Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with KS and recommend individual assessment of intellectual profile.

Smith‐Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night‐time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.

Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS.

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Background Williams syndrome (WS-OMIM 194050, orphaned number: Orpha 904) is a rare condition mostly associated with intellectual disability. People with Williams syndrome are 8 times more likely to have anxiety disorders than the general population. Therapeutic solutions to treat the anxiety remain limited, particularly nonpharmacological therapy. However, cognitive behavioral therapy (CBT) has been found efficacious in managing anxiety disorders and can be used for people with intellectual disability. Objective This paper describes a protocol to assess the efficiency of a CBT program based on digital support for people with Williams syndrome and anxiety based on a research methodology designed for rare diseases. Methods We will recruit 5 individuals with Williams syndrome and anxiety. They will participate in 9 CBT sessions. Participants will perform daily self-assessments of anxiety using a digital app, which will allow for ecological and repeated evaluation of their anxiety. This digital app will provide support for each therapy session. Anxiety and quality of life will be externally assessed before and after the program and at a 3-month follow-up. This is a single-case intervention research design with multiple baselines implying repeated measures of judgment criteria. The present protocol ensures high internal validity and will help identify encouraging contributions for later clinical trials. Results Participant recruitment and data collection began in September 2019, and we project that the study findings will be available for dissemination by spring 2023. Conclusions This study will allow the assessment of the efficiency of a CBT program based on digital support to treat anxiety in people with Williams syndrome. Finally, the program could be used as an example of nonpharmacological therapy for rare diseases. Trial Registration ClinicalTrials.gov ID: NCT03827525; https://clinicaltrials.gov/ct2/show/NCT03827525 International Registered Report Identifier (IRRID) DERR1-10.2196/44393

BACKGROUND Williams syndrome (WS-OMIM 194050; Orpha 904) is a rare condition mostly associated with intellectual disability. People with Williams syndrome are eight times more likely to have anxiety disorders than the general population. Therapeutic solutions to treat the anxiety remain limited, particularly concerning non-pharmacological therapy. However, cognitive behavioural therapy (CBT) has been found efficacious in managing anxiety disorders and can be used for people with intellectual disability. OBJECTIVE This study assessed the efficiency of a CBT program based on a smartphone app for people with Williams syndrome and anxiety. METHODS We used a single-case experimental design with multiple baselines implying repeated measures of judgement criteria. Five adults with Williams syndrome and anxiety underwent nine CBT sessions. Participants performed daily self-assessments of anxiety by using a smartphone app that allowed for ecological and repeated evaluation of the anxiety. Anxiety and quality of life were externally assessed before and after the program. Participants were assessed during a 3-month follow-up. RESULTS We found a significant reduction in anxiety for all participants between the start and end of therapy as well as between the start of therapy and the 3-month post-therapy follow-up. Quality of life was improved but without reaching statistical significance. We also found an impact on other anxiety-related elements. Participants who were accompanied by a loved one at each session more regularly performed their daily self-assessments using the smartphone app than did others. CONCLUSIONS This is the first study to highlight the benefits of a smartphone-based CBT protocol for anxiety in patients with Williams syndrome, using a protocol adapted to small sample sizes. It underscores the value of psychotherapeutic management with smartphone support, allowing for adapting tools for patients with intellectual disabilities. CLINICALTRIAL ClinicalTrials.gov ID: NCT03827525; https://clinicaltrials.gov/ct2/show/NCT03827525 INTERNATIONAL REGISTERED REPORT RR2-10.2196/44393

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We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.