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Supravalvar aortic stenosis (SVAS) severity guides management, including decisions for surgery. Physiologic and technical factors limit the determination of SVAS severity by Doppler echocardiography and cardiac catheterization in Williams syndrome (WS). We hypothesized SVAS severity could be determined by the sinotubular junction-to-aortic annulus ratio (STJ:An). We reviewed all preintervention echocardiograms in patients with WS with SVAS cared for at our center. We measured STJ, An, peak and mean Doppler gradients, and calculated STJ:An. We created 2 mean gradient prediction models. Model 1 used the simplified Bernoulli's equation, and model 2 used computational fluid dynamics (CFD). We compared STJ:An to Doppler-derived and CFD gradients. We reviewed catheterization gradients and the waveforms and analyzed gradient variability. We analyzed 168 echocardiograms in 54 children (58% male, median age at scan 1.2 years, interquartile range [IQR] 0.5 to 3.6, median echocardiograms 2, IQR 1 to 4). Median SVAS peak Doppler gradient was 24 mm Hg (IQR 14 to 46.5). Median SVAS mean Doppler gradient was 11 mm Hg (IQR 6 to 21). Median STJ:An was 0.76 (IQR 0.63 to 0.84). Model 1 underpredicted clinical gradients. Model 2 correlated well with STJ:An through all severity ranges and demonstrated increased pressure recovery distance with decreased STJ:An. The median potential variability in catheterization-derived gradients in a given patient was 14.5 mm Hg (IQR 7.5 to 19.3). SVAS severity in WS can be accurately assessed using STJ:An. CFD predicts clinical data well through all SVAS severity levels. STJ:An is independent of physiologic state and has fewer technical limitations than Doppler echocardiography and catheterization. STJ:An could augment traditional methods in guiding surgical management decisions.

International audience; Elastic fibers, made of elastin (90%) and fibrillin-rich microfibrils (10%), are the key extracellular components, which endow the arteries with elasticity. The alteration of elastic fibers leads to cardiovascular dysfunctions, as observed in elastin haploinsufficiency in mice (Eln+/-) or humans (supravalvular aortic stenosis or Williams–Beuren syndrome). In Eln+/+ and Eln+/- mice, we evaluated (arteriography, histology, qPCR, Western blots and cell cultures) the beneficial impact of treatment with a synthetic elastic protein (SEP), mimicking several domains of tropoelastin, the precursor of elastin, including hydrophobic elasticity-related domains and binding sites for elastin receptors. In the aorta or cultured aortic smooth muscle cells from these animals, SEP treatment induced a synthesis of elastin and fibrillin-1, a thickening of the aortic elastic lamellae, a decrease in wall stiffness and/or a strong trend toward a reduction in the elastic lamella disruptions in Eln+/- mice. SEP also modified collagen conformation and transcript expressions, enhanced the aorta constrictive response to phenylephrine in several animal groups, and, in female Eln+/- mice, it restored the normal vasodilatory response to acetylcholine. SEP should now be considered as a biomimetic molecule with an interesting potential for future treatments of elastin-deficient patients with altered arterial structure/function.

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS. Ministerio de Ciencia, Innovacion y Universidades FPU13/01867 Alba Navarro-Romero Ministerio de Ciencia e Innovacion BES-2016-077950 Lorena Galera-Lopez Ministerio de Ciencia e Innovacion RTI2018-099282-B-I00 Andres Ozaita Ministerio de Ciencia e Innovacion SAF2017-84060-R Rafael Maldonado Generalitat de Catalunya 2017SGR-669 Rafael Maldonado Ministerio de Ciencia e Innovacion SAF2016-78508-R Victoria Campuzano Basque Country Government IT1454-22 Rafael Rodriguez-Puertas Instituto de Salud Carlos III PI20/00153, co-funded by the European Union (ERDF "A way to make Europe") Rafael Rodriguez-Puertas Institucio Catalana de Recerca i Estudis Avancats Rafael Maldonado Ministerio de Economia y Competitividad #MDM-2014-0370 Alba Navarro-Romero Ministerio de Economia y Competitividad #MDM-2014-0370 Eduardo Eyras Ministerio de Ciencia e Innovacion PRE2019-087644 Lucia de los Reyes-Ramirez Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Andres Ozaita Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Rafael Maldonado Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Victoria Campuzano Ministerio de Economia y Competitividad FEDER Alba Navarro-Romero Ministerio de Economia y Competitividad FEDER Eduardo Eyras Ministerio de Economia y Competitividad IPEP MdM-2017 Eduardo Eyras Ministerio de Ciencia e Innovacion UE Andres Ozaita Ministerio de Ciencia e Innovacion UE Rafael Maldonado Ministerio de Economia y Competitividad UE Alba Navarro-Romero Ministerio de Ciencia e Innovacion UE Victoria Campuzano Ministerio de Economia y Competitividad EU Eduardo Eyras FRAXA Research Foundation Lorena Galera-Lopez The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

BACKGROUND There is very little research on the cognitive profile of young children with Williams syndrome (WS). METHOD The present study utilised the Differential Ability Scales - Second Edition to examine the early cognitive abilities of 22 young children with WS (aged 3.98 to 7.70 years, 10 male and 12 female participants). RESULTS Overall, IQ ranged from 38 (severely impaired) to 81.00 (low average). Consistent with Mervis et al. who looked at an older sample, over half (59.08%) of our young WS sample showed a significant and abnormal weakness in spatial ability relative to verbal ability. Moreover, 81.82% showed a significant and clinically unusual weakness in spatial ability relative to nonverbal reasoning ability. At the subtest level, only 4.55% of our sample showed a significant strength in naming vocabulary compared with verbal comprehension, while 13.64% showed a significant weakness in naming vocabulary relative to verbal comprehension. CONCLUSIONS The results of the present study show cognitive heterogeneity, consistent with the literature on older children and adults with WS. There were variable levels of intellect and variable patterns of cognitive strength and weakness across both index and subtest scores. Findings highlight the need for individual assessment and management of young children with WS but also indicate that for the majority of WS individuals spatial skills are indeed an area of significant and abnormal weakness and should be a focus for early intervention.

Comprising two parts, Ed Zigler's developmental approach has greatly influenced how one conceptualizes children with intellectual disabilities (ID). In part one, Zigler championed a “two-group approach” concerning the cause of children's ID. He distinguished persons with a clear, organic cause of their ID from those displaying no clear cause. Members of this “organic” group often displayed IQs below 50 and co-occurring physical–medical conditions. The second, “cultural–familial” group, mostly showed IQs of 50–70, did not possess co-occurring physical or health problems, and often came from families of lower IQs and lower socioeconomic status. While the presence of these two groups has been supported, recent advances have also further differentiated the organic group, mostly in relation to behavioral phenotypes of persons with several genetic etiologies. In part two, Zigler championed the child with ID as a “whole person.” Originally focused on the child's reactions to social deprivation and failure, recent studies directly examine parent–child, within-family, and wider system interactions throughout the life span. For decades a force within the ID field, Zigler's developmental approach to children with ID continues to influence researchers, interventionists, and policymakers.

Background Williams-Beuren syndrome (WS) is characterized by cardiovascular abnormalities associated with a multigene deletion on 7q11.23, in particular elastin (ELN). Peripheral pulmonary artery stenosis (PPAS) frequently affects pediatric patients with WS. Molecular investigation of WS pulmonary arterial (PA) tissue is limited by tissue scarcity. Methods We compared transcriptomes, tissue architecture, and localized changes in protein expression in PA tissue from patients with WS (n = 8) and donors (n = 5). Results Over 100 genes were differentially expressed at the ≥4-fold level, including genes related to the serotonin signaling pathway: >60-fold downregulation of serotonin transporter SLC6A4 and >3-fold upregulation of serotonin receptor HTR2A. Histologic examination revealed abnormal elastin distribution and smooth muscle cell morphology in WS PA, with markedly shorter, disorganized elastin fibers, and expanded proteoglycan-rich extracellular matrix between muscle layers. Conclusions There were significant abnormalities in the PA expression of genes regulating serotonin signaling, metabolism, and receptors in WS. Those changes were associated with distinct changes in the arterial structure and may play a role in the stenosis-promoting effects of elevated shear stress at PA bifurcations in WS. Impact Serotonin pathway signaling is significantly altered in the pulmonary arteries of patients with Williams syndrome and severe peripheral arterial stenosis. The present study compares the histological and biochemical characteristics of pulmonary arteries from patients with Williams syndrome to those of controls, something that has not, to our knowledge, been done previously. It demonstrates marked abnormalities in the pulmonary arteries of patients with Williams syndrome, especially significant pathologic alterations in the signaling of the serotonin pathway. The findings of this study provide direction for the development of potential therapies to treat pulmonary artery stenosis in patients with Williams syndrome.

Mid-aortic syndrome (MAS) is a rare condition characterized by stenosis of the distal thoracic and/or abdominal aorta. Williams-Beuren syndrome (WBS) is a relatively rare cause of MAS. We report a case of incidentally diagnosed MAS caused by WBS without typical manifestations caused by an atypical small-sized deletion in chromosome 7q11.23, which was initially misdiagnosed as Takayasu arteritis.

BACKGROUND People with intellectual disability face a number of barriers to participation in physical activity. This paper aimed to determine rates of sport and physical activity participation in an Australian sample of adults with intellectual disability, compared with rates of participation in the general Australian population. A secondary aim was to investigate factors that may contribute to participation of adults with intellectual disability. METHOD Participants were part of the Australian Child to Adult Development (ACAD) study, consisting of a community sample with intellectual disability (n = 305), groups of adults with autism (n = 94), Down syndrome (n = 64), fragile X syndrome (n = 52), Williams syndrome (n = 45), and Prader-Willi syndrome (n = 30). Participation in sport/physical activity was reported over the past 3 months. Rates of participation were reported for adults with intellectual disability and compared with rates in a general Australian population sample. The relationship between participation in physical activity and age, degree of intellectual disability, physical mobility, living situation, socio-economic disadvantage, and behaviour and emotional problems were also conducted. RESULTS Participants in the ACAD community sample with intellectual disability participated in sport/physical activity at lower rates than the general Australian population (42% compared with 71%). Having no physical mobility impairment was significantly associated with higher rates of participation. Those with Down syndrome participated in sport/physical activity at higher rates than the community sample with intellectual disability, while no difference in sport/physical activity participation was observed in the groups with autism or other syndromes. CONCLUSION Australian adults with intellectual disability participate in sport and physical activity at lower rates than the general population. Having a physical mobility impairment was associated with lower rates of participation. However, people living in supported accommodation were more likely to participate than those in other living situations. Having Down syndrome was associated with a higher participation rate than the community sample.

Williams-Beuren syndrome (WBS) is a genetic, well-defined, rare, neurodevelopmental disorder characterized by intellectual disability, congenital heart defects, abnormal facial features, and growth, endocrine, and genitourinary abnormalities. The genitourinary abnormalities in WBS frequently include congenital structural renal defects, vesicoureteral reflux, nephrocalcinosis, proteinuria, and chronic renal insufficiency. Treatment of patients with posterior urethral valve (PUV) remains a clinical challenge, requiring long-term management from early infancy into adulthood in order to avoid progressive renal insufficiency. To my knowledge, this is the first worldwide case of WBS with PUV in a 12-year-old boy. Due to the delayed detection of the defect, chronic renal disease occurred as a risk for him. This case demonstrates the importance of early diagnosis of genitourinary anomalies such as PUV to prevent chronic renal disease in boys and especially in patients with WBS.

To describe special facial features of children with Williams syndrome in China by using method of three-dimensional craniofacial anthropometry. Using three-dimensional stereo photogrammetric device, 14 craniofacial anthropometric measurements were performed and five indices were calculated in 52 children with Williams syndrome and 208 age and sex matched controls of Han Chinese ethnicity. Except intercanthal width, mouth breadth, morphological face height, nasal height-breadth index, nasal breadth-depth index, morphological ear index, the Williams syndrome group under 3 years old were smaller than the control group in the other 12 variables. Compared with the control group, the Williams syndrome group aged 3-5 years old had smaller biocular breadth, nasal length, nasorostral angle, bitragal breadth, ear width, morphological ear index and face depth. The Williams syndrome group aged above 6 years old had smaller biocular breadth, nasal breadth, bitragal breadth, ear width, ear length and face depth than the control group. The craniofacial variability index of the Williams syndrome group was greater than the control group. Greater variation was found among children with Williams syndrome than normal in China, specifically at eye, nose, ear and face shape, which demonstrate the usefulness of three-dimensional stereo photogrammetric analysis in supporting accurate diagnose of the patient with Williams syndrome.

While children with developmental language disorder or Williams syndrome appear to use hand gestures to compensate for specific cognitive and communicative difficulties, they have different cognitive strength-weakness profiles. Their semantic and visuospatial skills potentially affect gesture quality such as iconicity. The present study focuses on untangling the unique contribution of these skills in the quality of gestures. An explicit gesture elicitation task was presented to 25 participants with developmental language disorder between 7 and 10 years of age, 25 age-matched peers with typical development, and 14 participants with Williams Syndrome (8−23 years). They gestured pictures of objects without using speech (pantomime). The iconicity, semantic richness, and representation technique of the pantomimes were coded. Participants’ semantic association and visuospatial skills were formally assessed. Iconicity was slightly lower in individuals with Williams syndrome, which seems related to their visuospatial deficit. While semantic saliency was similar across participant groups, small differences in representation technique were found. Partial correlations showed that visuospatial skills and semantic skills were instrumental in producing clear pantomimes. These findings indicate that clinicians aiming to enhance individuals’ natural iconic gestures should consider achieved iconicity, particularly in individuals with low visuospatial skills. ispartof: Augmentative And Alternative Communication vol:36 issue:3 pages:179-189 ispartof: location:England status: published

Background The lack of available measures that can reliably characterize early developmental skills in children with neurogenetic syndromes (NGS) poses a significant challenge for research on early development in these populations. Although syndrome-specific measures may sometimes be necessary, a more cost- and time-efficient solution would be to identify existing measures that are appropriate for use in special populations or optimize existing measures to be used in these groups. Reliability is an important metric of psychometric rigor to consider when auditing and optimizing assessment tools for NGS. In this study, we use Generalizability Theory, an extension of classical test theory, as a novel approach for more comprehensively characterizing the reliability of existing measures and making decisions about their use in the field of NGS research. Methods We conducted generalizability analyses on a popular early social communication screener, the Communication and Symbolic Behavior Scales—Infant-Toddler Checklist (CSBS-ITC), collected on 172 children (41 Angelman syndrome, 30 Prader-Willi syndrome, 42 Williams syndrome, 59 low-risk controls). Results Overall, the CSBS-ITC demonstrated at least adequate reliability in the NGS groups included in this study, particularly for the Prader-Willi and Williams syndrome groups. However, the sources of systematic error variance in the CSBS-ITC varied greatly between the low-risk control and NGS groups. Moreover, as unassessed in previous research, the CSBS-ITC demonstrated substantial differences in variance sources among the NGS groups. Reliability of CSBS-ITC scores was highest when averaging across all measurement points for a given child and was generally similar or better in the NGS groups compared to the low-risk control group. Conclusions Our findings suggest that the CSBS-ITC communicates different information about the reliability of stability versus change, in low-risk control and NGS samples, respectively, and that psychometric approaches like Generalizability Theory can provide more complete information about the reliability of existing measures and inform decisions about how measures are used in research on early development in NGS.

Background: Unusual sensory responses were included in the diagnostic criteria for autism spectrum disorder (ASD), yet they are also common among individuals with other neurodevelopmental disorders, including Williams syndrome (WS). Cross‐syndrome comparisons of sensory atypicalities and the evaluation of their syndrome specificity however have rarely been undertaken. We aimed to (1) examine and compare the sensory profiles in ASD and WS groups and (2) investigate whether autistic symptoms, including sensory processing scores, can predict a group membership. Methods: Parents of 26 children with ASD and intellectual disability, 30 parents of children with ASD (no intellectual disability) and 26 with WS aged between 4 and 16 years were recruited. Parents completed the Sensory Profile to provide information about their children's sensory experiences and the Social Responsiveness Scale – Second Edition (SRS‐2) to assess the degree of social impairment in their children. Results: No significant differences were found in sensory processing scores between the three groups. Binary logistic regression analyses were undertaken with sensory quadrants and SRS‐2 total score as factors. Models significantly predicted group membership, with Low Registration, Sensory Sensitivity and SRS‐2 total score being significant predictors. Conclusions: The findings suggest that high rates of sensory atypicalities are a common neurodevelopmental characteristic that do not reliably distinguish between WS and ASD groups. Low Registration and Sensory Sensitivity‐related behaviours might, however, be more specific to ASD. Further work is needed to explore what behaviours within sensory profiles can discriminate between neurodevelopmental disorders and should be included in diagnostic classifications.

Supplemental Digital Content is available in the text., Objective: Elastin gene deletion or mutation leads to arterial stenoses due to vascular smooth muscle cell (SMC) proliferation. Human induced pluripotent stem cells–derived SMCs can model the elastin insufficiency phenotype in vitro but show only partial rescue with rapamycin. Our objective was to identify drug candidates with superior efficacy in rescuing the SMC phenotype in elastin insufficiency patients. Approach and Results: SMCs generated from induced pluripotent stem cells from 5 elastin insufficiency patients with severe recurrent vascular stenoses (3 Williams syndrome and 2 elastin mutations) were phenotypically immature, hyperproliferative, poorly responsive to endothelin, and exerted reduced tension in 3-dimensional smooth muscle biowires. Elastin mRNA and protein were reduced in SMCs from patients compared to healthy control SMCs. Fourteen drug candidates were tested on patient SMCs. Of the mammalian target of rapamycin inhibitors studied, everolimus restored differentiation, rescued proliferation, and improved endothelin-induced calcium flux in all patient SMCs except one Williams syndrome. Of the calcium channel blockers, verapamil increased SMC differentiation and reduced proliferation in Williams syndrome patient cells but not in elastin mutation patients and had no effect on endothelin response. Combination treatment with everolimus and verapamil was not superior to everolimus alone. Other drug candidates had limited efficacy. Conclusions: Everolimus caused the most consistent improvement in SMC differentiation, proliferation and in SMC function in patients with both syndromic and nonsyndromic elastin insufficiency, and offers the best candidate for drug repurposing for treatment of elastin insufficiency associated vasculopathy.

Background Children with Williams syndrome (WS) show a marked interest in music, a characteristic often explored in clinical settings. However, the actual musical abilities of patients with WS remain debatable due to some of the relevant data being derived from experimental tasks that require a verbal response, despite the known language impairments in WS. The present study aimed to examine musical ability in children with WS using a newly invented pitch discrimination task with minimal involvement of language and clarify its relationship with language skill. Methods Eleven children with WS participated in the study. We used a novel pitch discrimination task that required minimal language use. Two piano tones were presented sequentially, and children were asked to give a non-verbal response as to whether the second tone was higher than, lower than, or the same as the first tone. Results Pitch discrimination performance in children with WS was lower than the level predicted for their chronological age (CA), even in the non-verbal task. Pitch discrimination ability and verbal mental age (VMA) were shown to be dissociated, such that children with WS with a lower skill level for language showed an unexpectedly higher level of pitch discrimination ability and vice versa. Conclusions Our results indicated reduced musical ability with respect to CA in children with WS. The dissociation between musical ability and language skills may indicate unique developmental relationships that differ from those in normal children. These findings provide new evidence to support the importance of assessing actual musical ability in WS prior to implementing interventional music therapy.

Cardiovascular manifestations occur in over 80% of Williams syndrome (WS) patients and are the leading cause of morbidity and mortality. One-third of patients require cardiovascular surgery. Renal artery stenosis (RAS) is common in WS. No studies have assessed postoperative cardiac surgery-related acute kidney injury (CS-AKI) in WS. Our objectives were to assess if WS patients have higher risk of CS-AKI postoperatively than matched controls and if RAS could contribute to CS-AKI.This was a retrospective study of all patients with WS who underwent cardiac surgery at our center from 2010 to 2020. The WS study cohort was compared with a group of controls matched for age, sex, weight, and surgical procedure.Patients underwent cardiac surgery and postoperative care at Lucile Packard Children's Hospital Stanford.There were 27 WS patients and 43 controls (31% vs 42% female; p = 0.36). Median age was 1.8 years (interquartile range [IQR], 0.7-3.8 yr) for WS and 1.7 years (IQR, 0.8-3.1 yr) for controls.None.Postoperative hemodynamics, vasopressor, total volume input, diuretic administration, and urine output were collected in the first 72 hours. Laboratory studies were collected at 8-hour intervals. Multivariable analysis identified predictors of CS-AKI.Controlled for renal perfusion pressure (RPP) and vasoactive inotrope score (VIS), compared with controls, the odds ratio (OR) of CS-AKI in WS was 4.2 (95% CI, 1.1-16; p = 0.034). Higher RPP at postoperative hours 9-16 was associated with decreased OR of CS-AKI (0.88 [0.8-0.96]; p = 0.004). Increased VIS at hour 6 was associated with an increased OR of CS-AKI (1.47 [1.14-1.9]; p = 0.003). Younger age was associated with an increased OR of CS-AKI (1.9 [1.13-3.17]; p = 0.015).The OR of CS-AKI is increased in pediatric patients with WS compared with controls. CS-AKI was associated with VIS at the sixth postoperative hour. Increases in RPP and mean arterial pressure were associated with decreased odds of CS-AKI.

Background: Children with autism spectrum disorder (ASD) and those with Williams syndrome (WS) have difficulties with learning, though the nature of these remains unclear. Methods: In this study, we used novel eye-tracking and behavioral paradigms to measure how 36 preschoolers with ASD and 21 age- and IQ-matched peers with WS attend to and learn novel behaviors (1) from the outcomes of their own actions (non-social learning), (2) through imitation of others' actions (social learning), and across situations in which imitative learning served either an instrumental function or fulfilled social affiliation motives. Results: The two groups demonstrated similar abilities to learn from the consequences of their own actions and to imitate new actions that were instrumental to the achievement of a tangible goal. Children with WS, unlike those with ASD, increased their attention and imitative learning performance when the model acted in a socially engaging manner. Conclusions: Learning abnormalities in ASD appear to be linked to the social rather than instrumental dimensions of learning.

Most laboratories adopt the results of metaphase fluorescent in situ hybridization (FISH) for the diagnosis of microdeletion syndromes. To investigate the discrepancy between the results of interphase and metaphase, we compared the quantitative results of FISH for 5 kinds of microdeletion syndrome and gender determination disorders (SDD).A total of 282 (135 for DiGeorge syndrome, 20 for Kalmann syndrome, 7 for Miller-Dieker syndrome, 38 for Prader Willi/Angelman syndrome, 62 for Williams syndrome, and 20 for SDD (SRY FISH)) were enrolled. For SRY FISH, we artificially mixed fresh blood of male and female with various ratios and then compared the results of metaphase and interphase SRY FISH. Using a bio-cell chip, we performed interphase FISH in 168 patients with microdeletion syndromes and compared the results with manual interphase.The concordance rate between the results of metaphase and interphase was 100% in microdeletion syndrome. In the disorders of gender development, SRY FISH showed 100% concordance between interphase and metaphase when we counted 50 metaphase cells and 100 interphase cells. Comparison with mixtures of male and female blood at various ratios also showed 100% concordance. The results of bio-cell chip showed 100% concordance between previous interphase FISH results.Considering the complete concordance between interphase and metaphase in microdeletion syndrome, the application of interphase FISH without performing metaphase FISH can be a screening test for microdeletion syndrome. Confirmation by metaphase FISH can be performed only in cases with abnormal results by interphase FISH.

Psychopathology is prevalent in Williams (WS), fragile X (FXS) and Prader–Willi (PWS) syndromes. However, little is known about the potential correlates of psychopathology in these groups. A questionnaire study was completed by 111 caregivers of individuals with WS (n = 35); FXS (n = 50) and PWS (n = 26). Mean age was 26 years (range 12–57 years); 74 (67%) were male. Multiple regression analyses indicated that higher rates of health problems and sensory impairments predicted higher psychopathology in WS (p

Boundaries are crucial to our representation of the geometric shape of scenes, which can be used to reorient in space. Behavioral research has shown that children and adults share exquisite sensitivity to a defining feature of a boundary: its vertical extent. Imaging studies have shown that this boundary property is represented in the parahippocampal place area (PPA) among typically developed (TD) adults. Here, we show that sensitivity to the vertical extent of scene boundaries is impaired at both the behavioral and neural level in people with Williams syndrome (WS), a genetic deficit that results in severely impaired spatial functions. Behavioral reorientation was tested in three boundary conditions: a flat Mat, a 5 cm high Curb, and full Walls. Adults with WS could reorient in a rectangular space defined by Wall boundaries, but not Curb or Mat boundaries. In contrast, TD age-matched controls could reorient by all three boundary types and TD 4-year-olds could reorient by either Wall or Curb boundaries. Using fMRI, we find that the WS behavioral deficit is echoed in their neural representation of boundaries. While TD age-matched controls showed distinct neural responses to scenes depicting Mat, Curb, and Wall boundaries in the PPA, people with WS showed only a distinction between the Wall and Mat or Curb, but no distinction between the Mat and Curb. Taken together, these results reveal a close coupling between the representation of boundaries as they are used in behavioral reorientation and neural encoding, suggesting that damage to this key element of spatial representation may have a genetic foundation.

Recent theories of episodic memory (EM) posit that the hippocampus provides a spatiotemporal framework necessary for representing events. If such theories hold true, then does the development of EM in children depend on the ability to first bind spatial and temporal information? And does this ability rely, at least in part, on normal hippocampal function? We investigated the development of EM in children 2–8 years of age (Study 1) and its impairment in Williams Syndrome, a genetic neurodevelopmental disorder characterized by visuospatial deficits and irregular hippocampal function, (Study 2) by implementing a nonverbal object-placement task that dissociates the what, where, and when components of EM. Consistent with the spatiotemporal-framework view of hippocampal EM, our results indicate that the binding of where and when in memory emerges earliest in development, around the age of 3, and is specifically impaired in WS. Space-time binding both preceded and was critical to full EM (what + where + when), and the successful association of objects to spatial locations seemed to mediate this developmental process.

Cardiovascular involvement in COVID-19 has different features. Here we report the ominous fate of a neglected adolescent with Williams syndrome that was infected by SARS-CoV-2 and ended by acute aortic dissection.

We present a case of a 42-year-old male patient with severe supravalvular aortic stenosis associated with aortic and mitral valve stenosis as well as an anomalous origin of the right coronary ostium caused by deletion in the q11.23 region of the human chromosome 7 in a patient with Williams–Beuren syndrome.

Previous studies suggest that tasks dependent on the mental number line may be difficult for Williams Syndrome (WS) and Down Syndrome (DS) groups. However, few have directly assessed number line estimation in these groups. The current study assessed 28 WS, 25 DS and 25 typically developing (TD) participants in non-verbal intelligence, number familiarity, visuo-spatial skills and number line estimation. Group comparisons indicated no differences in number line estimation. However, the WS group displayed difficulties with visuo-spatial skills and the DS group displayed difficulties with number familiarity. Differential relationships between number line estimation and visuo-spatial/number familiarity skills were observed across groups. Data is discussed in the context of assessment of skills in neurodevelopmental disorders.

Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial personality. Clear knowledge of the circumscribed set of genes that are affected in Williams syndrome, along with the well-characterized neurobehavioural phenotype, offers the potential to elucidate neurogenetic principles that may apply in genetically and clinically more complex settings. The intraparietal sulcus, in the dorsal visual processing stream, has been shown to be structurally and functionally altered in Williams syndrome, providing a target for investigating resting-state functional connectivity and effects of specific genes hemideleted in Williams syndrome. Here, we tested for effects of the LIMK1 gene, deleted in Williams syndrome and important for neuronal maturation and migration, on intraparietal sulcus functional connectivity. We first defined a target brain phenotype by comparing intraparietal sulcus resting functional connectivity in individuals with Williams syndrome, in whom LIMK1 is hemideleted, with typically developing children. Then in two separate cohorts from the general population, we asked whether intraparietal sulcus functional connectivity patterns similar to those found in Williams syndrome were associated with sequence variation of the LIMK1 gene. Four independent between-group comparisons of resting-state functional MRI data (total n = 510) were performed: (i) 20 children with Williams syndrome compared to 20 age- and sex-matched typically developing children; (ii) a discovery cohort of 99 healthy adults stratified by LIMK1 haplotype; (iii) a replication cohort of 32 healthy adults also stratified by LIMK1 haplotype; and (iv) 339 healthy adolescent children stratified by LIMK1 haplotype. For between-group analyses, differences in intraparietal sulcus resting-state functional connectivity were calculated comparing children with Williams syndrome to matched typically developing children and comparing LIMK1 haplotype groups in each of the three general population cohorts separately. Consistent with the visuospatial construction impairment and hypersocial personality that typify Williams syndrome, the Williams syndrome cohort exhibited opposite patterns of intraparietal sulcus functional connectivity with visual processing regions and social processing regions: decreased circuit function in the former and increased circuit function in the latter. All three general population groups also showed LIMK1 haplotype-related differences in intraparietal sulcus functional connectivity localized to the fusiform gyrus, a visual processing region also identified in the Williams syndrome-typically developing comparison. These results suggest a neurogenetic mechanism, in part involving LIMK1, that may bias neural circuit function in both the general population and individuals with Williams syndrome.

Background Supravalvular aortic stenosis (SVAS) represents a heterogeneous group, including Williams syndrome, familial elastin arteriopathy, sporadic cases, and others. This study sought to evaluate long-term outcomes of SVAS repair. Methods A total of 87 patients underwent surgical repair of congenital SVAS at Boston Children’s Hospital in Boston, Massachusetts, between 1997 and 2017. A total of 41 patients had Williams syndrome, and 46 did not. Of the 46 patients who did not have Williams syndrome, 23 had sporadic SVAS, and 13 had familial elastin arteriopathy. Demographic data and outcomes were reviewed and analyzed from medical records. Results The median age at operation was 2.9 years. Mean z score of the sinotubular junction was -3.29 ± 1.42 and of the aortic root was −0.09 ± 1.19. A total of 26% (n = 22) patients had coronary ostium stenosis, and 41% (n = 9) of them required patch plasty. Survival rates at 5, 10, and 20 years were all 94.3%. Freedom from left ventricular outflow tract reoperation at 5, 10, and 20 years was 78.5%, 70.3%, and 70.3%, respectively. Freedom from aortic arch reintervention at 5, 10, and 20 years was 98.6%, 94.3%, 89.3%, respectively. In risk factors analysis, age younger than 1 year, z scores of the aortic valve and aortic root, and concomitant right ventricular outflow tract surgical repair were predictive of the need for reoperation and reintervention for left or right ventricular outflow tract obstruction. Conclusions Excellent long-term survival rates can be achieved with surgical repair of SVAS. Age younger than 1 year, small aortic valve and aortic root z scores, and concomitant right ventricular outflow tract surgical repair were predictors of reoperation and reintervention.

BACKGROUND Understanding adaptive functioning profiles in children with Williams syndrome (WS) and autism spectrum disorder (ASD) is critical to inform treatment strategies. However, knowledge in this area is limited and inconclusive. METHOD The current study aimed to characterise the early adaptive profiles of young children with WS (n = 18; Mage = 47 months) and ASD (n = 26; Mage = 45 months) matched on chronological age and developmental age using the Vineland Scales of Adaptive Behavior, Second Edition. RESULTS Results suggest that young children with WS and ASD do not differ on their overall level of adaptive functioning but that those with WS show relative strengths in the Socialisation scale compared with children with ASD. No other subscales differed between groups. Within groups, the WS group showed a profile of Communication, Daily Living Skills and Motor

It has been reported that approximate number sense (ANS) task performance is impaired in individuals with Williams syndrome (WS) and Down syndrome (DS). Research with infants has suggested this impairment is caused by sticky fixation in WS and sustained attention deficits for those with DS. This study examined looking patterns of older children and adults with WS (n = 24) and DS (n = 23) during an ANS task compared to typically developing controls matched for chronological age and those matched for mental age. Results showed that, although there were no group differences, looking patterns changed with chronological age for both the WS and DS groups. Looking behaviour related to ANS performance only in the WS group. Implications for interventions are discussed.

Autism spectrum disorder (ASD) and Williams syndrome (WS) share psychopathology relating to sensory processing and repetitive behaviors. The relationships between the sensory features and repetitive behaviors in both disorders, and the mechanisms underlying these relationships are not well understood. The aim of this study was to examine the relationships between sensory processing, repetitive behaviors, anxiety, and intolerance of uncertainty in children with ASD and those with WS to better understand the complexity of psychopathology in these disorders. Parents of 19 children with ASD and 16 children with WS, aged between 4 and 9 years, were asked to complete questionnaires assessing their children's sensory experiences, anxiety symptoms, severity and frequency of repetitive behaviors, and level of intolerance of uncertainty. Serial mediation analysis was performed. Direct significant relationships between sensory features and repetitive behaviors were found only for the ASD group. The relationship between sensory processing difficulties and repetitive behaviors was mediated via intolerance of uncertainty in WS. The findings support the value of considering the complexity of the mechanisms underlying the relationship between sensory processing and repetitive behaviors across neurodevelopmental disorders and the mechanisms underlying these aspects of psychopathology in these groups. Understanding these relationships will shed light on some of the most challenging and intractable characteristics of both conditions and inform suitable interventions to improve quality of life for individuals with either ASD or WS. Autism Research 2019, 12: 759-765. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In autism spectrum disorder (ASD) and Williams syndrome (WS) difficulties processing the sensory aspects of the environment, repetitive behaviors and high levels of anxiety co-occur, but the relationships between these features are not well understood. This study found that sensory difficulties were directly associated with repetitive behaviors in children with ASD, but not WS, and in WS this relationship was mediated by intolerance of uncertainty. The findings support the value of considering the complexity of the mechanisms underlying the relationship between sensory processing and repetitive behaviors across neurodevelopmental disorders.

Aim The aim of this study was to evaluate oral characteristics and comorbidities that may affect dental treatment of individuals with Williams syndrome (WS). Methods and results Fifty-two subjects diagnosed with WS were included in this observational study. Demographic data and medical history were compiled. Facial aspects, tooth abnormalities and oral characteristics were obtained through clinical and radiographic evaluation by a researcher/dentist. Among 52 subjects, 25 were also evaluated for temporomandibular and occlusal disorders, caries and periodontal disease. From the 52 subjects, 23 (44.2%) were female and the average age was of 20 years old (range from 4 to 35 years old). Cognitive impairment and congenital heart disease were the most common medical disorders found in all 52 (100%) and in 41 (78.8%) subjects, respectively. Among the 52 subjects, 51 (98%) presented at least one dental developmental abnormality, with generalized diastemas (72.5%) and hypodontia (50.9%) being the most frequent ones. Angle class III malocclusion was observed in 52% (13/25) of the subjects. Conclusions The dentist should be aware of the medical conditions of individuals with WS and thus offer an adequate dental treatment. The high prevalence of tooth abnormalities and occlusal disorders requires an early dental treatment planning.

Background Williams Syndrome is a developmental disorder characterized by a variable intellectual disability. People with Williams Syndrome need the intervention of several clinical and educational specialists throughout their life. However, little is known about the impact produced by this disability in their immediate environment, especially in families. The purpose was to know the level of quality of life described by families with Williams Syndrome. Methods The sample was made up of 33 families belong to Spanish Williams Syndrome Association who were evaluated using the Kidslife Scale. Their children and adolescents were between 4 and 20 years old. Eight main quality of life domains were evaluated: emotional well-being, physical well-being, material well-being, personal development, interpersonal relations, social inclusion, self-determination and rights Results The obtained data indicated that the degree and presence of intellectual disability did not homogeneously influence people’s quality of life, but many variables could alter their quality of life to a greater or lesser extent. There are no significant differences between quality of life areas but significant differences appeared for level of dependence in the self-determination subarea (p Conclusions These results led us to analyse the social and emotional implications for families and their environment.

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children's Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children's Anxiety Scale-Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.

to evaluate cochlear functionality in Williams syndrome (WS) individuals.a study with 39 individuals, being 22 with WS aged between 7 and 17 years, 15 male and 7 female, and 17 individuals with typical development and normal hearing. All individuals were evaluated using pure tone audiometry, acoustic immittance measurements, and Transient Evoked Otoacoustic Emissions (TEOAE). The audiological profile in individuals with WS was analyzed, and TEOAE responses were compared between WS individuals without hearing loss and typical developmental individuals.The hearing loss was observed in 50% of patients, being 78.95% sensorineural and 21.05% mixed. This hearing loss was predominantly mild to moderate, affecting mainly frequencies above 3 kHz. As for TEOAE, there was a higher incidence of absence and lower amplitude responses in individuals with WS.WS individuals have hair cell dysfunction, mainly in the basal region of the cochlea. Thus, TEOAE analysis is an important clinical resource to be considered in the routine audiological evaluation.avaliar o perfil audiológico e a funcionalidade coclear em indivíduos com SW.estudo com 39 indivíduos, sendo 22 indivíduos com SW com idade entre 7 e 17 anos, sendo 15 do sexo masculino e 7 do sexo feminino e 17 indivíduos com desenvolvimento típico e normo-ouvintes. Todos os indivíduos foram avaliados por meio da audiometria tonal limiar, medidas de imitância acústica e análise das Emissões Otoacústicas Transientes (EOAT). Foi avaliado o perfil audiológico dos indivíduos com SW, e também foram comparadas as respostas das EOAT entre os indivíduos com SW sem perda auditiva e indivíduos controles.perda auditiva foi observada em 50% dos pacientes, sendo 78,95% neurossensorial e 21,05% mista. Esta perda foi predominantemente de grau leve a moderado, acometendo principalmente as frequências a partir de 3 kHz. Quanto às EOAT, observou-se maior incidência de ausência e de respostas de menor amplitude em indivíduos com SW.indivíduos com SW apresentam disfunção das células ciliadas, principalmente da região basal da cóclea. Assim, a análise das EOAT é um recurso clínico importante a ser considerada na avaliação audiológica de rotina.

Background Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys. Methods Clinical features and genetic workup of a patient presenting with incidental schwannomatosis. Results A 19‐year‐old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1‐related schwannomatosis and 7q11.23 duplication syndrome. Conclusion We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries., A nineteen year old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1 related schwannomatosis and 7q11.23 duplication syndrome. We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries.

Williams-Beuren syndrome is a chromosomal disorder caused by a deletion at region 7q11.23. Lower urinary tract symptoms are highly prevalent and significantly affect quality of life. We assessed the long-term outcomes of lower urinary tract symptoms in children with Williams-Beuren syndrome.From February 2001 to July 2016, 90 patients with Williams-Beuren syndrome were evaluated in our hospital, of whom 31 (20 boys) had at least 5 years of followup. Baseline evaluation included a history of lower urinary tract symptoms, frequency-volume chart and the impact on quality of life measured on a scale of 0 (delighted) to 6 (terrible). Pharmacological therapy with oxybutynin or doxazosin was offered to symptomatic patients. We present the outcome of lower urinary tract symptoms after 5 and 10 years of followup.At baseline 27 (87.1%) patients were symptomatic. Median duration of followup was 10 (range 6-13) years. Pharmacological therapy was started for 25 (92.6%) symptomatic patients at baseline, including oxybutynin for 19 (76.0%), doxazosin for 1 (4.0%) and a combination of the 2 agents for 5 (20.0%). Medical therapy was still in use by 61.2% after 5 years and 52.9% after 10 years (p=0.043). Median duration of pharmacological treatment was 7 (range 6-11) years. A significant improvement of lower urinary tract symptoms was observed over time, with 35.5% and 29.5% patients considered symptomatic after 5 years and 10 years, respectively (p0.001). Quality of life was also markedly improved over time (p0.001).This long-term study showed significant improvement of lower urinary tract symptoms in children and adolescents with Williams-Beuren syndrome over time. Long-term pharmacological treatment was needed in most patients.

Purpose This case report highlights the functional and quality-of-life outcomes of an 8-week treadmill training program for an 18-month old child with Williams syndrome who is not walking. Summary of key points The child had clinical improvements in gross motor function and quality of life as determined by the Gross Motor Function Measure and Pediatric Quality of Life Inventory after 8 weeks of treadmill training as an outpatient. Statement of conclusion and recommendations for clinical practice Treadmill training is clinically feasible and effective for this child with Williams syndrome. Further research is necessary for generalizability. Treadmill training should be considered when developing a plan of care for children with Williams syndrome who are not walking or children with similar deficits.

Introduction Patients with Noonan and Williams–Beuren syndrome present similar facial phenotypes modulated by their ethnic background. Although distinctive facial features have been reported, studies show a variable incidence of those characteristics in populations with diverse ancestry. Hence, a differential diagnosis based on reported facial features can be challenging. Although accurate diagnoses are possible with genetic testing, they are not available in developing and remote regions. Methods We used a facial analysis technology to identify the most discriminative facial metrics between 286 patients with Noonan and 161 with Williams‐Beuren syndrome with diverse ethnic background. We quantified the most discriminative metrics, and their ranges both globally and in different ethnic groups. We also created population‐based appearance images that are useful not only as clinical references but also for training purposes. Finally, we trained both global and ethnic‐specific machine learning models with previous metrics to distinguish between patients with Noonan and Williams–Beuren syndromes. Results We obtained a classification accuracy of 85.68% in the global population evaluated using cross‐validation, which improved to 90.38% when we adapted the facial metrics to the ethnicity of the patients (p = 0.024). Conclusion Our facial analysis provided for the first time quantitative reference facial metrics for the differential diagnosis Noonan and Williams–Beuren syndromes in diverse populations., Although distinctive facial features have been reported between Noonan and Williams–Beuren syndromes, studies have found a variable incidence of those characteristics in populations with diverse ancestry. We sought to identify and quantify facial features discriminative of these two syndromes in population with diverse ancestry using facial analysis. We provide for the first time quantitative reference facial metrics in diverse populations that can be used both at the clinic and for training purposes.