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 W S 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 Received for publication February 27, 1989; revision received July 5, 1989. Address reprint requests to Kenneth Lee Jones, M.D., Professor of Pediatrics, University of California, San Diego, M-009-C, La Jolla, CA 92093.This manuscript was not an official contribution to the meeting.0 1990 Wiley-Liss, Inc.possibility that it may be responsible for some of the manifestations of WS. KEY WORDS: hypercalcemia, vitamin D,calcitonin, calcitonin-generelated peptide, supravalvular aortic stenosis INTRODUCTION The Williams syndrome (WS) is a well-defined symptom complex which is usually recognized and diagnosed by physicians who care for children. The list of associated findings in individuals with this diagnosis has grown beyond those originally described and continues to expand as reviews appear [Preus, 1984; Morris et al., 19881. As recognized patients with previously undescribed manifestations age and die, we expand our knowledge by postmortem information. Despite the increase of information about and interest in this condition, our understanding of its cause and pathogenesis has advanced little since its identification.The search for the etiology of WS has primarily pursued the causes and effects of the abnormalities of calcium metabolism which led to its original description as idiopathic infantile hypercalcemia (IIH). This may seem curious at this time, for though there is still controversy, many investigators now think that hypercalcemia is not a predominant or even frequent manifestation of WS [Jones and...

Clinical follow‐up of young adults affected by Williams syndrome: Experience of 45 Italian patients

“…The most commonly reported endocrine abnormality in WBS is infantile hypercalcemia [Morris et al, 1988;Jones, 1990]. The incidence of hypercalcemia was estimated to be about 15%.…”

Multisystem study of 20 older adults with Williams syndrome

“…The most commonly discussed endocrine abnormality in WS is hypercalcemia, with most reports focusing on infantile hypercalcemia [Jones, 1990]. Despite the attention paid to this complication, the incidence of hypercalcemia is at best imprecisely estimated at 15% [2001] and the etiology and natural history continue to be unknown.…”

Bone mineral status and metabolism in patients with Williams-Beuren syndrome

“…1 The causes of hypercalcaemia in WBS are unknown; however, the proposed mechanisms causing hypercalcaemia include vitamin D sensitivity, increased 1,25 dihydroxyvitamin D levels, and defective calcitonin synthesis or release. 1,6,7 Despite the multiple endocrine, cardiovascular, and gastroenterologic problems reported in these patients, studies looking at metabolism and bone quality are virtually absent from the literature. In a small clinical study conducted on 20 WBS adults of at least 30 years of age, the authors reported 12 individuals meeting criteria for either osteoporosis or osteopoenia at the femoral site, and 10 individuals meeting criteria for either osteoporosis or osteopoenia at the lumbar site.…”