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Understanding rickets
SYMPOSIUM: ENDOCRINOLOGY
Understanding rickets
calcium and phosphate absorption in the gastrointestinal tract and the incorporation and release of these minerals from the skeleton. Significant advances in the understanding of phosphate metabolism have been made in the past decade with the recognition that there are phosphate regulating hormones referred to as “phosphatonins”. The principal “phosphatonin” is Fibroblast Growth Factor 23 (FGF23) which has been shown to be elevated in many disorders characterized by reduced renal tubular phosphate reabsorption and reduced synthesis of 1,25-dihydroxy vitamin D. FGF23 is known to affect the sodiumephosphate co-transporters in the kidney leading to excess urinary phosphate excretion and also inhibits the activity of the 1-alpha-hydroxylase enzyme. In the normal physiological situation FGF23 is degraded into inactive components and thus does not produce these adverse effects. FGF23 is now recognized to be produced from the skeleton particularly from osteocytes and osteoblasts indicating that there is a boneekidney axis (Figure 2) controlling phosphate homeostasis.
Bharathi Pai Nick Shaw
Abstract Rickets is a condition that has been recognized for many centuries and is due to defective mineralization of the growth plate in growing children. This defect compromises the mechanical support and mineral reservoir functions of the skeleton which leads to the typical skeletal deformities and the disordered mineral metabolism. Either calcium and/or phosphate may be deficient in the aetiology of rickets. Considerable advances in the pathophysiology of hypophosphataemic rickets have been made in recent years. Advances in genetics have led to the identification of all forms of inherited rickets. However nutritional vitamin D deficiency rickets remains the most prevalent cause worldwide and has made a resurgence in many developed countries in recent years. This article reviews the current knowledge about the different causes of rickets and provides guidelines on diagnosis and management.
Classification of rickets This is based on whether there is predominantly a deficiency of calcium or phosphate. Calcipenic e due to calcium deficiency or interruption in the supply, metabolism or utilization of vitamin D B Calcium deficiency B Nutritional vitamin D deficiency B Vitamin D deficiency secondary to: - Malabsorption - Liver disease - Renal insufficiency B 25-hydroxylase deficiency B Vitamin D dependant rickets type I B Vitamin D dependant rickets type II Phosphopenic e due to inadequate dietary phosphate intake or excess renal tubular loss B Primary - X-linked dominant - Autosomal dominant - Autosomal recessive - X-linked recessive - Hereditary hypophosphataemia with hypercalciuria B Secondary - Oncogenic osteomalacia - Fibrous dysplasia: McCuneeAlbright syndrome - Ifosfamide nephrotoxicity - Fanconi syndrome - Low dietary phosphate intake
Keywords FGF23; hypophosphataemic; rickets; vitamin D
History Rickets has been described as early as second century AD in Roman children when Soranus of Ephesus wrote about it in his book ‘A Treatise on the Diseases of Women’. Hippocrates also described a disease which bore resemblance to rickets in 130 AD. More recently Francis Glisson published a detailed account of rickets in English children (1651). In the early 20th century the healing power of sunshine was established and subsequently the chemical structure of vitamin D was identified by Adolf Windaus in 1930.
Metabolism of vitamin D and phosphate Vitamin D is converted to the 25-hydroxy form by 25-hydroxylase in the liver (Figure 1). 25-hydroxy vitamin D circulates in plasma bound to vitamin D binding protein and the plasma concentration is directly related to intake and stores of the vitamin in the body. This metabolite is measured in laboratories to estimate vitamin D status. It is thereafter transformed into the active metabolite 1,25-dihydroxy vitamin D by the enzyme 1-alpha-hydroxylase in the kidneys under the influence of parathyroid hormone (PTH). 1,25-dihydroxy vitamin D mediates
Clinical manifestations Bharathi Pai MBBS MRCPCH is a Specialist Registrar in Endocrinology in the Department of Endocrinology at Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK. Conflict of interest: none.
The clinical history is important in establishing the diagnosis and type of rickets. Nutritional rickets due to vitamin D deficiency is more commonly seen in dark skinned children (South Asian, African Caribbean and Middle Eastern) who need a longer period of sunlight exposure to the skin to synthesize adequate amounts of vitamin D. This is especially important in countries such as the United Kingdom where there is insufficient sunlight for many months of the year. Certain ethnic communities who dress
Nick Shaw MB ChB FRCPCH is Consultant Paediatric Endocrinologist and Clinical Lead for Endocrinology in the Department of Endocrinology at Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK. Conflict of interest: none.
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Dietary intake of chole (D ) or ergo (D ) calciferol
UV light
Calciferol Skin production of cholecalciferol
Liver
25 hydroxylase
25 hydroxyvitamin D 1 α hydroxylase
1,25 dihydroxyvitamin D (biologically very active)
24,25 dihydroxyvitamin D (biologically inert)
Kidney
Figure 1 Diagram of the vitamin D metabolism pathway.
conservatively are predisposed to vitamin D deficiency again by virtue of deficient exposure to sunlight. Infants from such backgrounds who are breastfed and present with hypocalcaemia often have nutritional rickets reflecting maternal vitamin D deficiency. In recent times the liberal use of sunscreen contributes to the problem by compromising cutaneous vitamin D synthesis. A family history of rickets may suggest an inherited form of rickets of which X-linked hypophosphataemic rickets (XLHR) is the most common. A history of consanguinity and of alopecia may be pointers to the rare vitamin D dependent rickets type II. Chronic diseases such as renal, liver and malabsorptive states predispose to the development of rickets.
↑ FGF 23
The signs and symptoms of rickets vary depending on the age of presentation. The young infant may demonstrate craniotabes due to softening of the skull bones but this is not pathognomonic. Other features in infancy are bossing of the forehead, widening of wrists (when babies start crawling) and delayed closure of fontanelles. There can be delayed eruption of teeth with enamel hypoplasia in nutritional rickets in contrast to hypophosphataemic rickets where the enamel is normal but dental pulp abscesses can occur. Rarely, vitamin D deficiency can cause cardiomyopathy in infants which may be rapidly fatal if unrecognized. Toddlers and young children usually present with bow legs (genu varum). This can be physiological up to the second year of life where intercondylar distances less than 5 cm are physiological (Figure 3). Delayed walking beyond 18 months is another recognized presentation due to the myopathy seen with vitamin D deficiency. Short stature may be a presentation of hypophosphataemic rickets. Chest deformity with a rachitic rosary due to swollen costochondral junctions and Harrison’s sulci due to inward pull of the diaphragm on the softened lower ribs may be seen. The older child may have knock knees (genu valgum) and complain of bone pain and fatigue. There may be a history of fracture in the osteopenic bones of calcipenic rickets. Hypocalcaemia due to vitamin D deficiency rickets can cause stridor, tetany and convulsions.
Bone
↓ PO efflux ↓ PO reabsorption ↓ 1,25 (OH) D
↑ (Serum PO )
Kidney
Investigations
Gut
Biochemical features Table 1 lists suggested biochemical investigations. A key investigation is the measurement of serum parathyroid hormone (PTH) as it is invariably raised in calcipenic rickets but often normal in most forms of phosphopenic rickets. Plasma alkaline phosphatase is raised in all types of rickets but more significantly elevated in calcipenic rickets whereas may only be marginally raised in phosphopenic rickets. This is a reflection of the raised serum PTH in the former causing
↓ PO absorption
Small intestine Figure 2 Schematic diagram of the role of FGF23 in phosphate homeostasis.
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Urinary phosphate excretion is evaluated through calculation of the tubular phosphate reabsorption (TRP): TRP ð%Þ ¼ 1
where Up and Pp, Ucr and Pcr represent urine and plasma phosphorus, urine and plasma creatinine respectively (all variables must be expressed in the same unit e.g. mmol/l). A TRP level less than 85% would be regarded as abnormal. A more accurate index, the tubular maximum for phosphate reabsorption (TmPO4/GFR) can be derived from nomograms using the TRP and plasma phosphate. The typical biochemical abnormalities seen in vitamin D deficiency are low or normal plasma calcium and raised serum PTH (secondary hyperparathyroidism) leading to decreased renal tubular reabsorption of phosphate and low plasma phosphate. Plasma phosphate levels need to be interpreted with care as they are generally higher in healthy young children and infants (1.3e2.1 mmol/litre) than in adults (0.7e1.3 mmol/litre); therefore any value of 1 mmol/litre or below in young children is abnormal. X-linked hypophosphataemic rickets presents typically with normal plasma calcium, low plasma phosphate with normal levels of serum PTH and 25-hydroxy vitamin D. There is a normal urine calcium creatinine ratio with no proteinuria or glycosuria. Excess phosphate excretion as demonstrated by low TRP or TmPO4/GFR can be seen in both vitamin D deficiency and hypophosphataemic rickets e in the former due to the high PTH and the latter due to a primary renal tubular leak.
Figure 3 Determination of intercondylar distance in genu varum. For accurate measurement, the medial malleoli should just touch.
increased bone turnover. Though not very sensitive, it is useful in the monitoring of therapy as adequately treated patients demonstrate a progressive reduction. However there may be difficulty with rickets due to liver disease because of the elevated alkaline phosphatase in this situation. Vitamin D deficiency is confirmed by low 25-hydroxy vitamin D with levels usually less than 10 ng/ml (25 nmol/litre) causing rickets. 1,25-dihydroxy vitamin D analysis is reserved for those rarer forms due to defects in vitamin D metabolism. The genetic basis for most forms of inherited rickets is now established and therefore can be confirmed by DNA for genetic analysis. The urinary calcium creatinine ratio helps to establish calcium excretion in the urine (ideally a fasting specimen) which is elevated in hypophosphataemic rickets with hypercalciuria (HHRH) and Dent’s disease.
Imaging studies Radiographs of the epiphyseal growth plate (physis) are very useful in the diagnosis of rickets. The physis is composed of columns of cartilage cells arranged in four parallel zones: 1. Resting zone: site of little activity sites of active cell division and 2. Proliferative zone maturation. 3. Hypertrophic zone 4. Calcifying zone or zone of provisional calcification e osteoid matrix is formed and mineralized. The first three zones are radiolucent but the zone of provisional calcification is as dense as the mature mineralized bone. Therefore abnormalities in mineralization which is characteristic of rickets would appear in this region on radiographs. Actively growing parts of the skeleton are the most helpful (varies depending on the age of the child): radiographs of wrists and knees throughout most of childhood and chest (proximal humeri and anterior rib ends) in neonates, infants and young children. The typical changes are cupping, fraying and widening of the metaphysis. Centres of ossification may appear late and look pale and irregular. The long bones may show osteopenia and pathological fractures. Healing of rickets on treatment can be seen as a dense metaphyseal band e the newly repaired zone of provisional cartilage and is usually present in 2e3 weeks following initiation of therapy. In XLH, the rachitic changes though less dramatic than in vitamin D deficiency rickets are more severe in the knees than the wrists. The modelling defects manifest as short, squat long bones with coarse trabeculation of the axial skeleton.
Recommended investigations in suspected rickets Blood Calcium, phosphate, alkaline phosphatase Creatinine Liver function tests Serum PTH Plasma 25 OH Vitamin D Save serum for 1,25(OH)2D3 level Consider DNA for genetic analysis Urine Calcium, phosphate, creatinine Calculation of TRP & TmPO4/GFR Radiology X-ray wrist and knee Table 1
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Up Pcr 100 Pp Ucr
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Vitamin D deficiency rickets
Treatment of symptomatic rickets is with ergocalciferol (D2plant derived) or cholecalciferol (D3-animal derived) in the a daily dose of 3000 units in infants less than 6 months of age, 6000 units in children 6 monthse12 years and 10,000 units for older children up to 18 years for a period of 2e3 months. This is followed by maintenance with a recommended daily intake of 400 units. If associated hypocalcaemia is present oral calcium supplements may be required for a short period. Large single oral or intramuscular doses of vitamin D (150,000e300,000 units) can be used in children with severe disease associated with malabsorption or liver disease and especially those with compliance issues. In recent times, the magnitude of the problem related to vitamin D deficiency has been recognized by the Department of Health (UK). It has through the Healthy Start scheme recommended free vitamins (includes vitamin D 400 units) to all children between 6 months and 4 years and pregnant or breastfeeding mothers until their child is a year old.
Vitamin D deficiency has re-emerged as a significant public health problem in the UK and other developed countries in recent years. Nutritional vitamin D deficiency is the commonest cause in the absence of any malabsorption or disorder of liver, kidneys or vitamin D metabolism. The exact prevalence of the condition in children in the UK is not known. A survey from the West Midlands in 2001 estimated the incidence to be about 7.5 per 100,000 with ethnic differences e 38 per 100,000 in south Asians, 95 per 100,000 in AfricaneCaribbean and 0.4 per 100,000 in the white population. Vitamin D in our body is mainly (80%) derived from the action of UVB rays in the sunlight on 7-dehydrocholesterol in the skin and the rest (20%) comes from diet. Foods rich in vitamin D are oily fish, fish oils and eggs. In the UK, only a few items like breakfast cereal, margarine and baby formula feeds are fortified. During the Second World War fortification of food produced a dramatic reduction in the prevalence of rickets. However, there was an increase in cases of idiopathic hypercalcaemia in infants in the 1950’s and although evidence of vitamin D toxicity was not established it led to a reduction in food fortification. Cutaneous synthesis of the vitamin may be limited by clothing and use of sunscreen. In winter insufficient UVB reaches the Earth’s surface and people in countries above or below 35 latitude have very little vitamin D synthesis. In UK it is suggested about 15 min of exposure of hands, arms, face or back to suberythemal levels of sunlight in fair skinned population 2e3 times/week from April to September is sufficient to produce adequate vitamin D. Vitamin D deficiency is usually defined as serum levels below 25 nmol/litre (10 ng/ml) and insufficiency when levels are between 25 and 50 nmol/litre (10e20 ng/ml). However some studies suggest that higher levels of 75e87.5 nmol/litre (30e35 ng/ml) may be optimal. Based on these studies, the National Health and Nutrition Examination Survey in United States demonstrated that changing the definition from less than 11 to less than 20 ng/ml increased the prevalence of vitamin D deficiency amongst adolescents from 2 to 14% with significant public health implications. Currently the definition of vitamin D deficiency is a matter of considerable debate with interest in potential nonskeletal outcomes. There are three stages of vitamin D deficiency rickets: Stage I: hypocalcaemia due to decreased calcium absorption from the gut and reduced resorption from bone. This stage is usually short lived except in infants when it may be prolonged resulting in symptomatic hypocalcaemia. Stage II: hypocalcaemia triggers PTH release and secondary hyperparathyroidism which normalizes serum calcium but produces hypophosphataemia. Stage III: continued deficiency results in severe bone disease with recurrence of hypocalcaemia due to insufficient mobilization from bone. Presentation of vitamin D deficiency may be asymptomatic or less commonly with overt skeletal changes. Symptomatic hypocalcaemia is more often seen in extremes of childhoodeinfancy and adolescence when rapid growth occurs. Deficiency may also present with atypical features of cardiomyopathy in infants and unexplained aches and pains with muscle weakness especially in teenage girls.
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Calcium deficiency rickets This has been reported in Bangladesh, South Africa and Nigeria with presentation usually beyond 18 months. Vitamin D levels are normal but calcium is deficient in the diet. The clinical and radiological characteristics of rickets are similar to vitamin D deficiency except that craniotabes, hypotonia and tetany e features seen in infancy are typically absent. Treatment is with increased calcium in the diet and as supplements. There is evidence to suggest that calcium deficiency may contribute to the presentation of nutritional vitamin D deficiency rickets.
25-hydroxylase deficiency This rare autosomal recessive cause of rickets is due to mutations in the CYP2R1 gene which codes for the 25-hydroxylase enzyme responsible for hydroxylation of vitamin D in the liver. Two affected children presented with rickets with low 25-hydroxy vitamin D level despite adequate intake of the vitamin in the diet and exposure to sunlight.
Vitamin D dependent rickets type I This autosomal recessive condition is due to a deficiency of the 1-alpha-hydroxylase enzyme which converts 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. As a consequence, levels of 25hydroxy vitamin D are normal but 1,25-dihydroxy vitamin D levels are low. Mutations in CYP27B1 gene are responsible. Presentation of rickets is in the toddler age. Treatment is with alfacalcidol or calcitriol in the dose range of 0.5e2.0 mg/day.
Vitamin D dependent rickets type II This presents between 1 and 3 years of age due to a mutation in the gene for the vitamin D receptor with resistance to the action of the active metabolite and therefore patients show very high levels of 1,25(OH)2D. It is an autosomal recessive condition with alopecia in 50% of cases. Treatment is more difficult, as although some patients may respond to high-dose alfacalcidiol, many require intravenous calcium infusions via a central line to heal the rickets.
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Hypophosphataemic rickets
females due to random inactivation of the affected X chromosome in the latter as explained by Lyon’s hypothesis. The genetic defect in X-linked hypophosphataemia is known to be on the PHEX gene which is the phosphate regulatory gene located on the chromosome X p22.1 locus. Inactivating mutations (deletions, insertions, duplications, splice site, nonsense and missense mutations) of PHEX, a cell surface endopeptidase, is the cause of XLH. There is an increase in the expression of FGF23 in the bone which leads to inhibition of renal tubular reabsorption of phosphate and reduced production of 1-alphahydroxylase. Presentation of X-linked hypophosphataemia can be as early as 6 months with frontal bossing and flattening of back of head. However the usual presentation is with progressive bowing of the legs in infancy particularly once the child starts walking with a typical waddling gait. Bowing is especially seen in the femur and tibia with a characteristic anterior bowing deformity. Defects in dentine cause a predisposition to dental pulp abscesses. The diagnosis of XHR can be difficult in the first few months of life even with a positive family history and such infants can usually be diagnosed from about the 6th month of life based on reduced plasma phosphate, increased alkaline phosphatase and reduced renal tubular phosphate reabsorption (TRP). Knee radiographs may be useful as an adjunct in the diagnosis (Figure 4). Treatment for XLH is with a phosphate preparation along with a vitamin D analogue such as calcitriol or alfacalcidol. The dose of oral phosphate is 70e100 mg/kg/day divided in aliquots every 4e6 h due to rapid excretion by the kidneys. Alfacalcidol is given as 25e50 ng/kg once a day. Calcitriol is an alternative in a dose of 10e50 ng/kg/day; it is available only as a capsule, making it less suitable for infants and young children. Therapy is generally well tolerated and can result in improvements in height and reduction in severity and frequency of skeletal deformity especially when commenced early in infancy. However, it may produce significant side effects which
This group of genetic disorders is characterized by abnormalities in the sodiumephosphate co-transporter in the epithelial cell brush border of the renal proximal tubules which lead to increased urinary excretion of phosphate. Although there is a low plasma phosphate, levels of plasma calcium, serum 25-hydroxy vitamin D and PTH are usually normal in the untreated state. Serum 1,25-dihydroxy vitamin D levels are often in the normal range but inappropriately low in the face of a low plasma phosphate. Phosphopenia results in defective mineralization of the growth plates. The main types are X-linked dominant hypophosphataemia (XLH), autosomal dominant and recessive hypophosphataemia, X-linked recessive hypophosphataemia and hypophosphataemic rickets with hypercalciuria (HHRH). It has been demonstrated in animal models that hypophosphataemia is pivotal in the pathogenesis of all forms of rickets. Development of the endochondral skeleton (tubular, flat and cuboidal bones) involves mesenchymal condensation to start with, followed by cell differentiation into chondrocytes. Subsequently, the growing or proliferating chondrocytes in the epiphyseal cartilaginous growth plate develop into hypertrophic chondrocytes which are programmed to undergo apoptosis (cell death) and are then replaced by bone. This apoptosis is mediated via the activation of the caspase-9 mitochondrial pathway. Studies in the Hyp mouse model of X-linked hypophosphataemic rickets have shown that there is an expansion of this hypertrophic chondrocyte layer as a consequence of decreased apoptosis in the presence of reduced plasma phosphate levels. This hypertrophic growth plate is a consistent characteristic of rickets and in calcipenic rickets can be mediated by hypophosphataemia secondary to hyperparathyroidism. X-linked hypophosphataemic rickets (XLH) This condition is X-linked dominant and the prevalence worldwide is 1 in 20,000. Males are more severely affected than
Figure 4 X-rays of the knee in a child with vitamin D deficiency rickets (left) and hypophosphataemic rickets (right). Note the marked osteopenia in the former in contrast to the dense sclerotic bone in the latter.
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individuals also demonstrate elevated serum 1,25-dihydroxy vitamin D levels with proteinuria and hypercalciuria leading to nephrolithiasis, nephrocalcinosis and progressive renal failure in early adulthood. In females there is only hypercalciuria without evidence of any other biochemical abnormality. The genetic defect has been localized to the voltage-gated chloride channel gene CLCN5. Variable phenotypic expression of this single gene defect leads to different syndromes possibly due to the secondary influence of diverse genetic background and environmental factors like diet. Treatment of the rickets is with phosphate supplements only.
include hypercalcaemia due to tertiary hyperparathyroidism, hypercalciuria and nephrocalcinosis with the potential for deterioration in renal function. The appearance of these problems may necessitate withdrawal of treatment in some cases. Bolus doses of oral phosphate are responsible for lowering ionized calcium which stimulates PTH secretion and results in hyperparathyroidism. Failure to detect this effect and correction by adjustment of alfacalcidol dose can lead to the development of tertiary hyperparathyroidism which may require parathyroid surgery. Nephrocalcinosis is probably due to an effect of phosphaturia and vitamin D mediated enhanced absorption of calcium and phosphate from the gut. These complications have also been attributed to a rise in FGF23 levels with phosphate and vitamin D therapy which can limit effectiveness of treatment. Larger studies are required to establish if adjusting treatment with FGF23 monitoring to prevent its elevation may be beneficial in minimizing side effects. Cinacalcet, a calcimimetic drug licensed for use in hyperparathyroidism in adults has been shown to be promising as an adjunct in the treatment of hypophosphataemic rickets by suppressing PTH secretion and improving phosphate reabsorption in the renal tubules. Its effect on FGF23 is not yet clear but its use could lower the doses of phosphate and vitamin D and facilitate in reducing the complications. Another potential future treatment development would be the use of an antibody to FGF23 which has shown encouraging results in an animal model. In many affected children treatment improves growth but this may not be optimal. Growth hormone has been used in a number of studies although a recent Cochrane review found ‘no conclusive evidence to indicate that the use of recombinant human growth hormone therapy in children with X-linked hypophosphataemia is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, and body proportions’.
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) This condition presents between 6 months and 7 years of age with short stature, muscle weakness and rickets associated with bone pain with or without deformities of the lower extremities. The severity of the bone mineralization defect correlates inversely with the prevailing plasma phosphate concentration. In contrast to most other diseases wherein renal phosphate transport is affected, patients with HHRH exhibit increased 1,25dihydroxy vitamin D production which causes hypercalciuria by promoting calcium absorption in the gut, enhancing the renal load of calcium and inhibiting PTH secretion. Relatives of patients with evident HHRH may have less marked hypercalciuria and hypophosphataemia without the typical skeletal abnormalities suggesting a milder phenotype in the heterozygous state. The genetic basis of HHRH has been identified as due to mutations in the sodiumephosphate cotransporter gene SLC34A3. Treatment of HHRH is with high-dose phosphate supplements (1e2.5 g/day in five divided doses) only which results in improvement in rickets, bone pain, muscular strength and accelerated height velocity. Secondary forms of hypophosphataemic rickets are seen in several conditions but only oncogenic osteomalacia is discussed below.
Autosomal dominant hypophosphataemia (ADHR) In autosomal dominant hypophosphataemia, there may be incomplete penetrance with variable expression and age of onset. Males and females are equally affected. Lower limb deformities, fractures and tooth abscesses are common. Some affected women may show symptoms only in the second to fourth decade of life. ADHR is caused by inactivating mutations in the gene for FGF23 which protects it from proteolysis, leading to elevated circulating levels of FGF23 and secondary phosphate wasting in these patients.
Oncogenic osteomalacia or tumour-induced osteomalacia (TIO) Tumour induced osteomalacia is a rare paraneoplasic syndrome which presents with rickets or osteomalacia. It is more frequent in adults though may also be seen in children. Symptoms and signs which include bone pain and fractures are usually more severe than in XLH and muscle weakness is frequent. The mesenchymal tumours associated with TIO most commonly arise from the paranasal sinuses, neck and mandible. They are usually very small, benign and difficult to diagnose by routine physical examination or radiographs. Sophisticated imaging is often required for localizing these tumours. Secretion of FGF23 from these tumours has been implicated in the pathogenesis of TIO. Excision of the tumour helps to correct the biochemical abnormalities and symptoms.
Autosomal recessive hypophosphataemia (ARHR) Patients with ARHR have been found to have the same clinical and biochemical features to XLH and ADHR but inheritance is in an autosomal recessive manner. Two genetic defects have been identified due to abnormalities in the DMP1 or ENPP1 gene. The latter defect is also associated with generalized arterial calcification in infancy. There have been reports of elevated levels of FGF23 in affected individuals.
Differential diagnosis
X-linked recessive hypophosphataemia (Dent disease complex) In X-linked recessive hypophosphataemia, boys present in a similar manner to the X-linked dominant form. However these
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Metaphyseal chondrodysplasia (Pyle’s) which is a rare disorder manifests with flaring and irregularity of various metaphyses. The radiographic changes are similar to rickets, but calcium and
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Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA 5, 2005; 102: 9637e42. Makitie O, Doria A, Kooh SW, et al. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemicrickets. J Clin Endocrinol Metab 2003; 88: 3591e7. Wharton B, Bishop N. Rickets. Lancet 2003; 362: 1389e400. Shaw NJ. Vitamin D deficiency rickets. Endocr Dev 2003; 6: 93e104; Hochberg Z, ed. Vitamin D and rickets. Basel: Karger, 2003.
phosphorus metabolism is normal. Schmid, Schwachman and Jansen skeletal dysplasias may also be confused with rickets.
Summary Rickets is a disease of growing bones. Vitamin D deficiency is by far the commonest cause. Other forms of familial and vitamin D resistant or dependent rickets are less common and in these cases history and examination in combination with biochemical and genetic investigation are very important in teasing out the diagnosis. A
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FURTHER READING Hochberg Z. Rickets past and present. Introduction. Endocr Dev 2003; 6: 1e13. Hochberg Z, ed. Vitamin D and rickets. Basel: Karger, 2003. €ppner H. Disorders of phosphate homeostasis and tissue Bergwitz C, Ju mineralisation. Endocr Dev 2009; 16: 133e56. Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel: Karger, 2009. Allgrove J. A practical approach to rickets. Endocr Dev 2009; 16: 115e32; Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel: Karger, 2009. Maiya S, Sullivan I, Allgrove J, et al. Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart 2008; 94: 581e4. Callaghan AL, Moy RJD, Booth IW, Debelle G, Shaw NJ. Incidence of symptomatic vitamin D deficiency. Arch Dis Child 2006; 91: 606e7. Saintonge S, Bang H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial us adolescent population: the National Health and Nutrition Examination survey III. Pediatrics Mar 2009; 123: 797e803. Ladhani S, Srinivasan L, Buchanan C, Allgrove J. Presentation of vitamin D deficiency. Arch Dis Child Aug 2004; 89: 781e4. Koren R. Vitamin D receptor defects: the story of hereditary resistance to vitamin D. Pediatr Endocrinol Rev 2006; 3(suppl 3): 470e5.
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Rickets is due to defective mineralization of the growth plates in children. Hypophosphataemia is the underlying basis for all types of rickets. There is evidence of a boneekidney hormonal axis regulating phosphate metabolism. Vitamin D deficiency is regarded as levels of 25-hydroxyvitamin D below 25 nmol/litre (10 ng/ml) and insufficiency as levels between 25 and 50 nmol/litre (10e20 ng/ml). The clinical picture of vitamin D deficiency rickets depends on the age of presentation. Unusual presentations are severe progressive cardiomyopathy in infants and bone pain or muscle weakness in adolescents. Treatment of vitamin D deficiency is with oral ergocalciferol or cholecalciferol and not alfacalcidol. Vitamin D supplementation is important in children in high risk groups until the age of 4 years to prevent rickets. Hypophosphataemic rickets is treated with alfacalcidol or calcitriol and phosphate supplements. Early diagnosis and treatment in infancy are associated with better results with regards to growth and skeletal deformity. Apart from vitamin D deficiency all other causes of rickets have a genetic basis, the identification of which can aid accurate diagnosis and management.
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Understanding rickets
calcium and phosphate absorption in the gastrointestinal tract and the incorporation and release of these minerals from the skeleton. Significant advances in the understanding of phosphate metabolism have been made in the past decade with the recognition that there are phosphate regulating hormones referred to as “phosphatonins”. The principal “phosphatonin” is Fibroblast Growth Factor 23 (FGF23) which has been shown to be elevated in many disorders characterized by reduced renal tubular phosphate reabsorption and reduced synthesis of 1,25-dihydroxy vitamin D. FGF23 is known to affect the sodiumephosphate co-transporters in the kidney leading to excess urinary phosphate excretion and also inhibits the activity of the 1-alpha-hydroxylase enzyme. In the normal physiological situation FGF23 is degraded into inactive components and thus does not produce these adverse effects. FGF23 is now recognized to be produced from the skeleton particularly from osteocytes and osteoblasts indicating that there is a boneekidney axis (Figure 2) controlling phosphate homeostasis.
Bharathi Pai Nick Shaw
Abstract Rickets is a condition that has been recognized for many centuries and is due to defective mineralization of the growth plate in growing children. This defect compromises the mechanical support and mineral reservoir functions of the skeleton which leads to the typical skeletal deformities and the disordered mineral metabolism. Either calcium and/or phosphate may be deficient in the aetiology of rickets. Considerable advances in the pathophysiology of hypophosphataemic rickets have been made in recent years. Advances in genetics have led to the identification of all forms of inherited rickets. However nutritional vitamin D deficiency rickets remains the most prevalent cause worldwide and has made a resurgence in many developed countries in recent years. This article reviews the current knowledge about the different causes of rickets and provides guidelines on diagnosis and management.
Classification of rickets This is based on whether there is predominantly a deficiency of calcium or phosphate. Calcipenic e due to calcium deficiency or interruption in the supply, metabolism or utilization of vitamin D B Calcium deficiency B Nutritional vitamin D deficiency B Vitamin D deficiency secondary to: - Malabsorption - Liver disease - Renal insufficiency B 25-hydroxylase deficiency B Vitamin D dependant rickets type I B Vitamin D dependant rickets type II Phosphopenic e due to inadequate dietary phosphate intake or excess renal tubular loss B Primary - X-linked dominant - Autosomal dominant - Autosomal recessive - X-linked recessive - Hereditary hypophosphataemia with hypercalciuria B Secondary - Oncogenic osteomalacia - Fibrous dysplasia: McCuneeAlbright syndrome - Ifosfamide nephrotoxicity - Fanconi syndrome - Low dietary phosphate intake
Keywords FGF23; hypophosphataemic; rickets; vitamin D
History Rickets has been described as early as second century AD in Roman children when Soranus of Ephesus wrote about it in his book ‘A Treatise on the Diseases of Women’. Hippocrates also described a disease which bore resemblance to rickets in 130 AD. More recently Francis Glisson published a detailed account of rickets in English children (1651). In the early 20th century the healing power of sunshine was established and subsequently the chemical structure of vitamin D was identified by Adolf Windaus in 1930.
Metabolism of vitamin D and phosphate Vitamin D is converted to the 25-hydroxy form by 25-hydroxylase in the liver (Figure 1). 25-hydroxy vitamin D circulates in plasma bound to vitamin D binding protein and the plasma concentration is directly related to intake and stores of the vitamin in the body. This metabolite is measured in laboratories to estimate vitamin D status. It is thereafter transformed into the active metabolite 1,25-dihydroxy vitamin D by the enzyme 1-alpha-hydroxylase in the kidneys under the influence of parathyroid hormone (PTH). 1,25-dihydroxy vitamin D mediates
Clinical manifestations Bharathi Pai MBBS MRCPCH is a Specialist Registrar in Endocrinology in the Department of Endocrinology at Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK. Conflict of interest: none.
The clinical history is important in establishing the diagnosis and type of rickets. Nutritional rickets due to vitamin D deficiency is more commonly seen in dark skinned children (South Asian, African Caribbean and Middle Eastern) who need a longer period of sunlight exposure to the skin to synthesize adequate amounts of vitamin D. This is especially important in countries such as the United Kingdom where there is insufficient sunlight for many months of the year. Certain ethnic communities who dress
Nick Shaw MB ChB FRCPCH is Consultant Paediatric Endocrinologist and Clinical Lead for Endocrinology in the Department of Endocrinology at Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK. Conflict of interest: none.
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Dietary intake of chole (D ) or ergo (D ) calciferol
UV light
Calciferol Skin production of cholecalciferol
Liver
25 hydroxylase
25 hydroxyvitamin D 1 α hydroxylase
1,25 dihydroxyvitamin D (biologically very active)
24,25 dihydroxyvitamin D (biologically inert)
Kidney
Figure 1 Diagram of the vitamin D metabolism pathway.
conservatively are predisposed to vitamin D deficiency again by virtue of deficient exposure to sunlight. Infants from such backgrounds who are breastfed and present with hypocalcaemia often have nutritional rickets reflecting maternal vitamin D deficiency. In recent times the liberal use of sunscreen contributes to the problem by compromising cutaneous vitamin D synthesis. A family history of rickets may suggest an inherited form of rickets of which X-linked hypophosphataemic rickets (XLHR) is the most common. A history of consanguinity and of alopecia may be pointers to the rare vitamin D dependent rickets type II. Chronic diseases such as renal, liver and malabsorptive states predispose to the development of rickets.
↑ FGF 23
The signs and symptoms of rickets vary depending on the age of presentation. The young infant may demonstrate craniotabes due to softening of the skull bones but this is not pathognomonic. Other features in infancy are bossing of the forehead, widening of wrists (when babies start crawling) and delayed closure of fontanelles. There can be delayed eruption of teeth with enamel hypoplasia in nutritional rickets in contrast to hypophosphataemic rickets where the enamel is normal but dental pulp abscesses can occur. Rarely, vitamin D deficiency can cause cardiomyopathy in infants which may be rapidly fatal if unrecognized. Toddlers and young children usually present with bow legs (genu varum). This can be physiological up to the second year of life where intercondylar distances less than 5 cm are physiological (Figure 3). Delayed walking beyond 18 months is another recognized presentation due to the myopathy seen with vitamin D deficiency. Short stature may be a presentation of hypophosphataemic rickets. Chest deformity with a rachitic rosary due to swollen costochondral junctions and Harrison’s sulci due to inward pull of the diaphragm on the softened lower ribs may be seen. The older child may have knock knees (genu valgum) and complain of bone pain and fatigue. There may be a history of fracture in the osteopenic bones of calcipenic rickets. Hypocalcaemia due to vitamin D deficiency rickets can cause stridor, tetany and convulsions.
Bone
↓ PO efflux ↓ PO reabsorption ↓ 1,25 (OH) D
↑ (Serum PO )
Kidney
Investigations
Gut
Biochemical features Table 1 lists suggested biochemical investigations. A key investigation is the measurement of serum parathyroid hormone (PTH) as it is invariably raised in calcipenic rickets but often normal in most forms of phosphopenic rickets. Plasma alkaline phosphatase is raised in all types of rickets but more significantly elevated in calcipenic rickets whereas may only be marginally raised in phosphopenic rickets. This is a reflection of the raised serum PTH in the former causing
↓ PO absorption
Small intestine Figure 2 Schematic diagram of the role of FGF23 in phosphate homeostasis.
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Urinary phosphate excretion is evaluated through calculation of the tubular phosphate reabsorption (TRP): TRP ð%Þ ¼ 1
where Up and Pp, Ucr and Pcr represent urine and plasma phosphorus, urine and plasma creatinine respectively (all variables must be expressed in the same unit e.g. mmol/l). A TRP level less than 85% would be regarded as abnormal. A more accurate index, the tubular maximum for phosphate reabsorption (TmPO4/GFR) can be derived from nomograms using the TRP and plasma phosphate. The typical biochemical abnormalities seen in vitamin D deficiency are low or normal plasma calcium and raised serum PTH (secondary hyperparathyroidism) leading to decreased renal tubular reabsorption of phosphate and low plasma phosphate. Plasma phosphate levels need to be interpreted with care as they are generally higher in healthy young children and infants (1.3e2.1 mmol/litre) than in adults (0.7e1.3 mmol/litre); therefore any value of 1 mmol/litre or below in young children is abnormal. X-linked hypophosphataemic rickets presents typically with normal plasma calcium, low plasma phosphate with normal levels of serum PTH and 25-hydroxy vitamin D. There is a normal urine calcium creatinine ratio with no proteinuria or glycosuria. Excess phosphate excretion as demonstrated by low TRP or TmPO4/GFR can be seen in both vitamin D deficiency and hypophosphataemic rickets e in the former due to the high PTH and the latter due to a primary renal tubular leak.
Figure 3 Determination of intercondylar distance in genu varum. For accurate measurement, the medial malleoli should just touch.
increased bone turnover. Though not very sensitive, it is useful in the monitoring of therapy as adequately treated patients demonstrate a progressive reduction. However there may be difficulty with rickets due to liver disease because of the elevated alkaline phosphatase in this situation. Vitamin D deficiency is confirmed by low 25-hydroxy vitamin D with levels usually less than 10 ng/ml (25 nmol/litre) causing rickets. 1,25-dihydroxy vitamin D analysis is reserved for those rarer forms due to defects in vitamin D metabolism. The genetic basis for most forms of inherited rickets is now established and therefore can be confirmed by DNA for genetic analysis. The urinary calcium creatinine ratio helps to establish calcium excretion in the urine (ideally a fasting specimen) which is elevated in hypophosphataemic rickets with hypercalciuria (HHRH) and Dent’s disease.
Imaging studies Radiographs of the epiphyseal growth plate (physis) are very useful in the diagnosis of rickets. The physis is composed of columns of cartilage cells arranged in four parallel zones: 1. Resting zone: site of little activity sites of active cell division and 2. Proliferative zone maturation. 3. Hypertrophic zone 4. Calcifying zone or zone of provisional calcification e osteoid matrix is formed and mineralized. The first three zones are radiolucent but the zone of provisional calcification is as dense as the mature mineralized bone. Therefore abnormalities in mineralization which is characteristic of rickets would appear in this region on radiographs. Actively growing parts of the skeleton are the most helpful (varies depending on the age of the child): radiographs of wrists and knees throughout most of childhood and chest (proximal humeri and anterior rib ends) in neonates, infants and young children. The typical changes are cupping, fraying and widening of the metaphysis. Centres of ossification may appear late and look pale and irregular. The long bones may show osteopenia and pathological fractures. Healing of rickets on treatment can be seen as a dense metaphyseal band e the newly repaired zone of provisional cartilage and is usually present in 2e3 weeks following initiation of therapy. In XLH, the rachitic changes though less dramatic than in vitamin D deficiency rickets are more severe in the knees than the wrists. The modelling defects manifest as short, squat long bones with coarse trabeculation of the axial skeleton.
Recommended investigations in suspected rickets Blood Calcium, phosphate, alkaline phosphatase Creatinine Liver function tests Serum PTH Plasma 25 OH Vitamin D Save serum for 1,25(OH)2D3 level Consider DNA for genetic analysis Urine Calcium, phosphate, creatinine Calculation of TRP & TmPO4/GFR Radiology X-ray wrist and knee Table 1
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Up Pcr 100 Pp Ucr
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Vitamin D deficiency rickets
Treatment of symptomatic rickets is with ergocalciferol (D2plant derived) or cholecalciferol (D3-animal derived) in the a daily dose of 3000 units in infants less than 6 months of age, 6000 units in children 6 monthse12 years and 10,000 units for older children up to 18 years for a period of 2e3 months. This is followed by maintenance with a recommended daily intake of 400 units. If associated hypocalcaemia is present oral calcium supplements may be required for a short period. Large single oral or intramuscular doses of vitamin D (150,000e300,000 units) can be used in children with severe disease associated with malabsorption or liver disease and especially those with compliance issues. In recent times, the magnitude of the problem related to vitamin D deficiency has been recognized by the Department of Health (UK). It has through the Healthy Start scheme recommended free vitamins (includes vitamin D 400 units) to all children between 6 months and 4 years and pregnant or breastfeeding mothers until their child is a year old.
Vitamin D deficiency has re-emerged as a significant public health problem in the UK and other developed countries in recent years. Nutritional vitamin D deficiency is the commonest cause in the absence of any malabsorption or disorder of liver, kidneys or vitamin D metabolism. The exact prevalence of the condition in children in the UK is not known. A survey from the West Midlands in 2001 estimated the incidence to be about 7.5 per 100,000 with ethnic differences e 38 per 100,000 in south Asians, 95 per 100,000 in AfricaneCaribbean and 0.4 per 100,000 in the white population. Vitamin D in our body is mainly (80%) derived from the action of UVB rays in the sunlight on 7-dehydrocholesterol in the skin and the rest (20%) comes from diet. Foods rich in vitamin D are oily fish, fish oils and eggs. In the UK, only a few items like breakfast cereal, margarine and baby formula feeds are fortified. During the Second World War fortification of food produced a dramatic reduction in the prevalence of rickets. However, there was an increase in cases of idiopathic hypercalcaemia in infants in the 1950’s and although evidence of vitamin D toxicity was not established it led to a reduction in food fortification. Cutaneous synthesis of the vitamin may be limited by clothing and use of sunscreen. In winter insufficient UVB reaches the Earth’s surface and people in countries above or below 35 latitude have very little vitamin D synthesis. In UK it is suggested about 15 min of exposure of hands, arms, face or back to suberythemal levels of sunlight in fair skinned population 2e3 times/week from April to September is sufficient to produce adequate vitamin D. Vitamin D deficiency is usually defined as serum levels below 25 nmol/litre (10 ng/ml) and insufficiency when levels are between 25 and 50 nmol/litre (10e20 ng/ml). However some studies suggest that higher levels of 75e87.5 nmol/litre (30e35 ng/ml) may be optimal. Based on these studies, the National Health and Nutrition Examination Survey in United States demonstrated that changing the definition from less than 11 to less than 20 ng/ml increased the prevalence of vitamin D deficiency amongst adolescents from 2 to 14% with significant public health implications. Currently the definition of vitamin D deficiency is a matter of considerable debate with interest in potential nonskeletal outcomes. There are three stages of vitamin D deficiency rickets: Stage I: hypocalcaemia due to decreased calcium absorption from the gut and reduced resorption from bone. This stage is usually short lived except in infants when it may be prolonged resulting in symptomatic hypocalcaemia. Stage II: hypocalcaemia triggers PTH release and secondary hyperparathyroidism which normalizes serum calcium but produces hypophosphataemia. Stage III: continued deficiency results in severe bone disease with recurrence of hypocalcaemia due to insufficient mobilization from bone. Presentation of vitamin D deficiency may be asymptomatic or less commonly with overt skeletal changes. Symptomatic hypocalcaemia is more often seen in extremes of childhoodeinfancy and adolescence when rapid growth occurs. Deficiency may also present with atypical features of cardiomyopathy in infants and unexplained aches and pains with muscle weakness especially in teenage girls.
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Calcium deficiency rickets This has been reported in Bangladesh, South Africa and Nigeria with presentation usually beyond 18 months. Vitamin D levels are normal but calcium is deficient in the diet. The clinical and radiological characteristics of rickets are similar to vitamin D deficiency except that craniotabes, hypotonia and tetany e features seen in infancy are typically absent. Treatment is with increased calcium in the diet and as supplements. There is evidence to suggest that calcium deficiency may contribute to the presentation of nutritional vitamin D deficiency rickets.
25-hydroxylase deficiency This rare autosomal recessive cause of rickets is due to mutations in the CYP2R1 gene which codes for the 25-hydroxylase enzyme responsible for hydroxylation of vitamin D in the liver. Two affected children presented with rickets with low 25-hydroxy vitamin D level despite adequate intake of the vitamin in the diet and exposure to sunlight.
Vitamin D dependent rickets type I This autosomal recessive condition is due to a deficiency of the 1-alpha-hydroxylase enzyme which converts 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. As a consequence, levels of 25hydroxy vitamin D are normal but 1,25-dihydroxy vitamin D levels are low. Mutations in CYP27B1 gene are responsible. Presentation of rickets is in the toddler age. Treatment is with alfacalcidol or calcitriol in the dose range of 0.5e2.0 mg/day.
Vitamin D dependent rickets type II This presents between 1 and 3 years of age due to a mutation in the gene for the vitamin D receptor with resistance to the action of the active metabolite and therefore patients show very high levels of 1,25(OH)2D. It is an autosomal recessive condition with alopecia in 50% of cases. Treatment is more difficult, as although some patients may respond to high-dose alfacalcidiol, many require intravenous calcium infusions via a central line to heal the rickets.
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Hypophosphataemic rickets
females due to random inactivation of the affected X chromosome in the latter as explained by Lyon’s hypothesis. The genetic defect in X-linked hypophosphataemia is known to be on the PHEX gene which is the phosphate regulatory gene located on the chromosome X p22.1 locus. Inactivating mutations (deletions, insertions, duplications, splice site, nonsense and missense mutations) of PHEX, a cell surface endopeptidase, is the cause of XLH. There is an increase in the expression of FGF23 in the bone which leads to inhibition of renal tubular reabsorption of phosphate and reduced production of 1-alphahydroxylase. Presentation of X-linked hypophosphataemia can be as early as 6 months with frontal bossing and flattening of back of head. However the usual presentation is with progressive bowing of the legs in infancy particularly once the child starts walking with a typical waddling gait. Bowing is especially seen in the femur and tibia with a characteristic anterior bowing deformity. Defects in dentine cause a predisposition to dental pulp abscesses. The diagnosis of XHR can be difficult in the first few months of life even with a positive family history and such infants can usually be diagnosed from about the 6th month of life based on reduced plasma phosphate, increased alkaline phosphatase and reduced renal tubular phosphate reabsorption (TRP). Knee radiographs may be useful as an adjunct in the diagnosis (Figure 4). Treatment for XLH is with a phosphate preparation along with a vitamin D analogue such as calcitriol or alfacalcidol. The dose of oral phosphate is 70e100 mg/kg/day divided in aliquots every 4e6 h due to rapid excretion by the kidneys. Alfacalcidol is given as 25e50 ng/kg once a day. Calcitriol is an alternative in a dose of 10e50 ng/kg/day; it is available only as a capsule, making it less suitable for infants and young children. Therapy is generally well tolerated and can result in improvements in height and reduction in severity and frequency of skeletal deformity especially when commenced early in infancy. However, it may produce significant side effects which
This group of genetic disorders is characterized by abnormalities in the sodiumephosphate co-transporter in the epithelial cell brush border of the renal proximal tubules which lead to increased urinary excretion of phosphate. Although there is a low plasma phosphate, levels of plasma calcium, serum 25-hydroxy vitamin D and PTH are usually normal in the untreated state. Serum 1,25-dihydroxy vitamin D levels are often in the normal range but inappropriately low in the face of a low plasma phosphate. Phosphopenia results in defective mineralization of the growth plates. The main types are X-linked dominant hypophosphataemia (XLH), autosomal dominant and recessive hypophosphataemia, X-linked recessive hypophosphataemia and hypophosphataemic rickets with hypercalciuria (HHRH). It has been demonstrated in animal models that hypophosphataemia is pivotal in the pathogenesis of all forms of rickets. Development of the endochondral skeleton (tubular, flat and cuboidal bones) involves mesenchymal condensation to start with, followed by cell differentiation into chondrocytes. Subsequently, the growing or proliferating chondrocytes in the epiphyseal cartilaginous growth plate develop into hypertrophic chondrocytes which are programmed to undergo apoptosis (cell death) and are then replaced by bone. This apoptosis is mediated via the activation of the caspase-9 mitochondrial pathway. Studies in the Hyp mouse model of X-linked hypophosphataemic rickets have shown that there is an expansion of this hypertrophic chondrocyte layer as a consequence of decreased apoptosis in the presence of reduced plasma phosphate levels. This hypertrophic growth plate is a consistent characteristic of rickets and in calcipenic rickets can be mediated by hypophosphataemia secondary to hyperparathyroidism. X-linked hypophosphataemic rickets (XLH) This condition is X-linked dominant and the prevalence worldwide is 1 in 20,000. Males are more severely affected than
Figure 4 X-rays of the knee in a child with vitamin D deficiency rickets (left) and hypophosphataemic rickets (right). Note the marked osteopenia in the former in contrast to the dense sclerotic bone in the latter.
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individuals also demonstrate elevated serum 1,25-dihydroxy vitamin D levels with proteinuria and hypercalciuria leading to nephrolithiasis, nephrocalcinosis and progressive renal failure in early adulthood. In females there is only hypercalciuria without evidence of any other biochemical abnormality. The genetic defect has been localized to the voltage-gated chloride channel gene CLCN5. Variable phenotypic expression of this single gene defect leads to different syndromes possibly due to the secondary influence of diverse genetic background and environmental factors like diet. Treatment of the rickets is with phosphate supplements only.
include hypercalcaemia due to tertiary hyperparathyroidism, hypercalciuria and nephrocalcinosis with the potential for deterioration in renal function. The appearance of these problems may necessitate withdrawal of treatment in some cases. Bolus doses of oral phosphate are responsible for lowering ionized calcium which stimulates PTH secretion and results in hyperparathyroidism. Failure to detect this effect and correction by adjustment of alfacalcidol dose can lead to the development of tertiary hyperparathyroidism which may require parathyroid surgery. Nephrocalcinosis is probably due to an effect of phosphaturia and vitamin D mediated enhanced absorption of calcium and phosphate from the gut. These complications have also been attributed to a rise in FGF23 levels with phosphate and vitamin D therapy which can limit effectiveness of treatment. Larger studies are required to establish if adjusting treatment with FGF23 monitoring to prevent its elevation may be beneficial in minimizing side effects. Cinacalcet, a calcimimetic drug licensed for use in hyperparathyroidism in adults has been shown to be promising as an adjunct in the treatment of hypophosphataemic rickets by suppressing PTH secretion and improving phosphate reabsorption in the renal tubules. Its effect on FGF23 is not yet clear but its use could lower the doses of phosphate and vitamin D and facilitate in reducing the complications. Another potential future treatment development would be the use of an antibody to FGF23 which has shown encouraging results in an animal model. In many affected children treatment improves growth but this may not be optimal. Growth hormone has been used in a number of studies although a recent Cochrane review found ‘no conclusive evidence to indicate that the use of recombinant human growth hormone therapy in children with X-linked hypophosphataemia is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, and body proportions’.
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) This condition presents between 6 months and 7 years of age with short stature, muscle weakness and rickets associated with bone pain with or without deformities of the lower extremities. The severity of the bone mineralization defect correlates inversely with the prevailing plasma phosphate concentration. In contrast to most other diseases wherein renal phosphate transport is affected, patients with HHRH exhibit increased 1,25dihydroxy vitamin D production which causes hypercalciuria by promoting calcium absorption in the gut, enhancing the renal load of calcium and inhibiting PTH secretion. Relatives of patients with evident HHRH may have less marked hypercalciuria and hypophosphataemia without the typical skeletal abnormalities suggesting a milder phenotype in the heterozygous state. The genetic basis of HHRH has been identified as due to mutations in the sodiumephosphate cotransporter gene SLC34A3. Treatment of HHRH is with high-dose phosphate supplements (1e2.5 g/day in five divided doses) only which results in improvement in rickets, bone pain, muscular strength and accelerated height velocity. Secondary forms of hypophosphataemic rickets are seen in several conditions but only oncogenic osteomalacia is discussed below.
Autosomal dominant hypophosphataemia (ADHR) In autosomal dominant hypophosphataemia, there may be incomplete penetrance with variable expression and age of onset. Males and females are equally affected. Lower limb deformities, fractures and tooth abscesses are common. Some affected women may show symptoms only in the second to fourth decade of life. ADHR is caused by inactivating mutations in the gene for FGF23 which protects it from proteolysis, leading to elevated circulating levels of FGF23 and secondary phosphate wasting in these patients.
Oncogenic osteomalacia or tumour-induced osteomalacia (TIO) Tumour induced osteomalacia is a rare paraneoplasic syndrome which presents with rickets or osteomalacia. It is more frequent in adults though may also be seen in children. Symptoms and signs which include bone pain and fractures are usually more severe than in XLH and muscle weakness is frequent. The mesenchymal tumours associated with TIO most commonly arise from the paranasal sinuses, neck and mandible. They are usually very small, benign and difficult to diagnose by routine physical examination or radiographs. Sophisticated imaging is often required for localizing these tumours. Secretion of FGF23 from these tumours has been implicated in the pathogenesis of TIO. Excision of the tumour helps to correct the biochemical abnormalities and symptoms.
Autosomal recessive hypophosphataemia (ARHR) Patients with ARHR have been found to have the same clinical and biochemical features to XLH and ADHR but inheritance is in an autosomal recessive manner. Two genetic defects have been identified due to abnormalities in the DMP1 or ENPP1 gene. The latter defect is also associated with generalized arterial calcification in infancy. There have been reports of elevated levels of FGF23 in affected individuals.
Differential diagnosis
X-linked recessive hypophosphataemia (Dent disease complex) In X-linked recessive hypophosphataemia, boys present in a similar manner to the X-linked dominant form. However these
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Metaphyseal chondrodysplasia (Pyle’s) which is a rare disorder manifests with flaring and irregularity of various metaphyses. The radiographic changes are similar to rickets, but calcium and
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Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA 5, 2005; 102: 9637e42. Makitie O, Doria A, Kooh SW, et al. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemicrickets. J Clin Endocrinol Metab 2003; 88: 3591e7. Wharton B, Bishop N. Rickets. Lancet 2003; 362: 1389e400. Shaw NJ. Vitamin D deficiency rickets. Endocr Dev 2003; 6: 93e104; Hochberg Z, ed. Vitamin D and rickets. Basel: Karger, 2003.
phosphorus metabolism is normal. Schmid, Schwachman and Jansen skeletal dysplasias may also be confused with rickets.
Summary Rickets is a disease of growing bones. Vitamin D deficiency is by far the commonest cause. Other forms of familial and vitamin D resistant or dependent rickets are less common and in these cases history and examination in combination with biochemical and genetic investigation are very important in teasing out the diagnosis. A
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FURTHER READING Hochberg Z. Rickets past and present. Introduction. Endocr Dev 2003; 6: 1e13. Hochberg Z, ed. Vitamin D and rickets. Basel: Karger, 2003. €ppner H. Disorders of phosphate homeostasis and tissue Bergwitz C, Ju mineralisation. Endocr Dev 2009; 16: 133e56. Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel: Karger, 2009. Allgrove J. A practical approach to rickets. Endocr Dev 2009; 16: 115e32; Allgrove J, Shaw NJ, eds. Calcium and bone disorders in children and adolescents. Basel: Karger, 2009. Maiya S, Sullivan I, Allgrove J, et al. Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart 2008; 94: 581e4. Callaghan AL, Moy RJD, Booth IW, Debelle G, Shaw NJ. Incidence of symptomatic vitamin D deficiency. Arch Dis Child 2006; 91: 606e7. Saintonge S, Bang H, Gerber LM. Implications of a new definition of vitamin D deficiency in a multiracial us adolescent population: the National Health and Nutrition Examination survey III. Pediatrics Mar 2009; 123: 797e803. Ladhani S, Srinivasan L, Buchanan C, Allgrove J. Presentation of vitamin D deficiency. Arch Dis Child Aug 2004; 89: 781e4. Koren R. Vitamin D receptor defects: the story of hereditary resistance to vitamin D. Pediatr Endocrinol Rev 2006; 3(suppl 3): 470e5.
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Rickets is due to defective mineralization of the growth plates in children. Hypophosphataemia is the underlying basis for all types of rickets. There is evidence of a boneekidney hormonal axis regulating phosphate metabolism. Vitamin D deficiency is regarded as levels of 25-hydroxyvitamin D below 25 nmol/litre (10 ng/ml) and insufficiency as levels between 25 and 50 nmol/litre (10e20 ng/ml). The clinical picture of vitamin D deficiency rickets depends on the age of presentation. Unusual presentations are severe progressive cardiomyopathy in infants and bone pain or muscle weakness in adolescents. Treatment of vitamin D deficiency is with oral ergocalciferol or cholecalciferol and not alfacalcidol. Vitamin D supplementation is important in children in high risk groups until the age of 4 years to prevent rickets. Hypophosphataemic rickets is treated with alfacalcidol or calcitriol and phosphate supplements. Early diagnosis and treatment in infancy are associated with better results with regards to growth and skeletal deformity. Apart from vitamin D deficiency all other causes of rickets have a genetic basis, the identification of which can aid accurate diagnosis and management.
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