Williams syndrome: an historical perspective of its evolution, natural history, and etiology

Abstract

This review examines the Williams syndrome (WS) from an historical perspective, beginning with the early descriptions of idiopathic infantile hypercalcemia (IIH) and ending with some speculative ideas about a possible causative function of a recently discovered neuropeptide. The earliest reports of WS individuals are probably those which describe a "severe" subgroup of IIH and separate it from the epidemic of milder IIH reported in Post-WWII Great Britain and Europe. Most of these latter cases apparently resulted from hypervitaminosis D produced by excessive supplementation of government-supplied infant foods. With more extensive recognition and reporting of this "severe" subgroup, the diagnostic constellation of IIH, mental deficiency, elfin face, and supravalvular aortic stenosis (SVAS) evolved as WS. More of these reports emphasized the physical and behavioral manifestations as the key diagnostic features, and the frequency of occurrence and relative importance of SVAS and IIH in WS decreased. Despite the diminished consequence of hypercalcemia, calcium and vitamin D have continued to dominate the investigation of the cause of infantile hypercalcemia and led to the proposal and confirmation of deficient calcitonin secretion in individuals with WS. Though calcitonin is probably pertinent only to infantile hypercalcemia, its alternative gene product, calcitonin-gene-related product, is an important neuropeptide with physiological effects in the central nervous system and cardiovascular systems which raise the possibility that it may be responsible for some of the manifestations of WS.