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Abstract Context Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. Objective To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. Patients and Methods Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. Results The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was −0.70 ± 1.20 standard deviation score. Conclusions We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.

The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.

Testicular adrenal rest tumors (TARTs) are a common complication in male patients with congenital adrenal hyperplasia (CAH). The aim of our cross-sectional cohort study is to estimate the frequency of TARTs with the correlation of genotype and disease control on tumor development. Thirty-five male patients, aged 14–26 years, were included in the study, all followed by the same center of pediatric endocrinology in Bologna. We studied genotypes, hormonal profiles at different time intervals and testicular ultrasound. A logistic regression model with multivariant analysis was developed for the statistical analysis. TARTs were detected in 31.4% of the cases, 90.9% of them had a classic form with salt wasting, while 9.1% had a non-classic form. Additionally, a significant correlation between the incidence of TARTs and severity of genotype was detected. Patients with TARTs had markedly worse metabolic control on average (p = 0.027), reflected by high ACTH, 17OH progesterone, and overall delta4-androstenedione. In conclusion, a screening tool is mandatory, especially (but not exclusively) in patients with the most severe forms of CAH and poor endocrine control of the disease.

There is no agreed-upon definition for severe obesity (Sev-OB) in children. We compared estimates of Sev-OB as defined by different cut-points of body mass index (BMI) from the Centers for Disease Control and Prevention (CDC) or the World Health Organization (WHO) curves and the ability of each set of cut-points to screen for the presence of cardiometabolic risk factors. Cross-sectional, multicenter study involving 3,340 overweight/obese young subjects. Sev-OB was defined as BMI ≥ 99(th) percentile or ≥ 1.2 times the 95(th) percentile of the CDC or the WHO curves. High blood pressure, hypertriglyceridemia, low High Density Lipoprotein -cholesterol and impaired fasting glucose were considered as cardiometabolic risk factors. The estimated prevalence of Sev-OB varied widely between the two reference systems. Either using the cut-point ≥ 99(th) percentile or ≥ 1.2 times the 95(th) percentile, less children were defined as Sev-OB by CDC than WHO (46.8 vs. 89.5%, and 63.3 vs. 80.4%, respectively p<0.001). The CDC 99(th) percentile had lower sensitivity (58.5 vs 94.2), higher specificity (57.6 vs 12.3) and higher positive predictive value (34.4 vs 28.9) than WHO in identifying obese children with ≥ 2 cardiometabolic risk factors. These differences were mitigated using the 1.2 times the 95(th) percentile (sensitivity 73.9 vs. 88.1; specificity 40.7 vs. 22.5; positive predictive value 32.1 vs. 30.1). Substantial agreement between growth curves was found using the 1.2 times the 95(th) percentile, in particular in children ≤ 10 years. Estimates of Sev-OB and cardiometabolic risk as defined by different cut-points of BMI are influenced from the reference systems used. The 1.2 times the 95(th) percentile of BMI of either CDC or WHO standard has a discriminatory advantage over the 99(th) percentile for identifying severely obese children at increased cardiometabolic risk, particularly under 10 years of age.

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed.

La Convenzione di Palermo contro la criminalità organizzata transnazionale, cui oggi aderiscono 190 Stati su 193 membri dell'ONU, appare – a distanza di venti anni dalla sua adozione, avvenuta nel 2000 – sempre più come un formidabile strumento progettato guardando al futuro. Valorizzando la visione anticipatrice di Giovanni Falcone, che aveva compreso fino in fondo la dimensione economica delle mafie, la loro incessante evoluzione strutturale, la loro capacità di sfruttare il lato oscuro della globalizzazione, la Convenzione di Palermo rende possibile uno straordinario salto di qualità sia dal punto di vista operativo, sia dal punto di vista simbolico, concorrendo allo sviluppo di quella cultura della cooperazione che rappresenta una delle più importanti linee-guida dell'attività delle Nazioni Unite. Per far trarre al nostro Paese il massimo vantaggio dalle opportunità offerte dalla recente introduzione del Meccanismo di Revisione della Convenzione, è indispensabile avviare un'attività di analisi e riflessione, una sorta di bilancio su quelli che sono stati gli obiettivi raggiunti e gli strumenti rivelatisi efficaci e, al tempo stesso, sui profili che hanno generato maggiori criticità e ritardi. In questa prospettiva, il volume analizza tutte le disposizioni e gli istituti della Convenzione, illustrandone le potenzialità applicative nella prassi giudiziaria e investigativa anche alla luce dell'esperienza degli altri Stati, e fornendo una serie di indicazioni utili per sviluppare una risposta efficace contro il nuovo volto dei più pericolosi fenomeni criminali attraverso l'impiego a livello internazionale delle tecniche di indagine più moderne, come le operazioni sotto copertura, la sorveglianza elettronica, il captatore informatico. [Testo dell'editore]

Aims. To measure the friction force generated during sliding mechanics with conventional, self-ligating (Damon 3 mx, Smart Clip, and Time 3) and low-friction (Synergy) brackets using different archwire diameters and ligating systems in the presence of apical and buccal malalignments of the canine. Methods. An experimental setup reproducing the right buccal segment of the maxillary arch was designed to measure the friction force generated at the bracket/wire and wire/ligature interfaces of different brackets. A complete factorial plan was drawn up and a three-way analysis of variance (ANOVA) was carried out to investigate whether the following factors affect the values of friction force: (i) degree of malalignment, (ii) diameter of the orthodontic wire, and (iii) bracket/ligature combination. Tukey post hoc test was also conducted to evaluate any statistically significant differences between the bracket/ligature combinations analyzed. Results. ANOVA showed that all the above factors affect the friction force values. The friction force released during sliding mechanics with conventional brackets is about 5-6times higher than that released with the other investigated brackets. A quasilinear increase of the frictional forces was observed for increasing amounts of apical and buccal malalignments. Conclusion. The Synergy bracket with silicone ligature placed around the inner tie-wings appears to yield the best performance.

Study Objectives: To evaluate the effect of type 1 narcolepsy (NT1) on anthropometric and endocrine features in childhood/adolescence, focusing on patterns and correlates of weight, pubertal development, and growth in treated and untreated patients. Methods: We collected anthropometric (height, weight, body mass index (BMI) z-scores), pubertal, metabolic, and endocrine data from 72 NT1 patients at diagnosis and all available premorbid anthropometric parameters of patients from their pediatric files (n = 30). New measurements at 1-y reassessment in patients undergoing different treatments were compared with baseline data. Results: We detected a high prevalence of overweight (29.2%), obesity (25%), metabolic syndrome (18.8%), and precocious puberty (16.1%), but no signs of linear growth alterations at diagnosis. According to anthropometric records, weight gain started soon after NT1 onset. At 1-y follow-up reassessment, sodium oxybate treatment was associated with a significant BMI z-score reduction (−1.29 ± 0.30, p < 0.0005) after adjusting for baseline age, sex, sleepiness, and BMI. Conclusions: NT1 onset in children/adolescents is associated with rapid weight gain up to overweight/obesity and precocious puberty without affecting growth. In our study, sodium oxybate treatment resulted in a significant weight reduction in NT1 overweight/obese patients at 1-y follow-up. Citation: Ponziani V, Gennari M, Pizza F, Balsamo A, Bernardi F, Plazzi G. Growing up with type 1 narcolepsy: its anthropometric and endocrine features. J Clin Sleep Med 2016;12(12):1649–1657.

Differences of sex development are conditions with discrepancies between chromosomal, gonadal and phenotypic sex. In congenital hypogonadotropic hypogonadism, a lack of gonadotropin activity results primarily in the absence of pubertal development with prenatal sex development being (almost) unaffected in most patients. To expedite progress in the care of people affected by differences of sex development and congenital hypogonadotropic hypogonadism, the European Union has funded a number of scientific networks. Two Actions of the Cooperation of Science and Technology (COST) programmes — DSDnet (BM1303) and GnRH Network (BM1105) — provided the framework for ground-breaking research and allowed the development of position papers on diagnostic procedures and special laboratory analyses as well as clinical management. Both Actions developed educational programmes to increase expertise and promote interest in this area of science and medicine. In this Perspective article, we discuss the success of the COST Actions DSDnet and GnRH Network and the European Reference Network for Rare Endocrine Conditions (Endo–ERN), and provide recommendations for future research.

Background Melanocortin-4-receptor (MC4R) mutations represent the most frequent genetic cause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show a particular phenotype characterized by early onset, severe obesity and high stature. To verify whether MC4R mutations are associated with this particular phenotype in the Italian pediatric population, we decided to screen the MC4R gene in a group of obese children selected on the basis of their phenotype. Methods To perform this study, a multicentric approach was designed. Particularly, to be enrolled in the study subjects needed to meet the following criteria: Body mass index ≥ 3 deviation scores according to age and sex, familiar history of obesity (at least one parent obese), obesity onset before the 10 years old, height ≥ 2 deviation scores. The coding region of MC4R gene was screened in 240 obese children (mean age 8.3 ± 3.1, mean BMI 30.8 ± 5.4) and in 200 controls (mean age 8.1 ± 2.8; mean BMI 14.2 ± 2.5). Results Three mutations have been found in five obese children. The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously. The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showed that only Q307X impaired protein function. Conclusion The low prevalence of MC4R mutations (1.6%) in this group of obese children selected according to the obesity degree, the tall stature and the family history of obesity was similar to the prevalence observed in previous screenings performed in obese adults and in not phenotypically selected obese children.