Williams Syndrome: from genes to clinical features

textabstractIt all started with the discovery of a narrowing of the ascending aorta, beginning at the superior margin of the sinus of Valsalva in 1842 by N. Chevers (Burn, 1986;Chevers, 1842). This narrowing was named supravalvular aortic stenosis (SVAS) in 1930 by L. Mencarelli (Burn, 1986;Beuren, 1972;Mencarelli, 1930). It can vary from slight to severe concentric constriction to hypoplasia of the entire aorta (Beuren, 1972). In 1961 J.C. Williams and colleagues from New Zealand were the first to suggest that SVAS could be part of a previously unrecognized syndrome. They published the findings of four individuals with SVAS in association with mental retardation and a peculiar facial appearance (Williams et al., 1961). A year later Dr. Alois J. Beuren, a pediatric cardiologist from Germany, independently described four individuals with essentially the same findings and expanded the phenotype with peripheral pulmonary artery stenosis and dental anomalies (Beuren et al., 1962). In 1963 J. Black an R. Bonham-Carter noticed that the faces of individuals with infantile hypercalcemia (Fanconi et al., 1952) and the faces of the individuals described by Williams and Beuren had much in common (Black and Carter, 1963). It was Dr. Beuren who presented in 1972 compelling evidence that “Williams-Beuren syndrome” and infantile hypercalcemia are the same disorder (Beuren, 1972). In retrospect, E. Oppenheimer (Oppenheimer, 1938) was probably the first to describe an individual with the features of Williams syndrome: “ partial atresia of the main branches of the pulmonary artery occuring in infancy and accompanied by calcification of the pulmonary artery and aorta”. Naming the syndrome has been problematic. The disorder has been known in the past as the idiopathic hypercalcemia-supravalvular aortic stenosis syndrome in spite of the fact that both features are frequently absent. Because the faces in patients with infantile hypercalcemia were called “elfin facies” the term “elfin face” syndrome has been used in the past. But as stated by J. Burn who has never seen an elf this term should be dropped (Burn, 1986). Nowadays most authors use the name Williams syndrome (WS) although some authors prefer the name Williams-Beuren syndrome. We will use the name Williams syndrome. Today Williams syndrome (WS, OMIM #194050) is a well recognized multisystem genetic condition. Hundreds of individuals have been described in the medical literature and the data have been summarised in several reviews (Tassabehji, 2003;Bellugi et al., 1999). WS is caused by a submicroscopic hemizygous deletion of 1.55-1.84 Mb on chromosome 7q11.23, encompassing about 25 -30 genes. The exact links between the missing genes and the phenotype of WS is yet to be fully explored