Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features.

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.

Sex-Related Differences in Cardiovascular Risk in Adolescents with Overweight or Obesity.

Background: Pediatric obesity is closely associated with cardiometabolic comorbidities, but the role of sex in this relationship is less investigated. We aimed to evaluate sex-related differences on cardiometabolic risk factors and preclinical signs of target organ damage in adolescents with overweight/obesity (OW/OB). Methods: The main cross-sectional study included 988 adolescents (510 boys and 478 girls) with OW/OB aged 10-18 years. In all youths clinical and biochemical variables were evaluated and an abdominal echography was performed. Echocardiographic data for the assessment of left ventricular mass (LVM) and relative wall thickness (RWT) were available in an independent sample of 142 youths (67 boys and 75 girls), while echographic data of carotid intima media thickness (cIMT) were available in 107 youths (59 boys and 48 girls). Results: The three samples did not differ for age, body mass index, and sex distribution. In the main sample, boys showed higher waist-to-height ratio (WHtR) values (p < 0.0001) and fasting glucose levels (p = 0.002) than girls. Lower levels of estimates glomerular filtration rate (eGFR) were found in girls vs boys (p < 0.0001). No sex-related differences for prediabetes and hyperlipidemia were observed. A higher prevalence of WHtR ≥ 0.60 (57.3% vs 49.6%, p = 0.016) and fatty liver disease (FLD) (54.5% vs 38.3%, p < 0.0001) as well as a trend for high prevalence of hypertension (40.4 vs 34.7%, p = 0.06) were observed in boys vs girls. More, a higher prevalence of mild reduced eGFR (MReGFR) ( < 90 mL/min/1.73 m 2 ) was observed in girls vs boys (14.6% vs 9.6 %, p < 0.0001). In the sample with echocardiographic evaluation, boys showed higher levels of LVM (p = 0.046), and RWT (p = 0.003) than girls. Again, in the sample with carotid echography, boys showed higher levels of cIMT as compared to girls (p = 0.011). Conclusions: Adolescent boys with OW/OB showed higher risk of abdominal adiposity, FLD, and increased cardiac and vascular impairment than girls, whereas the latter had a higher risk of MReGFR. Risk stratification by sex for cardiometabolic risk factors or preclinical signs of target organ damage should be considered in youths with OW/OB.

Association of HDL-Cholesterol, hypertension and left ventricular hypertrophy in youths with overweight or obesity.

BACKGROUND AND AIM: To evaluate the relationship between HDL-Cholesterol (HDL-C), hypertension, and left ventricular hypertrophy (LVH) in a large sample of Caucasian youths with overweight/obesity (OW/OB). METHODS AND RESULTS: A cross-sectional multicenter study was performed in 1469 youths (age 6-16 years) with OW/OB observed in the period 2016-2020. An additional independent sample of 244 youths with an echocardiographic evaluation, observed in a single center was analyzed. The sample was divided in six quantiles (Q) of HDL-C: Q1: >56, Q2: ≤56 > 51, Q3: ≤51 > 45, Q4: ≤45 > 41, Q5: ≤41 > 39, Q6: <39 mg/dL. The nadir of the relationship was identified in youths in the first quantile. Among HDL-Cholesterol quantiles the distribution of hypertension was non-linear with a percentage of 25.0%, 40.1%, 33.6%, 31.3%, 35.2% and 39.7% in the six quantiles, respectively. The percentage of LVH was 21.8%, 43.6%, 48.8%, 35.5%, 38.5% and 52.0% in the six quantiles, respectively. The highest odds [95%Cl] of hypertension were 2.05 (1.33-3.16) (P < 0.01) in Q2, 1.67 (1.10-2.55) (P < 0.05) in Q3 and 1.59 (1.05-2.41) (P < 0.05) in Q6 vs Q1. The odds of LVH were 3.86 (1.15-10.24) (P < 0.05) in Q2, 4.16 (1.58-10.91) (P < 0.05) in Q3 and 3.60 (1.44-9.02) (P < 0.05) in Q6 vs Q1, independently by centers, age, sex, prepubertal stage, and body mass index. CONCLUSION: Contrary to the common belief, the present study shows that high levels of HDL-C may be not considered a negative predictor of hypertension and LVH, two risk factors for future CV disease.

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A.

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.

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

Methods to investigate advanced glycation end-product and their application in clinical practice.

Advanced glycation end-products (AGEs) are heterogeneous compounds of irreversible adducts principally derived from nonenzymatic glycation and glycoxidation of proteins. An increase in AGEs may be involved in the pathogenesis of metabolic and cardiovascular diseases, chronic degenerative diseases, neurological diseases and cancer, and it has been suggested as a biomarker of oxidative stress. AGEs have been evaluated in different biological fluids, as well as in tissues. The most utilized techniques for AGE measurement can be divided into immunochemical methods, such as ELISA, and bioanalytical methods, including fluorescence spectroscopy, high-performance liquid chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy. However, the lack of reference values, well-established standard molecules, and standardized methods to measure these compounds, could limit the application of AGE evaluation for clinical purpose. Aim of this review is to provide an overview on the state of the art of the most employed techniques for detection and measurement of AGEs and their application in clinical practice.

A new formula to improve the screening of impaired glucose tolerance in youths with overweight or obesity.

AIM: To assess a new formula to improve the screening of isolated impaired glucose tolerance (IGT) in youth with overweight/obesity (OW/OB). METHODS AND RESULTS: A cross-sectional study was performed in 1189 Caucasian youths with OW/OB aged 5-17 years, in whom impaired fasting glucose and high glycosylated hemoglobin were excluded. The sample was divided into training set (TS) (n = 883) and validation set (VS) (n = 306). Fasting (FG) and post-load plasma glucose, alanine aminotransferase (ALT), lipids and familial history for type 2 diabetes (FD) were available in all individuals. In the TS youths with IGT (n = 58, 7.0%) showed higher prevalence of female sex (FS), FD, and higher levels of FG, post-load glucose, ALT and lower levels of HDL-cholesterol vs individuals without IGT. The linear formula was obtained by logistic regression analysis in the TS: 0.05∗ALT + 0.07∗FG + 0.87∗FD + (0.06∗HDL∗ - 1) + 1∗FS. The best cut-off was 5.84. The performance of the formula vs IGT was: sensitivity: 0.74 and specificity: 0.71. Similar results were obtained in the VS. CONCLUSIONS: Using metabolic and anamnestic data we obtained a simple formula with a good performance for screening isolated IGT. This formula may support pediatricians to identify youths with OW/OB in whom the OGTT may be useful for detecting IGT.

Asprosin serum levels and glucose homeostasis in children with obesity.

PURPOSE: Asprosin is a novel adipokine involved in glucose homeostasis, food intake regulation and energy homeostasis. However, the role of asprosin in glucose homeostasis regulation remains still controversial, especially in pediatrics. Aims of the study were to compare fasting serum asprosin levels between obese children and controls and to investigate the relationships of asprosin with body mass index (BMI) and biochemical markers of insulin resistance, insulin sensitivity, ß-cell function and cardio-metabolic risk in obese non-diabetic children. METHODS: This cross-sectional, case-controlled, study included 43 obese children and 24 lean matched controls consecutively recruited. Children underwent clinical and biochemical assessments, including oral glucose tolerance test. Fasting asprosin serum levels were measured using an enzyme-linked immunosorbentassay (ELISA). Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of ß-cell function (HOMA-B), Matsuda-index, Insulinogenic-index, Areas Under the Curves for glucose and insulin were calculated. Successively, asprosin variable was dichotomized according to mean value in order to create two ordered classes of values. RESULTS: Fasting asprosin concentration was significantly lower in obese children compared to controls (331.9 ± 120.5 vs 358.1 ± 74.1 pg/ml; p = 0.013). Asprosin was lower in boys than in girls (313.7 ± 59.5 vs 361.1 ± 127.2 pg/ml; p = 0.044), while BMI standard deviation score (SDS) was higher in boys compared to girls (p = 0.024). Asprosin was negatively correlated with BMI (p = 0.024), BMI SDS (p = 0.044) and male sex (p = 0.043) in the entire cohort. No significant differences in asprosin levels were demonstrated between insulin resistant and non-insulin resistant obese children. Logistic regression models documented a significant negative association between BMI SDS and dichotomized asprosin. In particular, higher BMI SDS values were associated to lower asprosin serum levels class. A receiver operating characteristic (ROC) analysis showed existence of the best cut-off for BMI SDS (+2.7 SDS) variable into discriminating patients belonging to two asprosin classes in our cohort. CONCLUSIONS: In conclusion, asprosin serum levels were significantly lower in obese children compared to control. Fasting asprosin decreased with increasing BMI, but it was not significantly affected by IR.

Anthropometric characteristics of newborns with Prader-Willi syndrome.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

Gastrointestinal symptoms in children: Primary care and specialist interface.

AIMS: Gastrointestinal symptoms and diseases represent one of the major reasons for paediatricians' requests for specialist consultations and hospital admissions. One fourth of annual medical consultations for children younger than 6 years can be attributed to gastrointestinal symptoms. High-quality guidelines have been validated worldwide to provide clinical recommendations and support healthcare providers' practice. Nevertheless, overall compliance to standards of care is unsatisfactory, and children with gastrointestinal symptoms frequently undergo expensive, useless specialist consultations and laboratory evaluations. The aim of this study is to review the main epidemiological and clinical aspects, together with management strategies, of the most common gastrointestinal symptoms in children, pointing out pitfalls and practical tips in primary care management, and providing correct indications for specialist consultations. METHODS: For this review, articles published in English from 2000 to January 2018 were identified from the PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) database and selected on the basis of quality, relevance to the illness and importance in illustrating current management pathways. The search used the following keywords: gastrointestinal symptoms, functional gastrointestinal symptoms, children, primary care, specialist consultations and management. Particular emphasis was placed on evidence-based guidelines and high-quality studies. RESULTS: Functional gastrointestinal symptoms have a high impact on the quality of life of children and families and on healthcare costs. A complete medical history and clinical examination are often sufficient to guide the primary care provider in the diagnosis, further workup or referral to a paediatric gastroenterologist. CONCLUSION: Paediatric gastroenterology outpatients' clinics are among the most crowded specialists, and functional gastrointestinal symptoms and disorders are the most frequent reason for counselling. The number of specialist consultations could be reduced if guidelines were applied in primary care settings.

Biological Therapy in Pediatric Inflammatory Bowel Disease: A Systematic Review.

The incidence of inflammatory bowel disease (IBD) has increased steadily worldwide, both in adult and in children; approximately 25% of IBD patients are diagnosed before the age of 18. The natural history of IBD is usually more severe in children than in adults, and can be associated with linear growth impairment, delayed puberty onset, reduced bone mass index, malnutrition, and the need for surgery. Biological therapies, especially blocking tumor necrosis factor-α (TNFα), have radically modified the treatment strategies and disease course of IBD in children. In particular, drugs such as Infliximab and Adalimumab are routinely used in the treatment of pediatric IBD. The role of Infliximab and Adalimumab in the management of pediatric IBD has been recently updated in the Consensus guidelines of ECCO/ESPGHAN. Data regarding short-term and long-term efficacy and safety of these drugs in children, and the effects of "top-down" and "step-up" strategies, are lacking. In this paper, the authors will review current indications, efficacy, and safety of biological therapy in pediatric IBD patients, evaluating all articles published after ECCO/ESPGHAN guidelines publication. The authors carried out a systematic search through MEDLINE through PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) Embase, CINAHL, Cochrane Library, and gray literature, from January 2013 to January 2016. Anti-TNFα has been shown to be effective and safe to maintain remission and to achieve mucosal healing. Multicenter trials based on large sample size cohorts are needed to better clarify long-term efficacy of anti-TNFα and the real incidence of treatment-related complications in pediatric IBD.

Screening for central precocious puberty by single basal Luteinizing Hormone levels.

PURPOSE: To identify cut-off for basal LH levels and for pelvic ultrasound uterine and ovarian parameters indicating an Hypotalamic-Pituitary-Gonadal (HPG) axis activation as diagnostic of Central Precocious Puberty (CPP). METHODS: 248 girls referred for suspected precocious/early puberty who had undergone a GnRH stimulation test were enrolled and divided into three groups: Premature Idiopathic Thelarche (PIT), CPP, and Early Puberty (EA). For every patient basal serum Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH), basal LH/FSH ratio and pelvic ultrasonographic parameters were also collected. Through the use of Receiver Operating Curves (ROCs) the sensitivity (Se) and specificity (Sp) of basal LH, FSH, LH/FSH ratio and ultrasonographic parameters were evaluated at each level and Area Under the Curve (AUC) was measured. RESULTS: Basal LH model ≥0.14 mIU/mL reached the highest predictability (90.6% and 78.2%, Se and Sp, respectively). Basal LH/FSH ratio ≥0.1 showed a sensitivity of 85.90% and a specificity of 78.14%, while basal FSH cut-off (≥2.36 mIU/mL) had the lowest predictability, with a less favourable sensitivity (71%) and specificity (70.5%). Cut-off point for uterine length as 35 mm, (83.5% and 42.9% of Se and Sp, respectively) was calculated. For ovarian volumes, ROC curves showed very low sensitivity and specificity. CONCLUSION: A single basal LH measurement under the cut-off limit may be adequate to exclude an HPG axis activation as CPP.

Fasting and meal-related zonulin serum levels in a large cohort of obese children and adolescents.

Introduction: Zonulin 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. Methods: One 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. Results: Impaired 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. Discussion: Our 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.

Critical illness-related corticosteroid insufficiency (CIRCI) in paediatric patients: a diagnostic and therapeutic challenge.

Critical illness-related corticosteroid insufficiency or CIRCI is characterized by acute and life-threatening disfunction of hypothalamic-pituitary-adrenal (HPA) axis observed among intensive care unit- staying patients.It is associated with increased circulating levels of biological markers of inflammation and coagulation, morbidity, length of ICU stay, and mortality.Several mechanisms are involved in CIRCI pathogenesis: reduced CRH-stimulated ACTH release, peripheral resistance to glucocorticoids, altered cortisol synthesis, impaired cortisol-free fraction and bioavailability.Diagnostic and therapeutic management of this condition in children is still debated, probably because of the lack of agreement among intensive care specialists and endocrinologists regarding diagnostic criteria and prevalence of CIRCI in paediatric age.In the present narrative review, we focused on definition of CIRCI in paediatric age and we advise on how to diagnose and treat this poorly understood condition, based on current literature data.

Early adiposity rebound: predictors and outcomes.

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?

Prevalence of Endocrinopathies in a Cohort of Patients with Rett Syndrome: A Two-Center Observational Study.

Systematic data on endocrinopathies in Rett syndrome (RTT) patients remain limited and inconclusive. The aim of this retrospective observational two-center study was to assess the prevalence of endocrinopathies in a pediatric population of RTT patients. A total of 51 Caucasian patients (47 girls, 4 boys) with a genetically confirmed diagnosis of RTT were enrolled (mean age 9.65 ± 5.9 years). The patients were referred from the Rett Center of two Italian Hospitals for endocrinological evaluation. All the study population underwent clinical and auxological assessments and hormonal workups. MeCP2 mutations were detected in 38 cases (74.5%), CDKL5 deletions in 11 (21.6%), and FOXG1 mutations in 2 (3.9%). Overall, 40 patients were treated with anti-seizure medications. The most frequent endocrinological finding was short stature (47%), followed by menstrual cycle abnormalities (46.2%), weight disorders (45.1%), low bone mineral density (19.6%), hyperprolactinemia (13.7%) and thyroid disorders (9.8%). In the entire study population, endocrinopathies were significantly more frequent in patients with MeCP2 mutations (p = 0.0005), and epilepsy was more frequent in CDKL5 deletions (p = 0.02). In conclusion, our data highlighted that endocrinopathies are not rare in RTT, especially in patients with MeCP2 deletions. Therefore, in the context of a multidisciplinary approach, endocrinological evaluation should be recommended for RTT patients.

Growth Hormone Treatment to Final Height in Turner Syndrome: Systematic Review.

PURPOSE: Turner syndrome (TS) is the most common sex chromosomal abnormality found in female subjects. It is a result of a partial or complete loss of one of the X chromosomes. Short stature is a hallmark of TS. Attainment of adult height (AH) within the normal range for height within the general female population represents the usual long-term goal of growth hormone (GH) treatment. The aim of this systematic review was to understand the efficacy of GH therapy on AH of patients with TS. METHODS: The literature review yielded for analysis 9 articles published from 2010 to 2021. Using the data from this literature search, the goal was to answer 5 questions: (1) What is the efficacy of GH on AH of girls with TS?; (2) Is AH influenced by the age at initiation of GH treatment?; (3) What is the optimal dose of GH to improve AH?; (4) Can the timing of either spontaneous or induced puberty influence AH?; and (5) Can the karyotype influence AH in patients with TS? FINDINGS: GH therapy and adequate dose could enable patients with TS to achieve appropriate AH compared with the possible final height without therapy. The greatest increase in height during GH therapy occurs in the prepubertal years, and if therapy is continued to AH, there is no further increase. Furthermore, karyotype did not show a predictive value on height prognosis and did not affect the outcome of GH administration or the height gain in girls with TS. IMPLICATIONS: Even if GH therapy is safe, close monitoring is indicated and recommended. Further evidence is needed to understand what other parameters may influence AH in patients undergoing GH therapy.

Adrenal Cushing's syndrome: diagnosis and management in a 10-year-old boy with Carney complex.

INTRODUCTION: ACTH-independent Cushing's Syndrome (CS) is very rare condition in children. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of CS, which in most cases occurs in the context of Carney complex (CNC). CNC is an autosomal-dominantly inherited genetic syndrome, usually due to pathogenic variants of the PRKAR1A (regulatory subunit R1A of the protein kinase A) gene. The clinical picture is characterized by spotty skin pigmentation, cardiac, cutaneous and mammary myxomas, melanocytic schwannomas, endocrinopathies and tumours of the endocrine glands (mostly adrenal, pituitary and thyroid). CASE PRESENTATION: A 10-year-old boy first came to our Outpatient clinic due to severe obesity. During the first three months of follow-up the height growth rate was normal, but the response to dietary-behavioural indications was poor in term of weight loss. Later, 10 months after the last evaluation, there was evidence of significant worsening of obesity, growth failure, arterial hypertension and the occurrence of red skin striae at the trunk and root of the limbs. Endocrinological causes of obesity associated with growth failure were investigated. The circadian rhythm of cortisol, ACTH and cortisoluria were suggestive of ACTH-independent hypercortisolaemia. Iatrogenic causes were ruled out. Adrenal ultrasound and computer tomography initially indicated the presence of a nodule or hyperplasia of the medial arm of the left adrenal gland. Conversely, magnetic resonance imaging showed a significant increase in the global dimensions of the adrenals with a bilateral micronodular appearance. Considering the association between ACTH-independent hypercortisolism and PPNAD, a genetic investigation was performed, which found a pathogenic variant of the PRKAR1A gene. Patient started, and well tolerated, therapy with metyrapone during a two-year follow-up. The clinical picture has slightly improved, cortisoluria returned and remains within normal limits, but ACTH suppression persists. CONCLUSION: This is the first report on the clinical and biochemical effects of 2-year medical treatment with metyrapone of PPNAD-related hypercortisolaemia in a paediatric patient with CNC. Currently, there are no established protocols for the management of hypercortisolism in PPNAD and data are scarce especially in the paediatric field. Medical therapies may play a role in reducing the need, at least initially, for bilateral adrenalectomy. However, further studies are needed to clarify this aspect. In cases of CS due to PPNAD in which medical therapy was the initial approach, in the absence of clear clinical, auxological and biochemical improvements, metyrapone may have to be discontinued in favour of another approach, including surgery.

Treating Children and Adolescents with Obesity: Predictors of Early Dropout in Pediatric Weight-Management Programs.

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.

The Prevention of Childhood Obesity Is a Priority: The Preliminary Results of the "EpPOI: Education to Prevent Childhood Obesity" Project.

BACKGROUND: The increase in childhood obesity rates represents a serious public health problem. The project "EpPOI: Education to prevent childhood obesity" is aimed at a multidisciplinary approach to raise awareness of the importance of preventing childhood obesity through lifestyle education. METHODS: Two actions by experts were performed: an intervention with children in schools and a meeting for both parents and school staff. Participants completed a questionnaire structured as a Likert scale. RESULTS: The sample size was 96 people, and awareness of the childhood obesity problem as well as the need for obesity prevention was high among respondents. We also found great interest among participants in having more information on pediatric nutrition and physical activity, with a positive correlation with age. Furthermore, the multivariate regression model configured interest in having more information on nutrition and physical activity as an independent and statistically significant predictor of awareness of childhood obesity as a current issue. CONCLUSIONS: The results highlight the need to act on childhood obesity through lifestyle prevention strategies early in life.