Background/AimsTo characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS).MethodsFifty-seven patients with a diagnosis of WBS and five with SVAS underwent comprehensive ophthalmic evaluation at the National Institutes of Health from 2017 to 2020, including best-corrected visual acuity, slit-lamp biomicroscopy, optical biometry, dilated fundus examination, optical coherence tomography and colour fundus imaging.ResultsMean age of the 57 WBS patients was 20.3 years (range 3–60 years). Best-corrected visual acuity ranged from 20/20 to 20/400 with mean spherical equivalent near plano OU. Twenty-four eyes (21.8%) had an axial length (AL) less than 20.5 mm and 38 eyes (34.5%) had an AL measuring 20.5–22.0 mm. Stellate iris and retinal arteriolar tortuosity were noted in 30 (52.6%) and 51 (89.5%) WBS patients, respectively. Novel retinal findings in WBS included small hypopigmented retinal deposits (OD 29/57, OS 27/57) and broad foveal pit contour (OD 44/55, OS 42/51). Of the five patients with SVAS, none had stellate iris or broad foveal pit contour while 2/5 had retinal arteriolar tortuosity.ConclusionWBS is a complex multisystem genetic disorder with diverse ophthalmic findings that differ from those seen in isolated elastin mediated SVAS. These results suggest other genes within the WBS critical region, aside from ELN, may be involved in observed ocular phenotypes and perhaps broader ocular development. Furthermore, retinal arteriolar tortuosity may provide future insight into systemic vascular findings in WBS.
BackgroundWilliams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin (ELN), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition.MethodsComputed tomography (CT) angiogram (n = 11) and echocardiogram (n = 20) were performed in children with WBS aged 3.4–17.8 years. Controls (n = 11, aged 4.4–16.8 years) also underwent echocardiogram. Eln+/− mice were analyzed by invasive catheter, echocardiogram, micro-CT (μCT), histology, and pressure myography. We subsequently tested whether minoxidil resulted in improved pulmonary vascular endpoints.ResultsWBS participants with a history of main or branch pulmonary artery (PA) stenosis requiring intervention continued to exhibit increased right ventricular systolic pressure (RVSP, echocardiogram) relative to their peers without intervention (p < 0.01), with no clear difference in PA size. Untreated Eln+/− mice also show elevated RVSP by invasive catheterization (p < 0.0001), increased normalized right heart mass (p < 0.01) and reduced caliber branch PAs by pressure myography (p < 0.0001). Eln+/− main PA medias are thickened histologically relative to Eln+/+ (p < 0.0001). Most Eln+/− phenotypes are shared by both sexes, but PA medial thickness is substantially greater in Eln+/− males (p < 0.001). Eln+/− mice showed more acute proximal branching angles (p < 0.0001) and longer vascular segment lengths (p < 0.0001) (μCT), with genotype differences emerging by P7. Diminished PA acceleration time (p < 0.001) and systolic notching (p < 0.0001) were also observed in Eln+/− echocardiography. Vascular casting plus μCT revealed longer generation-specific PA arcade length (p < 0.0001), with increased PA branching detectable by P90 (p < 0.0001). Post-weaning minoxidil decreased RVSP (p < 0.01) and normalized PA caliber (p < 0.0001) but not early-onset proximal branching angle or segment length, nor later-developing peripheral branch number.ConclusionsVascular deficiencies beyond arterial caliber persist in individuals with WBS who have undergone PA stenosis intervention. Evaluation of Eln+/− mice reveals complex vascular changes that affect the proximal and distal vasculatures. Minoxidil, given post-weaning, decreases RVSP and improves lumen diameter, but does not alter other earlier-onset vascular patterns. Our data suggest additional therapies including minoxidil could be a useful adjunct to surgical therapy, and future trials should be considered.
Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). SVAS is present in 67% of those with WBS, but severity varies; 21% have clinically significant SVAS requiring surgical intervention while 33% have no appreciable aortic disease. Little is known about genetic modifiers outside the 7q11.23 region that might contribute to SVAS severity. To investigate, we collaboratively phenotyped 473 individuals with WBS and performed the largest whole-genome-sequencing study to date. We developed a set of strategies for modifier discovery including extreme phenotyping (surgical SVAS vs. no SVAS) and prioritization of non-synonymous variants with increased predicted functional impact along with an allele frequency difference between the extreme phenotype groups. We identified pathways enriched in common or less frequent variants, followed by association testing of SVAS severity with the enriched pathways. The common variant analysis identified pathways including the extracellular matrix and the innate immune system, while pathways encompassing adaptive immunity, ciliary function, lipid metabolism and PI3KAKT were captured by both the common and less frequent variant analyses. Cell cycle and estrogen responsive pathways were among those identified through the less frequent variant analysis. Among the 69 genes reported in other large genome wide association studies assessing aortic traits, 11 genes, including PCSK9 and ILR6, were found in our study, suggesting overlapping disease mechanisms. In summary, this study presents novel strategies for identification of disease modifiers in rare conditions like WBS.
Williams–Beuren syndrome (WS) results from the deletion of 25–27 coding genes, including elastin (ELN), on human chromosome 7q11.23. Elastin provides recoil to tissues; emphysema and chronic obstructive pulmonary disease have been linked to its destruction. Consequently, we hypothesized that elastin insufficiency would predispose to obstructive features. Twenty-two adults with WS (aged 18–55) and controls underwent pulmonary function testing, 6 min walk, and chest computed tomography (CT). Lung and airspace dimensions were assessed in Eln+/− and control mice via microCT and histology. The forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) were lower in adults with WS (p < 0.0001 and p < 0.05, respectively). The FEV1/FVC ratio was more frequently below the lower limit of normal in cases (p < 0.01). The ratio of residual volume to total lung capacity (RV/TLC, percent predicted) was higher in cases (p < 0.01), suggesting air trapping. People with WS showed reduced exercise capacity (p < 0.0001). In Eln+/− mice, ex vivo lung volumes were increased (p < 0.0001), with larger airspaces (p < 0.001). Together these data show that elastin insufficiency impacts lung physiology in the form of increased air trapping and obstruction, suggesting a role for lung function monitoring in adults with WS.
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