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Vitamin D Deficiency (Rickets) and Excess


Rickets

Bone consists of a protein matrix called osteoid and a mineral phase, principally composed of calcium and phosphate, mostly in the form of hydroxyapatite . Osteomalacia occurs with inadequate mineralization of bone osteoid in children and adults. Rickets is a disease of growing bone caused by unmineralized matrix at the growth plates in children only before fusion of the epiphyses. Because growth plate cartilage and osteoid continue to expand but mineralization is inadequate, the growth plate thickens. Circumference of the growth plate and metaphysis is also greater, increasing bone width at the growth plates and causing classic clinical manifestations, such as widening of the wrists and ankles. The general softening of the bones causes them to bend easily when subject to forces such as weight bearing or muscle pull. This softening leads to a variety of bone deformities.

Rickets is principally caused by vitamin D deficiency and was rampant in northern Europe and the United States during the early years of the 20th century. Although largely corrected through public health measures that provided children with adequate vitamin D, rickets remains a persistent problem in developed countries, with many cases still secondary to preventable nutritional vitamin D deficiency. It remains a significant problem in developing countries and may be secondary to nutritional vitamin D deficiency and inadequate intake of calcium ( Table 64.1 ).

Table 64.1
Physical and Metabolic Properties and Food Sources of Vitamins D, E, and K
NAMES AND SYNONYMS CHARACTERISTICS BIOCHEMICAL ACTION EFFECTS OF DEFICIENCY EFFECTS OF EXCESS SOURCES
VITAMIN D
Vitamin D 3 (3-cholecalciferol), which is synthesized in the skin, and vitamin D 2 (from plants or yeast) are biologically equivalent; 1 µg = 40 IU vitamin D. Fat-soluble, stable to heat, acid, alkali, and oxidation; bile necessary for absorption; hydroxylation in the liver and kidney necessary for biologic activity Necessary for GI absorption of calcium; also increases absorption of phosphate; direct actions on bone, including mediating resorption Rickets in growing children; osteomalacia; hypocalcemia can cause tetany and seizures Hypercalcemia, which can cause emesis, anorexia, pancreatitis, hypertension, arrhythmias, CNS effects, polyuria, nephrolithiasis, renal failure Exposure to sunlight (UV light); fish oils, fatty fish, egg yolks, and vitamin D–fortified formula, milk, cereals, bread
VITAMIN E
Group of related compounds with similar biologic activities; α-tocopherol is the most potent and most common form Fat-soluble; readily oxidized by oxygen, iron, rancid fats; bile acids necessary for absorption Antioxidant; protection of cell membranes from lipid peroxidation and formation of free radicals Red cell hemolysis in premature infants; posterior column and cerebellar dysfunction; pigmentary retinopathy Unknown Vegetable oils, seeds, nuts, green leafy vegetables, margarine
VITAMIN K
Group of naphthoquinones with similar biologic activities; K 1 (phylloquinone) from diet; K 2 (menaquinones) from intestinal bacteria Natural compounds are fat-soluble; stable to heat and reducing agents; labile to oxidizing agent, strong acids, alkali, light; bile salts necessary for intestinal absorption Vitamin K–dependent proteins include coagulation factors II, VII, IX, and X; proteins C, S, Z; matrix Gla protein, osteocalcin Hemorrhagic manifestations; long-term bone and vascular health Not established; analogs (no longer used) caused hemolytic anemia, jaundice, kernicterus, death Green leafy vegetables, liver, certain legumes and plant oils; widely distributed
CNS, Central nervous system; GI, gastrointestinal; UV, ultraviolet.

Etiology

There are many causes of rickets, including vitamin D disorders, calcium deficiency, phosphorus deficiency, and distal renal tubular acidosis ( Table 64.2 ).

Table 64.2
Causes of Rickets

Vitamin D Disorders

  • Nutritional vitamin D deficiency

  • Congenital vitamin D deficiency

  • Secondary vitamin D deficiency

  • Malabsorption

  • Increased degradation

  • Decreased liver 25-hydroxylase

  • Vitamin D–dependent rickets types 1A and 1B

  • Vitamin D–dependent rickets types 2A and 2B

  • Chronic kidney disease

Calcium Deficiency

  • Low intake

  • Diet

  • Premature infants (rickets of prematurity)

  • Malabsorption

  • Primary disease

  • Dietary inhibitors of calcium absorption

Phosphorus Deficiency

  • Inadequate intake

  • Premature infants (rickets of prematurity)

  • Aluminum-containing antacids

Renal Losses

  • X-linked hypophosphatemic rickets *

    * Disorders secondary to excess fibroblast growth factor-23.

  • Autosomal dominant hypophosphatemic rickets *

  • Autosomal recessive hypophosphatemic rickets types 1 and 2 *

  • Hereditary hypophosphatemic rickets with hypercalciuria

  • Overproduction of fibroblast growth factor-23

  • Tumor-induced rickets *

  • McCune-Albright syndrome *

  • Epidermal nevus syndrome *

  • Neurofibromatosis *

  • Fanconi syndrome

  • Dent disease

  • Distal renal tubular acidosis

Clinical Manifestations

Most manifestations of rickets are a result of skeletal changes ( Table 64.3 ). 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 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. 64.1 ). Growth plate widening is also responsible for the enlargement at the wrists and ankles ( Fig. 64.2 ). The horizontal depression along the lower anterior chest known as Harrison groove occurs from pulling of the softened ribs by the diaphragm during inspiration. Softening of the ribs also impairs air movement and predisposes patients to atelectasis and pneumonia. Valgus or varus deformities of the legs are common; windswept deformity occurs when one leg is in extreme valgus and the other is in extreme varus ( Fig. 64.3 ).

Table 64.3
Clinical Features of Rickets

General

  • Failure to thrive (malnutrition)

  • Listlessness

  • Protruding abdomen

  • Muscle weakness (especially proximal)

  • Hypocalcemic dilated cardiomyopathy

  • Fractures (pathologic, minimal trauma)

  • Increased intracranial pressure

Head

  • Craniotabes

  • Frontal bossing

  • Delayed fontanel closure (usually closed by 2 yr)

  • Delayed dentition

    • No incisors by age 10 mo

    • No molars by age 18 mo

  • Caries

  • Craniosynostosis

Chest

  • Rachitic rosary

  • Harrison groove

  • Respiratory infections and atelectasis *

    * These features are most frequently associated with the vitamin D deficiency disorders.

Back

  • Scoliosis

  • Kyphosis

  • Lordosis

Extremities

  • Enlargement of wrists and ankles

  • Valgus or varus deformities

  • Windswept deformity (valgus deformity of one leg with varus deformity of other leg)

  • Anterior bowing of tibia and femur

  • Coxa vara

  • Leg pain

Hypocalcemic Symptoms †

† These symptoms develop only in children with disorders that produce hypocalcemia (see Table 64.4 ).

  • Tetany

  • Seizures

  • Stridor caused by laryngeal spasm

Fig. 64.1, Rachitic “rosary” in a child with rickets.

Fig. 64.2, Hands and forearms of a young child with rickets show prominence above the wrist, resulting from flaring and poor mineralization of lower end of the radius and ulna.

Fig. 64.3, Windswept deformity of the legs in an older child with rickets.

The clinical presentation of rickets may vary 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.

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 (malnutrition) and symptomatic hypocalcemia (see Chapters 588 to 590 ).

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. 64.4 and 64.5 ). 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.

Fig. 64.4, Radiographs of the wrist in A, normal child; and B, child with rickets, who has metaphyseal fraying and cupping of the distal radius and ulna.

Fig. 64.5, Radiographs of the knees in 7 yr old girl with distal renal tubular acidosis and rickets.

Diagnosis

The diagnosis of rickets is based on the presence of classic radiographic abnormalities. It is supported by physical examination findings, history, and laboratory results consistent with a specific etiology ( Table 64.4 ).

Table 64.4
Laboratory Findings in Various Disorders Causing Rickets
Disorder Ca Pi PTH 25-(OH)D 1,25-(OH) 2 D ALP URINE Ca URINE Pi
Vitamin D deficiency N, ↓ ↓ ↑ ↓ ↓, N, ↑ ↑ ↓ ↑
VDDR, type 1A N, ↓ ↓ ↑ N ↓ ↑ ↓ ↑
VDDR, type 1B N, ↓ ↓ ↑ ↓ N ↑ ↓ ↑
VDDR, type 2A N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
VDDR, type 2B N, ↓ ↓ ↑ N ↑↑ ↑ ↓ ↑
Chronic kidney disease N, ↓ ↑ ↑ N ↓ ↑ N, ↓ ↓
Dietary Pi deficiency N ↓ N, ↓ N ↑ ↑ ↑ ↓
XLH * N ↓ N, ↑ N RD ↑ ↓ ↑
ADHR * N ↓ N N RD ↑ ↓ ↑
HHRH N ↓ N, ↓ N ↑ ↑ ↑ ↑
ARHR, type 1 or type 2 * N ↓ N N RD ↑ ↓ ↑
Tumor-induced rickets † N ↓ N N RD ↑ ↓ ↑
Fanconi syndrome N ↓ N N RD or ↑ ↑ ↓ or ↑ ↑
Dent's disease N ↓ N N N ↑ ↑ ↑
Dietary Ca deficiency N, ↓ ↓ ↑ N ↑ ↑ ↓ ↑
ADHR, Autosomal dominant hypophosphatemic rickets; ALP, alkaline phosphatase; ARHR, autosomal recessive hypophosphatemic rickets; Ca, calcium; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; N, normal; Pi, inorganic phosphorus; PTH, parathyroid hormone; RD, relatively decreased (because it should be increased given the concurrent hypophosphatemia); VDDR, vitamin D–dependent rickets; XLH, X-linked hypophosphatemic rickets; 1,25-(OH) 2 D, 1,25-dihydroxyvitamin D; 25-OHD, 25-hydroxyvitamin D; ↓, decreased; ↑, increased; ↑↑, extremely increased.

* Elevated fibroblast growth factor-23 (FGF-23).

† FGF-23 elevated in some patients.

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 both 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” (e.g., soy milk) but are deficient in vitamin D and 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 breastfed ( Table 64.5 ). 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.

Table 64.5
Adapted from Munns CF, Shaw N, Kiely M, et al: Global consensus recommendations on prevention and management of nutritional rickets, J Clin Endocrinol Metab 101:394-415, 2016, p 401.
Risk Factors for Nutritional Rickets and Osteomalacia and Their Prevention

Maternal Factors

  • Vitamin D deficiency

    • Dark skin pigmentation

    • Full body clothing cover

    • High latitude during winter/spring season

    • Other causes of restricted sun (UVB) exposure, e.g., predominant indoor living, disability, pollution, cloud cover

    • Low–vitamin D diet

  • Low-calcium diet

    • Poverty, malnutrition, special diets

Infant/Childhood Factors

  • Neonatal vitamin D deficiency secondary to maternal deficiency/vitamin D deficiency

    • Lack of infant supplementation with vitamin D

    • Prolonged breastfeeding without appropriate complementary feeding from 6 mo

    • High latitude during winter/spring season

    • Dark skin pigmentation and/or restricted sun (UVB) exposure, e.g., predominant indoor living, disability, pollution, cloud cover

    • Low–vitamin D diet

  • Low-calcium diet

    • Poverty, malnutrition, special diets

Preventive Measures

  • Sun exposure (UVB content of sunlight depends on latitude and season)

  • Vitamin D supplementation

  • Strategic fortification of the habitual food supply

  • Normal calcium intake

The child's medication use is relevant, because certain medications, such as the anticonvulsants phenobarbital and phenytoin, increase degradation of vitamin D, and phosphate binders or 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; see Chapter 61, Chapter 65, Chapter 66 ).

A history of renal disease (proteinuria, hematuria, urinary tract infections) is an additional significant consideration, given the importance of chronic kidney disease as a cause of rickets. Polyuria can occur in children with chronic kidney disease 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 an 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 64.3 ). 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 (ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (1,25-D), creatinine, and electrolytes (see Table 64.4 for interpretation). Urinalysis is useful for detecting the glycosuria seen with Fanconi syndrome and low-molecular-weight proteinuria (positive dipstick for protein) in Fanconi syndrome or Dent disease. Evaluation of urinary excretion of calcium (24 hr collection for calcium or calcium:creatinine ratio) is helpful if hereditary hypophosphatemic rickets with hypercalciuria or Dent disease 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 Disorders

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 D 3 (3-cholecalciferol) by ultraviolet B (UVB) radiation from the sun. The efficiency of this process is decreased by melanin; therefore, 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 D 2 (which comes from plants or yeast) or vitamin D 3 . 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 the enzyme 1α-hydroxylase adds a second hydroxyl group, resulting in 1,25-D. The 1α-hydroxylase is upregulated by PTH and hypophosphatemia and inhibited by hyperphosphatemia and 1,25-D. Most 1,25-D circulates bound to vitamin D–binding protein.

1,25-Dihydroxyvitamin 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.

Etiology

Vitamin D deficiency most frequently occurs in infancy because of a combination of poor intake and inadequate cutaneous synthesis. Transplacental transport of vitamin D, mostly 25-D, typically provides enough vitamin D for the 1st 2 mo of life unless there is severe maternal vitamin D deficiency. Infants who receive formula receive adequate vitamin D, even without cutaneous synthesis. Because of the low vitamin D content of breast milk, breastfed infants rely on cutaneous synthesis or vitamin supplements. Cutaneous synthesis can be limited because of the ineffectiveness of the winter sun in stimulating vitamin D synthesis; avoidance of sunlight because of concerns about cancer, neighborhood safety, or cultural practices; and decreased cutaneous synthesis because of increased skin pigmentation.

The effect of skin pigmentation explains why most cases of nutritional rickets in the United States and northern Europe occur in breastfed children of African descent or other dark-pigmented populations. The additional impact of the winter sun is supported by such infants more often presenting in the late winter or spring. In some groups, complete covering of infants or the practice of not taking infants outside has a significant role, explaining the occurrence of rickets in infants living in areas of abundant sunshine, such as the Middle East. Because the mothers of some infants can have the same risk factors, decreased maternal vitamin D can also contribute, both by leading to reduced vitamin D content in breast milk and by lessening transplacental delivery of vitamin D. Rickets caused by vitamin D deficiency can also be secondary to unconventional dietary practices, such as vegan diets that use unfortified soy milk or rice milk.

Clinical Manifestations

The clinical features are typical of rickets (see Table 64.3 ), with a significant minority presenting with symptoms of hypocalcemia. Prolonged laryngospasm is occasionally fatal. These children have an increased risk of pneumonia and muscle weakness leading to a delay in motor development.

Laboratory Findings

Table 64.4 summarize the principal laboratory findings. Hypocalcemia is a variable finding because the elevated PTH acts to increase the serum calcium concentration. The hypophosphatemia is caused by PTH-induced renal losses of phosphate, combined with a decrease in intestinal absorption.

The wide variation in 1,25-D levels (low, normal, or high) is secondary to the upregulation of renal 1α-hydroxylase caused by concomitant hypophosphatemia and hyperparathyroidism. Because serum levels of 1,25-D are much lower than the levels of 25-D, even with low levels of 25-D there is often enough 25-D still present to act as a precursor for 1,25-D synthesis in the presence of upregulated 1α-hydroxylase. The level of 1,25-D is only low when there is severe vitamin D deficiency.

Some patients have a metabolic acidosis secondary to PTH-induced renal bicarbonate wasting. There may also be generalized aminoaciduria.

Diagnosis and Differential Diagnosis

The diagnosis of nutritional vitamin D deficiency is based on the combination of a history of poor vitamin D intake and risk factors for decreased cutaneous synthesis, radiographic changes consistent with rickets, and typical laboratory findings (see Table 64.4 ). A normal PTH level almost never occurs with vitamin D deficiency and suggests a primary phosphate disorder.

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