Published online October 1, 2004
PEDIATRICS Vol. 114 No. 4 October 2004, pp. 1091-1095 (doi:10.1542/peds.2003-1146-L)
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EXPERIENCE AND REASON

Severe Infantile Hypercalcemia Associated With Williams Syndrome Successfully Treated With Intravenously Administered Pamidronate

Andrew P. Cagle, MD*, Steven G. Waguespack, MD{ddagger}, Bruce A. Buckingham, MD§, R. Ravi Shankar, MD* and Linda A. DiMeglio, MD*

* Department of Pediatrics, Section of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, Indiana
{ddagger} Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas
§ Section of Pediatric Endocrinology and Diabetology, Stanford University School of Medicine, Stanford, California


   ABSTRACT
TOP
 ABSTRACT
CASE REPORTS
 DISCUSSION
 REFERENCES
 
Infantile hypercalcemia occurs in ~15% of children with Williams syndrome (WS) and is typically not clinically severe. We report on 3 children with WS (confirmed with fluorescent in situ hybridization probes) who presented with severe symptomatic hypercalcemia. The first patient's severe hypercalcemia resolved with traditional therapies, whereas the subsequent 2 patients were treated with intravenously administered pamidronate after traditional measures proved only partially successful. Besides asymptomatic mild hypocalcemia, there were no complications resulting from pamidronate administration. We conclude that WS-associated hypercalcemia can be quite severe and symptomatic and that it can be successfully and safely treated with intravenously administered bisphosphonate in some cases.

Key Words: Williams syndrome • bisphosphonate • hypercalcemia • pamidronate

Abbreviations: WS, Williams syndrome • FISH, fluorescent in situ hybridization • PTH, parathyroid hormone • 25-OHD, 25-hydroxyvitamin D • 1,25-(OH)2D, 1,25-dihydroxyvitamin D • Ca/Cr, calcium/creatinine

Williams syndrome (WS) is an autosomal dominant disorder with a characteristic phenotype.1 Facial features include a sunken nasal bridge, epicanthal folds, long philtrum, small and widely spaced teeth, prominent chin, and mandibular hypoplasia. Heart defects are also characteristic, with supravalvular aortic stenosis being most common. Persons with WS also have mild mental retardation and a "cocktail party" personality. The facial features and other clinical characteristics of WS are seldom obvious in early infancy. However, the facial appearance becomes much more prominent as these children grow.

WS is the result of hemizygous submicroscopic deletions of 7q11.23.2,3 The deletions occur spontaneously and are thought to be attributable to unequal meiotic crossovers at misaligned repeat segments.4,5

More than 20 genes, many without well-defined functions, are found in this critical region. The gene encoding the extracellular matrix protein elastin is located in this region. Elastin deficiency accounts for the vascular and connective tissue abnormalities observed among WS patients.3,6–11 Because the gene encoding elastin is deleted in nearly all cases of WS, screening with a fluorescent in situ hybridization (FISH) probe for this gene deletion has become the diagnostic test of choice.6,8,12–15

Infantile hypercalcemia has been reported for ~15% of infants and children with WS.16 The hypercalcemia in infancy usually occurs in the first years of life, resolving in most cases by 4 years of age, but it may recur during puberty.16,17 The cause of the hypercalcemia is unknown. The hypercalcemia typically is mild and transient but occasionally can be severe and life-threatening. It may be accompanied by nephrocalcinosis.

None of the genes in the WS region have an identified role in calcium metabolism. Interestingly, the calcitonin receptor gene (CALCR), which was originally hypothesized to be important in the pathophysiologic development of WS-associated hypercalcemia, is found just outside the WS deletion area at 7q21.3.18

We report on 3 children with WS (confirmed with FISH probes) who presented with severe hypercalcemia. We provide the first description of successful treatment of WS-associated hypercalcemia with intravenously administered pamidronate, a bisphosphonate that inhibits bone resorption.


   CASE REPORTS
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 ABSTRACT
 CASE REPORTS
DISCUSSION
 REFERENCES
 
Patient 1
The first patient was a 9-month-old female patient who presented with a 6-month history of increasing irritability and feeding problems. At a well-child visit, she was noted to have poor weight gain and to have lost her ability to roll from her stomach to her back. Her physical examination was significant for generalized hypotonia, with poor head control and an inability to maintain grasp of a bottle at midline. She had subtle facial features of WS, with a long philtrum, thick lips, and epicanthal folds being evident (Fig 1). Initial tests indicated a total calcium level of 17.3 mg/dL (4.3 mmol/L), phosphorus level of 3.8 mg/dL (1.3 mmol/L), intact parathyroid hormone (PTH) level of 8 pg/mL (0.8 pmol/L), 25-hydroxyvitamin D (25-OHD) level of 27 ng/mL (67 nmol/L), 1,25-dihydroxyvitamin D [1,25-(OH)2D] level of 9 pg/mL (22 pmol/L), and urinary calcium/creatinine (Ca/Cr) ratio of 0.6 (Table 1). Renal ultrasound results were normal. FISH probe analysis was positive for WS. With 48 hours of intravenous fluid administration, furosemide administration, and dietary calcium restriction, the patient's calcium level trended toward the normal range (total calcium level: 11.4 mg/dL, 2.8 mmol/L), with dramatic improvement in irritability. At hospital discharge, the patient had mild hypercalcemia, which normalized by the following week with a low-calcium, vitamin D-restricted diet. By 17 months of age, the patient's diet had been gradually advanced to a normal calcium content. At the last follow-up visit, the patient was 31 months of age, with eucalcemia on an unrestricted diet.


Figure 1
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  		Fig 1. Patient 1 at presentation at 9 months of age. The classic facial features of WS, including long philtrum, thick lips, and epicanthal folds, should be noted.

 

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  		TABLE 1. Initial Laboratory Study Results

 
Patient 2
The second patient was an 11-month-old male patient who presented with a several-month history of decreased appetite, constipation, decreased tone, and increased irritability. Initial tests indicated a total calcium level of 17.7 mg/dL (4.4 mmol/L), ionized calcium level of 9.5 mg/dL (2.4 mmol/L), phosphorus level of 4.7 mg/dL (1.5 mmol/L), intact PTH level of 5 pg/mL (0.5 pmol/L), PTH-related peptide level of 0.3 pmol/L, 25-OHD level of 25 ng/mL (62 nmol/L), 1,25-(OH)2D level of 10 pg/mL (24 pmol/L), and urinary Ca/Cr ratio of 0.75. A renal ultrasound scan demonstrated nephrocalcinosis. FISH probe analysis was positive for WS. After 48 hours of intravenous fluid administration, furosemide administration, dietary calcium restriction, and administration of 2 doses of calcitonin, the symptomatic hypercalcemia persisted, with an ionized calcium level of 7.6 mg/dL (1.9 mmol/L). The patient received intravenously administered pamidronate (1 mg/kg) over 6 hours, with oral acetaminophen prophylaxis, and his serum calcium levels normalized in 2 days. Ten days after this treatment, the patient developed asymptomatic hypocalcemia, with an ionized calcium level of 3.4 mg/dL (0.8 mmol/L). The hypocalcemia resolved after liberalization of dietary calcium. This patient was also noted to have persistent hypertension during hospitalization, requiring treatment with captopril and hydralazine, which was diagnosed before pamidronate dosing. After hospital discharge, the patient was gradually advanced to a regular diet with an age-appropriate calcium intake. At the last follow-up visit, he was 24 months of age, with a normal serum total calcium level and urinary Ca/Cr ratio on an unrestricted diet.

Patient 3
The third patient was a male patient who had developed severe colic at age 1 month. A murmur was detected in the examination, and a subsequent echocardiogram revealed pulmonary stenosis. At 3 months of age, the patient's serum total calcium level was 12 mg/dL (3.0 mmol/L), with a repeat measurement obtained 1 week later reportedly being normal. At 4 months of age, an echocardiogram obtained because of a persistent murmur revealed supravalvular aortic stenosis. Subsequent FISH probe analysis was positive for WS. The patient remained a very irritable infant, often sleeping for only short periods of time overnight. At 13 months of age, his total calcium level was measured for the first time since 3 months of age and was found to be 13.9 mg/dL (3.5 mmol/L). Oral furosemide therapy was begun. After 3 weeks, the patient's symptoms had not improved and he was referred to the pediatric endocrine clinic. At that time, he demonstrated a total calcium level of 13.5 mg/dL (3.4 mmol/L), phosphorus level of 5.1 mg/dL (1.6 mmol/L), intact PTH level of 4 pg/mL (0.4 pmol/L), 25-OHD level of 30 ng/mL (75 nmol/L), 1,25-(OH)2D level of 13 pg/mL (31 pmol/L), and urinary Ca/Cr ratio of 1.3. A renal ultrasound scan revealed nephrocalcinosis. The patient received intravenously administered pamidronate (1 mg/kg) over 6 hours. Three weeks later, his total calcium level normalized and his symptoms resolved. Subsequently, the patient became irritable, with serum total calcium levels of >11.5 mg/dL (2.9 mmol/L), at ages 15 months, 20 months, and 23 months. Each time, he received additional pamidronate infusions at the same dose, with subsequent serum calcium level normalization and symptomatic improvement. The urinary Ca/Cr ratio was normal at 0.35 before the last dose of pamidronate. At 24 months of age, the patient was switched to a low-calcium, vitamin D-deficient formula and required no additional pamidronate infusions. At the last follow-up visit, he was 41 months of age, with eucalcemia on a low-calcium diet (used because of parental apprehension).


   DISCUSSION
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 ABSTRACT
 CASE REPORTS
 DISCUSSION
REFERENCES
 
In 1956, Schlesinger19 published the first photographs of patients with WS, in a report describing the association of unusual facies and infantile hypercalcemia. A few years later, Williams20 described the association of supravalvular aortic stenosis with similar unusual facies, mental retardation, and clinical signs of valvular cardiac disease. Despite these longstanding syndromic descriptions, the diagnosis of WS is often not readily made. This is partly because the subtle facial features are not typically apparent in infancy, becoming more prominent only as the child ages. The hypercalcemia that can occur during infancy in WS may also be missed, because the symptoms of hypercalcemia, such as irritability, feeding intolerance, and constipation, are nonspecific. For our patients, the hypercalcemia was not diagnosed promptly. Indeed, the diagnosis of WS for 2 of our patients was entertained only after hypercalcemia was discovered.

Hypercalcemia is addressed directly by the guidelines on health care supervision for children with WS published by the American Academy of Pediatrics, Committee on Genetics.16 This report recommends screening for hypercalcemia and nephrocalcinosis by measuring serum calcium levels and the urinary Ca/Cr ratio in the neonatal period or at the time of diagnosis. A bladder and renal ultrasound evaluation should be performed in the neonatal period or at the time of diagnosis, because of concerns regarding increased risks of renal and urinary tract malformations. The recommendations for monitoring include serum total calcium and urinary Ca/Cr ratio measurements in the neonatal period or at the time of diagnosis. If the initial findings are normal, then these measurements should be repeated every 2 years until the age of 5 years. For the ages of 5 to 18 years, the recommendations are for total calcium measurements every 4 years and urinary Ca/Cr ratio assessments every 2 years. A bladder and renal ultrasound study should be repeated in puberty and every 5 years thereafter, if results are normal.

The cause of hypercalcemia in WS is not well understood or sufficiently studied. Hypotheses are inconclusive and contradicting. The initial study to address the underlying cause of WS-associated hypercalcemia demonstrated that administration of vitamin D in large doses to pregnant rabbits resulted in a WS-like phenotype, with analogous craniofacial dysmorphologic findings, dental abnormalities, and heart defects.21The first human study was published in 1978 and described normal vitamin D-binding protein among normocalcemic WS patients and their mothers.22 The authors hypothesized that WS-associated hypercalcemia was attributable to either an excess of or a hypersensitivity to vitamin D during pregnancy. In 1986, a report described 2 brothers with WS, both of whom were normocalcemic; however, 1 had persistently elevated 1,25-(OH)2D levels in the first 2 years of life.23

Several articles have identified defects in vitamin D metabolism among patients with WS. In 1982, children with WS without a history of hypercalcemia were reported to have a defect in vitamin D metabolism, determined with a challenge with a pharmacologic dose of the vitamin.24 In 1985, Garabedian et al25 described an abnormality in vitamin D metabolism, with elevated 1,25-(OH)2D levels, among patients with hypercalcemia and "elfin facies," compared with age-matched control subjects with elfin facies and normocalcemia. In the same year, Culler et al26 compared normocalcemic children with WS with unrelated normal children before and after calcium and PTH infusions. They reported normal PTH and vitamin D metabolism but delayed calcium clearance and calcitonin deficiency.26 The largest study of calcium metabolism, published by Kruse et al27 in 1992, compared 27 normocalcemic patients with WS with age-matched healthy children and adults after calcium and PTH infusions. Contradicting previous studies, the authors reported no abnormalities in calcium clearance or vitamin D, PTH, or calcitonin levels. A 1993 case report described a 9-month-old patient with WS with an apparently normal physiologic response to hypercalcemia, with decreased levels of 1,25-(OH)2D.28

Our 3 cases demonstrated severe insidious hypercalcemia. All involved similar laboratory abnormalities, with severe hypercalcemia and hypercalciuria.29 Vitamin D studies were significant for normal 25-OHD levels and appropriately suppressed 1,25-(OH)2D levels. PTH levels were also appropriately suppressed in all cases, suggesting a non-PTH-mediated and likely a non-vitamin D-mediated cause of the hypercalcemia.

The first case demonstrates the hypercalcemia of infancy associated with WS being successfully treated with traditional therapies,30 which include intravenous fluid administration, furosemide treatment, and calcium restriction. Traditional therapies are directed toward reducing serum calcium levels by targeting the gastrointestinal tract and the kidneys. Calcium restriction reduces absorption of calcium by the gastrointestinal tract. Intravenously administered fluids restore intravascular volume, essentially diluting the serum calcium, and increase the glomerular filtration of calcium. Furosemide decreases the renal tubular reabsorption of calcium.

The second and third cases illustrate symptomatic hypercalcemia that persisted with traditional therapies. Less traditional methods were therefore used. Patient 2 received 2 doses of calcitonin. Calcitonin affects both kidneys and bone; it increases renal clearance of both calcium and phosphate and reduces calcium release from bone by suppressing osteoclast activity. Both patients were ultimately treated successfully with intravenously administered pamidronate, although patient 3 required multiple doses of pamidronate for treatment of recurring symptomatic hypercalcemia. Pamidronate, like the other bisphosphonates, is effective in treating hypercalcemia because it acts on bone to reduce osteoclast resorption. It is unclear, however, whether this ameliorated the hypercalcemia among these patients because they had a hyperresorptive state.

The biochemical response to pamidronate, coupled with hypercalciuria, leads to speculation that the hypercalcemia was the result of excessive calcium mobilization from bone. Although there might have been some component of gut hyperabsorption of calcium that initially contributed to the hypercalcemia, our patients were not eating well at the time of presentation and were therefore receiving little or no enteral calcium. Their normal renal function test results and elevated urinary Ca/Cr ratios demonstrate their ability to excrete calcium appropriately. This leaves only the possibility of increased release from bone, which is supported by the effectiveness of pamidronate. Unfortunately, good normative data for bone turnover in infants are not available, and bone biochemistries among children with hypercalcemia and WS are not well described. This may be a direction for future study.

Although there are many case reports of bisphosphonate use among children, relatively few controlled studies have been performed. There are currently no approved indications for bisphosphonate therapy for children; therefore, dosing guidelines are not available. Doses for intravenous pamidronate administration in pediatric studies for treatment of hypercalcemia resulting from different causes have varied from 0.35 to 1.2 mg/kg per dose.31 Short-term treatments with pamidronate appear to be generally safe and well tolerated. Although the intravenous administration of a bisphosphonate can be associated with fever and myalgias, neither of these was seen with pamidronate infusion among our patients. One patient (patient 2) did develop mild asymptomatic hypocalcemia 10 days after treatment. Potential long-term effects of prolonged pamidronate treatment among growing children (which may include delayed fracture healing32 and even osteopetrosis-like bone disease33) are not yet well characterized.

Children with WS and a history of hypercalcemia on low-calcium and vitamin D-deficient diets are certainly at risk for poor bone mineral accrual. Rickets has been reported for a child with WS on a restricted diet.34 Once the hypercalcemia has resolved, calcium can and should be reintroduced gradually into the diet, to prevent the effects of a deficient diet. This can be performed safely with close monitoring of serum and urinary calcium levels.

A recent study of 57 patients with WS reported only mild hypercalcemia for 1 patient and mild hypercalciuria for 2 patients, with no cases of nephrocalcinosis.35 The authors concluded that, in WS, hypercalcemia is not frequent and hypercalciuria is rare after the first 1 year of life; they speculated that the issue of disturbed calcium homeostasis in WS has been overemphasized in the past. Our report challenges these views, given the severity of hypercalcemia for patients 1 and 2, nephrocalcinosis for patients 2 and 3, and the age of onset and recurrence of hypercalcemia for patient 3. The low reported incidence of hypercalcemia in infancy could be explained by the transient nature and nonspecific symptoms of hypercalcemia (or asymptomatic hypercalcemia), which is typically mild and unrecognized by clinicians.

Our experiences highlight the insidious onset and potential severity of hypercalcemia among infants with WS. This report also illustrates the variability in responsiveness of these patients to treatment. Intravenous pamidronate administration appears to be a safe effective therapy for severe hypercalcemia among infants with WS that does not respond adequately to traditional treatments.


   FOOTNOTES
 
Accepted Apr 1, 2004.

Reprint requests to (L.A.D.) Department of Pediatrics, Section of Pediatric Endocrinology and Diabetology, Riley Hospital for Children, Room 5960, Indianapolis, IN 46202. E-mail: dimeglio{at}iupui.edu


   REFERENCES
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 ABSTRACT
 CASE REPORTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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