BACKGROUND:Down syndrome (DS) is a major cause of genetically defined intellectual disability, characterised by low IQ and cognitive deficits. Among the neurobiological causes of these deficits, disruptions in gamma-aminobutyric acid (GABA)ergic signalling in the hippocampus and an excitation/inhibition imbalance are thought to impair learning and memory. Evidence suggests that GABAA receptor-mediated signalling in DS is significantly depolarising and potentially excitatory rather than predominantly hyperpolarising and inhibitory, and is accompanied by increased hippocampal expression of the cation-chloride cotransporter NKCC1. The treatment with the NKCC1 inhibitor bumetanide restored GABAergic signals, synaptic plasticity, hippocampus-dependent memory and sleep quality in adult DS mice. We hypothesise that the use of bumetanide, by re-establishing GABAergic signals, may improve memory, learning and psychological characteristics in children and adolescents with DS. METHODS AND ANALYSIS:The present study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy of a 3-month treatment with the drug bumetanide (0.02 mg/kg two times per day or placebo) on memory and psychological functioning in children and adolescents with DS. We also aim to identify possible predictors and biological and genetic markers related to treatment.The target recruitment is 64 children and adolescents with DS (aged 10-17 years). Seven visits are scheduled for each participant, during which outcome and safety measures are assessed through various clinical and instrumental investigations.Outcome measures include neuropsychological and psychological assessments, as well as biomarkers. Neuropsychological measures consist of tests evaluating cognitive level, memory and executive functions. Psychological measures include parent-reported questionnaires on psychopathological and behavioural symptoms, quality of life, sleep and adaptive functioning. Biomarkers encompass electroencephalogram (EEG) and genomic, transcriptomic, proteomic and metabolomic evaluations from blood and urine samples.Safety measures include physical, nephrological, cardiological and audiometric evaluations, as well as blood and urine analysis, EEG, ECG and a pregnancy test (if applicable). Neuropsychological, psychological, biomarker and safety measures are collected at baseline (visit 1 (V1)), at the end of treatment (V6) and during follow-up (V7), which is scheduled for 2 months after the end of treatment. Interim psychological and safety assessments are conducted at 1 week (V2), 2 weeks (V3), 1 month (V4) and 2 months (V5) after the start of treatment. We expect bumetanide treatment to improve visual long-term memory skills (primary outcome). Additionally, we expect improvements in total scores and subdomain scores across other visual, verbal and spatial long-term memory tasks, as well as executive functions, psychopathological measures, adaptive functioning, sleep quality and quality of life scores (secondary outcomes). Furthermore, we expect potential differences in genomic, transcriptomic, proteomic and metabolomic profiles between patients who respond to therapy and those who do not. ETHICS AND DISSEMINATION:Ethical approval for this study was granted by the Bambino Gesù Children's Hospital Ethics Committee (process number 1042_OPBG_2016) and the Italian Medicines Agency. Substantial Amendment No 5 (ES5) was approved on 20 September 2023 by the Italian National Paediatric Ethics Committee and involved a revision and integration of the study protocol, now updated to version 8.1, in line with the recommendations of the Data Safety Monitoring Board.This study is being conducted in accordance with the Declaration of Helsinki. The present study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines and was prepared using the SPIRIT 2025 Checklist. In accordance with Good Clinical Practice, written informed consent is obtained from all participants' parents or caregivers, and assent is obtained from participants when possible. The main features of the study will be presented at both international and national conferences, during scientific meetings, in presentations to families and on social media using documentation approved by competent authorities. TRIAL REGISTRATION:The study was prospectively registered in the EudraCT portal on 16 August 2016, prior to the enrolment of the first participant on 11 January 2023 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-005780-16/IT). In accordance with Regulation (EU) 536/2014 for pharmacological interventional trials, the study was subsequently transitioned to the Clinical Trials Information System (EU CT No 2024-519342-71-00), with the initial record entered on 23 December 2024, and the transition authorised on 3 February 2025 (https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-519342-71-00). TRIAL REGISTRATION NUMBER:EudraCT 2015-005780-16.

Early identification of children at risk for Intellectual Disability (ID) is complex, as formal diagnoses are often deferred until school age. However, early signs may emerge during the preschool years. This study aims to examine longitudinal changes in cognitive, adaptive and emotional-behavioral functioning from preschool to school age, to identify early markers predictive of later ID. Eighty-eight children were assessed at two time points: preschool age (T0) and school age (T1). At T0, children were categorized into three diagnostic groups: Global Developmental Delay (GDD), Mixed Specific Developmental Disorder (MSDD), and Language Disorder (LD). At T1, the same children were re-evaluated and classified into: Intellectual Disability (ID), Language Disorder (LD), and Other Diagnoses (OD). Assessments included clinical observations, cognitive evaluations, and parent-reported questionnaires and interviews. Analyses were performed separately at T0, T1, and longitudinally. At T0, all groups showed impaired adaptive functioning but differed in cognitive abilities, with the GDD group displaying more pronounced delays. At T1, only the ID group maintained significant deficits in both adaptive and cognitive domains. Regarding emotional-behavioral functioning, children with GDD exhibited more attention problems at T0. At T1, the ID group showed increased internalizing and externalizing symptoms, whereas LD and OD groups did not present significant psychopathological issues. A substantial rise in ID diagnoses was also observed at school age. Monitoring developmental trajectories from an early age is essential to detect risk markers of ID. Early identification can support timely, targeted interventions for children and their families, improving long-term outcomes.

Background/Objectives: this paper investigates the local vs. global visual processing preference in typically developing (TD) children, youth with Down syndrome (DS), and youth with Williams syndrome (WS). In particular, the global precedence effect (GPE) and the global interference effect (GI) have recently been described as two distinct and at least partially independent effects. Methods: in this study, 50 participants (TD = 25, DS = 13, WS = 12) completed two experiments requiring the identification of either the global or local level of hierarchical stimuli, which consisted of letters and schematic faces. For each stimulus type, two separate blocks were conducted, one with the task to focus on the local elements and the other with the task to focus on the global shape. Results: our results indicate that TD children demonstrate a global precedence effect for letters but not for schematic faces, suggesting a developmental modulation of configural processing. In contrast, both DS and WS groups showed a global processing bias for schematic faces and a significant global interference effect in both conditions, likely reflecting deficits in inhibitory control. Conclusions: these findings challenge the notion that DS and WS individuals can be classified strictly as global or local processors, respectively, emphasizing the influence of stimulus type and cognitive demands. Implications for neurodevelopmental research and clinical interventions are discussed.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl−/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms.

Introduction22q11.2 deletion syndrome (22q11.2DS), also known as velo-cardiofacial syndrome or DiGeorge syndrome (DGS) is highly variable in phenotype, encompassing a wide range of physical and neuropsychiatric manifestations (ID, ADHD, ASD, anxiety, major depressive disorder,obsessive-compulsive disorder, schizophrenia). In this retrospective study, we aimed to assess the clinical significance of sleep disturbances and their relationship with functional impairment in a cohort of 52 children and adolescents with 22q11.2DS, as well as psychological distress in their parents. Standardized measures, including the Sleep Disturbance Scale for Children (SDSC) and the Parenting Stress Index-Short Form (PSI-SF), were administered to parents.MethodsThe sample consisted of 26 males and 26 females, aged 5 to 18 years. Participants were referred to the Day Hospital follow up of Child and Adolescent Neuropsychiatry Unit in the Bambino Gesù Children’s Hospital in Rome, Italy, between January 2023 and December 2023. The total cohort was divided into two main groups based on the presence of sleep problems: (1) Group 1, with sleep problems, and (2) Group 2, without sleep problems. Both groups demonstrated low mean IQ scores and low general adaptive functioning, as measured by the Wechsler Intelligence Scale for Children (WISC-IV) and the ABAS II General Adaptive Composite (GAC), respectively. Furthermore, Group 1 exhibited significantly lower functioning when assessed using the CGAS. Additionally, Group 1 reported higher levels of self-reported anxiety symptoms (MASC-2) compared to Group 2. While none of the results reached the clinical range, scores in Group 1 were generally higher, particularly on the “Performance Fears” subscale. A similar trend was observed in the “Negative Self-Esteem” subtest of the CDI 2 (self-report form). Although the average questionnaire scores did not fall within the clinical range, KSADS psychiatric diagnoses revealed the presence of various psychiatric disorders. Unexpectedly, these disorders were more prevalent in the group without sleep problems, except for anxiety disorders, which showed similar prevalence across both groups. Regarding parental stress, as measured by the PSI-SF, we did not observe a significant relationship between sleep disorders and parental stress, on the contrary to our expectations.Results and discussionOur study is one of the few to specifically investigate sleep problems in the pediatric population with 22q11.2DS and the first to use the Sleep Disturbance Scale for Children (SDSC) to assess various aspects of sleep disorders in this group. Further studies are required to draw more consistent conclusions.

CONTEXT:Monocarboxylate transporter (MCT) 8 facilitates thyroid hormone (TH) transport across the blood-brain barrier. Pathogenic variants in SLC16A2 cause MCT8 deficiency (Allan-Herndon-Dudley syndrome), characterized by intellectual and motor disability and abnormal thyroid function tests. MCT8 deficiency typically affects males due to its X-linked inheritance. OBJECTIVE:Here, we report 8 female patients with heterozygous pathogenic variants in SLC16A2 who presented with variable neurocognitive impairment, behavioral problems, and TH function abnormalities. METHODS:We performed X-chromosome inactivation studies in female patients in whom heterozygous pathogenic variants in SLC16A2 were identified. The effect of SLC16A2 variants on TH transport was assessed in transfected cells and patient-derived fibroblasts. RESULTS:In all patients (mean age 8.6 years; range, 2.3-25 years) routine care genetic analyses identified heterozygous variants in SLC16A2 (p.(R445C), p.(N193I), p.(G276R), t(X;20), resulting in a breakpoint in intron 1, t(X;19), resulting in a breakpoint in SLC16A2, p.(I562Sfs566*), p.(G221R)). All missense variants showed substantially reduced MCT8-mediated TH uptake in transiently transfected cells. X-chromosome inactivation studies in patient cells showed skewed X-inactivation in all 7 evaluated individuals. In 5 out of 7 evaluated cases, MCT8-mediated 3,5,3'-triiodothyronine (T3) uptake in patient-derived fibroblasts was impaired to a similar degree as in fibroblasts derived from male patients with MCT8 deficiency. CONCLUSION:Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation may present with variable neuro(psycho)logical, behavioral, and thyroid function test abnormalities. Female patients presenting with neurocognitive impairment and abnormal TH function tests (low free thyroxine and/or high total T3 concentrations) should be tested for genetic variants in SLC16A2.

Background/Objectives: Malan syndrome (MALNS) is an ultra-rare genetic disorder caused by aberrations in the NFIX gene, located at chromosome 19p13.2. Key features of MALNS include general overgrowth, a typical facial gestalt, muscle–skeletal abnormalities, speech difficulties and intellectual disability. Additionally, MALNS frequently presents with autism-like behaviour and social challenges. However, characterisation of the cognitive profile of MALNS, including social perception skills, is limited. Methods: Six children and adolescents with MALNS, whose clinical and emotional–behavioural features had been described in previous studies, were assessed by means of a single, co-normed neuropsychological battery covering multiple cognitive domains. Results: Consistent with their intellectual disability, performance was generally weak across all neuropsychological subtests. Nonetheless, memory for faces, visual attention and contextual (non-verbal) theory of mind emerged as relative strengths of the profile, both at group and individual levels. Conversely, tasks requiring verbal reasoning and language comprehension, such as comprehension of instructions and verbal theory of mind, represented weaknesses for all participants. Conclusions: These findings provide a further characterisation of cognitive and social functioning in MALNS, which can inform future research as well as clinical practice and rehabilitation

It has long been reported that neuropsychological deficits may be present in dystrophinopathies, specifically non-progressive cognitive impairment and a global deficit in executive functions; this neurocognitive profile has been less explored in patients with Becker than Duchenne muscular dystrophy (BMD/DMD). We conducted a longitudinal study to explore the evolution of neuropsychological and behavioural profile in a cohort of paediatric BMD. Seventeen patients with BMD without intellectual disability were assessed using a full battery of tests, including intellectual, adaptive and executive functioning, language and behavioral features. Tests were performed at baseline and after 12 months. The results showed adequate cognitive and adaptive profile with falls in Working Memory, as well as lower scores in executive functions. An improvement was observed in Processing Speed. Behavioral questionnaires confirmed a negative trend, while in normal ranges. We found a statistically significant difference between T0 and T1 in some items exploring executive functions. No statistically significant difference was observed stratifying patients by mutation site or IQ level. In conclusion, our study suggests that BMD patients have a stable neurocognitive profile, while a deflection in the executive functions may be observed. We recommend a careful monitoring to intercept learning disabilities and promptly start a multimodal rehabilitation.

Medical professionals frequently underestimate stress level of parents/caregivers of patients with rare disorders as RASopathies, the latter might experience elevated stress levels, with their own health frequently overlooked despite significant responsibilities and hurdles encountered. The aim of this study is to assess the stress experienced by parents of individuals with Noonan syndrome and related conditions. Forty-eight parents (20 fathers; 28 mothers), among the 31 recruited families, completed the Italian version of the Parenting Stress Index-Short Form. Our study shows abnormally elevated scores (≥ 85° percentile) in 35.4% of parents. Data retrieved from subscales reveal a perception of a difficult child in 25% of cases, a dysfunctional parental-child interaction in 20.8%, a general parental distress in 10.4% of cases, and an elevated overall stress in 18.8% of parents. Questionnaires as the Parenting Stress Index-Short Form are valuable tools to evaluate stress in parents/caregivers of children with RASopathies. Evaluation by professionals is fundamental to support parents and caregivers in managing stressors and to enhance their quality of life and relationships. To prevent stress escalation and parents' burnout, an early assessment to tailor a timely treatment should be introduced as soon as possible as good clinical practice.

Abstract Background and objectives Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children’s Hospital, conducted a survey among Italian participants. Method Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. Results Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. Conclusion FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

IntroductionX-linked PTCHD1 gene has recently been pointed as one of the most interesting candidates for involvement in neurodevelopmental disorders (NDs), such as intellectual disability (ID) and autism spectrum disorder (ASD). PTCHD1 encodes the patched domain-containing protein 1 (PTCHD1), which is mainly expressed in the developing brain and adult brain tissues. To date, major studies have focused on the biological function of the PTCHD1 gene, while the mechanisms underlying neuronal alterations and the cognitive-behavioral phenotype associated with mutations still remain unclear.MethodsWith the aim of incorporating information on the clinical profile of affected individuals and enhancing the characterization of the genotype–phenotype correlation, in this study, we analyze the clinical features of four individuals (two children and two adults) in which array-CGH detected a PTCHD1 deletion or in which panel for screening non-syndromal XLID (X-linked ID) detected a PTCHD1 gene variant. We define the neuropsychological and psychopathological profiles, providing quantitative data from standardized evaluations. The assessment consisted of clinical observations, structured interviews, and parent/self-reported questionnaires.ResultsOur descriptive analysis align with previous findings on the involvement of the PTCHD1 gene in NDs. Specifically, our patients exhibited a clinical phenotype characterized by psychomotor developmental delay- ID of varying severity. Interestingly, while ID during early childhood was associated with autistic-like symptomatology, this interrelation was no longer observed in the adult subjects. Furthermore, our cohort did not display peculiar dysmorphic features, congenital abnormalities or comorbidity with epilepsy.DiscussionOur analysis shows that the psychopathological and behavioral comorbidities along with cognitive impairment interfere with development, therefore contributing to the severity of disability associated with PTCHD1 gene mutation. Awareness of this profile by professionals and caregivers can promote prompt diagnosis as well as early cognitive and occupational enhancement interventions.

BACKGROUND:Individuals with intellectual disability (ID) are more vulnerable to traumatic and stressful events, increasing their risk of developing post-traumatic stress disorder (PTSD). AIMS:This study aimed to investigate differences in psychopathology, post-traumatic symptoms, and adaptive functioning in a sample of Italian children and adolescents with and without ID. It also sought to determine whether the type of interpersonal trauma was associated with distinct psychopathological outcomes. METHODS AND PROCEDURES:Sixty-six children and adolescents exposed to interpersonal trauma (physical/sexual abuse, domestic violence, and neglect), were selected and divided into two groups based on the presence or absence of ID. Assessment consisted of structured parent interviews and parent-reported questionnaires. For each scale, comparisons between subtests were performed. OUTCOMES AND RESULTS:Children and adolescents with ID were more likely to exhibit more severe post-traumatic symptoms, anxiety issues, social problems, and poorer adaptive functioning, with the exception of the practical domain, which appeared to be equally impaired in both groups. In terms of interpersonal trauma typology, exposure to physical/sexual abuse and domestic violence led to greater post-traumatic symptoms compared to neglect. CONCLUSION AND IMPLICATIONS:Interpersonal trauma significantly affects children and adolescents, with or without ID, highlighting the need for tailored treatments for both groups.

BACKGROUND:Transitioning into adulthood can be challenging for individuals with Autism Spectrum Disorder (ASD). Work is one of the most enduring and impactful aspects of adult life, as it plays a key role in helping people find meaning. However, research on the effectiveness of pre-employment programs in improving the health and well-being of autistic adolescents and young adults remains limited. This exploratory study aims to assess the impact of a nationwide internship program, "BottegaMente", on the adaptive functioning, emotion regulation, and quality of life of autistic teens, adults, and their families. METHOD:The program involved 82 participants, aged 13-36, and required active family involvement to ensure it addressed the needs of autistic individuals from the planning stages through implementation. Quantitative data were collected before (T0) and after the internship (T1). RESULTS:Our study demonstrated that the internship effectively enhanced adaptive skills, particularly in areas like home life and work skills for autistic adolescents and adults, as reflected by standardized outcomes at T1 compared to T0. CONCLUSION:This research is one of the pioneering efforts to evaluate the effectiveness of pre-employment internship programs for autistic adolescents and adults. Although preliminary, these findings could help to shape future studies on employment, an essential factor for overall quality of life and well-being.

Background Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder that leads to intellectual disability (ID) along with cognitive-behavioral difficulties. Research on psychosocial treatments in individuals FXS and ID is still lacking. This study aimed to investigate the effectiveness of a combined neuropsychological and cognitive behavioral group therapy (nCBT) among young adults with FXS. Method Ten young adults diagnosed with FXS took part in the second stage intervention of "Corp-osa-Mente" (CoM II), a group nCBT program previously outlined by Montanaro and colleagues in an earlier study, with the participants being the same as in the previous research. This report details the outcomes of an additional twelve-month group sections aimed at enhancing the ability to manage emotions and the socio-communicative skills of these young adults. Caregivers completed measures of adaptive functioning, emotional and behavior problems, executive function, communication skills and family quality of life at pre-treatment (T0) and post-treatment (T1). Results CoM II showed a decrease in depressive and anxiety symptoms from T0 to T1, along with increased socio-pragmatic and communication skills from pre-test to post-test intervention. Additionally, our analysis revealed improvements in the adapative behavior of participants and in the family quality of life. Conclusions These preliminary findings suggest that young adults with FXS and ID experienced positive outcomes through participation in CoM II, a group nCBT. However, it is recommended to undertake additional methodologically rigorous studies, such as randomized controlled trials (RCTs), to substantiate these initially promising findings.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

Malan syndrome (MALNS) is an ultra-rare genetic disorder caused by heterozygous chromosomal microdeletions involving the 19p13.2 region or loss-of-function variants in the NFIX gene. It is characterized by specific phenotypical features, intellectual disability (ID), and limitations in adaptive functioning and behavioral problems. In a previous work, we defined the cognitive, adaptive, linguistic and visuomotor ability profiles in a group of 15 MALNS individuals, providing quantitative data from standardized evaluations. Here, we further extend the characterization of MALNS by analyzing the behavioral and psychopathological comorbidities of the same cohort, administering standardized tests. Children were evaluated from October 2020 to January 2022. Retrospective data analysis was also performed. Assessment consisted of clinical observations, structured parent interviews, and parent-reported questionnaires. For each scale, comparisons between subtests were performed. Results of our analysis show that the most prevalent psychiatric comorbidities are represented by anxiety symptoms (including GAD, separation anxiety and specific phobias), ADHD, autistic symptoms, and social and attention problems. Of note, minimal or no signs of ASD were observed. In conclusion, our findings indicate that the psychopathological and behavioral comorbidities, together with cognitive impairment, language problems and sensory difficulties interfere with development, daily activities and social participation, therefore contributing to the severity of the disability associated with MALNS. Awareness of this profile by professionals and caregivers can promote prompt diagnosis and support cognitive and behavioral development.

IntroductionChildren and adolescents with intellectual disability (ID) exhibit higher rates of oppositional defiant disorder (ODD) than typically developing (TD) peers. However, studies focusing on the investigation of ODD prevalence in youth with Down syndrome (DS) are still limited. MethodsThe current study aimed to investigate the prevalence of ODD clinical and subclinical symptoms in a group of 101 youth with DS (63 boys, 38 girls) ranging in age from 6 to 18 years. Moreover, the prevalence of ODD symptoms, as detected by means of three parent-report questionnaires, was compared with that detected by a semi-structured psychopathological interview, namely, the Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime (K-SADS) Version Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). ResultsWe found that 17% of participants met diagnostic criteria for ODD on the K-SADS, whereas 24% exhibited subclinical symptoms. Results also suggest good specificity of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV), Conners' Parent Rating Scales Long Version (CPRS) and Child Behavior Checklist (CBCL) in detecting ODD symptoms. The investigation of the agreement in the prevalence rates of clinical and subclinical symptoms of ODD between K-SADS and the parent-report questionnaires indicated CPRS as the parent-report questionnaire with the best agreement with K-SADS. DiscussionThis study provides support for the use of parent-report questionnaires to assess ODD symptoms in children and adolescents with DS by evaluating their levels of agreement with a semi-structured psychopathological interview. In particular, our results suggest that CPRS could be considered a suitable screening tool for ODD clinical and subclinical symptoms in youth with DS.