X-linked hypophosphatemia
X-linked hypophosphatemia is an inherited disorder of excess FGF23 activity that causes renal phosphate wasting at the proximal tubule, producing rachitic bone disease in children and osteomalacia in adults despite normal serum calcium and vitamin D. First-line treatment is oral phosphate salts with calcitriol, or burosumab, an anti-FGF23 monoclonal antibody, given alone and never combined with oral phosphate or active vitamin D.
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What this article covers
- Overview
Definition: X-linked hypophosphatemia is an inherited renal phosphate-wasting disorder in which excess activity of fibroblast growth factor 23 (FGF23) increases phosphorus excretion at the proximal…
- Epidemiology
Inherited, X-linked pattern: the disorder is transmitted on the X chromosome and is commonly more severe in males, with females typically more mildly affected.
- Risk factors
Family history of X-linked hypophosphatemia or unexplained childhood rickets: the inherited phosphate-wasting defect runs in families along the X chromosome.
- Pathophysiology
FGF23 is the kidney's phosphaturic hormone: it normally fine-tunes renal phosphate handling; in X-linked hypophosphatemia, increased FGF23 activity drives excessive urinary phosphorus excretion regardless of the body's phosphate needs.
- Clinical features
Waddling gait from lower-extremity bowing: tibial and femoral bowing, together with ulnar and radial bowing, produces the characteristic gait abnormality as the child begins weight-bearing.
- Differential diagnosis
Nutritional vitamin D-deficient rickets: low calcium and low 25-hydroxyvitamin D, unlike the normal calcium and normal 25-hydroxyvitamin D of X-linked hypophosphatemia.
- Diagnosis
The diagnostic basis is the biochemical triad of low serum phosphorus with normal calcium and normal 25-hydroxyvitamin D, distinguishing this disease from nutritional rickets at the outset.
- Management
First, for conventional treatment, start oral phosphate salts together with calcitriol, because phosphate alone will not achieve adequate mineralization without active vitamin D, and calcitriol alone…
- Complications
Persistent skeletal deformity: untreated or undertreated bowing of the legs can persist into adulthood if rachitic changes are not corrected during growth.
- Prognosis
Chronic, lifelong condition: because the underlying renal phosphate leak is genetic, treatment is disease-modifying rather than curative and continues indefinitely.
- Prevention
Early recognition in children with a family history of X-linked hypophosphatemia allows treatment to begin before significant bowing and growth impairment develop.
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- Tumor-induced osteomalacia
Tumor-induced osteomalacia (oncogenic osteomalacia) is an acquired renal phosphate-wasting disorder caused by a phosphaturic mesenchymal tumor that secretes fibroblast growth factor 23, producing bone pain, muscle weakness, and pseudofractures from impaired mineralization. First-line management is oral phosphate and calcitriol supplementation to restore mineralization while the causative tumor is identified.
- Vitamin D deficiency rickets
Vitamin D deficiency rickets is defective mineralization of the growing cartilaginous growth plate from inadequate vitamin D, most often in a breastfed infant without supplementation, presenting with bowing of the legs, a rachitic rosary, and delayed motor development around 15 months of age. Diagnosis rests on a low 25-hydroxyvitamin D with elevated parathyroid hormone and characteristic metaphyseal cupping and fraying on long-bone radiographs, and first-line treatment is ergocalciferol 2,000 IU PO once daily for 6 weeks with calcium supplementation.
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Renal tubular acidosis is a normal anion gap metabolic acidosis caused by impaired renal bicarbonate reabsorption (type 2, proximal) or impaired distal acid excretion (type 1, hypokalemic distal, or type 4, hyperkalemic distal from aldosterone deficiency or resistance). The urine anion gap, serum potassium, and urine pH distinguish the three types, which are treated respectively with alkali replacement plus a thiazide, potassium citrate, and correction of the underlying cause plus mineralocorticoid replacement when appropriate.