OVERVIEW: What every practitioner needs to know

Are you sure your patient has hypocalcemia? What are the typical findings for this disease?

Hypocalcemia may present with irritability, tetany, seizures, apnea (in the neonate), laryngospasm or paresthesias (in the older child). The presence of a prolonged QT interval by electrocardiography is a physiologic marker of hypocalcemia. In the neonate, maternal diet, deficient in vitamin D, limited sun exposure, impaired maternal health, gestational insults (maternal diabetes mellitus, toxemia of pregnancy), difficult delivery, and family history must be considered when evaluating hypocalcemia in this population.

Symptomatic hypocalcemia may develop in newborns of mothers with unrecognized hypercalcemia due to hyperparathyroidism or in newborns with marked vitamin D deficiency due to maternal deficiency of this vitamin or Mg deficiency.Marked hypocalcemia in the neonate or infant may result in dilated cardiomyopathy and life-threatening congestive heart failure. Hypoparathyroidism may result from genetic disorders that impair parathyroid gland development, synthesis of PTH, PTH receptor (PTHR1) function, or the G-protein (Gsa) that transduces the signal of PTHR1 (pseudohypoparathyroidism).

Hypoparathyroidism in the infant and child is recognized by persistently low serum calcium, high serum phosphorus, appropriately low urinary calcium values and low or “inappropriately normal” PTH levels for the level of calcium.

Acute hypocalcemic seizures or tetany in the neonate is treated by careful administration of 10% calcium gluconate at a rate not to exceed 1 mL/minute (or total dose of 10 mL) with monitoring of EKG and the duration of the QT interval to avoid bradycardia and asystole. When seizures abate, IV calcium gluconate, 500 mg/kg/24 hours, may be provided as parenteral therapy if needed. Non-acute, early onset hypocalcemia should be treated with an oral calcium supplement when serum calcium is </=6 mg/dL in the preterm infants and </=7 mg/dL in the term infant or older child.

Early neonatal hypocalcemia (before 3 days of age)

In full term neonates, cord serum total calcium values approximately 11-12 mg/dL. Serum calcium levels normally decline to nadir values (9 mg/dL) at 24 hours of age as the newborn is abruptly withdrawn from the transplacental supply of maternal calcium, and then increase to steady state values as secretion of PTH increases and that of calcitonin declines. The process is exaggerated in premature, small for gestational age (SGA), low birth weight (LBW), asphyxiated infants and infants of diabetic mothers; hyperphosphatemia, and hypomagnesemia are often present.

Maternal factors such as severe vitamin D deficiency or occult hypercalcemia due to unrecognized hyperparathyroidism may both result in early neonatal hypocalcemia. Symptoms of hypocalcemia (irritability, tetany, laryngospasm, seizures, feeding problems, respiratory distress, apnea) may develop when the infant begins to ingest a cow’s milk formula with high content of phosphate. Hypocalcemia is also associated with exchange transfusion for hyperbilirubinemia and exposure to phototherapy. Infants with rotavirus infection and severe diarrhea are at risk for hypocalcemic seizures.

Aminoglycoside antibiotics may contribute to hypocalcemia. Substances that complex and sequester calcium such as citrate in transfused blood, phosphates that alter the calcium x phosphate product, fatty acids administered in hyperalimentation fluids, and phytates present in soy milk may lower calcium concentrations. Acute administration of bicarbonate to correct acidosis increases albumin bound calcium and lowers the Ca2+ concentration, as does respiratory alkalosis from hyperventilation. Neonates with osteopetrosis may present with early or late neonatal hypocalcemia and dense bones on radiographs.

Late neonatal hypocalcemia (after 3 days of age)

Hypocalcemia occurring after 3 days of age may result from increased intake of phosphate, hypomagnesemia, hypoparathyroidism, or vitamin D deficiency. High phosphate content of evaporated milk or cow milk formulas blocks calcium absorption. Early introduction of high fiber cereal into the baby’s diet also impedes calcium absorption. Newborns with renal hypoplasia or obstructive uropathies are often hypocalcemic, hyperphosphatemic, and azotemic with secondary hyperparathyroidism.

Hypomagnesemia impairs PTH release and end organ responsiveness to PTH. Magnesium deficiency is to be considered when calcium replacement fails to correct hypocalcemia. Hypocalcemia due to fetal and neonatal deficiency of vitamin D occurs in offspring whose mothers are vitamin D-deficient. Hypocalcemia associated with low phosphate values suggests a disorder involving vitamin D. Mutations in the gene encodes 5-hydroxyvitamin D-1 alpha hydroxylase and in that encoding the vitamin D receptor also lead to hypocalcemia. Hypocalcemia with high serum phosphate values suggests hypoparathyroidism. If hypocalcemia persists beyond or develops after 1 month of age, hypoparathyroidism should be considered.

Infants who have required long-term NICU care and/or prolonged parental alimentation and who may have received marginal amounts of calcium, phosphorus, and vitamin D are at risk for development of hypocalcemia associated with rickets/osteopenia. Dysmorphic babies with congenital heart disease and/or velopalatal abnormalities with hypocalcemia may have the DGS. A positive family history of hypocalcemia may indicate a disorder of the calcium sensing receptor.

Hypocalcemia in infants, children and adolescents

Patients with hypocalcemia developing in later infancy, childhood or adolescence may complain of paresthesias or tetany, laryngospasm or generalized seizures. Physical findings of hypocalcemia include the Chvostek sign (twitching of muscles controlled by the facial nerve with light tapping of the cheek) and the Trousseau sign (carpopedal spasm after maintaining blood pressure midway between the systolic and diastolic blood pressures for 3 minutes). Hypocalcemia may be suspected when an electrocardiogram has a prolonged Q-T interval.


Congenital hypoparathyroidism results most commonly from dysgenesis or agenesis of the PTGs often in association with other anomalies such as the velocardiofacial/conotruncal anomaly/DiGeorge syndromes. The DGS is the most common form of PTG dysgenesis in infancy and is present in 70% of children with isolated hypoparathyroidism. It is associated with microdeletions of chromosome 22q11.2. The DGS triad includes 1) hypocalcemia, 2) immunologic defects such as abnormal T-lymphocyte function and impaired cell-mediated immunity due to partial or complete agenesis of the thymus, and 3) maldevelopment of the heart and aortic arch. These changes are summarized in the acronym CATCH-22 (cardiac defects, abnormal face, thymic hypoplasia, cleft palate and hypocalcemia).

The typical face of the DGS patient consists of ocular hypertelorism, short palpebral fissures, puffy eyelids, dysmorphic nose, small mouth, low set folded ears, shortened philtrum, micrognathia, malar hypoplasia, and velopharyngeal insufficiency. Laboratory findings in patients with hypoparathyroidism include hypocalcemia, hyperphosphatemia, and low levels of PTH. Hypoparathyroidism may be transient, and resolve during infancy only to recur during intercurrent illness or rapid growth in childhood or adolescence.

Isolated congenital hypoparathyroidism may also result from faulty PTG embryogenesis or synthesis of an abnormal PTH molecule. It may be sporadic or familial, transmitted as an autosomal dominant, recessive or X-linked recessive trait. Hypoparathyroidism may be associated with syndromic disorders including Barakat or HDR syndrome (hypoparathyroidism, sensorineural deafness, renal disease); Sanjad-Sakati syndrome (poor growth, developmental delay, dysmorphic features); Kenny-Caffey syndrome, (KCS1 – short stature, medullary stenosis, osteosclerosis, basal ganglion calcifications, eye defects, recurrent bacterial infections).

Blomstrand osteochondrodysplasia (due to inactivating mutations of PTHR1), Kearns-Sayre syndrome, and MELAS (mitochondial encephalopathy, lactic acidosis and stroke-like episodes) are other illnesses associated with hypoparathyroidism.

In patients with dominant activating mutations of CASR, the calcium sensing receptor gene, autosomal dominant hypocalcemia develops. In this disorder, the CaSR is inappropriately “sensitive” to even low Ca2+ levels, thus suppressing PTH secretion and lowering renal tubular reabsorption of calcium. Although some affected patients may be asymptomatic, infants and children develop hypocalcemia with tetany and seizures during intercurrent illnesses. The condition is recognized by the paradoxically high levels of urine calcium despite hypocalcemia.

Pseudohypoparathyroidism (PHP)

In addition to mutations in PTHR1 that result in resistance to the biologic effects of PTH, resistance to PTH is also encountered in patients with pseudohypoparathyroidism (PHP) resulting from loss of function mutations in GNAS, the gene encoding the G alpha stimulating subunit (Gsa) of the G-protein to which PTHR1 is linked. There may also be resistance to other hormones that act through G-protein activation (e.g., TSH, LH, FSH).

Patients with Albright’s hereditary osteodystrophy have a phenotype of truncal obesity, growth retardation, brachydactyly, short neck, heterotopic calcification, dental defects and developmental delay. Laboratory findings include hypocalcemia, hyperphosphatemia, and elevated concentrations of PTH. Clinical manifestations reflect different mutations of GNAS and its promoter region:

PHP 1a: AHO phenotype, PTH resistance

PHP lb: Normal phentoype, PTH resistance

PPHP: (pseudopseudohypoparathyroidism) – AHO phenotype, normal PTH response

PHPlc: AHO phenotype, no mutations in GNAS

PHPII: Normal phenotype; normal nephrogenous cyclic AMP response but subnormal phosphaturic response to exogenous PTH

Acquired hypoparathyroidism

Acquired hypoparathyroidism may result from autoimmune insult to the PTGs due to APS-type l, often a familial disorder with autosomal recessive inheritance characterized by mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, and other autoimmune endocrinopathies. This disorder has also been termed APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). Chronic active hepatitis, thyroiditis, hypogonadism, and diabetes mellitus may result from antibodies directed against the respective organs.

The disorder results from loss of function mutations of the autoimmune regulator gene (AIRE – chromosome 21q22.3) that is highly expressed in the thymus. Some patients with isolated hypoparathyroidism may also have a mutation in AIRE. Hypoparathyroidism may also result from surgical or radiation injury or by deposition in and destruction of the PTGs by copper (Wilson disease) or iron (hemochromatosis).

Hypocalcemia due to disorders of vitamin D intake or metabolism

Newborns of markedly vitamin-D deficient mothers may have rachitic bone changes at birth, fractures, and tetany due to hypocalcemia. Bowing of the forearms, craniotabes, frontal bossing, and enlarged fontanelles are preambulatory signs of rickets in older infants. In children, genu varum or valgum, and windswept deformities of the legs may occur. Rachitic infants and children often have “flaring” (widening) of the wrists, knobby prominence of costochondral junctions (“rachitic rosary”), and a prominent indentation along the lower ribcage (Harrison’s groove).

Radiographs reveal poorly calcified, “cupped” epiphyses, metaphyseal widening, and occasional areas of osteitis fibrosa cystica. Dental eruption may be delayed and tooth enamel hypoplastic. Short stature and “failure to thrive” are common. Vitamin D-deficient subjects may also have muscle weakness, delay in walking, anorexia, and increased risk of infection, especially pneumonia; a reversible cardiomyopathy may occur.

Vitamin D deficiency is seen primarily in dark skinned infants and toddlers, many of lower socioeconomic status, who subsist on a low vitamin D diet, i.e., one lacking milk, meat, eggs or fish. They may be breast-fed and have limited exposure to sunlight. Vitamin D deficiency accompanies disorders of fat absorption including celiac disease, biliary obstruction, gastric resection or bypass, and various forms of pancreatic insufficiency. Hypovitaminosis D may also result from ingestion of calcium binding drugs such as cholestyramine, used to treat hypercholesterolemia, or accelerated vitamin D degradation by anticonvulsant agents such as phenytoin.

Vitamin D-dependent rickets type l or pseudovitamin D deficiency rickets (PDDR) is due to loss-of-function mutations in CYP27B1, the gene encoding the renal tubular enzyme that catalyzes one alpha hydroxylation of calcidiol to calcitriol.This autosomal recessive disorder usually appears in the first year of life with bowing of the forearms, growth delay, weakness, and occasionally hypocalcemic seizures.

Biochemically, PDDR is typified by a normal serum level of calcidiol but low concentration of calcitriol. Homozygous or compound heterozygous inactivating mutations of VDR, the gene encoding the nuclear vitamin D receptor, lead to resistance to the biologic action of calcitriol (designated autosomal-recessive vitamin D-dependent rickets type II or vitamin D-resistant rickets). There is infantile-onset of severe rickets, growth delay, alopecia, hypocalcemia with hypophosphatemia, and markedly increased concentrations of calcitriol and PTH.

What other disease/condition shares some of these symptoms?


Magnesium is essential for PTH release. PTH secretion in response to hypocalcemia is blunted when serum magnesium concentrations are low and rapidly restored by magnesium replacement. Hypomagnesemia may be due to congenital defects in its intestinal absorption or renal tubular reabsorption or may be acquired in older subjects.


Tetany and seizures may occur in subjects with hyponatremia of diverse pathogenesis. Congenital malformations of the central nervous system (CNS) or acquired CNS insults (traumatic, infectious, metabolic) may result in hyperirritability and/or seizures.

What caused this disease to develop at this time?

Please see preceding discussion of causes and manifestations of disorders associated with hypocalcemia in

Are you sure your patient has hypocalcemia? What are the typical findings for this disease?

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

See Figure 1 for evaluation of hypocalcemia chart.

Figure 1.n
History Physical Examination

Studies should precede initial therapy of hypocalcemia whenever possible and should include measurements of serum concentrations of:

-Total calcium and Ca2+ (In the presence of altered serum levels of albumin or total protein, algorithms may be employed to estimate the true concentration of serum calcium; e.g., total calcium values decline by approximately 0.8 mg/dL for each 1 g/dL reduction in serum albumin without change in the Ca2+ value.)


-Phosphate (High serum phosphate concentrations in the presence of hypocalcemia and low iPTH values suggest hypoparathyroidism; high phosphate levels with hypocalcemia and high iPTH values suggest either renal impairment or resistance to PTH; low phosphate concentrations with hypocalcemia and high iPTH levels suggest vitamin D deficiency).


-Intact PTH (Reduced serum concentrations of iPTH are common in newborns with early-onset hypocalcemia and those with hypomagnesemia. Persistence of low iPTH levels indicates impaired PTH secretion. High iPTH levels are found in patients with vitamin D deficiency or insensitivity, PTH resistance due to loss-of-function mutations of PTHRl or GNAS, or impaired renal function).

-Calcidiol and calcitriol (Serum values of 25OHD below 12-15 ng/mL in children indicate severe vitamin D deficiency; 25OHD concentrations above 20 ng/mL are usually sufficient for normal mineral homeostasis. Low concentrations of calcidiol indicate reduced body stores of vitamin D or in rare instances a defect in vitamin D-25 hydroxylation. Serum concentrations of calcitriol in vitamin D-deficient patients may be low, normal, or high. Low levels of calcitriol are present in patients with hypoparathyroidism, substantial impairment of renal tubular function, or a mutation in the gene controlling renal tubular 1-alpha hydroxylation. Very high calcitriol concentrations [300-1000 pg/mL] suggest vitamin D resistance due to a mutated vitamin D receptor.)

-Spot urinary calcium and creatinine concentrations.

-Later studies may involve FISH del 22q11 and/or genotyping of TBX1, GNAS, PTHR1, CYP27B1.

Would imaging studies be helpful? If so, which ones?

  • Skeletal radiographs (rickets)
  • Chest radiograph (absence of thymus)
  • Dual energy x-ray absorptiometry (DEXA) (osteopenia).
  • Renal sonography (small or malformed kidneys)
  • Electrocardiogram (short QT interval in hypocalcemic subjects)

If you are able to confirm that the patient has hypocalcemia, what treatment should be initiated?

  • Hypocalcemic neonates, infants, and children with tetany or seizures – administer 10% calcium gluconate (elemental calcium 9.3 mg/mL) at a dose of 0.5 mL/kg to maximum of 10 mL over 15 minutes, with rate of administration less than one mL/minute intravenously, and total dose not to exceed 10 mL. During infusion of calcium, it is essential to monitor cardiac rate and rhythm and EKG QT interval in order to prevent bradycardia or asystole.
  • The infusion of calcium gluconate may be repeated once if tetany uncontrolled by initial dose.
  • After stabilization:
  • In neonates – 500 mg calcium gluconate/kg/24hours by continuous intravenous infusion.
  • In infants and children – continuous intravenous infusion of 1-3 mg of elemental calcium/kg/hour.
  • In the child with marked hyperphosphatemia, parenteral calcium infusion should be accompanied by infusion of normal saline sufficient to maintain urine output =/> 2 mL/kg/hour.
  • Hypomagnesemia – magnesium sulfate 0.1-0.2 mg/kg is administered intravenously or intramuscularly with monitoring of cardiac rate and rhythm; repeat every 12-24 hours as necessary. The patient with primary hypomagnesemia may require daily parenteral doses of magnesium sulfate. Continuous overnight nasogastric infusion of magnesium may mitigate the gastrointestinal side effects of oral doses of magnesium. Milder transient forms of hypomagnesemia may be treated with oral magnesium oxide, magnesium gluconate, or tribasic magnesium citrate.
  • Asymptomatic early neonatal hypocalcemia is treated if the total serum calcium value is <6 mg/dL in the preterm neonate or <7 mg/dL in the term newborn. These patients may be treated by providing an oral intake in which the elemental calcium/phosphorus intake is 4/1.
  • In the asymptomatic hypocalcemic child or adolescent (total calcium >7.5 mg/dL), treatment may be temporarily deferred until the cause of the hypocalcemia has been determined.
  • In patients with hypoparathyroidism or pseudohypoparathyroidism, calcitriol (20-60 ng/kg/day) in 2 divided doses will usually restore eucalcemia when administered in conjunction with oral calcium glubionate or calcium citrate – 30-75 mg elemental calcium/kg/day in divided doses.
  • In patients with PHP1A, associated disorders may include hypothyroidism, ovarian dysfunction, or resistance to somatotropin, and should be treated with appropriate replacement therapy.
  • Vitamin D deficiency is best prevented. The pregnant and breast-feeding woman should receive vitamin D 2,000 IU/day. The breast-feeding neonate and infant should receive at least 400 IU/day of vitamin D and intakes to 1,000 IU/day appear to be safe. The formula-fed neonate and infant should also receive 400-1,000 IU/day of vitamin D. In the older child, 800-1000 IU/day of vitamin D is usually recommended depending on the extent of exposure to sunlight.
  • In the severely vitamin D-deficient child or adolescent, oral administration of cholecalciferol (vitamin D3) 2,000 to 10,000 IU daily for 4 to 6 weeks or 50,000 IU orally every week for 8 weeks may be prescribed. Administration of a single oral or intramuscular dose of 150,000 to 600,000 units of vitamin D3 may also be employed. At initiation of treatment, the vitamin D-deficient child must also receive elemental calcium, 40 mg/kg/day in divided doses in order to avoid the precipitous hypocalcemia that occurs with rapid remineralization of bone matrix (“hungry bone syndrome”).
  • Patients with deficiency of renal 1-alpha hydroxylase respond to treatment with 10-20 ng/kg/day of calcitriol. Life-long therapy is required.
  • Patients with mutations of the gene encoding the vitamin D receptor require very large doses of calcitriol in conjunction with parenteral administration of calcium and phosphorus to restore eucalcemia and skeletal integrity.
  • In patients with del22q11, problems related to cardiac anomalies and innube function must be addressed.

What are the adverse effects associated with each treatment option?

Very rapid intravenous infusion of calcium may result in bradycardia or asystole.

Extravasation of calcium during intravenous administration may result in soft tissue injury with subsequent scarring.

Long term therapy with vitamin D and calcium may result in hypercalcemia.

Long term therapy with vitamin D and calcium may result in hypercalciuria, nephrocalcinosis, renal calculi, and renal failure.

Patients with autosomal dominant hypocalcemia due to activating mutations of CaSR are extremely sensitive to small doses of calcitriol that may result in hypercalciuria despite minimal rise in serum calcium concentrations. Addition of hydrochlorothiazide, 0.5-2.0 mg/kg/day, to the treatment regimen results in increased renal tubular reabsorption of calcium and permits a lower calcitriol dose.

What are the possible outcomes of hypocalcemia?

The prognosis for the child with hypocalcemia depends on its etiology. When known, information about the disorder, its cause, treatment, natural history, importance to the family, and prognosis should be fully conveyed to the family of the patient.

What causes this disease and how frequent is it?

Please see preceding discussion of causes and manifestations of disorders associated with hypocalcemia in

Are you sure your patient has hypocalcemia? What are the typical findings for this disease?

How can hypocalcemia be prevented?

Vitamin D deficiency is best prevented. The pregnant and breast-feeding woman should receive vitamin D 2000 IU/day. The breast-feeding neonate and infant should receive at least 400 IU/day of vitamin D and intakes to 1000 IU/day appear to be safe. The formula-fed neonate and infant should also receive 400-1,000 IU/day of vitamin D. In the older child, 800-1000 IU/day of vitamin D is usually recommended depending on the extent of exposure to sunlight.

What is the evidence?

Root, AW, Sperling, MA. “Disorders of calcium and phosphorus homeostasis in the newborn and infant”. Pediatric Endocrinology. 2014. pp. 209-276.

Root, AW, Diamond, FB, Sperling, MA. “Disorders of mineral homeostasis in children and adolescents”. Pediatric Endocrinology. 2014. pp. 734-845.