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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., (© 2024. The Author(s).)

Introduction: Individuals with Down syndrome (DS) often exhibit a severe speech impairment, with important consequences on language intelligibility. For these cases, the use of Augmentative Alternative Communication instruments, that increase an individual's communication abilities, becomes crucial. Talkitt is a mobile application created by Voiceitt Company, exploiting speech recognition technology and artificial intelligence models to translate in real-time unintelligible sounds into clear words, allowing individuals with language production impairment to verbally communicate in real-time., Methods: The study evaluated the usability and satisfaction related to the Talkitt application use, as well as effects on adapted behavior and communication, of participants with DS. A final number of 23 individuals with DS, aged 5.54 to 28.9 years, participated in this study and completed 6 months of training. The application was trained to consistently recognize at least 20 different unintelligible words (e.g., nouns and/or short phrases)/person., Results: Results revealed good usability and high levels of satisfaction related to the application use. Moreover, we registered improvement in linguistic abilities, particularly naming., Discussion: These results paves the road for a potential role of Talkitt application as a supportive and rehabilitative tool for DS., Competing Interests: DW and SS have a commercial and financial interest in the Talkitt application, since they are, respectively, CoFounder and CEO and Director of Business Development of Voiceitt. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Costanzo, Fucà, Caciolo, Ruà, Smolley, Weissberg and Vicari.)

Malan Syndrome (MS) is an ultra-rare overgrowth genetic syndrome due to heterozygous variants or deletions in the Nuclear Factor I X (NFIX ) gene. It is characterized by an unusual facial phenotype, generalized overgrowth, intellectual disability (ID) and behavioral problems. Even though limitations in cognitive and adaptive functioning have been previously described, systematic studies on MS cohorts are still lacking. Here, we aim to define the cognitive and adaptive behavior profile of MS children and adolescents, providing quantitative data from standardized evaluations. Subjects included in this study were evaluated from October 2020 to January 2022 and the study is based on a retrospective data archive: fifteen MS individuals were recruited and underwent evaluation with Wechsler Intelligence Scales, Leiter International Performance Scales and Griffith Mental Development Scales for cognitive profiles and with Vineland Adaptive Behavior Scales-II Edition (VABS-II) for adaptive functioning. Language skills and visuomotor integration abilities were assessed too. Comparisons and correlations between scales and subtests were performed. All the assessed MS individuals showed both low cognitive and adaptive functioning. One subject presented with mild ID, five had moderate ID and eight showed severe ID. One female toddler received a diagnosis of psychomotor delay. Linguistic skills were impaired in all individuals, with language comprehension relatively more preserved. Results revealed significant differences between VABS-II subdomains and a strong relationship between cognitive and adaptive functioning. All subjects exhibited mild to moderate ID and adaptive behavior lower than normal, with communication skills being the most affected. Regarding the daily living skills domain, personal and community subscale scores were dramatically lower than for the domestic subdomain, highlighting the importance of considering behavior within developmental and environmental contexts. Our cognitive and adaptive MS characterization provides a more accurate quantitative MS profiling, which is expected to help clinicians to better understand the complexity of this rare disorder.

Background: Malan syndrome (MALNS) is a recently described ultrarare syndrome lacking guidelines for diagnosis, management and monitoring of evolutive complications. Less than 90 patients are reported in the literature and limited clinical information are available to assure a proper health surveillance., Results: A multidisciplinary team with high expertise in MALNS has been launched at the "Ospedale Pediatrico Bambino Gesù", Rome, Italy. Sixteen Italian MALNS individuals with molecular confirmed clinical diagnosis of MALNS were enrolled in the program. For all patients, 1-year surveillance in a dedicated outpatient Clinic was attained. The expert panel group enrolled 16 patients and performed a deep phenotyping analysis directed to clinically profiling the disorder and performing critical revision of previously reported individuals. Some evolutive complications were also assessed. Previously unappreciated features (e.g., high risk of bone fractures in childhood, neurological/neurovegetative symptoms, noise sensitivity and Chiari malformation type 1) requiring active surveillance were identified. A second case of neoplasm was recorded. No major cardiovascular anomalies were noticed. An accurate clinical description of 9 new MALNS cases was provided., Conclusions: Deep phenotyping has provided a more accurate characterization of the main clinical features of MALNS and allows broadening the spectrum of disease. A minimal dataset of clinical evaluations and follow-up timeline has been proposed for proper management of patients affected by this ultrarare disorder., (© 2022. The Author(s).)

Interstitial deletions of 7q11.23 cause the well-known Williams-Beuren Syndrome (WBS), while duplication of the same region leads to duplication 7 syndrome (Dup7). Children with WBS share a distinct neurobehavioral phenotype including mild to severe intellectual disability, severely impaired visual spatial abilities, relatively preserved verbal expressive skills, anxiety problems, enhanced social motivation (i.e., hypersociable behaviors) and socio-communicative problems. Children with Dup7 syndrome exhibit some "inverted" features when compared to those of individuals with WBS, such as reduced social motivation and impairment of expressive language. Direct comparison of WBS and Dup7 represents a unique opportunity for the neurobehavioral characterization of the 7q11.23 section. However, most of the available data come from qualitative analysis between different studies. To the best of our knowledge, there are no studies directly comparing features of two matched samples of individuals with WBS and Dup7 syndromes. In this pilot study, we compare the adaptive functioning - measured with the Vineland Adaptive Behavior Scales, Second Edition - of two relatively small samples of children with molecularly confirmed diagnosis of WBS and Dup7 matched for IQ and chronological age, with a particular attention to socialization domain and expressive subdomain. Contrary to our assumption, we have not found any significant difference on socialization domain and expressive subdomains. This pilot investigation suggests that, when matched for chronological age and cognitive level, children with WBS and Dup7 share more similarities than expected. The inverted features that emerge in clinical settings on expressive language and social motivation seem not to differently interfere with the daily abilities to communicate and socialize with meaningful others during daily lives. Differences highlighted by previous undirected comparisons could be due to general and non-specific factors such as cognitive level, which is more severely impaired in individuals with WBS than Dup7. Implications for assessment and treatment are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alfieri, Scibelli, Montanaro, Caciolo, Bergonzini, Dentici and Vicari.)

Atypical development of numerical cognition (dyscalculia) may increase the onset of neuropsychiatric symptoms, especially when untreated, and it may have long-term detrimental social consequences. However, evidence-based treatments are still lacking. Despite plenty of studies investigating the effects of transcranial electrical stimulation (tES) on numerical cognition, a systematized synthesis of results is still lacking. In the present systematic review (PROSPERO ID: CRD42021271139), we found that the majority of reports (20 out of 26) showed the effectiveness of tES in improving both number (80%) and arithmetic (76%) processing. In particular, anodal tDCS (regardless of lateralization) over parietal regions, bilateral tDCS (regardless of polarity/lateralization) over frontal regions, and tRNS (regardless of brain regions) strongly enhance number processing. While bilateral tDCS and tRNS over parietal and frontal regions and left anodal tDCS over frontal regions consistently improve arithmetic skills. In addition, tACS seems to be more effective than tDCS at ameliorating arithmetic learning. Despite the variability of methods and paucity of clinical studies, tES seems to be a promising brain-based treatment to enhance numerical cognition. Recommendations for clinical translation, future directions, and limitations are outlined.

KBG syndrome (KBGS) is a rare Mendelian condition caused by heterozygous mutations in ANKRD11 or microdeletions in chromosome 16q24.3 encompassing the gene. KBGS is clinically variable, which makes its diagnosis difficult in a significant proportion of cases. The present study aims at delineating the cognitive profile and adaptive functioning of children and adolescents with KBGS. Twenty-four Italian KBGS with a confirmed diagnosis by molecular testing of the causative ANKRD11 gene were recruited to define both cognitive profile as measured by the Wechsler Intelligence Scale and adaptive functioning as measured by Vineland Adaptive Behavior Scales-II Edition or the Adaptive Behavior Assessment System-II Edition. Among children and adolescents, 17 showed intellectual disability, six presented borderline intellectual functioning and only one child did not show cognitive defects. Concerning cognitive profile, results revealed significant differences between the four indexes of Wechsler Intelligence Scale. Namely, the verbal comprehension index was significantly higher than the perceptual reasoning index, working memory index and the processing speed index. Concerning adaptive functioning, no difference between the domains was found. In conclusion, in our cohort, a heterogeneous profile has been documented in cognitive profiles, with a spike on verbal comprehension, while a flat-trend has emerged in adaptive functioning. Our cognitive and adaptive characterization drives professionals to set the best clinical supports, capturing the complexity and heterogeneity of this rare condition.

Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras-MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.

Noonan syndrome (NS) and the clinically related NS with multiple lentiginous (NMLS) are genetic conditions characterized by upregulated RAS mitogen activated protein kinase (RAS-MAPK) signaling, which is known to impact hippocampus-dependent memory formation and consolidation. The aim of the present study was to provide a detailed characterization of the recognition memory of children and adolescents with NS/NMLS. We compared 18 children and adolescents affected by NS and NMLS with 22 typically developing (TD) children, matched for chronological age and non-verbal Intelligence Quotient (IQ), in two different experimental paradigms, to assess familiarity and recollection: a Process Dissociation Procedure (PDP) and a Task Dissociation Procedure (TDP). Differences in verbal skills between groups, as well as chronological age, were considered in the analysis. Participants with NS and NSML showed reduced recollection in the PDP and impaired associative recognition in the TDP, compared to controls. These results indicate poor recollection in the recognition memory of participants with NS and NSML, which cannot be explained by intellectual disability or language deficits. These results provide evidence of the role of mutations impacting RAS-MAPK signaling in the disruption of hippocampal memory formation and consolidation.

7q11.23 Microduplication (dup7q11.23) syndrome is a rare autosomal dominant disorder due to a recurring 1.5 to 1.8 Mb duplication of the Williams-Beuren Syndrome critical region. Dup7q11.23 has been associated with several neuro-behavioral characteristics such as low cognitive and adaptive functioning, expressive language impairment, anxiety problems and autistic features. In the present study, we analyze the clinical features of ten individuals in which array-CGH detected dup7q11.23, spanning from 1.4 to 2.1 Mb. The clinical characteristics associated with dup7q11.23 are discussed with respect to its reciprocal deletion. Consistent with previous studies, we confirm that individuals with dup7q11.23 syndrome do not have a homogeneous clinical profile, although some recurring dysmorphic features were found, including macrocephaly, prominent forehead, elongated palpebral fissures, thin lip vermilion and microstomia. Minor congenital malformations include patent ductus arteriosus, cryptorchidism and pes planus. A common finding is hypotonia and joint laxity, resulting in mild motor delay. Neuropsychological and psychodiagnostic assessment confirm that mild cognitive impairment, expressive language deficits and anxiety are recurring neurobehavioral features. New insights into adaptive, psychopathological and neurodevelopmental profiles are discussed.

Increasing evidence links heterozygosity for NRXN1 gene deletions to a clinically wide spectrum of neurodevelopmental, psychiatric, and neurological disorders. However, to date, the neurocognitive and social communication features of children carrying this genomic rearrangement have not been assessed in detail. The cognitive and behavioral profiles of five children carrying a heterozygous NRXN1 deletion were investigated through systematic assessment of the cognitive and developmental levels, adaptive profile and presence of behavioral symptoms and autistic features. Furthermore, four transmitting parents were assessed by means of cognitive, psychopathological and parental stress tests. A below-average cognitive level was documented in all children, and defective adaptive levels were observed in four of them. Three of the five children were diagnosed as having autism spectrum disorder in comorbidity with intellectual disability/global developmental delay, with a major impairment in social communication skills. The remaining two children presented with isolated intellectual disability and an unclassifiable neurodevelopmental disorder, respectively. This study provide data contributing to a more accurate characterization of the neurobehavioral phenotype of individuals carrying heterozygous NRXN1 deletions. This analysis indicates that these structural rearrangements are associated with a variable expression of neuropsychiatric symptoms, and cast some doubts about the incomplete penetrance of the disorder., (© 2020 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Background: Noonan Syndrome is a developmental disorder characterized by a distinctive phenotype including facial dysmorphism, webbed neck, short stature, heart defects, and variable cognitive deficits as major features. Over the years, neuropsychological and behavioral studies explored alteration of cognitive functioning and related domains, such as learning, memory, and attention. To our knowledge, however, data concerning the language profile in this disorder is scarce. The aim of the present study was to detect specific language functioning combining nonverbal intelligence quotient and language abilities and to pinpoint strengths and weaknesses in the language domains., Methods: The language profile of 37 Italian participants with molecularly confirmed diagnosis of Noonan Syndrome was evaluated using specific tools to assess vocabulary and grammar comprehension and production, as well as phonological development., Results: We observed that 78% of affected individuals exhibited language impairment. Within language domains, the strong area was lexical production and grammar production was the weak area. Almost half the participants manifested a similar trend of specific language impairment. Nonverbal intelligence quotient only correlated with grammar comprehension., Conclusion: Our study expands present knowledge about the language profile in NS, and provides data that could enable more effective patient management and appropriate intervention., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

KBG syndrome is a rare multisystem developmental disorder caused by ankyrin repeat domain-containing protein 11 (ANKRD11) gene haploinsufficiency, resulting from either intragenic loss-of-function mutations or microdeletions encompassing the gene. Concerning the behavioral phenotype, a limited amount of research has been focused on attention deficit and hyperactivity disorder, autistic-like features, anxiety and impairments in emotion regulation, and no study has provided a systematic assessment. The aim of the present work is to investigate the psychopathological profile in children, adolescents, and young adults with KBG syndrome. Seventeen subjects with molecularly confirmed diagnoses were evaluated to investigate cognitive abilities and psychopathological features. Parametric and nonparametric indexes were used to describe the patient cohort according to type and distribution of specific measures. The KBG subjects were characterized by a low mean IQ score, with a distribution characterized by a variability similar to that occurring in the general population. Prevalence of neuropsychiatric disorders were computed as well as the corresponding confidence intervals to compare their prevalence to that reported for the general population. The KBG subjects were characterized by higher prevalence of obsessive-compulsive, tic, depressive and attention deficit and hyperactivity disorders. Obsessive-compulsive disorder is a peculiar aspect characterizing the psychopathological profile of KBG patients, which does not seem to be related to the cognitive level. The present study provides new relevant information towards the definition of a psychopathological phenotype of KBG syndromes useful to plan a better treatment for patients., Competing Interests: The authors declare no conflict of interest.

Background: Kabuki syndrome (KS) is a disorder characterized by multiple congenital anomalies affecting development and function of multiple systems. Over the years, researchers have attempted to characterize the neurobehavioral phenotype of KS in cohorts of patients enrolled on the basis of clinical assessment. The availability of molecular testing now allows for recruitment of patients with confirmed KS due to KMT2D and KDM6A., Methods: The aims of the present study were to investigate the neuropsychological and behavioral profiles of individuals with molecularly confirmed diagnosis of KS, and determine the extent of heterogeneity occurring in these profiles between individuals with clinical diagnosis of KS with and without mutations in KMT2D. We also described performance of our cohort in any neuropsychological domain investigated., Results: We documented a marked variation in the neuropsychological profile of subjects with clinical diagnosis of KS, even though a relatively homogeneous impairment in linguistic domains and motor skills was observed. No significant difference occurred between mutation-positive and mutation-negative groups. Phonological disorders and oromotor dysfunctions were also found, and adaptive functioning was characterized by low performance in daily living and in motor domain., Conclusion: The present study allowed identification of a distinctive neurobehavioral profile in a cohort of individuals affected by KS with or without molecularly confirmed diagnosis. These findings are expected to help clinicians define more accurately targeted protocols for individualized intervention., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

In the present study we evaluated long term memory in twenty individuals with molecularly confirmed diagnosis of Noonan syndrome and LEOPARD syndrome, two disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. The profile of explicit long term memory abilities was investigated using PROMEA, which includes a battery of tests specifically developed to assess memory and learning in verbal, visual and spatial domains. Ten individuals (50%) had impaired (≤5th percentile) or below average (≤15th percentile) performance on a delayed verbal free recall memory task, four (20%) on a delayed visual recognition memory task, and only one (5%) on a delayed spatial recognition memory task. Our data suggest that dysregulation of the RAS-MAPK cascade may be associated with a pattern of reduced verbal recall memory performance but relative sparing of visual and spatial recognition memory.