Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

The developmental trajectories of the behavioral phenotype and neuropsychiatric functioning in Cornelia de Lange and Rubinstein Taybi syndromes: A longitudinal study.

Several changes in the behavioral phenotype arise with the growth of children affected by Cornelia de Lange Syndrome (CdLS) and Rubinstein-Taybi Syndrome (RSTS). However, previous research relied on a cross-sectional study design turning into age-related comparisons of different syndromic cohorts to explore age-dependent changes. We aim to outline the variating pathways of the neuropsychiatric functioning across the lifespan in CdLS and RSTS, through the setting up of a longitudinal study design. The sample included 14 patients with CdLS and 15 with RSTS. The assessments were carried out in two different timepoints. Our findings highlight that the cognitive profile of CdLS is subjected to a worsening trend with decreasing Intellectual Quotient (IQ) scores from T0 to T1, whereas RSTS shows a stable IQ over time. Patients affected by RSTS show greater improvements compared to CdLS in communication, daily living skills, social abilities, and motor skills across the lifespan. Both syndromes report an upward trend in behavioral and emotional difficulties even if CdLS exhibit a significant and major deterioration compared to individuals with RSTS. Being aware of the early dysfunctional patterns which might pave the way for later neuropsychiatric impairments is the first step for planning preventive interventions.

Effect of a parenting intervention on decreasing adolescents' behavioral problems via reduction in attachment insecurity: A longitudinal, multicenter, randomized controlled trial.

INTRODUCTION: Secure attachment in adolescence, related to caregiving quality, is a robust predictor of positive behavioral adjustment in early adulthood and beyond. Nevertheless, few attempts have been made to develop treatments to promote parent-adolescent attachment security. METHODS: Using a longitudinal, multicenter, randomized controlled trial design, two questionnaire-based studies were run in Italy (Study 1: n = 100 mothers of adolescents, 60% boys, Mage = 14.89, SD = 1.58; Study 2: n = 40 mothers and 40 adolescents, 60% boys, Mage = 14.90, SD = 1.91) to test the effectiveness of an attachment-based parenting intervention (i.e., Connect) in reducing adolescents' behavioral problems and attachment insecurity 2 weeks post-intervention (t2) and at a 4-month follow-up (t3). It was further investigated whether a decrease in avoidant and anxious attachment at t2 would account for changes in externalizing and internalizing problems, respectively, at t3. All adolescents belonged to two-parent intact families. RESULTS: Mothers who completed Connect reported significantly fewer adolescent behavioral problems and lower adolescent attachment insecurity, compared to mothers in the waitlist group, at both t2 and t3 (Study 1). These findings were confirmed in a second subsample (Study 2), considering both mothers' and adolescents' reports. Controlling for pre-intervention behavioral problems, reductions in internalizing and externalizing problems were observed in both studies at t3 via a decrease in anxious and avoidant attachment, respectively, at t2. CONCLUSIONS: The findings point to the malleability of attachment security in adolescence and highlight the importance of targeting parenting quality to promote adolescent behavioral adjustment.

Rubinstein-Taybi syndrome: New neuroradiological and neuropsychiatric insights from a multidisciplinary approach.

Rubinstein-Taybi syndrome is a rare, autosomal dominant, plurimalformative disorder that is clinically characterized by intellectual disability and a wide spectrum of congenital anomalies; facial dysmorphisms are typical, and broad thumbs and great toes are particularly distinctive. Its genetic basis is only partially known, with a detection rate of approximately 65-70%; specifically, microdeletions or mutations in the CREBBP or EP300 genes can be found. Much is known about its clinical features and health-care protocols, but some areas of clinical knowledge are currently unsolved. In particular, few efforts have been made until now to understand the variability in the neuropsychological and neurobehavioral profile and to deepen knowledge of the neuroradiological malformative pattern. Consequently, little is known about the possible genotype-phenotype correlations of these issues. Here, we report clinical and genetic data from a cohort of 23 RSTS Italian patients. The most common features in brain magnetic resonance imaging (MRI) were dysmorphic aspects of the corpus callosum (73.6%) with or without minor dysmorphisms of cerebellar vermis, periventricular posterior white matter hyperintensity, and other less common anomalies. The most interesting feature on the whole spine MRI scans was the tendency for a low-lying conus medullaris without terminal filum thickening. These data will help to improve neuropsychiatric and neuroradiological knowledge and highlight specific genotype-phenotype correlations.

Communication, cognitive development and behavior in children with Cornelia de Lange Syndrome (CdLS): preliminary results.

In this study, we present preliminary data on cognitive, behavioral and communication domains of individuals with Cornelia de Lange Syndrome (CdLS), collected through a specific protocol combining direct and indirect tools. Seventeen subjects with CdLS were assessed, 2.5- to 13.4-year-old. Cognitive level of the subjects differed from what previously described in literature, showing more patients with normal or borderline cognitive abilities. We found a relation between severe autistic behavior and comprehension impairments: all children with high CARS score have severe receptive language disability. A correlation was also found between CARS score and ID: high CARS score occurred only in patients with profound levels of ID. Results of this study support the need for a specific assessment protocol tailored for the characteristics of subjects with multiple disabilities, to be able to identify their strengths avoiding the avalanche effect of weaknesses. Most tests on neuropsychological functions have been developed and standardized for typically developing children, and require the integrity of other functions aside the one that is evaluated, determining an underestimation of the level of functioning. This study could be a starting point to develop new models applicable to other genetic syndromes and complex situations; new and wider studies are needed in order to allow a more complete and accurate assessment, thereby ensuring more efficient and family-centered treatment plans.

CRISIS AFAR: an international collaborative study of the impact of the COVID-19 pandemic on mental health and service access in youth with autism and neurodevelopmental conditions.

BACKGROUND: Heterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services. METHODS: Using a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups. RESULTS: Clustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup. LIMITATIONS: Notable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic. CONCLUSIONS: Concomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

Age-related hallmarks of psychopathology in Cornelia de Lange and Rubinstein-Taybi syndromes.

BACKGROUND AND AIM: There is mounting evidence highlighting that Cornelia de Lange Syndrome (CdLS) and Rubinstein-Taybi Syndrome's (RSTS) behavioral phenotypes are not stable over individual developmental trajectories and that several psychiatric disorders might arise with age. Our study aims to examine the specific hallmarks of psychopathology and behavioral phenotypes in four different age ranges: infancy and toddlerhood, early childhood, middle childhood, and adolescence, in both genetic syndromes. METHOD: The sample included 44 patients with CdLS (48% boys, age = 6.67 ± 4.36) and 31 with RSTS (48% boys, age = 6.89 ± 4.58) recruited through follow-ups. Cognitive, behavioral, and autism assessments were carried out with Griffith's scales or the Leiter-R, the Child Behavior Checklist, and the Child Autism Rating Scales 2. Multiple ANOVA 2 × 4 were run to outline behavioral phenotypic age-related syndromic markers and ANCOVA to value the weight of IQ and ASD-related traits on the psychopathological outcome. RESULTS: Findings showed that anxiety is a crucial phenotypic hallmark, independent of IQ but associated with autistic traits, that increases from infancy to adolescence in both CdLS and RSTS. CONCLUSION AND IMPLICATIONS: Being aware of the developmental challenges that growing children are called to face is essential for drawing up proper standards of assessment turning into target age-related interventions, ensuring these patients personalized healthcare and improvement in life quality.

Salivary microRNA profiling dysregulation in autism spectrum disorder: A pilot study.

Introduction: Autism spectrum disorders (ASD) are the most prevalent neurobiological disorders in children. The etiology comprises genetic, epigenetic, and environmental factors such as dysfunction of the immune system. Epigenetic mechanisms are mainly represented by DNA methylation, histone modifications, and microRNAs (miRNA). The major explored epigenetic mechanism is mediated by miRNAs which target genes known to be involved in ASD pathogenesis. Salivary poly-omic RNA measurements have been associated with ASD and are helpful to differentiate ASD endophenotypes. This study aims to comprehensively examine miRNA expression in children with ASD and to reveal potential biomarkers and possible disease mechanisms so that they can be used to improve faction between individuals by promoting more personalized therapeutic approaches. Materials and methods: Saliva samples were collected from 10 subjects: 5 samples of children with ASD and 5 from healthy controls. miRNAs were analyzed using an Illumina Next-Generation-Sequencing (NGS) system. Results: Preliminary data highlighted the presence of 365 differentially expressed miRNAs. Pathway analysis, molecular function, biological processes, and target genes of 41 dysregulated miRNAs were assessed, of which 20 were upregulated, and 21 were downregulated in children with ASD compared to healthy controls. Conclusion: The results of this study represent preliminary but promising data, as the identified miRNA pathways could represent useful biomarkers for the early non-invasive diagnosis of ASD.

A Pilot COVID-19 Surveillance Program at the Zendrini Center in Milan (Italy) for Unaccompanied Foreign Minors.

During the COVID-19 pandemic, not only crowded refugee camps and immigration detention centers, but also receptions were places in which outbreaks occurred. To date there has been no report of the application of a COVID-19 surveillance system in reception centers for unaccompanied foreign minors only, who most of all deserve the utmost attention. Aware of this critical issue, we implemented a pilot COVID-19 surveillance program at the Zendrini center in Milan. It was started in September 2021 and was carried out for 4 months. Nasopharyngeal antigenic swabs were adopted. One day a week, two forensic physicians performed the first antigenic swab to minors who had just entered the center, or a monitoring swab after 15 days to those who were still hosted at the center. Operators were also swabbed for surveillance. A total of 80 subjects were enrolled and divided into 68 (72.5%) unaccompanied foreign minors and 22 (27.5%) operators. A total of 178 antigenic nasopharyngeal swabs were performed and tested negative. Regarding the monitoring activities, it was found that the minimum number of swabs per subject was 1 and the maximum number was 7, with an average value of 2.2 per individual. Having been able to confirm the absence of SARS-CoV-2 within the community represented a way to protect individual and collective health that could not have been pursued otherwise. Only inclusive approaches can allow communities and societies to respond more effectively to this crisis, and reduce the risk of future ones, intended as both upcoming COVID-19 waves and new infectious diseases.

Point of view of the Italians pediatric scientific societies about the pediatric care during the COVID-19 lockdown: what has changed and future prospects for restarting.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is currently rare in children and they seem to have a milder disease course and better prognosis than adults. However, SARS-Cov-2 pandemic has indirectly caused problems in pediatric medical assistance. In view of this we wanted to draw a picture of what happened during health emergency and analyze future prospects for restarting. METHODS: We involved the Italian pediatric scientific societies institutionally collected in the Italian Federation of Associations and Scientific Societies of the Pediatric Area (FIARPED); We sent a questionnaire to all scientific societies about the pediatric care activity during the COVID-19 emergency and future perspectives for the phase of post-containment. RESULTS: The analysis of the questionnaires showed significant decrease of:admission, outpatient visits and specialist consultancy activities during the COVID-19 emergency, primarily linked to the fear of infection. Instead it was increased the serious degree of diseases admitted. Most of scientific societies maintained the relationship with chronic patients through some form of telemedicine, reporting a strong positive opinion about this modality. Finally showed the need to give life a new approach for hospitalizations and outpatient visits through a greater use of telemedicine, educational programs on families and a more decisive role of family pediatricians. CONCLUSIONS: Our study highlighted many aspects that can be improved in pediatric care. We think that It will be necessary a new shared strategy to improve the management and continuity of care for pediatric patients, primarily developing a network of collaboration between families, family pediatrician and hospitals and by enhancing the use of new methods of telecommunications.

A Regional ADHD Center-Based Network Project for the Diagnosis and Treatment of Children and Adolescents With ADHD.

OBJECTIVE: We aimed to define the sociodemographic, clinical, and prescription profiles of the participants enrolled in the Italian Lombardy ADHD Register. METHOD: Data on patients evaluated by the 18 regional ADHD reference centers in the 2012 to 2013 period were analyzed. RESULTS: Seven hundred fifty-three of 1,150 (65%) suspected patients received a diagnosis of ADHD. In 24% of cases, there was a family history of ADHD. Four hundred eighty-three (64%) patients had at least one psychopathological disorder, the more common of which were learning disorders (35%). Eighty-four percent of patients received a prescription for psychoeducational interventions, 2% received only pharmacological treatment, and 14% a combination of both. Compared with patients treated with psychoeducational intervention alone, patients with drug prescriptions more commonly presented values of Clinical Global Impressions - Severity scale (CGI-S) of 5 or higher ( p < .0001). CONCLUSION: A continuous and systematic monitoring of patterns of care is essential in promoting significant improvements in clinical practice and ensuring an efficient and homogeneous quality of care.

Secondary school teachers and mental health competence: Italy-United Kingdom comparison.

AIM: The aim of this study was to evaluate the differences between teachers' knowledge about early psychosis among three different Italian cities and a UK sample. METHODS: The sample consisted of 556 secondary school teachers from three different cities in Italy (Milan, Rome and Lamezia Terme) and London (UK). The research was based on the Knowledge and Experience of Social Emotional Difficulties Among Young People Questionnaire. The Italian version of the questionnaire was used in Italy. RESULTS: Overall, 67.6% of English teachers, 58.5% of Milan's teachers, 41.8% of Rome's teachers and 33.3% of Lamezia Terme's teachers were able to recognize psychotic symptoms from a case vignette. Logistic regression analysis showed that 'city' was the only independent variable significantly related to the correct/wrong answer about diagnosis. CONCLUSIONS: We found statistically significant differences between the three Italian samples and the UK sample regarding teachers' knowledge about first signs of psychosis. English teachers showed a better knowledge than Italian teachers in general. Teachers from Milan, where a specific early detection program was established in 2000, seemed to be more familiar with early signs of psychosis than teachers in the other two Italian towns.

Interleukin-18 and CD30 serum levels in patients with moderate-severe depression.

Interleukin-18 (IL-18), a pro-inflammatory cytokine that plays an important role in the T-cell-helper type 1 response, is a new member of the family of cytokines produced in the brain. CD30 is a marker of T-cell-helper type 2 lymphocytes. We evaluated IL-18 and CD30 serum levels in 10 patients affected by moderate-severe depression (MSD). We demonstrated for the first time that serum IL-18 levels of MSD patients were significantly higher than those of healthy donors. On the contrary, no significant difference was found between serum CD30 levels of MSD patients compared with those of healthy donors. These data strengthen the hypothesis that MSD disease is associated with an inflammatory response, mainly T-cell-helper type 1, and suggest an important role for IL-18 in the pathophysiology of MSD.