Pediatric Hypercalcemia Clinical Presentation

Updated: Aug 11, 2017
  • Author: Pisit (Duke) Pitukcheewanont, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Presentation

History

Hypercalcemia can cause symptoms at levels as low as 12 mg/dL and consistently causes symptoms at 15 mg/dL. Hypercalcemia initially and predominantly affects the GI and nervous systems. Symptoms include the following:

  • Nervous system
    • Personality changes
    • Malaise
    • Headache
    • Hallucinations
    • Unsteady gait
    • Proximal muscle weakness
    • CNS depression
    • Irritability
    • Confusion
  • GI system
    • Hypercalcemia can cause a paralytic ileus, with resultant abdominal cramping, constipation, anorexia, nausea, and vomiting.
    • Ectopic calcification can lead to symptoms of pancreatitis, with epigastric pain and vomiting.
    • Increased gastric acid secretion may produce symptoms consistent with gastritis.
  • Renal symptoms
  • Musculoskeletal system - Bone pain
  • Ectopic calcification
    • Pruritus
    • Conjunctivitis
  • Miscellaneous symptoms
    • Congenital deformity
    • Other symptoms of malignancy
    • Symptoms of other underlying causes of hypercalcemia
    • Hypercalcemia-associated acute respiratory distress syndrome (rare) [3]
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Physical

See the list below:

  • Vital signs include the following:
  • Neurologic examination findings include the following:
    • Depressed sensorium
    • Confusion
    • Gait disturbances
    • Hyporeflexia
    • Proximal muscle weakness
  • Even at lower levels, patients can have renal failure and ectopic calcification, including renal stones and pancreatitis.
  • Ectopic calcification can also manifest as conjunctivitis or band keratopathy on eye examinations.
  • Neonates may be asymptomatic or may have vomiting, hypotonia, hypertension, or seizures.
  • At levels of 17 mg/dL, calcium phosphate precipitation through the blood and soft tissues can lead to coma or lethal cardiac arrest.
  • Hypercalcemia is often asymptomatic. If hypercalcemia is symptomatic, the differential diagnosis rests heavily on the predominating symptom.
  • Weakness and altered sensorium may be symptomatic of a myriad of neurologic disorders, as well as toxins (eg, organophosphate poisoning), lupus, or thyroid dysregulation.
  • Weakness alone may be confused with hypokalemia, whereas ataxia is found in phenytoin overdoses, mass lesions, stroke syndromes, and encephalitides.
  • Hypertension may indicate a cardiac or renal problem.
  • Many manifestations of hypercalcemia (eg, pancreatitis, renal stones, gastritis, conjunctivitis) may be caused by etiologies different from hypercalcemia.
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Causes

Etiologies vary by age and other factors.

  • Neonates
    • Neonatal primary hyperparathyroidism can begin as soon as the parathyroid glands, functional in the first trimester of pregnancy, become hyperplastic.
      • Infants have malaise, constipation, and vomiting; serum calcium and parathyroid hormone (PTH) concentrations are elevated, and serum phosphate concentration is decreased. Aminoaciduria occurs. Rarification of bones leads to easier fracturing.
      • Rehydration with isotonic sodium chloride solution and forced diuresis with furosemide are urgently required, as well as administration of subcutaneous calcitonin. Common side effects of subcutaneous calcitonin include facial flushing, nausea, and vomiting.
      • Definitive treatment is performed by means of surgical resection, often with reimplantation of a small amount of tissue into a more accessible ectopic site (eg, forearm).
      • Neonatal primary hyperparathyroidism stems from a homozygous inactivating mutation in a calcium-sensing receptor.
    • Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant heterozygous mutation of the same calcium receptor-sensing gene (CASR) that is abnormal in the homozygous state in neonatal primary hyperparathyroidism.
      • If symptoms are observed (eg, chondrocalcinosis, pancreatitis, renal disease, neuropsychiatric disease), they generally begin in the neonatal period; however, patients are often asymptomatic. If the patient is asymptomatic, no treatment is required.
      • Because of the mutation, levels of calcium that are higher than usual are required to decrease secretion of PTH. The serum PTH concentration, although within the reference range, is inappropriately high for the degree of hypercalcemia.
      • Other laboratory findings include a decreased or normal serum phosphorus level, an increased magnesium level in 50% of babies, normal levels of alkaline phosphatase and serum 25-hydroxyvitamin D, and an appropriate level (to the PTH) of 1,25-dihydroxyvitamin D. Serum calcium levels rarely rise above 14 mg/dL. Urine calcium excretion is decreased to less than 200 mg/d, but the level of urine cyclic adenosine monophosphate (cAMP) is normal.
      • Radiographic findings are normal.
    • Excessive supplementation of calcium causes hypercalcemia.
    • Williams syndrome, which is associated with a deletion of elastin genes on chromosome 7, occurs as transient neonatal hypercalcemia, perhaps secondary to increased sensitivity to vitamin D. [4] The syndrome is associated with characteristic elfin facies, mental retardation, and supravalvar aortic stenosis. Generally, hypercalcemia is symptomatic, with poor feeding and constipation, and spontaneously remits by age 9-18 months. Treatment is a dietary restriction of calcium to 100 mg/d and limited vitamin D intake. Hydrocortisone at 10-25 mg/kg/d or calcitonin is sometimes helpful.
    • Severe autosomal recessive hypophosphatasia is a disease of bone mineralization due to a deficiency in tissue nonspecific alkaline phosphatase (TNSALP). Associations vary from rachitic changes to fetal death. These children require a low-calcium high-phosphate diet.
    • Secondary hyperparathyroidism is a neonatal response to maternal hypocalcemia with similar symptoms to primary hyperparathyroidism, except that the child undergoes a progression from hypocalcemia to normocalcemia to hypercalcemia quickly after birth. PTH is generally elevated. During the first few months, the parathyroid glands and skeletal lesions normalize; therefore, only symptomatic nonsurgical treatment is required.
    • Idiopathic infantile hypercalcemia is a poorly understood disorder possibly related to non–malignancy-associated PTH-related protein (PTHrP), which spontaneously resolves by age 12 months.
    • Blue diaper syndrome is a selective defect in the intestinal transport of tryptophan. The diagnosis is confirmed by analyzing urine indoles.
    • Jansen metaphyseal chondrodysplasia is a rare disease of endochondral bone formation characterized by short stature, leg bowing, short-limbed dwarfism, and a waddling gait. Neonatally, these children appear normal but have radiographic and laboratory abnormalities. In early childhood, the external changes become more obvious. The condition arises from an activating mutation in the PTH/PTHrP receptor. Radiographic findings reveal cupped and ragged metaphyses and osteitis fibrosa cystica, and laboratory findings reveal a serum calcium level of 13-15 mg/dL, a low phosphate level, a high level of 1,25-dihydroxyvitamin D, a high alkaline phosphatase level, and urine hydroxyproline.
  • Infants: Subcutaneous fat necrosis, which manifests in neonate as violaceous plaques or nodules overlying fatty areas, can lead to life-threatening hypercalcemia at age 1-6 months. It is likely mediated by prostaglandin E (PGE) or due to macrophage production of 1,25-dihydroxyvitamin D. Treatment includes corticosteroids and symptomatic support of patient.
  • School-aged children
    • Hyperparathyroidism secondary to parathyroid adenoma or autosomal dominant hereditary hyperparathyroidism is a rare problem in older children. Children may be asymptomatic or symptomatic with constipation and personality changes. Levels of urine and serum calcium are high, whereas the serum phosphorus level is low and urine phosphorus level is high. Unlike in most forms of hypercalcemia, which are associated with systemic alkalosis, patients with hyperparathyroidism tend to have acidosis. This acidosis is due to a loss of bicarbonate in the urine, giving a picture consistent with renal tubular acidosis. Radiographic findings of osteitis fibrosa cystica may be present. Treatment is surgical, and corticosteroids have no role. [5]
    • Multiple endocrine neoplasia (MEN) type 1 (ie, Wermer syndrome) is a rare autosomal dominant constellation of hyperparathyroidism, pancreatic tumors, and pituitary tumors treated by subtotal parathyroidectomy. Molecular diagnosis is now available for MEN types 1 and 2.
  • General factors
    • Malignancies produce hypercalcemia much less frequently in the pediatric patients than in adults. However, pediatric malignancies that can elevate calcium include the following:
    • Three different mechanisms are responsible, and resultant laboratory abnormalities slightly differ.
      • Primarily in leukemia, PTHrP increases osteoclast resorption of bone, renal reabsorption of calcium, and renal loss of phosphorous, leading to decreased serum phosphate levels, increased urinary cAMP, and detectable PTHrP.
      • Burkitt lymphoma and multiple myeloma, as well as bony tumors or sarcomas with bony metastases, can cause cytokine-mediated bone resorption.
      • Hodgkin and non-Hodgkin lymphoma may cause increased intestinal absorption of calcium via production of 1,25-dihydroxyvitamin D by macrophages, which contain 1-alpha-hydroxylase activity, and may maintain a normal serum phosphorus level.
    • Generally, patients with malignancy-induced hypercalcemia have decreased chloride levels, alkalosis, increased BUN levels, increased uric acid levels, urine calcium levels higher than 400 mg/dL, and increased urine cAMP levels. Serum alkaline phosphatase levels may be elevated, and serum PTH levels are decreased, except in the uncommon setting of direct stimulation of PTH production by the tumor. Serum calcium levels greater than 14 require treatment, primarily with hydration and steroids at a dose of 1.5-2 mg prednisone equivalent/kg/d for several days.
    • Thyrotoxicosis can cause sufficient bone resorption to increase serum calcium in 20% of cases. In these patients, thyrotoxicosis can also decrease serum PTH and increase urine excretion of cAMP and calcium. Although hypercalcemia is rarely subjectively symptomatic to the patient, it can lead to nephrocalcinosis and renal failure. This condition is rare in childhood, but it is possible in neonates of mothers with Graves disease or in older children who develop Graves disease.
    • Granulomatous disease, including sarcoidosis, tuberculosis (TB), Wegener disease, berylliosis, and Pneumocystis carinii pneumonia, may cause hypercalcemia via overproduction of 1,25-dihydroxyvitamin D by macrophages and increased extrarenal alpha1-hydroxylase activity.
    • Adrenal insufficiency can decrease the renal clearance of calcium.
    • Hypercalcemia may appear in the oliguric phase of acute renal failure due to the PTH increase stimulated by hyperphosphatemia. Also, children with renal failure treated with calcitriol for secondary hyperparathyroidism can develop a mild hypercalcemia. [7]
    • Immobilization can cause hypercalcemia.
  • Medication and iatrogenic causes
    • Total parenteral nutrition may cause hypercalcemia.
    • Vitamin D intoxication due to ingestion of more than 50 mcg/d in infants or more than 500 mcg/d in adults can cause hypercalcemia, even in the absence of a markedly elevated 1,25-dihydroxyvitamin D. Symptoms of hypercalcemia, including hypertension, aortic valvular sclerosis, retinopathy, renal damage, and bony abnormalities, can also occur 1-3 months after a large overdose of vitamin D. Serum PTH is decreased. Levels of water-soluble preparations can drop quickly, but hypercalcemia from an excess intake of fat-soluble preparations may persist for months.
    • Vitamin A in high doses, such as those found in retinoid therapy for acne, can directly stimulate bone resorption by functioning as a transcription factor in osteoclast stimulation. Trans -retinoic acid, used for treatment of some leukemias, can elevate calcium with this mechanism, particularly when coupled with voriconazole. [8]
    • Thiazide diuretics (eg, Diuril) may cause hypercalcemia because of their action on the distal tubule.
    • Lithium causes a mild increase in serum calcium, which can occasionally increase further in the few months after cessation of the drug secondary to parathyroid hyperplasia or adenoma.
    • Tamoxifen and oral contraceptives can exacerbate existing hypercalcemia.
    • Milk-alkali syndrome (ie, Burnett syndrome) from exogenous ingestion of calcium-containing antacids leads to renal insufficiency and metastatic calcinosis with increased phosphorus levels, increased levels of 1,25-dihyroxyvitamin D, decreased PTH levels, normal levels of serum alkaline phosphatase, normal urine calcium levels, and decreased urine phosphate levels. [9] If continued over time, this may lead to osteomalacia. This condition is particularly sensitive to the development of hypocalcemia following treatment with bisphosphonates.
    • Theophylline can cause increases in calcium via beta-adrenergic stimulation. This may be treated with propranolol.
    • Oral dietary phosphate deficiency may cause hypercalcemia.
    • Vitamin-D receptor modulators (eg, paricalcitol) are newer medications used to treat malignancy and hyperparathyroidism, which can increase serum calcium levels.
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