Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Incidental Diagnosis of Williams Syndrome in an Adult With Recurrent Hypercalcemia.

Williams syndrome (WS) is a rare genetic disorder with multisystem involvement associated with hypercalcemia. The cause of this hypercalcemia is poorly understood and while primarily associated with WS children, it is also observed in adults. A 51-year-old woman with intellectual disability, renal insufficiency, recurrent pancreatitis, and intermittent hypercalcemia despite partial parathyroidectomy presented with hypercalcemia to 14 mg/dL (3.49 mmol/L; normal 8.6-10.5 mg/dL [2.12-2.62 mmol/L]) at routine follow-up. Laboratory testing was notable for acute-on-chronic renal failure with unremarkable vitamin D, urine calcium, and parathyroid hormone. She presented to the emergency department and was admitted. Treatment with bisphosphonates, calcitonin, and intravenous fluids decreased calcium to 9.4 mg/dL (2.35 mmol/L) and improved kidney function. She was discharged with recommendations for increased oral hydration, a low-calcium diet, and outpatient follow-up. Her phenotype was suspicious for WS, later confirmed with genetic testing. This case exemplifies both the increased risk of hypercalcemia in WS adults and the need to consider WS in hypercalcemic adults with intellectual disability. It also serves to illustrate the importance of recognizing WS features in potentially undiagnosed adults and reviews guidelines for hypercalcemia surveillance and management in WS adults.

Optical coherence tomography angiography findings in Williams-Beuren syndrome.

PURPOSE: Williams-Beuren syndrome (WBS) is a rare genetic disease characterized by psychomotor delay, cardiovascular, musculoskeletal, and endocrine problems. Retinal involvement, which is not well characterized, has also been described. The purpose of this cross-sectional study is to describe the characteristics in optical coherence tomography (OCT) and OCT-angiography (OCTA) of patients with WBS. METHODS: We included patients with WBS confirmed by genetic analysis. The patients underwent OCT (30° × 25°, 61 B-scans) and OCTA (10° × 10° and 20° × 20°) examinations, all centered on the. Data on retinal thickness (total, inner and outer layers) and foveal morphology on OCT and vessel and perfusion density in OCTA (VD and PD, respectively) were collected. These data were compared with an age-matched control group. RESULTS: 22 eyes of 22 patients with WBS (10 females, mean age 31.5 years) were included. Retinal thickness (and specifically inner retinal layers) in OCT was significantly reduced in all sectors (central, parafoveal, and perifoveal) compared to the control group (p < 0.001 in all sectors). Fovea in WBS eyes was broader and shallower than controls. The PD and VD in both 10 and 20 degrees of fields in OCTA was significantly reduced in patients with WBS, in all vascular plexa (all p < 0.001). CONCLUSIONS: This study is the first to quantify and demonstrate retinal structural and microvascular alterations in patients with WBS. Further studies with longitudinal data will reveal the potential clinical relevance of these alterations.

Lethal Fungal Aortitis In Surgically Corrected Supravalvular Aortic Stenosis In A Child With Williams Syndrome.

Williams syndrome (WS), is a multisystem disorder occurring in 1 in 10,000 live births with supravalvular aortic stenosis (SVAS) being the most common cardiovascular manifestation. We present the case of a 2.5 years old male, a known case of WS who presented with cognitive delay, a history of right-sided stroke and left hemiplegia. Echocardiography revealed severe SVAS with a gradient of 105 mmHg. The diameter of the Sino tubular junction was 4 mm. Computerized tomography angiogram showed diffuse stenosis of ascending aorta with intraluminal thrombus. At surgery, the ascending aorta was augmented with autologous pericardial patches and end-to-end anastomosis of the proximal and distal aorta completed the reconstruction. The patient was discharged in a stable condition. He presented 6 weeks post-op with a pulsating pseudoaneurysm through the sternal wound. Emergency surgery with the removal of fungal vegetation and reconstruction of the ascending aorta was performed. He expired due to fungal sepsis a week later.

Dysfunctional Mitochondria in the Cardiac Fibers of a Williams-Beuren Syndrome Mouse Model.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder that, together with a rather characteristic neurocognitive profile, presents a strong cardiovascular phenotype. The cardiovascular features of WBS are mainly related to a gene dosage effect due to hemizygosity of the elastin (ELN) gene; however, the phenotypic variability between WBS patients indicates the presence of important modulators of the clinical impact of elastin deficiency. Recently, two genes within the WBS region have been linked to mitochondrial dysfunction. Numerous cardiovascular diseases are related to mitochondrial dysfunction; therefore, it could be a modulator of the phenotype present in WBS. Here, we analyze mitochondrial function and dynamics in cardiac tissue from a WBS complete deletion (CD) model. Our research reveals that cardiac fiber mitochondria from CD animals have altered mitochondrial dynamics, accompanied by respiratory chain dysfunction with decreased ATP production, reproducing alterations observed in fibroblasts from WBS patients. Our results highlight two major factors: on the one hand, that mitochondrial dysfunction is probably a relevant mechanism underlying several risk factors associated with WBS disease; on the other, the CD murine model mimics the mitochondrial phenotype of WBS and could be a great model for carrying out preclinical tests on drugs targeting the mitochondria.

Parallel deletion and duplication at 7q11.23 in a silent carrier for two reciprocal syndromic disorders.

Partial deletions at chromosome 7q11.23 are causative for the autosomal-dominant Williams-Beuren syndrome (WBS), whereas the partial duplication of this region leads to the 7q11.23 duplication syndrome. Both syndromes are highly penetrant and occur with a frequency of 1:7500-10,000 (WBS) and 1:13,000-20,000 (7q11.23 duplication syndrome). They are associated with multiple organ defects, intellectual disability, and typical facial dysmorphisms showing broad phenotypic variability. The 7q11.23 region is susceptible to chromosomal rearrangements due to flanking segmental duplications and regions of long repetitive DNA segments. Here, we report on a family with two children affected by WBS and clinically unaffected parents. Interestingly, metaphase fluorescence in situ hybridization (FISH) revealed a deletion on 7q11.23 in the father. Intensive genetic testing, using interphase FISH, whole genome sequencing and optical genome mapping led to the confirmation of a 1.5 Mb deletion at one 7q11.23 allele and the identification of a reciprocal 1.8 Mb duplication at the other allele. This finding is highly important regarding genetic counseling in this family. The father is a silent carrier for two syndromic disorders, thus his risk to transmit a disease-causing allele is 100%. To the best of our knowledge we, here, report on the first case in which the phenotype of a microdeletion/microduplication syndrome was compensated by its reciprocal counterpart.

Prenatal phenotype features and genetic etiology of the Williams-Beuren syndrome and literature review.

Objective: To share our experience on prenatal diagnosis of Williams-Beuren syndrome(WBS) and to improve the awareness, diagnosis, and intrauterine monitoring of the fetuses of this disease. Methods: The study retrospectively evaluated 14 cases of WBS diagnosed prenatally by single nucleotide polymorphism array (SNP-array). Clinical data from these cases were systematically reviewed, including maternal demographics, indications for invasive prenatal diagnosis, ultrasound findings, SNP-array results, trio-medical exome sequencing (Trio-MES) results, QF-PCR results, pregnancy outcomes and follow-ups. Results: A total of 14 fetuses were diagnosed with WBS and their prenatal phenotypes were assessed retrospectively. In our case series, the most common ultrasound features were intrauterine growth retardation (IUGR), congenital cardiovascular defects, abnormal fetal placental doppler indices, thickened nuchal translucency(NT) and polyhydramnios. Other less common ultrasound features include fetal hydrops, hydroderma, bilateral pleural effusion, subependymal cysts, etc. Parental chromosome analysis was performed in seven pairs of parents, and all the deletions on chromosome 7q11.23 were de novo. Conclusion: Prenatal ultrasound features of WBS cases are highly variable, with IUGR, cardiovascular abnormalities and abnormal fetal placental doppler indices, being the most common intrauterine phenotypes. Our case series expand the intrauterine phenotypes of WBS, including cardiovascular abnormalities right aortic arch(RAA) combined with persistent right umbilical vein(PRUV) and elevated the ratio of end-systolic peak flow velocity to end-diastonic peak flow velocity(S/D). In the meantime, with the decrease in the cost of the next-generation sequencing, the method may become widely used in prenatal diagnosis in the near future.

Prenatal Diagnosis of Williams-Beuren Syndrome Based on Suspected Fetal Hypotonia in Early Pregnancy.

In this report, we describe a rare case of prenatal diagnosis of Williams-Beuren syndrome (WBS). While the prenatal diagnosis of WBS is very rare, in the current case, WBS was diagnosed in early pregnancy. The key element was the detection of fetal hands hypotonia and generalized fetal hypotonia at 17 weeks of gestation. This led to the diagnosis of WBS by molecular karyotyping, specifically array comparative genomic hybridization (arrayCGH) of the fetal DNA. The genetic material was acquired by extraction from the fetal cells which are abundant in the amniotic fluid drawn by amniocentesis. Clinical hypotonia of the affected individuals is a clinical characteristic that is widely associated with WBS; however, fetal hypotonia has not been described as a diagnostic criterion for the prenatal diagnosis of WBS.

Heart Rate Variability Analysis May Identify Individuals With Williams-Beuren Syndrome at Risk of Sudden Death.

BACKGROUND: Williams-Beuren syndrome (WBS) (Online Mendelian Inheritance in Man #194050) is a rare genetic multisystem disorder resulting from a chromosomal microdeletion at 7q11.23. The condition is characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis. Those with WBS have an increased risk of sudden death, but mechanisms underlying this phenotype are incompletely understood. OBJECTIVES: The aim of this study was to quantify and compare autonomic activity as reflected by heart rate variability (HRV) measures in a cohort of individuals with WBS (n = 18) and age- and sex-matched control subjects (n = 18). METHODS: We performed HRV analysis on 24-hour electrocardiography recordings using nonlinear, time and frequency domain analyses on a cohort of subjects with WBS and age- and sex-matched control subjects enrolled in a prospective cross-sectional study designed to characterize WBS disease natural history. RESULTS: WBS subjects demonstrated diminished HRV (reflected by the SD of the NN intervals [P = 0.0001], SD of the average NN interval for 5-minute intervals over 24 hours [P < 0.0001], average of the 5-minute SDs of NN intervals for 24 hours [P = 0.0002], root mean square of successive differences of NN intervals [P = 0.0004], short axis of the Poincaré plot (SD1) [P < 0.0001], and long axis of the Poincaré plot [P < 0.0001]) and indirect markers of parasympathetic activity (reflected by the percent of NN intervals different from previous by 50% or more of local average [P < 0.0007], root mean square of successive differences of NN intervals [P = 0.0004], natural log high-frequency power [P = 0.0038], and SD1 [P < 0.0001]). Additional parameters were also significantly different, including natural log very low-frequency power (decreased; P = 0.0002), natural log low-frequency power (decreased; P = 0.0024), and SD1 divided by the long axis of the Poincaré plot (decreased; P < 0.0001). CONCLUSIONS: Individuals with WBS demonstrate significant HRV abnormalities consistent with diminished autonomic reserve. Future studies will be needed to determine the relationship between autonomic dysregulation observed and sudden death risk seen in these patients. (Impact of Elastin Mediated Vascular Stiffness on End Organs; NCT02840448).

Williams-Beuren syndrome with pseudoaneurysm of aortic arch and infective vegetations for modified broms procedure: anesthetic concerns & Echocardiographic illustrations.

Williams-Beuren syndrome is a rare genetic malformation with predilection for supravalvular aortic stenosis. Apart from cardiovascular malformation, hypocalcemia, developmental delay, and elfin facies, challenging airway make perioperative management more eventful. Association of infective endocarditis within the aortic arch and pseudoaneurysm formation is infrequent. We, hereby report a case of pseudoaneurysm formation and infective vegetation within the aortic arch in a patient with Williams syndrome and the role of transthoracic echocardiography in its perioperative management.

The Combined Treatment of Curcumin with Verapamil Ameliorates the Cardiovascular Pathology in a Williams-Beuren Syndrome Mouse Model.

Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.

Williams-Beuren syndrome associated with hammock mitral valve: First case report.

Williams-Beuren syndrome (WBS) is a multisystem congenital disorder, whose cardiovascular defects are the leading cause of death. We present the case of a 38-year-old man with features of heart failure. The imaging studies showed a typical supravalvular aortic stenosis and a hammock mitral valve, this last, being a rare congenital disease. This is the first case reported of a hammock mitral valve in a patient with this chromosomopathy.

Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients.

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome.

GTF2IRD1, a gene on chromosome 7 which encodes a transcription factor, is of significant clinical interest due to its heterozygous loss as part of the classical deletion associated with Williams-Beuren syndrome (WBS). However, biallelic variants in GTF2IRD1 alone as part of an autosomal recessive disease have not been previously reported. Here, we present two full brothers with variants in trans of GTF2IRD1 at c.1231C > T (p.Arg411Trp) and c.2632C > G (p.Leu878Val). A detailed clinical phenotype is described, which includes severe neurodevelopmental disability, facial dysmorphology, and pectus excavatum. Importantly, out of eight full siblings, only these two brothers harboring both variants in trans present with the profound described phenotype. We present the possibility that these brothers represent the identification of a new syndrome characterized by biallelic variants in GTF2IRD1, which may also have important implications for the molecular etiology of WBS.

First description of frequent occurrence of supernumerary lumbar ribs and transitional vertebrae in children with Williams-Beuren syndrome.

BACKGROUND: Williams-Beuren syndrome is a rare multisystemic genetic disorder with an incidence of 1 in 7,500 live births. Because these children often have scoliosis, they undergo routine radiographic examinations of the spine. During these examinations we have found many children with supernumerary lumbar ribs arising from the first lumbar vertebra, often associated with lumbosacral transitional vertebrae. OBJECTIVE: To describe the incidence of supernumerary ribs and transitional vertebrae in children with Williams-Beuren syndrome and compare it to the incidence in a general population. Our hypothesis is that these findings are common, but they have not been described in the literature concerning Williams-Beuren syndrome. MATERIALS AND METHODS: From January 2015 to October 2021, 308 patients (138 male) with Williams-Beuren syndrome were treated at our hospital. Of these, 106 (47 male) underwent diagnostic imaging, mostly for suspected scoliosis. Panoramic radiographs of the whole spine were performed in 88 patients and radiographs of regions of the spine, chest radiographs, CT, MRI or fluoroscopy in 18 patients. We retrospectively analysed the images concerning the number of ribs and vertebrae. We correlated the frequency of lumbar ribs and transitional vertebrae in comparison to a general population as described in the literature. RESULTS: After exclusions for insufficient imaging, we analysed imaging in 91 patients. Of these, 67 patients (73.6%) had 13 ribs, of which 85% were located on both sides, 9% on the right and 6% on the left side. Of the 67 patients with supernumerary lumbar ribs, 38 (57%) also had transitional vertebrae. CONCLUSION: Supernumerary lumbar ribs arising from the first lumbar vertebra, often accompanied by lumbosacral transitional vertebrae, are common in children with Williams-Beuren syndrome.

Fluorescence in situ hybridization (FISH) as an irreplaceable diagnostic tool for Williams-Beuren syndrome in developing countries: a literature review / Hibridização in situ fluorescente (FISH) como ferramenta diagnóstica insubstituível para a síndrome de Williams-Beuren em países em desenvolvimento: uma revisão de literatura

ABSTRACT Objective: The aim of this study was to sum up and characterize all Williams-Beuren syndrome cases diagnosed by fluorescence in situ hybridization (FISH) since its implementation, as well as to discuss FISH as a cost-effective methodology in developing countries. Data source: From January 1986 to January 2022, articles were selected using the databases in PubMed (Medline) and SciELO. The following terms were used: Williams syndrome and In Situ Hybridization, Fluorescence. Inclusion criteria included Williams-Beuren syndrome cases diagnosed by FISH with a stratified phenotype of each patient. Only studies written in English, Spanish, and Portuguese were included. Studies with overlapping syndromes or genetic conditions were excluded. Data synthesis After screening, 64 articles were included. A total of 205 individuals with Williams-Beuren syndrome diagnosed by FISH were included and further analyzed. Cardiovascular malformations were the most frequent finding (85.4%). Supravalvular aortic stenosis (62.4%) and pulmonary stenosis (30.7%) were the main cardiac alterations described. Conclusions: Our literature review reinforces that cardiac features may be the key to early diagnosis in Williams-Beuren syndrome patients. In addition, FISH may be the best diagnostic tool for developing nations that have limited access to new technologic resources.

RESUMO Objetivo: Caracterizar todos os casos de síndrome de Williams-Beuren (SWB) diagnosticados por hibridização in situ fluorescente (FISH) desde sua implementação, assim como discutir a relação custo-benefício da metodologia de FISH em países em desenvolvimento. Fontes de dados: Entre janeiro de 1986 e janeiro de 2022 foi realizada uma busca nas bases de dados PubMed (Medical Literature Analysis and Retrieval System Online — Medline) e Scientific Electronic Library Online (SciELO) usando os seguintes termos: síndrome de Williams e hibridização in situ fluorescente. O critério de inclusão utilizado foi conter a descrição detalhada de caso(s) de SWB por FISH. Apenas estudos escritos em inglês, espanhol e português foram incluídos. Trabalhos que apresentavam sobreposição de síndromes/condições genéticas foram excluídos. Síntese dos dados: Após os processos de inclusão, 64 artigos e 205 indivíduos com SWB diagnosticados por meio do método de FISH foram incluídos. O achado mais frequente entre os indivíduos foi a presença de algum tipo de malformação cardíaca (85,4%). A estenose aórtica supravalvar (62,4%) e a estenose pulmonar (30,7%) foram as alterações cardíacas mais descritas. A maioria dos estudos era proveniente dos continentes Europa, Ásia e América do Norte. Conclusões: A presente revisão de literatura reitera que as malformações cardíacas podem ser a chave para o diagnóstico precoce em pacientes com SWB. Ainda, a técnica de FISH parece ser a melhor ferramenta de diagnóstico para os países em desenvolvimento, cujo acesso às novas tecnologias ainda é escasso.

[Williams-Beuren syndrome: a retrospective study of a series of 11 cases at the Mohammed VI University Hospital in Marrakech]. / Syndrome de Williams-Beuren: étude rétrospective d'une série de 11 cas du Centre Hospitalier Universitaire Mohammed VI de Marrakech.

Williams-Beuren syndrome is a rare genetic disease (1/20 000) characterized by a microdeletion at 7q11.23 encompassing about 28 genes, including the elastin gene, ELN. It is a sporadic disease in the majority of cases. Easily identifiable in childhood, this developmental disorder associates suggestive face dysmorphism, cardiac defect, psychomotor retardation and specific behavioural and cognitive profile. We conducted a retrospective study of 11 patients with Williams-Beuren syndrome whose data were collected in the Genetics Department of the Mohammed VI University Hospital of Marrakech. The average age of patients was 6.05 years (SD=6.56; interquartile range=5), with a female predominance (64%; 7/11 patients). Almost all patients were mentally retarded and the diagnosis was confirmed in 100% (11) of patients using fluorescence in situ hybridisation (FISH).

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome.

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.

Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system ­ which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins ­ has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells.

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.

Complicated Diverticulitis in a 35-Year-Old Patient With Williams Syndrome: A Case Report.

Williams syndrome is caused by a deletion of the elastin gene on chromosome 7. One of the main roles of this gene is to maintain the strength and elasticity of the intestinal wall, and the absence of the elastin gene may predispose these patients to gastrointestinal pathology such as diverticulitis. Our patient was a 35-year-old Caucasian female with Williams syndrome who presented to the emergency department with diffuse abdominal pain for two days. A computed tomography (CT) scan of her abdomen and pelvis initially showed locally perforated sigmoid diverticulitis with pelvic abscess and acute peritonitis. Surgical management was indicated after the patient failed to respond to conservative treatment. She was treated with Hartmann's procedure which showed purulent peritoneal fluid intraoperatively. Her hospital course was complicated by postoperative ileus and a peri-incisional abscess. After a 15-day hospital stay, she was discharged home with plans for ostomy reversal in six months. Patients with Williams syndrome have an increased risk of developing diverticulitis at a younger age than the general population due to their propensity for chronic constipation stemming from their child-like eating habits and low dietary fiber. Thus, we emphasize the importance of treating constipation in patients with Williams syndrome to prevent diverticulitis. If these patients present to the emergency department with acute diverticulitis, aggressive surgical management may be beneficial because rapid progression could ensue.