A 2-year-old boy is brought to the pediatrician by his mother, who reports that the boy appears more irritable lately and does not seem to be growing. After further questioning, the mother mentions that her child has also complained of leg pain and a “waddling” gait. On exam, the boy has widening of the wrists and bowing of his legs and prominence of the costochondral junctions (rachitic rosary; Figures 198-1 and 198-2). The pediatrician asks about the child’s diet, and the mother reveals that the patient is a very picky eater and drinks only fruit juice that is not fortified with vitamin D. The pediatrician is concerned about rickets and orders a serum alkaline phosphatase, which is elevated, and vitamin D level (25-OH Vitamin D), which is low. X-ray of the tibia and femur demonstrated widening of the growth plate and metaphysis (Figure 198-3). The pediatrician prescribes vitamin D and calcium supplementation for the child. After 3 months of supplementation, the boy’s symptoms have resolved and repeat x-ray showed a dense zone of calcification at the metaphysis with improvement in the widened growth plate.
FIGURE 198-2
Prominence of the costochondral junction (rachitic rosary) in the same child as in Figure 198-1. (Used with permission from Cleveland Clinic Children’s Hospital Photo Files.)
Rickets is a defect in bone mineralization that occurs in children prior to epiphyseal fusion, resulting in widening of the growth plates, bone pain, decreased strength of bone, bone deformities, and signs of hypocalcemia.1–3 This condition is primarily due to nutritional deficiency, specifically vitamin D deficiency, but can also occur with calcium or phosphorus deficiency. There are also hereditary and secondary (renal losses of calcium and phosphate) causes of rickets. Management of rickets depends on the specific etiology. Nutritional deficiencies can be treated with supplementation.
Nutritional rickets in the US is relatively uncommon; in case reports published between 1986 to 2003, there were 166 cases of documented rickets.4
The prevalence of hypovitaminosis D in the US ranges from 1 to 78 percent with breastfed infants born in the winter being the most likely to be vitamin D-deficient. Vitamin D deficiency was associated with older age, winter season, higher body mass index, African-American race, and elevated parathyroid hormone as a result.5
Hereditary causes of rickets are very rare, the most common being X-linked hypophosphatemic rickets (XLH), which has a prevalence of 1/20,000.6
Rickets is defined as a defect of bone mineralization of the osteoid, or protein matrix, of growing bone (prior to epiphyseal fusion). The mineral component of bone consists of calcium and phosphate hydroxyapatite crystals. When there is inadequate mineralization of growing bone, there is impaired growth at the metaphysis and a general decrease in bone strength.1
The regulation of bone mineralization depends on the calcium*phosphorus product, which is modulated by vitamin D, parathyroid hormone (PTH), and phosphatonin.
The majority of vitamin D is generated from skin following ultraviolet B exposure. Vitamin D can also be obtained from vitamin D2 found in plants and vitamin D3 found in animal products such as milk. Vitamin D is converted to Calcidiol (25(OH)-D) via 25-hydroxylase in the liver. 25(OH)-D is then converted to Calcitriol (1,25(OH)2-D) by 1-α-hydroxylase in the kidneys. 1,25(OH)2-D is the active form of vitamin D and upregulates calcium and phosphorus absorption.2
Low ionized calcium stimulates PTH release. To maintain calcium homeostasis, PTH increases bone resorption to release calcium from bone, upregulates 1,25(OH)2-D synthesis, and increases phosphorus excretion to decrease the calcium*phosphorus product to promote calcium release.2
Phosphatonins, specifically fibroblast growth factor-23 (FGF-23), are proteins secreted by osteocytes in bone that decrease renal tubular reabsorption of phosphate and 1-α-hydroxylase activity.7
The etiology of rickets can be widely classified based on the defect in mineralization: vitamin D disorders, calcium deficiency, phosphorus deficiency, and defects in renal regulation.
Vitamin D disorders can be further classified as nutritional (vitamin D deficiency), secondary (due to malabsorption or chronic kidney disease), or hereditary (vitamin D-dependent rickets type 1 and 2).
Nutritional vitamin D deficiencies are due to inadequate sun exposure; darker-skinned children, and those with decreased dietary intake, are more at risk.
Secondary vitamin D disorders can occur with gastrointestinal disorders such as Crohn disease or other disturbances impairing fat absorption and thus vitamin D absorption. Chronic kidney disease manifests with impaired synthesis of 1,25(OH)2-D, resulting in vitamin D deficiency.
Vitamin D-dependent rickets type 1 is an autosomal recessive disorder resulting in a mutation in 1-α-hydroxylase that impairs 1,25(OH)2-D synthesis. Vitamin D-dependent rickets type 2 is also an autosomal recessive disorder characterized by a defect in the vitamin D receptor preventing patients from responding appropriately to 1,25(OH)2-D.8
Deficiency in calcium, which is found in leafy vegetables and dairy products, typically arises in children who are on unconventional diet or have milk allergies. Phosphorus deficiency rarely occurs in healthy children, but can arise in anorexics and malabsorptive processes.
Defects in renal regulation of calcium and phosphorus homeostasis can also be classified into hereditary (X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and hereditary hypophosphatemic rickets with hypercalciuria) and secondary causes (Fanconi Syndrome, renal tubular acidosis, or tumor-induced).
XLH rickets occurs due to a gene mutation in PHEX, which inactivates the phosphatonin FGF-23. Consequently, there is an increase in FGF-23 expression, which normally inhibits phosphate reabsorption and 1-α-hydroxylase. This leads to decreased phosphate reabsorption and decreased 1,25(OH)2-D production.
Autosomal dominant hypophosphatemic rickets (ADHR) involves a mutation in FGF-23 that impairs degradation of the protein. Similar to XLH, increased FGF-23 levels results in decreased reabsorption of phosphate and decreased 1,25(OH)2-D production.
Autosomal recessive hypophosphatemic rickets is a very rare disorder due to a mutation in dentin matrix protein 1 that also leads to elevated FGF-23. This is characterized by decreased reabsorption of phosphate and decreased 1,25(OH)2-D production.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder due to a mutation in the sodium-phosphate channel in the proximal tubule. The subsequent decrease in serum phosphate stimulates 1,25(OH)2-D production, which suppresses PTH and increases calcium absorption in the gut resulting in hypercalciuria.
Secondary losses of calcium and phosphate are due to defects in proximal tubule reabsorption. These disorders include Fanconi syndrome, characterized by generalized dysfunction of the proximal tubules that cause hypophosphatemia, and renal tubular acidosis, which can cause impaired calcium reabsorption.1
Another secondary cause of rickets is tumor-induced rickets which can occur when mesenchymal tumors secrete phosphatonins leading to increased phosphate excretion and low 1,25(OH)2-D.
