696 Familial Hypophosphatemia (Vitamin D-Resistant Rickets, X-Linked Hypophosphatemia)
The most commonly encountered non-nutritional form of rickets is familial hypophosphatemia. The usual mode of inheritance is X-linked dominant; some mothers of affected children exhibit clinical evidence of disease, such as bowing or short stature, whereas others show only fasting hypophosphatemia. Autosomal dominant and sporadic forms have also been reported.
Pathogenesis.
Pathogenic mechanisms involve defects in the proximal tubular reabsorption of phosphate and in the conversion of 25(OH)D to 1,25(OH)2D. The latter defect is evidenced by low-normal serum 1,25(OH)2D levels despite hypophosphatemia and by the finding that further phosphate depletion of subjects with familial hypophosphatemia does not stimulate 1,25(OH)2D synthesis as it does in normal subjects. Both a renal tubular reabsorption defect and reduced 1,25(OH)2D synthesis are found in an animal model of this disease. In addition, oral phosphate supplementation alone cannot completely heal bone disease; the correction of osteomalacia requires 1,25(OH)2D therapy. The activity of the Na+-dependent phosphate transporter in the renal proximal tubule is reduced, resulting in excessive urinary phosphate excretion; however, this transporter protein is encoded on chromosome 5. Because the X-linked dominant disorder has an X-linked inheritance pattern, the abnormal gene found at Xp 22.1 is termed PHEX or phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In the autosomal dominant form of hypophosphatemic rickets, mutations in the fibroblast growth factor, F6F23, are found. F6F23 appears to be a natural substrate for PHEX; and if F6F23 is not cleaved, it will diminish renal tubular phosphate transport and the synthesis of 1,25(OH)2D.
Clinical Manifestations.
Children with familial hypophosphatemia present with bowing of the lower extremities related to weight bearing at the age of walking. Tetany is not present, and the profound myopathy, rachitic rosary, and Harrison groove (pectus deformity) characteristic of calcium-deficient rickets are not evident (see Chapter 44.10). These children develop a waddling gait, smooth (rather than angular) bowing of the lower extremities, coxa vara, genu varum, genu valgum, and short stature. The adult height of untreated patients is 130-165 cm.
Pulp deformities and lesions of intraglobular dentin are characteristic tooth abnormalities, although enamel defects are found only occasionally. By contrast, calcium-deficient rickets usually results in enamel defects. Periapical infections are found in both forms of rickets. Therapy for metabolic bone disease does not correct the defect in intraglobular dentin in this condition.
Radiographic findings include metaphyseal widening and fraying and coarse-appearing trabecular bone. Cupping of the metaphysis occurs at the proximal and distal tibia and at the distal femur, radius, and ulna.
Laboratory Findings.
Patients have a normal or slightly reduced serum calcium level (9-9.4 mg/dL; 2.24-2.34 mM), a moderately reduced serum phosphate level (1.5-3 mg/dL; 0.48-0.96 mM), elevated alkaline phosphatase activity, and no evidence of secondary hyperparathyroidism. Urinary phosphate excretion is large, despite hypophosphatemia, indicating a defect in renal tubular phosphate reabsorption possibly related to failure of PHEX to cleave and reduce F6F23 action. This disorder is typical of pure phosphate-deficient rickets, because aminoaciduria, glucosuria, bicarbonaturia, and kaliuria are never found. In potential obligate heterozygotes, who later develop disease, serum phosphate levels may remain normal for the first several months of life. The first laboratory abnormality is often a rise in serum alkaline phosphatase activity. The serum phosphate level probably remains normal for several months, because the glomerular filtration rate is quite low in neonates. Parathyroid hyperplasia with elevated serum parathyroid hormone (PTH) values is occasionally found, sometimes in sporadic cases.
Treatment.
Oral phosphate supplements coupled with a vitamin D analogue to offset the secondary hyperparathyroidism that may accompany an oral phosphate load is the preferred treatment. Oral phosphate is usually given every 4 hr at least five times a day, because urinary excretion is constant and patients quickly become hypophosphatemic. Young children should receive 0.5-1 g/24 hr, whereas older children require 1-4 g/24 hr. Phosphate can be given as Joulie solution (dibasic sodium phosphate, 136 g/L, and phosphoric acid, 58.8 g/L), which contains 30.4 mg of phosphate/mL. Thus, a 5 mL dose given every 4 hr five times daily provides 760 mg of phosphate. This solution must be formulated by a pharmacist. A capsule form of phosphate (Neutra-Phos) is commercially available and provides 250 mg of phosphorus per capsule. Patient compliance is readily assessed because most of this dose is excreted in a 24-hr urine collection. The main side effect of oral phosphate therapy is diarrhea, which often improves spontaneously.
Providing a vitamin D analogue is important for complete bone healing and prevention of secondary hyperparathyroidism. Classically, vitamin D2 was used at 2,000 IU/kg/24 hr, but more recently, dihydrotachysterol at a dosage of 0.02 mg/kg/24 hr or 1,25(OH)2D at 50-65 ng/kg/24 hr has been effectively used. Hydrochlorothiazide may reduce the hypercalciuria evident after vitamin D therapy.
Familial hypophosphatemia was previously treated with 50,000-200,000 IU/24 hr (1.25-10 mg) of vitamin D2, but this caused hypervitaminosis D with nephrocalcinosis, hypercalcemia, and permanent renal damage (see Chapter 44.12).
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The term vitamin D-resistant rickets was used in the past to describe rickets in which patients failed to respond to a dose of vitamin D that would cure vitamin D deficiency. If appropriate doses of vitamin D or any of its metabolites fail to heal rickets, and if serum phosphate is not reduced, metaphyseal dysplasia should be considered (see Chapter 692).
With early diagnosis and good compliance, the bowing deformities can be minimized, and an adult height above 170 cm may be achievable. However, the influence of therapy on final height is controversial, because most patients remain short while in some studies good growth patterns are evident. For this reason trials of growth hormone therapy have been employed. Corrective osteotomies should always be deferred until rickets appears healed radiographically and until the serum alkaline phosphatase level is in the normal range. Surgery before bone healing may be followed by redevelopment of deformity and bowing. In some patients, aggressive medical management may obviate the need for surgical intervention. Patients undergoing osteotomy should stop taking all vitamin D preparations before surgery and should not start them again until they are again ambulating to avoid immobilization hypercalcemia. Because 1,25(OH)2D has such a short half-life, it can be stopped just before surgery, whereas vitamin D2 should be discontinued at least 1 mo before surgery. An additional advantage of 1,25(OH)2D therapy is that it augments intestinal phosphate absorption and may improve phosphate balance. However, 1,25(OH)2D should not be used without concomitant oral phosphate.
Certain patients have hypophosphatemia and hyperphosphaturia but no radiographic evidence of rickets. This condition, inherited as an autosomal dominant disorder, has been called hypophosphatemic bone disease. The serum concentrations of 1,25(OH)2D are normal, and the renal tubular phosphate excretion defect is not as marked as in familial hypophosphatemic rickets, possibly because PHEX is normal and substrates other than F6F23 may influence phosphate transport. Short stature is not as prominent. Oral phosphate and 1,25(OH)2D have been used to treat this disorder.
Printed from: Nelson Textbook of Pediatrics (on 24 April 2006)
© 2006 Elsevier