Etiology

There are many causes of rickets (Table 48-2), including vitamin D disorders, calcium deficiency, phosphorous deficiency, and distal renal tubular acidosis.

Clinical Manifestations

Most manifestations of rickets are due to skeletal changes (Table 48-3). Craniotabes is a softening of the cranial bones and can be detected by applying pressure at the occiput or over the parietal bones. The sensation is similar to the feel of pressing into a Ping-Pong ball and then releasing. Craniotabes may also be secondary to osteogenesis imperfecta, hydrocephalus, and syphilis. It is a normal finding in many newborns, especially near the suture lines, but it typically disappears within a few months of birth. Widening of the costochondral junctions results in a rachitic rosary, which feels like the beads of a rosary as the examiner’s fingers move along the costochondral junctions from rib to rib (Fig. 48-1). Growth plate widening is also responsible for the enlargement at the wrists and ankles. The horizontal depression along the lower anterior chest known as Harrison groove occurs from pulling of the softened ribs by the diaphragm during inspiration (Fig. 48-2). Softening of the ribs also impairs air movement and predisposes patients to atelectasis and pneumonia.

Figure 48-1 Rachitic rosary in a young infant.

Figure 48-2 Deformities in rickets showing curvature of the limbs, potbelly, and Harrison groove.

There is some variation in the clinical presentation of rickets based on the etiology. Changes in the lower extremities tend to be the dominant feature in X-linked hypophosphatemic rickets. Symptoms secondary to hypocalcemia occur only in those forms of rickets associated with decreased serum calcium (Table 48-4).

The chief complaint in a child with rickets is quite variable. Many children present because of skeletal deformities, whereas others have difficulty walking owing to a combination of deformity and weakness. Other common presenting complaints include failure to thrive and symptomatic hypocalcemia (Chapter 565).

Radiology

Rachitic changes are most easily visualized on posteroanterior radiographs of the wrist, although characteristic rachitic changes can be seen at other growth plates (Figs. 48-3 and 48-4). Decreased calcification leads to thickening of the growth plate. The edge of the metaphysis loses its sharp border, which is described as fraying. The edge of the metaphysis changes from a convex or flat surface to a more concave surface. This change to a concave surface is termed cupping and is most easily seen at the distal ends of the radius, ulna, and fibula. There is widening of the distal end of the metaphysis, corresponding to the clinical observation of thickened wrists and ankles as well as the rachitic rosary. Other radiologic features include coarse trabeculation of the diaphysis and generalized rarefaction.

Figure 48-3 Wrist x-rays in a normal child (A) and a child with rickets (B). The child with rickets has metaphyseal fraying and cupping of the distal radius and ulna.

Figure 48-4 X-rays of the knees in a 7 yr old girl with distal renal tubular acidosis and rickets. A, At initial presentation, there is widening of the growth plate and metaphysical fraying. B, Dramatic improvement after 4 mo of therapy with alkali.

Diagnosis

Most cases of rickets are diagnosed based on the presence of classic radiographic abnormalities. The diagnosis is supported by physical examination findings (see Table 48-3) and a history and laboratory test results that are consistent with a specific etiology.

Clinical Evaluation

Because the majority of children with rickets have a nutritional deficiency, the initial evaluation should focus on a dietary history, emphasizing intake of vitamin D and calcium. Most children in industrialized nations receive vitamin D from formula, fortified milk, or vitamin supplements. Along with the amount, the exact composition of the formula or milk is pertinent, because rickets has occurred in children given products that are called milk (soy milk) but are deficient in vitamin D and/or minerals.

Cutaneous synthesis mediated by sunlight exposure is an important source of vitamin D. It is important to ask about time spent outside, sunscreen use, and clothing, especially if there may be a cultural reason for increased covering of the skin. Because winter sunlight is ineffective at stimulating cutaneous synthesis of vitamin D, the season is an additional consideration. Children with increased skin pigmentation are at increased risk for vitamin D deficiency because of decreased cutaneous synthesis.

The presence of maternal risk factors for nutritional vitamin D deficiency, including diet and sun exposure, is an important consideration when a neonate or young infant has rachitic findings, especially if the infant is breast-fed. Determining a child’s intake of dairy products, the main dietary source of calcium, provides a general sense of calcium intake. High dietary fiber can interfere with calcium absorption.

The child’s medication use is relevant, because certain medications such as the anticonvulsants phenobarbital and phenytoin increase degradation of vitamin D, and aluminum-containing antacids interfere with the absorption of phosphate.

Malabsorption of vitamin D is suggested by a history of liver or intestinal disease. Undiagnosed liver or intestinal disease should be suspected if the child has gastrointestinal (GI) symptoms, although occasionally rickets is the presenting complaint. Fat malabsorption is often associated with diarrhea or oily stools, and there may be signs or symptoms suggesting deficiencies of other fat-soluble vitamins (A, E, and K; Chapters 45, 49, and 50).

A history of renal disease (proteinuria, hematuria, urinary tract infections) is an additional significant consideration, given the importance of chronic renal failure as a cause of rickets. Polyuria can occur in children with chronic renal failure or Fanconi syndrome.

Children with rickets might have a history of dental caries, poor growth, delayed walking, waddling gait, pneumonia, and hypocalcemic symptoms.

The family history is critical, given the large number of genetic causes of rickets, although most of these causes are rare. Along with bone disease, it is important to inquire about leg deformities, difficulties with walking, or unexplained short stature, because some parents may be unaware of their diagnosis. Undiagnosed disease in the mother is not unusual in X-linked hypophosphatemia. A history of a unexplained sibling death during infancy may be present in the child with cystinosis, the most common cause of Fanconi syndrome in children.

The physical examination focuses on detecting manifestations of rickets (see Table 48-3). It is important to observe the child’s gait, auscultate the lungs to detect atelectasis or pneumonia, and plot the patient’s growth. Alopecia suggests vitamin D-dependent rickets type 2.

The initial laboratory tests in a child with rickets should include serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D₃, creatinine, and electrolytes (see Table 48-4 for interpretation). Urinalysis is useful for detecting the glycosuria and aminoaciduria (positive dipstick for protein) seen with Fanconi syndrome. Evaluation of urinary excretion of calcium (24 hr collection for calcium or calcium:creatinine ratio) is helpful if hereditary hypophosphatemic rickets with hypercalciuria or Fanconi syndrome is suspected. Direct measurement of other fat-soluble vitamins (A, E, and K) or indirect assessment of deficiency (prothrombin time for vitamin K deficiency) is appropriate if malabsorption is a consideration.

Vitamin D Physiology

Vitamin D can be synthesized in skin epithelial cells and therefore technically is not a vitamin. Cutaneous synthesis is normally the most important source of vitamin D and depends on the conversion of 7-dehydrochlesterol to vitamin D₃ (3-cholecalciferol) by ultraviolet B radiation from the sun. The efficiency of this process is decreased by melanin; hence, more sun exposure is necessary for vitamin D synthesis in people with increased skin pigmentation. Measures to decrease sun exposure, such as covering the skin with clothing or applying sunscreen, also decrease vitamin D synthesis. Children who spend less time outside have reduced vitamin D synthesis. The winter sun away from the equator is ineffective at mediating vitamin D synthesis.

There are few natural dietary sources of vitamin D. Fish liver oils have a high vitamin D content. Other good dietary sources include fatty fish and egg yolks. Most children in industrialized countries receive vitamin D via fortified foods, especially formula and milk (both of which contain 400 IU/L) and some breakfast cereals and breads. Supplemental vitamin D may be vitamin D₂ (which comes from plants or yeast) or vitamin D. Breast milk has a low vitamin D content, approximately 12-60 IU/L.

Vitamin D is transported bound to vitamin D–binding protein to the liver, where 25-hydroxlase converts vitamin D into 25-hydroxyvitamin D (25-D), the most abundant circulating form of vitamin D. Because there is little regulation of this liver hydroxylation step, measurement of 25-D is the standard method for determining a patient’s vitamin D status. The final step in activation occurs in the kidney, where 1α-hydroxylase adds a second hydroxyl group, resulting in 1,25-dihydroxyvitamin D (1,25-D). The 1α-hydroxylase is upregulated by PTH and hypophosphatemia; hyperphosphatemia and 1,25-D inhibit this enzyme. Most 1,25-D circulates bound to vitamin D–binding protein.

1,25-D acts by binding to an intracellular receptor, and the complex affects gene expression by interacting with vitamin D–response elements. In the intestine, this binding results in a marked increase in calcium absorption, which is highly dependent on 1,25-D. There is also an increase in phosphorus absorption, but this effect is less significant because most dietary phosphorus absorption is vitamin D independent. 1,25-D also has direct effects on bone, including mediating resorption. 1,25-D directly suppresses PTH secretion by the parathyroid gland, thus completing a negative feedback loop. PTH secretion is also suppressed by the increase in serum calcium mediated by 1,25-D. 1,25-D inhibits its own synthesis in the kidney and increases the synthesis of inactive metabolites.

Nutritional Vitamin D Deficiency

Vitamin D deficiency remains the most common cause of rickets globally and is prevalent, even in industrialized countries. Because vitamin D can be obtained from dietary sources or from cutaneous synthesis, most patients in industrialized countries have a combination of risk factors that lead to vitamin D deficiency.

Congenital Vitamin D Deficiency

Congenital rickets is quite rare in industrialized countries and occurs when there is severe maternal vitamin D deficiency during pregnancy. Maternal risk factors include poor dietary intake of vitamin D, lack of adequate sun exposure, and closely spaced pregnancies. These newborns can have symptomatic hypocalcemia, intrauterine growth retardation, and decreased bone ossification, along with classic rachitic changes. More subtle maternal vitamin D deficiency can have an adverse effect on neonatal bone density and birthweight, cause a defect in dental enamel, and predispose infants to neonatal hypocalcemic tetany. Treatment of congenital rickets includes vitamin D supplementation and adequate intake of calcium and phosphorus. Use of prenatal vitamins containing vitamin D prevents this entity.

Secondary Vitamin D Deficiency

Vitamin D–Dependent Rickets, Type 1

Children with vitamin D–dependent rickets type 1, an autosomal recessive disorder, have mutations in the gene encoding renal 1α-hydroxylase, preventing conversion of 25-D into 1,25-D. These patients normally present during the 1st 2 yr of life and can have any of the classic features of rickets (see Table 48-3), including symptomatic hypocalcemia. They have normal levels of 25-D but low levels of 1,25-D (see Table 48-4). Occasionally, 1,25-D levels are at the lower limit of normal, inappropriately low given the high PTH and low serum phosphorus levels, both of which should increase the activity of renal 1α-hydroxylase and cause elevated levels of 1,25-D. As in nutritional vitamin D deficiency, renal tubular dysfunction can cause a metabolic acidosis and generalized aminoaciduria.

Vitamin D–Dependent Rickets, Type 2

Patients with vitamin D–dependent rickets type 2 have mutations in the gene encoding the vitamin D receptor, preventing a normal physiologic response to 1,25-D. Levels of 1,25-D are extremely elevated in this autosomal recessive disorder (see Table 48-4). Most patients present during infancy, although rickets in less severely affected patients might not be diagnosed until adulthood. Less-severe disease is associated with a partially functional vitamin D receptor. Approximately 50-70% of children have alopecia, which tends to be associated with a more severe form of the disease and can range from alopecia areata to alopecia totalis. Epidermal cysts are a less common manifestation.

Chronic Renal Failure (Chapter 529.2)

With chronic renal failure, there is decreased activity of 1α-hydroxylase in the kidney, leading to diminished production of 1,25-D. In chronic renal failure, unlike the other causes of vitamin D deficiency, patients have hyperphosphatemia as a result of decreased renal excretion (see Table 48-4).

Pathophysiology

Rickets secondary to inadequate dietary calcium is a significant problem in some countries in Africa, although there are cases in other regions of the world, including industrialized countries. Because breast milk and formula are excellent sources of calcium, this form of rickets develops after children have been weaned from breast milk or formula and is more likely to occur in children who are weaned early. Rickets develops because the diet has low calcium content, typically <200 mg/day. There is little intake of dairy products or other sources of calcium. In addition, because of reliance on grains and green leafy vegetables, the diet may be high in phytate, oxalate, and phosphate, which decrease absorption of dietary calcium. In industrialized countries, rickets due to calcium deficiency can occur in children who consume an unconventional diet. Examples include children with milk allergy who have low dietary calcium and children who transition from formula or breast milk to juice, soda, or a calcium-poor soy drink, without an alternative source of dietary calcium.

This type of rickets can develop in children who receive intravenous nutrition without adequate calcium. Malabsorption of calcium can occur in celiac disease, intestinal abetalipoproteinemia, and after small bowel resection. There may be concurrent malabsorption of vitamin D.

Clinical Manifestations

Children have the classic signs and symptoms of rickets (see Table 48-3). Presentation can occur during infancy or early childhood, although some cases are diagnosed in teenagers. Because calcium deficiency occurs after the cessation of breast-feeding, it tends to occur later than the nutritional vitamin D deficiency that is associated with breast-feeding. In Nigeria, nutritional vitamin D deficiency is most common at 4-15 mo of age, whereas calcium-deficiency rickets typically occurs at 15-25 mo of age.

Diagnosis

Laboratory findings include increased levels of alkaline phosphatase, PTH, and 1,25-D (see Table 48-4). Calcium levels may be normal or low, although symptomatic hypocalcemia is uncommon. There is decreased urinary excretion of calcium, and serum phosphorus levels may be low due to renal wasting of phosphate from secondary hyperparathyroidism, which can also cause aminoaciduria. In some children, there is coexisting nutritional vitamin D deficiency, with low 25-D levels.

Treatment

Treatment focuses on providing adequate calcium, typically as a dietary supplement (doses of 700 [1-3 yr age], 1,000 [4-8 yr age], 1,300 [9-18 yr age] mg/day of elemental calcium are effective). Vitamin D supplementation is necessary if there is concurrent vitamin D deficiency (discussed earlier). Prevention strategies include discouraging early cessation of breast-feeding and increasing dietary sources of calcium. In countries such as Kenya, where many children have diets high in cereal with negligible intake of cow’s milk, school-based milk programs have been effective in reducing the prevalence of rickets.

Inadequate Intake

With the exception of starvation or severe anorexia, it is almost impossible to have a diet that is deficient in phosphorus, because phosphorus is present in most foods. Decreased phosphorus absorption can occur in diseases associated with malabsorption (celiac disease, cystic fibrosis, cholestatic liver disease), but if rickets develops, the primary problem is usually malabsorption of vitamin D and/or calcium.

Isolated malabsorption of phosphorus occurs in patients with long-term use of aluminum-containing antacids. These compounds are very effective at chelating phosphate in the GI tract, leading to decreased absorption. This decreased absorption results in hypophosphatemia with secondary osteomalacia in adults and rickets in children. This entity responds to discontinuation of the antacid and short-term phosphorus supplementation.

Phosphatonin

Phosphatonin is a humoral mediator that decreases renal tubular reabsorption of phosphate and therefore decreases serum phosphorus. Phosphatonin also decreases the activity of renal 1α-hydroxylase, resulting in a decrease in the production of 1,25-D. Fibroblast growth factor–23 (FGF-23) is the most well characterized phosphatonin, but there are a number of other putative phosphatonins (discussed later). Increased levels of phosphatonin cause many of the phosphate-wasting diseases (see Table 48-2).

X-Linked Hypophosphatemic Rickets

Among the genetic disorders causing rickets due to hypophosphatemia, X-linked hypophosphatemic rickets (XLH) is the most common, with a prevalence of 1/20,000. The defective gene is on the X chromosome, but female carriers are affected, so it is an X-linked dominant disorder.

Autosomal Dominant Hypophosphatemic Rickets

Autosomal dominant hypophosphatemic rickets (ADHR) is much less common than XLH. There is incomplete penetrance and variable age of onset. Patients with ADHR have a mutation in the gene encoding FGF-23. The mutation prevents degradation of FGF-23 by proteases, leading to increased levels of this phosphatonin. The actions of FGF-23 include decreased reabsorption of phosphate in the renal proximal tubule, which results in hypophosphatemia, and inhibition of the 1α-hydroxylase in the kidney, causing a decrease in 1,25-D synthesis.

In ADHR, as in XLH, abnormal laboratory findings are hypophosphatemia, an elevated alkaline phosphatase level, and a low or inappropriately normal 1,25-D level (see Table 48-4). Treatment is similar to the approach used in XLH.

Autosomal Recessive Hypophosphatemic Rickets

Autosomal recessive hypophosphatemic rickets is an extremely rare disorder due to mutations in the gene encoding dentin matrix protein 1, which results in elevated levels of FGF-23, leading to renal phosphate wasting, hypophosphatemia, and low or inappropriately normal levels of 1.,25-D. Treatment is similar to the approach used in XLH.

Hereditary Hypophosphatemic Rickets with Hypercalciuria

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder that is mainly described in the Middle East.

Overproduction of Phosphatonin

Tumor-induced osteomalacia is more common in adults than in children, where it can produce classic rachitic findings. Most tumors are mesenchymal in origin and are usually benign, small, and located in bone. These tumors secrete a number of different putative phosphatonins (FGF-23, frizzled-related protein 4, and matrix extracellular phosphoglycoprotein); different tumors secrete different phosphatonins or combinations of phosphatonins. These phosphatonins produce a biochemical phenotype that is similar to XLH, including urinary phosphate wasting, hypophosphatemia, elevated alkaline phosphatase levels, and low or inappropriately normal 1,25-D levels (see Table 48-4). Curative treatment is excision of the tumor. If the tumor cannot be removed, treatment is identical to that used for XLH.

Renal phosphate wasting leading to hypophosphatemia and rickets (or osteomalacia in adults) is a potential complication in McCune-Albright syndrome, an entity that includes the triad of polyostotic fibrous dysplasia, hyperpigmented macules, and polyendocrinopathy (Chapter 556.6). Affected patients have inappropriately low levels of 1,25-D and elevated levels of alkaline phosphatase. The renal phosphate wasting and inhibition of 1,25-D synthesis are related to the polyostotic fibrous dysplasia. Patients have elevated levels of the phosphatonin FGF-23, presumably produced by the dysplastic bone. Hypophosphatemic rickets can also occur in children with isolated polyostotic fibrous dysplasia. Although it is rarely possible, removal of the abnormal bone can cure this disorder in children with McCune-Albright syndrome. Most patients receive the same treatment as children with XLH. Bisphosphonate treatment decreases the pain and fracture risk associated with the bone lesions.

Rickets is an unusual complication of epidermal nevus syndrome (Chapter 643). Patients have hypophosphatemic rickets due to renal phosphate wasting and also have an inappropriately normal or low level of 1,25-D due to excessive production of FGF-23. The timing of presentation with rickets varies from infancy to early adolescence. Resolution of hypophosphatemia and rickets has occurred after excision of the epidermal nevi in some patients but not in others. In most cases, the skin lesions are too extensive to be removed, necessitating treatment with phosphorus supplementation and 1,25-D. Rickets due to phosphate wasting is an extremely rare complication in children with neurofibromatosis (Chapter 589.1), again presumably due to the production of a phosphatonin.

Fanconi Syndrome

Fanconi syndrome is secondary to generalized dysfunction of the renal proximal tubule (Chapter 523.1). There are renal losses of phosphate, amino acids, bicarbonate, glucose, urate, and other molecules that are normally reabsorbed in the proximal tubule. Some patients have partial dysfunction, with less generalized losses. The most clinically relevant consequences are hypophosphatemia due to phosphate losses and proximal renal tubular acidosis due to bicarbonate losses. Patients have rickets as a result of hypophosphatemia, with exacerbation from the chronic metabolic acidosis, which causes bone dissolution. Failure to thrive is a consequence of both rickets and renal tubular acidosis. Treatment is dictated by the etiology (Chapters 523.1 and 523.4).

Dent Disease (Chapter 525.3)

Dent disease is an X-linked disorder usually caused by mutations in the gene encoding a chloride channel that is expressed in the kidney. Some patients have mutations in the OCRL 1 gene, which can also cause Lowe syndrome (Chapter 523.1). Affected males have variable manifestations, including hematuria, nephrolithiasis, nephrocalcinosis, rickets, and chronic renal failure. Almost all patients have low molecular weight proteinuria and hypercalciuria. Other, less universal abnormalities are aminoaciduria, glycosuria, hypophosphatemia, and hypokalemia. Rickets occurs in approximately 25% of patients, and it responds to oral phosphorus supplements. Some patients also need 1,25-D, but this treatment should be used cautiously because it can worsen the hypercalciuria.

Pathogenesis

The transfer of calcium and phosphorus from mother to fetus occurs throughout pregnancy, but 80% occurs during the 3rd trimester. Premature birth interrupts this process, with rickets developing when the premature infant does not have an adequate supply of calcium and phosphorus to support mineralization of the growing skeleton.

Most cases of rickets of prematurity occur in infants with a birthweight <1,000 g. It is more likely to develop in infants with lower birthweight and younger gestational age. Rickets occurs because unsupplemented breast milk and standard infant formula do not contain enough calcium and phosphorus to supply the needs of the premature infant. Other risk factors include cholestatic jaundice, a complicated neonatal course, prolonged use of parenteral nutrition, the use of soy formula, and medications such as diuretics and corticosteroids.

Clinical Manifestations

Rickets of prematurity occurs 1-4 mo after birth. Infants can have nontraumatic fractures, especially of the legs, arms, and ribs. Most fractures are not suspected clinically. Because fractures and softening of the ribs lead to decreased chest compliance, some infants have respiratory distress due to atelectasis and poor ventilation. This rachitic respiratory distress usually develops >5 wk after birth, distinguishing it from the early-onset respiratory disease of premature infants. These infants have poor linear growth, with negative effects on growth persisting beyond 1 yr of age. An additional long-term effect is enamel hypoplasia. Poor bone mineralization can contribute to dolichocephaly. There may be classic rachitic findings, such as frontal bossing, rachitic rosary, craniotabes, and widened wrists and ankles (see Table 48-3). Most infants with rickets of prematurity have no clinical manifestations, and the diagnosis is based on radiographic and laboratory findings.

Laboratory Findings

Due to inadequate intake, the serum phosphorus level is low or low-normal in rickets of prematurity. The renal response is appropriate, with conservation of phosphate leading to a low urine phosphate level; the tubular reabsorption of phosphate is >95%. Most patients have normal levels of 25-D, unless there has been inadequate intake or poor absorption (discussed earlier). The hypophosphatemia stimulates renal 1α-hydroxylase, so levels of 1,25-D are high or high-normal. These high levels can contribute to bone demineralization, because 1,25-D stimulates bone resorption. Serum levels of calcium are low, normal, or high, and patients often have hypercalciuria. Elevated serum calcium levels and hypercalciuria are secondary to increased intestinal absorption and bone dissolution due to elevation of 1,25-D levels and the inability to deposit calcium in bone because of an inadequate phosphorus supply. The hypercalciuria indicates that phosphorus is the limiting nutrient for bone mineralization, although increased provision of phosphorus alone often cannot correct the mineralization defect; increased calcium is also necessary. Hence, there is an inadequate supply of calcium and phosphorus, but the deficiency in phosphorus is greater.

Alkaline phosphatase levels are often elevated, but some affected infants have normal levels. In some instances, normal alkaline phosphatase levels may be secondary to resolution of the bone demineralization because of an adequate mineral supply despite the continued presence of radiologic changes, which take longer to resolve. However, alkaline phosphatase levels may be normal despite active disease. No single blood test is 100% sensitive for the diagnosis of rickets. The diagnosis should be suspected in infants with an alkaline phosphatase level that is >5-6 times the upper limit of normal for adults (unless there is concomitant liver disease) or a phosphorus level <5.6 mg/dL. The diagnosis is confirmed by radiologic evidence of rickets, which is best seen on films of the wrists and ankles. Films of the arms and legs might reveal fractures. The rachitic rosary may be visible on chest x-ray. Unfortunately, x-rays cannot show early demineralization of bone because changes are not evident until there is >20-30% reduction in the bone mineral content.

Diagnosis

Because many premature infants have no overt clinical manifestations of rickets, screening tests are recommended. These tests should include weekly measurements of calcium, phosphorus, and alkaline phosphatase. Periodic measurement of the serum bicarbonate concentration is also important, because metabolic acidosis causes dissolution of bone. At least 1 screening x-ray for rickets at 6-8 wk of age is appropriate in infants who are at high risk for rickets; additional films may be indicated in very high risk infants.

Prevention

Provision of adequate amounts of calcium, phosphorus, and vitamin D significantly decreases the risk of rickets of prematurity. Parenteral nutrition is often necessary initially in very premature infants. In the past, adequate parenteral calcium and phosphorus delivery was difficult because of limits secondary to insolubility of these ions when their concentrations were increased. Current amino acid preparations allow higher concentrations of calcium and phosphate, decreasing the risk of rickets. Early transition to enteral feedings is also helpful. These infants should receive either human milk fortified with calcium and phosphorus or preterm infant formula, which has higher concentrations of calcium and phosphorus than standard formula. Soy formula should be avoided because there is decreased bioavailability of calcium and phosphorus. Increased mineral feedings should continue until the infant weighs 3-3.5 kg. These infants should also receive approximately 400 IU/day of vitamin D via formula and vitamin supplements.

Treatment

Therapy for rickets of prematurity focuses on ensuring adequate delivery of calcium, phosphorus, and vitamin D. If mineral delivery has been good and there is no evidence of healing, then it is important to screen for vitamin D deficiency by measuring serum 25-D. Measurement of PTH, 1,25-D, and urinary calcium and phosphorus may be helpful in some cases.

Etiology

Hypervitaminosis D is secondary to excessive intake of vitamin D. It can occur with long-term high intake or with a substantial, acute ingestion (see Table 48-1). Most cases are secondary to misuse of prescribed or over-the-counter vitamin D supplements, but other cases have been secondary to accidental overfortification of milk, contamination of table sugar, and inadvertent use of vitamin D supplements as cooking oil. The recommended upper limits for long-term vitamin D intake are 1,000 IU for children <1 year old and 2,000 IU for older children and adults. Hypervitaminosis D can also result from excessive intake of synthetic vitamin D analogs (25-D, 1,25-D). Vitamin D intoxication is never secondary to excessive exposure to sunlight, probably because ultraviolet irradiation can transform vitamin D₃ and its precursor into inactive metabolites.

Pathogenesis

Although vitamin D increases intestinal absorption of calcium, the dominant mechanism of the hypercalcemia is excessive bone resorption.

Clinical Manifestations

The signs and symptoms of vitamin D intoxication are secondary to hypercalcemia. GI manifestations include nausea, vomiting, poor feeding, constipation, abdominal pain, and pancreatitis. Possible cardiac findings are hypertension, decreased Q-T interval, and arrhythmias. The central nervous system effects of hypercalcemia include lethargy, hypotonia, confusion, disorientation, depression, psychosis, hallucinations, and coma. Hypercalcemia impairs renal concentrating mechanisms, which can lead to polyuria, dehydration, and hypernatremia. Hypercalcemia can also lead to acute renal failure, nephrolithiasis, and nephrocalcinosis, which can result in chronic renal insufficiency. Deaths are usually associated with arrhythmias or dehydration.

Laboratory Findings

The classic findings in vitamin D intoxication are hypercalcemia and extremely elevated levels of 25-D (>150 ng/mL). Hyperphosphatemia is also common. PTH levels are appropriately decreased owing to hypercalcemia. Hypercalciuria is universally present and can lead to nephrocalcinosis, which is visible on renal ultrasound. Hypercalcemia and nephrocalcinosis can lead to renal insufficiency.

Surprisingly, levels of 1,25-D are usually normal. This may be due to downregulation of renal 1α-hydroxylase by the combination of low PTH, hyperphosphatemia, and a direct effect of 1,25-D. There is evidence indicating that the level of free 1,25-D may be high, owing to displacement from vitamin D–binding proteins by 25-D. Nephrocalcinosis is often visible on ultrasound or CT scan. Anemia is sometimes present; the mechanism is unknown.

Diagnosis and Differential Diagnosis

The diagnosis is based on the presence of hypercalcemia and an elevated serum 25-D level, although children with excess intake of 1,25-D or another synthetic vitamin D preparation have normal levels of 25-D. With careful sleuthing, there is usually a history of excess intake of vitamin D, although in some situations (overfortification of milk by a dairy) the patient and family may be unaware.

The differential diagnosis of vitamin D intoxication focuses on other causes of hypercalcemia. Hyperparathyroidism produces hypophosphatemia, whereas vitamin D intoxication usually causes hyperphosphatemia. Williams syndrome is often suggested by phenotypic features and accompanying cardiac disease. Subcutaneous fat necrosis is a common cause of hypercalcemia in young infants; skin findings are usually present. The hypercalcemia of familial benign hypocalciuric hypercalcemia is mild, asymptomatic, and associated with hypocalciuria. Hypercalcemia of malignancy is an important consideration. High intake of calcium can also cause hypercalcemia, especially in the presence of renal insufficiency. Questioning about calcium intake should be part of the history in a patient with hypercalcemia. Occasionally, patients are intentionally taking high doses of calcium and vitamin D.

Treatment

The treatment of vitamin D intoxication focuses on control of hypercalcemia. Many patients with hypercalcemia are dehydrated as a result of polyuria from nephrogenic diabetes insipidus, poor oral intake, and vomiting. Rehydration lowers the serum calcium level via dilution and corrects prerenal azotemia. The resultant increased urine output increases urinary calcium excretion. Urinary calcium excretion is also increased by high urinary sodium excretion. The mainstay of the initial treatment is aggressive therapy with normal saline, often in conjunction with a loop diuretic to further increase calcium excretion.

Normal saline, with or without a loop diuretic, is often adequate for treating mild or moderate hypercalcemia. More significant hypercalcemia usually requires other therapies. Glucocorticoids decrease intestinal absorption of calcium by blocking the action of 1,25-D. There is also a decrease in the levels of 25-D and 1,25-D. The usual dosage of prednisone is 1-2 mg/kg/24 hr.

Calcitonin, which lowers calcium by inhibiting bone resorption, is a useful adjunct, but its effect is usually not dramatic. There is an excellent response to intravenous or oral bisphosphonates in vitamin D intoxication. Bisphosphonates inhibit bone resorption through their effects on osteoclasts. Hemodialysis using a low or 0 dialysate calcium can rapidly lower serum calcium in patients with severe hypercalcemia that is refractory to other measures.

Along with controlling hypercalcemia, it is imperative to eliminate the source of excess vitamin D. Additional sources of vitamin D such as multivitamins and fortified foods should be eliminated or reduced. Avoidance of sun exposure, including the use of sunscreen, is prudent. The patient should also restrict calcium intake.

Prognosis

Most children make a full recovery, but hypervitaminosis D may be fatal or can lead to chronic renal failure. Because vitamin D is stored in fat, levels can remain elevated for months, necessitating regular monitoring of 25-D, serum calcium, and urine calcium.