What are the other Names for this Condition? (Also known as/Synonyms)

• Excess Blood Calcium in Children
• Hypercalcemia in Children
• Neonatal Hypercalcemia

What is Pediatric Hypercalcemia? (Definition/Background Information)

• Pediatric Hypercalcemia is characterized by elevated levels of calcium in blood in a child. It may be caused by genetic mutation(s) in CASR gene, certain inherited disorders (such as blue diaper syndrome), excess vitamin D, hyperparathyroidism (due to a tumor), and certain cancers
• The condition may also affect newborn children born prematurely, or when the mother had had ingested excess vitamin D during pregnancy. In such cases, it is termed Neonatal Hypercalcemia
• Newborns may present with poor feeding, vomiting, lethargy, and listlessness. Older children may present with signs and symptoms including weakness, increased urination, dehydration, constipation, and bone pain
• The primary treatment method of Pediatric Hypercalcemia is to increase excretion of calcium in urine through the use of diuretics. The treatment is based on the cause of the condition and may include the surgical removal of parathyroid gland tumor and prevention of bone loss, if needed
• The prognosis for Pediatric Hypercalcemia is good, if it results from a benign and treatable condition. However, if increased calcium in blood occurs due to a serious illness, the outcome may be dictated by the severity of the underlying condition

Who gets Pediatric Hypercalcemia? (Age and Sex Distribution)

• Pediatric Hypercalcemia is relatively rare when compared to hypercalcemia in adults
• Children of both genders, of all races and ethnicities, may be affected
• Approximately, 0.4-0.7% of children with cancer may develop Pediatric Hypercalcemia

What are the Risk Factors for Pediatric Hypercalcemia? (Predisposing Factors)

The following are some known risk factors for Neonatal Hypercalcemia:

• Premature birth
• Excessive vitamin D intake by a woman during pregnancy
  • Family history of genetic disorders known to cause hypercalcemia:
  • Mutation(s) in calcium sensing receptor gene CASR, that causes familial hypocalciuric hypercalcemia
  • Congenital lactase deficiency
  • Blue diaper syndrome
  • Hypophosphatasia
• Feeding with formula containing excess calcium

The following are some known risk factors for Pediatric Hypercalcemia (in older children):

• Family history of genetic disorders such as:
  • Mutation(s) in calcium sensing receptor gene CASR, that causes familial hypocalciuric hypercalcemia
  • Williams syndrome
  • Jansen metaphyseal chondrodysplasia
  • Hypophosphatasia
• Excess calcium in food
• Excessive intake of vitamin D
• Excessive intake of vitamin A
• Hyperparathyroidism
• Immobilization or bed rest due to an illness
• Cancer 

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Pediatric Hypercalcemia? (Etiology)

The major causes of Neonatal Hypercalcemia include:

• Premature birth
• Excessive ingestion of vitamin D, vitamin A, or calcium by the mother during pregnancy causing intoxication in the baby after birth
• Blue diaper syndrome
• Congenital lactase deficiency
  • Mutation(s) in calcium sensing receptor gene (CASR gene)
  • The CASR gene codes for calcium sensing receptor (CaSR)
  • This receptor, when activated, blocks the release of calcium into blood
  • Mutation(s) in the CASR gene lead to dysregulation of calcium metabolism, causing hypercalcemia
  • The gene mutation(s) are inherited in an autosomal dominant or recessive manner
  • The autosomal recessive condition, when no receptor activity is observed, can lead to neonatal severe hyperparathyroidism (NSHPT)
• Feeding improperly fortified formula milk to babies

The major causes of Pediatric Hypercalcemia (in infants, toddlers, and older children) include:

• Mutation(s) in calcium sensing receptor gene (CASR gene), leading to familial hypocalciuric hypercalcemia as described
• Certain genetic disorders that interfere with calcium metabolism including:
  • Williams syndrome
  • Blue diaper syndrome
  • Jansen metaphyseal chondrodysplasia
  • Congenital lactase deficiency
• Primary hyperparathyroidism or an increase in parathyroid hormone (PTH), generally due to an enlargement or a benign growth or tumor (adenoma) in parathyroid glands. This elevation in PTH can lead to the following:
  • Increased osteoclastic bone resorption, causing increased release of calcium from bone to blood
  • Decreased serum phosphate
  • Increased activation of vitamin D
• Endogenous vitamin D intoxication due to excessive intake of vitamin D, whose active form can cause the following:
  • Increased calcium resorption in kidneys
  • Increased mineralization of bones
  • Increased calcium absorption in the intestines
• Inactivity due to an illness: In inactive or bedridden children, decreased bone formation with corresponding increase in release of calcium in blood may result in this condition
• Presence of malignant tumors, which can cause:
  • Bone invasion causing mineralization
  • Secrete factors that circulate in blood (such as parathyroid hormone related peptide or PTHrP) and cause increased release of calcium from bones to blood
• Chronic vitamin A ingestion, leading to increased release of calcium into blood from bones
• Infectious diseases, such as leprosy and histoplasmosis, wherein the release of activated T cells and macrophages may in turn activate vitamin D, causing vitamin D intoxication

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Pediatric Hypercalcemia?

The signs and symptoms of Hypercalcemia in Children may be non-specific in the initial stages. The type and severity of signs and symptoms may depend not only on the levels of calcium in blood, but also on how rapidly these levels increase, and the underlying condition associated with it.

Signs and symptoms of Neonatal Hypercalcemia may include:

• Poor feeding
• Failure to thrive
• Irritability
• Nodules in skin that are firm to touch and may be purple in color
• Acid reflux
• Vomiting
• Hypertension
• Seizures

Signs and symptoms of Pediatric Hypercalcemia in infants, toddlers, and older children may include:

• Weakness
• Bone inflammation, bone lesions, and bone pain
• Low muscle tone; muscle weakness in upper limbs
• Listlessness
• Seizures, in rare cases
• Frequent urination, dehydration, and excessive thirst
• Constipation
• Calcium deposit in kidneys causing kidney stones
• Diabetes insipidus
• Disuse osteoporosis or loss of bone mass due to immobility

How is Pediatric Hypercalcemia Diagnosed?

Pediatric Hypercalcemia is diagnosed on the basis of the following tests and exams:

• A complete physical examination 
• Assessment of signs and symptoms, when symptoms are present. It has to be noted that clinically significant symptoms may not be reported, since they can be vague during the initial stages of the condition
• Evaluation of personal and family medical history
• Blood tests to check for serum calcium levels; a child is determined to be hypercalcemic, if serum calcium levels are above 11.5 mg/dL
• Blood tests to check for levels of parathyroid hormone, vitamin D, and phosphate
• Additional tests, pertaining to causative conditions that led to Pediatric Hypercalcemia may be necessary for an accurate diagnosis and treatment

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Pediatric Hypercalcemia?

The potential complications of Pediatric Hypercalcemia include:

• Loss of bone mass, leading to weak bones
• Death of bone tissue (osteonecrosis)
• Cardiovascular collapse, causing sudden loss of blood flow to the brain and other organs
• Brain disease or encephalopathy
• Coma

How is Pediatric Hypercalcemia Treated?

The treatment for Pediatric Hypercalcemia may include the following measures:

• Increase excretion of calcium with infusion of saline and diuretics (such as furosemide)
• Calcitonin injection: Calcitonin increases excretion of calcium in urine and decreases loss of calcium from bones
• Nitrogen-containing bisphosphonates, such as pamidronate, to prevent calcium loss from bones and osteoporosis
• Glucocorticoid treatment in children with excess vitamin D
• If the cause of hypercalcemia is a tumor in the parathyroid gland, then surgery to remove the tumor is recommended
• Additional treatment methods pertaining to the underlying condition that caused Pediatric Hypercalcemia may be necessary

How can Pediatric Hypercalcemia be Prevented?

• If Pediatric Hypercalcemia occurs as a consequence of genetic mutation(s) in the CASR gene or other congenital disorders, there are no methods or guidelines for its prevention at the present time
• If there is a family history of the condition, then genetic counseling before planning for a child may aid in understanding the risks better
• Regular medical screening at periodic intervals with tests and physical examinations are highly recommended for pregnant women, who take vitamins and calcium, to ensure balanced mineral levels in the body
• Undertaking adequate treatment of pre-existing conditions that may lead to hypercalcemia is essential in maintaining normal levels of calcium in blood

What is the Prognosis of Pediatric Hypercalcemia? (Outcomes/Resolutions)

• The prognosis of Pediatric Hypercalcemia is good, if it occurs as a result of a benign condition or a treatable illness
• If the levels of calcium in blood rise quickly to abnormal high levels, serious complications that may be life-threatening, such as a cardiac collapse or coma, may occur
• In general, the overall outcome of Hypercalcemia in Children may be determined by the severity of the underlying causative condition and its response to treatment

Additional and Relevant Useful Information for Pediatric Hypercalcemia:

Calcium is an important mineral for several cellular functions, which ultimately impact the whole body. Calcium is involved in the following functions in the body:

• Cell-cell communication
• Muscle contraction
• Conduction of nerve signals
• Activation of enzyme cascades
• Blood clotting, since calcium is also known as coagulation factor IV, and is required for certain enzymes in the clotting cascade to work effectively
• Exocrine secretions such as bile and pancreatic juice