A 10-year-old girl presented to our institution for evaluation of refractory hypocalcemia. About 36 hours prior, the patient had been admitted to another hospital for nausea and vomiting in the setting of recent urinary tract infection with urticarial rash. She was found to be hypocalcemic, with a serum calcium level of 6.4 mg/dL (normal range, 9.6–10.6 mg/dL). The hypocalcemia she had resisted treatment with intravenous (IV) calcium gluconate at a dose of 2 g every 6 hours, with her levels remaining between 6.3 and 7.1 mg/dL. After 24 hours of treatment with no improvement in calcium levels, she was transferred to our institution.
The patient reported itching from her rash but no other symptoms. The patient had no history of seizures, parathesias, muscle spasms, or fractures. Her mother reported good growth with pubic hair and breast development over the last year but no menstruation. She had a history of developmental delay in her physical milestones and speech delay as well. Prior to this episode, she had been taking no medications. Because the patient's mother was adopted there was no family history available from the maternal side, and there was no paternal history of hypocalcemia.
On physical examination, the patient was well-appearing with a round face but no dysmorphic features. Vital signs were within normal limits, and height and weight in the 97th percentile for her age. Auscultation yielded normal S1 and S2 with no murmurs and clear lung fields bilaterally. Muscle tone and strength were normal. Chvostek sign was positive on the right side of her face. A skin examination showed a urticarial rash on her abdomen, back, face, arms, and legs. There was no shortening of the metacarpals. A bedside electrocardiogram was performed to further assess cardiac symptoms of hypocalcemia, and it revealed a prolonged QT interval of 0.46 milliseconds. While continuing treatment with 2 g of IV calcium gluconate every 6 hours, endocrinology service was consulted. They recommended a series of tests to determine the etiology of her hypocalcemia. The tests yielded the results shown in Table 1.
Signs and Symptoms of Hypocalcemia
Hypocalcemia is a potentially life-threatening electrolyte derangement. Of most concern are cardiac sequelae such as prolonged QT interval, cardiomyopathy, and congestive heart failure.1 Hypocalcemia can also cause seizures, so it must be ruled out in any child with unexplained seizure.2 Other neurologic/neuromuscular complications include paresthesias, tetany, muscle cramps, and muscle weakness.1,2 Skin and bone growth are affected, with risk increased for dental caries, atopy, psoriasis, delayed tooth eruption, delayed growth, and osteoporosis.1 Other complications may include smooth muscle dysfunction and psychological abnormalities such as confusion, irritability, fatigue, difficulty concentrating, and poor memory.1 Physical examination findings in a child with hypocalcemia may include facial muscle irritability (Chvostek sign, elicited by tapping on the maxilla) or carpopedal spasm (Trousseau sign), which can be seen by inflating a sphygmomanometer to 20 mm Hg above the systolic blood pressure for 3 to 5 minutes.1,2
Initial calcium measurements should include ionized calcium (iCa), which is the active form of calcium that participates in cell signaling and electrical condition, in addition to serum calcium and albumin. Routine serum calcium levels include calcium bound to albumin and iCa, so it is possible for the iCa to be normal when serum calcium is low, depending on serum albumin concentrations. If a child is asymptomatic with low serum calcium levels, it is necessary to measure both the iCa and serum albumin levels to determine if the child is truly hypocalcemic or instead has factitious hypocalcemia caused by low albumin.3 If albumin levels are determined to be normal in the context of low ionized calcium, serum calcium will suffice for tracking levels after the initial measurement.
Approach to Refractory Hypocalcemia
In the acute setting, increased stress, consumption, or binding of calcium causes abrupt decreases in calcium. Causes of this acute hypocalcemia include sepsis, rhabdomyolysis, pancreatitis, tumor lysis syndrome, or blood transfusions.3 In these situations, when the underlying disease process is corrected, the calcium level also corrects. For a child presenting in the nonacute setting with refractory hypocalcemia, the differential diagnosis can be restricted to two broad categories of chronic hypocalcemia: hypocalcemia with high parathyroid hormone (PTH) and hypocalcemia with low PTH levels. PTH is the primary regulator of calcium homeostasis, a hormone that enhances bone resorption, promotes the conversion of 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D, and increases intestinal and renal calcium absorption and phosphate renal excretion.4 A few key laboratory tests, particularly assessing PTH in relation to calcium and other markers, have hallmark values that suggest diagnoses for underlying calcium disorders (Table 2).
Laboratory Results for Etiologies of Chronic Hypocalcemia
Hypocalcemia with Low PTH
Hypocalcemia with low PTH, also called hypoparathyroidism, involves dysfunction of the parathyroid gland itself.4 Causes include congenital absence of the parathyroid glands and genetic defects in the calcium-sensing receptor.4 The most well-known of the parathyroid gland developmental problems is DiGeorge syndrome. In addition to hypocalcemia, the child with DiGeorge syndrome will also have cardiovascular abnormalities, facial abnormalities, and thymic hypoplasia.4 Autoimmune diseases and destruction or infiltrative disorders of the parathyroids can also cause hypoparathyroidism.5 When investigating dysfunction of the parathyroid gland, it is important to also investigate the thyroid gland, as they are adjacent to each other. Dysfunction in the thyroid gland, such as a tumor, may cause issues with PTH secretion and function.4,6
Hypocalcemia with High PTH
Disorders of vitamin D. The most common cause of hypocalcemia with high PTH is hypovitaminosis D (ie, rickets) and other disorders of vitamin D.4 These may result from lack of sunlight exposure (ultraviolet B radiation), inadequate consumption of vitamin D, fat malabsorption, liver dysfunction, renal dysfunction, end organ resistance to vitamin D, or defects in the activating enzyme 1-alpha hydroxylase.5 Clues in patient history include little time spent outdoors, greasy stools, poor diet, edema, easy bruising, or abnormal urine appearance.4,5 Family history may include renal diseases or liver diseases.4 Laboratory results will reveal low phosphate and high PTH concentrations in addition to low calcium. The 25-hydroxyvitamin D concentration will be low when liver dysfunction or vitamin D deficiency is the underlying cause of the hypocalcemia. In renal dysfunction, 1, 25-hydroxyvitamin D, the active form, will be low whereas the 25-hydroxyvitamin D concentration may be normal or high. Assessing renal dysfunction can be aided by the urine calcium to urine creatinine ratio, which will be elevated if the kidneys are not reabsorbing calcium properly. With end-organ resistance to vitamin D, the concentration of 1, 25-hydroxyvitamin D will be high.5
Pseudohypoparathyroidism. A rare cause of hypocalcemia with high PTH is pseudohypoparathyroidism (PHP), a constellation of genetic diseases involving dysfunction of the GNAS gene on chromosome 20q13.7,8 This gene encodes the alpha-subunit of the stimulatory G protein (G alpha subunit), which is attached to the PTH receptor.7,8 Dysfunction of this gene prevents the cell signaling cascade that stimulates the kidney to reabsorb calcium and excrete phosphate. Thus, calcium levels remain low while PTH and phosphate levels are high. PHP is inherited in an autosomal dominant manner with imprinting—the paternal allele is always silenced. Thus, PHP is inherited from the mother.8
PHP type 1 is divided into subtypes 1a, 1b, and 1c.8,9 PHP types 1a and 1c present with stereotyped physical features and endocrine abnormalities collectively known as Albright's hereditary osteodystrophy (AHO).9 Patients with AHO have short stature, hypothyroidism, hypogonadism, and mental retardation, as well as ovulatory, gustatory, and auditory dysfunction.8 They may also have round facies, shortening of the metacarpals, and subcutaneous calcifications.8 However, if mutations are passed down from the father, that allele is silenced and the biochemical and mineral abnormalities seen in PHP type 1a are not seen (ie, these patients will not be hypocalcemic). They will display only the features of AHO, which is called pseudo-pseudohypoparathyroidism.10
PHP type 1b is usually sporadic with unknown mutations but may involve microdeletions of the GNAS gene.9–11 It presents as isolated hypocalcemia with high PTH and high phosphate.8,9 This form may be discovered later in life, as patients remain asymptomatic for years and have no overt physical abnormalities. PHP type 2 is rarely seen, and the molecular defect responsible for this variant is unknown.7 Because calcium and vitamin D replacement correct the kidney's response to PTH in these patients, it is hypothesized that this type of PHP may be not be a genetic defect and instead may be acquired in the setting of vitamin D deficiency.11,12 Children suspected of having PHP should be screened and treated for comorbid endocrine disorders such as hypothyroidism, hypogonadism, and growth hormone deficiency.13,14
Based on her clinical presentation and laboratory testing, our patient was diagnosed with pseudohypoparathyroidism. She began treatment with 0.25 mcg of calcitriol by mouth daily, 5,000 IU of vitamin D by mouth daily, and 2.5 g of calcium carbonate by mouth every 8 hours. Her calcium and phosphate levels were checked every 6 hours and electrocardiograms were performed daily throughout her admission to monitor her QT interval. After 1 day in the hospital, her calcium levels climbed to 8.1 mg/dL and her QT interval decreased to 0.41 milliseconds. At this time, she was discharged home on her inpatient regimen with instructions to obtain weekly calcium levels at a laboratory near her home and forward them to our endocrinology department.
Hypocalcemia is an important diagnosis to recognize, as persistent hypocalcemia can be life threatening and detrimental to bone growth and overall health. In the nonacute setting, refractory hypocalcemia can be divided into two broad groups: hypocalcemia with either high or low PTH. By looking at the PTH in relation to levels of 1, 25-hydroxyvitamin D, 25-hydroxyvitamin D, and phosphate, clinicians can determine the underlying disruption in calcium homeostasis and suggest a diagnosis.