The first cases of Williams syndrome were included in early reports detailing the clinical characteristics of children who had infantile hypercalcemia, short stature, and variable congenital malformations [Fanconi et al., 1952]. After an epidemic of infantile hypercalcemia in Britain resolved with adjustment of vitamin D supplementation in food, Stapleton et al. [1957] noted that there was a group of infants with persistent symptoms including failure to thrive, developmental delay, and systolic murmurs. The next decade saw cardiology reports describing a condition with dysmorphic facial features, supralvar aortic stenosis (SVAS) (OMIM 185500) and mental retardation [Williams et al., 1961; Beuren et al., 1962]. Isolated SVAS, a rare cause of left ventricular outflow tract obstruction, had been described by Chevers [1842], and more recently Eisenberg et al. [1964] reported autosomal dominant inheritance. In 1963, geneticists recognized that SVAS could segregate in families, but also could occur sporadically as part of a syndrome that included mental retardation [Merritt et. al., 1963]. Astute clinicians observed that the facial features of idiopathic hypercalcemia of infancy (IHC) and syndromic SVAS were similar [Black and Carter, 1963; Hooft et al., 1963]. The connection was proven when Garcia et al. [1964] described SVAS in a child who had documented IHC. The early recognition of hypercalcemia in WS led to a hypothesis that hypersensitivity to vitamin D caused the syndrome. Friedman and Roberts [1966] found that rabbits exposed prenatally to high doses of vitamin D developed aortic lesions and abnormal shortened craniofacies. (Interestingly, because high doses of vitamin D inhibit tropoelastin deposition, the observed phenotype was likely due to a secondary elastin deficiency.) These first reports of WS also made note of the characteristic behioral phenotype, describing loquacity, anxiety, and friendliness [Beuren et al.,1964; von Arnim and Engel, 1964].
In the 1970s, larger series defined the WS phenotype [Beuren 1972; Jones and Smith, 1975]. However, by 1984, there were few reports of adults with WS. A mother’s questions, “What happens when they grow up? Do they grow up?” inspired me to initiate a study of the natural history of WS during my fellowship in medical genetics and dysmorphology at the University of Utah [Morris et al., 1988, Morris et al., 1990]. Subsequently, a colleague, Dr. Cynthia Moore at Indiana University, had observed some members of a family with autosomal dominant SVAS who had learning disabilities and some facial features reminiscent of WS. We wondered if WS could represent an “iceberg dominant” with WS being the most severe manifestation SVAS. A visit to Indiana University revealed a 25-year archive of families evaluated by their genetics program, including several multigenerational families with SVAS. Dr. Gregory Ensing, pediatric cardiologist at Indiana University, performed echocardiograms to classify family members in several SVAS kindreds as affected or unaffected. Samples were collected for linkage analysis performed by Amanda Ewart in the molecular genetics laboratory of Dr. Mark Keating at the University of Utah. Linkage to the elastin gene was established [Ewart et al.,1993a]. Subsequently, one of the SVAS families was found to he a 6;7 translocation that disrupted the elastin gene [Curran et al., 1993; Morris et al., 1993], demonstrating that elastin mutation caused SVAS. Ewart et al. [1993b] then discovered that WS was associated with ELN deletion, a finding that was rapidly confirmed [Lowery et al., 1995, Mari et al., 1995], and led to the first laboratory test for the disorder. The family that had prompted the genetic study was later found to he a ~500 kb deletion in the WSCR that included the elastin gene [Morris et al., 2003]. Currently, diagnostic testing for the deletion may be accomplished by fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MPLA), or chromosome microarray.