Antenatal ultrasound features of isolated recurrent copy number variation in 7q11.23 (Williams syndrome and 7q11.23 duplication syndrome).

OBJECTIVE: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes. METHODS: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France. RESULTS: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated. CONCLUSION: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.

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.

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.

Neuroanatomical correlates of social approach in Williams Syndrome and down syndrome.

Individuals with Williams Syndrome (WS) or Downs Syndrome (DS) are often described as hypersociable, friendly and overly trusting of others. This hypersociability is a major concern for parents/caregivers due to the associated increased risk of exploitation and victimisation. Two brain regions - the amygdala and the orbitofrontal cortex (OFC) - have been implicated in driving this hypersociability in WS, and in the general population and have associations with emotional evaluation, threat detection and social motivation. However, there has been little neuroimaging research on this topic, especially in DS, to date. The aim of the present study was to investigate the potential neuroanatomical and neuropsychological correlates of hypersociability in WS and DS. Twelve individuals with WS (M = 22 years of age) and eleven individuals with DS (M = 26 years of age) completed a neuropsychological battery of executive functioning and social measures, including informant ratings on an ecologically measure of social approach. Clinical groups and twelve typically developing controls (M = 23 years) underwent a magnetic resonance imaging scan to investigate volumetric differences in the OFC and the amygdala. As expected, WS individuals displayed the highest overall social approach, especially in relation to need to approach strangers and drive to interact with strangers, as well as inappropriate/overfriendly behaviours. Both groups rated similarly in terms of social trust and unconditional positive regard. Emotion recognition abilities were similar across groups, with the DS group displaying some difficulties with negative emotions (especially anger). Inhibition and flexibility were similarly impaired across WS and DS. Compared to neurotypical controls, the DS group showed increased amygdala volumes bilaterally, while the WS group showed an enlarged right medial OFC. Approach ratings were significantly correlated with left amygdala and medial and left lateral OFC volumes in WS, and with these same regions bilaterally in DS. Results provide potential biological explanations for the hypersociability seen in WS and DS. Future research should focus on other potential neural correlates, as well as potential genetic and hormonal contributions to approach.

Moyamoya Syndrome in a Patient with Williams Syndrome: A Case Report.

INTRODUCTION: Moyamoya syndrome associated with Williams syndrome is very rare but has been reported to have severe outcomes. Here, we reported a case of Williams syndrome with moyamoya syndrome that was confirmed by the presence of an RNF213 mutation. CASE PRESENTATION: A 6-year-old boy with Williams syndrome presented with right hemiparesis induced by hyperventilation. Magnetic resonance angiography and cerebral angiography showed severe stenosis of the bilateral internal carotid arteries and development of moyamoya vessels. Genetic analysis identified a heterozygous c.14576G>A (p.R4859K) mutation in RNF213. Moyamoya syndrome was diagnosed, and bilateral indirect revascularization surgery was conducted without complications and with a good postoperative course. In moyamoya syndrome associated with Williams syndrome, adequate perioperative management of both the moyamoya arteries and the cardiovascular abnormalities is important to prevent complications. CONCLUSION: This was the first report on a case in which moyamoya syndrome associated with Williams syndrome was confirmed by the presence of a heterozygous RNF213 mutation. Similar to the workup of moyamoya disease, confirmation of RNF213 mutation in Williams syndrome may be useful in predicting the development of moyamoya syndrome that can lead to severe complications.

Mid-trimester isolated bilateral rocker bottom feet leading to prenatal diagnosis of 7q11.23 microdeletion: Williams syndrome.

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.

Determination of craniofacial and dental characteristics of individuals with Williams-Beuren syndrome by using 3D facial scans and radiographs.

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.

Left Ventricular Outflow Tract Gradient Is Associated With Coronary Artery Obstruction in Children With Williams-Beuren Syndrome.

OBJECTIVES: 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. DESIGN: 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. SETTING: Single-center university teaching hospital. PARTICIPANTS: The study included 49 patients with Williams-Beuren syndrome who underwent transthoracic echocardiogram, cardiac catheterization, and/or surgical interventions. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSION: LVOT gradient can serve as a good predictor of the presence of coronary obstruction in patients with Williams-Beuren syndrome.

Aortic Geometry in Patients with Duplication 7q11.23 Compared to Healthy Controls.

The aim of this study was to compare the size and geometry of the aorta in patients with 7q11.23 duplication (Dup7) to healthy controls. We retrospectively reviewed all echocardiograms in all patients with Dup7 evaluated at our institutions from June 2017 through September 2019. All standard aortic diameter measurements were made and recorded. Z-scores for the measurements were calculated. For comparison, a set of control echocardiograms was developed by randomly selecting 24 normal echocardiograms in age-matched patients who had undergone echocardiograms for an indication of either chest pain or syncope. In 58 echocardiograms from 21 Dup7 patients, all aortic measurements were increased compared to controls (p < 0.0001). Effacement of the sinotubular junction (STJ) of the aorta was present in all Dup7 patients. Our novel STJ-to-aortic annulus ratio of ≥ 1.15 had a 98.28% sensitivity (95% CI 90.76-99.96) and 100% specificity (95% CI 85.75-100) for distinguishing Dup7 from controls with a positive predictive value of 100% and a negative predictive value of 96.00% (95% CI 77.47-99.41). All patients in our study with Dup7 had echocardiographic evidence of aortopathy. Effacement of the STJ was present in all Dup7 patients. The STJ-to-annulus ratio is a better indicator of aortopathy in Dup7 than the aortic Z-score.

Williams-Beuren Syndrome: The Role of Cardiac CT in Diagnosis.

Williams-Beuren syndrome is a multisystem genetic disorder associated with cardiovascular abnormalities, the most common of which is some variation of arterial stenosis. We describe a case of Williams-Beuren syndrome with multiple cardiovascular structural and arterial abnormalities and demonstrate the unique role of cardiac computed tomography in diagnosis.

The importance of FDG PET/CT in the diagnostic process of the middle aortic syndrome in a 15-year-old boy patient with suspected systemic vasculitis and final diagnosis of Williams-Beuren syndrome.

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

Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity.

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

Successful mitral valve repair for isolated mitral regurgitation in a child with Williams syndrome.

Williams syndrome is a genetic disorder associated with various cardiovascular abnormalities, most commonly supravalvar aortic stenosis and peripheral pulmonary stenosis. However, isolated severe mitral regurgitation necessitating surgical intervention is extremely rare. Here, we present the case of a 14-year-old child with Williams syndrome and isolated severe mitral regurgitation who underwent successful mitral valve repair.

Variaciones anatómicas de la silla turca en radiografías laterales de cráneo. Hospital "Faustino Pérez", 2017-2018 / Anatomic variants of sella turcica in lateral crania radiographies. Hospital “Faustino Pérez¨, 2017-2018

RESUMEN Introducción: diversos autores reflejan que la morfología de la silla turca constituye un factor predisponente para algunas enfermedades. Por ejemplo, se considera que existe correlación entre la morfología de esta estructura anatómica y varias patologías; como el síndrome de la silla turca vacía, síndrome de Williams, paladar hendido, entre otras. Objetivo: describir las variaciones anatómicas de la silla turca que se observan en las radiografías laterales de cráneo del Hospital Universitario "Faustino Pérez" de la ciudad de Matanzas, en el período de enero del 2017 a enero del 2018. Materiales y métodos: el universo fue 140 radiografías laterales de cráneo, de estas 85 pertenecieron al sexo femenino y 55 al masculino. Las variables estudiadas fueron edad, sexo y variaciones anatómicas de la silla turca. Se emplearon métodos teóricos y empíricos. Resultados: se observó un predominio de la variación anatómica de la silla turca en forma de U, en ambos sexos. Seguido de la forma de J, predominando la variación en forma de U en el grupo etario de 41 a 50 años y la forma de J en los pacientes mayores de 60 años. Conclusiones: es imprescindible el conocimiento de la anatomía normal de la silla turca y de sus variaciones anatómicas, tanto para las especialidades quirúrgicas como para las no quirúrgicas. Un análisis exhaustivo de la morfología de esta estructura es necesario para establecer parámetros que excluyan determinadas patologías (AU).

ABSTRACT Introduction: several authors declare that sella turcica morphology is a predisposing factor to several diseases. For example, it is considered that there is a correlation between the morphology of this anatomical structure and several pathologies like empty sella turcica syndrome, Williams syndrome, cleft palate and others. Objective: to describe the anatomical variants of sella turcica observed in side cranial radiographies of the University Hospital ¨Faustino Perez¨ of Matanzas, in the period January 2017-January 2018. Materials and methods: the universe was 140 side cranial radiography: 85 belonged to female patients and 55 to male patients. The studied variables were age, sex and sella turcica anatomical variables. Theoretic and empirical methods were used. Results: it was observed a predominance of the U-shaped sella turcica anatomical variant in both sexes, followed by the J-shaped one. The U-shaped form predominated in the 41-50-years-old age-group and the J-shaped form in patients elder than 60 years. Conclusions: it is essential to know sella turcica normal anatomy and its anatomical variables, both for the surgical specialties and for the non-surgical ones. It is necessary the exhaustive analysis of this structure to establish parameters excluding several pathologies (AU).

Variaciones anatómicas de la silla turca en radiografías laterales de cráneo. Hospital "Faustino Pérez", 2017-2018 / Anatomic variants of sella turcica in lateral crania radiographies. Hospital "Faustino Pérez¨, 2017-2018

RESUMEN Introducción: diversos autores reflejan que la morfología de la silla turca constituye un factor predisponente para algunas enfermedades. Por ejemplo, se considera que existe correlación entre la morfología de esta estructura anatómica y varias patologías; como el síndrome de la silla turca vacía, síndrome de Williams, paladar hendido, entre otras. Objetivo: describir las variaciones anatómicas de la silla turca que se observan en las radiografías laterales de cráneo del Hospital Universitario "Faustino Pérez" de la ciudad de Matanzas, en el período de enero del 2017 a enero del 2018. Materiales y métodos: el universo fue 140 radiografías laterales de cráneo, de estas 85 pertenecieron al sexo femenino y 55 al masculino. Las variables estudiadas fueron edad, sexo y variaciones anatómicas de la silla turca. Se emplearon métodos teóricos y empíricos. Resultados: se observó un predominio de la variación anatómica de la silla turca en forma de U, en ambos sexos. Seguido de la forma de J, predominando la variación en forma de U en el grupo etario de 41 a 50 años y la forma de J en los pacientes mayores de 60 años. Conclusiones: es imprescindible el conocimiento de la anatomía normal de la silla turca y de sus variaciones anatómicas, tanto para las especialidades quirúrgicas como para las no quirúrgicas. Un análisis exhaustivo de la morfología de esta estructura es necesario para establecer parámetros que excluyan determinadas patologías.

ABSTRACT Introduction: several authors declare that sella turcica morphology is a predisposing factor to several diseases. For example, it is considered that there is a correlation between the morphology of this anatomical structure and several pathologies like empty sella turcica syndrome, Williams syndrome, cleft palate and others. Objective: to describe the anatomical variants of sella turcica observed in side cranial radiographies of the University Hospital ¨Faustino Perez¨ of Matanzas, in the period January 2017-January 2018. Materials and methods: the universe was 140 side cranial radiography: 85 belonged to female patients and 55 to male patients. The studied variables were age, sex and sella turcica anatomical variables. Theoretic and empirical methods were used. Results: it was observed a predominance of the U-shaped sella turcica anatomical variant in both sexes, followed by the J-shaped one. The U-shaped form predominated in the 41-50-years-old age-group and the J-shaped form in patients elder than 60 years. Conclusions: it is essential to know sella turcica normal anatomy and its anatomical variables, both for the surgical specialties and for the non-surgical ones. It is necessary the exhaustive analysis of this structure to establish parameters excluding several pathologies.

Rare copy number variants contribute pathogenic alleles in patients with intestinal malrotation.

BACKGROUND: Intestinal malrotation is a potentially life-threatening congenital anomaly due to the risk of developing midgut volvulus. The reported incidence is 0.2%-1% and both apparently hereditary and sporadic cases have been reported. Intestinal malrotation is associated with a few syndromes with known genotype but the genetic contribution in isolated intestinal malrotation has not yet been reported. Rare copy number variants (CNVs) have been implicated in many congenital anomalies, and hence we sought to investigate the potential contribution of rare CNVs in intestinal malrotation. METHODS: Analysis of array comparative genomic hybridization (aCGH) data from 47 patients with symptomatic intestinal malrotation was performed. RESULTS: We identified six rare CNVs in five patients. Five CNVs involved syndrome loci: 7q11.23 microduplication, 16p13.11 microduplication, 18q terminal deletion, HDAC8 (Cornelia de Lange syndrome type 5 and FOXF1) as well as one intragenic deletion in GALNT14, not previously implicated in human disease. CONCLUSION: In the present study, we identified rare CNVs contributing pathogenic or potentially pathogenic alleles in five patients with syndromic intestinal malrotation, suggesting that CNV screening is indicated in intestinal malrotation with associated malformations or neurological involvements. In addition, we identified intestinal malrotation in two known syndromes (Cornelia de Lange type 5 and 18q terminal deletion syndrome) that has not previously been associated with gastrointestinal malformations.

Three-Patch Aortic Root Reconstruction With Extended Left Main Coronary Artery Patch Augmentation in Neonates and Infants.

Left main coronary artery (LMCA) stenosis is present in approximately 5% of patients with congenital supravalvular aortic stenosis (SVAS) (Fig. 1)1 and is associated with an increased risk of sudden cardiac death.2 However, patients undergoing coronary artery intervention at the time of SVAS repair are at the highest risk of experiencing major adverse cardiac events.3 Literature reports of surgical techniques and outcomes of concomitant coronary artery repair in these high-risk patients are diverse and inconsistently described. We have recently adopted a standardized surgical technique for management of this complex pathology by combining extended LMCA patch augmentation with a 3-patch aortic root reconstruction (Brom's technique). In this report, we describe our contemporary surgical technique of 3-patch aortic root reconstruction with extended LMCA patch augmentation for patients with congenital SVAS with ostial LMCA stenosis and bilateral outflow tract obstruction. Institutional review board approval was obtained for retrospective review of patient charts.