children with MAS. A systematic research was carried out through MEDLINE via PubMed, EMBASE, Web of Science, Semantic Scholar, Cochrane Library.

ObjectivesThe objectives were to evaluate (1) the metabolic profile and cardiometabolic risk in overweight/obese children at first assessment, stratifying patients according to severity of overweight and age; and (2) to investigate the relationship between family history (FH) for obesity and cardiometabolic diseases and severity of childhood obesity.MethodsIn this cross-sectional, retrospective, observational study, 260 children (139 female), aged between 2.4 and 17.2 years, with overweight and obesity were recruited. Data regarding FH for obesity and cardiometabolic diseases were collected. Each patient underwent clinical and auxological examination and fasting blood sampling for metabolic profile. Homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride-to-high-density lipoprotein cholesterol ratio, and atherogenic index of plasma were calculated. To evaluate the severity of obesity, children were divided into two groups for BMI standard deviation (SD) ≤2.5 and BMI SD >2.5. Moreover, study population was analyzed, dividing it into three groups based on the chronological age of patient (11 years).ResultsBMI SD was negatively correlated with chronological age (p 2.5) were younger (p