Immobility-induced hypercalcemia is a rare cause of hypercalcemia in children, and to our knowledge it has never been reported in an infant. Infants and children are in a state of high bone turnover. Therefore, they are prone to the imbalance of osteoblastic and osteoclastic activity that occurs with prolonged immobilization, leading to hypercalcemia. Here we present the case of an infant with hypercalcemia who presented with fatigue, irritability, and failure to thrive after prolonged immobilization. Therapeutic interventions were conservative and included hydration and increased mobility leading to complete resolution. This case highlights the importance of including this rare entity in a differential diagnosis of hypercalcemia as well as screening postsurgical patients with prolonged immobility for hypercalcemia.
- CASR —
- Ca2+-sensing receptor gene
- FHH —
- familial hypocalciuric hypercalcemia
- NSHPT —
- neonatal severe hyperparathyroidism
- PTH —
- parathyroid hormone
Hypercalcemia is a rare condition in infants and children, but when detected can have significant clinical implications such as poor weight gain, polyuria, dehydration, cardiac arrhythmias, or nephrocalcinosis. Albright et al1 first described immobility-induced hypercalcemia in 1941. They presented a 14-year-old boy who developed hypercalcemia and hypercalciuria after being immobilized secondary to a femoral neck fracture. The mechanism underlying immobility-induced hypercalcemia relates to the loss of balance between osteoblastic bone formation and osteoclastic bone resorption.1–4 However, immobility is not included in the differential diagnosis for hypercalcemia in neonates and infants, as mentioned by Lietman et al2 and others.5–7 This case highlights the value of considering this diagnosis in an infant who presents with hypercalcemia and a history of prolonged immoblization.
We present a rare case of immobility-induced hypercalcemia in a 2-month-old female infant. The infant was a 39-week-gestation female with a history of bladder exstrophy, an anteriorly displaced anus, and bilateral hip dysplasia. She underwent reconstruction of her midline structures at day of life 11, including bilateral ileac osteotomies, closure of the symphysis pubis, labioplasty, and monsplasty. She was placed in a hip spica cast from day of life 11 to day of life 42. Her cast was removed after a total of 32 days, and she was subsequently noted to have increased irritability.
She presented to the emergency department at day of life 53 with visible signs of fatigue, irritability, and failure to regain birth weight. Laboratory evaluation revealed hypercalcemia with serum calcium of 14.5 mg/dL (normal: 6.9–11.0 mg/dL). On further review of past medical history, it was noted that a routine renal ultrasound performed 7 days after the removal of the hip spica cast (day of life 49) as follow-up of her genito-urinary abnormalities had shown interval development of bilateral medullary nephrocalcinosis. Her electrocardiogram did not show abnormalities such as PR, QT, or QRS interval changes. She was managed with intravenous hydration and switched from exclusive breastfeeding to CalciLo XD (Abbott Nutrition, Columbus, Ohio), a low-calcium vitamin D–free formula. She did not tolerate the formula change and was placed back on breastfeeding with Similac Sensitive (Abbott Nutrition, Columbus Ohio) formula supplementation. She showed resolution of her hypercalcemia by day 3 of hospitalization (day of life 56) and was taken off intravenous hydration and maintained on oral feedings. She was discharged from the hospital on day 12 of hospitalization (day of life 64) after showing stable calcium levels and steady weight gain. After hospital discharge, her diet was maintained with breastfeeding and Similac Sensitive formula. As of age 30 months, she has not had any further recurrence of hypercalcemia.
Differential Diagnosis and Laboratory Evaluation
Workup for this case began with an evaluation of the more common etiologies of hypercalcemia.2 A full summary of laboratory evaluations is shown in Table 1. The differential diagnosis for neonatal/infant hypercalcemia is extensive, but the clinician should be familiar with all the possible etiologies to achieve a focused evaluation.
Iatrogenic causes of hypercalcemia include vitamin D excess, formulas with excess calcium, or inadequate phosphate from feedings, all of which increase the risk of mineralization defects and hypercalcemia. Hypophosphatemia causes suppression of the phosphate regulator fibroblast growth factor 23 (FGF23), which then leads to increased calcitriol production. Calcitriol increases intestinal absorption of calcium as well as osteoclastic bone resorption. In neonates/infants, hypervitaminosis D would be most likely due to excess maternal intake during pregnancy or excess supplementation, leading to elevated 25-hydroxyvitamin D and subsequent hypercalcemia. Our patient had low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels (see Table 1).
Neonatal hyperparathyroidism can be due to diffuse parathyroid gland hyperplasia, which is rare, or to maternal hypoparathyroidism in which maternal hypocalcemia triggers neonatal hyperparathyroidism. We did not have maternal data regarding serum electrolytes or intact parathyroid hormone (PTH) levels. Hyperparathyroidism was ruled out with the presence of appropriate hypercalciuria, suppressed serum PTH, and normal serum phosphate in the setting of hypercalcemia.
Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), which are due to inactivating mutations of the Ca2+-sensing receptor gene (CASR), are also causes of neonatal hyperparathyroidism and hypercalcemia. FHH is due to a 1-allele mutation of CASR and is generally characterized by asymptomatic hypercalcemia. NSHPT is due to 2-allele mutations of CASR and results in severe and life-threatening hypercalcemia. In FHH and NSHPT, laboratory evaluation reveals inappropriately normal or elevated serum PTH and hypocalciuria with hypercalcemia, which was not seen in our patient.
Other conditions causing hypercalcemia include severe congenital hypothyroidism, hyperthyroidism, hypoadrenalism, and vitamin A intoxication. These were ruled out on the basis of normal laboratory evaluation as shown in Table 1. Subcutaneous fat necrosis should be considered, especially after a complicated delivery. The mechanism for hypercalcemia is due to excess production of calcitriol by macrophages at the site of fat necrosis. A basic physical examination can help to rule out this condition, and our patient had a normal physical examination with regard to these specific findings. Williams syndrome is also associated with hypercalcemia, usually occurring in infancy and resolving by 2 to 4 years of age. This syndrome is associated with distinct facial features and congenital heart disease, usually supravalvular aortic stenosis. Our patient did not have any dysmorphic facial features. Other possible causes include hypophosphatasia, metabolic acidosis, and disaccharidase deficiency.
After excluding the more common causes of hypercalcemia in an infant and observing our patient’s clinical response to treatment with intravenous hydration alone, we focused on more rare conditions. Given her history of prolonged immobilization of 32 days, immobility-induced hypercalcemia was our primary diagnosis.
A literature review revealed case reports mostly in adult patients; however, it was noted that this condition is more common in children and adolescents in whom bone turnover is high.3,8 Under normal conditions, there is a balance between osteoblastic bone formation and osteoclastic bone resorption. However, during times of increased bone turnover, the reduction in osteoblastic activity and increase in osteoclastic activity that occur with immobility lead to increased skeletal calcium release and hypercalcemia, which is also known as resorptive hypercalcemia.8 A low alkaline phosphatase may be seen due to the reduced osteoblastic activity, but this was not the case with our patient, who had a slightly elevated alkaline phosphatase. The hypercalcemia leads to a reduced level of consciousness, impaired thirst and appetite, nephrogenic diabetes insipidus causing excess water excretion, and impaired sodium reabsorption resulting in dehydration, reduced glomerular filtration rate, and a further reduction in calcium excretion. Increased urinary calcium excretion is seen at ∼2 to 4 weeks of acute immobilization; however, we did not have data on our patient regarding her values during the time course of her spica cast.9,10 On average, the onset of hypercalcemia occurs at ∼4 weeks of immobilization, which was approximately the length of immobility in our patient.8 Please refer to Table 2 to review the trend in serum calcium, serum phosphorus, and ionized calcium levels in our patient.
The level of intervention and management of hypercalcemia depends on the severity and etiology.2,5 In general, hypercalcemia causes dehydration as described above and one of the first steps in management involves intravenous fluid hydration with normal saline to help with calcium excretion. The use of loop diuretics, such as furosemide, to further increase renal calcium excretion should be used with caution because they can cause further dehydration and worsen hypercalcemia. For mild hypercalcemia, calcium restriction and close follow-up can be sufficient to normalize serum levels. In the setting of moderate to severe hypercalcemia, which is generally due to increased osteoclastic activity, agents that inhibit this process can be considered such as calcitonin or bisphosphonates.
Calcitonin works rapidly to decrease serum calcium levels by inhibiting osteoclast-induced bone resorption, but resistance can occur. Bisphosphonates decrease bone resorption by directly decreasing osteoclastic activity and indirectly by stimulating osteoblast production of an inhibitor of osteoclast formation.11 Studies regarding the efficacy and safety of bisphosphonate use in adults are abundant but are lacking in children. These agents, however, have been used in many pediatric conditions, such as osteogenesis imperfecta and fibrous dysplasia of bone as seen in McCune-Albright syndrome. Their use in pediatrics, specifically intravenous pamidronate, may be warranted in conditions such as symptomatic osteoporosis or severe neonatal hyperparathyroidism.11,12 In a recent review article, the use of bisphosphonates for secondary forms of osteoporosis, such as immobility, and for severe symptomatic hypercalcemia (serum calcium >14 mg/dL), was considered to be efficacious but, again, long-term data regarding safety are lacking.13
Glucocorticoids have been used to treat hypercalcemia due to vitamin D excess and work by decreasing gastrointestinal reabsorption of calcium, but they should be used with caution due to adverse effects, such as impairment in linear growth and bone mineralization. In severe cases, hemodialysis may be necessary with a low-calcium dialysate.
On the basis of our literature review, no cases of immobility-induced hypercalcemia in neonates and infants have been reported. Although immobilization is not part of the differential diagnosis for neonates and infants, this case shows the importance of including it on the list of possible causes of hypercalcemia in any neonate or infant with a history of prolonged immobilization.2,5–7 Also of note, per our experience, routine laboratory evaluation is not performed in infants who are placed in hip spica casts for repair of hip dysplasia. Cases of transient hypercalcemia due to the prolonged immobilization after this procedure may be more common than we think, and physicians should consider screening such patients, especially those exhibiting poor weight gain or dehydration.
- Accepted December 23, 2015.
- Address correspondence to Neha Vyas, MD, Division of Pediatric Endocrinology, 11100 Euclid Ave, Suite 737, Cleveland, OH 44106. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2016 by the American Academy of Pediatrics