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Children and adolescents with Williams-Beuren syndrome (WBS) have been described as having specific memory abilities and emotional reactivity. Although it is well established in the literature that emotion can enhance memory, no such studies have been undertaken in individuals with WBS. In three experiments, the present study tested whether the negative or positive emotional valence of stimuli can influence verbal, visual and visuo-spatial memory by specifically evaluating two memory components: item and associative memory. Sixteen 8- to 18-year-old individuals with WBS performed the first two experiments and, among them, twelve participated in the third. They were compared to equivalent groups of typically developing control children. Participants completed intentional-encoding tasks followed by immediate item recognition, associative recall or item recall tasks. Event-related potential measures during encoding and recognition of pictures were also added in the third experiment. Results demonstrated, for the first time, effects of emotions on visual item memory and visuo-spatial associative memory in individuals with WBS, that were similar to those observed in typically developing children. By combining behavioral and neural measures, our study provides new knowledge of the interaction between emotion and memory in WBS individuals, which seems to be unaffected by their atypical development.

El síndrome de Williams-Beuren es una enfermedad congénita rara por microdeleción del cromosoma 7, que ocurre principalmente por una mutación de novo, y en menor frecuencia por herencia autosómica dominante. Se caracteriza por presentar alteraciones multisistémicas típicas, que incluyen apariencia facial de duendecillo, retraso del crecimiento y alteraciones neurológicas, como retraso mental y comportamiento hipersocial. Alrededor del 80% de los pacientes manifiestan anomalías cardiovasculares estructurales relacionadas con estenosis arterial aórtica o pulmonar. El objetivo de este reporte es presentar el primer caso de síndrome de Williams-Beuren en el departamento del Cauca, de un paciente de 24 meses de edad, atendido por el servicio de Genética Clínica en el Hospital Universitario San José de Popayán, en el cual el diagnóstico clínico se confirmó con el análisis molecular.

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.

Introduction: Williams-Beuren syndrome (WBS) is a gene deletion disorder characterized by distinct facial features, cardiovascular anomalies, and intellectual disability. Many genes are involved in WBS, of which the elastin (ELN) gene deletion is almost present in all cases. Limited data exist about pulmonary diseases in children with WBS. Furthermore, pleural effusion (PE) has not been reported in these patients. Case Presentation: A term, small-for-gestational-age (SGA) male Caucasian newborn presented with respiratory distress shortly after vaginal birth. A chest radiograph showed significant pulmonary edema with bilateral pleural effusion. A 2D Echocardiogram demonstrated supravalvular aortic stenosis and branch pulmonary stenosis suspecting WBS. A genetic evaluation revealed an interstitial 1.5Mb deletion in the long arm of chromosome 7 involving band q11.23 confirming the diagnosis of WBS. The child underwent surgical repair at 4 months for age due to cardiac disease progression. Conclusions: An unexplained finding of pulmonary edema and PE in a newborn can be associated with genetic disorders and warrants investigation for WBS, especially in SGA newborns.

Williams–Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26–28 genes. An estimated 2–5% of patients have “atypical” deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation.

The Dlx homeodomain transcription factors play important roles in the differentiation and migration of GABAergic interneuron precursors. The mouse and human genomes each have six Dlx genes organized into three convergently transcribed bigene clusters (Dlx1/2, Dlx3/4, and Dlx5/6) with cis-regulatory elements (CREs) located in the intergenic region of each cluster. Amongst these, the I56i and I12b enhancers from the Dlx1/2 and Dlx5/6 locus, respectively, are active in the developing forebrain. I56i is also a binding site for GTF2I, a transcription factor whose function is associated with increased sociability and Williams–Beuren syndrome. In determining the regulatory roles of these CREs on forebrain development, we have generated mutant mouse-lines where Dlx forebrain intergenic enhancers have been deleted (I56i(–/–), I12b(–/–)). Loss of Dlx intergenic enhancers impairs expression of Dlx genes as well as some of their downstream targets or associated genes including Gad2 and Evf2. The loss of the I56i enhancer resulted in a transient decrease in GABA+ cells in the developing forebrain. The intergenic enhancer mutants also demonstrate increased sociability and learning deficits in a fear conditioning test. Characterizing mice with mutated Dlx intergenic enhancers will help us to further enhance our understanding of the role of these Dlx genes in forebrain development.

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.

Williams-Beuren syndrome (WBS) is a genetic disorder, caused by a deletion of chromosome 7. WBS characterized by typical facies and personality, cardiovascular disease, connectivetissue growth and endocrine abnormalities. In the oral cavity, malocclusion, micrognathism, hypodontia, enamel hypoplasia, microdontia are among the wide spectrum of abnormalities identifiedin this disease. In this study, orofacial features of a 14-year-old male patient with WBS were presented. This case, contrary the literature, had multiple supernumerary teeth. The literature was reviewed because of this rare condition. Williams Beuren sendromu (WBS) kromozom 7’de mikrodelesyonların neden olduğu genetik bir bozukluktur. WBS kardiyovasküler hastalık, karakteristik fasiyal ve kişilik özellikleri, bağ dokusu büyümesi ve endokrin anormallikleri ile karakterizedir. İntraoral olarak maloklüzyon,mikrognati, hipodonti, mine hipoplazisi ve mikrodonti tespit edilen geniş anomali yelpazesi arasındadır. Bu çalışmada, WBS'li 14 yaşındaki bir erkek hastanın orofasiyal özellikleri sunulmuştur. Buolguda, literatürün aksine, multipl sürnumere dişler mevcuttur. Nadir görülen olgu hakkında literatür bilgileri yeniden gözden geçirilmiştir.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients. This work was supported by Ministerio de Ciencia e Innovación (SAF 2017-83039-R to GE and SAF 2016-78508-R (AEI/MINEICO/FEDER, UE) to VC) from the association “Autour des Williams” to VC and Generalitat de Catalunya (2017-SGR1794) to VC.

Background The Williams-Beuren syndrome (WBS) is a multiple phylogenetic disorder, caused by the hemizygous deletion of 1.55 to 1.84 Mb on chromosome 7q11.23, which encodes a fragment of 26 to 28 genes. Among these genes, the deletion of the elastin (ELN) gene haplotype is the main cause of cardiovascular abnormalities. Other genes, such as CLIP2, GTF2IRD1, and GTF2I, may be associated with specific cognitive and craniofacial features. However, genes associated with specific neurocognitive phenotypes are still controversially discussed. The purpose of this study is to further explore the mechanism of neurodevelopmental disorders in patients with Williams-Beuren syndrome.Patients and methods Patients who had been diagnosed with WBS were recruited. The deletion was precisely defined by chromosome microarray analysis and the clinical phenotype was evaluated. Results This study identified nine patients with atypical deletions from 111 patients with WBS. One patient had normal neurodevelopmental with deletion of Williams-Beuren syndrome chromosomal region (WBSCR) telomere side genes, including GTF2I and GTF2IRD1, while another patient retained these genes but showed neurodevelopmental abnormalities. Seven of the eight patients with the WBSCR22 gene deletion developed growth restriction.Conclusions By comparing the genotype and phenotype of patients with typical deletions and atypical deletions, the deletion of GTF2I and GTF2IRD1 genes alone insufficient to induce typical neurocognitive phenotypes in WBS patients. The BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS. Furthermore, the deletion of the WBSCR22 gene may be the main cause of physical growth restriction in WBS patients.

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.

Supplemental Digital Content is available in the text., Background: Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (ELN) causes Williams-Beuren syndrome (WBS), while single nucleotide variants in ELN cause nonsyndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and nonsyndromic SVAS. Methods: Patients (81 WBS, 42 nonsyndromic SVAS) with cardiovascular disease were included in this retrospective single center study. Freedom from surgical and catheter interventions and reinterventions was compared. Vascular tissue from 8 patients and 6 controls was analyzed for arterial wall architecture. Results: Patients with nonsyndromic SVAS presented at a younger age (median 0.3 [0.4–0.7] years) compared with patients with WBS (1.3 [0.2–3.0] years) and had lower freedom from surgical/catheter interventions compared with patients with WBS, with median event-free survival 1.1 (0.3–5.9) versus 4.7 (2.4–13.3) years, respectively (hazard ratio, 1.62 [95% CI, 1.02–2.56]; P=0.04). Patients with nonsyndromic SVAS also had a lower freedom from reinterventions (P=0.054 by log-rank test). This was related in part to a higher frequency of primary and reinterventions for concomitant valvar aortic stenosis. Histology revealed abnormal intimal and medial thickening, disorganized and fragmented elastic fibers, reduced smooth muscle calponin expression, and increased macrophage marker, CD68, expression in the arterial walls in patients with WBS and nonsyndromic SVAS compared with controls. Conclusions: Patients with nonsyndromic SVAS require early and more frequent vascular and valvular interventions and reinterventions, in particular for concomitant valvar aortic stenosis compared with patients with WBS. This provides important prognostic information to guide counseling of affected families with cardiovascular disease and may guide primary intervention strategies based on predicted risk of restenosis.

Williams–Beuren syndrome (WBS) is caused by an haploinsufficiency of the 7q11.2 region which involves the elastin gene (ELN). A deficiency of elastin is a known pathophysiological mechanism of emphysema/chronic obstructive pulmonary disease (COPD). A previous study hypothesized a higher risk of COPD in WBS patients. Herein, this phenomenon was further investigated looking for a possible correlation between COPD and WBS. Dynamic lung volumes (forced vital capacity [FVC], FEV1, FEV1/FVC) were measured in 22 patients (age range 18.9 ± 7.4 years) affected with WBS, genetically confirmed, correlating these parameters to respiratory risk factors. Dyspnea, cough and wheezing were detected in 6/22 (27%) patients. Obstructive and restrictive patterns were identified in 6/22 (27%) and 2/22 (9%) cases, respectively with no evidence of irreversible obstruction. CVF, FEV1 and FEV1/CVF mean values were all normal, with values of 91.3% (n.v. > 80%), 84.2% (n.v. > 80%) and 0.82 (n.v. > 0.7), respectively. The severity of the comorbidities did not show a cause-effect relation with the respiratory patterns, nevertheless patients treated with anti-hypertensive drugs had poorer pulmonary function. Our findings are in accordance with previous observations, showing that emphysema/COPD is not a typical finding in young patients with WBS. However, a respiratory function assessment should be included in the follow-up of WBS patients, especially in adolescents/young adults under treatment with anti-hypertensive drugs.

Williams-Beuren syndrome is a rare disease with manifestations such as cardiovascular changes, distinct facial features, mental retardation, and learning disabilities. Oral manifestations are not commonly described and can often be misdiagnosed. This report describes the case of a male patient diagnosed with Williams-Beuren syndrome presenting classic clinical features that affect the face as a convex profile, with maxillary protrusion and mandibular retrusion, a discreetly acute nasolabial angle, passive labial sealing, and an open mandibular angle characteristic of Class II skeletal pattern. In addition, the patient has oral manifestations such as the absence of some dental elements, a Class II of Angle 1st division, dental cross bite, and atresic arches. The periodontal condition presents with generalized gingivitis. Knowledge about the possible manifestations of Williams-Beuren syndrome is important to improve the ability of orthodontists to better serve these patients.

Williams-Beuren Syndrome (WBS; OMIM #194050) is a rare neurodevelopmental disorder that results from a deletion at 7q11.23 spanning 25-27 genes. We performed chromosomal microarray analysis (CMA) in 9 Taiwanese patients with WBS to confirm the diagnosis. These samples had already been examined by FISH and diagnosed as WBS. Pathogenic copy number variations (CNVs) were identified in all patients, including 24 genes (spanning from FKBP6 to GTF2I) with typical 7q11.23 microdeletion. A deletion in TRIM50 was common in Taiwanese patients with WBS (8/9). Furthermore, 1 patient had 2 additional gene deletions in NCF1 and GTF2IRD2. We also found 4 patients with duplications of 4p16.1, 16p13.11, 10q26.3, and 21q22.3. All 9 WBS patients exhibited distinctive facial dysmorphisms, including a wide mouth, thick prominent lips, short nose with anteverted nares, and periorbital puffiness. However, cardiac defects were not frequent in our patients (3/9). In conclusion, we detected CNVs associated with WBS in a Taiwanese population using CMA. Although CMA is expensive and labor-intensive, it is useful for identifying typical/atypical CNVs, delineating distal break points, and detecting other CNVs.

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26–28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams–Beuren syndrome (WBS), a multisystem disorder characterized by “hyper-sociability” and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the “canine WBS locus” were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary.

Abstract: Williams syndrome is a rare genetic disorder, that occurs equally in all ethnic groups and both sexes. The diagnosis might be missed during childhood in mild cases. However, establishing the diagnosis is important, not only to find the cause of intellectual disability but to look for cardiovascular, endocrine, psychiatry, urology and other conditions, which can occur at any age in the patients’ lifetime. This case report presents the story of 47-year-old woman, who was admitted with haematemesis. During her stay on the ward, in the light of the distinctive facial features, mental retardation, and social behaviour patterns, the possibility of Williams syndrome emerged. Later, the diagnosis was confirmed by genetic analysis. This female is the oldest living patient with Williams syndrome in Hungary. Orv Hetil. 2017; 158(47): 1883–1888.

Williams–Beuren syndrome (WBS) is a rare multisystem disorder caused by a hemizygous deletion of the elastin gene on chromosome 7q11.23. WBS patients have characteristic skeletal features and dental anomalies accompanied by mental retardation, a friendly outgoing personality, and mild to moderate intellectual disability or learning problems. In this case report, we present the combined orthodontic and surgical treatment of a WBS patient with an isolated cleft palate through a long-term follow-up from the age of 5 to 24 years. During the period of active treatment, comprehensive orthodontic treatment combined with maxillary anterior segmental distraction osteogenesis and prosthetic treatment using dental implants were effective in dramatically improving the patient’s malocclusion. The patient’s mental abilities and the cooperation shown by the patient and her family were crucial for the success of this complex and long-term treatment course.

Objective: This case report is the first to describe functional parathyroid disease in Williams-Beuren Syndrome (WBS). We report a patient with hypercalcemia in infancy and later in adulthood whose unusual complex of elfin facies and multiple medical comorbidities, including hypercalcemia, ultimately led to a diagnosis of WBS by fluorescent in situ hybridization. While hypercalcemia is a common finding in patients with WBS, parathyroid hormone levels are typically suppressed.Methods: This study consists of a case report and literature review conducted in a high-volume university endocrine surgery center. We describe a 58-year-old patient with elfin facies, recurrent hyperparathyroidism, friendly personality, cognitive impairment, recurrent cystitis, hypertension, and stroke who was treated surgically for primary hyperparathyroidism with durable cure of his hypercalcemia. Outcomes are measured with long-term biochemical confirmation of cure after several re-operative surgical interventions.Results: After two parathyroid explorations failed to cure the patient's primary hyperparathyroidism, re-operative resection of an abnormal parathyroid gland resulted in intra-operative parathyroid hormone normalization (300 pg/mL to 57 pg/mL) and subsequent long-term normocalcemia (25 months).Conclusion: Though hypercalcemia is a known feature of WBS, it has not been reported in association with primary hyperparathyroidism. In the setting of WBS, hypercalcemia should be thoroughly evaluated to exclude this condition, which can be surgically cured.Abbreviations:IIH = idiopathic infantile hypercalcemiaIV = intravenousPHP = primary hyperparathyroidismPTH = parathyroid hormoneTRPC3 = transient receptor potential C3WBS = Williams-Beuren syndrome

Williams-Beuren Syndrome (WBS) is a multisystemic disorder with prevalence of 1/7500 [1], affects both genders equally and it is caused by a microdeletion of 26-28 genes, including elastin and NCF1 genes, of the chromosome region 7q11.23 [1,2]. The disease is transmitted in an autosomal dominant fashion, but almost all cases are the result of de novo mutations [1].

Williams-Beuren syndrome (SWB) has genetic etiology, is caused by microdeletions in the region of chromosome 7 q11-23, and presents as clinical manifestations facial dysmorphology, short stature, hypotonia, mental retardation, congenital heart disease, infantile hypercalcemia, and dental anomalies. This study describes a 10-year-old male patient, clinically diagnosed as having SWB, with congenital aortic stenosis and mental retardation, who was followed up by a cardiologist, psychologist, geneticist, speech therapist, and physiotherapist. The patient attended the dental service, evidencing the presence of a mixed dentition, dental calculus, and edematous gingiva as a consequence of poor hygiene. The treatment plan was established through radiographic examinations of the elements 16, 26, 36, and 46; complete blood count; prophylactic antibiotic prescription; medical release for extraction of teeth 85, 84, 74, 53, and 65; restorations; and prophylaxis. At the end of the procedures, the patient returned after 7 days for suture removal, with continuity only for routine examinations.

Adaptive behavior (AB) is defined as the skills acquired in response to everyday life demands. AB profiles of genetic syndromes have been proposed, but the literature on them has not been conclusive, mainly due to the large number of these syndromes and marked within-profile variability. The aim of the present study was to analyze the different ABs observed in subjects with Williams-Beuren Syndrome (WBS), Down Syndrome (DS) and Autistic Spectrum Disorder (ASD) through a literature review using the PubMed and Scopus database. The results indicated that Socialization strongly affects WBS; however, this group demonstrated the greatest amount of difficulty in the domain of daily living. The DS group demonstrated better performance in Socialization and Daily Living compared to Communication. The ASD group displayed better performance in Daily Living and Communication and the worst performance in socialization. Although the reviewed studies appear to demonstrate controversial results related to how ABs occur in each group, the main skills and shortages remained similar to each corresponding diagnostic behavioral characteristic. We conclude that it is possible to build AB profiles in the analyzed diagnostic groups, and we believe that these profiles may facilitate the construction of intervention plans.

The differential diagnosis in children with the systemic vasculopathy is still a challenge for clinicians. The progress in vascular imaging and the latest recommendations improve the diagnostic process, but only single reports describe the use of new imaging tests in children. The publication aims to demonstrate the important role of 18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography combined with anatomical computed tomography angiography (PET/CTA) imaging in the case of a 15-year-old boy with chest pain, intermittent claudication, hypertension and features of middle aortic syndrome in computed tomography angiography (CTA). The patient was suspected to have Takayasu arteritis, but was finally diagnosed with Williams–Beuren syndrome. The case indicates that the FDG PET/CT imaging might be essential in the diagnostic process of middle aortic syndrome in children. We suggest that this imaging technique should be considered in the diagnostic process of systemic vasculopathy particularly in children.

Funding this work was funded by grants from the Spanish Ministry of economy and competiveness (FiS Pi16/00369 and Pi1302481 cofunded by FeDer, and 'Programa de excelencia María de Maeztu' MDM-2014-0370), and the generalitat de catalunya (2017Srg01974 and icrea-acadèmia program). Mc-r had a predoctoral fellowship of Ministry of education, culture and Sport (FPU16/06907) and DP-g had a predoctoral fellowship from the instituto de Salud carlos iii (Fi11/00656). Background The hallmark of the neurobehavioural phenotype of Williams-Beuren syndrome (WBS) is increased sociability and relatively preserved language skills, often described as opposite to autism spectrum disorders (ASD). However, the prevalence of ASD in WBS is 6-10 times higher than in the general population. We have investigated the genetic factors that could contribute to the ASD phenotype in individuals with WBS. Methods We studied four males and four females with WBS and a confirmed diagnosis of ASD by the Autism Diagnostic Interview-Revised. We performed a detailed molecular characterisation of the deletion and searched for genomic variants using exome sequencing. Results A de novo deletion of 1.55 Mb (6 cases) or 1.83 Mb (2 cases) at 7q11.23 was detected, being in 7/8 patients of paternal origin. No common breakpoint, deletion mechanism or size was found. Two cases were hemizygous for the rare T allele at rs12539160 in MLXIPL, previously associated with ASD. Inherited rare variants in ASD-related or functionally constrained genes and a de novo nonsense mutation in the UBR5 gene were identified in six cases, with higher burden in females compared with males (p=0.016). Conclusions The increased susceptibility to ASD in patients with WBS might be due to additive effects of the common WBS deletion, inherited and de novo rare sequence variants in ASD-related genes elsewhere in the genome, with higher burden of deleterious mutations required for females, and possible hypomorphic variants in the hemizygous allele or cis-acting mechanisms on imprinting.

Oxidative stress is the result of an imbalance in the redox state in a cell or a tissue. When the production of free radicals, which are physiologically essential for signaling, exceeds the antioxidant capability, pathological outcomes including oxidative damage to macromolecules, aberrant signaling, and inflammation can occur. Down syndrome (DS) and Williams-Beuren syndrome (WBS) are well-known and common genetic conditions with multi-systemic involvement. Their etiology is linked to oxidative stress with important causative genes, such as SOD-1 and NCF-1, respectively, of the diseases being primarily involved in the regulation of the redox state. Early aging, dementia, autoimmunity, and chronic inflammation are some of the main characteristics of these conditions that can be associated with oxidative stress. In recent decades, there has been a growing interest in the possible role of oxidative stress and inflammation in the pathology of these conditions. However, at present, few studies have investigated these correlations. We provide an overview of the current literature concerning the role of oxidative stress and oxidative damage in genetic syndromes with a focus on Down syndrome and WBS. We hope to provide new insights to improve the management of complications related to these diseases.

Background Williams-Beuren syndrome (WS) is as a rare multisystem genetic syndrome, caused by the hemizygous deletion of approximately 26–28 genes on chromosome 7q11.23. Fluorescence in-situ hybridization (FISH) is considered the gold standard for its diagnosis. However, FISH does not allow the detection of the exact size of the deletion. This study aimed to compare the efficiency and validity of Multiplex Ligation-Dependent Probe Amplification (MLPA) and (FISH) techniques in diagnosing and confirming clinically diagnosed WS. Patients and methods The study comprised twenty-three WS patients they were clinically assessed, cardiovascular evaluation, and laboratory tests, including plasma calcium level, thyroid function tests and glucose tolerance test, were performed. FISH and MLPA analysis were performed for all patients. The MLPA kit (SALSA P029) contained probes for eight genes in the WS critical region: FKBP6, FZD9, TBL2, STX1A, ELN, LIMK1, RFC2, and CYLN2. Results Nineteen patients out of 23 studied cases (82.6%) showed positive deletion of the WS chromosome region (WBSCR) by both FISH and MLPA techniques. One patient (4.3%) showed negative result by FISH while a duplication of the WBSCR was detected by MLPA. Three patients (13.1%) were negative for both FISH and MLPA. In conclusion This is the largest cohort of Egyptian patients with WS, where both FISH and MLPA analysis were used to confirm the diagnosis. MLPA analysis has an advantage over FISH as it is less time consuming and detects smaller, atypical deletions and duplications in the WS.

Williams-Beuren syndrome (WBS; OMIM #194050) is a developmental disorder characterized by congenital heart disease, intellectual disability, dysmorphic facial features and ophthalmologic abnormalities. Virtually every organ and system can be affected in WBS as a result of haploinsufficiency. Most cases are sporadic, although familial cases with autosomal dominant inheritance have been reported. Oral abnormalities are also described in clinical manifestations of the disease. This study describes orofacial features in 17 patients with WBS. Patients with a confirmed molecular diagnosis of WBS were examined for oral abnormalities through clinical oral evaluations and panoramic radiography. Malocclusion, specifically with dental midline deviation, and high-arched palate were the most common oral findings. The present study contributes to the knowledge of orofacial manifestations in WBS. Since such patients with WBS may develop severe oral abnormalities, early detection and treatment can help to improve their quality of life.

Chapter 13 describes the structured pediatric cardiac examination of a patient before an elective cardiovascular intervention. Systematic and targeted clinical- and apparatus-guided assessment is mandatory to allow a correct and full set of diagnostic procedures. The results should provide the most timely, reliable, and effective possible pharmacological, catheter interventional, or surgical treatment. Analysis by means of a classification of heart defects according to functional viewpoints helps engender a regular, pathophysiologically based, pediatric cardiology mindset and avoid typical pitfalls.

Bastug F, Nalcacioglu H, Bas VN, Tekatli-Celik B, Cetinkaya H, Yel S. Acute renal failure due to severe hypercalcemia and nephrocalcinosis treated with two doses of pamidronate in an infant with Williams-Beuren syndrome. Turk J Pediatr 2018; 60: 210-215. Infantile hypercalcemia has been reported in 15% of infants and children with Williams-Beuren syndrome (WBS) and has generally mild clinical symptoms. However, the need for pamidronate treatment in a few infants with severe hypercalcemia associated with WBS has been reported in literature. Many disorders, such as primary hyperoxaluria, associated with nephrocalcinosis can lead to renal failure, but there are only a few reports in infants with WBS who have decreased renal function and nephrocalsinosis. We present a 23-month-old girl with WBS (confirmed with fluorescent in situ hybridization probes) who presented with acute renal failure with severe symptomatic hypercalcemia and nephrocalcinosis, which responded to two infusions of pamidronate.

Hypercalcemia may occur in approximately 15% of children with the Williams-Beuren syndrome. The episodes of hypercalcemic crisis usually respond well to initial hyperhydration, loop diuretics and calcitonin, bisphosphonates, or subsequent dialysis. However, many patients suffer from recurrent or persistent hypercalcemia after the resolution of the hypercalcemic crisis. Although hypercalcemia in the Williams-Beuren syndrome is generally considered transient, it may last for several months, result in significant morbidity, and compromise physical growth. There are no guidelines for the management of persistent or recurrent hypercalcemia in patients with the Williams-Beuren syndrome. In this report, we describe our experience of conducting oral corticosteroid therapy in a child with the Williams-Beuren syndrome who continued to have hypercalcemia after the resolution of the hypercalcemic crisis.Hiperkalcemia może wystąpić u około 15% dzieci z zespołem Williamsa-Beurena. Incydent hiperkalcemicznego przełomu zazwyczaj dobrze odpowiada na leczenie za pomocą nawodnienia, diurtetyków pętlowych, kalyctonimy, bifosfonianów czy późniejszej dializy. Jednak wielu pacjentów, po przebyciu przełomu hiperkalcemicznego, cierpi z powodu nawracającej hiperkalcemii. Chociaż uważa się, że hiperkalcemia w zespole Williamsa-Beurena ma postać przejściową, może jednak trwać kilka miesięcy i prowadzić do istotnego wpływu na przebieg choroby i rozwój fizyczny dziecka. Nie istnieją wytyczne co do postępowania w przetrwałej lub nawracającej hiperkalcemii u pacjentów z zespołem Williamsa-Beurena. W tym doniesieniu, opisujemy nasze doświadczenia z zastosowaniem terapii kortykosteroidami u dziecka z zespołem Williamsa-Beurena, u którego po przebyciu przełomu hiperkalcemicznego utrzymywała się nadal hiperkalcemia.

Williams-Beuren syndrome, also known as Williams syndrome (WS) is a genetic disorder involving the elastin gene on chromosome 7q11.23. Elastin is important for elasticity of vascular walls, and its deficiency can lead to widespread arteriopathy, most notably supravalvar aortic stenosis of the ascending aorta and coronary artery stenosis. Because of these cardiac defects, patients with WS are at high risk for cardiac arrest under anesthesia with a documented incidence around 5%. Appropriate perioperative management of all anesthetics includes a multidisciplinary approach to risk stratification, precise anesthetic management, and disaster planning. This chapter reviews the etiology, pathogenesis, diagnosis, and manifestations of WS. The authors also discuss the preoperative workup and anesthetic implications of WS, as well as issues related to cardiac arrest and extracorporeal cardiopulmonary resuscitation.

WOS: 000446494100005, PubMed ID: 30024395, Objective: The aim of this study was to evaluate the efficacy and safety of the Doty surgical approach in pediatric patients with congenital supravalvular aortic stenosis (SVAS) by examining early and mid-term outcomes. Methods: Surgical repair using the Doty technique was performed in a total of 10 pediatric patients with SVAS between January 2005 and July 2015 at this clinic. These patients were evaluated retrospectively. Demographic characteristics, echocardiographic findings, and clinical outcomes were analyzed. Results: The mean patient age was 4.8 +/- 3.9 years. Williams-Beuren syndrome was diagnosed in 4 of the patients. Early mortality was observed in 1 patient with diffuse SVAS. At the final follow-up (mean follow-up: 3.7 +/- 1.2 years; range: 6-61 months), echocardiograms revealed a mean pressure gradient of 14 +/- 4.2 mmHg. Two patients displayed minimal aortic insufficiency during the follow-up period. No reoperation or reintervention was required. Conclusion: The Doty technique is an anatomically and technically effective surgical approach to treating SVAS.

A 17-year-old male patient diagnosed with Williams-Beuren syndrome presented with a gradual decline in vision in both eyes during a 3-year period. The ophthalmologic examination was notable for numerous loop-shaped tortuous vessels accompanying normal appearing retinal vessels and cystoid macular edema (CME). Mild foveal hypoplasia with a persistence of inner retinal layers was noted on spectral-domain optical coherence tomography (OCT). OCT angiography showed that the abnormal vessels were not retinal vessels but were compatible with prepapillary vascular loops. The CME persisted despite repeated intravitreal bevacizumab treatment. The resolution was observed following an intravitreal triamcinolone acetonide injection. [ Ophthalmic Surg Lasers Imaging Retina . 2019;50:514–518.]

Background Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams–Beuren syndrome (WS). Of particular interest is the unusual social‐cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD‐like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified. Method Here, we deeply phenotyped 85 individuals with WS and used exome sequencing to analyze common and rare variation for association with the remaining variance in social behavior as assessed by the Social Responsiveness Scale. Results We replicated the previously reported unusual juxtaposition of behavioral symptoms in this new patient collection, but we did not find any new alleles of large effect in the targeted analysis of the remaining copy of genes in the Williams syndrome critical region. However, we report on two nominally significant SNPs in two genes that have been implicated in the cognitive and social phenotypes of Williams syndrome, BAZ1B and GTF2IRD1. Secondary discovery driven explorations focusing on known ASD genes and an exome wide scan do not highlight any variants of a large effect. Conclusions Whole exome sequencing of 85 individuals with WS did not support the hypothesis that there are variants of large effect within the remaining Williams syndrome critical region that contribute to the social phenotype. This deeply phenotyped and genotyped patient cohort with a defined mutation provides the opportunity for similar analyses focusing on noncoding variation and/or other phenotypic domains.