Hypercalcemia in Patients with Williams-Beuren Syndrome

Abstract

Objective: To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study.

Study design: Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities.

Results: On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported.

Conclusions: Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.

Keywords: calcium; not in the title: QTc; pediatric reference intervals.

Figure 1

A, Plasma Ca plotted against subject age. Solid lines indicate upper and lower limits of normal. Pediatric-adjusted norms. Points above the dotted line are clinically actionable. B, Plasma Ca plotted by age in the cohort with WBS against controls. C, Plasma Ca plotted for subjects with actionable hypercalcemia with more than 1 Ca value.

Figure 2

A, GFR is reduced and B, BUN is increased in subjects with actionable hypercalcemia compared with those with mild hypercalcemia or no history of hypercalcemia. Plots are shown with mean (IQR) in the box and maximum to minimum depicted in the whiskers. **P < .01; ***P < .001.

Figure 3

Plasma Ca levels plotted against the QTc interval for the contemporaneous ECG. The regression line is shown in black. Gray bars highlight QTc intervals of ≤370 ms and >470 ms.