This is a 16 month old female, who presents to the ED with an acute onset of her hands and feet "drawing up". Her parents report that she cries when touched in her hands and feet and has refused to walk. She had a low-grade fever, vomiting, diarrhea, and decreased urine output attributed to a viral gastroenteritis beginning four days ago. Past medical history reveals that she had been a healthy term infant with no previous hospitalizations or significant illnesses.
Exam: VS T 37.7, P 140, R 20, BP 90/64, length 74.5 cm (10%ile), wt 9.2 kg (10%ile). She is fussy but awake and alert. HEENT, neck, heart, lungs and abdomen exams are normal. Both her hands are flexed at the wrists with hyperextended fingers at the proximal and distal interphalangeal joints and flexion at the metacarpophalangeal joints. Both thumbs are flexed upon the palm. Her feet are plantar flexed. Neurologic exam reveals symmetric hyperreflexia, decreased muscle strength and tone.
Laboratory: Na 135, K 3.8, Cl 102, bicarbonate 24, BUN 5 mg/dL, creatinine 0.3 mg/dL, glucose 82 mg/dL, calcium 5.6 mg/dL (normal 8.5 to 10.5), phosphorus 2.2 mg/dL (normal 3.5 to 6), alkaline phosphatase 1020 U/L (normal 125 to 450), ionized calcium 0.50 mmol/L (normal 1.00 to 1.30). CXR shows enlargement of the costochondral junctions. The normal enlarged thymic shadow of infants and toddlers is present. Radiographs of hands/wrists demonstrate cuffing, fraying, and widening of the epiphysis and metaphysis.
A diagnosis of vitamin D deficiency rickets with acute hypocalcemic tetany is made and she is treated with 1 mL/kg of 10% Ca gluconate solution IV over 1 hour. A dietary history reveals that she had been breast-fed since birth that has continued at least twice a day at present. Table foods were introduced at 10 months of age, but she is described as a picky eater and does not drink whole milk. She does not take any vitamin supplements. A review of her growth curve shows her decreasing from the 50%ile for length and weight at birth to the 10%ile for both parameters now. The diagnosis is confirmed with serum 25-OH vitamin D level of <5 ng/mL (normal 10 to 55), with an appropriately increased PTH level of 270 pg/mL (normal 10 to 55). 1,25-dihydroxy vitamin D level is 40 pg/mL (normal 15 to 90) (The plasma concentration of 25-OH D is the most sensitive index of vitamin D nutritional status. Most untreated vitamin D deficient patients have normal or elevated levels of 1,25-dihydroxy vitamin D due to secondary hyperparathyroidism which increases activity of renal 1 alpha-hydroxylase, which converts 25-OH D to 1,25-diOH D).
She is admitted to the hospital and treated with oral supplementation of 250 mg calcium carbonate every six hours and 4,000 IU of vitamin D (ergocalciferol) per day. She has no further episodes of tetany and is discharged 2 days later continuing on calcium and vitamin supplementation. Clinical and radiographic improvement is noted over the next several months, and the vitamin D dose is reduced to the recommended daily allowance of 400 IU.
Calcium (1,3) is an essential component of the mineral portion of bone and as its divalent cation (Ca++) is necessary for the function of every cell. Maintenance of calcium homeostasis is a dynamic process involving calcium absorption and excretion in the intestine, filtration and reabsorption in the kidneys, and storage and mobilization in the skeleton. Nearly all of the total body calcium (98%) is present in very slowly exchangeable skeletal hydroxyapatite crystal. It is the rapidly exchangeable calcium in recently deposited bone (1% of body calcium) and in the extracellular, intracellular, and vascular spaces (1%), that plays critical roles in intracellular communication, interneuronal transmission, muscle contraction, clotting, cellular proliferation, synthesis of secretion of endocrine and exocrine factors, and as an enzyme cofactor. Total serum calcium is divided into three fractions: 40% is bound to albumin and globulin, 10% is complexed to anions, while 50% exists in the free ionized state that is necessary for most metabolic functions.
The serum concentration of calcium is maintained at normal levels by an integrated system involving the Ca++ sensing receptor (CaSR), parathyroid hormone (PTH), vitamin D, and calcitonin. The CaSR is a membrane protein that binds Ca++ and determines the set-point for PTH secretion. PTH is an 84 amino acid peptide that increases calcium concentration by stimulating reabsorption of calcium in the kidney, enhancing the rate of calcium resorption from bone and increasing the rate of absorption of calcium from the intestine through increased renal formation of 1-25-dihydroxy vitamin D (1,25-diOH-D). Vitamin D3 (cholecalciferol) is synthesized in the skin from 7-dehydrocholesterol by exposure to UV light and heat. Vitamin D3 is hydroxylated in the liver to 25-OH-D (calcidiol), then further hydroxylated in the kidney to the biologically active 1,25-diOH-D (calcitriol). 1,25-diOH-D stimulates the absorption or reabsorption of calcium in the intestines, bone, and kidney. Calcitonin is a 32 amino acid peptide secreted by the parafollicular (C) cells of the thyroid gland, secreted in response to a rise in the serum calcium concentration. Its major biological effect is to decrease the calcium resorption in bone by inhibiting osteoclast activity.
Etiology of Hypocalcemia in Children and Adolescents (2,3,4)
. . . . . Congenital
. . . . . . . . Transient neonatal
. . . . . . . . Familial
. . . . . . . . DiGeorge syndrome
. . . . . Acquired
. . . . . . . . Autoimmune
. . . . . . . . Post-surgical
. . . . . . . . Infiltrative
. . . . . Resistance to PTH
. . . . . . . . Pseudohypoparathyroidism
. . . . . . . . Pseudopseudohypoparathyroidism
2. Vitamin D deficiency
. . . . . Ca deficiency
. . . . . Hypomagnesemia
. . . . . Hyperphosphatemia
. . . . . . . . Includes chronic renal failure (renal osteodystrophy)
. . . . . Hypoproteinemia
. . . . . Drugs (furosemide, calcitonin, antineoplastic agents)
. . . . . "Hungry bones"
. . . . . Critical illness
The child with hypocalcemia may be asymptomatic and identified through chemistries obtained for another reason or present with intermittent muscular cramping, paresthesias, tetany, carpopedal spasms, laryngospasms, or seizures. Review of symptoms and past medical history may reveal intermittent symptoms associated with hypocalcemia. Commonly, the physical exam is unremarkable other than that of increased neuromuscular irritability: hyperreflexia, Chvostek sign (twitching of the circumoral muscles when tapping lightly over the facial nerve) or Trousseau sign (carpopedal spasm when maintaining a blood pressure cuff 20 mmHg above the systolic blood pressure for 3 minutes), and occasionally cataracts or abnormal dentition. The physical exam may disclose the characteristic phenotype of Albright hereditary osteodystrophy (short stature, round facies, shortened metacarpals, subcutaneous calcification; pseudohypoparathyroidism type Ia), the DiGeorge syndrome (typical facies, cardiac abnormalities), or rachitic changes (bowed legs or "knock knees", widened metaphyses of the long bones, prominent costochondral junctions, frontal bossing) in the case vitamin D deficiency.
DiGeorge syndrome is usually classified as an immune deficiency, but it usually presents initially with congenital heart disease or with hypocalcemic seizures or tetany. During embryogenesis, the thymus and parathyroid glands originate from the same branchial pouch, which explains why the two abnormalities occur together. Congenital heart disease may be detected during the newborn period. Subsequently, the child will present with hypocalcemic tetany or seizures during the first few months of life, before any opportunistic infection is likely to occur. A chest X-ray will show a cardiac silhouette without the usual thymic shadow. Thymic absence with hypocalcemia, is highly indicative of DiGeorge syndrome.
The laboratory evaluation of a hypocalcemic child requires measuring serum total and ionized calcium, PTH, magnesium, phosphate, creatinine, alkaline phosphatase, and urinary calcium. If there are concerns of a metabolic bone disease, serum levels of 25-OH-D and 1,25-diOH-D should also be obtained.
Calcium and magnesium tend to be antagonistic, so hypocalcemia will occur in association with a high magnesium load, which most commonly occurs in premature neonates of mothers treated with magnesium tocolytics. Severe hypomagnesemia will also result in hypocalcemia since magnesium is a required co-factor for PTH release. Thus, both extremes of magnesium, will result in hypocalcemia.
A patient with hypocalcemia, hypocalciuria, hyperphosphatemia, and low serum PTH levels has hypoparathyroidism caused by a primary defect in PTH synthesis or secretion. An elevated PTH level indicates a compensatory increase in response to hypocalcemia or a resistance to PTH (pseudohypoparathyroidism).
Management of symptomatic acute hypocalcemia is intravenous 10% calcium gluconate (93 mg elemental Ca in 10 mL), 1-2 mL/kg over 10 minutes. Although calcium chloride can also be used, some texts discourage the use of calcium chloride because it can lead to metabolic acidosis. After acute symptoms have resolved, an intravenous infusion of calcium should be initiated at a rate to keep the serum calcium levels in the low normal range while an investigation of the etiology ensues. Therapy for patients with hypo- or pseudohypoparathyroidism is individualized using calcitriol (20-60 ng/kg/day) and supplemental oral calcium (30-75 mg elemental Ca/kg/day). Frequent measurements of serum calcium and creatinine and renal ultrasonography are done to monitor for hypercalcemia, hypercalciuria, and nephrocalcinosis.
Etiologies of Hypercalcemia in Children and Adolescents (2,3,4)
. . . . . Sporadic
. . . . . Familial (isolated or MEN 1 and 2A)
. . . . . Secondary/tertiary (renal failure)
2. Familial hypocalciuric hypercalcemia (FHH)
3. Hypervitaminosis D
. . . . . Nutritional
. . . . . Granulomatous disease (sarcoidosis, TB, histoplasmosis)
. . . . . Bony metastases
. . . . . Production of PTH related protein (PTHrP)
. . . . . Cytokine/osteoclast-activator production
. . . . . Hyperphosphatemia
. . . . . Drugs (thiazides, lithium, vitamin A, alkali)
. . . . . Hyperthyroidism
. . . . . Hypoadrenalism
. . . . . Pheochromocytoma
Clinical features are dependent on the underlying disorder and degree of hypercalcemia. Nonspecific symptoms include polydipsia, polyuria, anorexia, constipation, nausea, vomiting, abdominal pain, weakness, and altered consciousness. The patient may show signs of dehydration or altered mental status, otherwise the physical exam is usually normal. Commonly a shortened QT interval can be found on EKG and nephrocalcinosis and renal calculi demonstrated by ultrasonography.
The initial laboratory evaluation of a hypercalcemic child requires measuring serum total and ionized calcium, urinary calcium, PTH, phosphate, creatinine, 25-OH-D and 1,25-diOH-D levels. If the patient is hypocalciuric, the probable etiology is FHH (familial hypocalciuric hypercalcemia). This diagnosis can be confirmed by finding asymptomatic hypocalciuric hypercalcemia in one of the parents. In the absence of secondary hyperparathyroidism (chronic renal failure, ingestion of thiazides or lithium), consistently elevated PTH levels are indicative of primary hyperparathyroidism. Calcidiol levels are increased in patients with hypercalcemia caused by excessive intake of vitamin D. Calcitriol levels are increased in patients with granulomatous, chronic inflammatory, and lymphomatous diseases or those receiving that vitamin. PTHrP (PTH related peptide) levels are high in the children with humoral hypercalcemia of malignancy.
Appropriate management depends on the severity and cause of the high calcium levels. If the calcium level is <12 mg/dL and the patient asymptomatic, treatment may be delayed pending evaluation of the cause. Symptomatic patients and those with calcium levels >12 mg/dL should be treated because of the adverse effects of hypercalcemia on the cardiac, renal, gastrointestinal, and central nervous systems.
Treatments are: 1) intravenous fluid therapy (NS at twice maintenance) to restore volume, dilute serum Ca++ levels, and promote calciuresis; 2) calciuresis by IV furosemide (1 mg/kg) only after restoration of volume; and 3) inhibition of bone resorption by bisphosphonates or calcitonin. Dialysis may be indicated if the patient is resistant to conventional therapy.
Surgery is indicated for primary hyperparathyroidism. The secondary hyperparathyroidism of chronic renal failure is best treated by lowering the serum phosphate to the extent possible while maintaining the serum calcium level in the low-normal range with calcitriol (1,25-diOH-D).
Glucocorticoids are effective in lowering excess calcium levels due to vitamin D ingestion, granulomatous and inflammatory diseases, or malignancies, by inhibiting renal 25-OH-D-1-alpha-hydroxylase activity. A low calcium diet, copious fluids, avoidance of vitamin D, and early mobilization are indicated in the immobilized child to avoid hypercalcemia.
Etiologies of Rickets (2,5)
1. Abnormality of vitamin D intake or metabolism
. . . . . Nutritional deprivation (low birth weight infant, malabsorption, drugs)
. . . . . Metabolic factors
. . . . . 25-hydroxylase deficiency (loss-of-function mutation, severe liver disease)
. . . . . 25-OH-D-1-alpha-hydroxylase deficiency (loss-of-function mutation, chronic renal insufficiency)
. . . . . Loss-of-function mutation of vitamin D receptor
2. Calcium deficiency
. . . . . Nutritional
. . . . . Hypercalciuria
3. Phosphorus deficiency
. . . . . Nutritional (low birth weight infant, aluminum-containing antacids)
. . . . . Hyperphosphaturia
. . . . . . . . X-linked familial hypophosphatemic rickets
. . . . . . . . X-linked recessive hypophosphatemic rickets
. . . . . . . . Autosomal recessive hypophosphatemic rickets with hypercalciuria
. . . . . . . . Autosomal dominant hypophosphatemic rickets
. . . . . . . . Oncogenic hypophosphatemic osteomalacia
. . . . . . . . Renal tubular acidosis
Rickets and osteomalacia are disorders that result from demineralization of bone matrix. Rickets occurs in the growing child and involves the growth plate and can lead to skeletal deformities. Osteomalacia refers to demineralization of mature bone and is associated with an increased fracture risk. Rickets is primarily calcipenic (nutritional deficiency of calcium or vitamin D or abnormality in vitamin D action) or phosphopenic (abnormality in renal reabsorption of phosphate).
Clinical signs of rickets in ambulatory children include bowed legs or "knock knees", widening of the long bones metaphyses, prominence of costochondral junction (rachitic rosary), frontal bossing, and short stature. Symptoms may include hypotonia, weakness, anorexia, and delayed walking. Hypocalcemia, tetany, and seizures may be seen in a severely vitamin D deficient infant.
Radiographically, the long bones are the earliest and most common sites of change. There is decreased bone density, thinning of the cortex, and widening, cupping, and fraying of the distal ends of the shaft.
In children with vitamin D deficiency, the serum calcium levels are normal or low, phosphate low, alkaline phosphatase elevated, calcidiol low, and calcitriol variable (i.e., it is sometimes normal as in the case). Prevention is the best treatment for vitamin D deficiency, but once deficiency has been established, treatment consists of vitamin D replacement (1000-4000 IU/day orally for several weeks; 10,000-50,000 IU IM monthly for 3-6 months; or 600,000 IU IM once). Calcium supplementation (elemental Ca 40 mg/kg/d) should be given to avoid hypocalcemia resulting from remineralization ("hungry bone" syndrome).
There is an association of prolonged breast-feeding and vitamin D deficiency. Breast milk has only 15-30 IU/L vitamin D. In 1997, the American Academy of Pediatrics issued a statement recommending vitamin D supplementation "for those infants whose mothers are vitamin D deficient or those infants not exposed to adequate sunlight" (6). However in 2003, the AAP revised this statement recommending vitamin D supplementation for all infants and children (7).
Rickets caused by inadequate dietary calcium has been observed in infants and children receiving a diet containing less than 200 mg elemental calcium per day. Ensuring adequate calcium intake established for growing children (1000-1300 mg/d) is preventative and therapeutic. Phosphate is abundantly present in most foods, so rickets from dietary phosphate deficiency is unusual. Dietary phosphate deficiency can be found in patients taking aluminum-binding antacids (which bind phosphate), or in patients on prolonged parental nutrition with inadequate phosphate, and in premature infants on breast milk without phosphate supplementation.
Rickets caused by a liver 25-hydroxylase deficiency is exceedingly rare since there appears to be several enzymes capable of carrying out this reaction. A loss-of-function mutation in the 25-OH-D-1-alpha-hydroxylase enzyme is termed pseudovitamin D-deficiency rickets (PDDR) or vitamin D-dependent rickets type I. There is hypocalcemia, hypophosphatemia, and hyperphosphatasia, and elevated PTH levels. Serum calcidiol levels are normal and calcitriol levels low and do not respond to administration of vitamin D. Treatment is with small doses of calcitriol (10-20 ng/kg/d). An inactivating mutation of the vitamin D receptor leads to resistance to calcitriol and is termed vitamin D-dependent rickets type II. Patients have the typical biochemical and radiographic findings of rickets, and their serum calcitriol and PTH levels are markedly elevated. Clinically patients also exhibit severe onset of bone deformities in infancy, alopecia, and growth retardation. Treatment consists of high dose calcitriol (up to 6 mcg/kg/d) and supplemental calcium (up to 3 gm/kg/d elemental calcium).
X-linked hypophosphatemic rickets is one of the most common causes (1:20,000 births) of rickets in developed countries. It is caused by an as yet unidentified phosphaturic agent produced possibly by osteoblasts. Serum calcium, PTH, calcidiol levels are normal, and there is marked hypophosphatemia and hyperphosphaturia. Calcitriol levels are inappropriately low. The primary agents employed in treatment are calcitriol (30-70 ng/kg/d) and elemental phosphorus (0.25-2 gm/kg/d in 4-6 divided doses).
1. True/False: The main biochemical findings in hypoparathyroidism are hyperphosphatemia and hypocalcemia.
2. True/False: Calcitonin injections can be used to raise a patient's serum calcium level.
3. True/False: Breast feeding prevents rickets.
4. True/False: Elevated levels of parathyroid hormone always result in hypercalcemia.
5. True/False: Vitamin D alone is curative all various forms of rickets.
1. Root AW, Diamond FB. Calcium Metabolism. In: Sperling MA (ed). Pediatric Endocrinology, 2nd edition. 2002, Philadelphia: W.B. Saunders, pp. 65-96.
2. Root AW, Diamond FB. Disorders of Calcium Metabolism in the Child and Adolescent. In: Sperling MA (ed). Pediatric Endocrinology, 2nd edition. 2002, Philadelphia: W.B. Saunders, pp. 629-670.
3. Aarskog D, Harrison H. Disorders of Calcium, Phosphate, PTH and Vitamin D. In: Kappy MS, Blizzard RM, Migeon CJ (eds). The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 4th edition. 1994, Springfield: Thomas, pp. 1027-1092.
4. Fouser L. Disorders of calcium, phosphorus, and magnesium. Pediatr Ann 1995;24:38-46.
5. Klein GL. Nutritional Rickets and Osteomalacia. In: Favus MJ (ed). Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 2nd edition. 1993, New York: Raven Press, pp. 264-268.
6. American Academy of Pediatrics: Breast-feeding and the use of human milk. Pediatrics 1997;100:1035-1039.
7. American Academy of Pediatrics, April 2003: http://www.aappolicy.org
DiGeorge Syndrome: Yamamoto LG. Seizure and VSD in a 2-month Old Infant. In: Yamamoto LG, Inaba AS, DiMauro R. Radiology Cases In Pediatric Emergency Medicine, 1995, volume 2, case 2. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v2c02.html
Rickets: Mendez D. Elbow Swelling In a 2 Year Old With Liver Disease. In: Yamamoto LG, Inaba AS, DiMauro R. Radiology Cases In Pediatric Emergency Medicine, 1999, volume 6, case 5. Available online at: www.hawaii.edu/medicine/pediatrics/pemxray/v6c05.html
Answers to questions
2. False. Calcitonin lowers serum calcium levels.
3. False. Breast milk contains low levels of vitamin D. Vitamin D supplementation will prevent rickets.
4. False. A compensatory increase in PTH in response to hypocalcemia (such as with rickets) will usually result in low or normal calcium levels. High PTH levels should result in hypercalcemia; however, pseudohypoparathyroidism is an end-organ resistance to PTH, so despite an elevated PTH, patients have hypocalcemia.
5. False. The mainstay of therapy in hypophosphatemic rickets is oral phosphate replacement. Calcitriol is used to decrease the amount of phosphate needed (increases intestinal phosphate absorption), and prevent hypocalcemia and secondary hyperparathyroidism.