Williams-Beuren syndrome--stretching to learn big lessons from small patients

Abstract

Paediatric patients usually play a minor role in the grand arena of hypertension and cardiovascular disease. Patients with Williams–Beuren syndrome (WBS), comprising a rare small subset of the paediatric hypertensive population, would not necessarily be expected to be of outstanding interest. However, the elucidation of the small gene region which is deleted in WBS has led to fascinating pathophysiological insights, shedding light on a large array of molecular mechanisms involved in hypertension and opening treatment perspectives far beyond established antihypertensive drug therapy. WBS was first described in 1961 as a combination of stenoses of the largeand medium-sized arteries combined with facial dysmorphic signs, short stature, failure to thrive and mild to moderate mental retardation [1,2]. Other facultative features include transient hypercalcaemia in infancy, small teeth, joint stiffness, scoliosis, sensorineural hearing loss, hyperreflexia, problems of visio-spatial processing, anxiety, phobic and perseverative tendencies (for a full list of clinical features of WBS, see OMIM #194050). The syndrome is caused by heterozygous microdeletion of the ‘WBS critical region’ on the long arm of chromosome 7 encompassing about 28 genes [3,4]. The most important gene in this region in terms of cardiovascular changes is the elastin (ELN) gene. Heterozygous disruptions of ELN alone without other gene losses in the WBS critical region cause autosomal dominant familial supravalvular aortic stenosis (SVAS) without other features of WBS (for a full list of clinical features of WBS, see OMIM #194050; for a full list of clinical descriptions of familial SVAS, see OMIM #185500). Tropoelastin, the ELN gene product, is exported to the extracellular matrix, assembled on a microfibrillar scaffold and enzymatically cross-linked into large polymers named elastin, which make up the bulk of elastic fibres. Besides its structural functions, elastin interacts with surrounding cells of the extracellular matrix. Impaired elastogenesis causes smooth muscle cells to proliferate and migrate [5]. Reduced elastin synthesis combined with increased smooth muscle cell proliferation of the intima and media is not only seen in the ‘elastin arteriopathy’ of WBS, familial SVAS and their corresponding animal models [6], but also in vascular proliferative disorders such as atherosclerosis and coronary restenosis. Elastic fibres are initially deposited in plaques but later diminish with increasing lipid and calcium deposition [7]. Elastin levels are particularly low in ruptured aortic atheromas [8], suggesting that elastin could be a key to understanding why and when plaques rupture. The therapeutic potential of elastin lies in its capability to prevent the proliferation of smooth muscle cells and stabilize their mature phenotype. Covering coronary artery stents in pigs with elastin limits the neointimal proliferation which often leads to restenosis [5]. Addition of soluble elastin to cell cultures can restore their normal phenotype in Eln−/− animal cells and in human cells from patients with WBS or familial SVAS [5,6]. The inhibition of matrix metalloproteinases, which are involved in the remodelling of extracellular matrix by degrading elastin, is another therapeutic approach to vascular proliferation [9]. Other drugs such as glucocorticoids [10] and retinoids [11] can increase elastin expression, but to date have been tested exclusively in animal models of foetal and neonatal lung development. Even a number of nutritional approaches have been investigated with compounds which affect the enzymatic crosslinking, deposition or degradation of elastin, such as copper, β-aminopropionitrile, dill extract, ellagic acid and tannic acid [3]. Despite this wealth of exciting research about elastin, there are still many unanswered questions regarding WBS and the pathophysiology of many of its clinical features. The origin of arterial hypertension, for example, which is present in about 17% of WBS patients [3], is still a matter of debate. In this issue of NDT, Bouchrieb et al. report on a French series of 41 patients with WBS and hypertension. Whereas renal artery stenosis can clearly cause hypertension in WBS, it was found only in 58% of hypertensive WBS patients in this study. This corresponds well to a previous report by Rose et al. where only nine of 17 hypertensive WBS patients (53%) had renal artery stenosis, while six (35%) had narrowing of the thoracic or suprarenal aorta and two had normal aortas [12]. Rather than considering suprarenal aortic narrowing to be a