Etiology and treatment of calcipenic rickets in children

INTRODUCTION — Calcipenic rickets comprises a group of disorders in which supply of calcium or its intestinal absorption is too low to match the calcium demands imposed by bone growth.

The most common cause of calcipenic rickets is dietary deficiency of vitamin D and/or calcium, resulting in an inadequate supply of calcium for bone mineralization. Alternatively, calcipenic rickets may be caused by decreased vitamin D activity (eg, lack of conversion to the active metabolite or resistance to the active metabolite) or secondary causes of reduced intestinal calcium absorption. Patients with calcipenic rickets usually have secondary hyperparathyroidism and characteristic changes of the growth plates and metaphyseal bone.

EVALUATION — The clinical features of rickets and diagnostic evaluation to determine the cause of rickets are discussed in a separate topic review. (See "Overview of rickets in children".)

In brief, patients with calcipenic rickets are identified by elevated parathyroid hormone (PTH) and normal or low serum inorganic phosphorus (algorithm 1). Serum calcium levels are usually low in calcipenic rickets but may be normal in early stages of the disease due to a compensatory increase in PTH. Measurement of serum 25-hydroxyvitamin D (25OHD) helps to categorize the disorder into one of the following subcategories, which are discussed in detail in this topic review (algorithm 2):

●Dietary vitamin D deficiency (the "classic" form of rickets)

●Dietary calcium deficiency

●Deficiency of 1-alpha-hydroxylase, the enzyme that converts 25OHD to its active metabolite, 1,25-dihydroxyvitamin D (1,25[OH]₂D)

●25-hydroxylase deficiency

●Hereditary resistance to vitamin D (HRVD), caused by dysfunction of the vitamin D receptor

Chronic renal failure can also alter vitamin D metabolism and cause calcipenic rickets. This mechanism is discussed in separate topic reviews. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and "Overview of vitamin D", section on 'Metabolism'.)

NUTRITIONAL RICKETS — Classic forms of nutritional rickets, caused by inadequate intake of vitamin D and/or calcium, continues to be prevalent in many parts of the world and often is associated with other conditions [1]. In Ethiopia, for example, rickets affects a large proportion of children who present with severe infectious diseases [2].

Although infrequent, nutritional rickets can also occur as a result of phosphate deprivation [3]. This may occur in premature infants who receive breast milk as their sole source of nutrition and reflects the relatively low phosphate content of breast milk. It has also been described in a case series of young children with complex disease who were fed an elemental, amino acid-based formula, probably because of low phosphate bioavailability [4]. For this reason, serum phosphate levels should be monitored in such settings. These and other types of phosphopenic rickets are discussed separately. (See "Overview of rickets in children", section on 'Phosphopenic rickets'.)

Vitamin D deficiency

Etiology — An infant's vitamin D status depends upon the amount of vitamin D transferred from the mother prenatally and upon the amount of vitamin D ingested or produced by the skin during exposure to ultraviolet light postnatally [5]. Maternofetal transfer of vitamin D is mostly in the form of 25-hydroxyvitamin D (25OHD), which readily crosses the placenta [6]. The half-life of 25OHD in an infant is approximately two to three weeks [5]. Thus, the serum concentration of vitamin D falls rapidly after birth unless additional sources are available. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Pathogenesis and risk factors'.)

Vitamin D deficiency rickets typically presents between three months and three years of age, when growth rates (and calcium needs) are high, and exposure to sunlight may be limited [7-9].

Risk factors for vitamin D deficiency rickets are (see "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Pathogenesis and risk factors'):

●Maternal vitamin D deficiency during pregnancy – When a woman has very severe vitamin D deficiency during pregnancy, her offspring can have signs of rickets at birth or during the first three months of life [10].

●Breastfeeding – In infants from resource-abundant settings, the main reasons for inadequate vitamin D supply are prolonged breastfeeding without vitamin D supplementation and concomitant avoidance of sun exposure [7-9]. The recommended intake of vitamin D to prevent deficiency is 400 international units (10 mcg) daily in healthy infants and 600 international units (15 mcg) daily for children 1 to 18 years old [11]. Human milk typically contains less than 25 international units (0.6 mcg) of vitamin D per liter [12-14], unless the mother receives vitamin D supplementation in high doses (eg, more than 2000 international units [50 mcg] daily) [15,16].

●Skin pigmentation and low sun exposure – Dark skin is an additional risk factor for developing rickets in breastfed infants because dark-skinned individuals produce less vitamin D in response to sunlight [7,9,10]. The vitamin D concentration of the breast milk of dark-skinned mothers is less than that of lighter-skinned individuals [13]. Most mothers of breastfed infants with rickets also are deficient in vitamin D. Thus, all at-risk mothers should be evaluated for vitamin D deficiency [17,18]. Siblings of infants with rickets should also be considered at high risk for vitamin D deficiency and should be appropriately evaluated.

●Other causes – Other causes of vitamin D deficiency resulting from diminished absorption are cystic fibrosis or other disorders of exocrine pancreatic function, gastrectomy or extensive bowel surgery, celiac disease, inflammatory bowel disease, and other malabsorptive conditions. Certain anticonvulsants and antiretroviral drugs used to treat HIV infection can cause vitamin D deficiency by enhancing catabolism of 25OHD and 1,25-dihydroxyvitamin D (1,25[OH]₂D). Obesity is associated with low serum concentrations of vitamin D, but the mechanisms and clinical significance of this association have not been established. Selective food avoidance has led to nutritional rickets in children with autism, avoidant restrictive food intake disorder, and chronic neurologic diseases [19,20].

The effects of lockdowns during the coronavirus disease 2019 (COVID-19) pandemic have also been implicated as increasing the incidence of rickets [21].

Prevention — In North America, infant formula, cow's milk, and cereals are fortified with vitamin D. All infant formulas in the United States contain at least 400 international units/L (10 mcg/L) of vitamin D [22]. Nonetheless, the diet of exclusively breastfed infants and of partially formula-fed infants does not provide the recommended intake of vitamin D. As a result, vitamin D supplementation is recommended for these infants. Vitamin D supplementation is also recommended for children who consume less than 1000 mL (33 oz) of vitamin D-fortified milk daily, unless they have ample regular exposure to direct sunlight. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention'.)

Most nutritional rickets are prevented by adherence to these guidelines. However, infants born to mothers with severe vitamin D deficiency may rarely develop rickets, even if they are fed adequate amounts of vitamin D-fortified formula and are growing normally [7]. An increased total daily intake of up to 800 international units (20 mcg) may be necessary for premature infants, dark-skinned infants, and those who live at latitudes above 40º [5]. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention in the perinatal period and in infants'.)

Clinical course — Vitamin D deficiency rickets has three stages with increasing severity (table 1) [23,24]. Stage one is caused by impaired intestinal calcium absorption, resulting in hypocalcemia, whereas serum inorganic phosphorus is normal. Hypophosphatemia develops in stages two and three, coinciding with clinically apparent rickets. Serum calcium is normal in stage two because of a compensatory increase in parathyroid hormone (PTH) secretion but becomes low again in stage three, when the hyperparathyroidism is unable to compensate for the severe restriction in available calcium, and the clinical and radiologic findings of rickets are severe. Because later stages of the disorder are characterized by severe secondary hyperparathyroidism, hyperaminoaciduria and hyperphosphaturia may occur.

The clinical features of and diagnostic evaluation for hypocalcemic rickets are discussed separately. Of note, in settings where resources are limited, the elevation in total serum alkaline phosphatase activity (generally >350 international units/L) is a very good marker for nutritional rickets in children [25]. (See "Overview of rickets in children".)

Treatment

●Daily therapy – The most widely used treatment for vitamin D deficiency rickets consists of daily replacement doses of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). The following dosing scheme is recommended for children without underlying defects in intestinal absorptive function:

•Infants <1 month old – 1000 international units (25 mcg) daily for up to three months, followed by maintenance dosing of 400 international units (10 mcg) daily.

•Infants 1 to 12 months old – 1000 to 2000 international units (25 to 50 mcg) daily for up to three months, followed by maintenance dosing of 400 international units (10 mcg) daily.

•Children 1 to 12 years – 2000 to 6000 international units (50 to 150 mcg) daily for three months, followed by maintenance dosing of 600 international units (15 mcg) daily.

•Children ≥12 years old – 6000 international units (150 mcg) daily for three months, followed by maintenance dosing of 600 international units (15 mcg) daily.

Children with malabsorption, those on medications that impact vitamin D metabolism, and obese children with vitamin D deficiency may require higher replacement doses (two to three times higher than in children without these conditions), followed by higher maintenance dosing. Dose titration may be necessary in view of the variable degrees of malabsorption and supplemental requirements.

Treatment should also include the provision of 30 to 50 mg of elemental calcium/kg body weight per day, from dietary sources or supplements. This is particularly important in patients with elevated levels of PTH to avoid the so-called "hungry bone" syndrome (worsening hypocalcemia after the start of vitamin D therapy).

Global Consensus Recommendations suggest somewhat higher doses for infants (vitamin D 2000 international units [50 mcg] daily) [26]. However, because of risks of inducing hypercalcemia in small infants [27], we suggest the lower doses outlined above and emphasize the need to perform biochemical monitoring and to titrate doses as indicated.

This regimen of vitamin D and calcium supplementation should lead to resolution of the biochemical and radiologic abnormalities within three months. We repeat the biochemical evaluation within one month of starting therapy for safety reasons, and we check radiographs for evidence of healing after two to three months of treatment. (See 'Monitoring' below.)

●Stoss therapy – An alternative treatment protocol is the so-called "stoss therapy," which consists of a high dose of vitamin D given on a single day. The Global Consensus prefers daily therapy rather than stoss therapy, but recognizes that stoss therapy is sometimes more practical, and provides the following dosing recommendations, using oral vitamin D3 (cholecalciferol) and not vitamin D2 [26]:

•Infants <3 months of age – Stoss therapy not recommended

•Infants 3 to 12 months of age – A single dose of 50,000 international units (1250 mcg)

•Children 1 to 12 years – A single dose of 150,000 international units (3750 mcg)

•Children ≥ 12 years – A single dose of 300,000 international units (7500 mcg)

This amount of vitamin D should be sufficient to induce healing of the growth plate within three months. Stoss therapy may be advantageous when compliance with therapy and/or follow-up is anticipated to be a problem [5,28]. However, high doses of vitamin D may lead to hypercalcemia. Finally, in older children, a modified higher-dose approach has been successfully used, particularly when there is concern about adherence to a daily regimen. The regimen consists of weekly doses of 50,000 international units (1250 mcg) of vitamin D for two to three months. Adequate calcium intake should also be assured when using stoss therapy (as with daily therapy).

●Vitamin D deficiency without rickets – Expert opinion varies regarding doses for vitamin D replacement in infants and children with serum levels of 25OHD less than 20 ng/mL (50 nmol/L) but without clinical evidence of rickets. Some authorities recommend the same dosing scheme that is used for children with rickets, as outlined above [5]. In our own practice, we tend to use somewhat lower doses (400 international units [10 mcg] daily in children less than one month of age and up to 1000 international units [25 mcg] daily for older children). We feel that this reduces the risk of inducing hypercalcemia, especially in children who may not reliably return for biochemical monitoring after one month of therapy. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Vitamin D deficiency or insufficiency'.)

Monitoring — Serum calcium, phosphorus, alkaline phosphatase concentrations, and urinary calcium:creatinine ratio should be measured four weeks after the start of therapy in children who are being treated for vitamin D deficiency rickets. At this time, serum calcium and phosphorus levels should have normalized and alkaline phosphatase should have started to decrease towards the reference range. The urinary calcium:creatinine ratio may still be low. These tests should be repeated monthly until doses are adjusted downward to a typical daily replacement amount. This typically occurs by three months of therapy, at which time radiographs can be obtained to document the healing of rachitic lesions.

Orthopedic consultation usually is not indicated, because skeletal deformities regress completely after successful medical therapy. Correction of bow defects is a more chronic process and may take months to years to correct after the radiographic appearance of the growth plates has normalized. Orthopedic intervention may be necessary if deformities do not eventually improve.

If the radiographs do not show evidence of healing, or biochemical parameters are not improving, the possibility of poor adherence to treatment, malabsorption of vitamin D, or other forms of rickets should be considered. Consideration of an alternate diagnosis is particularly important when the original biochemical profile had borderline values. As an example, modest elevations in serum PTH are occasionally observed in X-linked hypophosphatemia, leading to an erroneous diagnosis of calcipenic rickets. (See "Overview of rickets in children", section on 'Further evaluation'.)

An additional biochemical parameter of the adequacy of calcium and vitamin D supplementation that may be useful in older children is the reappearance of normal levels of urinary calcium excretion, showing that the body's vitamin D and calcium stores have been replenished. If the patient has low urinary calcium excretion after three months of treatment, continuation of the same treatment regimen for another three months is advisable.

Monitoring is also important to ensure that no toxicity has occurred, particularly if the vitamin D dose was erroneously dispensed or administered. We have encountered hypercalcemia in the setting where high doses were continued for a longer duration than intended due to poor compliance with follow-up visits.

Calcium deficiency

Etiology — Rickets can occur despite adequate vitamin D levels if calcium intake is very low. This problem generally does not occur unless calcium intake is very low, because vitamin D increases intestinal calcium absorption [29,30]. Most children with calcium deficiency rickets have normal serum 25OHD and high serum 1,25(OH)₂D concentrations, indicating adequate intake of vitamin D. These children may have an increased vitamin D requirement when measured by their response to vitamin D replacement [31]. Thus, vitamin D requirements may be higher than expected in children who are calcium deficient [32]. Indeed, the turnover of vitamin D is accelerated in the setting of calcium deficiency; the two nutrients are inherently linked, such that limited availability of one will result in limited supply of the other. Thus, it is likely that rickets due to a combination of calcium and vitamin D deficiency accounts for many cases. This interaction between the two nutrients can be quantified: A reanalysis of data from earlier studies describing the Nigerian population with calcium deficiency (discussed below) has shown that the vitamin D requirement necessary to prevent rickets varies inversely with dietary calcium intake [33].

Calcium deficiency rickets was well documented in a randomized, double-blind, controlled trial of 123 Nigerian children with rickets [34]. In this population, the baseline intake of calcium was very low (approximately 200 mg per day) and the children responded to treatment with calcium, with or without vitamin D [34]. However, other factors in addition to calcium intake must play a role because control children without rickets had similarly low calcium intake [35]; this may include mutations in CYP2R1, which encodes the principal vitamin D 25-hydroxylase (see '25-hydroxylase deficiency' below). Although most of the studies on calcium deficiency rickets were performed in Africa, similar dietary deficiencies occur in North America [30,36-38].

Interestingly, rickets does not often occur in typical primary hypoparathyroidism, perhaps in view of elevated phosphorus levels or a possible role of PTH in mediating the growth plate lesion. (See "Etiology of hypocalcemia in infants and children", section on 'Hypocalcemia with low PTH (hypoparathyroidism)'.)

Treatment — As shown by the study of Nigerian children described above [34], calcium deficiency rickets can be treated by ensuring a daily intake of 1000 mg of calcium and maintenance of vitamin D intake at the recommended daily value.

DEFECTS IN VITAMIN D METABOLISM — Vitamin D from the diet or dermal synthesis is biologically inactive and requires enzymatic conversion in the liver and kidney to the active metabolite, 1,25-dihydroxyvitamin D (1,25[OH]₂D) (figure 1). Physiologic or genetic disturbances in this process may lead to vitamin D deficiency and rickets, often with hypocalcemia and compensatory parathyroid hormone (PTH) secretion.

Hepatic or renal dysfunction — Patients with severe liver disease may have impaired 25-hydroxylation of vitamin D. Some drugs, including certain anticonvulsants, also reduce available 25-hydroxylated vitamin D by increasing its catabolism. Similarly, renal failure may interfere with normal renal formation of 1,25(OH)₂D. (See "Etiology of hypocalcemia in infants and children", section on 'Hepatic dysfunction' and "Etiology of hypocalcemia in infants and children", section on 'Renal dysfunction'.)

Genetic disorders

25-hydroxylase deficiency — Mutations in CYP2R1, the gene that encodes the enzyme principally responsible for 25-hydroxylation of vitamin D, causes a form of "hydroxylation-deficient" rickets (MIM #600081). This disorder is exceedingly rare and has been described in only a few case reports [39-41]. In a Nigerian population, individuals with heterozygous CYP2R1 mutation are distinguished by rickets that responds more effectively to calcium rather than vitamin D supplementation and by a familial pattern of inheritance [39]. Individuals with homozygous mutations of CYP2R1 show modest responses to high-dose vitamin D supplementation (as ergocalciferol or cholecalciferol) or calcium [40] and theoretically would respond well to physiologic doses of 25-hydroxyvitamin D. Nevertheless, phenotypes and severity vary [41].

1-alpha-hydroxylase deficiency — 1-alpha-hydroxylase deficiency (MIM #264700) is a somewhat more common form of vitamin D-resistant rickets, first identified in 1961 [42]. It was previously known as pseudovitamin D deficiency rickets, or vitamin D-dependent rickets type I because of its "dependence" on pharmacologic dosing of vitamin D.

●Etiology – 1-alpha-hydroxylase deficiency, an autosomal recessive disorder, is characterized by defective conversion of 25-hydroxyvitamin D (25OHD) to 1,25(OH)₂D [43]. The characteristic biochemical findings of 1-alpha-hydroxylase deficiency are normal serum levels of 25OHD and low levels of 1,25(OH)₂D (table 2).

Patients with 1-alpha-hydroxylase deficiency have inactivating mutations in the CYP27B1 gene [44-46], which encodes the enzyme (25-hydroxyvitamin D 1-alpha-hydroxylase or, simply, 1-alpha-hydroxylase) responsible for the conversion of 25OHD to 1,25(OH₎₂D. Mice with inactivation of the gene encoding 1-alpha-hydroxylase mimic the 1-alpha-hydroxylase deficiency phenotype [47,48]. Mutation analysis of the CYP27B1 gene can confirm the diagnosis.

●Clinical manifestations – 1-alpha-hydroxylase deficiency is characterized by early onset of skeletal disease (within the first year of life) and severe hypocalcemia (sometimes with tetany) and secondary hyperparathyroidism with modest to moderate hypophosphatemia. Enamel hypoplasia may occur. These features differ from those encountered in X-linked hypophosphatemic rickets (previously known as X-linked vitamin D-resistant rickets), which is characterized by markedly low serum phosphorus and a normal or slightly elevated serum PTH level, and serum calcium is usually normal prior to treatment. Although the condition is somewhat rare, it continues to be regularly identified; the author is aware of this disorder being occasionally misdiagnosed as X-linked hypophosphatemia. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'X-linked hypophosphatemia'.)

●Treatment – The treatment for 1-alpha-hydroxylase deficiency is replacement therapy with the activated vitamin D metabolite, 1,25(OH)₂D₃ (calcitriol), an off-label use of this drug [46]. The dose depends upon the severity of disease and the child's body weight. A suggested initial dose for florid rickets is 1 mcg daily. Treatment is continued at this dose until bones are healed. Thereafter, the maintenance dose varies between 0.2 and 2 mcg daily, depending on the results of biochemical analyses, as described in the next paragraph. The aims of the treatment are to achieve normal serum calcium levels, maintain PTH levels within normal limits, and avoid hypercalciuria [46]. It is important to maintain adequate intake of dietary calcium (30 to 75 mg/kg daily of elemental calcium). An alternative approach that is more readily available than calcitriol in some countries is 1-alpha-OHD₃ (alfacalcidol), used in doses of 1 to 3 mcg daily [49].

●Monitoring – Close supervision is needed during the initial phase of treatment, including a physical examination and biochemical evaluation every two to three weeks. The biochemical evaluation should include measurement of serum calcium, phosphorus, alkaline phosphatase, and PTH levels. Radiographs should show clear improvement after four weeks of therapy and should be repeated after three months, when the growth plates should have regained a normal appearance. Patients may be evaluated at three-month intervals during maintenance therapy. Hand radiographs are performed once per year to check for the reappearance of rachitic changes.

Possible side effects of 1,25(OH)₂D₃ therapy include hypercalcemia, hypercalciuria, nephrocalcinosis, and intraocular calcifications [46]. Therefore, it is important to monitor the urinary calcium:creatinine ratio and kidney function (eg, serum creatinine) at each visit. Renal ultrasound should be performed once per year. Ophthalmic consultation and slit-lamp examination should be considered if manifestations of chronic hypercalcemia are evident, such as nephrocalcinosis.

Increased catabolism of vitamin D — Gain-of-function variants in CYP3A4, the gene encoding a vitamin D catabolic enzyme, cause increased degradation of both 25OHD and the active 1,25(OH)₂D metabolite. Patients with this apparently exceedingly rare mutation have low circulating levels of both 25OHD and 1,25(OH)₂D, indicating genetic dysregulation of vitamin D catabolism [50].

DEFECT IN VITAMIN D ACTION

Hereditary resistance to vitamin D — Hereditary resistance to vitamin D (HRVD) was previously called vitamin D-dependent rickets type II and is characterized by end-organ resistance to vitamin D [51]. It is another rare form of rickets.

●Etiology – HRVD is an autosomal recessive disorder. It is associated with end–organ resistance to 1,25-dihydroxyvitamin D (1,25[OH]₂D), usually caused by mutations in the gene encoding the vitamin D receptor. The defect in the receptor interferes with the function of the hormone-receptor complex, thereby preventing 1,25(OH)₂D action [51].

●Clinical features – The clinical spectrum of HRVD varies widely, probably reflecting the type of mutation within the vitamin D receptor and the amount of residual vitamin D receptor activity. Affected children usually appear normal at birth but develop rickets within the first two years of life. Alopecia and ectodermal anomalies resulting from the lack of vitamin D receptor activity within keratinocytes develops in approximately two-thirds of cases and is a marker of disease severity (HRVD type 2A, MIM #277440) [52,53]. Other patients have the classical rickets phenotype but without alopecia or other ectodermal anomalies; some of these patients have been found to abnormally express a hormone response element-binding protein that interferes with the normal function of the vitamin D receptor (HRVD type 2B, MIM %600785). In view of the rarity of the condition and the specialized management required, genetic testing for these conditions is recommended.

●Treatment – The treatment of HRVD involves a therapeutic trial of 1,25(OH)₂D (calcitriol) and calcium supplementation. The individual response is difficult to predict because the severity of the receptor defect varies among patients. Therapy may start at daily doses of 2 mcg of 1,25(OH)₂D and 1000 mg of elemental calcium. However, administration of extremely high doses of 1,25(OH)₂D (up to 30 to 60 mcg daily) and calcium (up to 3 g daily) may be necessary to restore normocalcemia and mineralize depleted bones.

Long-term infusion of calcium into a central vein is a possible alternative therapeutic option for severely resistant patients [54,55]. Although early regimens were given for many months, reports indicate that brief, intermittent intravenous infusions may be effective [56]. Oral calcium therapy may be sufficient once radiographic healing has been observed [55].

●Monitoring – During treatment, patients should initially be evaluated at least once per week. Serum concentrations of calcium, phosphorus, alkaline phosphatase, creatinine, 1,25(OH)₂D, and parathyroid hormone (PTH) and the urinary calcium:creatinine ratio should be measured.

If the biochemical parameters do not respond, the dose of 1,25(OH)₂D should be gradually increased to reach serum concentrations of up to 100 times the normal mean value. Failure of therapy should be considered if no biochemical response occurs after three to five months of treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin D deficiency" and "Society guideline links: Pediatric bone health".)

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SUMMARY AND RECOMMENDATIONS

●Definition and categorization – Calcipenic rickets comprises a group of disorders in which intestinal absorption of calcium is insufficient to match the calcium requirements for bone growth. Calcipenic rickets is characterized by elevated parathyroid hormone (PTH) and normal or low serum inorganic phosphorus concentrations (algorithm 1) and may have concomitant hypocalcemia. Measurement of the serum 25-hydroxyvitamin D (25OHD) level helps to identify the cause (algorithm 2 and table 2). (See 'Evaluation' above.)

●Vitamin D deficiency rickets – Vitamin D deficiency rickets usually presents between three months and three years of age, when growth rates (and calcium needs) are high. The main reasons for inadequate vitamin D supply in infants from resource-abundant settings are prolonged breastfeeding without vitamin D supplementation and concomitant avoidance of sun exposure. Vitamin D deficiency may also be caused by malabsorptive conditions. (See 'Etiology' above.)

•Prevention – To prevent vitamin D deficiency, vitamin D supplementation is recommended for all breastfed infants. Older children also may require supplements depending on their dietary sources of vitamin D and sun exposure. (See 'Prevention' above.)

•Treatment – Infants and children with any stage of vitamin D deficiency rickets should be treated with vitamin D. We use oral vitamin D2 (ergocalciferol) or D3 (cholecalciferol); a variety of dosing schemes are effective. For patients with elevated levels of PTH, an oral calcium supplement should be prescribed to avoid "hungry bone" syndrome. (See 'Treatment' above.)

•Subclinical vitamin D deficiency – We also suggest vitamin D replacement for infants and children with serum levels of 25OHD less than 20 ng/mL (50 nmol/L) but without clinical evidence of rickets (Grade 2C). For these children with subclinical vitamin D deficiency, we use replacement doses of 400 international units (10 mcg) daily in children less than one month of age and up to 1000 international units (25 mcg) daily for older children. (See 'Treatment' above.)

•Monitoring – During treatment for vitamin D deficiency rickets, children should be monitored with laboratory tests and radiographs should be obtained to document healing of rachitic lesions (see 'Monitoring' above). Children who do not respond despite adherence to treatment may have a defect in vitamin D absorption or metabolism, or increased catabolism. (See 'Genetic disorders' above.)

●Calcium deficiency rickets – Less commonly, dietary deficiency of calcium may cause nutritional rickets. This is suggested by the presence of rickets in countries where the incidence of hypocalcemic rickets is high, despite ample sunlight and adequate exposure to the sunlight (in the absence of sunscreen) and normal serum concentrations of vitamin D. Because children who are calcium deficient may have higher than expected requirements for vitamin D, they should be treated with both calcium and vitamin D supplementation. Many cases are likely due to combined deficiencies of calcium and vitamin D. (See 'Calcium deficiency' above.)

●Genetic causes of calcipenic rickets – Genetic causes of calcipenic rickets include:

•Deficiencies of 25-hydroxylase or 1-alpha hydroxylase, the enzymes responsible for conversion of vitamin D to the active form

•Increased catabolism of 25OHD caused by gain-of-function variants in CYP3A4

•Hereditary resistance to vitamin D due to end–organ resistance

These disorders can be distinguished by characteristic biochemical findings (table 2) and confirmed by genetic testing. (See 'Genetic disorders' above.)