An Unusual Cause of Bone Pain in a 3-Year-Old Girl

A 3-year-old previously healthy female with history of a cow's milk allergy presents to the emergency department with a 2-week history of intermittent leg pain, chapped lips, and decreased oral intake. Her mother states that 2 weeks ago she noticed that her daughter had chapped lips and was eating less frequently. One week ago, she also developed an intermittent, pruritic rash on her arms that improved with cetirizine. She acutely became more tired 2 days prior to presentation and was refusing to walk or stand, prompting a visit to the emergency department for further evaluation.She does not take any medications other than a daily multivitamin. She follows a dairy-free diet and drinks up to 3 cups of rice milk per day. The patient has been afebrile. There is no known trauma or recent infections. Review of systems is negative for vision or hearing changes, shortness of breath, increased thirst, nausea, vomiting, diarrhea, or constipation. Other than expressive speech delay, developmental milestones are appropriate for age.Her vital signs are within normal limits. She weighs 11.9 kg (seventh percentile), with a body mass index of 13 kg/m2 (0.3 percentile). On physical exam she is tired but nontoxic appearing. She has dry mucous membranes and cheilitis. Her lower extremities are tender to palpation, and she is unwilling to bear weight. A pruritic, erythematous, blanching, maculopapular rash is present along the posterior trunk and several excoriation marks are noted on her upper arms, back, and abdomen. Heart, lung, and abdominal exams are unremarkable.Initial laboratory results (Table 1) reveal an elevated calcium at 13.1 mg/dL (8.8–10.8 mg/dL) with an ionized calcium of 1.68 mmol/L (1.12–1.32 mmol/L). Phosphate is 5.8 mg/dL (3.2–5.5 mg/dL). Erythrocyte sedimentation rate (ESR) is 30 mm/h (0–10 mm/h) and C-reactive protein is 0.3 mg/dL (<0.5 mg/dL). Complete blood count is normal. An electrocardiogram is obtained and is normal. Because of her level of hypercalcemia, a baseline renal ultrasound is obtained and demonstrates medullary nephrocalcinosis. Given the patient's elevated calcium level, she is admitted for further workup and management.The differential diagnosis for hypercalcemia is broad. Potential causes of hypercalcemia include mechanisms that lead to increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal excretion of calcium.1 A summary of a diagnostic pathway for hypercalcemia is provided in Figure 1.Parathyroid hormone (PTH), calcitriol (vitamin D:1,25 OH), and calcitonin are responsible for calcium homeostasis in the body. Once hypercalcemia is identified in a patient, the first step is to identify the level of PTH. A normal or increased PTH may point toward a differential diagnosis of familial hypocalciuric hypercalcemia or primary hyperparathyroidism respectively. The patient's PTH is low at 6.4 pg/mL (15.0–65.0 pg/mL) and urinary calcium/creatine ratio is 1337.0 mg/g (<400.0 mg/g), suggesting against both primary hyperparathyroidism and familial hypocalciuric hypercalcemia.In normal homeostasis, PTH secretion is sensitive to changes in serum calcium levels, with increased calcium levels inhibiting PTH release.2 Given that our patient's PTH levels were appropriately low, the next step is to determine the level of parathyroid related peptide (PTHrP). PTHrP can be ectopically secreted by malignant tumors and mimics biologic effects of PTH leading to paraneoplastic hypercalcemia.1,2 If PTHrP is normal or low however, the differential then includes vitamin D toxicity, vitamin A toxicity, granulomatous disease, hyperthyroidism, and pheochromocytoma.A PTHrP laboratory is performed. However, this laboratory test typically takes up to 5 days to determine a result, so in the meantime a broad workup is pursued. The elevated ESR noted on admission is thought to be secondary to an inflammatory state from hypercalcemia.3 Otherwise, in our patient, thyrotropin (TSH) is low at 0.25 uIU/mL (0.7–5.90 uIU/mL) and T4 is normal at 1.33 ng/dL (0.80–1.75 ng/dL), ruling out hyperthyroidism. Bilateral lower extremity imaging is obtained, which demonstrates dense metaphyseal bands seen in vitamin D toxicity, abnormalities in calcium-phosphate homeostasis, or malignancy (Figure 2).4 Vitamin D (25 OH) is normal at 46 ng/mL (25–80 ng/mL) and vitamin D (1,25 OH) is low at 10 pg/mL (20–70 pg/mL), ruling out vitamin D toxicity and granulomatous disease respectively. To screen for malignancy, a chest x-ray is obtained, which is normal. Lactate dehydrogenase and uric acid studies are normal. Urine catecholamines are within normal limits, suggesting against pheochromocytoma. Ultimately, PTHrP is low at 1.1 pmol/L (<4.2 pmol/L).The patient is found to have an elevated vitamin A level of 80 μg/dL (11.3–64.7 μg/dL). Additional nutrition history identified that the patient drinks 12 oz of rice milk per day (which contains 90 μg of vitamin A/ oz) and therefore averages up to 1080 μg of vitamin A daily. The recommended daily dose of vitamin A for her age is 300 μg.3,5,6 In addition, her grandmother also allows her to eat as many gummy vitamins as she desires and describes that she eats them "like candy." Further inquiry does not reveal that the patient has access to any other medications. She is diagnosed with vitamin A toxicity as the cause of her hypercalcemia.Vitamin A toxicity is a rare entity with few case reports represented in the literature.3,5 Vitamin A is a fat-soluble compound that is essential for growth, bone health, vision, and cell differentiation, and can only be acquired by diet.7 Vitamin A has a long biological half-life and accumulates in adipose tissue. Given that it is rapidly absorbed and slowly cleared, vitamin A toxicity can either be due to a large ingestion of vitamin A causing acute toxicity or chronic toxicity after prolonged intake of several doses.5,7 Signs and symptoms of vitamin A toxicity include headaches, nausea, vomiting, cheilitis, abdominal pain, rash, pruritus, bone pain, dysuria or polyuria, dizziness, and altered mental status.7 At toxic levels, vitamin A can also lead to bone resorption ultimately leading to hypercalcemia, though the mechanism is not well understood.5 Therefore, some symptoms present in vitamin A toxicity may also overlap with those present in patients with hypercalcemia. Additionally, excess vitamin A is associated with development of idiopathic intracranial hypertension, papilledema, and elevated triglycerides, which in turn may cause elevated liver enzymes as seen in this patient.7 Excess vitamin A is stored in stellate cells in the liver and accumulation can lead to their activation leading to liver injury.8The management of vitamin A toxicity starts with discontinuing further consumption of vitamin A. Given that vitamin A is stored in adipose tissue and is slowly cleared, close follow-up is needed to monitor the trend in levels.7Next, hypercalcemia secondary to vitamin A toxicity needs to be addressed. Treatment of hypercalcemia depends on the severity of the hypercalcemia as well as the symptoms the patient experiences.1,9,10 Hypercalcemia is classified as mild (Ca <12 mg/dL), moderate (Ca 12–14 mg/dL), or severe (Ca >14 mg/dL).1 Mild hypercalcemia does not necessarily require treatment if the patient is asymptomatic. Signs and symptoms of hypercalcemia include nephrocalcinosis, bone pain, nausea, vomiting, constipation, abdominal pain, neuropsychiatric manifestations (such as lethargy, confusion, or fatigue), muscle weakness, and cardiac arrhythmias.1,9The goals for treatment of hypercalcemia include stabilizing and reducing the calcium level with adequate hydration, increasing urinary calcium excretion, and inhibiting osteoclast activity in the bone.5 Therefore, the first step is to give intravenous hyperhydration, sometimes necessitating up to 2 times the maintenance fluid rate to achieve effect. If during treatment there is concern for fluid overload, diuretics such as furosemide may be needed to help with renal filtration of calcium. For some patients, hyperhydration is enough to correct hypercalcemia. Patients with symptomatic moderate hypercalcemia and severe hypercalcemia, regardless of symptoms, require more aggressive treatment and will need medications such as calcitonin or bisphosphonates to inhibit further osteoclastic resorption to correct the hypercalcemia.1,5,11 Calcitonin is approved for children to treat acute refractory hypercalcemia and was our choice because of its rapid onset of action; however, tachyphylaxis occurs quickly and persistent hypercalcemia will require bisphosphonate therapy. These are all temporizing measures and once the underlying etiology is resolved, the patient's calcium levels will also return to normal.Our patient's primary signs and symptoms from her hypercalcemia included bone pain, abdominal pain, decreased oral intake, and fatigue. Her initial calcium level was 13.1 mg/dL, placing her in the category of symptomatic moderate hypercalcemia. She was hyperhydrated with intravenous fluids running at 2 times her maintenance rate. Given her persistent hypercalcemia and worsening renal function, she was given a single dose of calcitonin (4 units/kg). This ultimately allowed her corrected calcium to stabilize at 11.7 mg/dL the following day. She started to have improved energy and oral intake and was able to stand prior to discharge.In the setting of her vitamin A toxicity, she was also found to have hypertriglyceridemia of 136 mg/dL and elevated liver enzymes with aspartate aminotransferase (AST) at 107 U/L. Prior to discharge, she was evaluated by ophthalmology for a routine eye exam and did not have papilledema from her vitamin A toxicity. Prior to discharge, her family was provided with a list of vitamin A rich foods to avoid (such as carrots, leafy green vegetables, and fortified milk).After 1 month of avoiding vitamin A intake, her calcium leveled to 9.5 mg/dL (8.8–10.8 mg/dL) and her vitamin A level was normal at 38 μg/dL (11.3–64.7 μg/dL). Her creatinine returned to normal to 0.27 mg/dL (0.26–0.42 mg/dL) and AST returned to 61 U/L (<77 U/L). Additional follow-up studies, including TSH and T4, were normal. One month after discharge, her energy level had improved, her bone pain had resolved, and she was able to ambulate without issue.Vitamin A toxicity is a potential cause of hypercalcemia and can present with leg pain, pruritus, rash, and cheilitis.Vitamin A toxicity sequelae include idiopathic intracranial hypertension, papilledema, and hypertriglyceridemia.Hypercalcemia treatment is guided by the severity of the calcium level and presence of symptoms and may include interventions such as intravenous hydration, diuretics, and medications that inhibit osteoclast activity in the bone.