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Rickets and osteomalacia

What’s new ?
• Identification of phosphatonins – circulating factors
that cause phosphaturia and hypophosphataemic
rickets and osteomalacia

Michael P Whyte
Rajesh V Thakker

• Discovery of the gene defects that cause heritable
forms of rickets and osteomalacia

• Vitamin D2 and vitamin D3 are prohormones transported by
a high-affinity binding protein in the blood to muscle or fat for
storage, or to the liver and then the kidney for bioactivation.
• Vitamin D is hydroxylated in hepatocyte mitochondria by the
enzyme P450c25, forming the 25-hydroxyvitamin D metabolite,
which is also called calcidiol.
• Regulated by circulating ionized calcium, inorganic phosphate
and parathyroid hormone (PTH) levels, 25-hydroxyvitamin D is further hydroxylated in renal proximal convoluted tubule cells by the
enzyme 25-hydroxyvitamin D, 1α-hydroxylase (1α-hydroxylase).
The product is the potent 1,25-dihydroxyvitamin D metabolite,
which is also called calcitriol.
• Calcitriol circulates to target organs, where it binds to the
vitamin D receptor.
• The vitamin D receptor activates transcription of genes in
bone, kidney, and enterocytes to ensure adequate extracellular
concentrations of minerals by increasing gut absorption of calcium,
suppressing PTH synthesis, increasing urinary calcium reclamation
by the kidneys, and facilitating bone resorption.

Rickets is the clinical consequence of impaired mineralization of
matrix throughout a growing skeleton. Infants, children and adolescents can be affected. Osteomalacia results from this disturbance
after growth plates fuse (i.e. adulthood).
There are three principal causes (Figure 1) of rickets and
• The most common explanation is deficiency of vitamin D, which
may result from lack of exposure to sunlight leading to inadequate
cutaneous biosynthesis, poor dietary intake, or malabsorption as
a result of hepatobiliary or gastrointestinal disease. This often
leads to hypocalcaemia, secondary hyperparathyroidism and
• Occasionally, renal tubule dysfunction results in urinary phosphate wasting, leading to hypophosphataemia, often associated
with impaired bioactivation of vitamin D.
• Rarely, disturbances of chondrocytes and osteoblasts, defective
bone matrix or other disruptions block calcium and phosphate
entry into the skeleton.
In rickets, there are defects in growth, shaping (modelling)
and turnover of bone in accordance with metabolic, structural,
and repair requirements (remodelling), and patients exhibit short
stature (physeal disturbances). Osteomalacia is usually not deforming (unless fractures occur), because growth plates are fused and
modelling has essentially ceased; only remodelling is deranged.
Accordingly, impaired mineralization of skeletal matrix in osteomalacia is less apparent clinically and radiographically.

Clinical features
The major features of rickets and osteomalacia are:
• bone pain and tenderness
• skeletal deformity
• muscle weakness
• occasionally, signs of tetany from associated hypocalcaemia.
An underlying cause (Figure 1) is often suggested by the history
(e.g. bowel disturbance, positive family history). The features of
specific types of rickets and osteomalacia are discussed below.
Rickets manifests during growth, and the signs are most prominent in areas where bone growth is most rapid. Thus, the signs of
rickets vary with age.
• At birth, the skull is growing most rapidly. Neonatal rickets
may therefore present as craniotabes, in which the cranial vault
has the consistency of a ping-pong ball.
• In the first year of life, rickets swells epiphyses at the wrists
and causes ‘beading’ of the costochondral junctions (‘rachitic
rosary’). The pull of the diaphragm produces a groove in the rib
cage (Harrison’s sulcus).
• In toddlers, rickets causes bow-leg deformities; knock-knees
are characteristic in later childhood. Both occasionally occur as
‘windswept’ legs.
Rickets myopathy is part of the differential diagnosis of the
‘floppy baby’. If muscle weakness is sufficiently severe to prevent
walking, it may limit deformity of the lower limbs. Short stature
is common. Pathological fractures in the shafts of the long bones
can occur in severe forms of rickets.

Vitamin D
Most of the vitamin D in healthy, active individuals is derived via
a cutaneous synthesis pathway. In the skin, 7-dehydrocholesterol
is converted to cholecalciferol (vitamin D3) by 290–310 nm ultraviolet light. Ergocalciferol (vitamin D2) is the product of ultraviolet
irradiation of ergosterol extracted from animal or plant tissues,
and is used as a supplement or as a pharmaceutical. Vitamin D
should be regarded as a steroid hormone, not a nutrient, because
it undergoes two bioactivation steps, circulates, and then binds
to a receptor, as follows.

Michael P Whyte is Director of the Center for Metabolic Bone Disease and
Molecular Research at Shriners Hospitals for Children, and Professor of
Medicine, Pediatrics and Genetics at Washington University School of
Medicine, St Louis, USA. Conflicts of interest: none declared.
Rajesh V Thakker is May Professor of Medicine and Head of the Academic
Endocrine Unit at the University of Oxford, UK. Conflicts of interest: none



© 2005 The Medicine Publishing Company Ltd

but does not provide a diagnosis. even when it is undoubtedly present. coeliac disease) • Hepatobiliary disease • Pancreatic insufficiency Chronic renal failure Metabolic acidosis Drugs and toxins • Anticonvulsants • Phosphate-binding antacids (e. the vertebrae become compressed. The vertebrae may develop a ‘rugger-jersey’ appearance. The nature of osteomalacia pain and muscle weakness is often vague and can lead to misdiagnosis. and measurement of serum 25-hydroxyvitamin D is a useful alternative. aluminium hydroxide) • Bisphosphonates • Fluoride Miscellaneous forms • Phosphate depletion (intestinal phosphate binders) • Calcium depletion • Magnesium depletion • Primary hyperparathyroidism Oncogenic Hereditary forms • Hypophosphataemia (X-linked and autosomal dominant) • Vitamin D-dependent rickets type 1 and type 2 • Proximal renal tubular disorders (Fanconi’s syndrome) • Distal renal tubular disorders (renal rickets with nephrocalcinosis and dwarfism) • Hypophosphatasia 1 Osteomalacia in adults may cause vague symptoms. housebound and other institutionalized groups • Food faddists Secondary vitamin D deficiency • Partial gastrectomy • Small bowel malabsorption syndromes (e.g. and the medial cortex of the proximal femora. Localized pain (e. the metaphyses are splayed. However.BONE DISORDERS Causes of rickets and osteomalacia Investigations Biochemical investigations – hypocalcaemia is usually more severe in vitamin D-deficiency rickets than in osteomalacia. Gait should be assessed. spine. Quantification of circulating vitamin D levels directly assesses vitamin D status. ribs and pelvis). the scapulae. MEDICINE 33:12 Principles of management The aims of treatment are: • reversal of short stature and deformity in rickets • relief of bone pain and fracture prevention in osteomalacia.g. Intervertebral discs may compress softened end-plates. Secondary hyperparathyroidism causes mild hyperchloraemic metabolic acidosis. Bone scanning is usually unnecessary in children with rickets. and patients become immobilized and chair-bound. but assays for these prohormones are not readily available. it is commonly described as ‘waddling’. bone scanning helps to detect focal complications of osteomalacia such as fractures and pseudofractures. which can be seen on radiography. rickets or osteomalacia can produce a ‘superscan’. nondecalcified stained sections reveal abundant osteoid covering bone surfaces. Histopathology – biopsy showing defective mineralization of skeletal tissue is the definitive investigation. which features hypophosphatasaemia. The final dose is taken several days before the transiliac biopsy. Radiology – in rickets. but is more useful in osteomalacia because radiographic studies are less helpful. anteroposterior radiography of the knees and posteroanterior radiography of the wrists show widening of growth plates. and most often affect the pubic and ischial rami. causing biconcave (‘cod-fish’) vertebrae. but fluorescence microscopy fails to show two discrete tetracycline ‘labels’ produced by ongoing mineralization. Instead. and the epiphyses appear as though held within a cup. and sometimes paradoxically results in hyperphosphataemia by directly affecting renal tubules. but need not be measured routinely. However. A specimen of iliac crest obtained using a 5 mm internal diameter trephine is ideal. hence. Two 3-day courses of oxytetracycline or demeclocycline hydrochloride. Ideally. ragged and concave. A simple test for myopathy is failure to rise from a sitting position unaided with the arms folded in front. in the groin) may result from an undisplaced femoral neck fracture or an underlying Looser’s zone (pseudofracture). In osteomalacia. the most painful bones are generally those with the thinnest cortices. In rickets and osteomalacia. absent or indistinct fluorescence is seen. it may be difficult clinically to detect myopathy if there is pain. Tenderness may be elicited by spinal percussion or by sternal and lateral rib compression.g. Radiographic signs of secondary hyperparathyroidism are seen best as subperiosteal erosions involving the radial border of the middle phalanx of the index finger. electromyographic abnormalities are nonspecific and can be absent. 20 mg/kg/day in divided doses. Enhanced radioisotope uptake occurs when osteoidosis is present. It is not required routinely in rickets. Levels of other markers of skeletal turnover can be disturbed. Both cortical and trabecular bone are sampled. Primary (nutritional) vitamin D deficiency • Classic vitamin D deficiency (e. the exception is hypophosphatasia. the ribs. In severe osteomalacia. Bone scintigraphy is useful. are given (separated by a 2-week interval) for in vivo tetracycline labelling of bone tissue. Bone pain usually occurs in the axial skeleton (shoulders. and erosion of the distal ends of the clavicles and symphysis pubis. Serum alkaline phosphatase (ALP) activity is elevated in almost all patients with rickets or osteomalacia. significant metabolic acidosis suggests Fanconi’s syndrome. Osteomalacia myopathy has a characteristic proximal distribution. This may 71 © 2005 The Medicine Publishing Company Ltd . reflecting increased renal excretion of bicarbonate. pseudofractures can occur anywhere (except in the skull). Hypocalcaemia may be suggested by a positive Chvostek’s and/or Trousseau’s sign. In adults. the primary pathological process is corrected.g. Typically. in Asian children) – infants and puberty (‘late’ rickets) • Immigrant adults in developed countries • Elderly.

Calcium excretion in 24-hour urine collections (corrected for creatinine content) guides therapy and helps monitor for impending toxicity. 1 2 MEDICINE 33:12 72 © 2005 The Medicine Publishing Company Ltd . tablets are more convenient than liquid preparations. in oil2 Time to maximum 4–10 weeks effect Persistence of effect 6–30 weeks after cessation Calcifediol 25-hydroxyvitamin D3 • Capsules. serum 25-hydroxyvitamin D and 1. Unless there is renal failure or fixed elevation of circulating PTH levels (reclaiming calcium from the glomerular filtrate). 2 µg/ml in propylene glycol 0. Because hypocalciuria characterizes most forms of rickets and osteomalacia. Unless there is significant hypoproteinaemia. including ageing. Achievement of straight lower limbs when growth ceases. Low dietary calcium intake is an important exacerbating factor. rising urinary calcium levels suggest effective therapy. ALP activity.25 mg • Injection. they do not replenish deficient vitamin D stores. Calcium gluconate is expensive.) Various factors reduce cutaneous vitamin D biosynthesis. physeal stapling (epiphysiodesis) or osteotomy may be helpful. taste better. but Pharmaceutical preparations of vitamin D and active metabolites Drug Dihydrotachysterol Calciferol1 Vitamin D3 or D2 DHT • Capsules. Careful monitoring is required. Institutionalized/housebound individuals. Low serum 25-hydroxyvitamin D concentration confirms the diagnosis of vitamin D deficiency. Active metabolites of vitamin D can circumvent defective vitamin D bioactivation.5 µg • Injection. though toxicity can easily be corrected.5 mg/ml i. Dose reductions may be necessary once healing is complete (maintenance therapy).5–1 week 0. 20 and 50 µg Calcitriol 1. 2Prolonged effect. and have a more rapid onset of action. these agents are expensive and have shorter biological half-lives. 0.m. often with mineral supplementation. 24-hour urine collections (not random specimens) assayed for calcium and creatinine are particularly important for followup. with the physes aligned parallel to the ground.50 and 1 µg • Liquid.BONE DISORDERS not be possible. Preparations containing high levels of sodium should be avoided.5–1 week Calciferol may contain cholecalciferol or ergocalciferol. For phosphate supplementation.25. 0.25(OH)2D3 • Capsules. because the skeleton no longer acts as a sump for mineral deposition. Thus. Mineral supplementation – many calcium and phosphate preparations are available. 0. levels less than about 8 ng/ml (normal 10–50 ng/ml) are diagnostic. are more potent than vitamin D itself. and seem less likely to cause diarrhoea. The most useful biochemical parameters are serum calcium and phosphate. the poor.5 µg (100 IU) in adults. Infants who are breast-fed beyond 6 months of age or who drink non-fortified milk or formula are also susceptible if they are insufficiently exposed to sunlight. Leg-bracing. is needed. and vitamin D (or an active metabolite). Intramedullary rodding may be necessary to heal pseudofractures or prevent fractures in some patients with osteomalacia. Furthermore. and PTH levels. residence at latitudes at which only low-intensity UV exposure is possible.25 mg • Liquid. Patient/parent education and correction of adverse socioeconomic factors could help to prevent and treat vitamin D deficiency.25 mg/ml and 1. may forestall osteoarthritis. Surgery – consultation and follow-up with an orthopaedic surgeon is often an important aspect of the management of rickets. hypercalciuria generally precedes hypercalcaemia. economic and/or cultural factors that prevent sufficient exposure to sunlight (Figure 1). Oral calcium carbonate is least expensive. pigmentation. However. food faddists and some religious groups (because of diet and dress) are at risk. They differ in potency and biological half-life. Types of rickets and osteomalacia Primary (nutritional) vitamin D deficiency – the minimum daily requirement for vitamin D is 10 µg (400 IU) in children and 2. and use of sunscreens that block the access of UV light to the skin. the elderly.5–1 week 2–8 weeks 4–12 weeks 0.25dihydroxyvitamin D concentrations may also be helpful. 1 µg/ml 2–4 weeks 4–20 weeks 0. Satiation of ‘hungry bones’ can abruptly increase urinary calcium excretion. extent of clothing. Vitamin D preparations (Figure 2) – five sterols with vitamin D activity are currently available. (About 20 minutes on the face and arms is required on several occasions each week. 7. 2 µg/ml • Injection.5–1 week Alfacalcidiol 1α(OH)D3 • Capsules. 0. Depending on the aetiology and pathogenesis of the rickets or osteomalacia. 0. and correction of previously abnormal biochemical findings heralds hypercalciuria. but calcium citrate is better absorbed. and cessation of therapy leads rapidly to return of the disturbance of mineral homeostasis.25 and 0. Lower doses of vitamin D and mineral supplements may then be needed. Primary (‘nutritional’) rickets or osteomalacia occurs as a result of social. Maintenance of normal urinary calcium levels typically indicates adequate treatment.

and vitamin D therapy and follow-up must be individualized. Alkali therapy should be continued after the mineralization defect is corrected. the associated osteopathy is often osteoporosis. • Etidronate is a first-generation bisphosphonate used in Paget’s bone disease (see page 66) and hypercalcaemia of malignancy. Oncogenic osteomalacia (or rickets) is a rare disorder typically caused by a benign mesenchymal tumour in soft tissues. calciferol preparations). but sufficient for skeletal remineralization. Phenobarbital can alter hepatic vitamin D metabolism. activating mutations in the gene encoding FGF23 are associated with autosomal dominant hypophosphataemia (see below). drug therapy is inexpensive. The prevalence is about 1/20. Notably. can be used in adults. effective and works rapidly (Figure 2). Rarely. 1α-hydroxyvitamin D3. Metabolic acidosis can cause rickets or osteomalacia. Secondary vitamin D deficiency – vitamin D deficiency can be due to malabsorption despite normal exposure to sunlight. leading to urinary phosphate wasting and hypophosphataemic skeletal disease. Urinary calcium levels must be monitored frequently. ethnic and other groups that do not consume dairy products are at risk.e. this disorder is now rare.25-dihydroxyvitamin D is increased. Bone mineralization responds gradually to calcium supplementation and cessation of fluoride poisoning. skeletal disease usually reflects secondary or tertiary hyperparathyroidism leading to rapid bone remodelling (osteitis fibrosa cystica).. • Ifosfamide can cause transient or permanent renal tubule damage. Thus. The mechanism is often complex. Many such individuals also have primary vitamin D deficiency. 50. XLH causes short stature and bowing of the lower limbs in toddlers as they begin to bear weight. predisposing patients to vitamin D depletion. 25-hydroxyvitamin D3. All races are affected. It may be several months before serum ALP activity returns to normal. with careful follow-up until healing occurs. Heritable rickets and osteomalacia – several heritable disorders can cause rickets or osteomalacia (Figure 3). Poor dietary calcium intake can also exacerbate vitamin D-deficiency rickets. Conversely. Affected children can seem clumsy but otherwise well. In secondary hyperparathyroidism. Urinary phosphate assays reveal low levels. should be effective and are relatively inexpensive. Excessive or prolonged therapy can cause rickets or osteomalacia.000 live births. Renal failure – in uraemia. and excessive use of aluminiumcontaining antacids is to be avoided and substituted with calcium carbonate or other phosphate binders. In addition. sufficient doses of oral vitamin D. Phosphate supplementation or vitamin D therapy is unnecessary. Low calcium – profound deficiency of dietary calcium despite intact stores of vitamin D can also impair skeletal mineralization. Additionally. despite raised serum phosphate levels. Patients are profoundly weak and hypophosphataemic with low (or undetectable) plasma 1. Some feature renal phosphate wasting.25-dihydroxyvitamin D3 and dihydrotachysterol are more potent and act more rapidly.000 IU thrice weekly p. A few are inborn errors of metabolism caused by enzyme deficiencies. Serum 25-hydroxyvitamin D assays document vitamin D deficiency and are essential for monitoring progress. pancreatic or hepatobiliary disease may be responsible. because metabolic acidosis per se causes hypercalciuria. some patients with hypocalcaemia alone from hypoparathyroidism or pseudohypoparathyroidism develop rickets or osteomalacia. Drugs and toxins • Rickets and osteomalacia have been reported in institutionalized individuals receiving anticonvulsants. In fact. Several causes have been documented. Vitamin D. there is enterohepatic circulation of vitamin D and its derivatives. Inadequate calcium intake has caused so-called calciopenic rickets in premature infants and in children fed a cereal-based diet. These disturbances are complex. hypophosphataemia from secondary hyperparathyroidism or primary renal phosphate wasting can cause defective matrix mineralization. Members of religious. Furthermore. but the skeletal disease responds well to vitamin D and alkali therapy. Despite malabsorption. Vitamin D is a fatsoluble secosterol and bile salts are necessary for its absorption. The skull is often 73 © 2005 The Medicine Publishing Company Ltd . However. Extirpation of the tumour cures the condition.g. Some tumours have been shown to produce fibroblast growth factor 23 and other putative ‘phosphatonins’. primary biliary cirrhosis). Hypophosphataemia impairs skeletal mineralization.25-dihydroxyvitamin D concentrations. some reflect disturbances in the bioactivation or action of vitamin D. Correcting the diet or using calcium supplements should readily reverse this disorder. Vitamin D treatment repletes the stores and is readily converted to 25-hydroxyvitamin D by hepatocytes even with parenchymal liver disease. but all fail to correct depleted stores of vitamin D. treatment for osteoporosis) can cause osteomalacia. and elimination of antacid exposure rapidly corrects this. Significant hypophosphataemia can occur. and malabsorption of calcium exacerbates vitamin D deficiency. industrial exposure. in the form of calciferol. 1. steatorrhea and malabsorption can lead to vitamin D depletion. The pathogenesis is poorly understood. Rickets has occurred when these preparations were added to infant formula to treat colic. Excessive fluoride intake (well water. However. hepatobiliary/pancreatic disease or short bowel syndrome causing deficiency of bile salts. Gastrointestinal. Vitamin D deficiency can result from subclinical malabsorption (e. and 25-hydroxyvitamin D stores may be diminished by this mechanism. Dietary phosphate intake is quite variable. Calcium and potassium supplementation may be necessary at initiation of alkali therapy to prevent hypocalcaemia and hypokalaemia. • Uraemic patients who are exposed excessively to aluminiumcontaining antacids or to contaminated dialysis fluid or parenteral feeds have developed osteomalacia. some patients exhibit defective mineralization of the skeletal matrix. these patients may hyperabsorb dietary calcium and become hypercalciuric because hypophosphataemia stimulates MEDICINE 33:12 renal 1α-hydroxylase activity. • X-linked hypophosphataemia (XLH) is the most common heritable form of rickets (‘vitamin D-resistant rickets’) and osteomalacia. kidney stones develop.BONE DISORDERS are often difficult to achieve. conversion of 25-hydroxyvitamin D to 1. With increasing use of calcium carbonate for phosphate-binding and corrected dialysate and parenteral nutrition.o. • Osteomalacia can result from excessive use of phosphatebinding antacids (magnesium and aluminum hydroxides). the small bowel mediates dietary calcium uptake. Vitamin D deficiency should be treated using vitamin D (i.g. Aluminium is also toxic to osteoblasts and directly inhibits skeletal mineralization. coeliac disease). In some conditions in which osteomalacia might be anticipated (e.

Serum calcium levels are low-normal. Bioactivated forms of vitamin D (e. San Diego: Academic Press. Glorieux F H. eds. features mild rickets that appears during adolescence. autosomal recessive disorders that mimic vitamin D-deficiency rickets by reduced biosynthesis of. Pike J W. are used in treatment. In: Feldman D. Glorieux F H. 74 © 2005 The Medicine Publishing Company Ltd . • McCune–Albright syndrome. In: Royce P M. Whyte M P. 2002: 765–87. Connective tissue and its heritable disorders: medical. Steinmann B. New York: Wiley-Liss. eds. Treatment with 1. Beaudet A L. encoding an inositol polyphosphate phosphatase. Glorieux F H. phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Sly W S et al. an especially rare form of renal phosphate wasting. FGF23. In: Wass J A H. voltage-gated chloride channel 5 gene. 2002: 697–715. It is caused by gain-of-function mutation of FGF23. In: Scriver C R. respectively. Kumar R. TNSALP. 2005: 1029–48. • Vitamin D-dependent rickets types I and II are rare.  dolichocephalic. bicarbonate and uric acid. Heritable rickets and osteomalacia. Pike J W. Whyte M P. Vitamin D pseudodeficiency. mutations of which cause Dent’s disease. New York: McGraw-Hill. 65: 1–14. ranging from premature loss of MEDICINE 33:12 FURTHER READING Glorieux F H. San Diego: Academic Press. St-Arnaud R. Vitamin D. calcitriol). which encodes a putative endopeptidase (Figure 3). 2nd ed. Kidney Int 2004. CLCN5.22 CLCN5 12p13 FGF23 Xq25–q26 OCRL 12q14 12q12–q14 1p34–1p36.25dihydroxyvitamin D. causing low serum phosphate.g. Rickets and osteomalacia (acquired and heritable forms). 1. 2001: 5313–29. tyrosinaemia and Lowe’s syndrome. 2005: 1097–205. eds. due to activating mutation of the α subunit of the G-protein. XLH is caused by inactivating mutations of the PHEX gene. Contrary to almost all other forms of rickets. together with oral phosphate supplements.. Shalet S M. Schiavi S C. because hypercalciuria can occur. Treatment with 1. Fractures are uncommon. but usually not distinctly reduced. 1991. potassium. but efficacy may be difficult to assess because of premature closure of growth plates and the underlying fibrodysplastic disease. and 100–160 different mutations have been discovered in the gene that encodes ALP expressed in bone. The severity is remarkably variable. New York: Raven Press. Approach to the patient with metabolic bone disease. VDR. the renal 1α-hydroxylase gene. Oxford textbook of endocrinology and diabetes.25-dihydroxyvitamin D3 receptor gene. but the chest and upper extremities are not deformed. Hypophosphatasia. Rickets. Vitamin D. Skeletal disease occasionally presents with knock-knees. Bone biopsy interpretation may be difficult because of widespread fibrous dysplasia. In: Feldman D. 2nd ed. Parfitt A M. eds. oculocerebrorenal syndrome of Lowe.BONE DISORDERS Genes in hereditary rickets Disease • X-linked dominant hypophosphataemia • X-linked recessive hypophosphataemia • Autosomal dominant hypophosphataemia • Lowe’s syndrome (Fanconi’s syndrome) • Vitamin D-dependent type 1 • Vitamin D-dependent type 2 • Hypophosphatasia Chromosomal location Xp22. Glorieux F H. 8th ed. Whyte M P. 1. In: Feldmann D. genetic. OCRL. Vitamin D. 1αOHase. heritable form of rickets featuring deficient activity of the tissue-nonspecific isoenzyme of ALP. 2005: 913–29. Whyte M P. Pike J W. but urinary calcium levels must be monitored carefully. Vitamin D and the pathogenesis of rickets and osteomalacia.1 Gene PHEX Xp11. San Diego: Academic Press. Causes include cystinosis. 2nd ed. 2nd ed. • Autosomal dominant hypophosphataemia. eds. and target tissue resistance to. muscle weakness does not occur. fibroblast growth factor 23.25-dihydroxyvitamin D3 and phosphate supplementation is helpful.25-dihydroxyvitamin D3 and phosphate controls the rickets.1 1αOHase VDR TNSALP PHEX. eds. can cause hypophosphataemic rickets. The metabolic and molecular bases of inherited disease. • Fanconi’s syndrome features renal phosphate wasting and other manifestations of proximal renal tubule dysfunction. tissue nonspecific alkaline phosphatase 3 teeth to intrauterine death from profound skeletal hypomineralization. and aminoaciduria. • Hypophosphatasia is a rare. and molecular aspects. The phosphatonin pathway: new insights in phosphate homeostasis. Oxford: Oxford University Press.