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Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by special facial gestalt, delayed development, and supravalvular aortic stenosis or/and stenosis of the branches of the pulmonary artery. We aim to develop and optimize accurate models of facial recognition to assist in the diagnosis of WBS, and to evaluate their effectiveness by using both five-fold cross-validation and an external test set. We used a total of 954 images from 135 patients with WBS, 124 patients suffering from other genetic disorders, and 183 healthy children. The training set comprised 852 images of 104 WBS cases, 91 cases of other genetic disorders, and 145 healthy children from September 2017 to December 2021 at the Guangdong Provincial People's Hospital. We constructed six binary classification models of facial recognition for WBS by using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. Transfer learning was used to pre-train the models, and each model was modified with a variable cosine learning rate. Each model was first evaluated by using five-fold cross-validation and then assessed on the external test set. The latter contained 102 images of 31 children suffering from WBS, 33 children with other genetic disorders, and 38 healthy children. To compare the capabilities of these models of recognition with those of human experts in terms of identifying cases of WBS, we recruited two pediatricians, a pediatric cardiologist, and a pediatric geneticist to identify the WBS patients based solely on their facial images. We constructed six models of facial recognition for diagnosing WBS using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. The model based on VGG-19BN achieved the best performance in terms of five-fold cross-validation, with an accuracy of 93.74% ± 3.18%, precision of 94.93% ± 4.53%, specificity of 96.10% ± 4.30%, and F1 score of 91.65% ± 4.28%, while the VGG-16BN model achieved the highest recall value of 91.63% ± 5.96%. The VGG-19BN model also achieved the best performance on the external test set, with an accuracy of 95.10%, precision of 100%, recall of 83.87%, specificity of 93.42%, and F1 score of 91.23%. The best performance by human experts on the external test set yielded values of accuracy, precision, recall, specificity, and F1 scores of 77.45%, 60.53%, 77.42%, 83.10%, and 66.67%, respectively. The F1 score of each human expert was lower than those of the EfficientNet-b3 (84.21%), ResNet-50 (74.51%), VGG-16 (85.71%), VGG-16BN (85.71%), VGG-19 (83.02%), and VGG-19BN (91.23%) models. Conclusion: The results showed that facial recognition technology can be used to accurately diagnose patients with WBS. Facial recognition models based on VGG-19BN can play a crucial role in its clinical diagnosis. Their performance can be improved by expanding the size of the training dataset, optimizing the CNN architectures applied, and modifying them with a variable cosine learning rate. What Is Known: • The facial gestalt of WBS, often described as "elfin," includes a broad forehead, periorbital puffiness, a flat nasal bridge, full cheeks, and a small chin. • Recent studies have demonstrated the potential of deep convolutional neural networks for facial recognition as a diagnostic tool for WBS. What Is New: • This study develops six models of facial recognition, EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN, to improve WBS diagnosis. • The VGG-19BN model achieved the best performance, with an accuracy of 95.10% and specificity of 93.42%. The facial recognition model based on VGG-19BN can play a crucial role in the clinical diagnosis of WBS. [ABSTRACT FROM AUTHOR]

Introduction: Williams-Beuren syndrome is a contiguous gene syndrome caused by microdeletion of the locus 7q11.23. It is a clinically recognizable condition whose cardinal features include growth deficiency, variable degrees of neurodevelopmental disorders, congenital cardiac defects, outgoing personality, and typical facies. Case Series Presentation: This retrospective study analyzed 38 consecutive patients in a single center for rare diseases, diagnosed by Preus criteria modified by the Sugayama scoring system, comprising 17 male and 21 female individuals aged 1 month to 55 years. Cases were divided into two groups concerning (a) exclusive clinical diagnosis or (b) clinical diagnosis followed by a laboratory cytogenetic or cytogenomic test; except for hypertension, no significant difference was seen among both groups. The most frequent findings were intellectual deficiency, developmental delay, typical facies, and overfriendliness, all above 80% of the total sample. On the other hand, supravalvar aortic stenosis was found in only 32.4%, while other congenital heart diseases were seen in 56.7% of the sample. Unusual features included one individual with 13 pairs of ribs, another with unilateral microphthalmia, and three with unilateral renal agenesis. Comorbidities comprised 9 cases of hypothyroidism and 1 case each of precocious puberty, segmental vitiligo, type 1 diabetes mellitus, and congenital adrenal hyperplasia. Conclusion: Preus criteria modified by the Sugayama scoring system are still efficient and helpful for clinical diagnosis. This is the second report on microphthalmia and the first study describing the association between vitiligo, type 1 diabetes mellitus, and congenital adrenal hyperplasia in individuals with Williams-Beuren syndrome. [ABSTRACT FROM AUTHOR]

Williams–Beuren syndrome (WBS) is a rare genetic condition caused by a chromosomal microdeletion at 7q11.23. It is a multisystem disorder characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis (SVAS). Those with WBS are at increased risk of sudden death, but mechanisms underlying this remain poorly understood. We recently demonstrated autonomic abnormalities in those with WBS that are associated with increased susceptibility to arrhythmia and sudden cardiac death (SCD). A recently introduced method for heart rate variability (HRV) analysis called "heart rate fragmentation" (HRF) correlates with adverse cardiovascular events (CVEs) and death in studies where heart rate variability (HRV) failed to identify high-risk subjects. Some argue that HRF quantifies nonautonomic cardiovascular modulators. We, therefore, sought to apply HRF analysis to a WBS cohort to determine 1) if those with WBS show differences in HRF compared with healthy controls and 2) if HRF helps characterize HRV abnormalities in those with WBS. Similar to studies of those with coronary artery disease (CAD) and atherosclerosis, we found significantly higher HRF (4 out of 7 metrics) in those with WBS compared with healthy controls. Multivariable analyses showed a weak-to-moderate association between HRF and HRV, suggesting that HRF may reflect HRV characteristics not fully captured by traditional HRV metrics (autonomic markers). We also introduce a new metric inspired by HRF methodology, significant acute rate drop (SARD), which may detect vagal activity more directly. HRF and SARD may improve on traditional HRV measures to identify those at greatest risk for SCD both in those with WBS and in other populations. NEW & NOTEWORTHY: This work is the first to apply heart rate fragmentation analyses to individuals with Williams syndrome and posits that the heart rate fragmentation parameter W3 may enable detection and investigation of phenomena underlying the proarrhythmic short-long-short RR interval sequences paradigm known to precede ventricular fibrillation and ventricular tachycardia. It also forwards a novel method for quantifying sinus arrhythmia and sinus pauses that likely correlate with parasympathetic activity. [ABSTRACT FROM AUTHOR]

Williams–Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one‐third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often‐complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state‐of‐the‐art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

The widespread introduction of molecular genetic research methods into health care practice has made it possible to diagnose rare microdeletion syndromes in patients with multiple congenital malformations. Aim of the study is to present the results of a literature search and demonstrate a clinical observation of Williams-Beuren syndrome in 10-month-old monochorionic twins with congenital malformations of the cardiovascular system in combination with kidney pathology and an additional spleen. Results. Williams-Beuren syndrome (WBS) is a rare congenital disorder characterized by specific craniofacial dysmorphisms (elphic face) and a hoarse voice in combination with cardiovascular damage, mental retardation, musculoskeletal disorders, and hypercalcemia. WBS occurs in the population with a frequency of 1:7,500-1000 infants. The presence of a specific phenotype is associated with a hemizygous microdeletion of the long arm of chromosome 7 at region 7q11.23. The size of the deletion varies from 1.5 to 1.8 Mb and results in the loss of several neighboring genes. The diagnosis is made syndromologically and confirmed by modern molecular cytogenetic methods. Pathologically significant WBS mutations include loss of the ELN gene and loss of neighboring genes such as LIMK1, RFC2, BAZ1B, GTF2I, STX1A, CLIP2, GTF2IRD, NCF. Haploinsufficiency of ELN gene is the main marker of WBS and causes insufficient synthesis of elastin protein, which leads to development of pathology of heart and blood vessels (elastin arteriopathy), disorders of connective apparatus of joints, abnormalities of vocal cords and skin. LIMK1 hemizygosity is associated with impaired visual-spatial constructive cognition. Deletion of the RFC2 gene can cause growth retardation and developmental delay. Reduced intelligence can be caused by a mutation of the GTF2I gene and hypercalcemia by a mutation of the BAZ1B gene. The phenotypic manifestations of WBS are also thought to be influenced by the reduced expression of flanking intact genes. The diagnosis, treatment, and adjustment of patients with WBS require an interdisciplinary team of specialists. The presented clinical case demonstrates multisystem pathology in 10-month-old monochorionic dizygotic twins in whom Williams-Beuren syndrome was clinically diagnosed and confirmed by FISH: ish del (7)(q11.23q11.23)(ELN-). Conclusion. To confirm the genetic component in congenital multisystem pathology, it is necessary to use modern molecular genetic diagnostic methods. Determination of genetic mutation, its size and origin is important for medical genetic counseling. Early confirmation of the WBS allows to make an individual prognosis of the child's life and development, as well as to determine in time the optimal methods of treatment and adaptation, and to advise the parents in planning the next birth of children in the family. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Background/aim: Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a reliable diagnostic test, WBS is becoming more widely recognized in childhood. Adaptive behavior skills and/or maladaptive behavior are important for the prognosis of individuals with WBS. The aim of this study was to investigate the clinical and developmental characteristics of patients with WBS and further increase awareness about it by evaluating the adaptive skills and maladaptive behaviors of the patients. Materials and methods: The data of WBS patients followed-up at the Developmental Behavioral Pediatrics Unit were reviewed. Patient data on perinatal and postnatal history, developmental stages, physical and neurological examination findings were collected. The International Guide for Monitoring Child Development (GMCD) was administered to each child. In addition, semistructured interviews were conducted with the parents using the Vineland Adaptive Behavior Scales, Second edition (Vineland-II). Results: A total of 12 patients diagnosed with WBS via detection of the 7q11.23 deletion, of whom 6 were girls, were retrospectively reviewed. The mean age at the time of review was 54.6 ± 32.5 months. The mean age at first presentation to the Developmental Behavioral Pediatrics Outpatient Clinic was 15 ± 11.5 months. In the first developmental evaluation using the GMCD, there was a delay in fine and gross motor domains in 6 patients, in the language domains in 4 patients, and in all of the domains in 2 patients. Findings with Vineland-II showed socialization and communication domains as strengths, but the daily living skills and motor skills domains were weaknesses. In terms of maladaptive behavior, the patients tended to frequently have behavioral problems, neurodevelopmental disease, anxiety disorders, eating problems, and sleeping problems. Conclusion: This retrospective review of 12 patients indicated a general delay in overall development, and confirmed impairment in both adaptive and maladaptive functioning in WBS. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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.

Abstract Background There are a few literature reports of prenatal ultrasound manifestations of Williams-Beuren syndrome. We aimed to explore the prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis and describe the prenatal ultrasound performance of this syndrome. Methods In this retrospective study, we reported eight cases of Williams-Beuren syndrome diagnosed at our prenatal diagnostic center from 2016 to 2021. We systematically reviewed clinical data from these cases, including indications for invasive testing, sonographic findings, QF-PCR results, chromosomal microarray analysis results, and pregnancy outcomes. Results In this study, the common ultrasound features were ventricular septal defect (37.5%), intrauterine growth retardation (25%), and aortic coarctation (25%). Moreover, all patients were found to have a common deletion in the Williams-Beuren syndrome chromosome region at the 7q11.23 locus, which contained the elastin gene. Deletion sizes ranged from 1.42 to 2.07 Mb. Seven parents asked for termination of pregnancy, and one patient was lost to follow-up. Conclusions This study is the most extensive prenatal study using chromosomal microarray analysis technology for detailed molecular analysis of Williams-Beuren syndrome cases. We reported three cases combined with first-reported ultrasound manifestations. Case 1 was concomitant with multicystic dysplastic kidney and duodenal atresia combined with case 3. Notably, case 4 was combined with multiple cardiovascular malformations: Tetralogy of Fallot, right aortic arch, and supravalvar aortic stenosis. These manifestations expand the intrauterine ultrasound phenotype of Williams-Beuren syndrome in previous literature reports.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Genes associated with specific neurocognitive phenotypes in Williams–Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams–Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams–Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1. However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS.

Genes associated with specific neurocognitive phenotypes in Williams–Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams–Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams–Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1. However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS. [ABSTRACT FROM AUTHOR]

Williams syndrome is a multisystem disorder characterized by developmental delay, characteristic facial features, growth abnormalities, and cardiovascular abnormalities. The disorder is an autosomal dominant genetic syndrome that occurs due to microdeletion at chromosomal locus 7q11.23. Seizures occur uncommonly in association with Williams syndrome. Mutations in the  TNK2  gene have been found in rare cases of autosomal recessive infantile-onset epilepsy. We describe a rare co-occurrence of Williams syndrome and  TNK2  gene-related epilepsy in a child born of consanguineous parents. This case report emphasizes the role of genetic testing in the diagnosis of rare diseases. This is the fourth case report of epilepsy with biallelic mutations in the  TNK2  gene, to the best of the authors' knowledge., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Aster CMI Hospital Institutional Ethics Committee issued approval IEC Letter no Aster/IEC/Other/001/2023-24. This case report was considered and approved under “exempt” category by institutional ethics committee. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Angel et al.)

Williams-Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one-third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often-complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state-of-the-art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

Aim:Williams-Beuren syndrome, which is characterized by dysmorphic facial features, cardiovascular findings, intellectual disability, endocrine abnormalities and a typical cognitive profile, is caused by a microdeletion in the 7q11.23 region. In this study, we aimed to evaluate the dysmorphic and clinical manifestations of patients with Williams-Beuren syndrome.Materials and Methods:We retrospectively collected data from 27 Turkish patients who had clinically and genetically confirmed Williams- Beuren syndrome. Their multisystemic manifestations, demographic data and dysmorphic facial features were recorded.Results:All patients had the characteristic facial phenotype. The most frequent dysmorphic facial features were periorbital fullness, short nose, broad nasal tip and wide mouth. Aortic stenosis (59.2%) and pulmonary stenosis (37%) were the most common cardiac findings. Short stature (25.9%), idiopathic central precocious puberty (7.4%), hypothyroidism (congenital, non-congenital or subclinical) (40.7%) and hypercalcemia (3.7%) were the major endocrine manifestations in the patients. Genitourinary abnormalities were detected in 6 patients. All patients had some degree of intellectual disability; most of the patients (62.9%) had mild intellectual disability. Additionally, behavioral problems were frequently detected and the most common abnormality was overfriendliness (77.7%). Renal abnormalities (double collecting system, bladder diverticula and renal calculi) were also detected.Conclusion:Dysmorphic facial features, which have a crucial role in the diagnosis of Williams-Beuren syndrome, should be assessed in suspected patients with supravalvular aortic stenosis and concomitant intellectual disability in order to make an early diagnosis. It should be kept in mind that endocrine abnormalities, musculoskeletal, neurologic and psychiatric manifestations are also common in patients with Williams-Beuren syndrome, necessitating a multidisciplinary approach.

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 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.

Background: Williams‐Beuren syndrome (WBS) is caused by a microdeletion on chromosome 7q11‐23 and clusters a variety of systemic affectations. Aim: To investigate whether 3D facial scans can detect WBS by objectively addressing their craniofacial, skeletal and dental characteristics, compared with those of a non‐affected control group. Materials and Methods: 3D facial surface scans of 17 WBS individuals and 33 normal developing patients were analysed. Additionally, cephalometric and panoramic radiographs of subjects with WBS were compared with those of non‐affected individuals. Results: The 3D surface scans showed significant facial differences around the nose and mouth area. The cephalometric aspects of individuals with WBS differed mainly at the lower incisor region. Additionally, hypoplastic tooth morphology seems to be more often present in WBS. Conclusion: 3D images are a non‐invasive, efficient method to observe facial anomalies and facilitate an early diagnosis of WBS. Additionally, the analysis of the cephalometric and panoramic images revealed significant differences in dental characteristics. Together with early diagnosis through 3D images, these can help in the establishment of adequate medical, dental and orthodontic treatment planning. [ABSTRACT FROM AUTHOR]

Background: There are a few literature reports of prenatal ultrasound manifestations of Williams-Beuren syndrome. We aimed to explore the prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis and describe the prenatal ultrasound performance of this syndrome. Methods: In this retrospective study, we reported eight cases of Williams-Beuren syndrome diagnosed at our prenatal diagnostic center from 2016 to 2021. We systematically reviewed clinical data from these cases, including indications for invasive testing, sonographic findings, QF-PCR results, chromosomal microarray analysis results, and pregnancy outcomes. Results: In this study, the common ultrasound features were ventricular septal defect (37.5%), intrauterine growth retardation (25%), and aortic coarctation (25%). Moreover, all patients were found to have a common deletion in the Williams-Beuren syndrome chromosome region at the 7q11.23 locus, which contained the elastin gene. Deletion sizes ranged from 1.42 to 2.07 Mb. Seven parents asked for termination of pregnancy, and one patient was lost to follow-up. Conclusions: This study is the most extensive prenatal study using chromosomal microarray analysis technology for detailed molecular analysis of Williams-Beuren syndrome cases. We reported three cases combined with first-reported ultrasound manifestations. Case 1 was concomitant with multicystic dysplastic kidney and duodenal atresia combined with case 3. Notably, case 4 was combined with multiple cardiovascular malformations: Tetralogy of Fallot, right aortic arch, and supravalvar aortic stenosis. These manifestations expand the intrauterine ultrasound phenotype of Williams-Beuren syndrome in previous literature reports. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Williams-Beuren Syndrome (SWB) is a neurodevelopmental disorder caused by the deletion of an area on chromosome 7q11.23. It is a major cause of intellectual disability, with a specific linguistic and cognitive phenotype. This article presents the language characteristics of infants with SWB, with an emphasis on the skills and weaknesses of these children, and investigation of if and how these characteristics persist in adolescence. From review of current research and clinical findings, the cognitive characteristics of the syndrome are analyzed, with emphasis on the relationship between the language and cognitive profile. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundWilliams-Beuren Syndrome (WBS) is a genetic disorder associated with multisystemic abnormalities, including craniofacial dysmorphology and cognitive defects. It is caused by a hemizygous microdeletion involving up to 28 genes in chromosome 7q11.23. Genotype/phenotype analysis of atypical microdeletions implicates two evolutionary-related transcription factors, GTF2I and GTF2IRD1, as prime candidates for the cause of the facial dysmorphology.ResultsUsing a targeted Gtf2ird1 knockout mouse, we employed massively-parallel sequencing of mRNA (RNA-Seq) to understand changes in the transcriptional landscape associated with inactivation of Gtf2ird1 in lip tissue. We found widespread dysregulation of genes including differential expression of 78 transcription factors or coactivators, several involved in organ development including Hey1, Myf6, Myog, Dlx2, Gli1, Gli2, Lhx2, Pou3f3, Sox2, Foxp3. We also found that the absence of GTF2IRD1 is associated with increased expression of genes involved in cellular proliferation, including growth factors consistent with the observed phenotype of extreme thickening of the epidermis. At the same time, there was a decrease in the expression of genes involved in other signalling mechanisms, including the Wnt pathway, indicating dysregulation in the complex networks necessary for epidermal differentiation and facial skin patterning. Several of the differentially expressed genes have known roles in both tissue development and neurological function, such as the transcription factor Lhx2 which regulates several genes involved in both skin and brain development.ConclusionsGtf2ird1 inactivation results in widespread gene dysregulation, some of which may be due to the secondary consequences of gene regulatory network disruptions involving several transcription factors and signalling molecules. Genes involved in growth factor signalling and cell cycle progression were identified as particularly important for explaining the skin dysmorphology observed in this mouse model. We have noted that a number of the dysregulated genes have known roles in brain development as well as epidermal differentiation and maintenance. Therefore, this study provides clues as to the underlying mechanisms that may be involved in the broader profile of WBS.

Patients with Williams-Beuren syndrome are associated with a high risk of hemodynamic collapse during sedation and/or anesthesia, presumably due to occult coronary obstruction. The objective of this study was to determine the association between transthoracic echocardiogram findings and the presence of coronary obstruction to examine if coronary obstruction can be predicted by transthoracic echocardiogram before anesthesia. Retrospective data analysis of patients with Williams-Beuren syndrome who underwent transthoracic echocardiogram, cardiac catheterization, and/or surgical interventions to determine the correlation between echocardiogram findings and the presence of coronary obstruction determined by cardiac catheterization and/or surgery. Single-center university teaching hospital. The study included 49 patients with Williams-Beuren syndrome who underwent transthoracic echocardiogram, cardiac catheterization, and/or surgical interventions. The only variable associated with coronary artery obstruction was the maximum instantaneous gradient (MIG) across the left ventricular outflow tract (LVOT) on a transthoracic echocardiogram. LVOT MIG ≥ 75 mmHg as the optimal cutoff value was associated with coronary artery obstruction (area under the curve 0.659, odds ratio 6.71, 95% CI 1.31-34.35, p = 0.022). LVOT gradient can serve as a good predictor of the presence of coronary obstruction in patients with Williams-Beuren syndrome. [ABSTRACT FROM AUTHOR]

We present an 18‐month‐old male with Tetralogy of Fallot, retrognathia, short stature, global developmental delay, and dysmorphic features who was found to have dual diagnoses of both Williams syndrome and 22q11.2 deletion syndrome (22q11.2DS). To our knowledge, this is the second case of such a co‐occurrence documented in the medical literature. Our patient presents with a blended physical phenotype of these two conditions and a behavioral phenotype that is distinct from what is typically observed in either disorder alone. We compare our patient's phenotype to the previously reported case and to the typical phenotypes for each individual condition. Additionally, we discuss why the occurrence of these two disorders together seems to be so rare, and the benefit of a genetics evaluation to an inpatient service team and the patient. [ABSTRACT FROM AUTHOR]

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.

Supravalvular aortic stenosis (SVAS) is a congenital malformation associated with Williams-Beuren syndrome. It is characterized by severe stenosis of the sinotubular junction. The smooth muscle layer is thickened due to an alteration of the Elastin gene. The treatment is surgical and there are several techniques to relieve obstruction which range from the single-patch technique to the replacement of all three aortic sinuses with three patches. However, the optimal technique is still unclear. The objective of this article is to carry out a bibliographic review of surgical techniques for SVAS and the description of the application of the Doty technique for a 4-year-old infant at the Roberto Gilbert Elizalde Hospital.

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA (miRNA) cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to larger dendritic spines, increased excitatory synaptic transmission, and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, is sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members are reciprocally dysregulated in isogenic human induced pluripotent stem cell (iPSC)-derived neurons harboring a deletion present in patients with Williams-Beuren syndrome, characterized by hypersocial behavior. Together, our results show an miRNA-actomyosin pathway involved in social behavior regulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Williams syndrome was first reported by Williams and Beuren in 1961-1962. It is a genetic disorder that is caused by a sporadic microdeletion of chromosome 7, which includes the elastin gene. The development of gastrointestinal pathology, such as diverticular disease, is associated with the deletion of this specific gene. Almost one-third of patients with Williams syndrome develop diverticular disease. The first episode of diverticulitis appears in 8% of patients, diagnosed with Williams syndrome, before the age of 40. According to the literature, in the case of complicated diverticulitis (Hinchey III) in patients with WS, the treatment is mainly surgical resection of sigmoid and colostomy (Hartmann procedure) or anastomosis. We present an interesting case with a 31-year-old male, with Williams syndrome and Hinchey III diverticulitis, who underwent laparoscopic lavage and primary closure of the perforation. To our knowledge, this is the first case in literature that a patient with Williams syndrome and complicated diverticulitis (Hinchey III) was treated this way and the results until now are encouraging., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tsaramanidis et al.)

Background: As research on diabetes continues to advance, more complex classifications of this disease have emerged, revealing the existence of special types of diabetes, and many of these patients are prone to misdiagnosis and underdiagnosis, leading to treatment delays and increased health care costs. The purpose of this study was to identify four causes of secondary diabetes., Case Summary: Secondary diabetes can be caused by various factors, some of which are often overlooked. These factors include genetic defects, autoimmune disorders, and diabetes induced by tumours. This paper describes four types of secondary diabetes caused by Williams-Beuren syndrome, Prader-Willi syndrome, pituitary adenoma, and IgG4-related diseases. These cases deviate significantly from the typical progression of the disease due to their low incidence and rarity, often leading to their neglect in clinical practice. In comparison to regular diabetes patients, the four individuals described here exhibited distinct characteristics. Standard hypoglycaemic treatments failed to effectively control the disease. Subsequently, a series of examinations and follow-up history confirmed the diagnosis and underlying cause of diabetes. Upon addressing the primary condition, such as excising a pituitary adenoma, providing glucocorticoid supplementation, and implementing symptomatic treatments, all patients experienced a considerable decrease in blood glucose levels, which were subsequently maintained within a stable range. Furthermore, other accompanying symptoms improved., Conclusion: Rare diseases causing secondary diabetes are often not considered in the diagnosis of diabetes. Therefore, it is crucial to conduct genetic tests, antibody detection and other appropriate diagnostic measures when necessary to facilitate early diagnosis and intervention through proactive and efficient management of the underlying condition, ultimately improving patient outcomes., Competing Interests: Conflict-of-interest statement: All the authors declare no conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Prenatal sonographic depiction of congenital vertical talus (rocker bottom feet), describing a prominent calcaneus and rounded convex appearance of the ventral aspect of the foot, has been reported with fetal Trisomies 18, 13, 9 HOXD10 mutations and recently 2q13 microdeletion. We present a 24 year old in whom mid-trimester sonographic finding of isolated bilateral rocker bottom feet led to diagnosis of 7q11.23 microdeletion—Williams syndrome. This association has not been reported previously. This case emphasizes the critical assessment of detail microarray upon prenatal sonographic notation of abnormal structural fetal features. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: Williams-Beuren syndrome, which is characterized by dysmorphic facial features, cardiovascular findings, intellectual disability, endocrine abnormalities and a typical cognitive profile, is caused by a microdeletion in the 7q11.23 region. In this study, we aimed to evaluate the dysmorphic and clinical manifestations of patients with Williams-Beuren syndrome. Materials and Methods: We retrospectively collected data from 27 Turkish patients who had clinically and genetically confirmed Williams-Beuren syndrome. Their multisystemic manifestations, demographic data and dysmorphic facial features were recorded. Results: All patients had the characteristic facial phenotype. The most frequent dysmorphic facial features were periorbital fullness, short nose, broad nasal tip and wide mouth. Aortic stenosis (59.2%) and pulmonary stenosis (37%) were the most common cardiac findings. Short stature (25.9%), idiopathic central precocious puberty (7.4%), hypothyroidism (congenital, non-congenital or subclinical) (40.7%) and hypercalcemia (3.7%) were the major endocrine manifestations in the patients. Genitourinary abnormalities were detected in 6 patients. All patients had some degree of intellectual disability; most of the patients (62.9%) had mild intellectual disability. Additionally, behavioral problems were frequently detected and the most common abnormality was overfriendliness (77.7%). Renal abnormalities (double collecting system, bladder diverticula and renal calculi) were also detected. Conclusion: Dysmorphic facial features, which have a crucial role in the diagnosis of Williams-Beuren syndrome, should be assessed in suspected patients with supravalvular aortic stenosis and concomitant intellectual disability in order to make an early diagnosis. It should be kept in mind that endocrine abnormalities, musculoskeletal, neurologic and psychiatric manifestations are also common in patients with Williams-Beuren syndrome, necessitating a multidisciplinary approach. [ABSTRACT FROM AUTHOR]